'Guilting' teens into exercise won't increase activity

Adults who try to guilt middle-schoolers into exercising won’t get them to be any more active. The study found students who don't feel in control of their exercise choices or who feel pressured by adults to be more active typically aren't. Middle-schoolers who feel they can make their own decisions about exercising are more likely to see themselves as a person who exercises, which in turn makes them more likely to exercise. 

The study, which appears in the September issue of the journal Medicine & Science in Sports & Exercise, found students who don't feel in control of their exercise choices or who feel pressured by adults to be more active typically aren't. Middle-schoolers who feel they can make their own decisions about exercising are more likely to see themselves as a person who exercises, which in turn makes them more likely to exercise.
This age is a critical juncture in a child's life, as kids typically decrease their activity levels by 50 percent between fifth and sixth grades, said Rod Dishman, the study's lead author and a professor of kinesiology in the UGA College of Education.
"Our results confirm that the beliefs these kids hold are related to physical activity levels," Dishman said. "But can we put these children in situations where they come to value and enjoy the act of being physically active?"
Dishman and colleagues at the University of South Carolina are now looking at ways to help kids identify with exercise at a younger age, so that by the time they reach middle school they are more likely to identify as someone who exercises. This might mean teaching more structured games in elementary school, integrating physical activities into classroom lessons or expanding community recreational leagues to give kids more opportunities to improve on a particular sport.
"Just like there are kids who are drawn to music and art, there are kids who are drawn to physical activity," he said. "But what you want is to draw those kids who otherwise might not be drawn to an activity."
What parents and teachers don't want to create, Dishman cautioned, is a sense of guilt for not exercising. The research overwhelmingly found that students who felt obligated to be more active were less likely to embrace activity overall.
"The best thing is to do it because it's fun," Dishman said. "It's the kids who say they are intrinsically motivated who are more active than the kids who aren't."

Journal Reference:

1. ROD K. DISHMAN, KERRY L. MCIVER, MARSHA DOWDA, RUTH P. SAUNDERS, RUSSELL R. PATE. Motivation and Behavioral Regulation of Physical Activity in Middle School Students. Medicine & Science in Sports & Exercise, 2015; 47 (9): 1913 DOI: 10.1249/MSS.0000000000000616 

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Alirocumab dramatically lowers cholesterol in familial hypercholesterolemia patients

Alirocumab lowers cholesterol in patients with heterozygous familial hypercholesterolemia to levels unreachable with statins alone, according to new results. This analysis in more than 1 250 patients showed that alirocumab rapidly lowered low density lipoprotein cholesterol (LDL-C) to unprecedented levels and the reductions were maintained long term. 

"Heterozygous familial hypercholesterolemia is an inherited disease associated with very high levels of LDL-C that can put patients at risk for cardiovascular disease," said principal investigator Professor John JP Kastelein, professor of medicine in the Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, the Netherlands. "Approximately 80% of these patients are unable to reach their LDL-C goals."

The study included 1,257 patients with heterozygous familial hypercholesterolemia from four 18-month ODYSSEY trials (FH I, FH II, HIGH FH, LONG TERM). It assessed the benefits of adding the PCSK9 monoclonal antibody alirocumab to statins and other standard of care therapy, compared to standard of care therapy (including statins) and placebo. In FH I and FH II patients initially received alirocumab 75 mg (n=490) compared to placebo (n=245) while in HIGH FH and LONG TERM they initially received alirocumab 150 mg (n=348) compared to placebo (n=174). In addition, patients who initially received alirocumab 75 mg had their dose adjusted to 150 mg at week 12 if they did not achieve their pre-specified LDL-C goal by week eight.

The primary endpoint of all four trials was the percentage change in LDL-C from baseline to week 24, analysed by intention to treat. The researchers found that patients who initially received alirocumab 75 mg had an average 55.8% greater reduction in LDL-C from baseline versus placebo, and those who initially received alirocumab 150 mg had an average 56.4% greater reduction (p<0 .0001="" both="" comparisons="" for="" p=""> Using measures that were collected while patients were still receiving treatment (on-treatment analyses), LDL-C reductions were maintained over 78 weeks with an average 56.1% greater reduction versus placebo in the group initially treated with alirocumab 75 mg and potentially uptitrated to 150 mg and 63.2% greater reduction versus placebo in the patients treated only with alirocumab 150 mg group (p<0 .0001="" both="" comparisons="" for="" p="">
The average LDL-C level at baseline was 3.7 mmol/L (141.2 mg/dL) in the pool of FH I and FH II patients and 4.3 mmol/L (166.1 mg/dL) in the pool of HIGH FH and LONG TERM patients with heterozygous familial hypercholesterolemia. In on-treatment analyses, alirocumab reduced average LDL-C levels to less than 2.2 mmol/L (85 mg/dl) by week 12 and reductions were maintained to week 78. Treatment-emergent adverse events occurred in a similar proportion of patients on alirocumab (80.5%) and placebo (83%) leading to study discontinuation in 3.9% and 3.6% patients, respectively.

"This is the largest Phase 3 analysis of patients with heterozygous familial hypercholesterolemia," said Professor Kastelein. "Despite high baseline levels, alirocumab reduced LDL-C concentrations to less than 1.8 mmol/L (70 mg/dL) at week 24 in 63% of patients in FH I and II and in 56% of patients in the pool of HIGH FH and LONG TERM patients. Studies with other lipid lowering therapies have only reached LDL-C levels of less than 2.5 mmol/L (97 mg/dL) in around 20% of patients."

"The results show that adding alirocumab to statins in patients with heterozygous familial hypercholesterolemia rapidly lowers LDL-C to unprecedented levels that are unreachable with statins alone, and that these reductions are maintained in the long term," he continued. "Alirocumab is a PCSK9 inhibitor and belongs to a new class of cholesterol-lowering monoclonal antibodies. It works by preventing action of the PCSK9 protein, which in turn increases the number of LDL receptors and thus increases uptake of LDL-C from the circulation."

Professor Kastelein concluded: "Adding alirocumab to statins may be an important treatment strategy for patients not able to reach their LDL-C goals with statins alone."
 

Story Source:
The above post is reprinted from materials provided by European Society of Cardiology (ESC). Note: Materials may be edited for content and length.
 

Courtesy: ScienceDaily

 

 

Current school start times damaging learning and health of students

Scientists have found that current school and university start times are damaging the learning and health of students. Drawing on the latest sleep research, the authors conclude students start times should be 8:30 or later at age 10; 10:00 or later at 16; and 11:00 or later at 18. Implementing these start times should protect students from short sleep duration and chronic sleep deprivation, which are linked to poor learning and health problems.

A study by researchers from the University of Oxford, Harvard Medical School and the University of Nevada has found that current school and university start times are damaging the learning and health of students.

Drawing on the latest sleep research, the authors conclude students start times should be 08:30 or later at age 10; 10:00 or later at 16; and 11:00 or later at 18. Implementing these start times should protect students from short sleep duration and chronic sleep deprivation, which are linked to poor learning and health problems.
These findings arise from a deeper understanding of circadian rhythms, better known as the body clock, and the genes associated with regulating this daily cycle every 24 hours.
It is during adolescence when the disparity between inherent circadian rhythms and the typical working day come about. Circadian rhythms determine our optimum hours of work and concentration, and in adolescence these shift almost 3 hours later. These genetic changes in sleeping patterns were used to determine start times that are designed to optimize learning and health.
The US Department of Health has also recently published an article in favor of changing the start times for Middle and High Schools.
Corresponding author Paul Kelley (Honorary Clinical Research Associate, Sleep and Circadian Neuroscience Institute, University of Oxford) will be presenting Time: the key to really understanding our lives at the British Science Festival on Tuesday 8 September.

Journal Reference:

1. Paul Kelley, Steven W. Lockley, Russell G. Foster, Jonathan Kelley. Synchronizing education to adolescent biology: ‘let teens sleep, start school later’. Learning, Media and Technology, 2014; 40 (2): 210 DOI: 10.1080/17439884.2014.942666 

Courtesy: ScienceDaily

High protein foods boost cardiovascular health, as much as quitting smoking or getting exercise

Eating foods rich in amino acids could be as good for your heart as stopping smoking or getting more exercise -- according to new research. 

A higher intake of protein from animal sources was linked with lower levels of arterial stiffness.

Credit: © Africa Studio / Fotolia

 

A new study published today reveals that people who eat high levels of certain amino acids found in meat and plant-based protein have lower blood pressure and arterial stiffness.
And the magnitude of the association is similar to those previously reported for lifestyle risk factors including salt intake, physical activity, alcohol consumption and smoking.
Researchers investigated the effect of seven amino acids on cardiovascular health among almost 2,000 women with a healthy BMI. Data came from TwinsUK -- the biggest UK adult twin registry of 12,000 twins which is used to study the genetic and environmental causes of age related disease.
They studied their diet and compared it to clinical measures of blood pressure and blood vessel thickness and stiffness.
They found strong evidence that those who consumed the highest amounts of amino acids had lower measures of blood pressure and arterial stiffness.
But they found that the food source was important -- with a higher intake of amino acids from plant-based sources associated with lower blood pressure, and a higher intake from animal sources associated with lower levels of arterial stiffness.
Lead researcher Dr Amy Jennings, from UEA's Norwich Medical School, said: "This research shows a protective effect of several amino acids on cardiovascular health.
"Increasing intake from protein-rich foods such as meat, fish, dairy produce, beans, lentils, broccoli and spinach could be an important and readily achievable way to reduce people's risk of cardiovascular disease.
"Results from previous studies have provided evidence that increased dietary protein may be associated with lower blood pressure. We wanted to know whether protein from animal sources or plant-based sources was more beneficial -- so we drilled down and looked at the different amino acids found in both meat and vegetables.
"We studied seven amino acids -- arginine, cysteine, glutamic acid, glycine, histidine, leucine, and tyrosine. Glutamic acid, leucine, and tyrosine are found in animal sources, and a higher intake was associated with lower levels of arterial stiffness.
"All seven amino acids, and particularly those from plant-based sources, were associated with lower blood pressure.
"The really surprising thing that we found is that amino acid intake has as much of an effect on blood pressure as established lifestyle risk factors such as salt intake, physical activity and alcohol consumption. For arterial stiffness, the association was similar to the magnitude of change previously associated with not smoking.
"High blood pressure is one of the most potent risk factors for developing cardiovascular disease. A reduction in blood pressure leads to a reduction in mortality caused by stroke or coronary heart disease -- so changing your diet to include more meat, fish, dairy produce and pulses could help both prevent and treat the condition.
"Beneficial daily amounts equate to a 75g portion of steak, a 100g salmon fillet or a 500ml glass of skimmed milk," she added.
Prof Tim Spector from the department of Twin Research at King's college London said: "The finding that eating certain meat and plant proteins are linked to healthier blood pressure is an exciting finding. We need to understand the mechanism to see if it is direct or via our gut microbes."
 

Journal Reference:

1. A. Jennings, A. MacGregor, A. Welch, P. Chowienczyk, T. Spector, A. Cassidy. Amino Acid Intake Is Inversely Associated with Arterial Stiffness and Central Blood Pressure in Women. Journal of Nutrition, 2015; DOI: 10.3945/%u200Bjn.115.214700 

Courtesy: ScienceDaily
 

 

Capturing cancer: 3-D model of solid tumors explains cancer evolution

Researchers have developed the first model of solid tumors that reflects both their three-dimensional shape and genetic evolution. The new model explains why cancer cells have a surprising number of genetic mutations in common, how driver mutations spread through the whole tumor and how drug resistance evolves. 

This is a three-dimensional model of a tumor showing cell types in varying colors.

Credit: Bartek Waclaw and Martin Nowak

 

Though models have been developed that capture the spatial aspects of tumors, those models typically don't study genetic changes. Non-spatial models, meanwhile, more accurately portray tumors' evolution, but not their three-dimensional structure.
A collaboration between Harvard, Edinburgh, and Johns Hopkins Universities including Martin Nowak, Director of the Program for Evolutionary Dynamics and Professor of Mathematics and of Biology at Harvard, has now developed the first model of solid tumors that reflects both their three-dimensional shape and genetic evolution. The new model explains why cancer cells have a surprising number of genetic mutations in common, how driver mutations spread through the whole tumor and how drug resistance evolves. The study is described in an August 26 paper in Nature.
"Previously, we and others have mostly used non-spatial models to study cancer evolution," Nowak said. "But those models do not describe the spatial characteristics of solid tumors. Now, for the first time, we have a computational model that can do that."
A key insight of the new model, Nowak said, is the ability for cells to migrate locally.
"Cellular mobility makes cancers grow fast, and it makes cancers homogenous in the sense that cancer cells share a common set of mutations. It is responsible for the rapid evolution of drug resistance," Nowak said. "I further believe that the ability to form metastases, which is what actually kills patients, is a consequence of selection for local migration."
Nowak and colleagues, including Bartek Waclaw of the University of Edinburgh, who is the first author of the study, Ivana Bozic of Harvard University and Bert Vogelstein of Johns Hopkins University, set out to improve on past models, because they were unable to answer critical questions about the spatial architecture of genetic evolution.
"The majority of the mathematical models in the past counted the number of cells that have particular mutations, but not their spatial arrangement," Nowak said. Understanding that spatial structure is important, he said, because it plays a key role in how tumors grow and evolve.
In a spatial model cells divide only if they have the space to do so. This results in slow growth unless cells can migrate locally.
"By giving cells the ability to migrate locally," Nowak said, "individual cells can always find new space where they can divide.
The result isn't just faster tumor growth, but a model that helps to explain why cancer cells share an unusually high number of genetic mutations, and how drug resistance can rapidly evolve in tumors.
As they divide, all cells -- both healthy and cancerous -- accumulate mutations, Nowak said, and most are so called "passenger" mutations that have little effect on the cell.
In cancer cells, however, approximately 5 percent are what scientists call "driver" mutations -- changes that allow cells to divide faster or live longer. In addition to rapid tumor growth, those mutations carry some previous passenger mutations forward, and as a result cancer cells often have a surprising number of mutations in common.
Similarly, drug resistance emerges when cells mutate to become resistant to a particular treatment. While targeted therapies wipe out nearly all other cells, the few resistant cells begin to quickly replicate, causing a relapse of the cancer.
"This migration ability helps to explain how driver mutations are able to dominate a tumor, and also why targeted therapies fail within a few months as resistance evolves," Nowak said. "So what we have is a computer model for solid tumors, and it's this local migration that is of crucial importance."
"Our approach does not provide a miraculous cure for cancer." said Bartek Waclaw, "However, it suggests possible ways of improving cancer therapy. One of them could be targeting cellular motility (that is local migration) and not just growth as standard therapies do."
 

Journal Reference:

1. Bartlomiej Waclaw, Ivana Bozic, Meredith E. Pittman, Ralph H. Hruban, Bert Vogelstein, Martin A. Nowak. A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity. Nature, 2015; DOI: 10.1038/nature14971 

Courtesy: ScienceDaily
 

 

Microscopic fish are 3-D-printed to do more than swim

Nanoengineers at the University of California, San Diego used an innovative 3-D printing technology they developed to manufacture multipurpose fish-shaped microrobots -- called microfish -- that swim around efficiently in liquids, are chemically powered by hydrogen peroxide and magnetically controlled. These proof-of-concept synthetic microfish will inspire a new generation of 'smart' microrobots that have diverse capabilities such as detoxification, sensing and directed drug delivery, researchers said. 

3-D-printed microfish contain functional nanoparticles that enable them to be self-propelled, chemically powered and magnetically steered. The microfish are also capable of removing and sensing toxins.

Credit: J. Warner, UC San Diego Jacobs School of Engineering.

 

The technique used to fabricate the microfish provides numerous improvements over other methods traditionally employed to create microrobots with various locomotion mechanisms, such as microjet engines, microdrillers and microrockets. Most of these microrobots are incapable of performing more sophisticated tasks because they feature simple designs -- such as spherical or cylindrical structures -- and are made of homogeneous inorganic materials. In this new study, researchers demonstrated a simple way to create more complex microrobots.
The research, led by Professors Shaochen Chen and Joseph Wang of the NanoEngineering Department at the UC San Diego, was published in the Aug. 12 issue of the journal Advanced Materials.
By combining Chen's 3D printing technology with Wang's expertise in microrobots, the team was able to custom-build microfish that can do more than simply swim around when placed in a solution containing hydrogen peroxide. Nanoengineers were able to easily add functional nanoparticles into certain parts of the microfish bodies. They installed platinum nanoparticles in the tails, which react with hydrogen peroxide to propel the microfish forward, and magnetic iron oxide nanoparticles in the heads, which allowed them to be steered with magnets.
"We have developed an entirely new method to engineer nature-inspired microscopic swimmers that have complex geometric structures and are smaller than the width of a human hair. With this method, we can easily integrate different functions inside these tiny robotic swimmers for a broad spectrum of applications," said the co-first author Wei Zhu, a nanoengineering Ph.D. student in Chen's research group at the Jacobs School of Engineering at UC San Diego.
As a proof-of-concept demonstration, the researchers incorporated toxin-neutralizing nanoparticles throughout the bodies of the microfish. Specifically, the researchers mixed in polydiacetylene (PDA) nanoparticles, which capture harmful pore-forming toxins such as the ones found in bee venom. The researchers noted that the powerful swimming of the microfish in solution greatly enhanced their ability to clean up toxins. When the PDA nanoparticles bind with toxin molecules, they become fluorescent and emit red-colored light. The team was able to monitor the detoxification ability of the microfish by the intensity of their red glow.
"The neat thing about this experiment is that it shows how the microfish can doubly serve as detoxification systems and as toxin sensors," said Zhu.
"Another exciting possibility we could explore is to encapsulate medicines inside the microfish and use them for directed drug delivery," said Jinxing Li, the other co-first author of the study and a nanoengineering Ph.D. student in Wang's research group.
How this new 3D printing technology works
The new microfish fabrication method is based on a rapid, high-resolution 3D printing technology called microscale continuous optical printing (μCOP), which was developed in Chen's lab. Some of the benefits of the μCOP technology are speed, scalability, precision and flexibility. Within seconds, the researchers can print an array containing hundreds of microfish, each measuring 120 microns long and 30 microns thick. This process also does not require the use of harsh chemicals. Because the μCOP technology is digitized, the researchers could easily experiment with different designs for their microfish, including shark and manta ray shapes.
"With our 3D printing technology, we are not limited to just fish shapes. We can rapidly build microrobots inspired by other biological organisms such as birds," said Zhu.
The key component of the μCOP technology is a digital micromirror array device (DMD) chip, which contains approximately two million micromirrors. Each micromirror is individually controlled to project UV light in the desired pattern (in this case, a fish shape) onto a photosensitive material, which solidifies upon exposure to UV light. The microfish are built using a photosensitive material and are constructed one layer at a time, allowing each set of functional nanoparticles to be "printed" into specific parts of the fish bodies.
"This method has made it easier for us to test different designs for these microrobots and to test different nanoparticles to insert new functional elements into these tiny structures. It's my personal hope to further this research to eventually develop surgical microrobots that operate safer and with more precision," said Li.
 

Journal Reference:

1. Wei Zhu, Jinxing Li, Yew J. Leong, Isaac Rozen, Xin Qu, Renfeng Dong, Zhiguang Wu, Wei Gao, Peter H. Chung, Joseph Wang, Shaochen Chen. 3D-Printed Artificial Microfish. Advanced Materials, 2015; 27 (30): 4411 DOI: 10.1002/adma.201501372 

Courtesy: ScienceDaily
 

 

Revealed: Helicobacter pylori's secret weapon

Is the game up for Helicobactor pylori? Researchers have identified the molecular mechanism that the bacterium's best-known adhesion protein uses to attach to stomach sugars and evade the body's attempts to 'flush' it away. 

Discovered in 1982, Helicobacter pylori (H. pylori) is a disease-causing bacterium that survives in our stomachs despite the harsh acidic conditions. It is estimated that one in two people have got it, though most won't ever experience any problems. Even so, it is considered one of the most common bacterial infections worldwide and a leading cause of dyspepsia, peptic ulceration and gastric cancer.

Through unique evolutionary adaptations, H. pylori is able to evade the antiseptic effect of our stomach acid by hiding within the thick acid-resistant layer of mucus that coats the stomach wall. Once within the mucus layer, the bacterium latches onto sugars naturally found on the stomach wall using its adhesion proteins. This attachment is so effective that the bacterium can resist attempts by the body to 'flush' it away, allowing the pathogen to colonise with impunity.
But the game could be up for H. pylori. Researchers in the School of Pharmacy, at The University of Nottingham and AstraZeneca R&D have identified the molecular mechanism that the bacterium's best-known adhesion protein uses to attach to stomach sugars. The research is published today, August 14 2015, in the scientific journal Science Advances.
Powerful x-rays reveal special 'groove'
Finding the molecular interactions that make this pathogen so successful in such a harsh environment has, until now, proved elusive.
Naim Hage, the postgraduate researcher who worked on this project as part of his doctoral thesis, said: "Although it's still very early, the insight we've gained from this study is already very exciting news for patients."
Using extremely powerful x-rays, the scientists were able to study the interactions between the H. pylori adhesion protein BabA and Lewisb sugars of the gastric mucosa at the atomic level. They found that, right at its tip, BabA possesses a specific groove that enables it to securely attach to Lewisb using a network of hydrogen bonds (the same kind of interactions that keep water molecules together).
First exciting step
The research team also found that this network is finely tuned -- if a few of the hydrogen bonds are disrupted, the network doesn't function and binding can no longer occur. This insight into the molecular interactions required for adhesion is a promising lead for the development of new strategies for the treatment of H. pylori infections.
This study now forms the foundation for future research between The University of Nottingham and AstraZeneca R&D into "anti-adhesion strategies" that would work by clearing H. pylori out of the stomach through dislodging the bacterium off the stomach wall using BabA:Lewisb inhibitors. Such novel strategies are needed to help treat H. pylori infections, which are globally gaining resistance to conventional antibiotic therapies.
Naim said: "Because BabA is unique to H. pylori, we can specifically target, and hopefully eradicate, this bacterium without affecting the other good bacteria in our normal flora. If successful, this therapeutic strategy will also be extremely useful for treating H. pylori infections that are already resistant to antibiotics."
More research to be done
The principal investigator behind the project, Dr Franco Falcone, said: "While this study answers long-standing questions about how H. pylori colonises the stomach, it represents the very first step in the development of novel therapies. The next few years of laboratory-based research will be crucial to determine if an anti-BabA adhesion approach is viable and can progress to clinical development. A similar approach is already showing promising results for the treatment of urinary tract infections in preclinical models. Looking forward, we are excited to continue working closely with AstraZeneca R&D who have provided a tremendous amount of support to achieve this discovery."
 

Journal Reference:

1. Franco H. Falcone et al. Structural basis of Lewisb antigen binding by the Helicobacter pylori adhesin BabA. Science Advances, August 2015 DOI: 10.1126/sciadv.1500315 

Courtesy: ScienceDaily
 

Promising drug for Parkinson's disease: Study supports fast track to clinical trials

A drug which has already been in use for decades to treat liver disease could be an effective treatment to slow down progression of Parkinson's disease, scientists have discovered. 

The pioneering research led by academics from the Sheffield Institute of Translational Neuroscience (SITraN), in collaboration with scientists from the University of York, supports the fast-tracking of the drug ursodeoxycholic acid (UDCA) for a clinical trial in Parkinson's patients.
Dr Heather Mortiboys, Parkinson's UK Senior Research Fellow from the University of Sheffield, explained: "We demonstrated the beneficial effects of UDCA in the tissue of LRRK2 carriers with Parkinson's disease as well as currently asymptomatic LRRK2 carriers. In both cases, UDCA improved mitochondrial function as demonstrated by the increase in oxygen consumption and cellular energy levels."
Oliver Bandmann, Professor of Movement Disorders Neurology at the University of Sheffield and Honorary Consultant Neurologist at Sheffield Teaching Hospitals NHS Foundation Trust, added: "Whilst we have been looking at Parkinson's patients who carry the LRRK2 mutation, mitochondrial defects are also present in other inherited and sporadic forms of Parkinson's, where we do not know the causes yet. Our hope is therefore, that UDCA might be beneficial for other types of Parkinson's disease and might also show benefits in other neurodegenerative diseases."
The research is also the first to demonstrate beneficial effects of UDCA on dopaminergic neurons, the nerve cells affected in Parkinson's disease, in a fly model of Parkinson's disease which carries the same genetic change as some patients with the condition.
The study published in the journal Neurology is funded by Parkinson's UK, the Wellcome Trust and the Norwegian Parkinson Foundation.
A mutation in the LRRK2 gene is the single most common inherited cause of Parkinson's disease. However, the precise mechanism that leads to Parkinson's is still unclear.
Defects in mitochondria, and as a consequence reduced energy levels, are a factor in a number of diseases that affect the nervous system including Parkinson's and Motor Neuron Disease. Nerve cells have a particularly high energy demands, therefore defects in the cell's energy generators will crucially affect their survival.
Professor Bandmann added: "Following on from the promising results of our in vitro drug screen, we were keen to further investigate and confirm the potential of UDCA in vivo -- in a living organism.
"UDCA has been in clinical use for decades and thus could be advanced to the clinic rapidly if it proves beneficial in clinical trials."
Collaborators Rebecca Furmston, White Rose PhD student, and Dr Chris Elliott, from the University of York's Department of Biology, demonstrated the beneficial effects of UDCA in vivo using the fruit fly (Drosophila melanogaster). In fruit flies, the mitochondrial defects caused by the LRRK2 mutation to dopaminergic neurons can be monitored through the progressive loss of visual function. Flies carrying the mutation maintained their visual response when fed with UDCA.
Dr Elliott said: "The treatment of fruit flies carrying the faulty LRRK2 gene with UDCA showed a profound rescue of dopaminergic signalling. Feeding the flies with UDCA partway through their life slows the rate at which the fly brain then degenerates. Thus, mitochondrial rescue agents may be a promising novel strategy for disease-modifying therapy in LRRK2-related Parkinson's."
Dr Arthur Roach, Director of Research and Development at Parkinson's UK, which part-funded the study, said: "There is a tremendous need for new treatments that can slow or stop Parkinson's.
"Because of this urgency, the testing of drugs like UCDA, which are already approved for other uses, is extremely valuable. It can save years, and hundreds of millions of pounds.
"It's particularly encouraging in this study that even at relatively low concentrations the liver drug still had an effect on Parkinson's cells grown in the lab.
"This type of cutting-edge research is the best hope of finding better treatments for people with Parkinson's in years, not decades."
 

Journal Reference:

1. H. Mortiboys, R. Furmston, G. Bronstad, J. Aasly, C. Elliott, O. Bandmann. UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2G2019S carriers and in vivo. Neurology, 2015; DOI: 10.1212/WNL.0000000000001905 

Courtesy: ScienceDaily
 

Modern parenting may hinder brain development, research suggests

Social practices and cultural beliefs of modern life are preventing healthy brain and emotional development in children, according to an interdisciplinary body of research. 

"Life outcomes for American youth are worsening, especially in comparison to 50 years ago," says Darcia Narvaez, Notre Dame professor of psychology who specializes in moral development in children and how early life experiences can influence brain development.
"Ill-advised practices and beliefs have become commonplace in our culture, such as the use of infant formula, the isolation of infants in their own rooms or the belief that responding too quickly to a fussing baby will 'spoil' it," Narvaez says.
This new research links certain early, nurturing parenting practices -- the kind common in foraging hunter-gatherer societies -- to specific, healthy emotional outcomes in adulthood, and has many experts rethinking some of our modern, cultural child-rearing "norms."
"Breast-feeding infants, responsiveness to crying, almost constant touch and having multiple adult caregivers are some of the nurturing ancestral parenting practices that are shown to positively impact the developing brain, which not only shapes personality, but also helps physical health and moral development," says Narvaez.
Studies show that responding to a baby's needs (not letting a baby "cry it out") has been shown to influence the development of conscience; positive touch affects stress reactivity, impulse control and empathy; free play in nature influences social capacities and aggression; and a set of supportive caregivers (beyond the mother alone) predicts IQ and ego resilience as well as empathy.
The United States has been on a downward trajectory on all of these care characteristics, according to Narvaez. Instead of being held, infants spend much more time in carriers, car seats and strollers than they did in the past. Only about 15 percent of mothers are breast-feeding at all by 12 months, extended families are broken up and free play allowed by parents has decreased dramatically since 1970.
Whether the corollary to these modern practices or the result of other forces, an epidemic of anxiety and depression among all age groups, including young children; rising rates of aggressive behavior and delinquency in young children; and decreasing empathy, the backbone of compassionate, moral behavior, among college students, are shown in research.
According to Narvaez, however, other relatives and teachers also can have a beneficial impact when a child feels safe in their presence. Also, early deficits can be made up later, she says.
"The right brain, which governs much of our self-regulation, creativity and empathy, can grow throughout life. The right brain grows though full-body experience like rough-and-tumble play, dancing or freelance artistic creation. So at any point, a parent can take up a creative activity with a child and they can grow together."
Further information: http://ccf.nd.edu/symposium/2012-symposium-presentations/
 

Story Source:
The above post is reprinted from materials provided by University of Notre Dame. The original item was written by Susan Guibert. Note: Materials may be edited for content and length.
 

Courtesy: ScienceDaily

 

Ebola vaccine efficacy trial suggest vaccine provides high protection against disease

Tests of the experimental Ebola vaccine VSV-ZEBOV in over 7500 participants in Guinea suggest that the vaccine provides high protection against the disease as early as ten days after vaccination, in adults who have potentially been exposed to the virus by coming in close contact with a recently infected person. 

New research suggests that the vaccine is safe, and also provides the first evidence that unvaccinated people may be indirectly protected from Ebola virus disease (EVD) when the VSV-ZEBOV vaccine is delivered using a ring vaccination strategy.

Credit: © Anton Gvozdikov / Fotolia

The research, published in The Lancet, suggests that the vaccine is safe, and also provides the first evidence that unvaccinated people may be indirectly protected from Ebola virus disease (EVD) when the VSV-ZEBOV vaccine is delivered using a ring vaccination strategy.  The study was sponsored and led by the World Health Organisation (WHO).
Ring vaccination, which was used in the past to eradicate smallpox, is intended to create a buffer of protection to prevent the spread of the disease, by vaccinating and monitoring the contacts, and contacts of contacts (the “ring”), of each newly diagnosed Ebola case.
The Ebola ça Suffit (translation: “Ebola this is Enough”) trial took place in Basse-Guinea, the only area in Guinea with new Ebola cases at the start of the study on April 1, 2015. When a new (index) Ebola case was diagnosed, the researchers traced all individuals who may have been in close contact with this first case [2].  Adult contacts aged 18 or older (not pregnant or breastfeeding) were offered the vaccine. If consent was given, adults in the ring were randomised to receive either immediate or delayed (21 days after randomisation [3]) vaccination. Vaccinated volunteers were then visited at home on days 3, 14, 21, 42, 63, and 84 after vaccination to record any adverse events.
The study reports the incidence of EVD in the immediate rings compared to the delayed rings up to 20 July, 2015. In the 90 clusters who received either immediate vaccination (48; 4123 adults vaccinated) or delayed vaccination (42; 3528 adults vaccinated on day 21), a single intramuscular injection of VSV-ZEBOV gave complete (100%) protection against EVD 10 days after randomisation [4]. No cases of EVD were recorded 10 days after randomisation in the immediate group, compared to 16 cases in the delayed vaccination clusters (table 2).
“Before the trial started, in most clusters there had been a series of Ebola cases over the weeks prior to randomisation.  However, since the trial started, we have seen no new cases in vaccinated volunteers within 10 days of vaccination, regardless of whether vaccination was immediate or delayed,” explains co-author Dr Marie Paule Kieny, from the World Health Organisation (WHO) in Geneva, Switzerland.
Secondary analysis for the trial suggests that ring vaccination also reduced the risk of contracting EVD for non-vaccinated individuals in the clusters. The overall effectiveness of the vaccine in adults, including both those who consented to vaccination and those who did not, was 75% against EVD.  Additionally, in all members of the clusters, including non-vaccinated children and pregnant women, the risk of testing positive for EVD was reduced by around 76% (table 2 and figure 3).
The vaccine was well-tolerated – one vaccinated patient experienced an episode of fever, classed as a serious adverse event, that was found to be related to the vaccine.  Assessment of serious adverse events is ongoing as the trial progresses.
According to study co-author Professor John-Arne Røttingen, from the University of Oslo, Norway, “Our results are encouraging in that they suggest that ring vaccination could substantially reduce rates of Ebola virus disease in the community. Because the way that Ebola virus transmits has been shown to be consistent across countries and regions, we believe that these results are likely to be applicable to other regions of Guinea and to Sierra Leone and Liberia.  But whether this candidate vaccine could become a licensed vaccine for widespread use against Ebola outbreaks is still uncertain, and further evidence is needed to evaluate the safety and efficacy of the vaccine before it is used outside of a clinical trial setting.”
The study is an interim analysis of results from the Ebola ça Suffit trial, and the trial is now continuing in order to generate more data for the assessment of vaccine efficacy and safety.
A Lancet Editorial accompanying the Article states that, “This study will be the subject of intense scientific scrutiny and debate. But what do the results mean for those most at risk of Ebola virus infection in west Africa? The vaccine is not yet licensed. More data on efficacy are needed before it can be widely deployed. But if the evidence proves sufficient for licensing, a Global Ebola Vaccine Implementation Team, also under WHO's leadership, has been preparing the ground for its introduction-creating guidelines for the vaccine's use, strategies for community engagement, and mechanisms to expand country capacity for the vaccine's distribution and delivery. In addition, the GAVI Alliance has approved substantial funding for the procurement and deployment of the vaccine.”
The sponsor of the study is the World Health Organization (WHO); it is implemented by the Ministry of Health of Guinea, Médecins sans Frontières (MSF), EPICENTRE, the Norwegian Institute of Public Health and WHO. The trial is funded by WHO, with support from the Wellcome Trust (United Kingdom); MSF; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development. The trial team includes researchers from the University of Bern, the University of Florida, the London School of Hygiene and Tropical Medicine, Public Health England, and the European Mobile Laboratory among others.
FOOTNOTES:
[1] VSV-ZEBOV was developed by the Public Health Agency of Canada and is licensed to NewLink Genetics and Merck. The vaccine works by replacing a gene from a harmless virus known as vesicular stomatitis virus (VSV) with a gene encoding an Ebola virus surface protein. The vaccine does not contain any live Ebola virus. Earlier trials have shown VSV-ZEBOV to be safe and to produce consistently powerful immune responses in adults, thought to be important for protection against Ebola.
[2] This included contacts and contacts of contacts of the index case, around 50-100 people. Contacts included individuals who, within the last 21 days, lived in the same household, were visited by the index case after the onset of symptoms, or were in close physical contact with the patients’ body or body fluids, linen or clothes.
[3] This method is an alternative to using a placebo, but allows all consenting contacts to be vaccinated during the trial. The delayed vaccination group acts as a control group.
[4] Analyses of vaccine efficacy were restricted to events occurring 10 days or more after randomisation to account for the incubation period of Ebola and the unknown time for the vaccine to develop protective immunity.
 

Journal Reference:

1. Ana Maria Henao-Restrepo, Ira M Longini, Matthias Egger, Natalie E Dean, W John Edmunds, Anton Camacho, Miles W Carroll, Moussa Doumbia, Bertrand Draguez, Sophie Duraffour, Godwin Enwere, Rebecca Grais, Stephan Gunther, Stefanie Hossmann, Mandy Kader Kondé, Souleymane Kone, Eeva Kuisma, Myron M Levine, Sema Mandal, Gunnstein Norheim, Ximena Riveros, Aboubacar Soumah, Sven Trelle, Andrea S Vicari, Conall H Watson, Sakoba Kéïta, Marie Paule Kieny, John-Arne Røttingen. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. The Lancet, 2015 DOI: 10.1016/S0140-6736(15)61117-5 

Courtesy: ScienceDaily
 

How bees naturally vaccinate their babies

When it comes to vaccinating their babies, bees don't have a choice -- they naturally immunize their offspring against specific diseases found in their environments. Now for the first time, scientists have discovered how they do it. This opens the door for researchers to develop the first-ever vaccine for insects. This is particularly important for bees since they help keep fruit, nuts and vegetables in our diets and have been declining in numbers for six decades. 

With the discovery of how bees naturally vaccinate their babies, researchers can now develop the first vaccine for insects. This vaccine could be used to fight serious diseases that decimate beehives. This is an important development for food production.

Credit: Christofer Bang

Researchers from Arizona State University, University of Helsinki, University of Jyväskylä and Norwegian University of Life Sciences made the discovery after studying a bee blood protein called vitellogenin. The scientists found that this protein plays a critical, but previously unknown role in providing bee babies protection against disease.
The findings appear in the journal PLOS Pathogens.
"The process by which bees transfer immunity to their babies was a big mystery until now. What we found is that it's as simple as eating," said Gro Amdam, a professor with ASU's School of Life Sciences and co-author of the paper. "Our amazing discovery was made possible because of 15 years of basic research on vitellogenin. This exemplifies how long-term investments in basic research pay off."
Co-author Dalial Freitak, a postdoctoral researcher with University of Helsinki adds: "I have been working on bee immune priming since the start of my doctoral studies. Now almost 10 years later, I feel like I've solved an important part of the puzzle. It's a wonderful and very rewarding feeling!"
How it works
In a honey bee colony, the queen rarely leaves the nest, so worker bees must bring food to her. Forager bees can pick up pathogens in the environment while gathering pollen and nectar. Back in the hive, worker bees use this same pollen to create "royal jelly" -- a food made just for the queen that incidentally contains bacteria from the outside environment.
After eating these bacteria, the pathogens are digested in the gut and transferred to the body cavity; there they are stored in the queen's 'fat body' -- an organ similar to a liver. Pieces of the bacteria are then bound to vitellogenin -- a protein -- and carried via blood to the developing eggs. Because of this, bee babies are 'vaccinated' and their immune systems better prepared to fight diseases found in their environment once they are born.
Vitellogenin is the carrier of these immune-priming signals, something researchers did not know until now.
First edible vaccines for bees
While bees vaccinate their babies against some diseases, many pathogens are deadly and the insects are unable to fight them.
But now that Amdam and Freitak understand how bees vaccinate their babies, this opens the door to creating the first edible and natural vaccine for insects.
"We are patenting a way to produce a harmless vaccine, as well as how to cultivate the vaccines and introduce them to bee hives through a cocktail the bees would eat. They would then be able to stave off disease," said Freitak.
One destructive disease that affects bees is American Foul Brood, which spreads quickly and destroys hives. The bacterium infects bee larvae as they ingest food contaminated with its spores. These spores get their nourishment from the larvae, eventually killing them.
This disease is just one example where the researchers say a vaccine would be extremely beneficial.
Why this discovery is important to humans
It's widely known that pollinators, including bees, are facing serious environmental dangers.
During the past six decades, managed honey bee colonies in the United States have declined from 6 million in 1947 to only 2.5 million today. Not only are bees affected by diseases, they have been decimated by a phenomenon called colony collapse disorder. Researchers don't know exactly what causes this, but pesticides, pests, pathogens and nutrition problems may all be contributing factors.
According to a 2014 report by the U.S. government, pollinators are instrumental for a healthy economy and critical to food security, contributing 35 percent of global food production. In North America, insects pollinate 87 of the top 115 food crops and honey bees are vital in keeping fruits, nuts and vegetables in our diets.
Humans depend on bees and other pollinating insects for a huge portion of their food supply. Insect vaccines could play an important role in helping to combat colony collapse disorder, in addition to fighting a variety of diseases.
All egg-laying species have vitellogenin
This discovery could have far-reaching benefits for other species, as well as substantial, positive impacts on food production. All egg-laying species including fish, poultry, reptiles, amphibians and insects have vitellogenin in their bodies.
The food industry could implement the use of natural vaccines that would not only be inexpensive to produce, they could easily be used in developing countries.
"Because this vaccination process is naturally occurring, this process would be cheap and ultimately simple to implement. It has the potential to both improve and secure food production for humans," said Amdam.

Journal Reference:

1. Heli Salmela, Gro V. Amdam, Dalial Freitak. Transfer of Immunity from Mother to Offspring Is Mediated via Egg-Yolk Protein Vitellogenin. PLOS Pathogens, 2015; 11 (7): e1005015 DOI: 10.1371/journal.ppat.1005015 

Courtesy: ScienceDaily

Can we restart the heart?

What if you could use the proliferative and survival properties of cancer-prone cells to rejuvenate cardiac progenitor cells and get them dividing again, without forming tumors? Researchers are exploring the results of taking an enzyme, Pim, known to be associated with growth and survival of certain types of cancer cells, and causing it to be overexpressed in cardiac progenitor cells in mice. 

 

These photomicrograph cardiac stem cells isolated from mouse hearts clustered together in the shape of a heart.

Credit: Mark Sussman

This is all very simplified, of course, but it's the basic model described by Mark Sussman, chief research scientist at the San Diego State University Heart Institute, who was recently selected by the American Heart Association's Basic Cardiovascular Science division to receive this year's Distinguished Achievement Award.
The heart in particular seems to be resistant to developing cancerous cells.
"When's the last time you heard of anyone having heart cancer? It's almost unheard of," said Sussman.
That's not surprising from an evolutionary standpoint. If heart cells make a grave transcription error during cell division and your ticker ticks its last tock, there's no fixing the problem. So it makes sense that heart cells are incredibly careful when it comes to proliferating.
But it's this very meticulousness that makes heart disease such an intractable problem, Sussman explained. Over time, the cells burn themselves out. Their ability to repair themselves and generate fresh replacements gets progressively worse. By the time you reach old age and start experiencing symptoms of age-related heart disease, your cardiac cells are running on fumes and aren't able to properly divide into new cells.
"There's a razor's edge balancing cellular aging and cancer risk," he said.
What if you could use biotechnology to walk that razor's edge? To use the proliferative and survival properties of cancer-prone cells to rejuvenate cardiac progenitor cells -- a rare type of stem cell that replicates indefinitely into new heart cells--and get them dividing again, without forming tumors?
That's the aim of one arm of Sussman's research at SDSU. Sussman and his colleagues published a paper in the May 29 issue of the Journal of Biological Chemistry exploring the results of taking an enzyme, Pim, known to be associated with growth and survival of certain types of cancer cells, and causing it to be overexpressed in cardiac progenitor cells in mice.
In healthy cells, Pim helps facilitate chromosome splitting, a key part of the cellular division process.
The gene that encodes the production of this enzyme, PIM1, is what's known as a proto-oncogene. That means that by itself, the gene doesn't cause cancer. But when it teams up with another gene, Myc, tumors are likely to form.
Fortunately, the Pim/Myc combination isn't an issue in heart progenitor cells, meaning you could tweak those cells to overexpress the PIM1 gene without raising the risk of cancer.
That's exactly what Sussman's team did. They modified mouse heart progenitor cells to overexpress PIM1 in specific locations within the cell, targeting specific locations with more of the critical Pim enzyme in hopes that it would protect against aging-related heart disease.
And it worked. Compared to controls, the mice with overexpressed PIM1 lived longer and showed stronger cell proliferation. But interestingly, the way it worked was different depending on where in the cell the gene was overexpressed.
If the researchers caused PIM1 to be overexpressed in the progenitor cell's nucleus, they saw increased proliferation into new cells. If they overexpressed the gene in a different region of the cell, the mitochondria, they found that the enzyme inhibited the cell's natural self-destruct signals, causing them to live longer.
One technique enhanced cell division, the other warded off cell death. In humans, depending on a person's individual circumstance, either or both of these effects might help restore their cardiac cells to a younger, healthier state.
Sussman and his colleagues have replicated the results with human tissue obtained from people whose hearts have failed and who are living on a ventricular assist device that pumps their blood for them. The research team is currently trying to obtain funding to do human clinical trials wherein they obtain a patient's own cardiac progenitor cells, modify them to overexpress PIM1, then put them back into the patient's heart in hopes of rejuvenating the tissue and spurring the heart to repair itself.
"We're trying to dial back the clock to when their cells had more regenerative potential," Sussman said. "By understanding how and where Pim affe
cts these cells, we can create specialized Pim molecules that get you all the benefits of youthfulness without the risk of cancer."
 

Journal Reference:

1. Kaitlen Samse, Jacqueline Emathinger, Nirmala Hariharan, Pearl Quijada, Kelli Ilves, Mirko Völkers, Lucia Ormachea, Andrea De La Torre, Amabel M. Orogo, Roberto Alvarez, Shabana Din, Sadia Mohsin, Megan Monsanto, Kimberlee M. Fischer, Walter P. Dembitsky, Åsa B. Gustafsson, Mark A. Sussman. Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells. Journal of Biological Chemistry, 2015; 290 (22): 13935 DOI: 10.1074/jbc.M114.617431 

Courtesy: ScienceDaily
 

Supercharging stem cells to create new therapies

A new method for culturing stem cells has been developed, which sees the highly therapeutic cells grow faster and stronger. Stem cell therapy is showing promising signs for transplant patients, and the IL-17 treated stem cells should be even more effective at preventing and treating inflammation in transplant recipients -- particularly controlling rejection in transplant patients. 

The research, which was published in the international journal, Stem Cells, is expected to eventually lead to new treatments for transplant patients.
Kisha Sivanathan, a PhD student in the University of Adelaide's School of Medicine and the Renal Transplant Unit at the Royal Adelaide Hospital, says this is an exciting breakthrough in stem cell research.
"Adult mesenchymal stem cells, which can be obtained from many tissues in the body including bone marrow, are fascinating scientists around the world because of their therapeutic nature and ability to cultivate quickly. These stem cells have been used for the treatment of many inflammatory diseases but we are always looking for ways in which to increase stem cells' potency," says Ms Sivanathan, lead author on the study.
"Our research group is the first in the world to look at the interaction between mesenchymal stem cells and IL-17, a powerful protein that naturally occurs in the body during times of severe inflammation (such as during transplant rejection).
"We discovered that when cultured mesenchymal stem cells are treated with IL-17 they grow twice as fast as the untreated stem cells and are more efficient at regulating the body's immune response," she says.
Stem cell therapy is showing promising signs for transplant patients and according to Ms Sivanathan, the IL-17 treated stem cells should be even more effective at preventing and treating inflammation in transplant recipients -- particularly controlling rejection in transplant patients.
"Current drugs (immunosuppressant drugs) used to help prevent a patient rejecting a transplant suppress the whole immune system and can cause severe side effects, like cancer. However, stem cell therapy (used in conjunction with immunosuppressant drugs) helps patients 'accept' transplants while repairing damaged tissue in the body, resulting in less side effects," says Ms Sivanathan.
"We are yet to undertake clinical trials on the IL-17 treated stem cells but we anticipate that because this treatment produces more potent stem cells, they will be more effective than the untreated stem cells," she says.
 

Journal Reference:

1. Kisha Nandini Sivanathan, Darling M. Rojas-Canales, Christopher M. Hope, Ravi Krishnan, Robert P. Carroll, Stan Gronthos, Shane T. Grey, Patrick T. Coates. Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function. STEM CELLS, 2015; DOI: 10.1002/stem.2075 

Courtesy: ScienceDaily
 

Live imaging reveals how wound healing influences cancer

Scientists have known for some time that inflammation is one of the ten hallmarks of cancer. Cancer has also been described as a "wound that does not heal." Now researchers have studied the 'see-through' larvae of zebrafish to reveal how wound healing leads to melanoma. 

"Our results provide direct visual evidence of a physical link between wound-associated inflammation and the development of skin cancer," says EMBO Member Paul Martin, professor at Bristol University and the University of Cardiff. "White blood cells, in particular neutrophils, that typically serve as part of the body's built-in immune system are usurped by nearby precancerous skin cells in a way that leads to the proliferation of tumour cells in our zebrafish model experimental system of human melanoma."
Scientists have known for some time that inflammation is one of the ten hallmarks of cancer. Cancer has also been described as a "wound that does not heal." However details about how physical damage to body tissues might influence the progress of cancer have remained scarce.
The researchers used genetically modified larvae of zebrafish to watch the relationship between wound-associated inflammation and melanoma as the cancer took hold in the living fish. The cellular events and changes were observed by live imaging with a special confocal laser-scanning microscope.
In further experiments, the researchers were also able to show that a specific type of signaling molecule released by neutrophils, prostaglandin E2, is part of the signal that drives the splurge of cell growth linked to the cancer in their experimental system. High levels of neutrophils were also detected in human clinical samples of melanomas that had been obtained from individuals whose cancers had open ulcers. Importantly, neutrophils were linked to increased proliferation of melanoma cells and poor survival, which suggests that these findings in fish may have considerable relevance to cancer patients.
The authors note that the findings of the study may have implications for cancer surgery. Minimally invasive surgery is beneficial to cancer patients in many situations and often the preferred treatment. However, particularly in cases where all cancerous tissue cannot be removed, the inflammatory response might influence the remaining cancer cells in the body. "Our studies to date suggest that several strategies might improve outcomes for patients including the possible use of therapeutics to dampen damage-induced inflammatory responses," adds Martin.
Further work is in progress to better understand the relationship between the inflammatory response and skin cancer in the zebrafish model system. Studies are also needed to investigate what therapeutic or other strategies might bring better interventions for patients who have adverse tissue inflammation due to planned (for example biopsy or surgery) or unplanned (e.g. ulceration) tissue damage.
 

Journal Reference:

1. N. Antonio, M. L. Bonnelykke-Behrndtz, L. C. Ward, J. Collin, I. J. Christensen, T. Steiniche, H. Schmidt, Y. Feng, P. Martin. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. The EMBO Journal, 2015; DOI: 10.15252/embj.201490147 

Courtesy: ScienceDaily
 

Novel HIV vaccine regimen provides robust protection in non-human primates

A new study shows than an HIV-1 vaccine regimen, involving a viral vector boosted with a purified envelope protein, provided complete protection in half of the vaccinated non-human primates (NHPs) against a series of six repeated challenges with simian immunodeficiency virus (SIV), a virus similar to HIV that infects NHPs.

Based on these pre-clinical data, the HIV-1 version of this vaccine regimen is now being evaluated in an ongoing Phase 1/2a international clinical study sponsored by Crucell Holland B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson.
"We previously showed that adenovirus vector-based HIV-1 vaccine candidates offered partial protection against SIV when given alone," said lead author Dan H. Barouch, M.D., Ph.D., director of the Center for Virology and Vaccine Research at BIDMC and professor of medicine at Harvard Medical School. The paper describes two new studies in which investigators evaluated the protective efficacy of an adenovirus serotype 26 (Ad26) vectored vaccine boosted with a purified envelope protein.
The results demonstrate that viral vector priming plus protein boosting resulted in complete protection in half of the vaccinated animals. "This shows improvement over our previous results," said Barouch, who is also a steering committee member of the Ragon Institute of MGH, MIT, and Harvard. "Moreover, protection correlated with the magnitude and polyfunctionality of antibody responses. The data show the potential utility of envelope protein boosting following Ad26 priming."
"Bringing the global HIV epidemic under control requires new tools, bold strategies and collaboration among a number of stakeholders," said Hanneke Schuitemaker, one of the study authors and vice president, Viral Vaccines Discovery and Translational Medicine, Janssen. "In line with our company's commitment to address global health needs, we are committed to working with leading experts to develop a preventative HIV vaccine and our team is excited to advance this program into human clinical studies."
 

Journal Reference:

1. Dan H. Barouch, Galit Alter, Thomas Broge, Caitlyn Linde, Margaret E. Ackerman, Eric P. Brown, Erica N. Borducchi, Kaitlin M. Smith, Joseph P. Nkolola, Jinyan Liu, Jennifer Shields, Lily Parenteau, James B. Whitney, Peter Abbink, David M. Ng’ang’a, Michael S. Seaman, Christy L. Lavine, James R. Perry, Wenjun Li, Arnaud D. Colantonio, Mark G. Lewis, Bing Chen, Holger Wenschuh, Ulf Reimer, Michael Piatak, Jeffrey D. Lifson, Scott A. Handley, Herbert W. Virgin, Marguerite Koutsoukos, Clarisse Lorin, Gerald Voss, Mo Weijtens, Maria G. Pau, and Hanneke Schuitemaker. Protective efficacy of adenovirus-protein vaccines against SIV challenges in rhesus monkeys. Science, 2 July 2015 DOI: 10.1126/science.aab3886

 Courtesy: ScienceDaily

Prion trials and tribulations: Finding the right tools and experimental models

Prions are fascinating, enigmatic, and might teach us not only about rare prion diseases like Creutzfeld-Jakob disease, mad cow disease, or scrapie, but also about other more common neurodgenerative diseases. Two studies report progress with novel tools and paradigms to study prion disease. 

Prion protein, shown in red, can become infectious and cause neurodegenerative disease. Here four nerve cells in a mouse illustrate how infectious prion protein moves within cells along neurites -- wire-like connections the nerve cells use for communicating with adjacent cells.

Credit: NIAID, CC-BY

Several research groups have recently succeeded in generating infectious prions with prion protein produced by bacteria in test tubes under consistent and controlled conditions. Such synthetic prions are a critical tool to study how prions cause disease in general and to test the "protein-only" hypothesis, which states that the mutant prion protein itself can trigger the disease by co-opting other prion proteins to form aggregates that are toxic to nerve cells. Jiyan Ma, from the Van Andel Research Institute in Grand Rapids, USA, and colleagues tested whether the properties of synthetically generated prions are the same as those of natural disease-causing prions, and whether the disease caused by synthetic prions is identical to naturally occurring prion disease.
They demonstrate that similar to the classical disease-causing prions, synthetic prions are infectious in a concentration-dependent way, and are able to cause prion disease in normal mice not only by direct injection into the brain (which is the easiest but not a naturally occurring way of prion transmission) but also by other routes. The researchers also show that the synthetic prions induced pathological changes typical for classic prion disease, including the dissemination of disease-specific prion protein accumulation and the route and mechanism of invasion of nerve cells in the brain. They conclude that their results "demonstrate the similarity of synthetically generated prion to the infectious agent in TSEs [transmissible spongiform encephalopathies, another term for prion diseases] and provide strong supporting evidence for the prion hypothesis."
About 15% of human prion disease is heritable and caused by dominant mutations in the human PRP gene. The mutations are thought to predispose the resulting PRP protein proteins to adapt the disease conformation and trigger the cascade that kills nerve cells. Much of the study of inherited human prion disease in mice has focused on mixing mutant human prions--isolated from human patients or produced by transgenic mice carrying the mutant human gene--with normal mouse prions in order to establish whether the mutant human prions are infectious, i.e. whether they can change normal proteins to the disease-associated conformation (or shape).
John Collinge, from University College London, UK, and colleagues answered a crucial question regarding such studies, namely whether superimposition of pathogenic human PrP mutation into mouse PrP (which is similar but not identical) will have the same structural consequences as occur in the human brain. They focused on a specific mutation underlying an inherited form of human prion disease called Gerstmann-Sträussler-Scheinker (GSS) disease. This mutation causes an amino-acid substitution (proline-to-leucine) in the prion protein, human PrP 102L for short. In the brain of patients with GSS disease, this mutant prion (GSS-102L) co-exists with a heterogeneous mixture of normal PrP and other PrP derivatives, which it somehow manages to co-opt into forming aggregates that are toxic to the nerve cells.
To characterize the transmission capabilities of the GSS-associated prions, the researchers tested whether the ability of GSS P102L to cause prion disease in mice depended on what other types of prion proteins and derivatives were present. They examined whether GSS P102L prions could infect transgenic mice that express human mutant 102L PrP, human normal PrP, or normal mouse PrP. Injecting a pure preparation of GSS P102L prions into the brains of the three different types of mice, they found that GSS P102L prions can only infect transgenic mice expressing human 102L PrP, i.e. those carrying the identical mutant human gene. Mice expressing normal human PrP or normal mouse PrP were completely resistant to infection with GSS-102L prions.
"Collectively," the researchers say, their data "establish that GSS-102L prions which replicate with high efficiency in a host expressing human PrP 102L are unable to propagate using wild-type [normal] human PrP or wild-type mouse PrP as substrate." These results differ from the reported transmission properties of prions generated in GSS-P102L challenged mice expressing mouse PrP 101L (the equivalent mutation in the closely related but not identical mouse PrP): such prions readily infect animals expressing normal human or normal mouse PrP. Commenting on the discrepancy, the researchers suggest that the superimposition of the human on the mouse mutation might have generated experimental prion strains with different transmission characteristics from those of authentic human prion strains. Overall, they conclude that "future transgenic modeling of infectious prion diseases should focus exclusively on expression of mutant human PrP, as other approaches may generate novel experimental prion strains that are unrelated to human disease."
Better tools and better paradigms to study prion diseases should help the understanding of how these diseases spread and devastate mammalian brains, and eventually lead to efficient treatment and prevention strategies.
 

Journal References:

1. Xinhe Wang, Gillian McGovern, Yi Zhang, Fei Wang, Liang Zha, Martin Jeffrey, Jiyan Ma. Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion. PLOS Pathogens, 2015; 11 (7): e1004958 DOI: 10.1371/journal.ppat.1004958
2. Emmanuel A. Asante, Andrew Grimshaw, Michelle Smidak, Tatiana Jakubcova, Andrew Tomlinson, Asif Jeelani, Shyma Hamdan, Caroline Powell, Susan Joiner, Jacqueline M. Linehan, Sebastian Brandner, Jonathan D. F. Wadsworth, John Collinge. Transmission Properties of Human PrP 102L Prions Challenge the Relevance of Mouse Models of GSS. PLOS Pathogens, 2015; 11 (7): e1004953 DOI: 10.1371/journal.ppat.1004953 

Courtesy: ScienceDaily
 

Programming DNA to reverse antibiotic resistance in bacteria

New research introduces a promising new tool to combat the rapid, extensive spread of antibiotic resistance around the world. It nukes antibiotic resistance in selected bacteria, and renders other bacteria more sensitive to antibiotics. The research, if ultimately applied to pathogens on hospital surfaces or medical personnel's hands, could turn the tide on untreatable, often lethal bacterial infections. 

Growing bacteria in petri dishes. (stock image)

Credit: © kasto / Fotolia

New Tel Aviv University research published in PNAS introduces a promising new tool: a two-pronged system to combat this dangerous situation. It nukes antibiotic resistance in selected bacteria, and renders other bacteria more sensitive to antibiotics. The research, led by Prof. Udi Qimron of the Department of Clinical Microbiology and Immunology at TAU's Sackler Faculty of Medicine, is based on bacterial viruses called phages, which transfer "edited" DNA into resistant bacteria to kill off resistant strains and make others more sensitive to antibiotics.
According to the researchers, the system, if ultimately applied to pathogens on hospital surfaces or medical personnel's hands, could turn the tide on untreatable, often lethal bacterial infections. "Since there are only a few pathogens in hospitals that cause most of the antibiotic-resistance infections, we wish to specifically design appropriate sensitization treatments for each one of them," Prof. Qimron says. "We will have to choose suitable combinations of DNA-delivering phages that would deliver the DNA into pathogens, and the suitable combination of 'killing' phages that could select the re-sensitized pathogens."
Reprogramming the system
"Antibiotic-resistant pathogens constitute an increasing threat because antibiotics are designed to select resistant pathogens over sensitive ones," Prof. Qimron says. "The injected DNA does two things: It eliminates the genes that cause resistance to antibiotics, and it confers protection against lethal phages.
"We managed to devise a way to restore antibiotic sensitivity to drug-resistant bacteria, and also prevent the transfer of genes that create that resistance among bacteria," he continues.
Earlier research by Prof. Qimron revealed that bacteria could be sensitized to certain antibiotics -- and that specific chemical agents could "choose" those bacteria more susceptible to antibiotics. His strategy harnesses the CRISPR-Cas system -- a bacterial DNA-reprogramming system Prof. Qimron pioneered -- as a tool to expand on established principles.
According to the researchers, "selective pressure" exerted by antibiotics renders most bacteria resistant to them -- hence the epidemic of lethal resistant infections in hospitals. No counter-selection pressure for sensitization of antibiotics is currently available. Prof. Qimron's strategy actually combats this pressure -- selecting for the population of pathogens exhibiting antibiotic sensitivity.
"We believe that this strategy, in addition to disinfection, could significantly render infections once again treatable by antibiotics," said Prof. Qimron.
Prof. Qimron and his team are now poised to apply the CRISPR/phage system on pseudomonas aeruginosa -- one of the world's most prevalent antibiotic-resistant pathogens involved in hospital-acquired infections -- and to test whether bacterial sensitization works in a more complex microbial environment: the mouse cage.
 

Journal Reference:

1. Ido Yosef, Miriam Manor, Ruth Kiro, Udi Qimron. Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria. Proceedings of the National Academy of Sciences, 2015; 201500107 DOI: 10.1073/pnas.1500107112 

Courtesy: ScienceDaily
 

Why are 95% of people who live to 110 women? You're as old as your stem cells

Human supercentenarians share at least one thing in common--over 95 percent are women. Scientists have long observed differences between the sexes when it comes to aging, but there is no clear explanation for why females live longer. In a discussion of what we know about stem cell behavior and sex, researchers argue that it's time to look at differences in regenerative decline between men and women. This line of research could open up new explanations for how the sex hormones estrogen and testosterone, or other factors, modify lifespan.

"As the search continues for ways to ameliorate the aging process and maintain the regenerative capacity of stem cells, let us not forget one of the most effective aging modifiers: sex," authors write.

Credit: © ia_64 / Fotolia

It's known that estrogen has direct effects on stem cell populations in female mice, from increasing the number of blood stem cells (which is very helpful during pregnancy) to enhancing the regenerative capacity of brain stem cells at the height of estrus. Whether these changes have a direct impact on lifespan is what's yet to be explored. Recent studies have already found that estrogen supplements increase the lifespan of male mice, and that human eunuchs live about 14 years longer than non-castrated males.

More work is also needed to understand how genetics impacts stem cell aging between the sexes. Scientists have seen that knocking out different genes in mice can add longevity benefits to one sex but not the other, and that males in twin studies have shorter telomeres--a sign of shorter cellular lifespan--compared to females.

"It is likely that sex plays a role in defining both lifespan and healthspan, and the effects of sex may not be identical for these two variables," the authors write. "As the search continues for ways to ameliorate the aging process and maintain the regenerative capacity of stem cells, let us not forget one of the most effective aging modifiers: sex."

Journal Reference:

1. Ben Dulken, Anne Brunet. Stem Cell Aging and Sex: Are We Missing Something? Cell Stem Cell, 2015; 16 (6): 588 DOI: 10.1016/j.stem.2015.05.006 

Courtesy: ScienceDaily

Reprogramming of DNA observed in human germ cells for first time

A team of researchers has described for the first time in humans how the epigenome -- the suite of molecules attached to our DNA that switch our genes on and off -- is comprehensively erased in early primordial germ cells prior to the generation of egg and sperm. However, the study shows some regions of our DNA -- including those associated with conditions such as obesity and schizophrenia -- resist complete reprogramming. 

Cells (stock image). When an egg cell is fertilized by a sperm, it begins to divide into a cluster of cells known as a blastocyst, the early stage of the embryo. Within the blastocyst, some cells are reset to their master state, becoming stem cells, which have the potential to develop into any type of cell within the body.

Although our genetic information -- the 'code of life' -- is written in our DNA, our genes are turned on and off by epigenetic 'switches'. For example, small methyl molecules attach to our DNA in a process known as methylation and contribute to the regulation of gene activity, which is important for normal development. Methylation may also occur spontaneously or through our interaction with the environment -- for example, periods of famine can lead to methylation of certain genes -- and some methylation patterns can be potentially damaging to our health. Almost all of this epigenetic information is, however, erased in germ cells prior to transmission to the next generation
Professor Azim Surani from the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge, explains: "Epigenetic information is important for regulating our genes, but any abnormal methylation, if passed down from generation to generation, may accumulate and be detrimental to offspring. For this reason, the information needs to be reset in every generation before further information is added to regulate development of a newly fertilised egg. It's like erasing a computer disk before you add new data."
When an egg cell is fertilized by a sperm, it begins to divide into a cluster of cells known as a blastocyst, the early stage of the embryo. Within the blastocyst, some cells are reset to their master state, becoming stem cells, which have the potential to develop into any type of cell within the body. A small number of these cells become primordial germ cells with the potential to become sperm or egg cells.
In a study funded primarily by the Wellcome Trust, Professor Surani and colleagues showed that a process of reprogramming the epigenetic information contained in these primordial germ cells is initiated around two weeks into the embryo's development and continues through to around week nine. During this period, a genetic network acts to inhibit the enzymes that maintain or programme the epigenome until the DNA is almost clear of its methylation patterns.
Crucially, however, the researchers found that this process does not clear the entire epigenome: around 5% of our DNA appears resistant to reprogramming. These 'escapee' regions of the genome contain some genes that are particularly active in neuronal cells, which may serve important functions during development. However, data analysis of human diseases suggests that such genes are associated with conditions such as schizophrenia, metabolic disorders and obesity.
Walfred Tang, a PhD student who is the first author on the study, adds: "Our study has given us a good resource of potential candidates of regions of the genome where epigenetic information is passed down not just to the next generation but potentially to future generations, too. We know that some of these regions are the same in mice, too, which may provide us with the opportunity to study their function in greater detail."
Epigenetic reprogramming also has potential consequences for the so-called 'dark matter' within our genome. As much as half of human DNA is estimated to be comprised of 'retroelements', regions of DNA that have entered our genome from foreign invaders including bacteria and plant DNA. Some of these regions can be beneficial and even drive evolution -- for example, some of the genes important to the development of the human placenta started life as invaders. However, others can have a potentially detrimental effect -- particularly if they jump about within our DNA, potentially interfering with our genes. For this reason, our bodies employ methylation as a defence mechanism to suppress the activity of these retroelements.
"Methlyation is effective at controlling potentially harmful retroelements that might harm us, but if, as we've seen, methylation patterns are erased in our germ cells, we could potentially lose the first line of our defence," says Professor Surani.
In fact, the researchers found that a notable fraction of the retroelements in our genome are 'escapees' and retain their methylation patterns -- particularly those retroelements that have entered our genome in our more recent evolutionary history. This suggests that our body's defence mechanism may be keeping some epigenetic information intact to protect us from potentially detrimental effects.
 

Journal Reference:

1. Walfred W.C. Tang, Sabine Dietmann, Naoko Irie, Harry G. Leitch, Vasileios I. Floros, Charles R. Bradshaw, Jamie A. Hackett, Patrick F. Chinnery, M. Azim Surani. A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development. Cell, 2015; 161 (6): 1453 DOI: 10.1016/j.cell.2015.04.053 

Courtesy: ScienceDaily
 

Smoking induces early signs of cancer in cheek swabs

DNA damage caused by smoking can be detected in cheek swabs, finds research published in JAMA Oncology. The study provides evidence that smoking induces a general cancer program that is also present in cancers which aren't usually associated with it -- including breast and gynaecological cancers.

The research team, led by Professor Martin Widschwendter, Head of the Department of Women's Cancer at the UCL Institute for Women's Health and Dr Andrew Teschendorff (UCL Cancer Institute) looked at epigenetic alterations -- changes to the DNA that switch genes on and off. Epigenetic changes are associated with cancer development and can be caused by exposure to environmental factors such as cigarette smoke.
The researchers aimed to explore whether normal cells from the inside of the cheek would demonstrate epigenetic changes which are associated with lung and other epithelial cancers. These types of cancers originate in the epithelial cells -- which cover the outside of the body as skin or the inside of the body as lining for organs and body cavities -- and make up 85% of all cancer cases in the UK. The buccal cells taken from the cheek swabs are easy to collect and are directly exposed to cigarette smoke in those who smoke.
To do this, in collaboration with Prof Diana Kuh (UCL Epidemiology & Public Health) and her team, they analysed buccal samples from 790 women all born in 1946 and 152 matched blood samples from the Medical Research Council National Survey of Health and Development. The dataset included information about smoking history and smoking status at the time the samples were collected.
This analysis showed that buccal cells in women who have smoked had numerous changes to their epigenomes -- known as DNA-methylation (DNAme). Buccal cells showed a 40-fold increase in abnormal methylation sites compared to matched blood samples, making them a more reliable indicator of DNA changes.
The team then went on to analyse this smoke-triggered epigenetic program in over 5000 tissue samples, including normal tissue, pre-cancerous tissue and cancer tissue from 15 different epithelial cancer types. In doing so, they tested whether they were able to discriminate normal tissue from cancerous tissue. They found that this program -- which they originally derived in normal buccal cells of smokers -- is able to discriminate between normal and cancerous tissue with almost 100% sensitivity and 100% specificity irrespective of the organ from which the cancer arose.
Researchers also found that the absence or presence of this program was able to predict the fate of pre-invasive cancer lesions. The presence of the faulty program in the cells makes it very likely that a pre-invasive cancer will progress to a full-blown invasive cancer. However, the absence of the faulty program makes it likely that the pre-cancer can potentially regress and disappear.
An individuals' DNA works like the hardware within a cell, with the epigenome being the software. Smoking misprograms the epigenome and the genetic code becomes difficult or impossible to read. Misprogramming of a cells' software, in conjunction with genetic mutations, eventually lead to an inability of these cells to develop into specific differentiated cells. These cells are then trapped in an undifferentiated status and can grow indefinitely and spread into other organs.
Professor Martin Widschwendter commented: 'These are significant results for our core interest which is decoding women's cancers. We are a big step closer now to unravelling how environmental factors cause cancer. These results pave the way for other studies in which easily accessible cells can be used as proxies to highlight epigenetic changes that may indicate a risk of developing cancer at a site where cells are inaccessible. This is incredibly exciting for women's cancers such as ovary, breast and endometrial cancer where predicting the cancer risk is a big challenge,'
'The results also demonstrate that smoking-related DNA damage to the epigenome of certain genes had been reversed in ex-smokers who had quit 10 years previously before sample collection, highlighting the key health benefits of quitting smoking, or not taking it up at all.
Athena Lamnisos, CEO of The Eve Appeal said: 'We know that what's going to save most lives from gynaecological cancers is prevention -- decoding why these cancers start and stopping them. That's why we fund research into the earlier diagnosis, risk prediction and prevention. This research shows how signs of developing cancer may be detected using accessible cells from inside the mouth. It points the way for pioneering further studies that will help detect women's cancers.'
Lead author Andrew Teschendorff (UCL Cancer Institute) said: 'Our work shows that smoking has a major impact on the epigenome of normal cells that are directly exposed to the carcinogen. Of particular significance is that these epigenetic changes are also seen in both smoking-related and non-smoking related cancers, pointing towards a universal cancer program. This research gets us closer to understanding the very first steps in carcinogenesis and in future may provide us with much-needed tests for risk prediction and early detection.'
 

Journal Reference:

1. Andrew E. Teschendorff, Zhen Yang, Andrew Wong, Christodoulos P. Pipinikas, Yinming Jiao, Allison Jones, Shahzia Anjum, Rebecca Hardy, Helga B. Salvesen, Christina Thirlwell, Samuel M. Janes, Diana Kuh, Martin Widschwendter. Correlation of Smoking-Associated DNA Methylation Changes in Buccal Cells With DNA Methylation Changes in Epithelial Cancer. JAMA Oncology, 2015; DOI: 10.1001/jamaoncol.2015.1053 

 Courtesy: ScienceDaily