QUINTAIS IMORTAIS

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KTH The Royal Institute of Technology. "How a carb-restricted diet battles fatty liver disease." ScienceDaily. ScienceDaily, 15 February 2018. <www.sciencedaily.com/releases/2018/02/180215165152.htm>.

Nitrate in drinking water increases the risk of colorectal cancer, study finds

Date: February 20, 2018

Source: Aarhus University

Summary:

Nitrate in groundwater and drinking water, which primarily comes from fertilisers used in the agricultural production, has not only been subject to decades of environmental awareness -- it has also been suspected of increasing the risk of cancer. The largest epidemiological study ever carried out in this area now shows that there is a correlation -- also when the amount of nitrate in the drinking water is far below the current drinking water standard.

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Calcium may play a role in the development of Parkinson's disease

Date: February 19, 2018 Source: University of Cambridge Summary: Researchers have found that excess levels of calcium in brain cells may lead to the formation of toxic clusters that are the hallmark of Parkinson's disease.

Tyrosine hydroxylase positive neuron stained with a synaptic marker.

Credit: Janin Lautenschl?ger

Researchers have found that excess levels of calcium in brain cells may lead to the formation of toxic clusters that are the hallmark of Parkinson's disease.

The international team, led by the University of Cambridge, found that calcium can mediate the interaction between small membranous structures inside nerve endings, which are important for neuronal signalling in the brain, and alpha-synuclein, the protein associated with Parkinson's disease. Excess levels of either calcium or alpha-synuclein may be what starts the chain reaction that leads to the death of brain cells.

The findings, reported in the journal Nature Communications, represent another step towards understanding how and why people develop Parkinson's. According to the charity Parkinson's UK, one in every 350 adults in the UK -- an estimated 145,000 in all -- currently has the condition, but as yet it remains incurable.

Parkinson's disease is one of a number of neurodegenerative diseases caused when naturally occurring proteins fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. These amyloid deposits of aggregated alpha-synuclein, also known as Lewy bodies, are the sign of Parkinson's disease.

Curiously, it hasn't been clear until now what alpha-synuclein actually does in the cell: why it's there and what it's meant to do. It is implicated in various processes, such as the smooth flow of chemical signals in the brain and the movement of molecules in and out of nerve endings, but exactly how it behaves is unclear.

"Alpha-synuclein is a very small protein with very little structure, and it needs to interact with other proteins or structures in order to become functional, which has made it difficult to study," said senior author Dr Gabriele Kaminski Schierle from Cambridge's Department of Chemical Engineering and Biotechnology.

Thanks to super-resolution microscopy techniques, it is now possible to look inside cells to observe the behaviour of alpha-synuclein. To do so, Kaminski Schierle and her colleagues isolated synaptic vesicles, part of the nerve cells that store the neurotransmitters which send signals from one nerve cell to another.

In neurons, calcium plays a role in the release of neurotransmitters. The researchers observed that when calcium levels in the nerve cell increase, such as upon neuronal signalling, the alpha-synuclein binds to synaptic vesicles at multiple points causing the vesicles to come together. This may indicate that the normal role of alpha-synuclein is to help the chemical transmission of information across nerve cells.

"This is the first time we've seen that calcium influences the way alpha-synuclein interacts with synaptic vesicles," said Dr Janin Lautenschl?ger, the paper's first author. "We think that alpha-synuclein is almost like a calcium sensor. In the presence of calcium, it changes its structure and how it interacts with its environment, which is likely very important for its normal function."

"There is a fine balance of calcium and alpha-synuclein in the cell, and when there is too much of one or the other, the balance is tipped and aggregation begins, leading to Parkinson's disease," said co-first author Dr Amberley Stephens.

The imbalance can be caused by a genetic doubling of the amount of alpha-synuclein (gene duplication), by an age-related slowing of the breakdown of excess protein, by an increased level of calcium in neurons that are sensitive to Parkinson's, or an associated lack of calcium buffering capacity in these neurons.

Understanding the role of alpha-synuclein in physiological or pathological processes may aid in the development of new treatments for Parkinson's disease. One possibility is that drug candidates developed to block calcium, for use in heart disease for instance, might also have potential against Parkinson's disease.

Story Source:

Materials provided by University of Cambridge. The original story is licensed under a Creative Commons License. Note: Content may be edited for style and length.

Journal Reference:

Janin Lautenschläger, Amberley D. Stephens, Giuliana Fusco, Florian Ströhl, Nathan Curry, Maria Zacharopoulou, Claire H. Michel, Romain Laine, Nadezhda Nespovitaya, Marcus Fantham, Dorothea Pinotsi, Wagner Zago, Paul Fraser, Anurag Tandon, Peter St George-Hyslop, Eric Rees, Jonathan J. Phillips, Alfonso De Simone, Clemens F. Kaminski, Gabriele S. Kaminski Schierle. C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction. Nature Communications, 2018; 9 (1) DOI: 10.1038/s41467-018-03111-4

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University of Cambridge. "Calcium may play a role in the development of Parkinson's disease." ScienceDaily. ScienceDaily, 19 February 2018. <www.sciencedaily.com/releases/2018/02/180219071758.htm>.

D-galactose affects ageing male and female brains differently

Date: February 19, 2018 Source: Universitat Autònoma de Barcelona Summary: A research study demonstrates in mice the biological relevance of sex in the effects of accelerated ageing caused by a chronic treatment of D-galactose, a sugar found abundantly in milk and to a lesser extent in fruits and vegetables. At high doses, this substance accelerates ageing in males, affecting them at sensory and motor level and in their neuro-immuno-endocrine system, while females experience alterations in learning and their ability to register information about their surroundings and orientation. However, at low doses the treatment has positive effects, especially in males.

A research study by the Universitat Autònoma de Barcelona (UAB) in collaboration with the University of La Laguna (ULL) demonstrates in mice the biological relevance of sex in the effects of accelerated ageing caused by a chronic treatment of D-galactose, a sugar found abundantly in milk and to a lesser extent in fruits and vegetables. At high doses, this substance accelerates ageing in males, affecting them at sensory and motor level and in their neuro-immuno-endocrine system, while females experience alterations in learning and their ability to register information about their surroundings and orientation. However, at low doses the treatment has positive effects, especially in males.

A study coordinated by the UAB and in collaboration with the ULL reveals the biological relevance of sex in the alteration of behaviour and the neuro-immuno-endocrine system, caused by accelerated ageing with a chronic treatment of D-galactose, a sugar found abundantly in milk and in some fruits and vegetables. The research was recently published in the Journal of Gerontology: Biological Sciences and Medical Sciences.

For almost two decades, chronic treatments with D-galactose have been used as a tool to create animal models of accelerated ageing. Their neurotoxicity is due to abnormal ROS accumulation, molecules proper of oxidative stress and AGEs, proteins or lipids which become glycated as a result of exposure to sugars, both related to the acceleration of the multisystem functional decline occurring during ageing. These D-galactose induced biological products are also involved in the development or deterioration of many degenerative diseases such as diabetes, arteriosclerosis, kidney diseases, infections and Alzheimer's disease.

"The difficulty in research with accelerated ageing models using D-galactose lies in the fact that its neurotoxicity effects at biochemical level do not always translate into or are observable as pathological symptoms at behavioural level. In the study we found convincing evidence of some of them and observed important differences between the males and females," says Dr Lydia Giménez-Llort, lead researcher of the project.

Through a complete and multifunctional behavioural analysis researchers examined the chronic effects of low (50 mg/kg) and high (100 mg/kg) doses of D-galactose in male and female mice aged 6 months -- the equivalent of 40 human years. Based on the results of twelve tests they assessed the sensory, motor, emotional and cognitive fields and also explored the effects on the neuro-immuno-endocrine system, decisive in pinpointing the vital capacity or biological age of individuals.

The results point to the existence of different sensitivity thresholds depending on the sex of the animal with regards to their functional capacity to meet the performance level required for certain tasks: D-galactose had pro-ageing effects at sensory and motor level and on the immuno-endocrine system in males, while in females it altered their motor performance and some learning processes as well as their spatial memory -- the ability to register information about their surroundings and orientation, which depends on the hippocampus and cerebellum.

"The most surprising results are found in the low doses of D-galactose, which seem to trigger positive effects in males, such as improved learning and memory, while in females the expected dose-response ratio continues, with deteriorated motor and spatial learning, although there are improvements in some aspects such as memory. These results point to the complexity of the effects at functional level, and therefore all of these observations open the door to new lines of research which can clarify all these underlying neuronal mechanisms and help to understand the vulnerability and differential protection observed," explains Dr Rafael Castro, ULL researcher and co-author of the study.

"In the past few years, what is known as Gender-specific Medicine warns about the need and importance to research into sex and gender-specific aspects, as well as consider the age factor, having more knowledge in biology throughout a person's life and creating more personalised medicines. Our study demonstrates this need and reinforces the idea that the male and female genders must be considered two exceptional natural scenarios in which to study the biological, psychological, social and environmental roles, their functional interactions and their impact on the intercommunication of homeostatic networks, which guarantee a balance in health and are affected by diseases throughout their life cycle," Dr Giménez-Llort highlights.

The research also contributes to gaining more in depth knowledge in the study of biological and environmental determinants, as well as different lifestyles and habits at specific moments such as in mid-life, in which the ageing process gains speed and gradually reduces the organism's functional capacities, which begin to see a limitation in their biological anti-oxidant capacity to counteract imbalances caused by age.

The results of the study form part of the PhD thesis of Raquel Baeta-Corral, first author of the article, and are the product of a research led by Lydia Giménez-Llort, Director of the Medical Psychology Unit, Department of Psychiatry and Legal Medicine and researcher at the UAB Institute of Neuroscience, together with Dr Rafael Castro, Director of the Neurobiology and Gene Therapy Laboratory, Department of Basic Medical Sciences at the ULL, under the framework of the Health Research Fund project of the Institute of Health Carlos III.

Story Source:

Materials provided by Universitat Autònoma de Barcelona. Note: Content may be edited for style and length.

Journal Reference:

Raquel Baeta-Corral, Rafael Castro-Fuentes, Lydia Giménez-Llort. Sexual dimorphism in the behavioral responses and the immuno-endocrine status in D-galactose induced aging. J Gerontol A Biol Sci Med Sci, 2018 DOI: 10.1093/gerona/gly031/4868145

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Universitat Autònoma de Barcelona. "D-galactose affects ageing male and female brains differently." ScienceDaily. ScienceDaily, 19 February 2018. <www.sciencedaily.com/releases/2018/02/180219103900.htm>.

Low-fat or low-carb? It's a draw, study finds

Date: February 20, 2018 Source: Stanford Medicine Summary: New evidence might dismay those who have chosen sides in the low-fat versus low-carb diet debate. Cutting either carbs or fats shaves off excess weight in about the same proportion, according to the study.

What's the best diet? (stock image)

Credit: © Pavel Bobrovskiy / Fotolia

New evidence from a study at the Stanford University School of Medicine might dismay those who have chosen sides in the low-fat versus low-carb diet debate.

Neither option is superior: Cutting either carbs or fats shaves off excess weight in about the same proportion, according to the study. What's more, the study inquired whether insulin levels or a specific genotype pattern could predict an individual's success on either diet. The answer, in both cases, was no.

"We've all heard stories of a friend who went on one diet -- it worked great -- and then another friend tried the same diet, and it didn't work at all," said Christopher Gardner, PhD, professor of medicine and the lead author of the study. "It's because we're all very different, and we're just starting to understand the reasons for this diversity. Maybe we shouldn't be asking what's the best diet, but what's the best diet for whom?"

Past research has shown that a range of factors, including genetics, insulin levels (which helps regulate glucose in the body) and the microbiome, might tip the scales when it comes to weight loss. The new study, to be published Feb. 20 in JAMA, homed in on genetics and insulin, seeking to discover if these nuances of biology would encourage an individual's body to favor a low-carbohydrate diet or a low-fat diet. The senior authors of the study are Gardner; Abby King, PhD, professor of health research and policy and of medicine; Manisha Desai, PhD, professor of medicine and of biomedical data science; and John Ioannidis, MD, DSc, professor of medicine.

A tale of two diets

In his quest to find out if individual biological factors dictate weight loss, Gardner recruited 609 participants between the ages of 18 and 50. About half were men and half were women. All were randomized into one of two dietary groups: low-carbohydrate or low-fat. Each group was instructed to maintain their diet for one year. (By the end of that year, about 20 percent of participants had dropped out of the study, due to outside circumstances, Gardner noted.)

Individuals participated in two pre-study activities, the results of which were later tested as predictors of weight loss. Participants got part of their genome sequenced, allowing scientists to look for specific gene patterns associated with producing proteins that modify carbohydrate or fat metabolism. Then, participants took a baseline insulin test, in which they drank a shot of glucose (think corn syrup) on an empty stomach, and researchers measured their bodies' insulin outputs.

In the initial eight weeks of the study, participants were told to limit their daily carbohydrate or fat intake to just 20 grams, which is about what can be found in a 1.5 slices of whole wheat bread or in a generous handful of nuts, respectively. After the second month, Gardner's team instructed the groups to make incremental small adjustments as needed, adding back 5-15 grams of fat or carbs gradually, aiming to reach a balance they believed they could maintain for the rest of their lives. At the end of the 12 months, those on a low-fat diet reported a daily average fat intake of 57 grams; those on low-carb ingested about 132 grams of carbohydrates per day. Those statistics pleased Gardner, given that average fat consumption for the participants before the study started was around 87 grams a day, and average carbohydrate intake was about 247 grams.

What's key, Gardner said, was emphasizing that these were healthy low-fat and low-carb diets: A soda might be low-fat, but it's certainly not healthy. Lard may be low-carb, but an avocado would be healthier. "We made sure to tell everybody, regardless of which diet they were on, to go to the farmer's market, and don't buy processed convenience food crap. Also, we advised them to diet in a way that didn't make them feel hungry or deprived -- otherwise it's hard to maintain the diet in the long run," said Gardner. "We wanted them to choose a low-fat or low-carb diet plan that they could potentially follow forever, rather than a diet that they'd drop when the study ended."

Continuing to mine the data

Over the 12-month period, researchers tracked the progress of participants, logging information about weight, body composition, baseline insulin levels and how many grams of fat or carbohydrate they consumed daily. By the end of the study, individuals in the two groups had lost, on average, 13 pounds. There was still, however, immense weight loss variability among them; some dropped upward of 60 pounds, while others gained close to 15 or 20. But, contrary to the study hypotheses, Gardner found no associations between the genotype pattern or baseline insulin levels and a propensity to succeed on either diet.

"This study closes the door on some questions -- but it opens the door to others. We have gobs of data that we can use in secondary, exploratory studies," he said. Gardner and his team are continuing to delve into their databanks, now asking if the microbiome, epigenetics or a different gene expression pattern can clue them in to why there's such drastic variability between dieting individuals.

Perhaps the biggest takeaway from this study, Gardner said, is that the fundamental strategy for losing weight with either a low-fat or a low-carb approach is similar. Eat less sugar, less refined flour and as many vegetables as possible. Go for whole foods, whether that is a wheatberry salad or grass-fed beef. "On both sides, we heard from people who had lost the most weight that we had helped them change their relationship to food, and that now they were more thoughtful about how they ate," said Gardner.

Moving forward, he and his team will continue to analyze the reams of data collected during the yearlong study, and they hope to partner with scientists across Stanford to uncover keys to individual weight loss.

"I'm hoping that we can come up with signatures of sorts," he said. "I feel like we owe it to Americans to be smarter than to just say 'eat less.' I still think there is an opportunity to discover some personalization to it -- now we just need to work on tying the pieces together."

The study's other Stanford co-authors are postdoctoral scholars John Trepanowski, PhD, and Michelle Hauser, MD; research fellow Liana Del Gobbo; and senior biostatistician, Joseph Rigdon, PhD.

Gardner, Desai and Ioannidis are members of the Stanford Cancer Institute. Gardner and Ioannidis are members of the Stanford Cardiovascular Institute. Gardner and Desai are members of the Stanford Child Health Research Institute. Ioannidis is a member of Stanford Bio-X.

The study was funded by the National Institutes of Health (grants 1R01DK091831, T32HL007034 and 1K12GM088033), the Nutrition Science Initiative and Stanford's Clinical and Translational Science Award (grant UL1TR001085).

Stanford's departments of Medicine and of Health Research and Policy also supported the work.

Story Source:

Materials provided by Stanford Medicine. Original written by Hanae Armitage. Note: Content may be edited for style and length.

Journal Reference:

Christopher D. Gardner, John F. Trepanowski, Liana C. Del Gobbo, Michelle E. Hauser, Joseph Rigdon, John P. A. Ioannidis, Manisha Desai, Abby C. King. Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin Secretion: The DIETFITS Randomized Clinical Trial. JAMA, 2018; 319 (7): 667-679 DOI: 10.1001/jama.2018.0245

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Stanford Medicine. "Low-fat or low-carb? It's a draw, study finds." ScienceDaily. ScienceDaily, 20 February 2018. <www.sciencedaily.com/releases/2018/02/180220123124.htm>.

Experts challenge claims about medical marijuana's impact on teen recreational use and opioid deaths

Date: February 22, 2018 Source: Society for the Study of Addiction Summary: Two papers published today look at the current evidence of the effects of medical marijuana laws and conclude there is little support that such laws increase recreational marijuana use among adolescents or reduce opioid overdose deaths.

In 1996, California became the first US state to legalise marijuana use for medical purposes. Medical marijuana is now legal in 29 states. Opponents of medical marijuana argue that such laws increase recreational marijuana use among adolescents, while advocates contend that medical marijuana helps to address the US opioid crisis by reducing overdose deaths.

Two papers published today in the scientific journal Addiction look at the current evidence of the effects of medical marijuana laws and conclude that there is little support for either claim.

The first claim, that legalizing medical marijuana increases recreational use among adolescents, is addressed by a new meta-analysis that pooled the results of eleven separate studies of data from four large-scale US surveys dating back as far as 1991. Results of the meta-analysis indicate that no significant changes (increases or decreases) occurred in adolescent recreational use following enactment of medical marijuana laws. Far fewer studies examined the effects of medical marijuana laws among adults, although existing evidence suggests that adult recreational use may increase after medical marijuana laws are passed

Senior author Professor Deborah Hasin says, "Although we found no significant effect on adolescent marijuana use, we may find that the situation changes as commercialized markets for medical marijuana develop and expand, and as states legalize recreational marijuana use. However, for now, there appears to be no basis for the argument that legalising medical marijuana increases teens' use of the drug."

The second claim, that legalising medical marijuana reduces opioid overdose deaths by offering a less risky method of pain management, is addressed in an editorial co-authored by several members of Addiction's editorial board. Here, the evidence is clear but weak, being rooted in ecological studies whose results have not been confirmed through more rigorous methods. Although those studies show a correlation over time between the passage of medical marijuana laws and opioid overdose death rates, they do not provide any evidence that the laws caused the reduction in deaths. In fact, several recent studies have shown that chronic pain patients who use cannabis do not use lower doses of opioids. There are more plausible reasons for the reduction in opioid deaths that ought to be investigated.

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Materials provided by Society for the Study of Addiction. Note: Content may be edited for style and length.

Journal References:

Sarvet AL, Wall MM, Fink DS, Greene E, Le A, Boustead AE, Pacula RL, Keyes KM, Cerda M, Galea S, and Hasin DS. Medical marijuana laws and adolescent marijuana use in the United States: A systematic review and meta-analysis. Addiction, 2018; DOI: 10.1111/add.14136

Wayne Hall, Robert West, John Marsden, Keith Humphreys, Jo Neale, Nancy Petry. It is premature to expand access to medicinal cannabis in hopes of solving the US opioid crisis. Addiction, 2018; DOI: 10.1111/add.14139

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Society for the Study of Addiction. "Experts challenge claims about medical marijuana's impact on teen recreational use and opioid deaths." ScienceDaily. ScienceDaily, 22 February 2018. <www.sciencedaily.com/releases/2018/02/180222090343.htm>.

New symmetry-breaking method opens way for bioactive compounds

Date: February 22, 2018 Source: Ecole Polytechnique Fédérale de Lausanne Summary:

Chemists have developed a new catalytic method for symmetry breaking. The method can help synthesize important building blocks for bioactive compounds such as anticancer drugs.

A demonstration of molecular chirality using 3-D atomic models in the lab.

Credit: J. Waser/EPFL

Many chemical molecules can exist in nature together with their mirror counterparts; like hands, two compounds can be made up of the same atoms in the same overall structure but in opposite orientations, i.e. left-handed and right-handed. This phenomenon of symmetry is called "chirality," and can give mirror counterparts ("enantiomers") entirely different chemical properties. A famous and tragic example of chirality is thalidomide, which was originally sold as a mixture of both enantiomers. The problem was that one was a harmless sedative and the other highly toxic to fetuses, resulting in disturbing congenital deformities.

So today it has become imperative to synthesize compounds with what is known as high "optical purity," which is a measurement of chiral purity: the degree to which a sample contains one enantiomer in greater amounts than the other. But because enantiomers have very small structural differences and identical stability, synthesizing one over the other is a very challenging task.

One way to do this is what chemists call "desymmetrization" of a non-chiral compound that is similar to the target molecule. This involves modifying a molecule so that it loses the symmetry elements that prevented it to be chiral.

Researchers at Jérôme Waser's Laboratory of Catalysis and Organic Synthesis at EPFL have now developed a new desymmetrization strategy to access chiral building blocks containing urea sub-structures. Urea derivatives are important components of biomolecules such as biotin (vitamin B7) or bioactive natural products, such as the anticancer agelastatin A.

The researchers made two crucial innovations. First, they designed a non-chiral cyclopropane (three-membered carbon ring) precursor. This molecule offers enhanced reactivity and is ideal for reactions under mild conditions.

Second, the researchers engineered a new copper catalyst that can form an enantiomer of the desired product with high selectivity. The copper center binds and activates the cyclopropane precursor, causing its bonds to break. The precursor is then attacked by an indole, a molecule very important as structural element of bioactive compounds. As a result, the precursor loses its symmetry -- and therefore becomes chiral -- and can be used to selectively make the desired enantiomer.

The work is an important breakthrough, as desymmetrization has never been used to access chiral ureas from cyclopropanes before. "New building blocks can be now easily accessed as pure enantiomers, and can be tested for bioactivity or used to synthesize more complex chiral molecules," says Jérôme Waser. "Moreover, the new catalyst we have designed certainly will be useful for other applications in synthetic chemistry."

Story Source:

Materials provided by Ecole Polytechnique Fédérale de Lausanne. Note: Content may be edited for style and length.

Journal Reference:

Daniele Perrotta, Ming-Ming Wang, Jerome Waser. Lewis Acid Catalyzed Enantioselective Desymmetrization of Donor-Acceptor Meso-Diaminocyclopropanes. Angewandte Chemie International Edition, 2018; DOI: 10.1002/anie.201800494

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