PNAS

Quantum Chemistry Solves The Question of Why Life Needs So Many Amino Acids

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One of the oldest and most fundamental questions in biochemistry is why the 20 amino acids that support life are all needed, when the original core of 13 would do – and quantum chemistry might have just provided us with the answer.

According to new research, it’s the extra chemical reactivity of the newer seven amino acids that make them so vital to life, even though they don’t add anything different in terms of their spatial structure.

Quantum chemistry is a way of taking some of the principles of quantum mechanics – describing particles according to probabilistic, wave-like properties – and applying them to the way atoms behave in chemical reactions.

The international team of scientists behind the new study used quantum chemistry techniques to compare amino acids found in space (and left here by meteorite fragments) with amino acids supporting life today on Earth.

“The transition from the dead chemistry out there in space to our own biochemistry here today was marked by an increase in softness and thus an enhanced reactivity of the building blocks,” says one of the researchers, Bernd Moosmann from Johannes Gutenberg University Mainz in Germany.

It’s the job of amino acids to form proteins, as instructed by our DNA. These acids were formed right after Earth itself came into being, about 4.54 billion years ago, and so represent one of the earliest building blocks of life.

However, why evolution decided that we needed 20 amino acids to handle this genetic encoding has never been clear, because the first 13 that developed should have been enough for the task.

The greater “softness” of the extra seven amino acids identified by the researchers means they are more readily reactive and more flexible in terms of chemical changes.

If you were representing the amino acids as circles, they could be drawn as multiple concentric circles representing differing energy levels, rather than one single circle of the same chemical hardness and energy level – kind of like in the photo below.

amino acid circles (Michael Plenikowski)

Having determined the hypothesis through quantum chemistry calculations, the scientists were able to back up their ideas with a series of biochemical experiments.

Along the way the team determined that the extra amino acids – particularly methionine, tryptophan, and selenocysteine – could well have evolved as a response to increasing levels of oxygen in the biosphere in the planet’s youngest days.

Peering so far back in time is difficult, as the first organic compounds never left fossils behind for us to analyse, but this may have been part of the process that kicked off the formation of life on Earth.

As the very earliest living cells tried to deal with the extra oxidative stress, it was a case of survival of the fittest. The cells best able to cope with that additional oxygen – through the protection of the new amino acids – were the ones that lived on and flourished.

“With this in view, we could characterise oxygen as the author adding the very final touch to the genetic code,” says Moosmann.

The research has been published in PNAS.

The Thousands of Serengeti Wildebeest That Drown Each Year Serve a Greater Purpose

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It’s the largest, most spectacular animal migration on our planet. Every year, some 1.2 million wildebeest trample through the Serengeti and the perilous Mara River crossings where thousands of them succumb to the river rapids.

Ecologists know that animal migration, especially on grand scales, affects land ecosystems. But now for the first time they have measured the ecological contribution of mass drownings in the iconic Kenyan river. What they have found is an astonishing example of the circle of life that sustains the natural world.

When immense numbers of wildebeest embark on their annual migration across the savannas of East Africa, the stream of animals takes some 200,000 zebra and antelope along for the trip.

You have probably seen a natural documentary depiction of this epic pilgrimage, especially its most dramatic part around the Mara River where the animals have to make several crossings. Most of them brave the waters with success, but unlucky ones are often shown drowning or being eaten by crocodiles.

All those carcasses eventually pile up in the river, and are slowly consumed by the various creatures that inhabit the ecosystem, both in the river, on land and in the skies.

A team lead by ecologist Amanda Subalusky from the Cary Institute of Ecosystem Studies wondered about the crazy amount of biomass these drownings must represent.

“We used historical reports from 2001 to 2010 and field surveys from 2011 to 2015 to quantify the frequency and size of wildebeest mass drownings in the Kenyan portion of the Mara River,” the team writes in the paper.

Armed with data from field surveys and biochemical analysis, they calculated the fate of an animal carcass as it drowns and enters the river ecosystem.

The researchers found that, on average, 6,200 wildebeest drown each year in the Kenyan portion of Mara River, amounting to 1,100 tons of biomass.

“To put this in perspective, it’s the equivalent of adding ten blue whale carcasses to the moderately-sized Mara River each year. This dramatic subsidy delivers terrestrial nitrogen, phosphorus, and carbon to the river’s food web,” says one of the team, ecologist Emma Rosi.

The team used cameras to track scavenger birds, and a common aquatic ecosystem nutrient tracking method, stable isotope analysis, which allowed them to trace the nutrients from the drowned animals all the way down the food chain.

It turns out that each mass drowning represents a massive boon to the local river ecosystem, feeding everyone in the river. Only a small proportion – some 2 percent – of the wildebeest feast is eaten by crocs.

On land, up to 9 percent of the corpses are devoured by several vulture species. But the biggest winners are the various species of common fish in the river. When carcasses are abundant, they will make up half of the diet for these fish.

And once the drowned bodies have been picked clean, the bones end up leaching even more nutrients into the waters, continuing to feed the ecosystem for years to come.

As dramatic as it is to have thousands of animals go down in the turbulent waters every year, ultimately the gain for the ecosystem is much greater than the loss to the herd.

“These mass drownings have little impact on the wildebeest herd, comprising only 0.5 percent of the total herd size, but they provide huge short-term and long-term sources of nutrients to the Mara River,” write the researchers.

As humans have encroached on animal habitats, mass migration routes have altered. The researchers point out that loss of widespread drownings could be responsible for fundamentally altering river ecosystems.

But each year, the wildebeest still travel across the Serengeti plains, with unlucky ones still drowning in troves, providing sustenance to myriad river creatures long after their death.

“What is happening there is a window into the past, when large migratory herds were free to roam the landscape, and drownings likely played an important role in rivers throughout the world,” says Subalusky.

Source: PNAS.

Study Shows How LSD Mimics Infant’s Mind as Ego Dissolves.

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A groundbreaking series of experiments show how LSD (Lysergic acid diethylamide) alters the operation of the brain.  Scientists gave LSD to 20 healthy volunteers in a specialist research center and used cutting-edge brain scanning techniques to understand what happens once the LSD is ingested.

One significant finding of the experiments was that when volunteers took LSD, many parts of their brain contributed to visual processing, not just the visual cortex.  They could essentially see things that weren’t there, experiencing dreamlike hallucinations.

Dr Robin Carhart-Harris, from the Department of Medicine at Imperial College London, who led the research, elaborated on this discovery:

“We observed brain changes under LSD that suggested our volunteers were ‘seeing with their eyes shut’ — albeit they were seeing things from their imagination rather than from the outside world. We saw that many more areas of the brain than normal were contributing to visual processing under LSD — even though the volunteers’ eyes were closed. Furthermore, the size of this effect correlated with volunteers’ ratings of complex, dreamlike visions. “

Dr. Carthart-Harris explained further that under LSD, people’s brain networks behave in a “unified” way, with specialized functions like vision, movement and hearing working without separation.

He said: ”Our results suggest that this effect underlies the profound altered state of consciousness that people often describe during an LSD experience. It is also related to what people sometimes call ‘ego-dissolution’, which means the normal sense of self is broken down and replaced by a sense of reconnection with themselves, others and the natural world. This experience is sometimes framed in a religious or spiritual way — and seems to be associated with improvements in well-being after the drug’s effects have subsided.”

lsd study

FIG. 1: Whole-brain cerebral blood flow maps for the placebo and LSD conditions, plus the difference map (cluster-corrected, P < 0.05; n = 15).

Interestingly, Dr. Carthart-Harris also said that the brain in the LSD state resembles the free and unconstrained brain of infancy, with its inherent hyper-emotionality and imaginative nature.  He added that “our brains become more constrained and compartmentalized as we develop from infancy into adulthood, and we may become more focused and rigid in our thinking as we mature.”

It’s noteworthy that the study was crowdfunded, raising almost $80,000 from individual donations. You can see their crowdfunding pitch which explains some of their approaches here:

Additional research from the same team showed for the first time that listening to music while on LSD trigged more information to be received from the parahippocampus, which is involved in mental imagery and personal memory.  The combination of music and LSD triggered complex visions in the subjects, such as evoking scenes from their lives.

The researchers hope that their findings will eventually lead to new therapies involving LSD, in particular directed at conditions with entrenched negative thought patterns such as depression or addiction.  The intention is to disrupt negative patterns by employing psychedelics.

“Scientists have waited 50 years for this moment — the revealing of how LSD alters our brain biology. For the first time we can really see what’s happening in the brain during the psychedelic state, and can better understand why LSD had such a profound impact on self-awareness in users and on music and art. This could have great implications for psychiatry, and helping patients overcome conditions such as depression,” said Professor David Nutt, the senior researcher on the study and Edmond J Safra Chair in Neuropsychopharmacology at Imperial College London.

Source:Proceedings of the National Academy of Sciences (PNAS).

Vitamins A and C help erase cell memory

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Vitamin A
Retinol or Vitamin A 3D space model (balls model). 

Vitamins A and C aren’t just good for your health, they affect your DNA too. Researchers at the Babraham Institute and their international collaborators have discovered how vitamins A and C act to modify the epigenetic ‘memory’ held by cells; insight which is significant for regenerative medicine and our ability to reprogramme cells from one identity to another. The research is published today in Proceedings of the National Academy of Science (PNAS).

For regenerative medicine, the holy grail is to be able to generate a cell that can be directed to become any other cell, such as brain cells, heart cells and lung cells. Cells with this ability are present in the early embryo (, ESC) and give rise to the many different cell types in the body. For the purposes of regenerative medicine, we need to be able to force adult cells from a patient to regress back to possessing embryonic-like capabilities and to ‘forget’ their previous identity.

A cell’s identity is established at the DNA level by to the DNA. These changes don’t alter the order of the DNA letters but control which parts of the genome can be read and accessed. Consequently, every different cell type has a unique epigenetic fingerprint, enforcing and maintaining specific patterns of gene expression appropriate to the cell type. To reverse cells back to the naïve pluripotent state this epigenetic layer of information has to be lost to open up the full genome again.

Researchers from the Babraham Institute, UK, University of Stuttgart, Germany and University of Otago, New Zealand worked together to uncover how vitamins A and C affect the erasure of from the genome. They looked in particular at the epigenetic modification where a methyl chemical tag is added to the C letters in the DNA sequence. Embryonic stem cells show low levels of this C tagging, called cytosine methylation, but in established cell types much more of the genome is marked by this modification. Removing the methyl tags from the DNA, called demethylation, is a central part of achieving pluripotency and wiping epigenetic memory.

The family of enzymes responsible for active removal of the methyl tags are called TET. The researchers looked at the molecular signals that control TET activity to understand more about how the activity of the TET enzymes can be manipulated during cellular programming to achieve pluripotency.

They found that vitamin A enhances epigenetic memory erasure in naïve ESC by increasing the amount of TET enzymes in the cell, meaning greater removal of methyl tags from the C letters of the DNA sequence. In contrast, they found that vitamin C boosted the activity of the TET enzymes by regenerating a co-factor required for effective action.

Dr Ferdinand von Meyenn, postdoctoral researcher at the Babraham Institute and co-first author on the paper, explained: “Both vitamins A and C act individually to promote demethylation, enhancing the erasure of epigenetic memory required for cell reprogramming.” Dr Tim Hore, previously a Human Frontier Long Term Research Fellow at the Babraham Institute, now Lecturer at the University of Otago, New Zealand and co-first author on the paper, continued: “We found out that the mechanisms of how vitamins A and C enhance demethylation are different, yet synergistic.”

The improved understanding of the effect of vitamin A on the TET2 enzyme also potentially explains why a proportion of patients with acute promyelocytic leukaemia (once considered the deadliest form of acute leukaemia) are resistant to effective combination treatment with vitamin A. By providing a possible explanation for this insensitivity for further investigation, this work could point the way to better management of the vitamin A resistant cases.

Professor Wolf Reik, Head of the Epigenetics Programme at the Babraham Institute, said: “This research provides an important understanding in order to progress the development of cell treatments for . It also enhances our understanding of how intrinsic and extrinsic signals shape the epigenome; knowledge that could provide valuable insight into human disease, such as acute promyelocytic leukaemia and other cancers. Putting the full picture together will allow us to understand the full complexity of the epigenetic control of the genome.”

 

Significance

Naïve embryonic stem cells are characterized by genome-wide low levels of cytosine methylation, a property that may be intrinsic to their function. We found that retinol/retinoic acid (vitamin A) and ascorbate (vitamin C) synergistically diminish DNA methylation levels and in doing so enhance the generation of naïve pluripotent stem cells. This is achieved by two complementary mechanisms. Retinol increases cellular levels of TET proteins (which oxidize DNA methylation), whereas ascorbate affords them greater activity by reducing cellular Fe3+ to Fe2+. This mechanistic insight is relevant for the production of induced pluripotent stem cells used in regenerative medicine, and contributes to our understanding of how the genome is connected to extrinsic and intrinsic signals.

Abstract

Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood. Here we report that retinoic acid (RA) or retinol (vitamin A) and ascorbate (vitamin C) act as modulators of TET levels and activity. RA or retinol enhances 5hmC production in naïve embryonic stem cells by activation of TET2 and TET3 transcription, whereas ascorbate potentiates TET activity and 5hmC production through enhanced Fe2+ recycling, and not as a cofactor as reported previously. We find that both ascorbate and RA or retinol promote the derivation of induced pluripotent stem cells synergistically and enhance the erasure of epigenetic memory. This mechanistic insight has significance for the development of cell treatments for regenenerative medicine, and enhances our understanding of how intrinsic and extrinsic signals shape the epigenome.

Men and women ‘wired differently’

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Men and women’s brains are connected in different ways which may explain why the sexes excel at certain tasks, say researchers.

A US team at the University of Pennsylvania scanned the brains of nearly 1,000 men, women, boys and girls and found striking differences.

brain networksThe “connectome maps” reveal the differences between the male brain (seen in blue) and the female brain (orange)

Male brains appeared to be wired front to back, with few connections bridging the two hemispheres.

In females, the pathways criss-crossed between left and right.

These differences might explain why men, in general, tend to be better at learning and performing a single task, like cycling or navigating, whereas women are more equipped for multitasking, say the researchers in the journal Proceedings of the National Academy of Sciences (PNAS).

The same volunteers were asked to perform a series of cognitive tests, and the results appeared to support this notion.

But experts have questioned whether it can be that simple, arguing it is a huge leap to extrapolate from anatomical differences to try to explain behavioural variation between the sexes. Also, brain connections are not set and can change throughout life.

In the study, women scored well on attention, word and face memory, and social cognition, while men performed better on spatial processing and sensori-motor speed.

To look at brain connectivity, the researchers used a type of scan called DTI – a water-based imaging technique that can trace and highlight the fibre pathways connecting the different regions of the brain.

Study author Dr Ruben Gur said: “It’s quite striking how complementary the brains of women and men really are.

“Detailed connectome maps of the brain will not only help us better understand the differences between how men and women think, but it will also give us more insight into the roots of neurological disorders, which are often sex related.”

Complex organ

Prof Heidi Johansen-Berg, a UK expert in neuroscience at the University of Oxford, said the brain was too complex an organ to be able to make broad generalisations.

“We know that there is no such thing as ‘hard wiring’ when it comes to brain connections. Connections can change throughout life, in response to experience and learning.

“Often, sophisticated mathematical approaches are used to analyse and describe these brain networks. These methods can be useful to identify differences between groups, but it is often challenging to interpret those differences in biological terms.”

Dr Michael Bloomfield, Clinical Research Fellow at the Medical Research Council Clinical Sciences Centre in London, said: “It has been known for some time that there are differences between the sexes when it comes to how our bodies work and the brain is no exception.

However, he said care must be taken in drawing conclusions from the study, as the precise relationships between how our brains are wired and our performance on particular tasks needed further investigation.

“We cannot say yet that one is causing the other.

“Furthermore, the measure used in the study, called “connectivity”, is only one aspect of how our brains our wired.

“We think that there can also be differences in certain chemicals in the brain called neurotransmitters, for example, and so we need more research to fully understand how all these different aspects of brain structure and function work together to answer fundamental questions like “how do we think?”.

“One thing that remains unknown is what is driving these differences between the sexes. An obvious possibility is that that male hormones like testosterone and female hormones like oestrogren have different affects on the brain.

“A more subtle possibility is that bringing a child up in a particular gender could affect how our brains are wired.”