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A "Crick" in my neck,Ahhh! there's the rub:DNA Hoogsteen rules elementary Watson?

Tuesday, August 8th, 2006, 04:21 am  
I bet Martian DNA would be based partly on 33 and 19.5!  [Image: cheers.gif]
Don't gamble with improv. Naughty

Tuesday, August 8th, 2006, 04:34 am  
maybe it's a "sine" from above.° (rounded - actually 19.471°) is also significant as an expression of the ... The sine of 19.471° is .3333, so in essence it can be said that both numbers, ...

Scientists crack how primordial life on Earth might have replicated itself
May 15, 2018, Medical Research Council

[Image: 19-scientistscr.jpg]
Liquid brine containing replicating RNA molecules is concentrated in the cracks between ice crystals, as seen with an electron microscope. Credit: Philipp Holliger, MRC LMB

Scientists have created a new type of genetic replication system which demonstrates how the first life on Earth—in the form of RNA—could have replicated itself. The scientists from the Medical Research Council (MRC) Laboratory of Molecular Biology say the new RNA utilises a system of genetic replication unlike any known to naturally occur on Earth today.

A popular theory for the earliest stages of life on Earth is that it was founded on strands of RNA, a chemical cousin of DNA. Like DNA, RNA strands can carry genetic information using a code of four molecular letters (bases), but RNA can be more than a simple 'string' of information. Some RNA strands can also fold up into three-dimensional shapes that can form enzymes, called ribozymes, and carry out chemical reactions.

If a ribozyme could replicate folded RNA, it might be able to copy itself and support a simple living system.

Previously, scientists had developed ribozymes that could replicate straight strands of RNA, but if the RNA was folded it blocked the ribozyme from copying it. Since ribozymes themselves are folded RNAs, their own replication is blocked.

Now, in a paper published today in the journal eLife, the scientists have resolved this paradox by engineering the first ribozyme that is able to replicate folded RNAs, including itself.

It writes itself.
It rights itself.
Itza rite itself.

Normally when copying RNA, an enzyme would add single bases (C, G, A or U) one at a time, but the new ribozyme uses three bases joined together, as a 'triplet' (e.g. GAU). These triplet building blocks enable the ribozyme to copy folded RNA, because the triplets bind to the RNA much more strongly and cause it to unravel—so the new ribozyme can copy its own folded RNA strands.

The scientists say that the 'primordial soup' could have contained a mixture of bases in many lengths—one, two, three, four or more bases joined together—but they found that using strings of bases longer than a triplet made copying the RNA less accurate. (.3333...)

Dr. Philipp Holliger, from the MRC Laboratory of Molecular Biology and senior author on the paper, said: "We found a solution to the RNA replication paradox by re-thinking how to approach the problem—we stopped trying to mimic existing biology and designed a completely new synthetic strategy. It is exciting that our RNA can now synthesise itself.

"These triplets of bases seem to represent a sweet spot,(.3333...) where we get a nice opening up of the folded RNA structures, but accuracy is still high. Notably, although triplets are not used in present-day biology for replication, protein synthesis by the ribosome—an ancient RNA machine thought to be a relic of early RNA-based life—proceeds using a triplet code.

"However, this is only a first step because our ribozyme still needs a lot of help from us to do replication. We provided a pure system, so the next step is to integrate this into the more complex substrate mixtures mimicking the primordial soup—this likely was a diverse chemical environment also containing a range of simple peptides and lipids that could have interacted with the RNA."

The experiments were conducted in ice at -7°C, because the researchers had previously discovered that freezing concentrates the RNA molecules in a liquid brine in tiny gaps between the ice crystals. This also is beneficial for the RNA enzymes, which are more stable and function better at cold temperatures.(aka mars -like environment -EA)

Dr. Holliger added: "This is completely new synthetic biology and there are many aspects of the system that we have not yet explored. We hope in future, it will also have some biotechnology applications, such as adding chemical modifications at specific positions to RNA polymers to study RNA epigenetics or augment the function of RNA."

Dr. Nathan Richardson, Head of Molecular and Cellular Medicine at the MRC, said: "This is a really exciting example of blue skies research that has revealed important insights into how the very beginnings of life may have emerged from the 'primordial soup' some 3.7 billion years ago. Not only is this fascinating science, but understanding the minimal requirements for RNA replication and how these systems can be manipulated could offer exciting new strategies for treating human disease."

Explore further: Probing RNA function with 10,000 mutants

More information: James Attwater et al, Ribozyme-catalysed RNA synthesis using triplet building blocks, eLife (2018). DOI: 10.7554/eLife.35255

Journal reference: eLife
Provided by: Medical Research Council

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Quote: Wrote:
Quote: Wrote:The "Wow! signal" of the terrestrial genetic Code
[Image: 8617242969_480791a783_b.jpg]

[Image: 8617242969_480791a783_b.jpg]
Along the vines of the Vineyard.
With a forked tongue the snake singsss...

Quote:Jansen concludes that biological systems exhibit the same quantum effects as non-biological systems.

The observation techniques developed for this research project may be applied to different systems, both biological and non-biological. Jansen is happy with the results

Quantum effects observed in photosynthesis
May 21, 2018, University of Groningen

[Image: quantumeffec.jpg]
The figure shows the photosynthetic complex of light-harvesting green sulfur bacteria the green and yellow circles highlight the two molecules simultaneously excited. Credit: dr. Thomas la Cour Jansen/University of Groningen
Molecules that are involved in photosynthesis exhibit the same quantum effects as non-living matter, concludes an international team of scientists including University of Groningen theoretical physicist Thomas la Cour Jansen. This is the first time that quantum mechanical behavior was proven to exist in biological systems that are involved in photosynthesis. The interpretation of these quantum effects in photosynthesis may help in the development of nature-inspired light-harvesting devices. The results were published in Nature Chemistry on 21 May.

For several years now, there has been a debate about quantum effects in biological systems. The basic idea is that electrons in can be in two states at once, until they are observed. This may be compared to the thought experiment known as Schrödinger's Cat. The cat is locked in a box with a vial of a toxic substance. If the cap of the vial is locked with a quantum system, it may simultaneously be open or closed, so the cat is in a mixture of the states "dead" and "alive," until we open the box and observe the system. This is precisely the apparent behavior of electrons.


In earlier research, scientists had already found signals suggesting that light-harvesting molecules in bacteria may be excited into two states simultaneously. In itself this proved the involvement of quantum mechanical effects, however in those experiments, that excited state supposedly lasted more than 1 picosecond (0.000 000 000 001 second). This is much longer than one would expect on the basis of quantum mechanical theory.

Jansen and his colleagues show in their publication that this earlier observation is wrong. "We have shown that the quantum effects they reported were simply regular vibrations of the molecules." Therefore, the team continued the search. "We wondered if we might be able to observe that Schrödinger cat situation."


They used different polarizations of light to perform measurements in light-harvesting green sulfur bacteria. The bacteria have a photosynthetic complex, made up of seven light sensitive molecules. A photon will excite two of those molecules, but the energy is superimposed on both. So just like the cat is dead or alive, one or the other molecule is excited by the photon. "In the case of such a superposition, spectroscopy should show a specific oscillating signal," explains Jansen. "And that is indeed what we saw. Furthermore, we found quantum effects that lasted precisely as long as one would expect based on theory and proved that these belong to energy superimposed on two molecules simultaneously." Jansen concludes that biological systems exhibit the same quantum effects as non-biological systems.

The observation techniques developed for this research project may be applied to different systems, both biological and non-biological. Jansen is happy with the results. "This is an interesting observation for anyone who is interested in the fascinating world of quantum mechanics. Moreover, the results may play a role in the development of new systems, such as the storage of solar energy or the development of quantum computers."

 Explore further: Purple bacteria shine path to super-efficient light harvesting

More information: Erling Thyrhaug et al, Identification and characterization of diverse coherences in the Fenna–Matthews–Olson complex, Nature Chemistry (2018). DOI: 10.1038/s41557-018-0060-5

Journal reference: Nature Chemistry [/url]
Provided by: [url=]University of Groningen

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Qubit [Image: sheep.gif] QuTRIT

Quote: Wrote:Physically, entangled particles cannot be described as individual particles with defined states, but only as a single system.
Jansen concludes that biological systems exhibit the same quantum effects as non-biological systems.

The observation techniques developed for this research project may be applied to different systems, both biological and non-biological. Jansen is happy with the results

single system=entanglement / 3 =.3333.... [Image: holycowsmile.gif]

Stronger-than-binary correlations experimentally demonstrated for the first time
May 21, 2018 by Lisa Zyga, feature

[Image: strongerthan.jpg]
Two possible explanations for the quantum measurement process: (a) A binary measurement that generates the final outcome in two steps (first ruling out one of the three outcomes, then selecting between the two remaining outcomes), or (b) a …more
For the first time, physicists have experimentally demonstrated ternary—rather than binary—quantum correlations between entangled objects. The results show that the quantum measurement process cannot be described as a binary process (having two possible outcomes), but rather stronger-than-binary ternary measurements (which have three possible outcomes) should be considered in order to fully understand how the quantum measurement process works.

The physicists, Xiao-Min Hu and coauthors from China, Germany, Spain, and Hungary, have published a paper on the stronger-than-binary correlations in a recent issue of Physical Review Letters.

"We discovered and experimentally verified the existence of genuine ternary measurements," coauthor Matthias Kleinmann at the University of Siegen in Siegen, Germany, and the University of the Basque Country in Bilbao, Spain, told "The experimental conclusions are independent of any underlying theory (here: quantum theory) and establish that ternary measurements are a generic feature of nature."

Before now, stronger-than-binary correlations have been theoretically predicted to exist, but this is the first time that they have been experimentally observed. In their experiments, the researchers entangled two photonic qutrits, each of which has three possible states (0, 1, and 2), instead of just two (0 and 1) as for qubits. They then sent the qutrits to different laboratories where they measured the state of each qutrit, enabling them to determine the strength of the correlations between the two qutrits.

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Illustration of the experimental setup for demonstrating ternary correlations. Credit: Hu et al. ©2018 American Physical Society
If the quantum measurement process were binary, then measurements could be described as a two-step process in which first one of the three possible measurement outcomes is ruled out by a classical mechanism, and then a quantum binary measurement selects between the two remaining outcomes. In this binary measurement process, the maximum correlation between two entangled objects cannot exceed a certain value.

In their experiments, the researchers demonstrated that the strength of the correlations between the entangled qutrits exceed this maximum value. To do this, they performed a Bell-type experiment in which they showed that the observed correlations violate the maximum inequality for nonsignalling binary correlations with a very high statistical significance, corresponding to 9.3 standard deviations. The results imply that the measurement process in quantum theory cannot be explained by the two-step process with binary measurements. Instead, the measurement process here is genuinely ternary, where the quantum ternary measurement selects between all three of the possible states at once.

Overall, the researchers explain that the observations of stronger-than-binary correlations don't contradict previous experimental evidence of binary correlations, but add new possibilities for how the quantum measurement process works at the most fundamental level.

"Now that we have established the theoretical tools and the experimental methods to understand and create ternary correlations, we aim to proceed in two directions," Kleinmann said. "First, we hope for technological applications (for example, in randomness extraction) and second, we are now using our results as a new basis for a deeper understanding of quantum theory."

 Explore further: New quantum probability rule offers novel perspective of wave function collapse

More information: More information: Xiao-Min Hu et al. "Observation of Stronger-than-Binary Correlations with Entangled Photonic Qutrits." Physical Review Letters. DOI: 10.1103/PhysRevLett.120.180402 , Also at arXiv:1712.06557 [quant-ph]

Journal reference: Physical Review Letters

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With a forked tongue the snake singsss...

The changing shape of DNA

May 24, 2018, University of East Anglia
A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Credit: NHGRI

The shape of DNA can be changed with a range of triggers including copper and oxygen—according to new research from the University of East Anglia.

The structure of DNA is widely accepted to exist as a double helix, but different DNA structures also exist. New research published today points to a range of triggers that can manipulate its shape.

Applications for this discovery include nanotechnology—where DNA is used to make tiny machines, and in DNA-based computing—where computers are built from DNA rather than silicon.

Lead researcher Dr. Zoe Waller from UEA's School of Pharmacy said: "DNA is a genetic material, and its structure usually looks a bit like a twisted ladder—a double helix.

"But alternative DNA structures exist and are thought to potentially play a role in the development of genetic diseases, such as diabetes or cancer."

"It was previously known that the structure of a piece of DNA could be changed using acid, which causes it to fold up into a shape called an 'i-motif'.

"This system can be used as a switch—the DNA in the two different conditions has completely different shapes so we can recognise this as either 'on' or 'off'. This has been used for DNA nano-machine applications."

Dr. Waller's research previously showed that the shape of DNA can also be changed into a second structure called a hairpin by using copper salts. This change can then be reversed using EDTA (Ethylenediaminetetraacetic acid) - an agent commonly found in shampoo and other household products.

This expanded the capability of DNA into two switches instead of one.

Her new findings show that other triggers, including oxygen and a substance similar to Vitamin C, can also trigger DNA to change its shape.

The team added copper salts to DNA in oxygen free conditions in order to change its shape to an i-motif. By exposing the i-motif to oxygen in the air, it then changed from in i-motif into a hairpin.

The shape can then be changed from a hairpin back to an i-motif by adding sodium ascorbate, which is similar to vitamin C, and back to an unfolded state using a chelating agent.

"This research means that now we can not only change the shape of DNA using a change in pH, we can use copper salts and oxygen to have the same effect," said Dr. Waller.

"There are many applications that this research could be used for. The potential changes in shape can be used as on/off switches for logic gates in DNA computing. Our findings could also be used in nanotechnology, or to change the properties of materials such as gels," she added.

Explore further: How UEA research could help build computers from DNA

More information: 'Redox Dependent Control of i-Motif DNA Structure Using Copper Cations' Nucleic Acids Research, Friday, May 25, 2018.

Journal reference: Nucleic Acids Research search and more info website

Provided by: University of East Anglia

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A simple mechanism could have been decisive for the development of life

May 24, 2018, Technical University Munich
In the beginning was the phase separation
A team at the Technical University of Munich (TUM) has shown for the first time, that phase separation is an extremely efficient way of controlling the selection of chemical building blocks, providing advantages to certain molecules. This …more

The question of the origin of life remains one of the oldest unanswered scientific questions. A team at the Technical University of Munich (TUM) has now shown for the first time that phase separation is an extremely efficient way of controlling the selection of chemical building blocks and providing advantages to certain molecules.

Without energy, cells cannot move or divide, and cannot maintain even basic functions such as the production of simple proteins. If energy is lacking, more complex connections disintegrate quickly, and early life would have died off immediately.

Chemist Job Boekhoven and his team at TUM have now succeeded in using phase separation to find a mechanism in simple molecules that enables extremely unstable molecules such as those found in the primordial soup to have a higher degree of stability. They could survive longer, even if they had to survive a period without external energy supply.

The principle of simplicity

Job Boekhoven and his team were looking for a simple mechanism with primitive molecules that could produce lifelike properties. "Most likely, molecules were simple in the primordial soup," says Boekhoven. The researchers investigated what happened when they fed various carboxylic acid molecules with high-energy carbodiimide condensing agents, thus bringing them out of equilibrium.

The reaction produced unstable anhydrides. Mostly, these non-equilibrium products quickly disintegrate into carboxylic acids again. The scientists showed that the anhydrides that survived the longest were those that could form a kind of oil droplet in the aqueous environment.
In the beginning was the phase separation
Single droplets under a fluorescence microscope. Credit: Marta Tena-Solsona / TUM

Molecules in the garage

The effect can also be seen externally—the initially clear solution became milky. The lack of water in the oil droplets conferred protection, because anhydrides need water to disintegrate back into carboxylic acids.

Boekhoven explains the principle of phase separation with an analogy: "Imagine an old and rusty car. Leave it outside in the rain, and it continues to rust and decomposes because rusting is accelerated by water. Put it in the garage, and it stops rusting, because you separate it from the rain."

In a way, a similar process occurs in the primordial soup experiment. Inside the oil droplet (garage) with the long-chain anhydride molecules there is no water, so its molecules survive longer. If the molecules compete with each other for energy, those that can protect themselves by forming oil droplets are likelier to survive, while their competitors get hydrolyzed.

Next goal: viable information carriers

Since the mechanism of phase separation is so simple, it can possibly be extended to other types of molecular aggregations with lifelike properties, such as DNA, RNA or self-dividing vesicles. Studies have shown that these bubbles can divide spontaneously. "Soon we hope to turn primitive chemistry into a self-replicating information carrier that is protected from decay to a certain extent," says Boekhoven.

Explore further: Supramolecular materials with a time switch

More information: Marta Tena-Solsona et al, Self-selection of dissipative assemblies driven by primitive chemical reaction networks, Nature Communications (2018). DOI: 10.1038/s41467-018-04488-y

Journal reference: Nature Communications search and more info website

Provided by: Technical University Munich

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With a forked tongue the snake singsss...
Textbook-changing insights

More detail could be seen in the new systems than has ever been seen before in the standard chlorophyll-a systems. The chlorophylls often termed 'accessory' chlorophylls were actually performing the crucial chemical step, rather than the textbook 'special pair' of chlorophylls in the centre of the complex.

This indicates that this pattern holds for the other types of photosynthesis, which would change the textbook view of how the dominant form of photosynthesis works.

New type of photosynthesis discovered
June 14, 2018 by Hayley Dunning, Imperial College London

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Cross-section of beach rock (Heron Island, Australia) showing chlorophyll-f containing cyanobacteria (green band) growing deep into the rock, several millimetres below the surface. Credit: Dennis Nuernberg
The discovery changes our understanding of the basic mechanism of photosynthesis and should rewrite the textbooks.

It will also tailor the way we hunt for alien life and provide insights into how we could engineer more efficient crops that take advantage of longer wavelengths of light.

The discovery, published today in Science, was led by Imperial College London, supported by the BBSRC, and involved groups from the ANU in Canberra, the CNRS in Paris and Saclay and the CNR in Milan.

The vast majority of life on Earth uses visible red light in the process of photosynthesis, but the new type uses near-infrared light instead. It was detected in a wide range of cyanobacteria (blue-green algae) when they grow in near-infrared light, found in shaded conditions like bacterial mats in Yellowstone and in beach rock in Australia.

As scientists have now discovered, it also occurs in a cupboard fitted with infrared LEDs in Imperial College London.

Photosynthesis beyond the red limit

The standard, near-universal type of photosynthesis uses the green pigment, chlorophyll-a, both to collect light and use its energy to make useful biochemicals and oxygen. The way chlorophyll-a absorbs light means only the energy from red light can be used for photosynthesis.

Since chlorophyll-a is present in all plants, algae and cyanobacteria that we know of, it was considered that the energy of red light set the 'red limit' for photosynthesis; that is, the minimum amount of energy needed to do the demanding chemistry that produces oxygen. The red limit is used in astrobiology to judge whether complex life could have evolved on planets in other solar systems.

However, when some cyanobacteria are grown under near-infrared light, the standard chlorophyll-a-containing systems shut down and different systems containing a different kind of chlorophyll, chlorophyll-f, takes over.

Until now, it was thought that chlorophyll-f just harvested the light. The new research shows that instead chlorophyll-f plays the key role in photosynthesis under shaded conditions, using lower-energy infrared light to do the complex chemistry. This is photosynthesis 'beyond the red limit'.


Lead researcher Professor Bill Rutherford, from the Department of Life Sciences at Imperial, said: "The new form of photosynthesis made us rethink what we thought was possible. It also changes how we understand the key events at the heart of standard photosynthesis. This is textbook changing stuff."

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Colony of Chroococcidiopsis-like cells where the different colours represent photosynthesis driven by chlorophyll-a (magenta) and chlorophyll-f (yellow). Credit: Dennis Nuernberg
Preventing damage by light

Another cyanobacterium, Acaryochloris, is already known to do photosynthesis beyond the red limit. However, because it occurs in just this one species, with a very specific habitat, it had been considered a 'one-off'. Acaryochloris lives underneath a green sea-squirt that shades out most of the visible light leaving just the near-infrared.

The chlorophyll-f based photosynthesis reported today represents a third type of photosynthesis that is widespread. However, it is only used in special infrared-rich shaded conditions; in normal light conditions, the standard red form of photosynthesis is used.

It was thought that light damage would be more severe beyond the red limit, but the new study shows that it is not a problem in stable, shaded environments.

Co-author Dr. Andrea Fantuzzi, from the Department of Life Sciences at Imperial, said: "Finding a type of photosynthesis that works beyond the red limit changes our understanding of the energy requirements of photosynthesis. This provides insights into light energy use and into mechanisms that protect the systems against damage by light."

These insights could be useful for researchers trying to engineer crops to perform more efficient photosynthesis by using a wider range of light. How these cyanobacteria protect themselves from damage caused by variations in the brightness of light could help researchers discover what is feasible to engineer into crop plants.

Textbook-changing insights

More detail could be seen in the new systems than has ever been seen before in the standard chlorophyll-a systems. The chlorophylls often termed 'accessory' chlorophylls were actually performing the crucial chemical step, rather than the textbook 'special pair' of chlorophylls in the centre of the complex.

This indicates that this pattern holds for the other types of photosynthesis, which would change the textbook view of how the dominant form of photosynthesis works.

Dr. Dennis Nürnberg, the first author and initiator of the study, said: "I did not expect that my interest in cyanobacteria and their diverse lifestyles would snowball into a major change in how we understand photosynthesis. It is amazing what is still out there in nature waiting to be discovered."

Peter Burlinson, lead for frontier bioscience at BBSRC—UKRI says, "This is an important discovery in photosynthesis, a process that plays a crucial role in the biology of the crops that feed the world. Discoveries like this push the boundaries of our understanding of life and Professor Bill Rutherford and the team at Imperial should be congratulated for revealing a new perspective on such a fundamental process."

[Image: 1x1.gif] Explore further: Photosynthetic protein structure that harvests and traps infrared light

More information: Dennis J. Nürnberg et al, Photochemistry beyond the red limit in chlorophyll f–containing photosystems, Science (2018). DOI: 10.1126/science.aar8313

Journal reference: Science [Image: img-dot.gif] [Image: img-dot.gif]
Provided by: Imperial College London

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Microbe breaks 'universal' DNA rule by using two different translations
June 14, 2018, University of Bath

[Image: 5733573d86890.jpg]
Credit: CC0 Public Domain
DNA is often referred to as the blueprint for life, however scientists have for the first time discovered a microbe that uses two different translations of the DNA code at random. This unexpected finding breaks what was thought to be a universal rule, since the proteins from this microbe cannot be fully predicted from the DNA sequence.

Researchers from the Milner Centre for Evolution at the University of Bath and the Max-Planck Institute for Biophysical Chemistry in Göttingen, Germany have published their findings in the journal Current Biology.

All organisms receive genetic information from their parents which tell the cells how to make proteins—the molecules that do the chemistry in our bodies. This genetic information comprises DNA molecules made up of a sequence of four chemical bases represented by the letters A, T, C and G; the genetic code dictates to the cell which sequence of amino acids to join together to form each protein given the underlying sequence in the DNA.

In a similar way that "dot dot dot" in morse code translates as S, so too the genetic code is read in blocks of three bases (codons) to translate to one amino acid.

It was originally thought that any given codon always results in the same amino acid—just as dot dot dot always means S in morse code. GGA in the DNA for example translates as the amino acid glycine.

However a collaboration between Dr. Stefanie Mühlhausen and Professor Laurence Hurst at the Milner Centre for Evolution at the University of Bath, and Martin Kollmar and colleagues at the Max-Planck Institute for Biophysical Chemistry in Göttingen, Germany have now described the first—and unexpected—exception to this rule in a natural code.

The group examined an unusual group of yeasts in which some species have evolved an unusual non-universal code. While humans (and just about everything else) translate the codon CTG as the amino acid leucine, some of the species of yeast instead translate this as the amino acid serine whilst others translate it as alanine.

This is odd enough in itself. But the team was even more surprised to find one species, Ascoidea asiatica, randomly translated this codon as serine or leucine. Every time this codon is translated the cell tosses a chemical coin: heads for leucine, tails it's serine.


Laurence Hurst, Professor of Evolutionary Genetics and Director of the Milner Centre for Evolution at the University of Bath, said: "This is the first time we've seen this in any species.

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Along the vines of the Vineyard.
With a forked tongue the snake singsss...
Study reveals new geometric shape used by nature to pack cells efficiently
July 27, 2018, Lehigh University

[Image: 39-studyreveals.jpg]
a) Scheme representing planar columnar/cubic monolayerepithelia. Cells are simplified as prisms. b) Scheme illustrating a fold in a columnar/cubic monolayer epithelium. Cells adopt the called "bottle23 shape" that would be simplified as frusta. c) Mathematical model for an epithelial tube. d) Modelling clay figures illustrating two scutoids participating in a transition and two schemes for scutoids solids. Scutoids are characterized by having at least a vertex in a different plane to the two bases and present curvedsurfaces. e) A dorsal view of a Protaetia speciose beetle of the Cetoniidaefamily. The white lines highlight the resemblance of its scutum, scutellum and wings with the shape of the scutoids. Illustration from Dr. Nicolas Gompel, with permission. f) Three-dimensional reconstruction of the cells forming a tube. The four-cell motif (green, yellow, blue and red cells) shows an apico-basal cell intercalation. g) Detail of the apico-basal transition, showing how the blue and yellow cells contact in the apical part, but not in the basal part. The figure also shows that scutoids present concave surfaces. Credit: Luis M. Escudero (Seville University, Spain), Javier Buceta (Lehigh University, USA), Pedro Gomez-Galvez, Pablo Vicente-Munuera and scientists from Andalucian Center of Developmental Biology, and the Severo Ocha Center of Molecular Biology, among others.
As an embryo develops, tissues bend into complex three-dimensional shapes that lead to organs. Epithelial cells are the building blocks of this process forming, for example, the outer layer of skin. They also line the blood vessels and organs of all animals.

These cells pack together tightly. To accommodate the curving that occurs during embryonic development, it has been assumed that epithelial cells adopt either columnar or bottle-like shapes.

However, a group of scientists dug deeper into this phenomenon and discovered a new geometric shape in the process.

They uncovered that, during tissue bending, epithelial cells adopt a previously undescribed shape that enables the cells to minimize energy use and maximize packing stability. The team's results will be published in Nature Communications in a paper called "Scutoids are a geometrical solution to three-dimensional packing of epithelia".

The study is the result of a United States-European Union collaboration between the teams of Luis M. Escudero (Seville University, Spain) and that of Javier Buceta (Lehigh University, USA). Pedro Gomez-Galvez and Pablo Vicente-Munuera are the first authors of this work that also includes scientists from the Andalucian Center of Developmental Biology, and the Severo Ochoa Center of Molecular Biology, among others.

Buceta and colleagues first made the discovery through computational modeling that utilized Voronoi diagramming, a tool used in a number of fields to understand geometrical organization.

"During the modeling process, the results we saw were weird," says Buceta. "Our model predicted that as the curvature of the tissue increases, columns and bottle-shapes were not the only shapes that cells may developed. To our surprise the additional shape didn't even have a name in math! One does not normally have the opportunity to name a new shape."

The group has named the new shape the "scutoid," for its resemblance to the scutellum—the posterior part of an insect thorax or midsection.

To verify the model's predictions, the group investigated the three-dimensional packing of different tissues in different animals . The experimental data confirmed that epithelial cells adopted shapes and three-dimensional packing motifs similar to the ones predicted by the computational model.

Using biophysical approaches, the team argues that the scutoids stabilize the three-dimensional packing and make it energetically efficient. As Buceta puts it: "We have unlocked nature's solution to achieving efficient epithelial bending."

Their findings could pave the way to understanding the three-dimensional organization of epithelial organs and lead to advancements in tissue engineering.

"In addition to this fundamental aspect of morphogenesis," they write, "the ability to engineer tissues and organs in the future critically relies on the ability to understand, and then control, the 3-D organization of cells."

Adds Buceta: "For example, if you are looking to grow artificial organs, this discovery could help you build a scaffold to encourage this kind of cell packing, accurately mimicking nature's way to efficiently develop tissues."

[Image: 1x1.gif] Explore further: Constructing new tissue shapes with light

More information: Pedro Gómez-Gálvez et al, Scutoids are a geometrical solution to three-dimensional packing of epithelia, Nature Communications (2018). DOI: 10.1038/s41467-018-05376-1

Journal reference: Nature Communications [Image: img-dot.gif] [Image: img-dot.gif]
Provided by: Lehigh University

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Researchers reveal hidden rules of genetics for how life on Earth began
July 30, 2018, University of North Carolina Health Care

[Image: 27-researchersr.jpg]
In the beginning, somehow basic genetic building blocks got translated into proteins to lead to complex life as we know it. Credit: Christ-claude Mowandza-ndinga
All living things use the genetic code to "translate" DNA-based genetic information into proteins, which are the main working molecules in cells. Precisely how the complex process of translation arose in the earliest stages of life on Earth more than four billion years ago has long been mysterious, but two theoretical biologists have now made a significant advance in resolving this mystery.

Charles Carter, Ph.D., professor of biochemistry and biophysics at the UNC School of Medicine, and Peter Wills, Ph.D., an associate professor of biochemistry at the University of Auckland, used advanced statistical methods to analyze how modern translational molecules fit together to perform their job—linking short sequences of genetic information to the protein building blocks they encode.

The scientists' analysis, published in Nucleic Acids Research, reveals previously hidden rules by which key translational molecules interact today. The research suggests how the much-simpler ancestors of these molecules began to work together at the dawn of life.

"I think we have clarified the underlying rules and the evolutionary history of genetic coding," Carter said. "This had been unresolved for 60 years."

Wills added, "The pairs of molecular patterns we have identified may be the first that nature ever used to transfer information from one form to another in living organisms."

The discoveries center on a cloverleaf-shaped molecule called transfer RNA (tRNA), a key player in translation. A tRNA is designed to carry a simple protein building-block, known as an amino acid, onto the assembly line of protein production within tiny molecular factories called ribosomes. When a copy or "transcript" of a gene called a messenger RNA (mRNA) emerges from the cell nucleus and enters a ribosome, it is bound to tRNAs carrying their amino acid cargoes.

The mRNA is essentially a string of genetic "letters" spelling out protein-making instructions, and each tRNA recognizes a specific three-letter sequence on the mRNA. This sequence is called a "codon." As the tRNA binds to the codon, the ribosome links its amino acid to the amino acid that came before it, elongating the growing peptide. When completed, the chain of amino acids is released as a newly born protein.

Proteins in humans and most other life forms are made from 20 different amino acids. Thus there are 20 distinct types of tRNA molecules, each capable of linking to one particular amino acid. Partnering with these 20 tRNAs are 20 matching helper enzymes known as synthetases (aminoacyl-tRNA synthetases), whose job it is to load their partner tRNAs with the correct amino acid.


"You can think of these 20 synthetases and 20 tRNAs collectively as a molecular computer that evolution has designed to make gene-to-protein translation happen," Carter said.

[Image: 28-researchersr.jpg]
All living things use the genetic code to 'translate' DNA-based genetic information into proteins, which are the main working molecules in cells. Precisely how the complex process of translation arose in the earliest stages of life on Earth …more
Biologists have long been intrigued by this molecular computer and the puzzle of how it originated billions of years ago. In recent years, Carter and Wills have made this puzzle their principal research focus. They have shown, for example, how the 20 synthetases, which exist in two structurally distinct classes of 10 synthetases, likely arose from just two simpler, ancestral enzymes.

A similar class division exists for amino acids, and Carter and Wills have argued that the same class division must apply to tRNAs. In other words, they propose that at the dawn of life on Earth, organisms contained just two types of tRNA, which would have worked with two types of synthetases to perform gene-to-protein translation using just two different kinds of amino acids.

The idea is that over the course of eons this system became ever more specific, as each of the original tRNAs, synthetases, and amino acids was augmented or refined by new variants until there were distinct classes of 10 in place of each of the two original tRNAs, synthetases, and amino acids.

In their most recent study, Carter and Wills examined modern tRNAs for evidence of this ancient duality. To do so they analyzed the upper part of the tRNA molecule, known as the acceptor stem, where partner synthetases bind. Their analysis showed that just three RNA bases, or letters, at the top of the acceptor stem carry an otherwise hidden code specifying rules that divide tRNAs into two classes—corresponding exactly to the two classes of synthetases."It is simply the combinations of these three bases that determine which class of synthetase binds to each tRNA," Carter said.

The study serendipitously found evidence for another proposal about tRNAs. Each modern tRNA has at its lower end an "anticodon" that it uses to recognize and stick to a complementary codon on an mRNA. The anticodon is relatively distant from the synthetase binding site, but scientists since the early 1990s have speculated that tRNAs were once much smaller, combining the anticodon and synthetase binding regions in one. Wills and Carter's analysis shows that the rules associated with one of the three class-determining bases—base number 2 in the overall tRNA molecule—effectively imply a trace of the anticodon in an ancient, truncated version of tRNA.

"This is a completely unexpected confirmation of a hypothesis that has been around for almost 30 years," Carter said.

These findings strengthen the argument that the original translational system had just two primitive tRNAs, corresponding to two synthetases and two amino acid types. As this system evolved to recognize and incorporate new amino acids, new combinations of tRNA bases in the synthetase binding region would have emerged to keep up with the increasing complexity—but in a way that left detectable traces of the original arrangement.

"These three class-defining bases in contemporary tRNAs are like a medieval manuscript whose original texts have been rubbed out and replaced by newer texts," Carter said.

The findings narrow the possibilities for the origins of genetic coding. Moreover, they narrow the realm of future experiments scientists could conduct to reconstruct early versions of the translational system in the laboratory—and perhaps even make this simple system evolve into more complex, modern forms of the same translation system. This would further show how life evolved from the simplest of molecules into cells and complex organisms.

[Image: 1x1.gif] Explore further: Study offers insight into the origin of the genetic code

More information: Charles W Carter et al, Hierarchical groove discrimination by Class I and II aminoacyl-tRNA synthetases reveals a palimpsest of the operational RNA code in the tRNA acceptor-stem bases, Nucleic Acids Research (2018). DOI: 10.1093/nar/gky600

Journal reference: Nucleic Acids Research [Image: img-dot.gif] [Image: img-dot.gif]
Provided by: University of North Carolina Health Care

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Along the vines of the Vineyard.
With a forked tongue the snake singsss...
As an example of ''My Reading List"- currently this little note:

Quote:Specialized use of psychedelics has already changed our culture.  Two Nobel Prize winners attributed their breakthrough to their use of LSD.  Near his death , Francis Crick let it be known that his inner vision of the Double Helix of DNA was LSD enhanced.  The chemist Marry Mullis reported that LSD helped him develop the polymerase chain reaction to amplify specific DNA sequences, for which he received the prize.

From the book:The Psychedelic Explorers Guide by James Fradiman, Phd.  page 4, I'm only on page 50 of 336 including index.

I am sure to come across others in this book.

Bob... Ninja Assimilated
"The Morning Light, No sensation to compare to this, suspended animation, state of bliss, I keep my eyes on the circling sky, tongue tied and twisted just and Earth Bound Martian I" Learning to Fly Pink Floyd [Video:]
Quote:Amazingly, the atomic swaps barely changed the shape of the ribosome.

"It's totally unbelievable this would work because biology makes very specific use of things. Change one atom and it can wreck a whole protein," Williams said. "When we probed the structure, we saw that all three metals do essentially the same thing to the structure."

When they tested the performance of the translational system with iron replacing magnesium, it was 50 to 80 percent as efficient as normal (with magnesium). "Manganese worked even better than iron," Bray said.

"I think these may be textbook-rewriting results since the whole field of ribosome research involves magnesium," Bray said. "Now, with what we've done, it's no longer the case that only magnesium works."

Stripping the linchpins from the life-making machine reaffirms its seminal evolution
November 12, 2018, Georgia Institute of Technology

[Image: strippingthe.jpg]
The ribosome (upper middle) is the core of the translational system illustrated here. The system reads DNA via RNA and turns it into proteins to make all beings live. Credit: National Science Foundation, public domain
So audacious was Marcus Bray's experiment that even he feared it would fail.

In the system inside cells that translates genetic code into life, he replaced about 1,000 essential linchpins with primitive substitutes to see if the translational system would survive and function. It seemed impossible, yet it worked swimmingly, and Bray had compelling evidence that the great builder of proteins was active in the harsh conditions in which it evolved 4 billion years ago.

The experiment's success reaffirmed the translational system's place at the earliest foundations of life on Earth.

Every living thing exists because the translational system receives messages from DNA delivered to it by RNA and translates the messages into proteins. The system centers on a cellular machine called the ribosome, which is made of multiple large molecules of RNA and protein and is ubiquitous in life as we know it.

"There's nothing alive without ribosomes," said Loren Williams, a professor at the Georgia Institute of Technology's School of Chemistry and Biochemistry. "The ribosome is about the oldest and most universal part of biology, and its origins go very far back to a time not too long after Earth had formed and cooled."

Eat your magnesium

Those linchpins Bray yanked out and replaced were metal ions (atoms with charges, in this case positive).

In today's ribosome, and in the whole translational system, they are magnesium ions, and Bray's experiment replaced them all with iron ions and manganese ions, which were overabundant on primordial Earth. Williams and Jennifer Glass, the principal investigators in the new study, also had their doubts this was doable.

"I thought, 'It's not going to work, but we might as well try the moonshot'," said Williams who has led similar work before but on simpler molecules. "The fact that swapping out all the magnesium in the translational system actually worked was mind-boggling."

[Image: 1-strippingthe.jpg]
Marcus Bray, front, observes a sample inside a sealed atmospheric tent that has no breathable oxygen. The tent simulates atmospheric gas mixtures during Earth's earliest eon and allows researchers to work with samples by slipping their …more
That's because in living systems today, magnesium helps shape ribosomes by holding them together. Magnesium is also needed for some 20 additional enzymes of the translational system. It's one reason why dietary magnesium (Mg) is so important.

"The number of different things magnesium does in the ribosome and in the translational system is just enormous," said Williams. "There are so many types of catalytic activities in translation, and magnesium is involved in almost all of them."

Lava-belching Earth

When first life evolved, fissures in Earth's crust still belched lava and meteor impacts were still common. There was no breathable oxygen and the planet was brimming with iron and manganese.

This may have made them attractive for the translational system to use as the dominant ions. Magnesium was likely involved, too, though it was probably less available than today.

The researchers wanted to know if the translational system first evolved to function with those other metals as their linchpins. So, Bray, a graduate research assistant in Williams's and in Glass's lab, swapped out the magnesium ions for them, tabula rasa.

"We didn't have any substantial reason to believe it would work, and it was a huge surprise to all of us when it did," Bray said. And it strongly corroborated that the translational system would have thrived under early Earth conditions.

Bray, co-first author Timothy Lenz and co-principal investigators Glass and Williams published their results in the journal Proceedings of the National Academy of Scienceson November 9, 2018. The research was funded by the NASA Exobiology program. Glass is an assistant professor in Georgia Tech's School of Earth and Atmospheric Sciences.

[Image: 2-strippingthe.jpg]
Co-principal investigator Jennifer Glass in her lab at Georgia Tech. She is holding a piece of sedimentary rock full of iron that rusted out of the ocean when breathable oxygen filled Earth's waters and air. Before there was ample …more

'Textbook-rewriting results'

Amazingly, the atomic swaps barely changed the shape of the ribosome.

"It's totally unbelievable this would work because biology makes very specific use of things. Change one atom and it can wreck a whole protein," Williams said. "When we probed the structure, we saw that all three metals do essentially the same thing to the structure."

When they tested the performance of the translational system with iron replacing magnesium, it was 50 to 80 percent as efficient as normal (with magnesium). "Manganese worked even better than iron," Bray said.

"I think these may be textbook-rewriting results since the whole field of ribosome research involves magnesium," Bray said. "Now, with what we've done, it's no longer the case that only magnesium works."

Primordial gas tent

Bray incubated ribosomes in the presence of magnesium, iron, or manganese inside a special chamber with an artificial atmosphere devoid of oxygen, like the Earth four billion years ago.

He found that the magnesium replacement went far beyond atoms in the ribosome.

"Surrounding the ribosome is also a huge cloud of magnesium atoms. It's called an atmosphere, or shell, and engulfs it completely. I replaced everything, including that, and the whole system still worked."

Eons down the road, the evolution of the translational system in the presence of magnesium may have given it an adaptive advantage. As oxygen levels on Earth rose, binding up free manganese and iron, and making them less available to biology, magnesium probably comfortably assumed the thousands of roles it occupies in the translational system today.

[Image: 1x1.gif] Explore further: In creation of cellular protein factories, less is sometimes more

More information: Marcus S. Bray et al, Multiple prebiotic metals mediate translation, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1803636115 

Journal reference: Proceedings of the National Academy of Sciences [Image: img-dot.gif] [Image: img-dot.gif]
Provided by: Georgia Institute of Technology

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We now know how RNA molecules are organized in cells
November 8, 2018, University of Montreal

[Image: rna.png]
A hairpin loop from a pre-mRNA. Highlighted are the nucleobases (green) and the ribose-phosphate backbone (blue). Note that this is a single strand of RNA that folds back upon itself. Credit: Vossman/ Wikipedia
Working with colleagues in the U.S., a team of Université de Montreal researchers has for the first time visualized how RNA molecules are organized in cells.

In their study published in Molecular Cell, scientists at UdeM used super-resolution microscopy to investigate how the 3-D organization of mRNAs changes depending on the location of these molecules in cells and show that a decades-old dogma requires revision.

"The flow of information from DNA to protein implicates a copy of the DNA sequence called messenger RNA that serves as template for protein synthesis," said the study's senior author Daniel Zenklusen, an associate professor at UdeM's department of biochemistry and molecular medicine. "Just like DNA, RNA is a long polymer composed of nucleic acids. How these RNA polymers are compacted and organized in cells to allow protein synthesis was so far unknown, in part because we were lacking technologies to visualize these molecules in high resolution," Zenklusen said.

It has long been thought that all messenger RNA, or mRNA, molecules acquire a specific conformation during protein synthesis: the two ends of the molecule coming together to form a stable so-called closed-loop complex. This new study shows that this long-standing model is oversimplified, according to Zenklusen and his team.

"We observed that messenger RNAs exist in many different configurations in cells, but not in the previously suggested stable closed-loop conformation," said the study's first author Srivathsan Adivarahan, a doctoral student in Zenklusen's lab. "This was very surprising to us since this model is found in every text book describing the essential process of protein synthesis."

In collaboration with the laboratories of Olivia Rissland at the University of Colorado and Bin Wu at Johns Hopkins University in Baltimore, the UdeM scientists found that the messenger RNAs of cells can exist in many conformations but mostly as very compact molecules. This is most pronounced when protein synthesis is suppressed or messenger RNAs are sequestered to specific subcellular compartments such as stress granules, compartments similar to pathologic aggregates often found in neurodegenerative diseases that form under conditions of environmental pressure on cells.

"Our findings change how we think about many aspects of mRNA metabolism, and in particular on how the mRNA is organized during protein synthesis," said Zenklusen. "Regulating this process is essential for all cells, but it is particularly important for a cancer cell that requires high levels of protein synthesis to allow for unceasing growth. Therefore, different drugs affecting proteins synthesis are currently in development and some of these drugs target proteins previously implicated in the closed-loop model. The models of how these drugs affect protein synthesis will have to be revisited."

The new study also illustrates the importance of basic science and the need to continuously develop new technologies, he added. "Technological advances allow us to revisit questions we long thought to have been solved, just to realize once we look at them with new eyes that we are far from truly understanding them."

One of the next steps in Zenklusen's laboratory is therefore to continue to advance the technological approaches that enabled these new findings—single molecule and super-resolution microscopy—in order to gain an even more detailed insight into the mechanisms of gene regulation and how it's misregulated in various diseases.

[Image: 1x1.gif] Explore further: Scientists discover a new mechanism that prevents the proliferation of cancer cells

More information: "Spatial organization of single mRNPs at different stages of the gene expression pathway," by Daniel Zenklusen et al, was published November 8, 2018, in Molecular Cell. The study was financed by the Canadian Institutes of Health Research, Fonds de recherche du Québec - Santé and the Canada Foundation for Innovation. DOI: 10.1016/j.molcel.2018.10.010 

Journal reference: Molecular Cell [Image: img-dot.gif] [Image: img-dot.gif]
Provided by: University of Montreal

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Synthetic molecule invades double-stranded DNA
November 12, 2018 by Jocelyn Duffy, Carnegie Mellon University

[Image: syntheticmol.jpg]
Developed by researchers at Carnegie Mellon University, this janus gamma peptide nucleic acid (PNA) can invade the double helix of DNA and RNA. Credit: Carnegie Mellon University
Carnegie Mellon University researchers have developed a synthetic molecule that can recognize and bind to double-stranded DNA or RNA under normal physiological conditions. The molecule could provide a new platform for developing methods for the diagnosis and treatment of genetic conditions. Their findings are published in Communications Chemistry.

The work was carried out by an international team of experts, including Carnegie Mellon Professor of Chemistry Danith Ly, an expert in peptide nucleic acid design, chemistry postdoc Shivaji Thadke and chemistry graduate student Dinithi Perera, Chemistry Professor and nuclear magnetic resonance expert Roberto Gil, and Arnab Mukherjee, a computer scientist at The Indian Institute of Science Education and Research at Pune.

"Since the double-helical structure of DNA was first elucidated by Watson and Crick, scientists have been trying to design molecules that can bind to DNA and allow one to control the flow of genetic information," said Ly. "This is the first bifacial molecule that can invade double-stranded DNA or RNA under biologically relevant conditions."

DNA, which contains all of an organism's genetic information, is made up of two strands of nucleotides. The nucleotides connect with each other using hydrogen bonds, forming a helical chain of Watson-Crick base pairs. While these base pairs provide a relatively simple code to our genetic information, getting into the double helix to change the code is difficult due to the strong bonds between the base-pairs.

Ly and his colleagues at Carnegie Mellon University's Institute for Biomolecular Design and Discovery (IBD) and Center for Nucleic Acids Science and Technology (CNAST) are leaders in the design and development of gamma peptide nucleic acids (gamma PNAs). Synthetic analogs to DNA and RNA, gamma PNAs can be programmed to bind to the genetic material (DNA or RNA) that causes disease, allowing them to search for detrimental sequences and bind to them to prevent a gene from malfunctioning.

The group has created double-faced gamma PNAs called Janus gamma PNAs. Named after the two-faced Roman god, Janus PNAs are able to recognize and bind with both strands of a DNA or RNA molecule.

The concept of bifacial recognition, which is the basis of the Janus gamma PNAs, was first conceived more than two decades ago by Jean-Marie Lehn, a Nobel laureate known for his work in the field of supramolecular chemistry, and expounded on by other researchers in the field.

The advancement of this research has been held back by two obstacles. First, researchers had been able to only make a small number of Janus bases, and those bases varied considerably in shape and size. These limitations meant the different Janus bases could only recognize repeats of the same set of base pairs and couldn't be used together like building blocks to recognize more complex sequences in DNA or RNA.

Secondly, it was difficult to synthesize Janus bases for canonical base pairs. The complementary nature of the two sides of Janus bases made the molecules hybridize and bind to each other, preventing them from incorporating into DNA and RNA.

In the current study, Ly and colleagues overcome these obstacles. They created an entirely new set of bifacial nucleic acid recognition elements, 16 in total, that accounted for every possible combination of nucleobases that could be found in the genetic code. The Janus gamma PNAs can be used to recognize any combination of base pairs and mixed and matched to detect and bind to complex genetic sequences.

Thadke solved the chemical synthesis problem by devising a novel solution- and solid-phase synthetic method to develop the Janus gamma PNAs. He also deployed a trick inherent in the helical preorganization in the backbone of the gamma PNA to prevent self-complementary Janus bases from hybridizing to one another.

These new Janus gamma PNAs have an extraordinarily high binding energy and are the first to be able to invade a canonical base-paired DNA or RNA double helix at a physiologically relevant ionic strength and temperature.

They do this by taking advantage of when double-stranded DNA and RNA molecules "breathe" and the bonds between the base pairs open for fractions of a second. When this happens, the Janus PNA inserts itself between the separated strands. If the base pairs don't match up, the Janus PNA is ejected from the DNA molecule. But if they do match, the Janus PNA binds to both strands of the molecule.

Janus gamma PNAs have a wide-range of biological and biomedical uses. They can be designed to target genomic DNA for gene editing and transcriptional regulation. They also could be designed to bind sequence-specifically and selectively to the secondary and tertiary structures of RNA, something that traditional antisense agents and small-molecule ligands aren't able to do. For example, the Janus gamma PNAs could be programmed to bind to RNA-repeated expansions, which could lead to new treatments for a number of neuromuscular and neurodegenerative disorders, including myotonic dystrophy type 1 and Huntington's disease, or to noncoding RNAs, including pathogen's ribosomal and telomerase RNA, to combat genetic and infectious diseases.

The technology is being explored by startups as well as by pharmaceutical companies for therapeutic developments.

[Image: 1x1.gif] Explore further: Image: Janus from afar

More information: Shivaji A. Thadke et al, Shape selective bifacial recognition of double helical DNA, Communications Chemistry (2018). DOI: 10.1038/s42004-018-0080-5 

Provided by: Carnegie Mellon University
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[Image: proteinsfoun.jpg]

Synthetic DNA-delivered antibodies protect against Ebola in preclinical studies
Scientists at The Wistar Institute and collaborators have successfully engineered novel DNA-encoded monoclonal antibodies (DMAbs) targeting Zaire Ebolavirus that were effective in preclinical models. Study results, published ...

DNA structure impacts rate and accuracy of DNA synthesis

November 13, 2018 by Sam Sholtis, Pennsylvania State University

[Image: dnastructure.jpg]
The speed and error rate of DNA Synthesis differs between regions of the genome that form the usual DNA structure (B DNA) and those regions that can form other structures (non-B DNA). Regions that can form G-quadruplexes (illustrated) slow …more
The speed and error rate of DNA synthesis is influenced by the three-dimensional structure of the DNA. Using "third-generation" genome-wide DNA sequencing data, a team of researchers from Penn State and the Czech Academy of Sciences showed that sequences with the potential to form unusual DNA conformations, which are frequently associated with cancer and neurological diseases, can in fact slow down or speed up the DNA synthesis process and cause more or fewer sequencing errors. An article describing the study appears online in the journal Genome Research.

"We've been interested for a long time in trying to understand the factors that affect variation in mutation rates across the genome," said Kateryna Makova, Pentz Professor of Biology at Penn State and one of the leaders of the research team. "Sequences that can form non-B DNA, which form structures other than the common right-handed double-helix with ten bases per turn (B-DNA), make up about 13 percent of the human genome and play many important roles in cellular functions, including gene regulation and the protection of telomeres—the sequences that cap and stabilize the ends of chromosomes. Because these regions are also associated with many human diseases we were interested to see if they had any impact on the speed of the DNA synthesis reaction—also called "polymerization"—and on its error rates."

Non-B DNA includes sequences with runs of the "G" nucleotide, guanine, which can form G-quadruplex structures; "A"-rich regions, which can cause helix bending; and short tandem repeats—regions with the same one-to-six nucleotide motifs repeated over and over again (e.g. GATA GATA GATA ...)—that can form slipped strands and hairpins. Using Single-Molecule-Real-Time sequencing, or SMRT, which tracks the time between the incorporation of each successive nucleotide (the A, T, C, or G building blocks of DNA), during sequencing, the researchers compared regions of non-B DNA to B-DNA.

"There are hundreds of thousands of sequence motifs that are predicted to form non-B DNA across the genome," said Wilfried Guiblet, a graduate student in the bioinformatics and genomics program at Penn State and co-first author of the paper. "We used data from the SMRT sequencer from Pacific Biosciences to compare the nucleotide incorporation times along non-B DNA regions with those along regions of more common B-DNA." The comparison revealed that some forms of non-B DNA—G-quadruplexes, for example—caused the polymerase enzyme to slow down by as much as 70 percent, while other non-B DNA caused the enzyme to speed up.

"In order to analyze the data, we developed a novel Functional Data Analysis (FDA) statistical tool," said Francesca Chiaromonte, professor of statistics at Penn State and another leader of the research team. "This tool contrasts the nucleotide incorporation times in non-B and B-DNA regions treating them as curves, or mathematical functions." Marzia Cremona, Bruce Lindsay Visiting Assistant Professor of Statistics at Penn State and another co-first author of the paper, was instrumental in developing the new tool and performing the statistical analysis. A software package implementing the testing procedure is now publicly available.

In addition to changes in nucleotide incorporation times, the researchers also noted that the error rates of the sequencer increased in some types non-B DNA regions, for instance in G-quadruplex motifs. In these regions, the increased error rates lined up with increased DNA sequence variation among humans (using data from the "1000 Genomes Project"), as well as increased divergence between human and orangutan.

"To perform sequencing, SMRT uses an enzyme called polymerase, similar to the cell using polymerases to replicate DNA," said Makova. "It seems likely that the same phenomenon that is causing the increased error rate in the sequencer is also causing the increase we see in human variation and divergence from the orangutan. Understanding how the structure of non-B DNA impacts mutation rates is extremely interesting from the standpoint of genome evolution, and also because these regions have been implicated in human diseases."

[Image: 1x1.gif] Explore further: Disease-associated genes routinely missed in some genetic studies

More information: Wilfried Guiblet et al, Long-read sequencing technology indicates genome-wide effects of non-B DNA on polymerization speed and error rate, Genome Research (2018). DOI: 10.1101/gr.241257.118 

Journal reference: Genome Research [Image: img-dot.gif] [Image: img-dot.gif]
Provided by: Pennsylvania State University

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[Image: 5beb3b48cf6dd.jpg]

Visualizing 'unfurling' microtubule growth
Living cells depend absolutely on tubulin, a protein that forms hollow tube-like polymers, called microtubules, that form scaffolding for moving materials inside the cell. Tubulin-based microtubule scaffolding allows cells ...
Along the vines of the Vineyard.
With a forked tongue the snake singsss...
Quote:Itza chiral viral in the DNA Spirals -EA

The helix, of DNA fame, may have arisen with startling ease
January 24, 2019, Georgia Institute of Technology

[Image: thehelixofdn.jpg]
Artwork for the study shows the chemical structure of the helix that self-assembled in the lab, producing surprisingly bountiful results. Credit: Georgia Tech / Nick Hud

Trying to explain how DNA and RNA evolved to form such neat spirals has been a notorious enigma in science. But a new study suggests the rotation may have occurred with ease billions of years ago when RNA's chemical ancestors casually spun into spiraled strands.

In the lab, researchers at the Georgia Institute of Technology were surprised to see them do it under conditions thought to be common on Earth just before first life evolved: in plain water, with no catalysts, and at room temperature.

The neat spiraling also elegantly integrated another compound which today forms the backbone of RNA and DNA. The resulting structure had features that strongly resembled RNA.

Pivotal twists

The study has come a step closer to answering a chicken-egg question about the evolutionary path that led to RNA (from which DNA later evolved): Did the spiral come first, and did this structure influence which molecular components made it later into RNA because they fit well into the spiral?

"The spiraling could have had a reinforcing effect. It could have facilitated the molecules getting connected together that have the same chirality (curve) to connect into a common backbone that is compatible with the helical twist," said the study's principal investigator Nicholas Hud, a Regents Professor in Georgia Tech's School of Chemistry and Biochemistry.

The researchers published the new study in the journal Angewandte Chemie in December 2018. The research was funded by the National Science Foundation and the NASA Astrobiology Program under the Center for Chemical Evolution. The center is headquartered at Georgia Tech, and Hud is its principal investigator.

The study's resulting polymers were not RNA but could be have been an important intermediate step in the early evolution of RNA. For building blocks, the researchers used base molecules referred to as "proto-nucleobases," highly suspected to be precursors of nucleobases, main components that transport genetic code in today's RNA.

Nucleobase paradox

The study had to work around a paradox in chemical evolution:

Making RNA or DNA using their actual nucleobases in the lab without the aid of the enzymes of living cells that usually do this job is more than a herculean task. Thus, although RNA and DNA are ubiquitous on Earth now, their evolution on pre-life Earth would appear to have been an anomaly requiring erratic convergences of extreme conditions.

By contrast, the Georgia Tech researchers' model of chemical evolution holds that precursor nucleobases self-assembled easily to into ancestral prototypes—that were polymer-like and referred to as assemblies—which later evolved into RNA.

"We would call these 'proto-nucleobases' or 'ancestral nucleobases,'" Hud said. "For our overall model of chemical evolution, we're saying that these proto-nucleobases, which self-assemble into these long strands, could have been part of a very early stage before modern nucleobases were incorporated."

One main suspected proto-nucleobase in this experiment—and in previous experiments on the possible the evolution of RNA—was triaminopyrimidine (TAP). Cyanuric acid (CA) was another. The researchers highly suspect TAP and CA were parts of a proto-RNA.

The chemical bonds that hold together assemblies of the two suspected proto-nucleobases were surprisingly strong but non-covalent, which is akin to connecting two magnets. In RNA the main bonds holding together modern nucleobases are covalent bonds, akin to welding, and enzymes make those bonds in cells today.

Helical biases

A helix can spiral two ways, left-handed or right-handed. In chemistry, a molecule can also be handed, or chiral, making for "L" or "D" forms of the molecule.

[Image: 1-thehelixofdn.jpg]
A proto-nucleobase next to a nucleobase. Hard to tell the difference. Credit: Georgia Tech / Fitrah Hamid
Incidentally, the building blocks of today's RNA and DNA are all the D form, which make a right-handed helix. Why they evolved like this is still a mystery.

Batches of TAP and CA the researchers started out with produced roughly equal amounts of right and left-handed helices, but something stood out: Whole regions of a batch were biased in one direction and were separate from other regions that spiraled mostly the other way.

"The propensity for the molecules to choose one helical direction was so strong that large regions of the batches were made up predominantly of assemblies that were unidirectionally twisted," Hud said.

This was surprising because the individual molecules of TAP and CA had no chirality of their own, neither L nor D. Still, the twists had a preferred direction.

'world record'

The researchers added two more experiments to test how strongly their RNA-like assemblies preferred making one-handed helices.

First, they introduced a smidgeon of compounds similar to TAP and CA, but which had L or D chirality, to nudge the spiraling direction. The whole batch conformed to the chirality of the respective additive, resulting in assemblies twisting in a unified direction as helices do in RNA and DNA today.

"It was the new world record for the smallest amount of a chiral dopant (additive) that would flip a whole solution," said Suneesh Karunakaran, the study's first author and a graduate researcher in Hud's lab. "This demonstrated how easy it would be in nature to get abundant amounts of unified helices."

Second, they put the sugar compound ribose-5-phosphate together with TAP to more closely emulate the current building blocks of RNA. The ribose fell into place, and the resulting assembly spiraled in a direction dictated by the ribose chirality.

"This molecule easily formed an RNA-like assembly that was surprisingly stable, even though the pieces were only held together by non-covalent bonds," Karunakaran said.

Evolution revolution

The study's results under such simple conditions represent a leap forward in experimental evidence for how the helical twist of biomolecules could have already been in place long before life emerged.

The research also expands a growing body of evidence supporting an unconventional hypothesis by the Center for Chemical Evolution, which dispenses with the need for a narrative that rare cataclysms and unlikely ingredients were necessary to produce life's early building blocks.

Instead, most biomolecules likely arose in several gradual steps, on quiet, rain-swept dirt flats or lakeshore rocks lapped by waves. Precursor molecules with the right reactivity enabled those steps readily and produced abundant materials for further evolutionary steps.

Basement engineer

In the lab, helix self-assemblage was so productive that it outstripped a detection device's capacity to examine the output. Regions a square millimeter or more in size were packed with unidirectionally spiraled polymer-like assemblies.

"To look at them I had to make adjustments to the equipment," said Karunakaran. "I punched holes in a foil and put it in front of the beam of our spectropolarimeter."

That worked but needed improvement, so Hud took to his basement at home to build an automated scanner that could handle the experiment's bountiful results. It revealed large regions of helices with the same handedness.

[Image: 1x1.gif] Explore further: Missing links brewed in primordial puddles?

More information: Suneesh C. Karunakaran et al, Spontaneous Symmetry Breaking in the Formation of Supramolecular Polymers: Implications for the Origin of Biological Homochirality, Angewandte Chemie International Edition (2018). DOI: 10.1002/anie.201812808 

Journal reference: Angewandte Chemie [Image: img-dot.gif] [Image: img-dot.gif]Angewandte Chemie International Edition [Image: img-dot.gif] [Image: img-dot.gif]
Provided by: Georgia Institute of Technology

JANUARY 24, 2019
deCODE publishes the first full-resolution genetic map of the human genome
by deCODE genetics
[Image: 5c49959c49991.jpg]How crossover recombination and de novo mutation drive genetic diversity. Credit: deCODE genetics
Scientists at deCODE genetics in Iceland, a subsidiary of Amgen, today publish the first genetic map of the human genome developed using whole-genome sequence data.

The map provides the most detailed view to date of the location, rate and connection between two key drivers of human evolution: recombination—the reshuffling of the genome that occurs in the formation of eggs and sperm; and de novo mutation—the appearance in every one of our genomes of dozens of usually small variations that we did not inherit from either of our parents. Together these processes guarantee that every person is a unique version of our species, but de novo mutations are also a principal cause of rare diseases of childhood. The study appears today in the online edition of Science.
This paper presents the latest genetic map of the genome developed by deCODE using its unique population genetics resources in Iceland and made available to the scientific community. The first, published in 2002 with 6000 microsatellite markers, was instrumental in correctly assembling the first reference genome. In 2010, coinciding with the launch of the first commercial whole-genome sequencing machines, deCODE used 300,000 markers to create a more detailed map to guide the analysis of this new type of data. Today's study draws on sequence data from some 150,000 Icelanders from multiple generations, comprising nearly half the population and yielding the precise location of 4.5 million crossover recombinations and more than 200,000 de novo mutations.
"Over the past 20 years, we have been committed to studying and publishing on de novo mutation and recombination and their relevance to human evolution and disease. We have done this both because it is of fundamental interest to understand more about who we are as a species, and because here in Iceland we have unique resources to address these questions and their relevance to health and medicine," said Kari Stefansson, CEO of deCODE and an author on the paper.
"The classic premise of evolution is that it is powered first by random genetic change. But we see here in great detail how this process is in fact systematically regulated—by the genome itself and by the fact that recombination and de novo mutation are linked. We have identified 35 sequence variants affecting recombination rate and location, and show that de novo mutations are more than fifty times more likely at recombination sites than elsewhere in the genome. Furthermore, women contribute far more to recombination and men to de novo mutation, and it is the latter that comprise a major source of rare diseases of childhood. What we see here is that the genome is an engine for generating diversity within certain bounds. This is clearly beneficial to the success of our species but at great cost to some individuals with rare diseases, which are therefore a collective responsibility we must strive to address," Dr. Stefansson concluded.

More information: "Characterizing mutagenic effects of recombination through a sequence-level genetic map," Science (2019). … 1126/science.aau1043[/size]




The helix, of DNA fame, may have arisen with startling ease

January 24, 2019, Georgia Institute of Technology

[b][Image: thehelixofdn.jpg]
Artwork for the study shows the chemical structure of the helix that self-assembled in the lab, producing surprisingly bountiful results. Credit: Georgia Tech / Nick Hud

The ingredients were all there...  Arrow

Quote:The research also expands a growing body of evidence supporting an unconventional hypothesis by the Center for Chemical Evolution, which dispenses with the need for a narrative that rare cataclysms and unlikely ingredients were necessary to produce life's early building blocks.
Instead, most biomolecules likely arose in several gradual steps, on quiet, rain-swept dirt flats or lakeshore rocks lapped by waves. Precursor molecules with the right reactivity enabled those steps readily and produced abundant materials for further evolutionary steps.
Planetary collision that formed the moon made life possible on Earth
January 23, 2019, Rice University

[Image: 1-planetarycol.jpg]
A schematic depicting the formation of a Mars-sized planet (left) and its differentiation into a body with a metallic core and an overlying silicate reservoir. The sulfur-rich core expels carbon, producing silicate with a high carbon to nitrogen ratio. The moon-forming collision of such a planet with the growing Earth (right) can explain Earth's abundance of both water and major life-essential elements like carbon, nitrogen and sulfur, as well as the geochemical similarity between Earth and the moon. Credit: Rajdeep Dasgupta
Most of Earth's essential elements for life—including most of the carbon and nitrogen in you—probably came from another planet.

Earth most likely received the bulk of its carbon, nitrogen and other life-essential volatile elements from the planetary collision that created the moon more than 4.4 billion years ago, according to a new study by Rice University petrologists in the journal Science Advances.

"From the study of primitive meteorites, scientists have long known that Earth and other rocky planets in the inner solar system are volatile-depleted," said study co-author Rajdeep Dasgupta. "But the timing and mechanism of volatile delivery has been hotly debated. Ours is the first scenario that can explain the timing and delivery in a way that is consistent with all of the geochemical evidence."

The evidence was compiled from a combination of high-temperature, high-pressure experiments in Dasgupta's lab, which specializes in studying geochemical reactions that take place deep within a planet under intense heat and pressure.

In a series of experiments, study lead author and graduate student Damanveer Grewal gathered evidence to test a long-standing theory that Earth's volatiles arrived from a collision with an embryonic planet that had a sulfur-rich core.

The sulfur content of the donor planet's core matters because of the puzzling array of experimental evidence about the carbon, nitrogen and sulfur that exist in all parts of the Earth other than the core.

"The core doesn't interact with the rest of Earth, but everything above it, the mantle, the crust, the hydrosphere and the atmosphere, are all connected," Grewal said. "Material cycles between them."

One long-standing idea about how Earth received its volatiles was the "late veneer" theory that volatile-rich meteorites, leftover chunks of primordial matter from the outer solar system, arrived after Earth's core formed. And while the isotopic signatures of Earth's volatiles match these primordial objects, known as carbonaceous chondrites, the elemental ratio of carbon to nitrogen is off. Earth's non-core material, which geologists call the bulk silicate Earth, has about 40 parts carbon to each part nitrogen, approximately twice the 20-1 ratio seen in carbonaceous chondrites.

Grewal's experiments, which simulated the high pressures and temperatures during core formation, tested the idea that a sulfur-rich planetary core might exclude carbon or nitrogen, or both, leaving much larger fractions of those elements in the bulk silicate as compared to Earth. In a series of tests at a range of temperatures and pressure, Grewal examined how much carbon and nitrogen made it into the core in three scenarios: no sulfur, 10 percent sulfur and 25 percent sulfur.

"Nitrogen was largely unaffected," he said. "It remained soluble in the alloys relative to silicates, and only began to be excluded from the core under the highest sulfur concentration."

Carbon, by contrast, was considerably less soluble in alloys with intermediate sulfur concentrations, and sulfur-rich alloys took up about 10 times less carbon by weight than sulfur-free alloys.

[Image: planetarycol.jpg]
A study by Rice University scientists (from left) Gelu Costin, Chenguang Sun, Damanveer Grewal, Rajdeep Dasgupta and Kyusei Tsuno found Earth most likely received the bulk of its carbon, nitrogen and other life-essential elements from the …more
Using this information, along with the known ratios and concentrations of elements both on Earth and in non-terrestrial bodies, Dasgupta, Grewal and Rice postdoctoral researcher Chenguang Sun designed a computer simulation to find the most likely scenario that produced Earth's volatiles. Finding the answer involved varying the starting conditions, running approximately 1 billion scenarios and comparing them against the known conditions in the solar system today.

"What we found is that all the evidence—isotopic signatures, the carbon-nitrogen ratio and the overall amounts of carbon, nitrogen and sulfur in the bulk silicate Earth—are consistent with a moon-forming impact involving a volatile-bearing, Mars-sized planet with a sulfur-rich core," Grewal said.

Dasgupta, the principal investigator on a NASA-funded effort called CLEVER Planets that is exploring how life-essential elements might come together on distant rocky planets, said better understanding the origin of Earth's life-essential elements has implications beyond our solar system.

"This study suggests that a rocky, Earth-like planet gets more chances to acquire life-essential elements if it forms and grows from giant impacts with planets that have sampled different building blocks, perhaps from different parts of a protoplanetary disk," Dasgupta said.

"This removes some boundary conditions," he said. "It shows that life-essential volatiles can arrive at the surface layers of a planet, even if they were produced on planetary bodies that underwent core formation under very different conditions."

Dasgupta said it does not appear that Earth's bulk silicate, on its own, could have attained the life-essential volatile budgets that produced our biosphere, atmosphere and hydrosphere.

"That means we can broaden our search for pathways that lead to volatile elements coming together on a planet to support life as we know it."

Explore further: Earth's carbon points to planetary smashup

More information: D.S. Grewal el al., "Delivery of carbon, nitrogen, and sulfur to the silicate Earth by a giant impact," Science Advances (2019). DOI: 10.1126/sciadv.aau3669 , 

Journal reference: Science Advances 
Provided by: Rice University

Read more at:

Astronomers find star material could be building block of life
January 23, 2019, Queen Mary, University of London

[Image: 3-astronomersf.jpg]
The Rho Ophiuchi star formation region with IRAS16293-2422 B circled. Credit: ESO/Digitized Sky Survey 2. Acknowledgement: Davide De Martin
An organic molecule detected in the material from which a star forms could shed light on how life emerged on Earth, according to new research led by Queen Mary University of London.

The researchers report the first ever detection of glycolonitrile (HOCH2CN), a pre-biotic molecule which existed before the emergence of life, in a solar-type protostar known as IRAS16293-2422 B.

This warm and dense region contains young stars at the earliest stage of their evolution surrounded by a cocoon of dust and gas—similar conditions to those when our Solar System formed.

Detecting pre-biotic molecules in solar-type protostars enhances our understanding of how the solar system formed as it indicates that planets created around the star could begin their existence with a supply of the chemicalingredients needed to make some form of life.

This finding, published in the journal Monthly Notices of the Royal Astronomical Society: Letters, is a significant step forward for pre-biotic astrochemistry since glycolonitrile is recognised as a key precursor towards the formation of adenine, one of the nucleobases that form both DNA and RNA in living organisms.

IRAS16293-2422 B is a well-studied protostar in the constellation of Ophiuchus, in a region of star formation known as rho Ophiuchi, about 450 light-years from Earth.

[Image: 4-astronomersf.jpg]
The Rho Ophiuchi star formation region. Credit: ESO/Digitized Sky Survey 2. Acknowledgement: Davide De Martin
The research was also carried out with the Centro de Astrobiología in Spain, INAF-Osservatorio Astrofisico di Arcetri in Italy, the European Southern Observatory, and the Harvard-Smithsonian Center for Astrophysics in the USA.

Lead author Shaoshan Zeng, from Queen Mary University of London, said: "We have shown that this important pre-biotic molecule can be formed in the material from which stars and planets emerge, taking us a step closer to identifying the processes that may have led to the origin of life on Earth."

The researchers used data from the Atacama Large Millimeter/submillimetre Array (ALMA) telescope in Chile to uncover evidence for the presence of glycolonitrile in the material from which the star is forming—known as the interstellar medium.

[Image: 5-astronomersf.jpg]
Glycolonitrile Credit: Víctor M. Rivilla & Ben Mills & Herschel-SPIRE 500 microns
With the ALMA data, they were able to identify the chemical signatures of glycolonitrile and determine the conditions in which the molecule was found. They also followed this up by using chemical modelling to reproduce the observed data which allowed them to investigate the chemical processes that could help to understand the origin of this molecule.

This follows the earlier detection of methyl isocyanate in the same object by researchers from Queen Mary. Methyl isocyanate is what is known as an isomer of glycolonitrile—it is made up of the same atoms but in a slightly different arrangement, meaning it has different chemical properties.

 Explore further: ALMA finds ingredient of life around infant Sun-like stars

More information: S Zeng et al, First detection of the pre-biotic molecule glycolonitrile (HOCH2CN) in the interstellar medium, Monthly Notices of the Royal Astronomical Society: Letters (2019). DOI: 10.1093/mnrasl/slz002 

Journal reference: Monthly Notices of the Royal Astronomical Society Letters 
Provided by: Queen Mary, University of London

Read more at:
Along the vines of the Vineyard.
With a forked tongue the snake singsss...

Right where eye Left off...

Quote:Normally, the two strands of the DNA double helix wind around each other in a right-handed spiral. However, there is another conformation called Z-DNA in which the strands twist to the left.

JULY 19, 2019
Researchers report the function of reverse-twisting DNA
by InsideOutBio
[Image: adynamicgene.jpg]Zα mutations from one parental chromosome map directly to phenotype as there is no transcript from the other parental chromosome to cover up defects in the ADAR protein produced. Credit: Alan Herbert
Normally, the two strands of the DNA double helix wind around each other in a right-handed spiral. However, there is another conformation called Z-DNA in which the strands twist to the left. The function of Z-DNA has remained a mystery since its discovery. A newly published paper unambiguously establishes that the Z-conformation is key to regulating interferon responses involved in fighting viruses and cancer. The researchers analyzed families with variants in the Z-binding domain of the ADAR gene.

The peer-reviewed results, published online in the European Journal of Human Genetics, end the longstanding debate as to whether the unusual left-handed Z-conformation has any biological function. Z-DNA forms when right-handed B-DNA is unwound to make RNA. An analysis of genetic mutations in Mendelian families by Alan Herbert at InsideOutBio reveals that the Z-conformation regulates those type I interferon responses normally induced by viruses and tumors. The study confirms a biological role for the left-handed conformation in human disease and reveals that the human genome encodes genetic information using both shape and sequence. The two codes are overlapping, with three-dimensional shapes like Z-DNA and Z-RNA forming dynamically, altering the read-out of sequence information from linear, one-dimensional DNA chromosomal arrays.
One approach to understanding the biological role of Z-DNA has been to isolate proteins that bind specifically to the left-handed Z-DNA conformation and study their function. Alan Herbert and the late Alexander Rich led a team at MIT that identified the Zα domain, which binds very tightly to both Z-DNA and Z-RNA. X-ray studies revealed that the binding was specific for the Z-conformation without any sequence specificity. The co-crystals of Zα and Z-DNA allowed identification of key protein residues in their interaction.
[Image: 1-adynamicgene.jpg]

Under physiological conditions, certain sequences can adopt either the left-handed or right-handed DNA conformation and change the RNA readout from a gene, affecting how cells respond to their environment. These sequences, called flipons, encode genetic information by their shape. Credit: Alan Herbert
The Zα domain is present in a double-stranded RNA editing enzyme called ADAR. ADAR edits double-stranded RNAs (dsRNA) that usually form when an RNA transcript basepairs with itself. The enzyme changes adenosine to inosine, which is then read out as guanosine, changing both the information of the RNA and its downstream processing, generating many differing RNA products from a single transcript. Early studies suggested ADAR was involved in anti-viral interferon responses. However, most edited dsRNA in a cell originate from repetitive Alu elements, fragments of non-coding RNA that colonized the human genome early in its evolution through a process of copy and paste. Recent studies show that suppression of such dsRNAs by ADAR editing is vital to the survival of many tumors.

The discovery of families with mutations in the ADAR gene has now revealed a biological function for the left-handed conformation. Families with loss of function ADAR variants overproduce interferon, leading to a severe diseases such as Aicardi-Goutières syndrome (OMIM: 615010) and bilateral striatal necrosis/dystonia. In some families, due to the different ADAR variants inherited from each parent, only one parental chromosome is capable of making ADAR protein. In such families, it is possible to map a mutation directly to phenotype. Individuals with Zα ADAR variants that no longer bind the Z-conformation have impaired dsRNA editing and exaggerated dsRNA-induced interferon responses, confirming that the left-handed Z-conformation regulates these responses. The findings directly link Z-DNA to human disease and unambiguously establish a biological role for this alternative nucleic acid conformation.
The switch in shape from right-handed to left-handed DNA alters the readout from genes involved in the type I interferon pathway. Only a subset of sequences flip to form Z-DNA under physiological conditions. Their distribution within the genome is non-random. These flipons create phenotypic diversity by altering how genes generate RNA. They are subject to selection just like any other variation. The genomes that emerge encode genetic information in both shape and sequence with frequent overlap between the two different instruction sets.[/size]


Explore further
How viruses hijack part of your immune system and use it against you[/size]

More information: Alan Herbert, Mendelian disease caused by variants affecting recognition of Z-DNA and Z-RNA by the Zα domain of the double-stranded RNA editing enzyme ADAR, European Journal of Human Genetics (2019). DOI: 10.1038/s41431-019-0458-6[/size]
Along the vines of the Vineyard.
With a forked tongue the snake singsss...

Both sublinks at the bottom of the last post are excellent.

Discovery along this route will eventually be targeting pandemic flu viruses in vaccine development.
I am convinced that the extremely bad flu viruses use this same criteria,
to some degree to evade immune response.
Last two sentences from the link:
How viruses hijack part of your immune system and use it against you

Quote:"Evolutionarily, the story is fascinating. 
It is an interferon-inducible gene. 
Nobody thought that they could be a pro-viral factor. 
It's not how we think about it," says Cattaneo.

The group's discovery of how viruses hijack ADAR Whip

and the RNA threshold may lead to new antiviral therapies,
that target ADAR1,
so viruses cannot use it to hide from the immune system.

In an OTHER Thread ,it was said:
Sunday, September 15th, 2019, 04:35 pm (This post was last modified: Sunday, September 15th, 2019, 04:59 pm by EA.)

Quote: Wrote:Strikingly, the two halves of the enzyme communicate with each other via a string of water molecules that connects both halves. This water network allows the two halves to 'talk' to one another and share information about their catalytic state. This is crucial to the enzyme's function as only one half of the enzyme can ever be active at a given time.

SEPTEMBER 13, 2019
A molecular string phone at work
by Max Planck Institute for the Structure and Dynamics of Matter
[Image: amolecularst.jpg]Time-lapse images show that the enzyme ‘breathes’ during turnover: it expands and contracts aligned with the catalytic sub-steps. Its two halves communicate via a string of water molecules. Credit: Joerg M. Harms, MPSD

Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Potsdam (both in Germany) and the University of Toronto (Canada) have pieced together a detailed time-lapse movie revealing all the major steps during the catalytic cycle of an enzyme. Surprisingly, the communication between the protein units is accomplished via a water network akin to a string telephone. This communication is aligned with a 'breathing' motion, that is the expansion and contraction of the protein. This time-lapse sequence of structures reveals dynamic motions as a fundamental element in the molecular foundations of biology.

All life is dynamic and so are its molecular building blocks. The motions and structural changes of biomolecules are fundamental to their functions. However, understanding these dynamic motions at a molecular level is a formidable challenge. How is a protein able to accelerate a chemical reaction, which would take years to proceed without help?
To this end the researchers turned to an enzyme that splits the strongest single-bond in organic chemistry: the C-F bond. Fluorinated carbons can be found in materials such as Teflon or GoreTex and in many pharmaceuticals and pesticides. Fluorinated compounds have a particular influence in climate change, exceeding the effectiveness of CO2by orders magnitude. Therefore, the ability to better understand and eventually control the turnover of C-F bonds is of particular interest to climate change and bioremediation.
The researchers used time-resolved X-ray crystallography to take molecular snapshots during the turnover reaction of this natural enzyme at physiological temperatures. This time-lapse movie revealed eighteen time points from 30 milliseconds to 30 seconds, covering all key catalytic states that lead to the breaking of the C-F bond. Surprisingly, the movie also shows that the enzyme 'breathes' during turnover, that is it expands and contracts aligned with the catalytic sub-steps.
Strikingly, the two halves of the enzyme communicate with each other via a string of water molecules that connects both halves. This water network allows the two halves to 'talk' to one another and share information about their catalytic state. This is crucial to the enzyme's function as only one half of the enzyme can ever be active at a given time.
These dynamic changes have proven crucial to the enzyme's function. The researchers expect many other systems to exploit similar mechanisms for their activities.

[Image: 48737617983_7feb61b8f4_z.jpg]
Strange alien world found to have water vapor and possibly rain clouds
Exoplanet K2-18 b lies in the habitable zone of its host star some 110 light-years from Earth.
Sept. 11, 2019, 12:24 PM CST / Source:
By Chelsea Gohd,

[Image: 48737619158_8bb86a0179_z.jpg]
[b]More information:[/b] Pedram Mehrabi et al. Time-resolved crystallography reveals allosteric communication aligned with molecular breathing, Science (2019). DOI: 10.1126/science.aaw9904
[b]Journal information:[/b] Science [/url]

Provided by 
Max Planck Institute for the Structure and Dynamics of Matter 

Researchers... have pieced together a detailed time-lapse movie revealing all the major steps during the catalytic cycle of an enzyme. Surprisingly, the communication between the protein units is accomplished via a water network akin to a string telephone. This communication is aligned with a 'breathing' motion, that is the expansion and contraction of the protein. This time-lapse sequence of structures reveals dynamic motions as a fundamental element in the molecular foundations of biology. [Image: arrow.png]

SEPTEMBER 23, 2019
DNA is held together by hydrophobic forces
[Image: dnaisheldtog.jpg]For DNA to be read, replicated or repaired, DNA molecules must open themselves. This happens when the cells use a catalytic protein to create a hydrophobic environment around the molecule. Credit: Yen Strandqvist/Chalmers University of Technology
Researchers at Chalmers University of Technology, Sweden, have disproved the prevailing theory of how DNA binds itself. It is not, as is generally believed, hydrogen bonds which bind together the two sides of the DNA structureInstead, water is the key. The discovery opens doors for new understanding in research in medicine and life sciences. The findings are published in PNAS.

DNA is constructed of two strands consisting of sugar molecules and phosphate groups. Between these two strands are nitrogen bases, the compounds that make up genes, with hydrogen bonds between them. Until now, it was commonly thought that those hydrogen bonds held the two strands together.
But now, researchers from Chalmers University of Technology show that the secret to DNA's helical structure may be that the molecules have a hydrophobic interior, in an environment consisting mainly of water. The environment is therefore hydrophilic, while the DNA molecules' nitrogen bases are hydrophobic, pushing away the surrounding water. When hydrophobic units are in a hydrophilic environment, they group together to minimize their exposure to the water.
The role of the hydrogen bonds, which were previously seen as crucial to holding DNA helixes together, appear to be more to do with sorting the base pairs so that they link together in the correct sequence. The discovery is crucial for understanding DNA's relationship with its environment.
"Cells want to protect their DNA, and not expose it to hydrophobic environments, which can sometimes contain harmful molecules," says Bobo Feng, one of the researchers behind the study. "But at the same time, the cells' DNA needs to open up in order to be used."
"We believe that the cell keeps its DNA in a water solution most of the time, but as soon as a cell wants to do something with its DNA, like read, copy or repair it, it exposes the DNA to a hydrophobic environment."
Reproduction, for example, involves the base pairs dissolving from one another and opening up. Enzymes then copy both sides of the helix to create new DNA. When it comes to repairing damaged DNA, the damaged areas are subjected to a hydrophobic environment, to be replaced. A catalytic protein creates the hydrophobic environment. This type of protein is central to all DNA repairs, meaning it could be the key to fighting many serious sicknesses.
Understanding these proteins could yield many new insights into fighting resistant bacteria, for example, or potentially curing cancer. Bacteria use a protein called RecA to repair their DNA, and the researchers believe their results could provide new insight into how this process works—potentially offering methods for stopping it and thereby killing the bacteria.

In human cells, the protein Rad51 repairs DNA and fixes mutated DNA sequences, which otherwise could lead to cancer. "To understand cancer, we need to understand how DNA repairs. To understand that, we first need to understand DNA itself," says Bobo Feng. "So far, we have not, because we believed that hydrogen bonds were what held it together. Now, we have shown that instead it is the hydrophobic forces which lie behind it. We have also shown that DNA behaves totally differently in a hydrophobic environment. This could help us to understand DNA, and how it repairs. Nobody has previously placed DNA in a hydrophobic environment like this and studied how it behaves, so it's not surprising that nobody has discovered this until now."
The researchers also studied how DNA behaves in an environment that is more hydrophobic than normal, a method they were the first to experiment with. They used the hydrophobic solution polyethylene glycol, and changed the DNA's surroundings step-by-step from the naturally hydrophilic environment to a hydrophobic one. They aimed to discover if there is a limit where DNA starts to lose its structure, when the DNA does not have a reason to bind, because the environment is no longer hydrophilic. The researchers observed that when the solution reached the borderline between hydrophilic and hydrophobic, the DNA molecules' characteristic spiral form started to unravel.
Upon closer inspection, they observed that when the base pairs split from one another (due to external influence, or simply from random movements), holes are formed in the structure, allowing water to leak in. Because DNA wants to keep its interior dry, it presses together, with the base pairs coming together again to squeeze out the water. In a hydrophobic environment, this water is missing, so the holes stay in place.
"Hydrophobic catalysis and a potential biological role of DNA unstacking induced by environment effects" is published in Proceedings of the National Academy of Sciences (PNAS).

Explore further
Using mutant bacteria to study how changes in membrane proteins affect cell functions

[b]More information:[/b] Bobo Feng et al, Hydrophobic catalysis and a potential biological role of DNA unstacking induced by environment effects, Proceedings of the National Academy of Sciences (2019). DOI: 10.1073/pnas.1909122116
[b]Journal information:[/b] Proceedings of the National Academy of Sciences [/url]

Provided by 
Chalmers University of Technology
Along the vines of the Vineyard.
With a forked tongue the snake singsss...
cosmic dna.

SEPTEMBER 27, 2019
Life's building blocks may have formed in interstellar clouds
[Image: lifesbuildin.jpg]An inside look of an ultra-high vacuum reaction chamber that simulates chemical reactions in an interstellar cloud environment. Credit: Hokkaido University
An experiment shows that one of the basic units of life—nucleobases—could have originated within giant gas clouds interspersed between the stars.

Essential building blocks of DNA, compounds called nucleobases, have been detected for the first time in a simulated environment mimicking gaseous clouds that are found interspersed between stars. The finding, published in the journal Nature Communications, brings us closer to understanding the origins of life on Earth.
"This result could be key to unraveling fundamental questions for humankind, such as what organic compounds existed during the formation of the solar system and how they contributed to the birth of life on Earth," says Yasuhiro Oba of Hokkaido University's Institute of Low Temperature Science.
Scientists have already detected some of the basic organic molecules necessary for the beginnings of life in comets, asteroids, and in interstellar molecular clouds—giant gaseous clouds dispersed between stars. It is thought that these molecules could have reached Earth through meteorite impacts some 4 billion years ago, providing key ingredients for the chemical cocktail that gave rise to life. Learning how these molecules formed is vital to understanding the origins of life.
The basic structural unit of DNA and RNA is called a nucleotide, and is composed of a nucleobase, a sugar, and a phosphate group. Previous studies mimicking the expected conditions in interstellar molecular clouds have detected the presence of sugar and phosphate, but not of nucleobases.

[Image: 1-lifesbuildin.jpg]
The fundamental nucleobases detected in a simulated interstellar cloud environment. Credit: Hokkaido University
Now, Yasuhiro Oba and colleagues at Hokkaido University, Kyushu University, and the Japan Agency for Marine-Earth Science and Technology (JAMSTEC) have used advanced analytical methods to detect the fundamental nucleobases in a simulated interstellar cloud environment.
The team conducted their experiments in an ultra-high vacuum reaction chamber. A gaseous mixture of water, carbon monoxide, ammonia, and methanol was continuously supplied onto a cosmic-dust analogue at a temperature of -263 degrees Celsius. Two deuterium discharge lamps attached to the chamber supplied vacuum ultraviolet light to induce chemical reactions. The process led to the formation of an icy film on the dust analogue inside the chamber.

The team used a high-resolution mass spectrometer and a high-performance liquid chromatograph to analyze the product that formed on the substrate after warming it to room temperature. Recent advances in these technological tools allowed them to detect the presence of the nucleobases cytosine, uracil, thymine, adenine, xanthine, and hypoxanthine. They also detected amino acids, which are the building blocks of proteins, and several kinds of dipeptide, or a dimer of amino acid, in the same product.
The team suspects that past experiments simulating interstellar molecular cloud environments would have produced nucleobases, but that the analytical tools used were not sensitive enough to detect them in complex mixtures.
"Our findings suggest that the processes we reproduced could lead to the formation of the molecular precursors of life," says Yasuhiro Oba. "The results could improve our understanding of the early stages of chemical evolution in space."

Explore further
Meteorite impacts can create DNA building blocks

[b]More information:[/b] Yasuhiro Oba et al. Nucleobase synthesis in interstellar ices, Nature Communications (2019). DOI: 10.1038/s41467-019-12404-1
[b]Journal information:[/b] Nature Communications [/url]

Provided by [url=]Hokkaido University
Along the vines of the Vineyard.
With a forked tongue the snake singsss...
OCTOBER 3, 2019
New study discovers the three-dimensional structure of the genome replication machine
[Image: dna.png]DNA double helix. Credit: public domain
Mount Sinai researchers have discovered how the enzyme DNA polymerase delta works to duplicate the genome that cells hand down from one generation to the next. In a study published in Nature Structural & Molecular Biology, the team also reported how certain mutations can modulate the activity of this enzyme, leading to cancers and other diseases.

"DNA polymerase delta serves as the duplicating machine for the millions to billions of base pairs in human and other genomes. We were able to present for the first time a near-atomic-resolution structure of the complete enzyme in the act of DNA synthesis," says lead investigator Aneel Aggarwal, Ph.D., Professor of Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai. "This knowledge furthers our basic understanding of this complex enzyme which is essential for survival in higher organisms from humans to yeast. At the same time, our work provides insights into how cancers can arise when DNA polymerase delta is not functioning properly, and offers a novel basis for designing inhibitors of the polymerase that could potentially serve as effective treatment in certain cancers."
While DNA polymerase delta has been studied by scientists for decades, many questions remain about its overall architecture and dynamics. "We showed how the various pieces of this complicated machine work synchronously with one another to copy the genome with amazing accuracy," explains Dr. Aggarwal. His team, which included co-author Rinku Jain, Ph.D., Assistant Professor of Pharmacological Sciences at the Icahn School of Medicine, also mapped a number of inherited mutations (which are passed down from parent to child) and somatic mutations (which occur by chance during someone's lifetime) in DNA polymerase delta that are associated with "hypermutated" tumors. In addition to cancers, these mutations may be associated with multi-symptom mandibular hypoplasia, deafness, and lipodystrophy syndrome.
Essential to the Mount Sinai researchers' work were recent advances in cryo-electron microscopy. This technology, which allows for the imaging of rapidly frozen molecules in solution, is revolutionizing the field of structural biology through its high-resolution pictures. This technique allowed Dr. Aggarwal and his team to examine not only individual atoms of the DNA polymerase delta but also how they move to achieve accurate replication of the genome. Integral to this phase of the research was Mount Sinai's partnership with the Simons Electron Microscopy Center in New York City.
Building on its latest groundbreaking work around DNA polymerase delta, Mount Sinai will continue to explore the unique structure and mechanism of the polymerase, particularly its relationship to cancer and disease pathogenesis. "We know that certain cancers become dependent on this enzyme for their survival," says Dr. Aggarwal, "and inhibiting its activity could provide a valuable therapeutic window for future medical research."

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Researchers find structural basis for incidence of skin cancers in a genetic disorder

[b]Journal information:[/b] Nature Structural & Molecular Biology [/url]

Provided by [url=]The Mount Sinai Hospital
Along the vines of the Vineyard.
With a forked tongue the snake singsss...
Glycans found binding to mammalian RNA
by Bob Yirka ,
[Image: rna.jpg]Credit: CC0 Public Domain
A team of researchers at Stanford University has found evidence of glycans binding with mammalian RNA. The group has written a paper describing their findings and have posted it on the bioRxiv preprint server.

Glycans are a type of sugar thay typically play a role in modifying lipids and proteins to facilitate molecular interactions. In this new effort, the researchers were studying a process called glycosylation, a reaction that occurs when sugar molecules attach to proteins. As part of their research, one of the team members was labeling glycoproteins when he noticed what appeared to be a glycan attaching to RNA. Such an event had never been observed before. A closer look showed that it was a certain type of sugar called an N-linked glycan, and that it was sticking to Y RNA—a small RNA molecule that is believed to play a role in DNA replication.
RNA is typically found in the nucleus and cytosol inside of cells. Glycosylation generally takes place in the Golgi bodies and endoplasmic reticulum. Thus, for the two molecules to meet, one of them would have to enter cell compartments in ways that have not been seen before. Another possibility would be a molecule that serves as a go-between.
The researchers were naturally quite skeptical of the find, which led to efforts to show that it was an anomaly. As part of that effort, they tried separating out proteins, but discovered that the sample they had found was only sensitive to enzymes that tend to cut up RNA. Further tests showed that such bindings also occurred in hamster and mouse cell cultures. Finally convinced that they were on to something new, the researchers named the bound molecules glycolRNA.
After some further study of the bound molecules, the researchers report that they were not able to figure out how the sugars were binding to the RNA—attempts to separate them failed except when they used enzymes to destroy one or the other molecule. They suggest it appears likely that the linkage is not protein-based and that it seems possible that it could be due to covalent bonding.
The finding by the team has yet to be verified by others, but if confirmed, it will likely open up a whole new avenue of RNA research.

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The sugar-attaching enzyme that defines colon cancer

[b]More information:[/b] Ryan A. Flynn et al. Mammalian Y RNAs are modified at discrete guanosine residues with N-glycans, bioRxiv (2019). DOI: 10.1101/787614
Along the vines of the Vineyard.
With a forked tongue the snake singsss...
Researcher Receives £1.25 Million to Create New 'Living' Micro-Machines

The grant was given by the European Research Council, and covers research for the next five years.
Fabienne Lang
October 08th, 2019

[Image: living-micro-machines_resize_md.jpg]
Loughborough University academic and researcher, Dr. Tyler Shendruk, has just been awarded more than £1.25 million by the European Research Council in order to create 'living' micro-machines.

These minuscule machines should be able to self-assemble in their biological environments. Furthermore, these little machines will be able to draw energy from their surroundings to create and power themselves.
This grant is meant to cover the costs of this research project for the next five years.


Why is this research so important?

Meant to replicate the behaviors of biological molecules and microorganisms, these new man-made materials should, in theory, be able to function much in the same way.

Quote:[Image: ys-qTbFK_normal.jpg]

Loughborough Uni PR @lborouniPR

What's happening in the video below and how could it lead to the creation of ‘living’ micro-machines that self-assemble in biological environments?

Read the press release to find out: 
[Image: 1QpS06D6_normal.png] YouTube ‎@YouTube

[Image: T3CIO1Ww?format=jpg&name=280x280]

4:11 AM - Oct 7, 2019
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Dr. Shendruk will use a combination of two research areas — colloidal self-assembly, and active matter — to design 'living' colloidal liquid crystals.

Essentially, the idea is to copy the format of biological materials that are able to form, restructure, and move. For example, bacteria, like the Salmonella bacteria, can move and propel themselves into more favorable environments all on their own.

This type of self-operating living matter is what Dr. Shendruk hopes to recreate in lifeless human-created materials. 
How will Dr. Shendruk do this?

The scientist will use computational simulations for his research on biological matter. The final aim is to create 'living' colloidal liquid crystals — a new type of soft material that can form, restructure, and move themselves.

Colloids are small particles suspended in a fluid medium (gas or a liquid), which cannot be separated through regular filtration methods. For instance, coffee is a colloid as coffee grounds are small suspended, solid particles in hot water. 
Self-assembling is the process whereby colloids come together and create complex structures.

'Living' colloidal liquid crystals

Traditional liquid crystals move just like water — when forced by pressure, gravity, or another external push. 
However, this new class of 'living' fluids has the ability to move on their own — much like the bacteria mentioned above, that shift themselves to more favorable environments.

How do they do this? Their own organism stores their fuel, and these are referred to as 'living' liquids. 
If successful, this discovery could be useful for several applications.

Dr. Shendruk himself said, "Just like robots aren’t just for one single task but can do many things, I hope our ‘living’ colloidal liquid crystals might form micro-bots that could do all sorts tiny tasks."

 Dr. Tyler Shendruk. Source: Loughborough University

Shendruk continued: "The research aims to produce colloidal structures with autonomous functionality, including self-motility, self-revolution, and dynamical self-transformations, which are exactly the characteristics one would desire for a first generation of autonomous components of micro-biomechanical systems and soft micro-machines."

And he finished by saying, "As hybrids between biological active fluids and simple man-made materials, I hope they have the potential for autonomously tunable material properties, mimicking biological complexity, and maybe even someday working together with biology."


Bob... Ninja Assimilated 

"Coding Cells" can be done in Basic, C++, Java, PPH ????

If they succeed it may be possible to possible to make everyone pain free, or "thought free" depends on who is running the "Deep State" out there in the Moon, Mars and beyond ?
"The Morning Light, No sensation to compare to this, suspended animation, state of bliss, I keep my eyes on the circling sky, tongue tied and twisted just and Earth Bound Martian I" Learning to Fly Pink Floyd [Video:]

In rhw007's last post:

Quote:"As hybrids between biological active fluids  Hi
 and simple man-made materials  Assimilated
I hope they have the potential for autonomously tunable material properties, 
mimicking biological complexity  Horsepoop  
maybe even someday working together with biology."

These tiny robots ... "micro machines" ... have a great potential for ---> systemic  body infection.
You would not want some of the experimental stages of this crap to get into your bloodstream,
the environment in any way.
Morgellon's disease will be nothing compared to what could happen if the wrong "micro machine"
becomes an environmental contaminant.

Quote:These minuscule machines should be able to self-assemble in their biological environments. 

these little machines will be able to draw energy from their surroundings to create and power themselves.

think about those two statements above

Nano-bot flu?
Micro-machines causing joint arthritis?
Brain infections from "self assembled" mini-robots?
Couldn't take a shit today because your poop was clogged with replicating micro machines.



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