Biological Clocks Locked in Sync Scientists from EPFL's Institute of Bioengineering have discovered that the circadian clock and the cell-cycle are, in fact, synchronized. [26] Researchers at the University of Illinois at Chicago have identified a molecular switch that causes immune cells called macrophages to clean up cellular debris caused by infections instead of contributing to inflammation and tissue injury. [25] Working with mouse and human tissue, Johns Hopkins Medicine researchers report new evidence that a protein pumped out of some—but not all—populations of "helper" cells in the brain, called astrocytes, plays a specific role in directing the formation of connections among neurons needed for learning and forming new memories. [24] Researchers from Harvard University and the Broad Institute’s Stanley Centre for Psychiatric Research have developed reproducible brain organoids for the first time. [23] Researchers at the University of Twente have designed a tiny needle in which micro- channels can be used for extracting small liquid samples from a local area of the brain. [22] The ability to grow large protein crystals is the single biggest bottleneck that limits the use of neutron protein crystallography in structural biology. [21] The conclusion that proteins have a terrible conductance tallies well with their general physical characteristics – they lack both electronic conduction bands and high levels of structural order. [20] In their proof-of-concept study, the protein nanowires formed an electrically conductive network when introduced into the polymer polyvinyl alcohol. [19] Nanocages are highly interesting molecular constructs, from the point of view of both fundamental science and possible applications. [18] DNA flows inside a cell's nucleus in a choreographed line dance, new simulations reveal. [17] Chemist Ivan Huc finds the inspiration for his work in the molecular principles that underlie biological systems. [16]
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Biological Clocks Locked in Sync
Scientists from EPFL's Institute of Bioengineering have discovered that the circadian
clock and the cell-cycle are, in fact, synchronized. [26]
Researchers at the University of Illinois at Chicago have identified a molecular switch
that causes immune cells called macrophages to clean up cellular debris caused by
infections instead of contributing to inflammation and tissue injury. [25]
Working with mouse and human tissue, Johns Hopkins Medicine researchers report new
evidence that a protein pumped out of some—but not all—populations of "helper" cells
in the brain, called astrocytes, plays a specific role in directing the formation of
connections among neurons needed for learning and forming new memories. [24]
Researchers from Harvard University and the Broad Institute’s Stanley Centre for
Psychiatric Research have developed reproducible brain organoids for the first time.
[23]
Researchers at the University of Twente have designed a tiny needle in which micro-
channels can be used for extracting small liquid samples from a local area of the brain.
[22]
The ability to grow large protein crystals is the single biggest bottleneck that limits the
use of neutron protein crystallography in structural biology. [21]
The conclusion that proteins have a terrible conductance tallies well with their general
physical characteristics – they lack both electronic conduction bands and high levels of
structural order. [20]
In their proof-of-concept study, the protein nanowires formed an electrically conductive
network when introduced into the polymer polyvinyl alcohol. [19]
Nanocages are highly interesting molecular constructs, from the point of view of both
fundamental science and possible applications. [18]
DNA flows inside a cell's nucleus in a choreographed line dance, new simulations reveal.
[17]
Chemist Ivan Huc finds the inspiration for his work in the molecular principles that
Naturally, the circadian clock takes up a daily rhythm, but it turns out that also the cell cycle in many
systems involves a similar time scale. In addition, there is some evidence that suggests that both
clocks might actually influence each other.
Now, scientists from the lab of Felix Naef have found that the circadian and cell-cycle clocks are
actually synchronized. The breakthrough study is published in Nature Physics, and is also featured on
the journal's News and Views section.
To carry out the study, the scientists developed a "small data" methodology to build and identify
a mathematical model of the coupled clocks from time-lapse movies of thousands of single
cells from mice and humans.
The model allowed them to predict and measure phase shifts when the two clocks were synchronized
in a 1:1 and 1:2 pattern, and then look at how system noise influences this synchronization. Finally,
the researchers investigated as well how it might be modeled in a randomized way ("stochastically"),
which would better capture what happens in real cells.
The synchronization was also found to be remarkably robust against temperature changes, which is
known to affect the cell-cycle clock, changing the rhythm of cell divisions. The team found that this
circadian-cell cycle synchronization is common across different species including human, suggesting a
fundamental biological mechanism behind it.
"This interaction might play a physiological role," says Felix Naef. "It can explain why different body
tissues have their clocks set at slightly different times, a bit like world time zone wall clocks in an
airport."
The implications of the study are significant, and Nature's News & Views describes it as "a new
chapter in the story of how non-linear coupling mechanisms can be of fundamental importance to our
understanding of living systems." [26]
Boosting the anti-inflammatory action of the immune system Researchers at the University of Illinois at Chicago have identified a molecular switch that causes
immune cells called macrophages to clean up cellular debris caused by infections instead of
contributing to inflammation and tissue injury. Their findings are reported in the journal Proceedings
of the National Academy of Sciences.
Macrophages are a type of immune cell found throughout the body. These cells can produce
inflammation, which is good in moderation because inflammatory signals bring other immune
cells to a specific location to clear an infection. However, when inflammation gets out of control, as
it can in cases of inflammatory diseases, it can cause excess cellular and tissue damage, contributing
to a vicious cycle that is very difficult to reverse. But macrophages also play a significant role in
reducing inflammation when they engulf cellular debris or foreign microbes that contribute to
inflammation. The mechanism behind macrophages' ability to switch back and forth between these
two diametrically opposed roles has long-puzzled scientists.
Researchers led by Saroj Nepal, research assistant professor in the department of pharmacology at
the UIC College of Medicine, have found that a molecule called Gas6 is required to induce
macrophages to perform their anti-inflammatory role by engulfing and digesting cellular debris that
can contribute to inflammation. The molecule could serve as a potential drug target for drug makers
interested in coaxing the cells toward their anti-inflammatory state to help treat people.
In a mouse model of acute lung injury, Nepal and colleagues found that lung macrophages expressed
both inflammatory and anti-inflammatory proteins. One of the anti-inflammatory proteins was Gas6.
In a mouse model of acute lung injury where the animals' macrophages were artificially depleted of
Gas6, clearance of inflammatory molecules and proteins in the lungs was severely impaired, and the
inflammation could not be resolved. When they artificially boosted levels of Gas6 in the mouse
macrophages, inflammation was resolved much faster than in mice with normal macrophages.
"Harnessing the anti-inflammatory function of macrophages using the Gas6 switch holds great
potential for treating diseases ranging from heart disease to cancer to rheumatoid
arthritis, where inflammation is a key underlying feature," Nepal said. [25]
Researchers repair faulty brain circuits using nanotechnology Working with mouse and human tissue, Johns Hopkins Medicine researchers report new evidence
that a protein pumped out of some—but not all—populations of "helper" cells in the brain, called
astrocytes, plays a specific role in directing the formation of connections among neurons needed for
learning and forming new memories.
Using mice genetically engineered and bred with fewer such connections, the researchers conducted
proof-of-concept experiments that show they could deliver corrective proteins via nanoparticles to
replace the missing protein needed for "road repairs" on the defective neural highway.
Since such connective networks are lost or damaged by neurodegenerative diseases such
as Alzheimer's or certain types of intellectual disability, such as Norrie disease, the researchers say
their findings advance efforts to regrow and repair the networks and potentially restore normal brain
function.
The findings are described in the May issue of Nature Neuroscience.
"We are looking at the fundamental biology of how astrocytes function, but perhaps have discovered
a new target for someday intervening in neurodegenerative diseases with novel therapeutics," says
Jeffrey Rothstein, M.D., Ph.D., the John W. Griffin Director of the Brain Science Institute and professor
of neurology at the Johns Hopkins University School of Medicine.
"Although astrocytes appear to all look alike in the brain, we had an inkling that they might have
specialized roles in the brain due to regional differences in the brain's function and because of
observed changes in certain diseases," says Rothstein. "The hope is that learning to harness the
individual differences in these distinct populations of astrocytes may allow us to direct brain
features that give rise to the disease. In the future, I envisage we will be able to ask far more precise
questions about what goes wrong in the context of psychiatric illness.” [23]
Miniaturized neuroprobe for sampling neurotransmitters in the brain Researchers at the University of Twente have designed a tiny needle in which micro-channels can be
used for extracting small liquid samples from a local area of the brain. The needle is about as thick as
a human hair. Thanks to this invention, neuroscientists are now able to monitor dynamic processes
more quickly (within a few seconds) and accurately (micrometre precision). The research is to be
published in the renowned scientific journal Lab on a Chip.
The brain is a highly complex system, as a result of which neuroscientists have struggled to answer
such questions as, "Why does one person get a migraine attack, and the other not?"
Doctor Mathieu Odijk of the BIOS lab-on-a-chip group explains, "To answer questions of this kind, it is
important to be able to study in detail how the brain works. A key role in the working of the brain is
played by the chemicals—the neurotransmitters—that carry information. However, most existing
methods for monitoring neurotransmitters in the brain are not able to do so sufficiently quickly or
with such localized precision."
Minute water droplets The small needle that has been designed by Dr. Odijk and his colleagues, which is about as thick as a
human hair, has micro-channels through which tiny samples of liquid from a localized part of the
brain can be extracted. These samples are stored in minute water droplets of around 10 picolitre (one
millionth of a raindrop) in oil. It means the information about neurotransmitters is stored in a kind of
chemical memory, after which it can be processed and from which readings can be taken at a later
time. This invention allows neuroscientists to monitor dynamic processes in the brain within a few
seconds and to micrometre precision. [22]
Methods for large protein crystal growth for neutron protein
crystallography The ability to grow large protein crystals is the single biggest bottleneck that limits the use of neutron
protein crystallography in structural biology. Protein crystals need to have volumes in the region of at
least 0.1mm3. Theoretically there is no particular reason why crystals of this size cannot be grown. If
they can be, neutron protein crystallography can provide crucial information on the location of
hydrogen atoms details relating to hydration hydrogen bonding and ligand interactions. This type of
information is of direct relevance to academic and pharmacologically driven research in the life
sciences.
The challenge is thus to achieve large crystal growth in a reproducible, time-saving, labour-saving
way. It would be ideal if in the future, neutron crystallographers can, after suitable pre-
characterisation work, submit their solutions to an automated or semi-automated platform that
would allow the exploration of a large range of conditions in a highly systematic way and to allow
users to monitor growth from their remote computers.
Ashley Jordan at the Institut Laue-Langevin (ILL) in Grenoble, France, has been investigating two new
crystal growth methods: the development of a module that could allow larger scale automated
approaches in the future (task 1), and a flow crystallization system (task 2).
Task 1: A module for automated large crystal growth exploration This SINE2020 project has focused on the development of a temperature controllable multi-well
module in which crystal growth can be optimized. The idea of designing this module was to scale up
the approach so that multiple crystallization wells with individual (programmable) temperature
control could be used to explore a wide range of growth conditions. A prototype module was made
that consisted of a custom plate design containing 6 × 4 wells where the individual crystallisation
experiments can occur. Each well can be adapted to different conditions, with each having
independent temperature control. The wells are heated using Peltier heating elements with a
temperature feedback system that allows each well to be heated and cooled over a temperature
range of 4 degrees C to 60 degrees C, with an accuracy of 0.1 degree. The set-up was designed to
allow allow crystal growth to be monitored and recorded photographically.
Ashley Jordan, Ryo Mizuta and John Allibon (who developed the software) have built and tested the
prototype system. Crystallization tests have been carried out using trypsin and rubredoxin.
Post-SINE2020, the idea would be to make these modules "plug and play" so that a more extended
'robotic' approach could be used. Crystallogenesis runs could be removed by the user on completion
and other runs installed using another module – the module would be the working unit of a larger
array – with all being camera visualisable and providing time-lapse information to a user portal.
Task 2: Flow crystallization Another way of pursuing large crystal growth is the idea of a flow crystallization system. The idea is to
maintain steady-state batch conditions around a crystal at all times during its growth, by providing a
constant supply of fresh protein stock to the crystallization environment. This will maintain optimal
solution conditions at all times and help minimize accumulation of impurities on crystal surfaces –
such impurities may hinder crystal growth.
A Dolomite Mitos P-Pump was chosen to maintain the extremely low flow rate (between 70-1500 nl
min-1) required to regulate the system. A suitable crystallization chamber that can connect to the
pump was designed and made using a 3-D printer. This chamber creates a sealed environment and
provides ready access to the crystals once they have grown. [21]
STM measurements redefine protein conductances
“Properly connected, proteins are the world’s best molecular wires,” says Stuart Lindsay,
Director and Professor at the Biodesign Center for Single Molecule Biophysics at Arizona State
University (ASU). His comments refer to recent experiments at ASU to measure the conductance of
single proteins between electrodes for the first time with what he describes as “staggering” results
means that by pulling on one piece of DNA, it must hold onto and pull something else. The two
inward-pulling forces will cancel, giving zero net force and causing the DNA segment to contract. If
the machine instead pushes outward, the forces will similarly cancel, and the DNA segment will
extend.
These contractions and extensions take place within a gooey liquid that fills a cell's nucleus. The
movement of the DNA generates a flow in the liquid that can reorient nearby lengths of molecules.
Using computer simulations, the researchers modeled how contraction and extension affected a
jumble of chromatin confined within a spherical nucleus. When the lengths of DNA contracted, the
resulting flow pointed nearby strands in a different direction, blocking any choreographed
movements. Extension created streams of fluid that aligned nearby DNA in the same direction. That
alignment resulted in a cascading effect that shifted large patches of DNA in the same direction.
"It's like part of the nucleus suddenly decides that we're all going to move over this way a little, then
another bit says we're all going to move over this way," Shelley says. "The chromatin sort of wanders
around."
This DNA shimmy could help distribute throughout the nucleus the molecular machinery responsible
for expressing a particular gene, Shelley proposes. Finding out for sure, he says, will require more
complex simulations as well as additional experiments into how chromatin cuts a rug. [17]
Biomimetic chemistry—DNA mimic outwits viral enzyme Not only can synthetic molecules mimic the structures of their biological models, they can also take
on their functions and may even successfully compete with them, as an artificial DNA sequence
designed by Ludwig-Maximilians-Universitaet (LMU) in Munich chemist Ivan Huc now shows.
Chemist Ivan Huc finds the inspiration for his work in the molecular principles that underlie biological
systems. As the leader of a research group devoted to biomimetic supramolecular chemistry, he
creates 'unnatural' molecules with defined, predetermined shapes that closely resemble the major
biological polymers, proteins and DNA found in cells. The backbones of these molecules are referred
to as 'foldamers' because, like origami patterns, they adopt predictable shapes and can be easily
modified. Having moved to LMU from his previous position at Bordeaux University last summer, Huc
has synthesized a helical molecule that mimics surface features of the DNA double helix so closely
that bona fide DNA-binding proteins interact with it.
This work is described in a paper published in Nature Chemistry. The new study shows that the
synthetic compound is capable of inhibiting the activities of several DNA-processing enzymes,
including the 'integrase' used by the human immunodeficiency virus (HIV) to insert its genome into
that of its host cell. The successful demonstration of the efficacy of the synthetic DNA mimic might
lead to a new approach to the treatment of AIDS and other retroviral diseases.
The new paper builds on advances described in two previous publications in Nature
Chemistry published earlier this year. In the first of these papers, Huc and his colleagues developed a
pattern of binding interactions required to enable synthetic molecules to assume stable forms
similar to the helical backbones of proteins. In the second, they worked out the conditions required to
append their synthetic helix to natural proteins during synthesis by cellular ribosomes. "As always in
biology, shape determines function," he explains. In the new study, he introduces a synthetic
molecule that folds into a helical structure that mimics surface features of the DNA double helix, and
whose precise shape can be altered in a modular fashion by the attachment of various substituents.
This enables the experimenter to imitate in detail the shape of natural DNA double helix, in particular
the position of negative charges. The imitation is so convincing that it acts as a decoy for two DNA-
binding enzymes, including the HIV integrase, which readily bind to it and are essentially inactivated.
However, the crucial question is whether or not the foldamer can effectively compete for the
enzymes in the presence of their normal DNA substrate. "If the enzymes still bind to the foldamer
under competitive conditions, then the mimic must be a better binder than the natural DNA itself,"
Huc says. And indeed, the study demonstrates that the HIV integrase binds more strongly to the
foldamer than to natural DNA. "Furthermore, although initially designed to resemble DNA, the
foldamer owes its most useful and valuable properties to the features that differentiate it from DNA,"
Huc points out.
Thanks to the modular nature of foldamer design, the structures of these artificial DNA mimics can be
readily altered, which enables a broad range of variants to be produced using the same basic
platform. In the current study, Huc and his colleagues have focused on enzymes that are generically
capable of binding to DNA, irrespective of its base sequence. However, it may also be possible to use
the foldamer approach to develop DNA mimics that can block the action of the many important DNA-
binding proteins whose functions depend on the recognition of specific nucleotide sequences. [16]
Simulations document self-assembly of proteins and DNA What makes particles self-assemble into complex biological structures? Often, this phenomenon is
due to the competition between forces of attraction and repulsion, produced by electric charges in
various sections of the particles. In nature, these phenomena often occur in particles that are
suspended in a medium—referred to as colloidal particles—such as proteins, DNA and RNA. To
facilitate self-assembly, it is possible to "decorate" various sites on the surface of such particles with
different charges, called patches.
In a new study published in EPJE, physicists have developed an algorithm to simulate the molecular
dynamics of these patchy particles. The findings published by Silvano Ferrari and colleagues from the
TU Vienna and the Centre for Computational Materials Science (CMS), Austria, will improve our
understanding of what makes self-assembly in biological systems possible.
In this study, the authors model charged patchy particles, which are made up of a rigid body with only
two charged patches, located at opposite poles. They then develop the equations governing the
dynamics of an ensemble of such colloidal patchy particles.
Based on an existing approach originally developed for molecular particles, their simulation includes
additional constraints to guarantee that the electrical charge "decorations" are preserved over time.
In this regard, they develop equations for describing the particles' motion; the solutions to these
palladium. By switching a light on and off, they were able to control the speed at which two different
monomers, styrene and vinyl ether, become part of a polymer chain. When exposed to light, the
styrene monomer was found to be incorporated into the copolymer structure much more rapidly
than in the dark, resulting in a single copolymer chain with different compositions along its length.
Parts that are rich in styrene are more rigid than those rich in vinyl ether; by using different
on/off light sequences, they could create polymers with a range of physical properties e.g. different
"glass transition" temperatures, above which the polymer becomes softer.
The newly developed process is significantly simpler than existing methods. The team also found that
both types of monomer were built into the polymer via a mechanism known as non-radical
coordination-insertion; this is a generic mechanism, meaning that this new method might be applied
to make polymers using a wide range of catalysts and monomers, with the potential to overcome the
limited availability of monomer candidates. [13]
Artificial and biological cells work together as mini chemical factories Researchers have fused living and non-living cells for the first time in a way that allows them to work
together, paving the way for new applications.
The system, created by a team from Imperial College London, encapsulates biological cells within
an artificial cell. Using this, researchers can harness the natural ability of biological cells to process
chemicals while protecting them from the environment.
This system could lead to applications such as cellular 'batteries' powered by photosynthesis,
synthesis of drugs inside the body, and biological sensors that can withstand harsh conditions.
Previous artificial cell design has involved taking parts of biological cell 'machinery' - such as enzymes
that support chemical reactions - and putting them into artificial casings. The new study, published
today in Scientific Reports, goes one step further and encapsulates entire cells in artificial casings.
The artificial cells also contain enzymes that work in concert with the biological cell to produce new
chemicals. In the proof-of-concept experiment, the artificial cell systems produced a fluorescent
chemical that allowed the researchers to confirm all was working as expected.
Lead researcher Professor Oscar Ces, from the Department of Chemistry at Imperial, said: "Biological
cells can perform extremely complex functions, but can be difficult to control when trying to harness
one aspect. Artificial cells can be programmed more easily but we cannot yet build in much
complexity.
"Our new system bridges the gap between these two approaches by fusing whole biological cells with
artificial ones, so that the machinery of both works in concert to produce what we need. This is a
paradigm shift in thinking about the way we design artificial cells, which will help accelerate research
histone from the DNA. This process determines whether or not genes in specific parts of the DNA can
be read. Both proteins are involved in several regulatory processes in the body, such as cell division
and proliferation, and therefore also play a role when it comes to a number of diseases, including
cancer. Ben Schuler, professor at the Department of Biochemistry at UZH and head of the research
project published in Nature, says, "The interesting thing about these proteins is that they're
completely unstructured—like boiled noodles in water." How such disordered proteins should be able
to interact according to the key/lock principle had puzzled the team of researchers.
Notably, the two proteins bind to one another much more strongly than the average protein partners.
The research team used single-molecule fluorescence and nuclear magnetic
resonance spectroscopy to determine the arrangement of the proteins. Observed in isolation, they
show extended unstructured protein chains. The chains become more compact as soon as both
binding partners come together and form a complex. The strong interaction is caused by the strong
electrostatic attraction, since histone H1 is highly positively charged while prothymosin α is highly
negatively charged. Even more surprising was the discovery that the protein complex was also fully
unstructured, as several analyses confirmed.
To investigate the shape of the protein complex, the researchers labeled both proteins with
fluorescent probes, which they then added to selected sites on the proteins. Together with computer
simulations, this molecular map yielded the following results: Histone 1 interacts with prothymosin α
preferably in its central region, which is the region with the highest charge density. Moreover, it
emerged that the complex is highly dynamic: The proteins' position in the complex changes extremely
quickly—in a matter of approx. 100 nanoseconds.
The interaction behavior is likely to be fairly common. Cells have many proteins that contain highly
charged sequences and may be able to form such protein complexes. There are hundreds of such
proteins in the human body alone. "It's likely that the interaction between disordered, highly charged
proteins is a basic mechanism for how cells function and organize themselves," concludes Ben
Schuler. According to the biophysicist, textbooks will need revision to account for this new way of
binding. The discovery is also relevant for developing new therapies, since unstructured proteins are
largely unresponsive to traditional drugs, which bind to specific structures on the protein surface. [11]
Particles in charged solution form clusters that reproduce Dr Martin Sweatman from the University of Edinburgh's School of Engineering has discovered a simple
physical principle that might explain how life started on Earth.
He has shown that particles that become charged in solution, like many biological molecules, can
form giant clusters that can reproduce. Reproduction is shown to be driven by simple physics—a
balance of forces between short-range attraction and long-range repulsion. Once
cluster reproduction begins, he suggests chemical evolution of clusters could follow, leading
[9] Experiment demonstrates quantum mechanical effects from biological systems https://phys.org/news/2017-12-quantum-mechanical-effects-biological.html
[10] Particles in charged solution form clusters that reproduce https://phys.org/news/2017-12-particles-solution-clusters.html
[11] New interaction mechanism of proteins discovered https://phys.org/news/2018-02-interaction-mechanism-proteins.html
[12] Artificial and biological cells work together as mini chemical factories https://phys.org/news/2018-03-artificial-biological-cells-mini-chemical.html
[13] Custom sequences for polymers using visible light https://phys.org/news/2018-03-custom-sequences-polymers-visible.html
[14] Scientists explore the structure of a key region of longevity protein telomerase
[17] DNA 'dances' in first explanation of how genetic material flows through a nucleus https://phys.org/news/2018-10-dna-explanation-genetic-material-nucleus.html
[18] Nanocages in the lab and in the computer: how DNA-based dendrimers transport nanoparticles https://phys.org/news/2018-10-nanocages-lab-dna-based-dendrimers-nanoparticles.html
[19] Scientists make new 'green' electronic polymer-based films with protein nanowires https://phys.org/news/2018-10-scientists-green-electronic-polymer-based-protein.html
[20] STM measurements redefine protein conductances
[21] Methods for large protein crystal growth for neutron protein crystallography https://phys.org/news/2019-03-methods-large-protein-crystal-growth.html
[22] Miniaturized neuroprobe for sampling neurotransmitters in the brain