Biomolecular machines

[Phronesis]

DNA repair mechanisms relocate in response to stress

Like doctors making house calls, some DNA repair enzymes can relocate to the part of the cell that needs their help, a collaborative team of scientists at Emory University School of Medicine has found.

The signal that prompts relocation is oxidative stress, an imbalance of cellular metabolism connected with several human diseases.

The study integrated the expertise of three Emory groups and resulted in a new level of understanding of the cell's response to genetic damage. The finding could lead to new targets for anti-cancer drugs that interfere with DNA repair, says Paul Doetsch, PhD, professor of biochemistry, radiation oncology, and hematology and oncology at Emory University School of Medicine.

The results were published in the February 1 issue of Molecular and Cellular Biology. The journal's editors chose an image of yeast cells with fluorescent DNA repair enzymes for the cover.

"DNA damage and oxidative stress are very closely related," Doetsch says. "For example, the way radiation inflicts most of its damage on DNA is through oxidative stress. The more we know about how cells respond to oxidative stress, the more chances there could be to influence those responses for diagnostic or therapeutic purposes."

The DNA inside cells is continually under assault by heat, radiation and oxygen. Cells have an extensive set of repair enzymes that comb through DNA, continually excising and re-copying damaged segments. To complicate matters, mitochondria (cells' miniature power plants) have their own DNA.

Working with Doetsch, Emory graduate students Lyra Griffiths and Dan Swartzlander, and biochemists Anita Corbett and Keith Wilkinson, genetically modified strains of yeast so that two different DNA repair enzymes would be fluorescent. They were able to follow the enzymes around the cell when yeast was exposed to hydrogen peroxide, causing oxidative stress, or to other chemicals causing DNA damage.

One DNA repair enzyme they studied, Ntg1, moves to the nucleus or the mitochondria depending on where DNA damage is concentrated, the authors found. In contrast, a related enzyme, Ntg2, stays in the nucleus under all conditions.

Cells appear to direct Ntg1's relocation by briefly attaching a small protein called SUMO to what needs to be moved around, the authors found. SUMO is found in fungi, plants and animals and is already being investigated by several research groups as a possible target for anti-cancer drugs.

Bacteria have similar endonucleases. Here is the structure of the enzyme caught in the act of repair:

Structure 1p59​

 

[Phronesis]

A splice of life
Groundbreaking study reveals intermediary steps of genetic encoding for the first time.

Waltham, MA—In a new study this week in Nature, researchers at Brandeis University and the MRC Laboratory of Molecular Biology (Cambridge, U.K.) for the first time shed light on a crucial step in the complex process by which human genetic information is transmitted to action in the human cell and frequently at which point genetic disease develops in humans.

The scientists report that they were able to crystallize a very large complex of a macromolecular "machine" in the human cell and determine its structure or what it actually looks like, thereby zeroing in on the process of genetic encoding. Importantly, 15 to 20 percent of all human genetic disorders, including muscular dystrophy, are caused by defects in this genetic encoding process known as RNA splicing.

Using x-ray crystallography, the scientists for the first time were able to create a three-dimensional structure of an integral complex of the human spliceosome, which consists of specialized RNA and protein subunits. The spliceosome's job is to modify the message relayed from our genetic material—DNA—by clipping, or splicing, genetic bits in such a manner that they are acceptable for translation into protein. Importantly, the spliceosome also rearranges the genetic bits of the message in such a way that it can generate multiple and varied proteins which can and do have dramatic effects on human development, said lead author and Brandeis biochemist Daniel Pomeranz Krummel.

"The process of RNA splicing is vital to human cell development and survival," said Pomeranz Krummel. "In this process, the regions of our DNA encoding for protein are removed from non-encoding regions and brought together—quite often in alternative arrangements. Defects in this process can have disasterous repercussions in the form of genetic disorders," said Pomeranz Krummel, adding that neuronal development can be particularly affected when things go awry. Indeed, defects in this process have recently been implicated in various human neurological disorders, including epilepsy.

Specifically, this macromolecular machine clips, or splices, gene sequences transcribed as part of a precursor to the mRNA, removing them before the final mRNA product is translated into protein. The spliceosome must clip these sequences, known as introns, at the right place in the precursor mRNA.

"In human cells one gene can be made into a variety of proteins, so if the process just goes slightly wrong, the genetic alteration can lead to incredible disaster; yet on the other hand, this incredible complexity has led to our amazing evolutionary progress," said Pomeranz Krummel. "The human genome is not terribly different from the earthworm's with regards to its size, but the process of RNA splicing that occurs in our cells is different. The fundamental difference between us and the earthworm is that our cells have evolved to utilize this process of RNA splicing to generate a whole other dimension to the transmission of genetic information."

Pomeranz Krummel's lab will next focus on understanding how this complex interacts with other macromolecular machines in the human cell. The study was funded by the Medical Research Council (U.K.) and the Human Frontier Science Program.

Nice article about the RNA splicing machinery: Possibly the most complex macromolecular machine in the cell.

Good video to give an idea of the process.

The process is exquisitely controlled.

 

[Phronesis]

Cell cycling and DNA repair mechanisms​

Key Decision-point At Which Cells With Broken DNA Repair Themselves Or Die Identified
Journal reference:
1. Navasona Krishnan, Dae Gwin Jeong, Suk-kyeong Jung, Seong Eon Ryu, Andrew Xiao, C. David Allis, Seung Jun Kim, and Nicholas K. Tonks. Dephosphorylation of the C-terminal tyrosyl residue of the DNA damage-related histone H2A.X is mediated by the protein phosphatase Eyes Absent (EYA). Journal of Biological Chemistry, April 7, 2009 DOI: 10.1074/jbc.C900032200

Proteins of interest:
1) Eyes Absent (EYA). Involved in development of eyes, present way before the emergence of eye.
2) Histone H2A.X. New protein.

Cell signaling control​

New Insight Into An Old Reaction: Adenylylation Regulates Cell Signaling

ScienceDaily (Apr. 17, 2009) — A new study reveals the importance of adenylylation in the regulation of cell signaling from bacteria to higher organisms. The research, published in the April 10th issue of the journal Molecular Cell, provides new insight into bacterial pathogenesis and opens intriguing avenues for exploring post-translational modifications in eukaryotic cells.

Present in those simple nano-intentional critters: Bacteria.

DNA synthesis​

It does not "just happen" by chance. It is controlled.
New Chemical Reaction For DNA Production In Bacteria And Viruses Discovered

ScienceDaily (Apr. 17, 2009) — A team of researchers has discovered a new chemical reaction for producing one of the four nucleotides, or building blocks, needed to build DNA. The reaction includes an unusual first step, or mechanism, and unlike other known reactions that produce the DNA building block, uses an enzyme that speeds up, or catalyzes, the reaction without bonding to any of the compounds, or substrates, in the reaction.

The chemical reaction discovered by the researchers uses an enzyme called flavin-dependent thymidylate synthase, or FDTS. The enzyme is coded by the thyX gene and has been found primarily in bacteria and viruses, including several human pathogens and biological warfare agents. In the future, scientists may use this knowledge for the development of new antibacterial and antiviral drugs.

Supported with partial funding from the National Science Foundation (NSF) and led by Amnon Kohen, an associate professor in the departments of chemistry and molecular and cellular biology at the University of Iowa, the team reports their findings in the April 16, 2009, issue of Nature, Letters section.

Prior to the team's discovery, it was thought that thymidylate synthase, or TS, was the primary enzyme catalyzing a reaction that produced one of the four DNA building blocks called deoxy-thymidine monophosphate.

The TS enzyme is coded by the thyA and TYMS genes and is present in most multi-cellular forms of life, including humans.

Both the new and classical enzymatic reactions complete a key step in producing the DNA building block by adding a methyl group--one carbon atom attached to three hydrogen atoms--to the building block's precursor molecule called deoxy-uridine monophosphate, or dUMP.

Even though both reactions accomplish this key step, the reaction mechanisms, or steps, catalyzed by the FDTS and TS enzymes are structurally different.

Amnon Kohen, associate professor of chemistry in the UI College of Liberal Arts and Sciences, said that the study indicated a new mechanism by which certain organisms manufacture the DNA base thymidylate. This new mechanism is so very different from the way humans synthesize this base that drugs targeting this biosynthetic path in the pathogens are unlikely to affect the human path, thus resulting in very reduced side effects or no side effects at all.

Kohen suggested that the process is similar to feeding the "bad bugs" a poison that your own body's cells don't eat.

Kohen and his team identified these differences using a traditional chemical method labeled isotopic substitution and a contemporary form of mass spectrometry using electron spray ionization. In particular, the team identified that the first step of the FTDS-catalyzed reaction involves the transfer of a proton and two electrons, known as a hydride, from a flavin co-factor molecule to dUMP whereas the first step of the TS-catalyzed reaction involves an amino acid from the enzyme's active site forming a bond with dUMP.

"This work nicely illustrates how chemists using traditional techniques and contemporary instrumentation methods can make substantial contributions to important and interesting problems in biology," said Charles Pibel, a program director in NSF's Division of Chemistry.

Since the two chemical reaction mechanisms used for the production of the DNA building block, and therefore DNA, are structurally different in humans and bacteria and viruses, and the enzymes used to catalyze the chemical reactions are different, the researchers' findings may assist with the development of structure-based antibiotics and antiviral drugs that selectively inhibit the activity of FDTS enzymes with little effect on TS enzymes--thereby combating pathogens causing anthrax, tuberculosis, botulism, syphilis, pneumonia, Lyme disease and other human diseases without interfering with human DNA synthesis.

"The proposed new catalytic path of the FDTS enzyme appears to be so very different from that of the classical TS enzyme that we hope that specific inhibitors against it will have little effect on DNA production in humans and thus may lead to development of new drugs with low toxicity. Also, some aspects of the proposed chemistry are not common in enzymology or biological chemistry in general, making the future testing of this mechanism very interesting and of potential broader impact," said Kohen.

 

[Phronesis]

More machines
Stop-gap DNA Repair Needs A Second Step

ScienceDaily (May 5, 2009) — One can have a dream, two can make that dream so real, goes a popular song. Now a Weizmann Institute study has revealed that it takes two to perform an essential form of DNA repair.

The intricate process of DNA repair in order TO prevent excessive DNA damage but not perfect in order to allow adaptation can be looked up in a little detail here.
Nice video (among others)
These researchers just discovered another step in the process.

More about cell transcription and linking it to epigentics (histone modification etc.)
Key Function In Protein, Cell Transcription Identified

ScienceDaily (May 4, 2009) — When cells decide to make proteins, key building blocks of all organisms, they need to know where to start reading the instructions for assembling them.

An Iowa State University researcher has figured out a mechanism involved in marking where these instructions are located in a cell's DNA.

In the current edition of The Journal of Biological Chemistry, Michael Shogren-Knaak, assistant professor in biochemistry, biophysics and molecular biology, along with Shanshan Li, a graduate student in his lab, show how a protein, Gcn5, is involved in this process.

When a portion of the Gcn5 protein recognizes chemically modified proteins associated with DNA, called histones, this recognition facilitates further chemical modification of the histones.

This allows the information contained in that DNA, or genes, to be read more efficiently.

"This is very important in normal cell development from single cell organisms to us (humans)," said Shogren-Knaak.

Understanding how DNA is read should shed light on diseases where DNA is often inappropriately read.

"This is very likely to be significant for diseases like cancer," said Shogren-Knaak.

"Cancer is distinguished by containing a lots of genes that should be turned off but aren't, and by proteins that should be made but aren't," he said. "That leads to cells that grow in an uncontrolled and undesirable manner."

Oh, and junk DNA, well, it is a nonsense idea anyway...
What Regulates MicroRNAs? When Cells Reach Out And Touch

ScienceDaily (May 3, 2009) — MicroRNAs are single-stranded snippets that, not long ago, were given short shrift as genetic junk. Now that studies have shown they regulate genes involved in normal functioning as well as diseases such as cancer, everyone wants to know: What regulates microRNAs?

“All evidence points to the fact that physical contact -- when cells actually touch each other -- is the critical factor that revs up the production of microRNAs,” Mendell says. “Through additional experiments, we were able to identify the specific molecular steps at which microRNA production is affected. We expect that this phenomenon will profoundly influence how cells behave in normal development and disease.”

The team’s finding has practical importance for researchers who are investigating a range of biological processes that are most conveniently studied in cells growing in culture, Mendell says: “Little did we know the manufacture of microRNAs was so potently influenced simply by growing cells to different densities. We now recognize that this is a critical parameter that must be closely monitored when performing experiments with microRNAs in tissue culture.

And then there are dancing machines .
Scientists Discover 'Dancing' Algae

ScienceDaily (Apr. 30, 2009) — Scientists at the Cambridge University have discovered that freshwater algae can form stable groupings in which they dance around each other, miraculously held together only by the fluid flows they create.

How about designing compounds that can take advantage of evolutionary processes of optimization:
Evolution In A Test Tube: Scientists Make Molecules That Evolve And Compete, Mimicking Behavior Of Darwin's Finches

ScienceDaily (Apr. 30, 2009) — A group of scientists at The Scripps Research Institute has set up the microscopic equivalent of the Galapagos Islands—an artificial ecosystem inside a test tube where molecules evolve to exploit distinct ecological niches, similar to the finches that Charles Darwin famously described in "The Origin of Species" 150 years ago.

So, syringes are useful tools. been there long before we designed them though...
Details Of Bacterial 'Injection' System Revealed

ScienceDaily (Apr. 29, 2009) — New details of the composition and structure of a needlelike protein complex on the surface of certain bacteria may help scientists develop new strategies to thwart infection.

The different modes of cells... exquisitely controlled to adapt to the environment...
Computational Biology Illuminates How Cells Change Gears

ScienceDaily (Apr. 27, 2009) — Bioinformatics researchers from UC San Diego just moved closer to unlocking the mystery of how human cells switch from "proliferation mode" to "specialization mode." This computational biology work from the Jacobs School of Engineering's bioengineering department could lead to new ideas for curbing unwanted cell proliferation—including some cancers.

Resilient and Redundant

Based on the new research, it appears that the network of transcription factors from the human myeloid leukemia cell line is redundant and resilient, explained Ravasi.

The researchers turned-off or "knocked down" 52 transcription factors, one at a time, in order to study their individual role within the network. Most of the single knock-downs did not result in changes to cell differentiation or cell shape.

"The transcriptional network for this cell type appears quite redundant which likely makes the network resilient to mutations or environmental agents that could interfere with transcription factor function," said Ravasi. "My guess is that we will find similar redundancy in the transcription networks of other cell lines, and in the transcription networks that regulate other aspects of cell function, but we can't say that from these data."

Resiliency and redundancy... signs of an optimal system?

 

[Phronesis]

DNA replication is not perfect.... or is it perfect in order to allow variation for adaptation?
Chromosome Breakpoints Contribute To Genetic Variation

ScienceDaily (Apr. 27, 2009) — A new study reveals that – contrary to decades of evolutionary thought – chromosome regions that are prone to breakage when new species are formed are a rich source of genetic variation.

The functions of genes found in these “breakpoint regions” differ significantly from those occurring elsewhere in the chromosomes. This suggests that chromosomal organization plays an important evolutionary role, the researchers report.

The study, published in the journal Genome Research, is the first to show that different parts of chromosomes can have very different evolutionary histories, said University of Illinois animal sciences professor Harris Lewin, who led the research. Lewin directs the Institute for Genomic Biology and is part of an international team that sequenced the cow genome.

"Our results demonstrate that chromosome breakage in evolution is non-random and that the breakpoint regions and the more stable regions of chromosomes are evolving in distinctly different ways,” he said.

When egg or sperm cells form in animals, maternal and paternal chromosomes first pair up and then recombine. The chromosomes literally break and reattach to one another. In most cases, the new chromosomes have the same arrangement of genes as the parent cells, but with new combinations of maternal and paternal genes.

The “crossing over” of segments of maternal and paternal chromosomes to form hybrid chromosomes has long been acknowledged as a driver of genetic variation.

Sometimes, however, the wrong chromosomes recombine, segments of chromosomes become inverted or complete breakages and fissions occur. These rearrangements may lead to genetic diseases or may contribute to the development of new species.

Until now, scientists have been unable to determine how the organization of genes along chromosomes and variation within the breakpoint regions contribute to the evolution of an organism’s genome, Lewin said. Breakages sometimes disrupt genes or gene families that are regulated together, for example. Deletions, insertions and inversions can cause subtle or dramatic changes in how the genes function.

Scientists once hypothesized that chromosomal breakage and recombination occurred randomly along the chromosomes during evolution. But in 2003, a team from the University of California at San Diego and the Lewin laboratory reported that the breakpoints occurred more often in specific chromosomal regions than in others.

In 2004, Lewin and his colleagues reported a surprising finding: Breakpoint regions also contain a higher density of genes than other parts of the chromosome. In 2005, Lewin’s team showed that breakpoint regions also have higher numbers of segmental duplications, a type of mutation that increases the copy number of genes and the sequences that flank them.

“To me, this was completely counterintuitive. I thought we would have these breakpoints in gene deserts,” Lewin said. “We had to rethink the whole evolutionary hypothesis about what was going on in breakpoints.”

In the new study, Denis Larkin, a senior scientist on Lewin’s team, compared the chromosomes of nine mammals (human, chimp, macaque, rat, mouse, pig, cattle, dog, opossum) and a chicken. He found that the breakpoint regions contained many more copy number variants, insertions and deletions in their sequences than the other parts of the chromosomes. Such variations appear to make these regions more susceptible to breakage, Lewin said. (The chromosome analysis was facilitated by Evolution Highway, a powerful software tool developed in collaboration with Michael Welge and Loretta Auvil at the National Center for Supercomputing Applications at the University of Illinois.)

The researchers also found that different classes of genes appear in the breakpoint and break-resistant regions of chromosomes. Those in the breakpoint regions code for proteins involved in immunity and muscle contraction, for example. Rearrangements may cause copies of such genes to increase or change the way they are regulated. These new sources of variation may then be subject to natural selection, the mechanism of evolution proposed by Charles Darwin.

The genes in more stable parts of the chromosomes are involved in growth and development, particularly embryonic development. Disruptions to these genes would probably be harmful to the organism as a whole, Lewin said.

“If the chromosome rearrangement is really bad for the organism, it will be eliminated. It won’t survive,” he said. “So if something persists in the genome, it generally has to either be neutral, or it has to be of some benefit.”

Evolutionary biologists have historically focused on small changes in the genome – such as point mutations or the insertion of viral genes – that sometimes lead to the development of new forms, Lewin said.

“But by overlooking the importance of chromosome rearrangements, these earthquakes in the genome, they may have missed a key component of the mechanism for generating the variation used by natural selection,” he said.

Controlled variation....

More on the highly controlled processes in cells that ensures the productions of high fidelity components...
Recycler Protein Helps Prevent Disease

ScienceDaily (May 1, 2009) — Recycling is important not only on a global scale, but also at the cellular level, since key molecules tend to be available in limited numbers. This means a cell needs to have efficient recycling mechanisms. Researchers at the European Molecular Biology Laboratory (EMBL) and Heidelberg University, Germany, have now uncovered the first step in the recycling of a crucial molecular tag which ensures the instructions encoded in our genes are correctly carried out.

And a little more about calcium signalling... that molecule found in milk (not only)

How Cells Function: Missing Target For Calcium Signaling Identified

ScienceDaily (Apr. 29, 2009) — An international study led by Ohio State University neuroscience researchers describes one of the missing triggers that controls calcium inside cells, a process important for muscle contraction, nerve-cell transmission, insulin release and other essential functions.

 

[Phronesis]

Gotta love the name of this protein:
How An Enzyme Tells Stem Cells Which Way To Divide

ScienceDaily (May 13, 2009) — Driving Miranda, a protein in fruit flies crucial to switch a stem cell's fate, is not as complex as biologists thought, according to University of Oregon biochemists. They've found that one enzyme (aPKC) stands alone and acts as a traffic cop that directs which roads daughter cells will take.

aPKC is shown in green at the top half of a fruit fly neuroblast. Miranda, in blue, has been driven away to the opposite side. Upon division,
the top half will remain a stem cell, while the bottom will become a differentiated cell. (Credit: Courtesy of Kenneth Prehoda)​

 

[Phronesis]

A little more information about ATP synthase. The smallest and most efficient rotary engine.
Video

Torque generation and elastic power transmission in the rotary FOF1-ATPase

Makes this machine look a little archaic.

But, for it to be formed, other machines fold the proteins into the correct conformation. Chaperones and other quality control systems.
And for it to function, it needs an energy gradient that is supplied by protons generated in part by the the bc1-complex through a bifurcated electron transfer mechanism.

But this machine pales in comparison to the RNA splicing machinery: Possibly the most complex macromolecular machine in the cell. More here.

 

[Palimino]

DNA repair mechanisms relocate in response to stress



Bacteria have similar endonucleases. Here is the structure of the enzyme caught in the act of repair:

Structure 1p59​

I didn’t read all the posts in the thread (it’s very long) so this may have been posted before. A seminal work I believe would be the doctorate of Dr. Eric Drexler (unusual in that there was no-one [on the planet] competent to supervise it). An enabling technology was identified as chemistry (crude, brute-force method) and the medical field was identified as an area which may provide funding. There is some clever stuff in it. IMO one of the most enlightened Obama decisions was to remove Bush’s veto on stem cell research. Onward!

 

[Phronesis]

I didn’t read all the posts in the thread (it’s very long) so this may have been posted before. A seminal work I believe would be the doctorate of Dr. Eric Drexler (unusual in that there was no-one [on the planet] competent to supervise it). An enabling technology was identified as chemistry (crude, brute-force method) and the medical field was identified as an area which may provide funding. There is some clever stuff in it. IMO one of the most enlightened Obama decisions was to remove Bush’s veto on stem cell research. Onward!

Dr Drexler's work sure is interesting. I am however unsure how Obama's decision on stem cell research is related to nanotechnology and molecular machines. Embryos are not needed for stem cell research btw .

 

[Palimino]

Dr Drexler's work sure is interesting. I am however unsure how Obama's decision on stem cell research is related to nanotechnology and molecular machines. Embryos are not needed for stem cell research btw .

Drexler is primarily a nanotechnology fundi. But he has identified molecular machines (and chemistry) as an enabling (intermediate) step towards mature nanotechnology. Maybe embryos are no longer needed for stem cell research, but it goes towards the **climate** of stem cell research. A bit of a drag when ignorant religious fundamentalists burn-down your research facility because “You are interfering with God’s plan – the evil facility will be cleansed by fire and the spawns of Satan who work there will be killed”. “We are the Hammer of the Lord. Hallelujah!”

 

[Phronesis]

Facilities were burned down? Where? Please discuss these burnings in their appropriate thread, thanks.

 

[Palimino]

Facilities were burned down? Where? Please discuss these burnings in their appropriate thread, thanks.

A chanting mob of fundamentalists does not bode well. If **I** (not you) perceive something as relevant I will post it. What is the relevant thread? Is their a thread dedicated to the burning-down of facilities by religious morons?

 

[Phronesis]

A chanting mob of fundamentalists does not bode well. If **I** (not you) perceive something as relevant I will post it.
What is the relevant thread? Is their a thread dedicated to the burning-down of facilities by religious morons?

Can you honestly say to yourself

"A bit of a drag when ignorant religious fundamentalists burn-down your research facility because “You are interfering with God’s plan – the evil facility will be cleansed by fire and the spawns of Satan who work there will be killed”. “We are the Hammer of the Lord. Hallelujah!”

is relevant to:

"A thread to lump together all the interesting discoveries regarding the intracellular biomolecular machinery that are crucial for life to exist. Feel free to post interesting discoveries and perhaps describe the functionality of the intracellular biomolecular machines."

If so, fair enough...

However, rather try this thread...Thanks.

 

[rwenzori]

If **I** (not you) perceive something as relevant I will post it.

Good for you. Just ignore TelePhrone's frequent but futile attempts to control and regulate posts to threads he has started, as we all do.

 

[Palimino]

Good for you. Just ignore TelePhrone's frequent but futile attempts to control and regulate posts to threads he has started, as we all do.

The local forum Nazi?

 

[Palimino]

Can you honestly say to yourself is relevant to:
If so, fair enough...

However, rather try this thread...Thanks.

I am responding to a post by Teleological (round about the beginning of the thread) who spoke about ‘non-specialised cells’. These are stem cells. Bush’s discouragement of stem cell research (for religious reasons) crippled research in this area. There were religious killings in a closely related field (abortion). Protests were common. It is not a huge conceptual leap to postulate violence in the area of stem cell research, considering early efforts involved aborted foetuses. There was such a hoo-ha around this that I doubt mobs would trouble to establish that this was no longer the case before indulging in mindless violence.

In my estimation this is relevant.

 

[Phronesis]

A thread to lump together all the interesting discoveries regarding the intracellular biomolecular machinery that are crucial for life to exist. Feel free to post interesting discoveries and perhaps describe the functionality of the intracellular biomolecular machines.

There are many other threads to discuss Bush's antics or the antics of some fundamentalists (either to the left or the right). Please be so kind to stay on topic here. It is only a request out of civility. Thanks.

Also: post #102. I have never used them as sock puppets and I don't have any.

Here:

HIV-1's 'Hijacking Mechanism' Pinpointed

ScienceDaily (June 15, 2009) — Researchers at McGill University and the affiliated Lady Davis Institute for Medical Research at Montreal's Jewish General Hospital – along with colleagues at the University of Manitoba and the University of British Columbia – may have found a chink in the armour of the human immunodeficiency virus type 1 (HIV-1), the microorganism which causes AIDS. They have pinpointed the key cellular machinery co-opted by HIV-1 to hijack the human cell for its own benefit.

Once a cell is infected with HIV-1, activation of the virus's gene generates a large HIV-1 RNA molecule known as the RNA genome. This is then transported from the cell nucleus to the inner surface of the plasma membrane. The RNA genome can produce both structural proteins and enzymes, but once it arrives at the plasma membrane it can also assemble into new copies of the virus that actually bud out of the cell. Dr. Andrew J. Mouland and his colleagues have discovered how the RNA genome gets transported – or trafficked – from the nucleus to the plasma membrane.

"There is a highway inside the human cell," explained Dr. Mouland, Associate Professor at McGill's Departments of Medicine and Microbiology and Immunology and head of the HIV-1 RNA Trafficking Laboratory at the Lady Davis Institute. "When you drive your car to Toronto you're 'trafficking' the items in your trunk. Similarly, what we have shown is that HIV-1 commandeers the host cell's endosomal machinery to traffic its structural proteins and RNA genome. Imagine that it's essentially jumping on board for the ride and directing it to where it needs to go. This trafficking can occur very fast in cells; so this is how these key components of HIV-1 so efficiently get to the plasma membrane, where the virus can begin to assemble.

"The RNA genome is critical, because if it doesn't get trafficked to the right place at the plasma membrane, the virus will not be infectious," he explained.

This discovery is extremely exciting, Dr. Mouland said, because now that researchers understand a little more about how the cell's transport machinery is hijacked by HIV-1, they have hopes that they can now begin to devise strategies to block the process.

Their study was published in May in the Journal of Biological Chemistry. This work is substantiated by a co-submitted manuscript from the group of Édouard Bertrand at the Institut de génétique moléculaire de Montpellier, Centre national de recherche scientifique. The Bertrand group will publish its work in the same journal in June, 2009.

Now only to design a molecule that can throw a spanner in the works of this mechanism.

 

[Phronesis]

Cells Are Like Robust Computational Systems, Scientists Report

ScienceDaily (June 16, 2009) — Gene regulatory networks in cell nuclei are similar to cloud computing networks, such as Google or Yahoo!, researchers report today in the online journal Molecular Systems Biology. The similarity is that each system keeps working despite the failure of individual components, whether they are master genes or computer processors.

This finding by an international team led by Carnegie Mellon University computational biologist Ziv Bar-Joseph helps explain not only the robustness of cells, but also some seemingly incongruent experimental results that have puzzled biologists.

"Similarities in the sequences of certain master genes allow them to back up each other to a degree we hadn't appreciated," said Bar-Joseph, an assistant professor of computer science and machine learning and a member of Carnegie Mellon's Ray and Stephanie Lane Center for Computational Biology.

Between 5 and 10 percent of the genes in all living species are master genes that produce proteins called transcription factors that turn all other genes on or off. Many diseases are associated with mutations in one or several of these transcription factors. However, as the new study shows, if one of these genes is lost, other "parallel" master genes with similar sequences, called paralogs, often can replace it by turning on the same set of genes.

That would explain the curious results of some experiments in organisms ranging from yeast to humans, in which researchers have recently identified the genes controlled by several master genes. Researchers have been surprised to find that when they remove one master gene at a time, almost none of the genes controlled by that master gene are de-activated.

In the current work, the Carnegie Mellon researchers and their colleagues in Israel and Spain identified the most probable backup for each master gene. They found that removing the master genes that had very similar backups had almost no noticeable effect, but when they removed master genes with less similar backups, the effect was significant. Additional experiments showed that when both the master gene and its immediate backup were removed, the effects became very noticeable, even for those genes with a similar backup gene. In one example, when the gene Pdr1 was removed, researchers found almost no decrease in activation among the genes it controls; when Pdr1 and its paralog were removed, however, 19 percent of the genes Pdr1 controls failed to activate.

"It's extremely rare in nature that a cell would lose both a master gene and its backup, so for the most part cells are very robust machines," said Anthony Gitter, a graduate student in Carnegie Mellon's Computer Science Department and lead author of the Nature MSB article. "We now have reason to think of cells as robust computational devices, employing redundancy in the same way that enables large computing systems, such as Amazon, to keep operating despite the fact that servers routinely fail."

In addition to Bar-Joseph and Gitter, the authors include Itamar Simon, Zehava Siegfried and Michael Klutstein of Hebrew University Medical School in Jerusalem, Oriol Fornes of the Municipal Institute for Medical Research in Barcelona, and Baldo Oliva of Pompeu Fabra University, also in Barcelona.

This work was supported by grants from the National Science Foundation and the National Institutes of Health. Molecular Systems Biology is a peer-reviewed journal published by Nature Publishing Group.

Resiliency and redundancy... signs of an optimal system.

 

[Phronesis]

How Cells Reconcile Mixed Messages In Decisions About Growth

ScienceDaily (June 18, 2009) — The cells in our body are constantly receiving mixed messages. For instance, an epithelial cell might be exposed to one signal telling it to divide and, simultaneously, another telling it to stop dividing. Understanding the process by which these competing environmental cues are reconciled—as well as understanding the cues themselves—might allow bioengineers to promote tissue growth when and where it's needed, and to discourage it when and where it's not.

...The relationships between these competing influences "are really striking when you let them play out" under the influence of cell geography, says Asthagiri—that is, when the cells grow as a multicellular cluster. The reality is that not all cells in a cluster are exposed to the same amount of inhibition. For instance, the cells in the center of the group—pressed against other cells on all sides—will experience more contact, and will require a larger amount of growth factor if they are to overcome that inhibiting signal. The cells on the periphery of a cluster, on the other hand, get a relative whisper of an inhibitory signal; it doesn't take nearly as much growth factor to prompt those cells to divide.

Thus, it's possible to find a level of growth factor that will override the contact inhibition signal only for the peripheral cells, and then to find a second level that will allow division throughout the cluster. In other words, says Asthagiri, "You can tune the system; you can make the periphery grow more quickly relative to the rest of the area, or you can get the entire cluster to increase in size all at once."

"This is useful," he adds, "in thinking about how to engineer organs and tissues. I believe that this can become an important building block, a part of the tool set, that allows us to grow multicellular structures—and, ultimately, tissues—in specific, spatial ways."

And as for cancer? It's long been assumed that contact inhibition acts as a sort of switch that, when present, prevents tumor formation and, when absent, results in cell overgrowth and cancer. "Our findings support a more graded perspective of contact inhibition," the researchers write in the PNAS paper. Keeping in mind that cancer is often the result of an accumulation of genetic damage, they say, it seems likely that each "hit" to a cell's DNA might subtly lower the threshold at which EGF is capable of overriding contact inhibition to promote unbridled cell division and tumor growth.

"This tunability of the threshold amount of EGF," the researchers write, "would seem to be a fragility in cell cycle regulation that is exploited during cancer development."

Asthagiri's coauthors include Caltech graduate students Jin-Hong Kim, the paper's first author, and Keiichiro Kushiro, as well as former Caltech graduate student Nicholas A. Graham, who is now a postdoctoral fellow at the Crump Institute for Molecular Imaging at UCLA.

Computer Scientists Develop Model For Studying Arrangements Of Tissue Networks By Cell Division

ScienceDaily (June 17, 2009) — Computer scientists at Harvard have developed a framework for studying the arrangement of tissue networks created by cell division across a diverse set of organisms, including fruit flies, tadpoles, and plants.

"Even with modern imaging methods, we can rarely directly 'ask' the cell how it decided upon which way to divide. The computational tool allows us to generate and eliminate hypotheses about cell division. Looking at the final assembled tissue gives us a clue about what assembly process was used," explains Nagpal.

The model also sheds light on a prior discovery made by the team: that many proliferating epithelia, from plants to frogs, show a nearly identical cell shape distribution. While the reasons are not clear, the authors suggest that the high regularity observed in nature requires a strong correlation between how neighboring cells divide. While plants and fruit flies, for example, seem to have conserved cell shape distributions, the two organisms have, based on the computational and experimental evidence, evolved distinct ways of achieving such a pattern.

"Ultimately, the work offers a beautiful example of the way biological development can take advantage of very local and often random processes to create large-scale robust systems. Cells react to local context but still create organisms with incredible global predictability," says Nagpal.

Looking and trying to understand cellular networks and mechanisms is like looking into the future of our own designs.

One day we may even be able to use our model to help researchers understand other kinds of natural cellular networks, from tissues to geological crack formations, and, by taking inspiration from biology, design more robust computer networks," adds Nagpal.

 

[Phronesis]

Molecular Typesetting: How Errors Are Corrected While Proteins Are Being Built

ScienceDaily (June 23, 2009) — Researchers at the Universities of Leeds and Bristol have developed a model of how errors are corrected whilst proteins are being built.

Ensuring that proteins are built correctly is essential to the proper functioning of our bodies, but the ‘quality assurance’ mechanisms that take place during this manufacturing process are not fully understood.

“Scientists have been puzzled as to how this process makes so few mistakes”, says Dr Netta Cohen, Reader at the University of Leeds’ School of Computing.

To create a protein, the first step involves copying the relevant gene on our DNA onto a template, called RNA. This copying process is carried out by molecular machines called RNA polymerases.

“The RNA polymerase acts like an old fashioned newsprint typesetter, constructing newsprint by assembling letters one at a time. Similarly, RNA polymerase constructs RNA by reading the DNA and adding new letters to the RNA one at a time,” explains Dr Cohen.

There’s no way for the RNA polymerase to ensure that the correct letter is always incorporated at the right spot. “Statistically, we would expect to see a hundred-fold more errors than we actually do, so we know that some error correction must be happening. Otherwise, many more proteins in our bodies would malfunction,” says Dr Cohen.

Biological experiments have shown that the RNA polymerase slides both forwards and backwards along the RNA sequence it has created. What’s more, it has miniature scissors that can then cut out the last few letters of RNA.

So how are errors corrected? Intelligent typesetters would remove the last few letters when they spot an error. The new model suggests how the backward sliding stalls when passing an error, so wrong letters can be snipped off and copying can resume.

“The mechanism we’ve modelled has only recently been shown to be implicated in proofreading,” says Dr Cohen. “In fact, there is more than one identified mechanism for ensuring that genetic code is copied correctly. The challenge now is to find out – through a combination of experimental biology and modelling – which mechanism is dominant.”

Intelligent typesetters? Mmmm. Even bacteria have those.