Biomolecular machines

[Phronesis]

Does anyone actually read this stuff? It seems to be rather boring; maybe it would be better posted on a blog or in a scientific forum.

You find the inner workings of cells boring ? Ok fine, don't assume others do.
Blogs? Made them.
Isn't this a scientific forum? But it is posted elsewhere as well. Only people who do not seem to like this kind of information are w1zard, alloytoo, you and nauseous_monkey. See a trend there?

+1

Scientific findings regarding the inner workings of the cell seem to offend you? See a trend?

 

[Phronesis]

In order not to irritate those that are not interested in the biomolecular machinery in cells and find it boring.... MORE MACHINES .

A unique cell division machinery in the Archaea

There are Bacteria and Eukaryotes, and then there is Archaea. Not much is known about them, as most of the research has gone into understanding the other two domains. Now remember, without cell division machinery, cells do not self-replicate (obviously)... ever. All cells have it.

What about Archaea? From the article:

Several features of archaeal cell cycle progression have been elucidated in considerable detail including the overall organization of the cell cycle in certain species, and regulatory and mechanistic aspects of the replication process (2, 3). Conversely, the genome segregation machinery remains essentially uncharacterized in this domain. In archaeal species belonging to the Euryarchaeota phylum, and in bacteria, cell division is mediated by FtsZ protein filaments that form a constricting ring structure (4). In eukaryotes, division occurs with the help of a contractile actin-myosin ring or, in plant cells, by septum formation at a site initially marked by actin and microtubules (5). In contrast to bacteria, euryarchaea, and eukaryotes, no cell division components have been identified in the second main archaeal phylum, Crenarchaeota (2).

Here, we report on the identification of key components of the cell division system in the hyperthermophilic crenarchaeon Sulfolobus acidocaldarius, describe intracellular structures that are formed by the gene products during genome segregation and division, and show that the operon is subject to a checkpoint-like regulation. We also demonstrate that the division machinery is present in all crenarchaeal orders except Thermoproteales, and that it is related to the eukaryotic ESCRT-III sorting complex.

Similar to the eukaryotic ESCRT-III sorting complex. What is that?
The endosomal sorting complex required for transport. What does it do?

ESCRT ('endosomal sorting complex required for transport') protein complexes are required to sort ubiquitylated endosomal membrane proteins into the multivesicular body (MVB) pathway. This pathway, which leads to the vacuolar/lysosomal lumen, has a crucial role in sorting and downregulating/degrading activated cell-surface receptors. In addition, the ESCRT complexes have recently been shown to be required for the budding and release of retroviruses such as HIV. A detailed understanding of the molecular machinery for MVB sorting has been lacking, but, in two papers in Developmental Cell, Scott Emr and colleagues now report the characterization of two of the ESCRT complexes — ESCRT-II and ESCRT-III.

Shared machinery with distinct functions.



Feed back systems: Shape controlling form, and form controlling shape.
Cells Reorganize Shape To Fit The Situation, Scientists Discover

ScienceDaily (Nov. 24, 2008) — Flip open any biology textbook and you're bound to see a complicated diagram of the inner workings of a cell, with its internal scaffolding, the cytoskeleton, and how it maintains a cell’s shape. Yet the fundamental question remains, which came first: the shape, or the skeleton?

Now a research team led by Phong Tran, PhD, Assistant Professor of Cell and Developmental Biology at the University of Pennsylvania School of Medicine, has the answer: both.

The findings, published online this week in the journal Current Biology by co-senior authors Tran and Matthieu Piel of the Institut Curie, Paris, combine genetics, live-cell imaging, and microfluidics technology. They were able to force normally rod-shaped yeast cells to grow within tiny curved channels. Using the channels, they made rod-shaped cells deform into curved-shaped mutant cells and conversely, curved-shaped cells straighten out into a rod. The surprising finding: as the cells bend, they reorganize their cytoskeleton, and as they reorganize their internal skeletons, the cells further adjust their shape.

Cell shape gone awry has been implicated in some forms of cancer. In the future, one potential implication of Tran's findings is that it might be possible to rescue certain disease states via squeezing or otherwise applying mechanical pressure to tissues or organs. But that, he concedes, is “completely science fiction on my part.” Instead, he says at this point this study is pure, basic research. “It was just a cool experiment.”

The findings point to a type of feedback loop. “The cytoskeleton changes the shape of the cell and the shape of the cell also changes the organization of the cytoskeleton,” he says. “In fact they feed back on each other, so any perturbation on one system will change the other, and visa versa.”...

So which came first? The cytoskeleton that controls shape? Or shape that controls the cytoskeleton? Seems both work just fine together. Science proceeds to find ever increasing intricacies of life...

 

[Phronesis]

More mechanisms and machines, and less junk:
New RNA Processing Mechanism And New Class Of Small RNAs

ScienceDaily (Nov. 26, 2008) — A very small fraction of our genetic material--about 2%-- performs the crucial task scientists once thought was the sole purpose of the genome: to serve as a blueprint for the production of proteins, the molecules that make cells work and sustain life. This 2% of human DNA is converted into intermediary molecules called RNAs, which in turn carry instructions within cells for protein manufacture.

Initial argument from ignorance because of ignorant Darwinian non-teleological assumptions? You betcha .

Broader implications: a new RNA processing mechanism

Researchers now think that at least 40% of long, non-coding RNAs--a considerable chunk of RNA segments that float around the nucleus--may be processed to generate smaller RNA pieces such as mascRNA, and also other classes of RNA. While the hunt has begun for other tRNA-like small RNAs and their precursor RNAs like MALAT1, the new results from Spector's lab provide a first look at how these bits are produced.

In the case of coding RNAs, once their sequence has been "read" off a DNA template, a molecular complex snips off the tail end of this new piece and tacks on a signal at its end that protects the new molecule from degradation and marks it for export out of the nucleus. In non-coding MALAT1, however, the CSHL team found the protective signal was already embedded within the molecule, just ahead of the portion that later detached to form mascRNA. The molecular complex responsible for cleaving MALAT1 therefore knew precisely where to make its cut--right after the embedded signal--rather than at MALAT1's tail end. In this way, MALAT1 is effectively preconfigured to liberate the mascRNA fragment.

The mechanism that retains the long MALAT1 molecule within the nucleus while expelling the mascRNA fragment into the cytoplasm is still elusive. "The answer will come when we identify more and more RNAs that are built like the MALAT1 precursor and are processed to give rise to different types of RNAs," says Spector.

In the meantime, his lab's current work provides reason to believe that the community of non-coding RNAs has many more surprises to reveal. To the extent that its members can be shown to perform specific functions, it will seem increasingly inapt to consider non-coding RNAs the byproducts of "junk DNA."

JunkDNAnomore

 

[Claymore]

You find the inner workings of cells boring ? Ok fine, don't assume others do.

Is there *anyone* here who follows your posts with interest? If so, why aren't they commenting on them?

Blogs? Made them.

Halfway there!

Isn't this a scientific forum? But it is posted elsewhere as well.

This is a "science" section on a broadband forum.

 

[Phronesis]

Is there *anyone* here who follows your posts with interest? If so, why aren't they commenting on them?

I'll make a poll in the future if this is such an issue for you. You seem to comment here. Why do you if you don't follow? Logic?

Halfway there!0

100%

This is a "science" section on a broadband forum.

Are science related subjects not tolerated here then? Why don't you like scientific findings with regards to the inner workings of cells? Logic?

Hopefully this won't be a problem for you... More machines:

Memories may be stored on your DNA

REMEMBER your first kiss? Experiments in mice suggest that patterns of chemical "caps" on our DNA may be responsible for preserving such memories.

To remember a particular event, a specific sequence of neurons must fire at just the right time. For this to happen, neurons must be connected in a certain way by chemical junctions called synapses. But how they last over decades, given that proteins in the brain, including those that form synapses, are destroyed and replaced constantly, is a mystery.

They found that a day after the shock, methyl groups were being removed from a gene called calcineurin and added to another gene. Because the exact pattern of methylation eventually stabilised and then stayed constant for seven days, when the experiment ended, the researchers say the methyl changes may be anchoring the memory of the shock into long-term memory, not just controlling a process involved in memory formation.

"We think we're seeing short-term memories forming in the hippocampus and slowly turning into long-term memories in the cortex," says Miller, who presented the results last week at the Society for Neuroscience meeting in Washington DC.

"The cool idea here is that the brain could be borrowing a form of cellular memory from developmental biology to use for what we think of as memory," says Marcelo Wood, who researches long-term memory at the University of California, Irvine.

Here, once again another demonstration of the robustness of DNA as information storage material. Methylation and demethylation (of cytosine...remember that?) processes are controlled by the epigenetic machinery and also plays a role in development and evolution. Right from the beginning of life, a stable genetic code was present composed of material necessary for memories .

 

[Phronesis]

More cellular machinery anyone? A certain segment of the population seem to find these findings distressing.... Why ?

Keeping Chromosomes From Cuddling Up

ScienceDaily (Dec. 3, 2008) — If chromosomes snuggle up too closely at the wrong times, the results can be genetic disaster.

Cells are not "selected disasters", they automatically prevent disasters. How?

Now researchers have found the molecular machines in fruit flies that yank chromosomes, the DNA-carrying structures, apart when necessary.

The machines, proteins called condensin II, separate chromosomes by twisting them into supercoils that kink up and therefore can no longer touch.

Scientists had known of condensin II but did not know how it functioned inside cells.

Keeping specific parts of chromosomes from touching can change how the instructions carried in the DNA are read, said research team leader Giovanni Bosco of The University of Arizona in Tucson.

"It's like picking up your favorite book and, depending on what chair you chose to sit in, it turned into a different story -- even though the printed words in the book never changed," Bosco, a UA assistant professor of molecular and cellular biology, wrote in an e-mail.

"This now changes the way we think about genetic information. Taking a literal reading of it is not what actually happens," he wrote. "Instead, context matters."

Information storage and retrieval is a tricky business it seems. Nice to know mechanisms and machines are in play to keep it in tact, purposefully...

The team also found that condensin II plays a key role in making sure that fruit fly sperm cells each receive the proper number of chromosomes -- not too many, not too few.

Bosco suspects that condensin II plays the same role in the formation of human sperm and eggs.

Having too many or too few chromosomes in egg or sperm cells is the source of several important genetic disorders, including Down syndrome.

Abnormalities in chromosome number is also the cause of some miscarriages of early-term fetuses in humans.

The National Institutes of Health and the National Science Foundation funded the research.

These are not the only disorders that arise due to faulty chromosome segregation. Aneuploidy as a result of faulty replication machinery is a major cause of various cancers as well.

He said these findings are significant because more and more genetic tests to sequence people's DNA are becoming available, but the DNA sequence alone does not completely determine what diseases the person will have.

Even if it's in the genes, it might not show, he said. "It's what your cells are doing with your genes that's important."

To pull the chromosomes apart, condensin II changes its shape. Smith said the team's next step is figuring out how condensin II proteins are recruited to the chromosomes and how the condensin II proteins use the cellular energy packets known as ATP to change shape.

Genes are not the only thing that makes you "you". You have control.


And cell movement:
Cell Movements Totally Modular, Study Shows

ScienceDaily (Nov. 30, 2008) — A study describing how cells within blood vessel walls move en masse overturns an assumption common in the age of genomics — that the proteins driving cell behavior are doing so much multitasking that it would be near impossible to group them according to a few discrete functions.

But now researchers at the Stanford University School of Medicine have shown that distinct groups of proteins each control one of four simple activities involved in the cells' collective migration. The findings will be published in the Dec. 1 issue of Genes and Development.

Graduate student Philip Vitorino, the study's first author, began the project in 2004 in the laboratory of senior author Tobias Meyer, PhD, professor of chemical and systems biology. The work is part of the Meyer lab's larger effort to find order in the overwhelming complexity of the inner workings of cells.

"The cells don't need to activate and inactivate thousands of proteins to control sheet movements," Vitorino said. "Instead they simply coordinate the activity of four simple modules to generate efficient movements."

Vitorino also made some curious, though not immediately useful, observations about the impact of silencing genes for individual cells: "Some inactivations made them spiky, some made them long, some made them so they wouldn't stick together, some made them divide really fast, some, really slow," Vitorino said.

"The hardest part was organizing all of the data and making sense out of it," he added. Generating the data took only a year. Analyzing, retesting and making sense of these data took close to two more.

Cell biologists have a penchant for comparing the cell's workings to auto mechanics and Vitorino is no exception. "Using the human genome, biochemical studies and proteomic approaches, scientists have generated a comprehensive list of parts and also some information about where the parts sit under the hood," he said.

"What we have done is organized these parts into those that are involved in generating forward movement, those that are important for steering, those that signal to other cars or those that are important for braking.

"Ultimately, this allows us to simplify very complex behaviors and provides a powerful tool for developing new therapeutics," said Vitorino. "With an understanding of the individual parts of the machine, it will be easier to effectively modify the system to change cell behaviors and ultimately treat human disease."

This study was funded by the National Institutes of Health and the National Science Foundation Pre-Doctoral Fellowship Program.

Cells don't just randomly move about without direction, movement is exquisitely controlled down to the last protein.

 

[Phronesis]

The kinesin motor machine:
Nice pic

How Tiny Cell Proteins Generate Force To 'Walk'

ScienceDaily (Dec. 4, 2008) — MIT researchers have shown how a cell motor protein exerts the force to move, enabling functions such as cell division.

Kinesin, a motor protein that also carries neurotransmitters, "walks" along cellular beams known as microtubules. For the first time, the MIT team has shown at a molecular level how kinesin generates the force needed to step along the microtubules.

Remember microtubules, quantum physics, and consciousness? They form tracks for neurotransmitters to be transported and can possibly act as quantum computational structures.

The researchers, led by Matthew Lang, associate professor of biological and mechanical engineering, report their findings in the Nov. 24 online early issue of the Proceedings of the National Academy of Sciences.

Because kinesin is involved in organizing the machinery of cell division, understanding how it works could one day be useful in developing therapies for diseases involving out-of-control cell division, such as cancer.

The protein consists of two "heads," which walk along the microtubule, and a long "tail," which carries cargo. The heads take turns stepping along the microtubule, at a rate of up to 100 steps (800 nanometers) per second.

In the PNAS paper, Lang and his colleagues offer experimental evidence for a model they reported in January in the journal Structure. Their model suggests — and the new experiments confirm — that a small region of the protein, part of which joins the head and tail is responsible for generating the force needed to make kinesin walk. Two protein subunits, known as the N-terminal cover strand and neck linker, line up next to each other to form a sheet, forming the cover-neck bundle that drives the kinesin head forward.

"This is the kinesin power stroke," said Lang.

Next, Lang's team plans to investigate how the two kinesin heads communicate with each other to coordinate their steps.

Lead author of the PNAS paper is Ahmad Khalil, graduate student in mechanical engineering. Other MIT authors of the paper are David Appleyard, a graduate student in biological engineering; Anna Labno, a recent MIT graduate; Adrien Georges, a visiting student in Lang's lab; and Angela Belcher, the Germehausen Professor of Materials Science and Engineering and Biological Engineering. This work is a close collaboration with authors Martin Karplus of Harvard and Wonmuk Hwang of Texas A&M.

The research was funded by the National Institutes of Health and the Army Research Office Institute of Collaborative Biotechnologies.

Few videos describing the motor:
Kinesin Transport Protein
Kinesin Explanation

Mice with a few kinesin mutations? Look like there is something wrong with their neurphysiology, almost like they are not interacting with the environment in the correct way?
Kinesin mutations in mice

Ever wondered how cellular machinery causes replication of cells?
Awesome video:
Inside the cell
And it does not even remotely cover the intricate mechanisms controllong the process.

Another video of mitosis:
Mitosis
Active cyclinB/cdc2 plays a part in nuclear envelope breakdown, and destruction of cyclinB and abolition of cdc2 activity allows nuclear envelope formation.

In real life it looks something like this:

 

[Phronesis]

First 3-D Images Obtained Of Core Component Of Molecular Machinery Used For Cell Reproduction

ScienceDaily (Dec. 9, 2008) — For the first time, structural biologists have managed to obtain the detailed three-dimensional structure of one of the proteins that form the core of the complex molecular machine, called the replisome, that plant and animal cells assemble to copy their DNA as the first step in cell reproduction.

Currently, the process of DNA replication in eukaryote cells – cells that have their genetic information contained in a nucleus – is a "black box." Biologists know what goes in and what comes out but they know very little about how the process actual works at the molecular level. Because form causes function in the protein world, determining the 3D structure of the 30-40 proteins that combine to form the replisome is a necessary first step to figuring out the details of this critical process and understanding how it can go wrong.

Worth noting several components of the replisome have a virtually identical three-dimensional structure to components in archaea and bacteria, but have extremely low sequence similarity.

The researchers think that Mcm10 may play a role in positioning the other proteins in the replisome onto the single DNA strand so that it may be correctly read and duplicated, while acknowledging that they have very little information about how it functions.

The structure:

 

[Phronesis]

Biologist Modifies Theory Of Cells' Engines​

ScienceDaily (Dec. 11, 2008) — Biologists have known for decades that cells use tiny molecular motors to move chromosomes, mitochondria, and many other organelles within the cell, but no one has been able to understand what "steers" these engines to their destinations. Now, researchers at the University of Rochester have shed new light on how cells accomplish this feat, and the results may eventually lead to new approaches to fighting pathogens and neurological diseases.

Michael Welte, associate professor of biology, shows in a paper published in the December 11 issue of Cell that the mechanisms that control the molecular motors are quite different from what biologists have previously believed. Before these findings, scientists assumed that the number of motors attached to an organelle determined how far and fast the organelle could travel, but Welte and colleagues have discovered that it is not the number of motors, but yet-to-be-discovered molecules that are likely the master regulators.

What controls these yet-to-be-discovered master regulators ?

"The fact that motor number has nothing to do with regulating transport is extremely surprising, and somewhat unsettling to people working in vitro," says Welte. "It says we're really missing something when we study these motors only in the test tube instead of in a living cell."

Intracellular transport is crucial to a cell's health, says Welte. For instance, during cell division, one copy of each of the cell's chromosomes migrates to one side of the cell while the other copy moves to the other side. If this movement is disturbed, it could cause an imbalance of chromosomes in the daughter cells, which might die or become cancerous. Similarly, neurons, some of which are as much as three feet in length, manufacture proteins and organelles at one end and then must move that precious cargo all the way to the far end where they'll be used. This is an enormous task, says Welte, and defects in this transport are thought to cause a number of neurological diseases.

Given the difficulty of investigating these tiny motors acting within the cell, biologists have performed basic experiments on them outside of the cell in a carefully controlled environment. This led them to believe that the speed and distance an organelle could be transported depended on how many motors were pulling it, says Welte. Thus, the scientists reasoned, perhaps the cell simply attaches the right number of motors to an organelle to send it the right distance. Although this "multi-motor" hypothesis is very simple and elegant, says Welte, whether it actually holds true within living cells had never been tested.

Welte's graduate student, Susan Tran, decided to perform that test. She created fruit-fly eggs lacking a type of molecular motor called kinesin and found that certain organelles stopped moving—strong evidence that kinesin is responsible for their transport. Tran then made another type of mutant eggs, this time ones that produced only about half the number of kinesin motors of a regular egg. In both types of eggs, organelles were transported with the same speed and the same distance.

Welte needed to know if this equality was because the normal egg was simply utilizing only half the available kinesin motors, or if some master regulator was controlling the organelle's progress, regardless of the number of motors moving it. To do this, Welte turned to Steven Gross, associate professor of developmental and cell biology at the University of California. Gross' group uses an apparatus called "optical tweezers" that employs laser light to measure the tiny forces the motors generate. The team found that organelles in regular cells are pulled with twice the force of Tran's mutant, low-kinesin cells.

"That clinched it for us," says Welte. "Yes, there are multiple motors moving organelles around, but exactly how many doesn't matter. There is something else in the cell that's controlling all the motors. That opens up a big area for research—find what's driving these motors and maybe we can control them all by controlling one thing."

Welte and his team are now looking at where in the cell this signal comes from and how it influence the motors. Although Welte's team studied fruit fly eggs, the motors moving the organelles are present in all animals and employed for many tasks, including transport in human neurons.

Welte also points out that viruses, including HIV, make use of the same kind of motors to move about the cell, first to get from the site of penetration to the nucleus, where they multiply, and then to get progeny viruses back to the cell surface. If Welte and others can figure out how cells normally control these motors, it may be possible to prevent HIV from taking control of the motors and thus to keep it, and other intracellular pathogens, at the edge of the cell where they can do little harm.

Fascinating research awaits these guys. The rabbit hole gets deeper...

 

[Phronesis]

An interesting article by Antoine Danchin from the Pasteur Institut was published recently:
Bacteria as computers making computers

Abstract Various efforts to integrate biological knowledge into networks of interactions have produced a lively microbial systems biology. Putting molecular biology and computer sciences in perspective, we review another trend in systems biology, in which recursivity and information replace the usual concepts of differential equations, feedback and feedforward loops and the like. Noting that the processes of gene expression separate the genome from the cell machinery, we analyse the role of the separation between machine and program in computers. However, computers do not make computers. For cells to make cells requires a specific organization of the genetic program, which we investigate using available knowledge. Microbial genomes are organized into a paleome (the name emphasizes the role of the corresponding functions from the time of the origin of life), comprising a constructor and a replicator, and a cenome (emphasizing community-relevant genes), made up of genes that permit life in a particular context. The cell duplication process supposes rejuvenation of the machine and replication of the program. The paleome also possesses genes that enable information to accumulate in a ratchet-like process down the generations. The systems biology must include the dynamics of information creation in its future developments.

Even bacterial cells, traditionally viewed simple cells, outsmart our best efforts at AI. With more and more information being gathered on cellular mechanisms, cells can be seen as computers (machines expressing various programs), that are not only able govern cellular processes needed to sustain the software, but also contains the necessary software and machinery to reproduce the computing machine while replicating its program.

The quantum teleportation experiments have demonstrated that information can be viewed as a fundamental irreducible property of physics (informationalism). Systems biology is moving in that same direction, as viewing cells as computers with machinery and software makes it possible to view information as a fundamental category of nature and all future developments of systems biology can include this concept when looking at cells.

From the article:

Molecular biology relies heavily on concepts such as ‘control’, ‘coding’ or ‘information’, which are at the heart of arithmetic and computation.

Cellular processes are exquisitely controlled and carried out by remarkable biomolecular machines. The software needed to coordinate these processes is located in a fairly optimal genetic code that is optimized for evolution and maintains its own functional integrity.

Also from the article:

At least two further concepts were associated with the development of molecular biology. They are central to the engineering view of the cell that prevails in systems and synthetic biology (Kuldell, 2007). The role of control (regulation), via feedback (or feedforward and the like) loops (see e.g. Gorini, 1958), as in the lactose operon or in the bacteriophage lambda lytic/lysogenic transition, makes gene expression similar to electronic devices (D’Ari & Thomas, 2003; Alon, 2006). Although it is rather new in biology, the concept of feedback, which has been well understood since the XIX century, is one of the standard concepts of mechanical (‘clockwork’) processes. Much discussion and many experiments have involved feedback and feedforward loops, with their ‘nonlinear’ avatars in particular in systems biology (Alon, 2006; Barrett et al., 2006; Laub et al., 2007; Mitrophanov & Groisman, 2008). Despite its apparent modernity, this domain of biology is therefore typical of the Newtonian world that dominated the XVIII century [see the vogue of automata at that time (Offroy de la Mettrie (translation 1996))].
In sharp contrast, the role of coding in translation, which allows proteins to control protein expression, brought the novel and deep concept of recursivity into the heart of biology (Hofstadter, 1979), making cells fundamentally different from mechanical automata in the sense that they are capable of being creative in the strongest sense of the word (Danchin, 2003).

The article continues to discuss at length the parallels between our own created information processing systems (computers) and molecular processes fundamental to life. One striking feature that is different from life than any AI system so far, is that cellular processes are able to actively manipulate information (agency) as a means to an end... replication.

 

[Park@82]

Thanks for the posts Phronesis.

 

[Phronesis]

Thanks for the posts Phronesis.

Pleasure . I enjoy learning about these things... fascinating.

More machines and clockwork:

Clockwork That Drives Powerful Virus Nanomotor Discovered

Related article:
Biologists Learn Structure, Mechanism Of Powerful 'Molecular Motor' In Virus

ScienceDaily (Dec. 29, 2008) — Peering at structures only atoms across, researchers have identified the clockwork that drives a powerful virus nanomotor.

Because of the motor's strength--to scale, twice that of an automobile--the new findings could inspire engineers designing sophisticated nanomachines. In addition, because a number of virus types may possess a similar motor, including the virus that causes herpes, the results may also assist pharmaceutical companies developing methods to sabotage virus machinery.

Again, taking clues from cellular machinery to design our own optimal nanotechnology.

 

[Phronesis]

Primary Cilium As Cellular 'GPS System' Crucial To Wound Repair

ScienceDaily (Dec. 25, 2008) — The primary cilium, the solitary, antenna-like structure that studs the outer surfaces of virtually all human cells, orient cells to move in the right direction and at the speed needed to heal wounds, much like a Global Positioning System helps ships navigate to their destinations.

What we are dealing with is a physiological analogy to the GPS system with a coupled autopilot that coordinates air traffic or tankers on open sea," says Soren T. Christensen, describing his recent research findings on the primary cilium, the GPS-like cell structure, at the American Society for Cell Biology (ASCB) 48th Annual Meeting, Dec. 13-17, 2008 in San Francisco.

Christensen and his colleagues at the University of Copenhagen in Denmark and the Albert Einstein School of Medicine in the Bronx studied the primary cilia in lab cultures of mice fibroblasts, the cells that along with related connective tissues sculpt the bulk of the mammalian body.

So we think we have designed GPS systems?

"The really important discovery is that the primary cilium detects signals, which tell the cells to engage their compass reading and move in the right direction to close the wound," Christensen explains.

Purposefully communicating information as a means to an end... wound healing.

The researchers suspect this cellular GPS system plays roles other than wound healing. The primary cilia could serve as a fail-safe device against uncontrolled cell movement, says Christensen. Without chemical stimulation, the primary cilia would restrain cell migration, preventing the dangerous displacement of cells that is associated with invasive cancers and fibrosis, the scientists explain. On the other hand, defective primary cilia might fail to provide correct directional instructions during cell differentiation. This failure could be another link connecting primary cilia to severe developmental disorders, the researchers suggest.

Protruding through the cell membrane, primary cilia occur on almost every non-dividing cell in the body. Once written off as a vestigial organelle discarded in the evolutionary dust, primary cilia in the last decade have risen to prominence as a vital cellular sensor at the root of a wide range of health disorders, from polycystic kidney disease to cancer to left-right anatomical abnormalities.

Once again demonstrating the vacuity of preaching sub-optimal design... an idea from faulty Darwnian reasoning.

 

[w1z4rd]

Is there *anyone* here who follows your posts with interest? If so, why aren't they commenting on them?

I was just thinking the same thing. I got so bored of his posts a long time ago.. I can honestly say that when he spams his engineering analogies all over the place... I just switch off.

I dont think many people are paying attention to whats written here.

 

[Phronesis]

Putting cytosine deamination to work: How the immune system exploits the optimal properties of the genome for antibody diversification and immune function.​

The effect of cytosine deamination on a random pool of amino acids and how it might facilitate evolution has been described. The optimal features of the genetic code are exploited by the vertebrate immune system by "putting cytosine deamination to work". Antibody diversification is crucial in limiting the frequency of environmentally acquired infections and thereby increasing the fitness of the organism. Initial diversification of antibodies is achieved by assembling variable (V), diversity (D) and joining (J) gene segments (V(D)J recombination) by non-homologous recombination. Further diversification is carried out by somatic hypermutation (SHM) and Class Switch Recombination. Central to the initiation to these diversification processes is the activation-induced cytosine deaminase (AID) protein. AID deaminates cytosine to uracil in single stranded DNA (ssDNA - arising during gene transcription) and is dependent on active gene transcription of the various antibody genes. The induced mutation is resolved by at least 4 pathways (Figure 1):
1) Copying of the base by high-fidelity polymerases during DNA replication.
2) Short-Patch Base Excision Repair (SP-BER) by uracil-DNA glycosylase removal and subsequent repair of the base.
3) Long-Patch Base Excision Repair (LP-BER)
4) Mismatch repair (MMR)

Link to big picture

Figure 1: Activation induced cytosine deamination and the pathways involved in resolving the induced mutation. 1) Normal DNA replication results in a C:G→T:A transition. 2) Successful SP-BER resolves the mutation, however the recruitment of error-prone translesion polymerases results (e.g. REV1) in transversions (REV1; C:G→G:C) and transition. 3) LP-BER can also resolve the mutation, however recruitment of low-fidelity polymerases (e.g. Pol n) also causes transition and transversion mutations. 4) MMR repair can also resolve the mutation, however the recruitment of low-fidelity polymerases through this pathway is a major cause of A:T transitions.​

AID causes somatic hypermutation and its activity is limited to the certain genetic regions of the immune system. When the system runs unchecked, mutations might be introduced into proto-oncogenes, resulting in possible cancerous growth. The system is controlled (Figure 2). The activity and gene expression of AID is controlled. The type of error-repair pathway and the subsequent recruitment of various low-fidelity polymerases determine the type of mutations after the repair process and these also seem to be controlled. Current research focuses on the mechanisms of control of downstream repair pathways and why this system is selectively targeted to the small region of antibody genes.

Figure 2: Controlled variability of somatic hypermutation.​

Thus, the immune system exploits the properties the genetic code for the purpose of controlled variability. This system is not only limited to vertabrate. Cytosine deamninases are found in bacteria as well. Error-prone repair systems are also present together with an optimal code.

References:
Peled JU, Kuang FL, Iglesias-Ussel MD, Roa S, Kalis SL, Goodman MF et al. The biochemistry of somatic hypermutation. Annu Rev Immunol. 2008;26:481-511.

Teng G, Papavasiliou FN. Immunoglobulin somatic hypermutation. Annu Rev Genet. 2007;41:107-20.

Goodman MF, Scharff MD, Romesberg FE. Abstract AID-initiated purposeful mutations in immunoglobulin genes. Adv Immunol. 2007;94:127-55.

Basu U, Chaudhuri J, Phan RT, Datta A, Alt FW. Regulation of activation induced deaminase via phosphorylation. Adv Exp Med Biol. 2007;596:129-37

 

[Phronesis]

Protein's Essential Role In Repairing Damaged Cells Revealed

The process of cell division (self-replication) is exquisitely controlled and "takes micromanagement to the extreme". Several sensors purposefully monitor the integrity of the information storage system (DNA) and relays that information to effectors to purposefully repair any faults. These scientists determined one of the structures responsible for these processes.

ScienceDaily (Jan. 6, 2009) — University of Michigan researchers have discovered that a key protein in cells plays a critical role in not one, but two processes affecting the development of cancer.

The MRN complex, comprised of the Mre11, Rad50 and NBS1 proteins, senses DNA damage, known as double-strand breaks, within the cell. The complex then transmits that information to an enzyme called the ATM (ataxia-telangiectasia mutated) checkpoint kinase.

The ATM kinase controls the cell's response to double-strand breaks, and slows cell growth to give the cell opportunities to repair them, says Ferguson.

When the MRN complex doesn't work properly, inherited human neurological diseases, such as ataxia-telangiectasia-like syndrome and Nijmegen breakage syndrome, result. Both feature MRN mutations and significantly predispose a person to immunodeficiency and cancer.

What Ferguson and colleagues discovered is that Mre11 not only senses and communicates damage, it also repairs DNA double-strand breaks by acting as a nuclease, an enzyme that modifies and processes the broken DNA ends.

This complex operates during several checkpoints during the cell cycle to ensure the fidelity of the process. (nice link)

Figure 1 shows some of the interactions of various cellular processes.

Figure 1: Dynamic control of cell cycle events through cell signaling, checkpoints, nutrient availability and extracellular stress. (Click for larger version)​

The work has important implications in understanding neoplastic processes and will aid in the design and development of new, more effective anticancer compounds.

Implications

The work, called "virtuoso cell engineering" in a Cell preview article, holds particular promise for identifying mutations associated with many cancers.

"What's emerging in the literature from large-scale screening studies of human tumors is that Mre11 may be frequently mutated in certain cancers," Ferguson says.

"This may have implications for diagnoses because tumors associated with different mutations may have different prognoses and respond to different therapies," he says. In particular, mutations in Mre11 may predict how sensitive or resistant a particular tumor will be to treatments with DNA-damaging agents.

“The fact that we have now separated the functions of DNA repair from the checkpoint functions means we may have identified a target that can sensitize tumors to radiation and chemotherapeutic agents used in treating cancer."

 

[Phronesis]

Speaking of antibody diversification:

Evolution In Action: Our Antibodies Take 'Evolutionary Leaps' To Fight Microbes

ScienceDaily (Jan. 8, 2009) — With cold and flu season in full swing, the fact that viruses and bacteria rapidly evolve is apparent with every sneeze, sniffle, and cough. A new report explains for the first time how humans keep up with microbes by rearranging the genes that make antibodies to foreign invaders. This research fills a significant gap in our understanding of how the immune system helps us survive.

When the body encounters a foreign invader, like a virus or bacterium, it immediately begins to find a way to neutralize it by means of cellular or antibody-mediated defenses. Part of the process involves tailoring the genes that code for antibodies to specific viruses or bacteria.

Wonder what the reaction would be if the title was:
Teleological Evolution in Action: Our Antibodies Take 'Evolutionary Leaps' to fight Microbes

Why Teleological evolution? Well, the immune system purposefully manipulates information by using the optimality of the genetic code, random variation and selection as a means to an end… antibody diversification. (See how)

Teleological evolution is not limited to the immune system.
Somatic evolution of malignancy alse seem to have a teleological streak…
Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis?

Investigating the causes of increased aerobic glycolysis in tumors (Warburg Effect) has gone in and out of fashion many times since it was first described almost a century ago. The field is currently in ascendance due to two factors. Over a million FDG-PET studies have unequivocally identified increased glucose uptake as a hallmark of metastatic cancer in humans. These observations, combined with new molecular insights with HIF-1alpha and c-myc, have rekindled an interest in this important phenotype. A preponderance of work has been focused on the molecular mechanisms underlying this effect, with the expectation that a mechanistic understanding may lead to novel therapeutic approaches. There is also an implicit assumption that a mechanistic understanding, although fundamentally reductionist, will nonetheless lead to a more profound teleological understanding of the need for altered metabolism in invasive cancers. In this communication, we describe an alternative approach that begins with teleology; i.e. adaptive landscapes and selection pressures that promote emergence of aerobic glycolysis during the somatic evolution of invasive cancer. Mathematical models and empirical observations are used to define the adaptive advantage of aerobic glycolysis that would explain its remarkable prevalence in human cancers. These studies have led to the hypothesis that increased consumption of glucose in metastatic lesions is not used for substantial energy production via Embden-Meyerhoff glycolysis, but rather for production of acid, which gives the cancer cells a competitive advantage for invasion. Alternative hypotheses, wherein the glucose is used for generation of reducing equivalents (NADPH) or anabolic precursors (ribose) are also discussed.

Somatic evolution of malignancy:
The purposeful manipulating of information by using the optimality of the genetic code, random variation and selection as a means to an end… adaptation to hypoxic and acidic fitness landscapes.


Viewing cells as computers that make other computers and information as an irreducible property of nature makes this view tenable.

 

[Phronesis]

New Protein Function Discovered Related article: New Protein Function Discovered; Sheds Light On Intricate Mechanics Of Cell Division

ScienceDaily (Jan. 9, 2009) — A group of Dartmouth researchers has found a new function for one of the proteins involved with chromosome segregation during cell division. Their finding adds to the growing knowledge about the fundamental workings of cells, and contributes to understanding how cell function can go wrong, as it does with cancerous cells.

The researchers studied a protein called NOD, distantly related to the motor proteins that power diverse cellular activities, including intracellular transport, signaling, and cell division. They used X-ray crystallography to determine its structure, and then they used enzyme kinetics to find out how it performed. While this protein is found in fruit flies, the results are helpful in determining how related proteins work in humans.

Nucleotide-binding Oligomerization Domain (NOD)

"This study on NOD provided evidence for a new way a kinesin motor could function," said Jared Cochran, a postdoctoral fellow at Dartmouth and the lead author on the study. "Rather than moving on its own, it hitches a ride on the ends of microtubules which results in a dynamic cross-linking between the arms of chromosomes and the cell's growing spindle of microtubules. If NOD doesn't function properly, then the two cells end up with either both or none of that particular chromosome, which is lethal [to the cell and the organism] in most cases."

"Before this study, it had been shown that kinesin motors either walked along their microtubule tracks or functioned to break microtubules apart," says Jon Kull, the senior author on the paper, associate professor of chemistry at Dartmouth, and a 1988 Dartmouth graduate. "This work describes a novel mode for kinesin function, in which NOD does not walk, but rather alternates between grabbing on to and letting go of the end of the growing filament, thereby tracking the end as it grows. The diversity of function of these proteins is remarkable."

Original article:
ATPase Cycle of the Nonmotile Kinesin NOD Allows Microtubule End Tracking and Drives Chromosome Movement

 

[Phronesis]

How The Sensory Organs Of Bacteria Function

ScienceDaily (Jan. 17, 2009) — Bacteria can occur almost anywhere on earth and exist under the most varying conditions. If these tiny, microscopic organisms are to survive in these environments, they need to be able to rapidly detect changes in their surroundings and react to them. Scientists at the Johannes Gutenberg University of Mainz are currently investigating how bacteria manage to pass information on their environment across their membranes into their cell nuclei.

"The sixty-four-thousand- dollar question is how signals are transmitted across the cell membrane," explains Professor Gottfried Unden of the Institute of Microbiology and Vinology. Working in collaboration with the Max Planck Institute for Biophysical Chemistry in Göttingen, his research group has demonstrated that structural alterations to membrane-based sensors play a major role in the transfer of signals.

Some bacteria possess more than 100 different sensors that they use to form a picture of their environment. These sensors can show, for example, whether nutrient substrates and/or oxygen are present in the immediate neighborhood of the cell and what the external status of temperature and light is like. These sensors are mainly located in the cell membrane, i.e., the layer separating bacteria cells from the environment. From there they then transmit signals into the cell nucleus.

Thanks to the development of new methods of isolating these sensors and of other innovative techniques, it is now possible to discover how all this works. The researchers in Mainz have also managed to modify a sensor that detects an important bacterial substrate so that it can be analyzed making use of new spectroscopic techniques. "This is the first time that solid-body nuclear magnetic resonance (NMR) spectroscopy has been used to investigate large membrane proteins," stated Professor Unden. In addition to this functional analysis, the structural analysis undertaken by the biophysicist team in Göttingen headed by Professor Marc Baldus has identified important details of the signal transmission process: a stimulus molecule – carbonic acid in this case – binds to a part of the sensor that protrudes from the cell.

This appears to result in dissolution of the ordered structure of that segment of the sensor within the cell that is in non-stimulated status. It seems that it is this plasticity that elicits the subsequent activation of the enzymatic reaction cascade within the cell. This results in the cellular response, which, for example, can take the form of neosynthesis of enzymes or the development of protective mechanisms.

In addition to the new findings on signal transmission published in Nature Structural and Molecular Biology, the microbiologists of Mainz University have discovered a previously unknown and exceptional method of signal detection employed by the same sensor (designated DcuS), which they discuss in an article in the Journal of Biological Chemistry. This shows that bacteria react not only to their extracellular environment, but also to the intracellular situation. It is becoming apparent that it is not the sensors alone that detect stimuli.

A second stimulus detection pathway is represented by the transport system that channels substrates into the cell. Once the substrate – carbonic acid – has been taken up, the transporter notifies the sensor of this. Prof. Unden added, "We have been able to identify that segment of the transporter that is responsible for the control of sensor functioning. The transporter is of fundamental importance for the function of the sensor. Without the transporter, the sensor does not work correctly and is constantly in activated status," explained Professor Unden, who suspects that this function-related feedback on metabolic and transport activity is often more important for a cell than information concerning concentrations only.

So, bacteria forms a picture of their surroundings so they can adequately respond to the environment.

And cells seem to count as well.

How Do Cells Count? Scientists Take A Step Further In Unraveling Mystery Of How Cells Control Number Of Centrosomes

ScienceDaily (Jan. 12, 2009) — In the 13th January print edition of the journal Current Biology, IGC researchers provide insight into an old mystery in cell biology, and offer up new clues to understanding cancer. Inês Cunha Ferreira and Mónica Bettencourt Dias, working with researchers at the universities of Cambridge, UK, and Siena, Italy, unravelled the mystery of how cells count the number of centrosomes, the structure that regulates the cell’s skeleton, controls the multiplication of cells, and is often transformed in cancer.

This research addresses an ancient question: how does a cell know how many centrosomes it has? It is equally an important question, since both an excess or absence of centrosomes are associated with disease, from infertility to cancer.

Each cell has, at most, two centrosomes. Whenever a cell divides, each centrosome gives rise to a single daughter centrosome, inherited by one of the daughter cells. Thus, there is strict control on progeny! By using the fruit fly, the IGC researchers identified the molecule that is responsible for this ‘birth control policy’ of the cell – a molecule called Slimb. In the absence of Slimb, each mother centrosome can give rise to several daughters in one go, leading to an excess of centrosomes in the cell.

In recent years, Monica’s group has produced several important findings relating to centrosome control: they identified another molecule, SAK, as the trigger for the formation of centrosomes. When SAK is absent, there are no centrosomes, whereas if SAK is overproduced, the cell has too many centrosomes. These results were published in the prestigious journals Current Biology and Science, in 2005 and 2007. Now, the group has discovered the player in the next level up: Slimb mediates the destruction of SAK, and in so doing, ultimately controls the number of centrosomes in a cell.

Monica explains, ‘We carried out these studies in the fruit fly, but we know that the same mechanism acts in mice and even in humans. Knowing that Slimb is altered in several cancers opens up new avenues of research into the mechanisms underlying the change in the number of centrosomes seen in many tumours’.

Mónica first became interested in centrosomes and in SAK when she was an Associate Researcher at Cambridge University, UK, and has pursued this interest at the IGC, where she has been group leader of the Cell Cycle Regulation laboratory since 2006. Inês Cunha Ferreira travelled with Monica from Cambridge, and is now in her second year of the in-house PhD programme. Two other PhD students in the lab also contributed to this research, Ana Rodrigues Martins and Inês Bento.

Sensing, counting and manipulating information in order to control succesful self-replication. Exquisitely controlled .

 

[Phronesis]

Molecular Forklifts Overcome Obstacle To 'Smart Dust'

ScienceDaily (Jan. 19, 2009) — Algae is a livid green giveaway of nutrient pollution in a lake. Scientists would love to reproduce that action in tiny particles that would turn different colors if exposed to biological weapons, food spoilage or signs of poor health in the blood.

Now, University of Florida engineering researchers have tapped the working parts of cells to clear a major hurdle to creating such "smart dust." The feat, which signifies a new approach to technology known as the "lab on a chip," is to be reported January 18 in the journal Nature Nanotechnology.

"Instead of just changing one part of an existing system, we have a new and different way of doing things," said Henry Hess, a UF assistant professor of materials science and engineering and the senior author of the paper. "And we can do it this way because of building blocks from bionanotechnology, and that's what makes it very exciting."

Chip-based labs have been developed in recent years as portable tools to gauge the presence of bioweapons, pollution, or to conduct on-the-spot blood tests. They are essentially assays, or ways to test for different pathogens, chemicals or compounds.

Scientists have suggested that the ever-shrinking labs could be reduced to the size of tiny particles of "smart" dust. But although today's versions may be small, they require equipment that is hand-held at its smallest, and often large enough to require a lab bench.

"It's like a computer," Hess said. "The central processing unit is the really interesting thing, but you need all this other stuff to make it work."

The extra equipment is needed because the assay, which uses pairs of antibodies to latch onto target contaminants and the markers that give away their presence, requires repeated flushing with water. That requires pumps, which need power. To miniaturize the system, it's necessary to build miniature pumps and batteries. But that's a challenge, especially for miniaturization to the level required for individual pieces of smart dust, Hess said.

His research strips out all peripheral equipment by using an altogether unique and different approach: biologically powered molecular forklifts.

Lab-on-achip technologies offer exciting new challenges and possibilities. The ability of detecting gene expression patterns of entire tissues being one of them. This provides a source of information to further narrow down the treatment options and strategies of a particular disease.

His research strips out all peripheral equipment by using an altogether unique and different approach: biologically powered molecular forklifts.

The forklifts are assembled from natural motor proteins that are active in cell division. Hess and his team's main innovation is manipulating these tiny proteins to perform heavy lifting and transport tasks -- tasks that lead to a successful assay.

For a system rooted in biology, the process is uncannily mechanical.

Using standard laboratory methods, the researchers squirt the forklifts into the central zone of three-zone circular surface no larger than the period at the end of this sentence. They then attach the same antibodies used in traditional chip-based labs.

When the surface is exposed to a contaminant, the antibodies latch onto it, just as happens with traditional assays. But then, activated by a flash of light, molecular shuttles start pushing the forklifts into a second zone, where they load aboard fluorescent particles, or tags. They move their cargo to the third zone, at the edge of the circle. There, over several hours, they crowd against each other, accumulating to the point where their combined loads form a line visible under magnification – and providing the telltale indicator of the contaminant.

The process requires no rinsing. And instead of electricity, the naturally derived forklifts are powered by adenosine triphosphate, or ATP, the molecule that carries energy for cells.

"You have replaced all this washing with this active transport by molecular shuttles, so you don't need a pump or battery," Hess said.

Using biomolecular machinery to implement a new technique. Nice engineering...

Michael Sailor, a professor of chemistry and biochemistry at the University of California San Diego and prominent smart-dust researcher, called the research "quite promising."

"The key advance is that the authors incorporate a transport mechanism derived from a natural system into an artificial microsensor," he wrote in an e-mail. "The authors show how adding the ability to move around in an autonomous fashion can dramatically improve the performance of the microsensor."