The Most Scizzling Papers of 2013

 

The Scizzle Team

Bacteriophage/animal symbiosis at mucosal surfaces

The mucosal surfaces of animals, which are the major entry points for pathogenic bacteria, are also known to contain bacteriophages. In this study, Barr et al. characterized the role of these mucus associated phages. Phages were more commonly found on mucosal surfaces than other environments and adhere to mucin glycoproteins via hypervariable immunoglobulin like domains. Bacteriophage pre-treatment of mucus producing cells provided protection from bacterial induced death, but this was not the case for cells that did not produce mucus. These studies show that there may be a symbiotic relationship between bacteriophages and multicellular organisms which provides bacterial prey for the phages and antimicrobial protection for the animals.

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Interlocking gear system discovered in jumping insects

Champion jumping insects need to move their powerful hind legs in synchrony to prevent spinning. Burrows and Sutton studied the mechanism of high speed jumping in Issus coleoptratus juveniles and found the first ever example in nature of an interlocking gear system. The gears are located on the trochantera (leg segments close to the body’s midline) and ensure both hind legs move together when Issus is preparing and jumping. As the insect matures, the gear system is lost, leaving the adults to rely on friction between trochantera for leg synchronization.

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HIV-1 capsid hides virus from immune system

Of the two strains of HIV, HIV-1 is the more virulent and can avoid the human immune response, whereas HIV-2 is susceptible. This may be due to the fact that HIV-2 infects dendritic cells, which detect the virus and induce an innate immune response. HIV-1 cannot infect dendritic cells unless it is complexed with the HIV-2 protein Vpx, and even then the immune response isn’t induced until late in the viral life cycle, after integration into the host genome. Lahaye et al. found that only viral cDNA synthesis is required for viral detection by dendritic cells, not genome integration. Mutating the capsid proteins of HIV-1 showed that the capsid prevents sensing of HIV-1 cDNA until after the integration step. This new insight into how HIV-1 escapes immune detection may help HIV vaccine development.

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Transcription factor binding in exons affects protein evolution

Many amino acids are specified by multiple codons that are not present in equal frequencies in nature. Organisms display biases towards particular codons, and in this study Stamatoyannopoulos et al. reveal one explanation. They find that transcription factors bind within exonic coding sequences, providing a selective pressure determining which codon is used for that particular amino acid. These codons are called duons for their function as both an amino acid code and a transcription factor binding site.

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Chromosome silencing

Down syndrome is caused by the most common chromosomal abnormality in live-born humans: Trisomy 21. The association of the syndrome with an extra (or partial extra) copy of chromosome 21 was established in 1959. In the subsequent fifty years a number of advances have been made using mouse models, but there are still many unanswered questions about exactly why the presence of this extra chromosome should lead to the observed defects. An ideal experimental strategy would be to turn off the extra chromosome in human trisomy 21 cells and compare the “corrected” version of these cells with the original trisomic cells. This is exactly what a team led by Jeanne Lawrence at the University of Massachusetts Medical School has done. Down syndrome is not the only human trisomy disorder: trisomy 13 (Patau syndrome) and trisomy 18 (Edward’s syndrome), for example, produce even more severe effects, with life expectancy usually under one to two years. Inducible chromosome silencing of cells from affected individuals could therefore also provide insights into the molecular and cellular etiology of these diseases.

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Grow your own brain

By growing organs in a dish researchers can easily monitor and manipulate the organs’ development, gaining valuable insights into how they normally develop and which genes are involved. Now, however, a team of scientists from Vienna and Edinburgh have found a way to grow embryonic “brains” in culture, opening up a whole world of research possibilities. Their technique, published in Nature, has also already provided a new insight into the etiology of microcephaly, a severe brain defect.

[box style=”rounded”]Scizzling extra: In general, 2013 was a great year for growing your own kidneyspotentially a limb and liver. What organ will be next? [/box]

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Sparking metastatic cell growth

A somewhat controversial paper published in Nature Cell Biology this year showed that the perivescular niche regulates breast tumor cells dormancy. The paper showed how disseminated breast tumor cells (DTC) are kept dormant and how they can be activated and aggressively metastasize. Based on the paper, this is due to the interaction of interaction with the microvascularate, where thrombospondin-1 (TSP-1) induces quiescence in DTC and TGF-beta1 and periosstin induces DTC growth. This work opens the door for potential therapeutic against tumor relapse.

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Fear memories inherited epigenetically

Scientists showed that behavioral experiences can shape mice epigenetically in a way that is transmittable to offspring.  Male mice conditioned to fear an odor showed hypomethylation for the respective odor receptor in their sperm; offspring of these mice showed both increased expression of this receptor, and increased sensitivity to the odor that their fathers had been conditioned on.  Does this suggest that memories can be inherited?

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Grid cells found in humans

Scientists have long studied rats in a maze, but what about humans?  An exciting paper last August demonstrated that we, like out rodent counterparts, navigate in part using hippocampal grid cells.  Initially identified in the entorhinal cortex of rats back in 2005, grid cells have the interesting activity pattern of firing in a hexagonal grid in the spatial environment and as such are thought to underlie the activity of place cells. Since then grid cells have been found in mice, rats, and monkeys, and fMRI data has suggested grid cells in humans.  This paper used electrophysiological recordings to document grid cell activity in humans.

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Sleep facilitates metabolic clearance

Sleep is vital to our health, but researchers have never been entirely sure why.  It turns out part of the function of sleep may be washing waste products from the brain, leaving it clean and refreshed for a new day of use.  Exchange of cerebral spinal fluid (CSF), which is the primary means of washing waste products from the brain, was shown to be significantly higher when animals were asleep compared to waking.  This improved flow was traced back to increased interstitial space during sleep, and resulted in much more efficient clearance of waste products.  Thus, sleep may be crucial to flushing metabolites from the brain, leaving it fresh and ready for another day’s work.

[box style = “rounded”] Robert adds: As a college student my friends and I always had discussions about sleep and it was also this mysterious black box of why we actually need to sleep. Studies could show the effects of lack of sleep such as poor cognition and worse memory but this paper linked it to an actual mechanism by which this happens. First of all I found it very impressive that the researchers trained mice to sleep under the microscope. On top of that showing the shrinkage of the neurons and the flow of cerebrospinal fluid which cleans out metabolites finally linked the cognitive aspects of sleep deprivation to the physical brain. [/box]

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Poverty impedes cognitive function

People who are struggling financially often find it difficult to escape poverty, in part due to apparently poor decision making.  Investigators demonstrated that part of this vicious cycle may arise from cognitive impairment as a direct result of financial pressures.  The researchers found that thinking about finances reduced performance on cognitive tasks in participants who were struggling, but not in those who were financially comfortable.  Furthermore, farmers demonstrated poorer cognitive performance before harvest, at a time of relative poverty, compared to after harvest when money was more abundant.

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Gut Behavior

2013 has definitely been the year of the gut microbiome! Studies have shown that diet affects the composition of trillions of microorganisms in the human gut, and there is also a great deal of evidence pointing towards the gut microbiome affecting an individual’s susceptibility to a number of diseases. Recently published in Cell, Hsiao and colleagues report that gut microbiota also affect behavior, specifically in autism spectrum disorder (ASD). Using a mouse model displaying ASD behavioral features, the researchers saw that probiotic treatment not only altered microbial composition, but also corrected gastrointestinal epithelial barrier defects and reduced leakage of metabolites, as demonstrated by an altered serum metabolomic profile. Additionally, a number of ASD behaviors were improved, including communication, anxiety, and sensorimotor behaviors. The researchers further showed that a particular metabolite abundant in ASD mice but lowered with probiotic treatment is the cause of certain behavioral abnormalities, indicating that gut bacteria-specific effects on the mammalian metabolome influence host behavior.
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Your skin – their home

A paper published in Nature examined the diversity of the fungal and bacterial communities that call our skin home. The analysis done in this study revealed that the physiologic attributes and topography of skin differentially shape these two microbial communities. The study opens the door for studying how the pathogenic and commensal fungal and bacterial communities interact with each other and how it affects the maintenance of human health.

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Discovery of new male-female interaction can help control malaria

A study published in PLOS Biology provided the first demonstration of an interaction between a male allohormone and a female protein in insects.  The identification of a previously uncharacterized reproductive pathway in A. Gambiae has promise for the development of tools to control malaria-transmitting mosquito populations and interfere with the mating-induced pathway of oogenesis, which may have an effect on the development of Plasmodium malaria parasites.

[box style = “rounded”]Chris adds: “My friend chose this paper to present at journal club one week, because he thought it was well written, interesting etc etc. Unbeknownst to him, one of the paper’s authors was visiting us at the time. We sit down for journal club and one of the PIs comes in, sees the guy and exclaims (with mock exasperation) “you can’t be here!” Me and the presenter look at one another, confused. He presents journal club, and luckily enough, the paper is so well written, that he can’t really criticize it!” [/box]

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Using grapefruit to deliver chemotherapy

Published in Nature Communications, this paper describes how nanoparticles can be made from edible grapefruit lipids and used to deliver different types of therapeutic agents, including medicinal compounds, short interfering RNA, DNA expression vectors, and proteins to different types of cells. Grapefruit-derived nanovectors demonstrated the ability to inhibit tumor growth in two tumor animal models. Moreover, the grapefruit nanoparticles used in this study had no detectable toxic effects, could be manipulated or modified to target specific cells/ tissues, and were economical to create. Grapefruits may have a bad reputation for interfering with drugs, but perhaps in the future we will be using grapefruit products to deliver drugs more effectively!

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Getting CLARITY

In May, a new technique called CLARITY to effectively make tissue transparent through a new fixation technique was published in Nature. This new process has allowed them to clearly see neuron connection networks not possible before because they can now view the networks in thicker tissue sections. This new advancement will help researchers be able to better map the brain, but this new technology can also be to create 3-D images of other tissues such as cancer. This new ability allows us to gain better insight into the macroscopic networks within a specific tissue type.

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Crispier genome-editing

This year, the CRISPR technique was developed as an efficient gene-targeting method. The benefit of this method over the use of TALENS or a zinc-finger knockout is it allows for the rapid generation of mice that have multiple genetic mutations in just one step. The following review gives even more information on this new technique and compares its usefulness to that of TALENS and zinc-finger knockouts. Further, just couple of weeks ago, two back-to-back studies in Cell Stem Cell using the CRISPR-Cas9 system to cure diseases in mice and human stem cells.  In the first study the system was used in mice to correct the Crygc gene that causes cataracts; in the second study the CRSPR-Cas9 system was used to correct the CFTR locus in cultured intestinal stem cells of CF patients. These findings serve as a proof-of-concept that diseases caused by a single mutation can be “fixed” with genome editing using the CRISPR-Cas9 system.

What was your favorite paper this year? Let us know! And of course – use Scizzle to stay on top of your favorite topics and authors.

Division Doppelgangers

Alisa Moskaleva

 

Cyclin A is a confounded nuisance for cell biologists. Noticed serendipitously in 1982 in sea urchins and clams in an experiment that earned a share of the 2001 Nobel Prize in Physiology or Medicine, cyclin A and its doppelganger protein, cyclin B, help cells of all animals grow and divide properly. Cells stockpile both proteins before dividing, use them to control division, and then degrade them after they have served their purpose. If cells are deprived of cyclin A or cyclin B, they can’t divide. If cells have too much of these proteins they start dividing early and get stuck, unable to separate into two new cells. But whereas cyclin B sticks around until the step before the two new cells separate, when the two copies of the cell genome are all set to separate, cyclin A disappears several minutes earlier when those two copies of the genome are nowhere near ready to split. Why does a responsible regulator like cyclin A leave its post so scandalously early? And why does a cell need cyclin A to regulate division when it has cyclin B there willing and present?

Lilian Kabeche and Duane A. Compton begin to answer both of these questions in their October 3 Nature paper. They took a close, microscope-assisted look at what goes on during cell division. The general process of cell division has been known for over a hundred years. Before starting to divide, the cell replicates its contents, including its DNA, so it can pass on a copy to both cells of the new generation. Then, during the prometaphase stage, the cell packs up its DNA really tightly and simultaneously builds up lots of microtubules, which are long fibers of protein that act as miniature ropes and sprout from two opposite sides of the dividing cell. The microtubules attempt to lasso the DNA, so that half of the DNA is attached to microtubules from one end of the cell and the other half is attached to microtubules from the other end of the cell. At this time cyclin A disappears. Then, at a stage called metaphase when the DNA is all lined up in the middle of the cell and properly attached to microtubules, cyclin B disappears. What follows is separation of the two copies of DNA to the two sides of the cell, pulled by microtubules; this is called anaphase. Finally, in telophase the two cells pinch off from each other and resume growing.

Kabeche and Compton focused on how cyclin A may be regulating the way microtubules attach to DNA. The big blob of DNA inside a cell is quite easy to see under a microscope, but it’s much harder to see the thin individual microtubules. Thus, Kabeche and Compton labeled microtubules with a photoactivatable fluorescent protein, a protein that can be made to glow by shining a certain wavelength of light on it. Then they looked for microtubules that approached DNA, shone light on them to make them glow, and assessed whether the glowing microtubules would stay in place or wander off. They observed that in prometaphase microtubules were much more likely to wander off than in metaphase. This makes sense. In metaphase, the DNA is organized and aligned, so it should be easy for microtubules to grab it. In prometaphase, by contrast, the DNA is still unorganized and in the process of aligning, so mistakes in attaching microtubules are likely. Microtubules from both sides of the cell may grab the same copy of DNA. Or microtubules from only one side of the cell may grab both DNA copies. These attachment mistakes, if not corrected, would distribute DNA unevenly or even tear it up, leading to deleterious mutations. So, it’s good that microtubules in prometaphase do not attach stably. When Kabeche and Compton gave cells extra cyclin A, they saw that microtubules would wander much longer than normally even in cells that were in metaphase and had their DNA aligned properly. And when Kabeche and Compton deprived cells of cyclin A, they noticed that the DNA separated unevenly, suggesting that microtubules attached at the wrong place.

All of these observations suggest that cyclin A somehow makes microtubules restless, whereas cyclin B, still present when microtubules make stable attachments, does not. The cell uses cyclin A to control the attachment of microtubules to DNA, and then disposes of it, while relying on cyclin B to control the separation of DNA copies. Given its distinct function, cyclin A disappears not early, but at precisely the right time. If it were to stick around, microtubules would never attach to DNA and division would never proceed. On the other hand, if it were not present at all, microtubules would attach too early and in all the wrong places, leading to mistakes in partitioning the genome to the new generation. Of course, there are many vexing questions that remain to be answered, the most obvious of which is how does cyclin A cause microtubules to no longer attach to DNA? It looks like cyclin A has many more mysteries to reveal.

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Bees, Teas and Rational Design

Chris Spencer

BEES. You will have read me waxing lyrical about bees before, and I’m going to do it again. We all know the conventional benefits of bees (honey, pollination) but, I will admit they come with one certain sharp and aggressive downside – the stinger.

However, I’m here to make the case that the stinger isn’t all bad. Okay, the stinger itself is pretty bad, particularly if you are allergic, but the venom itself seems to have a few properties that we can take advantage of. The major active component of apitoxin (bee venom) is melittin, a 26 amino acid peptide. This peptide has been implicated as a potent antimicrobial – it has been shown to inhibit the Lyme disease pathogen Borrelia and also the opportunistic fungal pathogen Candida. In February this year, nanoparticles containing melittin were shown to destroy the HIV envelope, killing the virus.

A paper published in July this year by Shin et al gives a perspective on yet another property of melittin; that it is anti-angiogenic.

Angiogenesis is the process whereby new blood vessels grow from existing vessels. It’s a normal physiological process, and one which is very important. Certain cancers arise because of the malignment of this (and other) processes. One pathway in angiogenesis is the regulation of vascular endothelial growth factor (VEGF) – a signal protein which stimulates the growth of blood vessels. VEGF is itself regulated by HIF-1 – a transcription factor. In cancers, the improper regulation of VEGF is often what causes cancers to metastasize. If therefore, there were an inhibitor that we could use to neutralize VEGF, then there would be an opportunity to curb the invasiveness of cancer in patients, before it has a chance to develop.

Cue melittin. Shin et al. have shown that melittin acts to inhibit HIF-1, and furthermore, melittin was shown to have a potent anti-angiogenic effect in tumours.

What can be learned from this then? I’m not suggesting for one second that the more research that we do, the more we’ll come to realize that melittin is actually some sort of panacea that will cure everything forever. But one can certainly say that diseases that are currently seen as incurable will one day be very treatable using compounds that we have not yet discovered. One such example is a study by Somsak et al. that suggests that green tea helps with a malaria infection (one major cause of morbidity in malaria infection is renal failure, however green tea extract provides some protection against kidney damage).

Perhaps soon enough, the days of having to screen compound after compound to see if they have an inhibitory effect on a disease effector will be behind us. With the field of computer aided ligand design coming on in leaps and bounds in recent years, it might not be foolish to hope that, with knowledge of a disease pathway, it might be possible to simply design and manufacture a specific inhibitor that can be used to stop the progression of an illness. It’s a future which sounds incredibly appealing, and maybe it’s not too far off.

But then no one would be singing the praises of bee stings.

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What’s Chromatin Got to Do With It?

Alisa Moskaleva

 

We know that cells lead intricate lives of growth, change, and division. We also know that DNA has not only the four letters A, T, C, and G, but also an intricate grammar of modifications on DNA-associated proteins, termed chromatin, that changes over time. We can surmise that there is a connection between the life cycle of a cell, called the cell cycle, and its chromatin. But how does the cell cycle influence chromatin? Yang Xu and colleagues shed new light on this question in a paper in the latest issue of the Cell Cycle.

 

Before a cell can divide, it must first condense its chromatin into packages called mitotic chromosomes, so that its genome may be evenly divided between its two daughters. One of the chromatin modifications that promotes this condensation is the deubiquitination of histone H2A. It’s been known for six years that a protein called Ubp-M can deubiquitinate histone H2A. Now Xu and colleagues explain what causes Ubp-M to deubiquitinate histone H2A before mitosis and not at other times in the cell cycle.

 

Xu and colleagues focused on a phosphorylation on the 552nd amino acid, a serine, of Ubp-M. This serine is in a motif that a kinase called CDK1 likes to phosphorylate. CDK1 is to the cell cycle what a conductor is to the symphony orchestra: it coordinates all the events, so that they happen in the right sequence and at the appropriate time. By knocking down CDK1 and using chemical inhibitors, Xu and colleagues established that CDK1 indeed phosphorylates Ubp-M on its serine 552.

 

Phosphorylation changes interactions between proteins. To find the function of the phosphorylation of serine 552, Xu and colleagues looked at the interaction between Ubp-M and a nuclear exporter called CRM1. This is a particularly interesting interaction because Ubp-M spends most of the cell cycle in the cytoplasm, even though it must go to the nucleus to deubiquitinate histone H2A. Therefore, Ubp-M is actively exported from the nucleus, and Xu and colleagues used an inhibitor of CRM1 to show that CRM1 participates in this export. Interestingly, a mutant version of Ubp-M that cannot be phosphorylated on the 552nd amino acid does not get exported as much. This mutant version also decreases cell proliferation and reduces the number of cells that enter mitosis. However, the mutation has no effect on the ability of Ubp-M to deubiquitinate histone H2A. Since CDK1 becomes more active before mitosis, Xu and colleagues propose that it phosphorylates Ubp-M on serine 552 and increases the fraction of Ubp-M in the nucleus, thus promoting chromatin condensation and mitosis.

Serine 552 of Ubp-M is present in primates but is not conserved in the mouse or rat homolog of Ubp-M. Though this particular example of temporal control using phosphorylation and localization occurs in only a few animal species, the principle is likely more general. Moreover, Ubp-M may contain other more conserved phosphorylation sites that function in the same way. And it is intriguing to speculate what special function this phosphorylation may serve in primates. Regardless, Xu and colleagues flesh out a direct connection between the cell cycle and chromatin modification to a rare level of detail.