Source: Wen et al. (2008). Following translation by single ribosomes one codon at a time. Nature 452:598-603.
In terms of methodology, this is a very interesting paper. The results, on the other hand, can revolutionize our way of thinking regarding the ribosomes and the translation process. The authors employ the laser trap technology, formerly developed to measure the molecular forces (piconewtons) and displacements (nanometers) generated by a single myosin molecular motor as it interacts with a single actin filament, to follow a single ribosome translating an mRNA hairpin. Below, you can see their experimental set-up.
According to their results, translation does not occur continuously as we thought so. When the ribosome starts translocating, it opens up the hairpin, thus increasing the distance between the two beads which is measurable by the laser trap. As you see in the figure below, the ribosome goes through a translocation-pause cycles (shown with arrows in the top panel).
This is a really important change in how we look at translation. For example, each of these pause times (that differ in length quite drastically) can act as foci of post-transcriptional regulation.
Source: Stayrook et al. (2008). Crystal structure of the λ repressor and a model for pairwise cooperative operator binding. Nature 452:1022-1025.
My first reaction after seeing paper was, "THEY'RE STILL WORKING ON λ". Well, apparently they do and they have some paradigm shifting results. λ (cI) is the key trasncription factor for lysogeny in this bacteriophage. Simultanuous repression and activation of two distinct (and adjacent) promoters by 'alternate pairwise' binding of this protein is the key to the bistability of the lytic-lysogeny dicotomy. For background information, I refer you to wikipedia. The key question that the authors need to answer is the 'alternate pairwise' binding, where a pair of cI dimers can either take on OR1-OR2 or OR2-OR3 (if OR1 is mutated). Our structural knowledge of cI doesn't tell us why there is no OR1-OR2-OR3 trimer. This exactly what the authors explain through solving the structure of λ repressor in its complete dimer structure. Apparently, the inherent symmetry that we have in mind does not exist (see below; left: schematic cI structure, right: what it really looks like).
This assymetry impedes a third cI dimer from both binding the other cIs and DNA at the same time.
Source: Orlando et al. (2008). Global control of cell-cycle transcription by coupled CDK and network oscillators. Nature 453:944-947.
This short paper highlights the fact that the periodicity observed in the expression of many genes across the cell cycle, although initially attributed to the CDKs, is in fact additionally controlled by a transcription network. Their basic observation is that in a cyclin-mutant cell, the periodic expression of the genes, although aberrant, is largely intact; whereas, the cells are arrested in the G1-S transition.
Their results suggest a transcription network in which the transcription factors are sequentially activated in a cyclic manner as an independent clock based on which the cell determines its progression in the cell cycle. This apparent redundancy (i.e. the presence of two oscillators) in this system ensures the robustness of the cell cycle regulation in our cells.
Source: Spalding et al. (2008). Dynamics of fat cell turnover in humans. Nature 453:783-787.
I loved this paper... I thought it was brilliant... First, a couple of known facts:
- Obesity is a major issue. We might experience a decrease in life expectancy solely based on this factor.
- Fat mass is a function of both the volume and the number of adipocytes.
- The number of adipocytes, although different in individuals, stays the same throughout adulthood.
- The number of adipocytes is set during childhood and adolescence.
- While the number is constant, the turnover is not known.
This paper has tackled the last issue... The fact that the number of adipocytes doesn't change is not equivalent to the concept that these cells are immortal. We do know that these cells go through apoptosis and sometimes even necrosis in vitro but there are no data regarding this matter in living humans mainly due to the toxicity of the methods used for following cell progenies. In this paper, authors have used a modern and intersting method to estimate the rate of turnover in adipocytes. This method is based on the 14C level in the atmosphere. Following the nuclear bomb tests of the Cold War era, a rapid increase and notable increase in 14C level of the atmophere was reported. Upon the declaration of Test-Ban Treaty (1963), this level has decreased exponentially because 14C is assimilated by the plants as biomass which is then transferred to other ecological levels (including us). For example, someone who was 20 years old when those tests happened should have a pre-Cold War level of 14C if the adipocytes are immortal and don't regenerate. However, the measurements in this study prove otherwise. Integrating data from many samples followed by a mathematical modeling, the authors estimate an annual turnover rate of 10% for fat tissue.
The fact that 10% of the adipocytes are renewed annually is very important for developing drugs against obesity. If we can tackle the birth rate or increase the death rate then (theoretically) we should be able to control total body fat.
Source: Guelen et al. (2008). Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453:948-951.
This is a great paper with interesting methods and exciting results. The authors use DamID to identify the regions of the genome that interact with the nuclear lamina (NL). For this they make a DNA adenine methyltransferase (Dam) fused to human lamin B1. Upon formation of the nuclear structure, Dam methylates the nearby adenine nucleotides that can be later identified as foci of interaction. Upon mapping genome-NL interactions (lamina associated domains or LADs) they compare the NL-free regions with those that are attached. Their first observation is that NL-bound regions have a low frequency of coding sequences, and those that are there are generally expressed at low levels. Secondly, NL-bound regions are isolated from the other parts of the genome through insulator proteins, promoters directed away from the LADs and GC boxes.
This paper makes the case for a complex level of chromosome organization where domains can be seperated by LADs and thus acting as perfect insulators.
Source: McMurray et al. (2008). Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype. Nature 453: 1112-1116.
First of all, a couple of my friends have started a similar blog on parasitology (http://parasitediary.wordpress.com/); for those of you who are working in this field, I think they'll be thrilled if you visit their blog, leave comments or even better contribute.
Now back to our own post... well, tumorigenesis is a hot topic with many papers being published in very good journals solely based on a subject profiling. This paper, however, very well deserves its publication in Nature. The authors start with the notion that genes with synergistic effects across tumorigenic mutations should play a key role in the emergence of the transformed state and throughout the paper they provide evidence in support of their hypothesis. First, they profile the gene expressions in p53, ras, and p53/ras cell lines. Then, they focus on the genes in the double mutant with a fold-change larger than the sum of fold changes in the single mutants (i.e. synergistic genes). Note that these fold-changes can be both positive and negative; thus, we include both positive and negative synergism. An initial look at these genes shows a diversity of roles in signaling, transcription, apoptosis and adhesion that are generally deregulated in the available cancer gene-expression datasets.
To show that these genes are important in tumorigenesis, they restore the normal expression levels of 24 synergistic and 14 non-synergistic genes, one by one, in the double mutant background. For this, they employ retro-virus mediated re-expression or shRNA-dependent knockdown. They show that in 14/24 cases, for the synergistic genes, there is a significant reduction in tumorigenesis upon restoring normal expression levels; whereas, only 1/14 non-synergistic genes shows such level of effect.
To summarize, this paper makes the case for synergistic genes to be foci of transformation; thus, excellent genes for studying or therapeutic targeting.
Source: Berkman et al. (2008). Evolution and Creationism in America's Classromms: A National Portrait. PLoS Biology 6(5):e124.
"Evolution--more precisely opposition to it--is profoundly important to fundamentalist Christianity, where it has played a critical role in its early formation as doctrine and as a social movement". This is one of the key sentences in this paper, highlighted by the authors themselves. They make the case that despite recent judiciary victories of evolution over its petty imaginative counterpart (Intelligent Design [at least someone is intelligent]) in the courtroom, we (the scientists) are losing the case in the classrooms where the science teachers have to actually teach evolution. While only 16% of the science teachers believe in creationism (compared to 48% of the general public), they have a hard time devoting enough resources to this theory which is dubbed "a unifying theme in science" by the National Science Education Standards. As the authors put it, "community pressures place significant stress on teachers as they try to teach evolution, stresses that can lead them to de-emphasize, downplay, or ignore the topic".
The question is, why do we care? For example Richard Dawkins believes that any public discussion of this matter with creationists would bring them a sort of validity that they don't have and don't deservce (thus the question mark in the title of this post). Everyone treat this matter as if it is a personal decision to make. Believeing the Earth to be flat is not a personal decision, so is not evolution. Nowadays, science is pretty much speclizied with researchers deep into their specific knowledge. For example, I trust my friends in Math department when they say "the world has 11 dimensions" because I don't know squad about string theory. Or I don't question my doctor's diagnosis as absurd as they may seem to my untrained eyes (e.g. you go to them for headaches, they say there's something wrong with your stomach).... The same should hold for evolution... We know what we're talking about because we have studied this for years... We have a whole field that's working based on it.... When we say it holds, TRUST ME, it holds.
According to their results, translation does not occur continuously as we thought so. When the ribosome starts translocating, it opens up the hairpin, thus increasing the distance between the two beads which is measurable by the laser trap. As you see in the figure below, the ribosome goes through a translocation-pause cycles (shown with arrows in the top panel).
This is a really important change in how we look at translation. For example, each of these pause times (that differ in length quite drastically) can act as foci of post-transcriptional regulation.
