Following Folding Fast
Many protein functions involve conformational changes that occur on time-scales between tens of microseconds and milliseconds. This has limited the usefulness of all-atom molecular dynamics simulations, which are performed over shorter time-scales. Shaw et al. (p. 341) now report millisecond-scale, all-atom molecular dynamics simulations in an explicitly represented solvent environment. Simulation of the folding of a WW domain showed a well-defined folding pathway and simulation of the dynamics of bovine pancreatic trypsin inhibitor showed interconversion between distinct conformational states.
Shocking Radio Relic
Radio relics are diffuse, elongated radio sources located on the outskirts of galaxy clusters thought to trace shocks generated by collisions between galaxy clusters. Particles may be accelerated within the shock waves by a diffusive shock acceleration mechanism, which also accelerates particles in shock waves produced by supernova explosions. Van Weeren et al. (p. 347, published online 23 September) report the detection of a megaparsec-scale radio relic showing all the properties of diffusive shock acceleration expected at radio wavelengths. The results suggest that this acceleration mechanism operates on scales larger than those of supernova remnants and imply that merging clusters of galaxies can accelerate particles to energies much higher than those achieved in supernova remnants
Inflammation Response in Living Color
Besides responding to microbial infection, our immune system also plays an important role in responding to sterile injury, for example, during trauma or organ necrosis. In a mouse model of sterile liver inflammation, McDonald et al. (p. 362) used dynamic in vivo imaging to visualize the innate immune response, which is dominated by neutrophils. Neutrophils were rapidly recruited to the site of inflammation through intravascular channels. Adenosine triphosphate generated from necrotic cells at the injury site and the Nlrp3 inflammasome were required for neutrophils to exit the circulation into the vascular endothelium, where they used integrins to adhere. A luminal chemokine gradient guided integrin-dependent, intravascular migration toward the site of injury. Finally, formyl peptides provided a signal to override the chemokine gradient and draw neutrophils into the site of injury.
Taking the Cystine
Kidney stones that form from l-cystine are much less common than those forming from calcium oxalate monohydrate, but are more likely to cause chronic kidney disease. Rimer et al. (p. 337; see the cover; see the Perspective by Coe and Asplin) designed two structural mimics for l-cystine. Atomic force microscopy showed that at low concentrations, the mimics could change the l-cystine crystal habit and inhibit overall crystal growth. These structural mimics may thus offer hope for treating cystinuria.
Turning Up the Heat
The physical effect of atmospheric carbon dioxide on Earth's energy budget—that is, its “greenhouse effect”—has been understood for more than 100 years, but its role in climate warming is still not universally accepted. Lacis et al. (p. 356) conducted a set of idealized climate model experiments in which various greenhouse gases were added to or subtracted from the atmosphere in order to illustrate their roles in controlling the temperature of the air. The findings clearly show that carbon dioxide exerts the most control on Earth's climate, and that its abundance determines how much water vapor the atmosphere contains, even though the radiative effect of the water vapor is greater than that of carbon dioxide itself.
Hot Enough to See
Over the last decade, detection of fluorescence from individual molecules has allowed for increasingly detailed probing of biochemical reaction mechanisms. The key advantage of fluorescence detection is the absence of background; the signal appears as a glowing point in a void. However, not all molecules fluoresce, and so alternative detection methods are needed. Gaiduk et al. (p. 353) now show that a photothermal detection scheme can resolve absorption events by individual molecular dyes that exhibit poor fluorescence efficiency. The technique relies on each molecule's release of heat to the surrounding solvent after light absorption, an energy dissipation mechanism that is enhanced as fluorescence efficiency declines. The solvent heating alters the local refractive index just enough to scatter a portion of a probe beam backwards, revealing the absorption.
Packing the Core
The packing and arrangement of atoms in Earth's solid inner core can dictate processes such as core growth and rotation. Seismology and modeling suggest the inner core is composed primarily of iron, but the structure is less clear due to anisotropic splitting of seismic waves. Tateno et al. (p. 359) performed static compression experiments on pure iron at the extremely high pressures and temperatures found in the inner core and saw that iron prefers a hexagonal close-packed structure, as opposed to cubic structures. The results help to explain the observed seismic anisotropy, and also suggest that individual iron crystals in the core may prefer orienting themselves with their long crystallographic axes parallel to Earth's rotation axis.
In mammals, meiotic maturation of oocytes must be coordinated precisely with ovulation to produce a developmentally competent egg at the right time for fertilization. How is coordination achieved? Follicular granulosa cells prevent precocious resumption of meiosis in oocytes, maintaining meiotic arrest until the pre-ovulatory hormone surge. Granulosa cells produce cyclic guanosine monophosphate, which is delivered to oocytes and arrests meiotic progression by inhibiting oocyte cyclic adenosine monophosphate degradation. How cGMP production is regulated is unclear. Now, Zhang et al. (p. 366) report that NPPC (natriuretic peptide precursor type C), produced by mural granulosa cells, and its receptor NPR2, a guanylyl cyclase expressed by cumulus cells, together promote cGMP production by cumulus cells and are thus essential for maintaining meiotic arrest in mouse oocytes.
The decoding of messenger RNA (mRNA) into protein by eukaryotic ribosomes is constantly monitored to prevent errors. As well as mechanisms that detect and degrade messages with premature stop codons, no-go decay (NGD) results in the degradation of mRNA with inhibitory secondary structure or chemical damage. Shoemaker et al. (p. 369) show that in Saccharomyces cerevisiae the protein complex formed between Dom34 and Hbs1 is involved in NGD. The complex acts as a translational “reset button,” recognizing failed translation events and initiating an abortive program that results in the destruction of the stalled mRNA.
Time and Temperature
Daily cycles in environmental temperature are an important cue for many organisms to synchronize their endogenous circadian clock. However, mammals do not respond to this cue. Studying mouse tissue, Buhr et al. (p. 379; see the Perspective by Edery) find that this resistance to temperature is a feature specific to the suprachiasmatic nucleus (SCN), a region of the mammalian brain that functions as the body's master clock. In contrast, the clocks in peripheral tissues (for example, lung, liver) are fully capable of resetting in response to temperature changes and do so by a mechanism involving the heat shock pathway. The SCN drives daily rhythms in body temperature, and SCN-driven changes in temperature may synchronize the body's peripheral clocks. Without its intrinsic resistance to temperature, the SCN could be subject to disruptive feedback effects.
BDNF, Dopamine, and Cocaine Reward
The nucleus accumbens plays a crucial role in mediating the rewarding effects of drugs of abuse. Different subpopulations of nucleus accumbens projection neurons exhibit balanced but antagonistic influences on their downstream outputs and behaviors. However, their roles in regulating reward behaviors remains unclear. Lobo et al. (p. 385) evaluated the roles of the two subtypes of nucleus accumbens projection neurons, those expressing dopamine D1 versus D2 receptors, in cocaine reward. Deleting TrkB, the receptor for brain-derived neurotrophic factor, selectively in each cell type, and selectively controlling the firing of each cell type using optogenetic techniques allowed for confirmation that D1- and D2-containing neurons produced opposite effects on cocaine reward.
Salmonella Stealth Bomber
Salmonella secretes a virulence factor, SipA, which helps it to invade epithelial cells of the gut. During invasion, the host cell is triggered into synthesizing and secreting the apoptotic enzyme caspase-3. Srikanth et al. (p. 390) now show that instead of being extinguished as the host cell collapses into programmed cell death, during the early stages of infection, Salmonella diverts the host enzyme to its own use. The SipA protein has amino acid motifs that are recognized by caspase-3, which cleaves the bacterial protein into active virulence effectors: one stimulates actin polymerization to help cell entry and the other induces inflammation. If the caspase motif contains a single-point mutation, then virulence is lost in mouse models of infection. Conversely, caspase-deficient mice suffer less from Salmonella-induced gastroenteritis.
Block Copolymer Assembly
Despite their structural simplicity, block copolymers can assemble into complex and often surprising structures. Lee et al. (p. 349; see the Perspective by Peterca and Percec) demonstrate the formation of a new ordered phase in a diblock copolymer and a tetrablock copolymer formed from frustrated self-assembled spherical microdomains. Remarkably, this structure contains tetragonal unit cells with 30 spheres per lattice site and is related to dodecagonal quasicrystals. This structure was first described by Frank and Kasper as a sigma phase 50 years ago and is seen in some metal alloys.
Selection and Variation
In order to understand adaptation and evolution, it is necessary to understand the relationship between natural phenotypic variation and population genetics. Rockman et al. (p. 372; see the Perspective by Charlesworth) examined the level of genetic variance affecting gene expression through the comparison of two strains of the nematode Caenorhabditis elegans. Surprisingly, the variation observed in each trait was better explained by the genomic pattern of background selection than by selection on the traits themselves. Thus, the removal of deleterious mutations from the population by selection reduces phenotypic variability caused by genetic variation at closely linked neutral or nearly neutral sites, and quantitative variability in gene expression shows a similar pattern to sequence diversity and is affected by local rates of genetic recombination and the effective population size.
Fitness landscapes of RNA sequences can help us to see the connection between all possible phenotypes and all possible genotypes. In molecular evolution, the fitness landscape is formalized as the distribution of fitness in sequence space, a hyperdimensional object of staggering complexity. To better understand these complex processes, Pitt and Ferré-D'Amaré (p. 376; see the Perspective by Kluwe and Ellington) used deep sequencing to analyze the composition of a population of variants of an RNA ligase ribozyme, both before and after one round of in vitro selection. Relating the sequences of individuals in the population to a measure of their corresponding fitness provides a detailed picture of an evolutionary fitness landscape from empirical data.