Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity

A common viral immune evasion strategy involves mutating viral surface proteins in order to evade host neutralizing antibodies. Such immune evasion tactics have not previously been intentionally applied to the development of novel viral gene delivery vectors that overcome the critical problem of anti-vector immunity. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens have proved highly immunogenic in preclinical studies but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world. Here we show that rAd5 vectors can be engineered to circumvent anti-Ad5 immunity. We constructed novel chimaeric rAd5 vectors in which the seven short hypervariable regions (HVRs) on the surface of the Ad5 hexon protein were replaced with the corresponding HVRs from the rare adenovirus serotype Ad48. These HVR-chimaeric rAd5 vectors were produced at high titres and were stable through serial passages in vitro. HVR-chimaeric rAd5 vectors expressing simian immunodeficiency virus Gag proved comparably immunogenic to parental rAd5 vectors in naive mice and rhesus monkeys. In the presence of high levels of pre-existing anti-Ad5 immunity, the immunogenicity of HVR-chimaeric rAd5 vectors was not detectably suppressed, whereas the immunogenicity of parental rAd5 vectors was abrogated. These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are focused on epitopes located within the hexon HVRs. Moreover, these studies show that recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy.     

Watching hydrogen-bond dynamics in a beta-turn by transient two-dimensional infrared spectroscopy

X-ray crystallography and nuclear magnetic resonance measurements provide us with atomically resolved structures of an ever-growing number of biomolecules. These static structural snapshots are important to our understanding of biomolecular function, but real biomolecules are dynamic entities that often exploit conformational changes and transient molecular interactions to perform their tasks. Nuclear magnetic resonance methods can follow such structural changes, but only on millisecond timescales under non-equilibrium conditions. Time-resolved X-ray crystallography has recently been used to monitor the photodissociation of CO from myoglobin on a subnanosecond timescale, yet remains challenging to apply more widely. In contrast, two-dimensional infrared spectroscopy, which maps vibrational coupling between molecular groups and hence their relative positions and orientations, is now routinely used to study equilibrium processes on picosecond timescales. Here we show that the extension of this method into the non-equilibrium regime allows us to observe in real time in a short peptide the weakening of an intramolecular hydrogen bond and concomitant opening of a beta-turn. We find that the rate of this process is two orders of magnitude faster than the 'folding speed limit' established for contact formation between protein side chains.     

Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3

Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease. Cryopyrin (also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has been linked to the activation of intracellular host defence signalling pathways. Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the apoptosis-associated speck-like protein (ASC) and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1beta (ref. 4). Here we show the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for caspase-1 activation and IL-1beta and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-alpha and IL-6, as well as activation of NF-kappaB and mitogen-activated protein kinases (MAPKs) were unaffected by cryopyrin deficiency. Furthermore, we show that Toll-like receptors and cryopyrin control the secretion of IL-1beta and IL-18 through different intracellular pathways. These results reveal a critical role for cryopyrin in host defence through bacterial RNA-mediated activation of caspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.     

Half-metallic graphene nanoribbons

Electrical current can be completely spin polarized in a class of materials known as half-metals, as a result of the coexistence of metallic nature for electrons with one spin orientation and insulating nature for electrons with the other. Such asymmetric electronic states for the different spins have been predicted for some ferromagnetic metals--for example, the Heusler compounds--and were first observed in a manganese perovskite. In view of the potential for use of this property in realizing spin-based electronics, substantial efforts have been made to search for half-metallic materials. However, organic materials have hardly been investigated in this context even though carbon-based nanostructures hold significant promise for future electronic devices. Here we predict half-metallicity in nanometre-scale graphene ribbons by using first-principles calculations. We show that this phenomenon is realizable if in-plane homogeneous electric fields are applied across the zigzag-shaped edges of the graphene nanoribbons, and that their magnetic properties can be controlled by the external electric fields. The results are not only of scientific interest in the interplay between electric fields and electronic spin degree of freedom in solids but may also open a new path to explore spintronics at the nanometre scale, based on graphene.     

Strained silicon as a new electro-optic material

For decades, silicon has been the material of choice for mass fabrication of electronics. This is in contrast to photonics, where passive optical components in silicon have only recently been realized. The slow progress within silicon optoelectronics, where electronic and optical functionalities can be integrated into monolithic components based on the versatile silicon platform, is due to the limited active optical properties of silicon. Recently, however, a continuous-wave Raman silicon laser was demonstrated; if an effective modulator could also be realized in silicon, data processing and transmission could potentially be performed by all-silicon electronic and optical components. Here we have discovered that a significant linear electro-optic effect is induced in silicon by breaking the crystal symmetry. The symmetry is broken by depositing a straining layer on top of a silicon waveguide, and the induced nonlinear coefficient, chi(2) approximately 15 pm V(-1), makes it possible to realize a silicon electro-optic modulator. The strain-induced linear electro-optic effect may be used to remove a bottleneck in modern computers by replacing the electronic bus with a much faster optical alternative.     

Cells on chips

Microsystems create new opportunities for the spatial and temporal control of cell growth and stimuli by combining surfaces that mimic complex biochemistries and geometries of the extracellular matrix with microfluidic channels that regulate transport of fluids and soluble factors. Further integration with bioanalytic microsystems results in multifunctional platforms for basic biological insights into cells and tissues, as well as for cell-based sensors with biochemical, biomedical and environmental functions. Highly integrated microdevices show great promise for basic biomedical and pharmaceutical research, and robust and portable point-of-care devices could be used in clinical settings, in both the developed and the developing world.     

Earthquakes triggered by silent slip events on Kīlauea volcano, Hawaii

Slow-slip events, or 'silent earthquakes', have recently been discovered in a number of subduction zones including the Nankai trough in Japan, Cascadia, and Guerrero in Mexico, but the depths of these events have been difficult to determine from surface deformation measurements. Although it is assumed that these silent earthquakes are located along the plate megathrust, this has not been proved. Slow slip in some subduction zones is associated with non-volcanic tremor, but tremor is difficult to locate and may be distributed over a broad depth range. Except for some events on the San Andreas fault, slow-slip events have not yet been associated with high-frequency earthquakes, which are easily located. Here we report on swarms of high-frequency earthquakes that accompany otherwise silent slips on Kīlauea volcano, Hawaii. For the most energetic event, in January 2005, the slow slip began before the increase in seismicity. The temporal evolution of earthquakes is well explained by increased stressing caused by slow slip, implying that the earthquakes are triggered. The earthquakes, located at depths of 7-8 km, constrain the slow slip to be at comparable depths, because they must fall in zones of positive Coulomb stress change. Triggered earthquakes accompanying slow-slip events elsewhere might go undetected if background seismicity rates are low. Detection of such events would help constrain the depth of slow slip, and could lead to a method for quantifying the increased hazard during slow-slip events, because triggered events have the potential to grow into destructive earthquakes.