The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors

Mammalian Toll-like receptors (TLRs) function as sensors of infection and induce the activation of innate and adaptive immune responses. Upon recognizing conserved pathogen-associated molecular products, TLRs activate host defence responses through their intracellular signalling domain, the Toll/interleukin-1 receptor (TIR) domain, and the downstream adaptor protein MyD88 (refs 1-3). Although members of the TLR and the interleukin-1 (IL-1) receptor families all signal through MyD88, the signalling pathways induced by individual receptors differ. TIRAP, an adaptor protein in the TLR signalling pathway, has been identified and shown to function downstream of TLR4 (refs 4, 5). Here we report the generation of mice deficient in the Tirap gene. TIRAP-deficient mice respond normally to the TLR5, TLR7 and TLR9 ligands, as well as to IL-1 and IL-18, but have defects in cytokine production and in activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases in response to lipopolysaccharide, a ligand for TLR4. In addition, TIRAP-deficient mice are also impaired in their responses to ligands for TLR2, TLR1 and TLR6. Thus, TIRAP is differentially involved in signalling by members of the TLR family and may account for specificity in the downstream signalling of individual TLRs.     

Structural basis for signal transduction by the Toll/interleukin-1 receptor domains

Toll-like receptors (TLRs) and the interleukin-1 receptor superfamily (IL-1Rs) are integral to both innate and adaptive immunity for host defence. These receptors share a conserved cytoplasmic domain, known as the TIR domain. A single-point mutation in the TIR domain of murine TLR4 (Pro712His, the Lps(d) mutation) abolishes the host immune response to lipopolysaccharide (LPS), and mutation of the equivalent residue in TLR2, Pro681His, disrupts signal transduction in response to stimulation by yeast and gram-positive bacteria. Here we report the crystal structures of the TIR domains of human TLR1 and TLR2 and of the Pro681His mutant of TLR2. The structures have a large conserved surface patch that also contains the site of the Lps(d) mutation. Mutagenesis and functional studies confirm that residues in this surface patch are crucial for receptor signalling. The Lps(d) mutation does not disturb the structure of the TIR domain itself. Instead, structural and functional studies indicate that the conserved surface patch may mediate interactions with the down-stream MyD88 adapter molecule, and that the Lps(d) mutation may abolish receptor signalling by disrupting this recruitment.     

Technological forecasting with nonlinear models

The S-shaped growth curves such as Gompertz, logistic, normal and Weibuli are widely used for forecasting technological substitutions. A family of data-based transformed (DBT) models, which are linear in the regression parameters, including the above-mentioned four models as special cases has been shown to be quite useful for short-term forecasts. This paper explores modeling the technology penetration data directly with assumed S-shaped growth curves. The resulting models, which are nonlinear in the regression parameters, also incorporate proper dependence structure and power transformation. It appears that the nonlinear modeling is a viable alternative to the DBT and other conventional forecasting models in forecasting technological substitutions. Hence, an appropriate strategy is to consider the nonlinear modeling approaches as possible alternatives and use the data at hand to select, via pseudo-cross-validation, the best model for forecasting purposes.     

Controlling inelastic light scattering quantum pathways in graphene

Inelastic light scattering spectroscopy has, since its first discovery, been an indispensable tool in physical science for probing elementary excitations, such as phonons, magnons and plasmons in both bulk and nanoscale materials. In the quantum mechanical picture of inelastic light scattering, incident photons first excite a set of intermediate electronic states, which then generate crystal elementary excitations and radiate energy-shifted photons. The intermediate electronic excitations therefore have a crucial role as quantum pathways in inelastic light scattering, and this is exemplified by resonant Raman scattering and Raman interference. The ability to control these excitation pathways can open up new opportunities to probe, manipulate and utilize inelastic light scattering. Here we achieve excitation pathway control in graphene with electrostatic doping. Our study reveals quantum interference between different Raman pathways in graphene: when some of the pathways are blocked, the one-phonon Raman intensity does not diminish, as commonly expected, but increases dramatically. This discovery sheds new light on the understanding of resonance Raman scattering in graphene. In addition, we demonstrate hot-electron luminescence in graphene as the Fermi energy approaches half the laser excitation energy. This hot luminescence, which is another form of inelastic light scattering, results from excited-state relaxation channels that become available only in heavily doped graphene.     

Links between erosion, runoff variability and seismicity in the Taiwan orogen

The erosion of mountain belts controls their topographic and structural evolution and is the main source of sediment delivered to the oceans. Mountain erosion rates have been estimated from current relief and precipitation, but a more complete evaluation of the controls on erosion rates requires detailed measurements across a range of timescales. Here we report erosion rates in the Taiwan mountains estimated from modern river sediment loads, Holocene river incision and thermochronometry on a million-year scale. Estimated erosion rates within the actively deforming mountains are high (3-6 mm yr(-1)) on all timescales, but the pattern of erosion has changed over time in response to the migration of localized tectonic deformation. Modern, decadal-scale erosion rates correlate with historical seismicity and storm-driven runoff variability. The highest erosion rates are found where rapid deformation, high storm frequency and weak substrates coincide, despite low topographic relief.