A SNARE-adaptor interaction is a new mode of cargo recognition in clathrin-coated vesicles

Soluble NSF attachment protein receptors (SNAREs) are type II transmembrane proteins that have critical roles in providing the specificity and energy for transport-vesicle fusion and must therefore be correctly partitioned between vesicle and organelle membranes. Like all other cargo, SNAREs need to be sorted into the forming vesicles by direct interaction with components of the vesicles' coats. Here we characterize the molecular details governing the sorting of a SNARE into clathrin-coated vesicles, namely the direct recognition of the three-helical bundle H(abc) domain of the mouse SNARE Vti1b by the human clathrin adaptor epsinR (EPNR, also known as CLINT1). Structures of each domain and of their complex show that this interaction (dissociation constant 22 muM) is mediated by surface patches composed of approximately 15 residues each, the topographies of which are dependent on each domain's overall fold. Disruption of the interface with point mutations abolishes the interaction in vitro and causes Vti1b to become relocalized to late endosomes and lysosomes. This new class of highly specific, surface-surface interaction between the clathrin coat component and the cargo is distinct from the widely observed binding of short, linear cargo motifs by the assembly polypeptide (AP) complex and GGA adaptors and is therefore not vulnerable to competition from standard motif-containing cargoes for incorporation into clathrin-coated vesicles. We propose that conceptually similar but mechanistically different interactions will direct the post-Golgi trafficking of many SNAREs.     

Effect of evaporite deposition on Early Cretaceous carbon and sulphur cycling

The global carbon and sulphur cycles are central to our understanding of the Earth's history, because changes in the partitioning between the reduced and oxidized reservoirs of these elements are the primary control on atmospheric oxygen concentrations. In modern marine sediments, the burial rates of reduced carbon and sulphur are positively coupled, but high-resolution isotope records indicate that these rates were inversely related during the Early Cretaceous period. This inverse relationship is difficult to reconcile with our understanding of the processes that control organic matter remineralization and pyrite burial. Here we show that the inverse correlation can be explained by the deposition of evaporites during the opening of the South Atlantic Ocean basin. Evaporite deposition can alter the chemical composition of sea water, which can in turn affect the ability of sulphate-reducing bacteria to remineralize organic matter and mediate pyrite burial. We use a reaction-transport model to quantify these effects, and the resulting changes in the burial rates of carbon and sulphur, during the Early Cretaceous period. Our results indicate that deposition of the South Atlantic evaporites removed enough sulphate from the ocean temporarily to reduce biologically mediated pyrite burial and organic matter remineralization by up to fifty per cent, thus explaining the inverse relationship between the burial rates of reduced carbon and sulphur during this interval. Furthermore, our findings suggest that the effect of changing seawater sulphate concentrations on the marine subsurface biosphere may be the key to understanding other large-scale perturbations of the global carbon and sulphur cycles.     

Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers

Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. These anaesthetics block sodium channels and thereby the excitability of all neurons, not just sensory neurons. We tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. Here we show that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability. Inhibition by co-applied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 h) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits.     

A synaptic memory trace for cortical receptive field plasticity

Receptive fields of sensory cortical neurons are plastic, changing in response to alterations of neural activity or sensory experience. In this way, cortical representations of the sensory environment can incorporate new information about the world, depending on the relevance or value of particular stimuli. Neuromodulation is required for cortical plasticity, but it is uncertain how subcortical neuromodulatory systems, such as the cholinergic nucleus basalis, interact with and refine cortical circuits. Here we determine the dynamics of synaptic receptive field plasticity in the adult primary auditory cortex (also known as AI) using in vivo whole-cell recording. Pairing sensory stimulation with nucleus basalis activation shifted the preferred stimuli of cortical neurons by inducing a rapid reduction of synaptic inhibition within seconds, which was followed by a large increase in excitation, both specific to the paired stimulus. Although nucleus basalis was stimulated only for a few minutes, reorganization of synaptic tuning curves progressed for hours thereafter: inhibition slowly increased in an activity-dependent manner to rebalance the persistent enhancement of excitation, leading to a retuned receptive field with new preference for the paired stimulus. This restricted period of disinhibition may be a fundamental mechanism for receptive field plasticity, and could serve as a memory trace for stimuli or episodes that have acquired new behavioural significance.     

First-passage times in complex scale-invariant media

How long does it take a random walker to reach a given target point? This quantity, known as a first-passage time (FPT), has led to a growing number of theoretical investigations over the past decade. The importance of FPTs originates from the crucial role played by first encounter properties in various real situations, including transport in disordered media, neuron firing dynamics, spreading of diseases or target search processes. Most methods of determining FPT properties in confining domains have been limited to effectively one-dimensional geometries, or to higher spatial dimensions only in homogeneous media. Here we develop a general theory that allows accurate evaluation of the mean FPT in complex media. Our analytical approach provides a universal scaling dependence of the mean FPT on both the volume of the confining domain and the source-target distance. The analysis is applicable to a broad range of stochastic processes characterized by length-scale-invariant properties. Our theoretical predictions are confirmed by numerical simulations for several representative models of disordered media, fractals, anomalous diffusion and scale-free networks.     

Sexually antagonistic genetic variation for fitness in red deer

Evolutionary theory predicts the depletion of genetic variation in natural populations as a result of the effects of selection, but genetic variation is nevertheless abundant for many traits that are under directional or stabilizing selection. Evolutionary geneticists commonly try to explain this paradox with mechanisms that lead to a balance between mutation and selection. However, theoretical predictions of equilibrium genetic variance under mutation-selection balance are usually lower than the observed values, and the reason for this is unknown. The potential role of sexually antagonistic selection in maintaining genetic variation has received little attention in this debate, surprisingly given its potential ubiquity in dioecious organisms. At fitness-related loci, a given genotype may be selected in opposite directions in the two sexes. Such sexually antagonistic selection will reduce the otherwise-expected positive genetic correlation between male and female fitness. Both theory and experimental data suggest that males and females of the same species may have divergent genetic optima, but supporting data from wild populations are still scarce. Here we present evidence for sexually antagonistic fitness variation in a natural population, using data from a long-term study of red deer (Cervus elaphus). We show that male red deer with relatively high fitness fathered, on average, daughters with relatively low fitness. This was due to a negative genetic correlation between estimates of fitness in males and females. In particular, we show that selection favours males that carry low breeding values for female fitness. Our results demonstrate that sexually antagonistic selection can lead to a trade-off between the optimal genotypes for males and females; this mechanism will have profound effects on the operation of selection and the maintenance of genetic variation in natural populations.     

Coupling superconducting qubits via a cavity bus

Superconducting circuits are promising candidates for constructing quantum bits (qubits) in a quantum computer; single-qubit operations are now routine, and several examples of two-qubit interactions and gates have been demonstrated. These experiments show that two nearby qubits can be readily coupled with local interactions. Performing gate operations between an arbitrary pair of distant qubits is highly desirable for any quantum computer architecture, but has not yet been demonstrated. An efficient way to achieve this goal is to couple the qubits to a 'quantum bus', which distributes quantum information among the qubits. Here we show the implementation of such a quantum bus, using microwave photons confined in a transmission line cavity, to couple two superconducting qubits on opposite sides of a chip. The interaction is mediated by the exchange of virtual rather than real photons, avoiding cavity-induced loss. Using fast control of the qubits to switch the coupling effectively on and off, we demonstrate coherent transfer of quantum states between the qubits. The cavity is also used to perform multiplexed control and measurement of the qubit states. This approach can be expanded to more than two qubits, and is an attractive architecture for quantum information processing on a chip.