Synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins couple their stage-wise folding/assembly to rapid exocytosis of neurotransmitters in a Munc18-1-dependent manner. The functions of the different assembly stages in exocytosis and the role of Munc18-1 in SNARE assembly are not well understood. Using optical tweezers, we observed four distinct stages of assembly in SNARE N-terminal, middle, C-terminal, and linker domains (or NTD, MD, CTD, and LD, respectively). We found that SNARE layer mutations differentially affect SNARE assembly. Comparison of their effects on SNARE assembly and on exocytosis reveals that NTD and CTD are responsible for vesicle docking and fusion, respectively, whereas MD regulates SNARE assembly and fusion. Munc18-1 initiates SNARE assembly and structures t-SNARE C-terminus independent of syntaxin N-terminal regulatory domain (NRD) and stabilizes the half-zippered SNARE complex dependent upon the NRD. Our observations demonstrate distinct functions of SNARE domains whose assembly is intimately chaperoned by Munc18-1.DOI: http://dx.doi.org/10.7554/eLife.09580.001

Pseudo-spin and valley degrees of freedom engineered in photonic analogues of topological insulators provide potential approaches to optical encoding and robust signal transport. Here we observe a ballistic edge state whose spin–valley indices are locked to the direction of propagation along the interface between a valley photonic crystal and a metacrystal emulating the quantum spin–Hall effect. We demonstrate the inhibition of inter-valley scattering at a Y-junction formed at the interfaces between photonic topological insulators carrying different spin–valley Chern numbers. These results open up the possibility of using the valley degree of freedom to control the flow of optical signals in 2D structures.

Summary Intracellular membrane fusion is mediated by dynamic assembly and disassembly of soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors (SNAREs). α-SNAP guides NSF to disassemble SNARE complexes after membrane fusion. Recent experiments showed that α-SNAP also dramatically enhances SNARE assembly and membrane fusion. How α-SNAP plays roles in these opposing activities is not known. Here, we examined the effect of α-SNAP on the step-wise assembly of the synaptic SNARE complex using optical tweezers. We found that α-SNAP destabilized the linker domain (LD) of the SNARE complex but stabilized its C-terminal domain (CTD) through a conformational selection mechanism. In contrast, α-SNAP minimally affected assembly of the SNARE N-terminal domain (NTD), indicating that α-SNAP barely bound the partially assembled trans-SNARE complex. Thus, α-SNAP recognizes the folded CTD for SNARE disassembly with NSF and subtly modulates membrane fusion by altering the stabilities of the SNARE CTD and LD.

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Dynamic and steady state aspects of wave propagation are deeply connected in lossless open systems in which the scattering matrix is unitary. There is then an equivalence among the energy excited within the medium through all channels, the Wigner time delay, which is the sum of dwell times in all channels coupled to the medium, and the density of states. But these equivalences fall away in the presence of material loss or gain. In this paper, we use microwave measurements, numerical simulations, and theoretical analysis to discover the changing relationships among the internal field, transmission, transmission time, dwell time, total excited energy, and the density of states in with loss and gain, and their dependence upon dimensionality and spectral overlap. The field, including the contribution of the still coherent incident wave, is a sum over modal partial fractions with amplitudes that are independent of loss and gain. The total energy excited is equal to the dwell time. When modes are spectrally isolated, the energy is proportional to the sum of products of the modal contribution to the density of states and the ratio of the linewidth without and with absorption. When modes overlap, however, the total energy is further reduced by loss and enhanced by gain. In 1D, the average transmission time is independent of loss, gain, and scattering strength. In higher dimensions, however, the average transmission time falls with loss, scattering strength and channel number, and increases with gain. It is the sum over Lorentzian functions associated with the zeros as well as the poles of the transmission matrix. This endows transmission zeros with robust topological characteristics: in unitary media, zeros occur either singly on the real axis or as conjugate pairs in the complex frequency plane. The transmission zeros are moved down or up in the complex plane by an amount equal to the internal rate of decay or growth of the field. In weakly absorbing media, the spectrum of the transmission time of the lowest transmission eigenchannel is the sum of Lorentzians due to transmission zeros plus a background due to far-off-resonance poles. As the scattering strength increases, conjugate pairs of zeros are brought to the real axis and converted to two single zeros which are constrained to move on the real axis until they combine and leave the real axis as a conjugate pair. The average density of transmission zeros in the complex plane is found from the fall of the average transmission time with absorption as zeros are swept into the lower half of the complex frequency plane. As a sample is deformed, two single zeros and a conjugate pair of zeros may interconvert on the real axis with a square root singularity in the sensitivity of the spacing between transmission zeros to structural change. Thus, the disposition of poles and zeros in the complex frequency plane provides a framework for understanding and controlling wave propagation in non-Hermitian systems.

The detection of anomalies in time series has gained ample academic and industrial attention. However, no comprehensive benchmark exists to evaluate time-series anomaly detection methods. It is common to use (i) proprietary or synthetic data, often biased to support particular claims; or (ii) a limited collection of publicly available datasets. Consequently, we often observe methods performing exceptionally well in one dataset but surprisingly poorly in another, creating an illusion of progress. To address the issues above, we thoroughly studied over one hundred papers to identify, collect, process, and systematically format datasets proposed in the past decades. We summarize our effort in TSB-UAD, a new benchmark to ease the evaluation of univariate time-series anomaly detection methods. Overall, TSB-UAD contains 13766 time series with labeled anomalies spanning different domains with high variability of anomaly types, ratios, and sizes. TSB-UAD includes 18 previously proposed datasets containing 1980 time series and we contribute two collections of datasets. Specifically, we generate 958 time series using a principled methodology for transforming 126 time-series classification datasets into time series with labeled anomalies. In addition, we present data transformations with which we introduce new anomalies, resulting in 10828 time series with varying complexity for anomaly detection. Finally, we evaluate 12 representative methods demonstrating that TSB-UAD is a robust resource for assessing anomaly detection methods. We make our data and code available at www.timeseries.org/TSB-UAD. TSB-UAD provides a valuable, reproducible, and frequently updated resource to establish a leaderboard of univariate time-series anomaly detection methods.

The discovery of robust transport via topological states in electronic, photonic and phononic materials has deepened our understanding of wave propagation in condensed matter with prospects for critical applications of engineered metamaterials in communications, sensing, and controlling the environment. Topological protection of transmission has been demonstrated in the face of bent paths and on-site randomness in the structure. Here we measure the propagation of microwave radiation in a topological medium possessing time reversal symmetry with a cavity adjacent to the edge channel. A coupled-resonance model analysis shows that the cavity is not a spin-conserving defect and gives rise to negative time delay in transmission.

Synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins couple their stage-wise folding/assembly to rapid exocytosis of neurotransmitters in a Munc18-1-dependent manner. The functions of the different assembly stages in exocytosis and the role of Munc18-1 in SNARE assembly are not well understood. Using optical tweezers, we observed four distinct stages of assembly in SNARE N-terminal, middle, C-terminal, and linker domains (or NTD, MD, CTD, and LD, respectively). We found that SNARE layer mutations differentially affect SNARE assembly. Comparison of their effects on SNARE assembly and on exocytosis reveals that NTD and CTD are responsible for vesicle docking and fusion, respectively, whereas MD regulates SNARE assembly and fusion. Munc18-1 initiates SNARE assembly and structures t-SNARE Cterminus independent of syntaxin N-terminal regulatory domain (NRD) and stabilizes the halfzippered SNARE complex dependent upon the NRD. Our observations demonstrate distinct functions of SNARE domains whose assembly is intimately chaperoned by Munc18-1.