TY - JOUR AB - The electrolyte is one of the greatest challenges facing the development of the non‐aqueous Li–O2 battery. Although ether‐based electrolytes do from Li2O2 on the first discharge, it is shown by various techniques that they also decompose and that decomposition increases while Li2O2 decreases on cycling (see picture). Thus, these electrolytes are not suitable. AU - Freunberger, Stefan Alexander AU - Chen, Yuhui AU - Drewett, Nicholas E. AU - Hardwick, Laurence J. AU - Bardé, Fanny AU - Bruce, Peter G. ID - 7314 IS - 37 JF - Angewandte Chemie International Edition SN - 1433-7851 TI - The Lithium-Oxygen battery with ether-based electrolytes VL - 50 ER - TY - JOUR AB - Lithium-metal oxides with a high formal Li2O content, such as Li5FeO4 (5Li2O•Fe2O3) and a Li2MnO3•LiFeO2 composite ({Li2O•MnO2}•{Li2O•Fe2O3}) have been explored as electrocatalysts for primary and rechargeable Li-O2 cells. Activation occurs predominantly by Li2O removal, either electrochemically or chemically by acid-treatment. Superior electrochemical behavior is obtained if activation occurs by acid-treatment; Li2MnO3•LiFeO2 catalysts provide 2516 mAh/g (carbon) corresponding to 931 mAh/g (electrocatalyst + carbon) during the initial discharge. The reaction is reasonably reversible during the early cycles. The approach has implications for designing electrocatalysts that participate through electrochemical Li2O extraction/reformation reactions, offering exceptionally high capacities. AU - Trahey, L. AU - Johnson, C. S. AU - Vaughey, J. T. AU - Kang, S.-H. AU - Hardwick, L. J. AU - Freunberger, Stefan Alexander AU - Bruce, P. G. AU - Thackeray, M. M. ID - 7317 IS - 5 JF - Electrochemical and Solid-State Letters SN - 1099-0062 TI - Activated Lithium-Metal-Oxides as catalytic electrodes for Li–O2 cells VL - 14 ER - TY - JOUR AB - The nonaqueous rechargeable lithium–O2 battery containing an alkyl carbonate electrolyte discharges by formation of C3H6(OCO2Li)2, Li2CO3, HCO2Li, CH3CO2Li, CO2, and H2O at the cathode, due to electrolyte decomposition. Charging involves oxidation of C3H6(OCO2Li)2, Li2CO3, HCO2Li, CH3CO2Li accompanied by CO2 and H2O evolution. Mechanisms are proposed for the reactions on discharge and charge. The different pathways for discharge and charge are consistent with the widely observed voltage gap in Li–O2 cells. Oxidation of C3H6(OCO2Li)2 involves terminal carbonate groups leaving behind the OC3H6O moiety that reacts to form a thick gel on the Li anode. Li2CO3, HCO2Li, CH3CO2Li, and C3H6(OCO2Li)2 accumulate in the cathode on cycling correlating with capacity fading and cell failure. The latter is compounded by continuous consumption of the electrolyte on each discharge. AU - Freunberger, Stefan Alexander AU - Chen, Yuhui AU - Peng, Zhangquan AU - Griffin, John M. AU - Hardwick, Laurence J. AU - Bardé, Fanny AU - Novák, Petr AU - Bruce, Peter G. ID - 7316 IS - 20 JF - Journal of the American Chemical Society SN - 0002-7863 TI - Reactions in the rechargeable Lithium–O2 battery with alkyl carbonate electrolytes VL - 133 ER - TY - JOUR AB - Spectroscopic data (see picture) provide direct evidence that in non‐aqueous Li+ electrolyte, O2 is reduced to O2−, which then forms LiO2 on the electrode surface which disproportionates to Li2O2. On charging, Li2O2 decomposes directly, in a one‐step reaction to evolve O2 and does not pass through LiO2 as an intermediate. AU - Peng, Zhangquan AU - Freunberger, Stefan Alexander AU - Hardwick, Laurence J. AU - Chen, Yuhui AU - Giordani, Vincent AU - Bardé, Fanny AU - Novák, Petr AU - Graham, Duncan AU - Tarascon, Jean-Marie AU - Bruce, Peter G. ID - 7315 IS - 28 JF - Angewandte Chemie International Edition SN - 1433-7851 TI - Oxygen reactions in a non-aqueous Li+ electrolyte VL - 50 ER - TY - CONF AB - Synchronous distributed algorithms are easier to design and prove correct than algorithms that tolerate asynchrony. Yet, in the real world, networks experience asynchrony and other timing anomalies. In this paper, we address the question of how to efficiently transform an algorithm that relies on synchronization into an algorithm that tolerates asynchronous executions. We introduce a transformation technique from synchronous algorithms to indulgent algorithms [1], which induces only a constant overhead in terms of time complexity in well-behaved executions. Our technique is based on a new abstraction we call an asynchrony detector, which the participating processes implement collectively. The resulting transformation works for a large class of colorless tasks, including consensus and set agreement. Interestingly, we also show that our technique is relevant for colored tasks, by applying it to the renaming problem, to obtain the first indulgent renaming algorithm. AU - Alistarh, Dan-Adrian AU - Gilbert, Seth AU - Guerraoui, Rachid AU - Travers, Corentin ID - 757 TI - Generating fast indulgent algorithms VL - 6522 LNCS ER - TY - CONF AB - We study the complexity of renaming, a fundamental problem in distributed computing in which a set of processes need to pick distinct names from a given namespace. We prove an individual lower bound of Ω(k) process steps for deterministic renaming into any namespace of size sub-exponential in k, where k is the number of participants. This bound is tight: it draws an exponential separation between deterministic and randomized solutions, and implies new tight bounds for deterministic fetch-and-increment registers, queues and stacks. The proof of the bound is interesting in its own right, for it relies on the first reduction from renaming to another fundamental problem in distributed computing: mutual exclusion. We complement our individual bound with a global lower bound of Ω(k log (k/c)) on the total step complexity of renaming into a namespace of size ck, for any c ≥ 1. This applies to randomized algorithms against a strong adversary, and helps derive new global lower bounds for randomized approximate counter and fetch-and-increment implementations, all tight within logarithmic factors. AU - Alistarh, Dan-Adrian AU - Aspnes, James AU - Gilbert, Seth AU - Guerraoui, Rachid ID - 759 TI - The complexity of renaming ER - TY - CONF AB - We give two new randomized algorithms for strong renaming, both of which work against an adaptive adversary in asynchronous shared memory. The first uses repeated sampling over a sequence of arrays of decreasing size to assign unique names to each of n processes with step complexity O(log3 n). The second transforms any sorting network into a strong adaptive renaming protocol, with an expected cost equal to the depth of the sorting network. Using an AKS sorting network, this gives a strong adaptive renaming algorithm with step complexity O(log k), where k is the contention in the current execution. We show this to be optimal based on a classic lower bound of Jayanti. We also show that any such strong renaming protocol can be used to build a monotone-consistent counter with logarithmic step complexity (at the cost of adding a max register) or a linearizable fetch-and-increment register (at the cost of increasing the step complexity by a logarithmic factor). AU - Alistarh, Dan-Adrian AU - Aspnes, James AU - Censor Hillel, Keren AU - Gilbert, Seth AU - Zadimoghaddam, Morteza ID - 761 TI - Optimal-time adaptive strong renaming, with applications to counting ER - TY - CONF AB - A randomized implementation is given of a test-and-set register with O(log log n) individual step complexity and O(n) total step complexity against an oblivious adversary. The implementation is linearizable and multi-shot, and shows an exponential complexity improvement over previous solutions designed to work against a strong adversary. AU - Alistarh, Dan-Adrian AU - Aspnes, James ID - 760 TI - Sub-logarithmic test-and-set against a weak adversary VL - 6950 LNCS ER - TY - JOUR AU - Robinson, Matthew Richard ID - 7750 IS - 6 JF - Behavioral Ecology SN - 1465-7279 TI - Understanding intrasexual competition and sexual selection requires an evolutionary ecology framework VL - 22 ER - TY - JOUR AB - Chandelier (axoaxonic) cells (ChCs) are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells. However, their circuit role and the function of their clearly defined anatomical specificity remain unclear. Recent work has demonstrated that chandelier cells can produce depolarizing GABAergic PSPs, occasionally driving postsynaptic targets to spike. On the other hand, other work suggests that ChCs are hyperpolarizing and may have an inhibitory role. These disparate functional effects may reflect heterogeneity among ChCs. Here, using brain slices from transgenic mouse strains, we first demonstrate that, across different neocortical areas and genetic backgrounds, upper Layer 2/3 ChCs belong to a single electrophysiologically and morphologically defined population, extensively sampling Layer 1 inputs with asymmetric dendrites. Consistent with being a single cell type, we find electrical coupling between ChCs. We then investigate the effect of chandelier cell activation on pyramidal neuron spiking in several conditions, ranging from the resting membrane potential to stimuli designed to approximate in vivo membrane potential dynamics. We find that under quiescent conditions, chandelier cells are capable of both promoting and inhibiting spike generation, depending on the postsynaptic membrane potential. However, during in vivo-like membrane potential fluctuations, the dominant postsynaptic effect was a strong inhibition. Thus, neocortical chandelier cells, even from within a homogeneous population, appear to play a dual role in the circuit, helping to activate quiescent pyramidal neurons, while at the same time inhibiting active ones. AU - Woodruff, A. R. AU - McGarry, L. M. AU - Vogels, Tim P AU - Inan, M. AU - Anderson, S. A. AU - Yuste, R. ID - 8025 IS - 49 JF - Journal of Neuroscience SN - 0270-6474 TI - State-dependent function of neocortical chandelier cells VL - 31 ER - TY - JOUR AB - Cortical neurons receive balanced excitatory and inhibitory synaptic currents. Such a balance could be established and maintained in an experience-dependent manner by synaptic plasticity at inhibitory synapses. We show that this mechanism provides an explanation for the sparse firing patterns observed in response to natural stimuli and fits well with a recently observed interaction of excitatory and inhibitory receptive field plasticity. The introduction of inhibitory plasticity in suitable recurrent networks provides a homeostatic mechanism that leads to asynchronous irregular network states. Further, it can accommodate synaptic memories with activity patterns that become indiscernible from the background state but can be reactivated by external stimuli. Our results suggest an essential role of inhibitory plasticity in the formation and maintenance of functional cortical circuitry. AU - Vogels, Tim P AU - Sprekeler, H. AU - Zenke, F. AU - Clopath, C. AU - Gerstner, W. ID - 8074 IS - 6062 JF - Science SN - 0036-8075 TI - Inhibitory plasticity balances excitation and inhibition in sensory pathways and memory networks VL - 334 ER - TY - JOUR AB - The accurate experimental determination of dipolar-coupling constants for one-bond heteronuclear dipolar couplings in solids is a key for the quantification of the amplitudes of motional processes. Averaging of the dipolar coupling reports on motions on time scales up to the inverse of the coupling constant, in our case tens of microseconds. Combining dipolar-coupling derived order parameters that characterize the amplitudes of the motion with relaxation data leads to a more precise characterization of the dynamical parameters and helps to disentangle the amplitudes and the time scales of the motional processes, which impact relaxation rates in a highly correlated way. Here. we describe and characterize an improved experimental protocol – based on REDOR – to measure these couplings in perdeuterated proteins with a reduced sensitivity to experimental missettings. Because such effects are presently the dominant source of systematic errors in experimental dipolar-coupling measurements, these compensated experiments should help to significantly improve the precision of such data. A detailed comparison with other commonly used pulse sequences (T-MREV, phase-inverted CP,R18 5/2, and R18 7/1) is provided. AU - Schanda, Paul AU - Meier, Beat H. AU - Ernst, Matthias ID - 8469 IS - 2 JF - Journal of Magnetic Resonance KW - Nuclear and High Energy Physics KW - Biophysics KW - Biochemistry KW - Condensed Matter Physics SN - 1090-7807 TI - Accurate measurement of one-bond H–X heteronuclear dipolar couplings in MAS solid-state NMR VL - 210 ER - TY - JOUR AB - Adding a new dimension: 4D or 3D proton‐detected spectra of perdeuterated protein samples with 1H labelled amides and methyl groups permit collecting unambiguous distance restraints with high sensitivity and determining protein structure by solid‐state NMR (see picture). AU - Huber, Matthias AU - Hiller, Sebastian AU - Schanda, Paul AU - Ernst, Matthias AU - Böckmann, Anja AU - Verel, René AU - Meier, Beat H. ID - 8470 IS - 5 JF - ChemPhysChem KW - Physical and Theoretical Chemistry KW - Atomic and Molecular Physics KW - and Optics SN - 1439-4235 TI - A proton-detected 4D solid-state NMR experiment for protein structure determination VL - 12 ER - TY - JOUR AB - Nonsymmetric motion: Solid‐state NMR measurements of dipolar coupling tensors provide insight into protein dynamics. The hitherto ignored asymmetry of the dipolar coupling tensor contains valuable information about motional asymmetry, which was used in the first direct site‐resolved measurement of such tensors. Important motions such as rotamer jumps can now be directly detected in the solid state. AU - Schanda, Paul AU - Huber, Matthias AU - Boisbouvier, Jérôme AU - Meier, Beat H. AU - Ernst, Matthias ID - 8464 IS - 46 JF - Angewandte Chemie International Edition SN - 1433-7851 TI - Solid-state NMR measurements of asymmetric dipolar couplings provide insight into protein side-chain motion VL - 50 ER - TY - JOUR AU - Lalli, Daniela AU - Schanda, Paul AU - Chowdhury, Anup AU - Retel, Joren AU - Hiller, Matthias AU - Higman, Victoria A. AU - Handel, Lieselotte AU - Agarwal, Vipin AU - Reif, Bernd AU - van Rossum, Barth AU - Akbey, Ümit AU - Oschkinat, Hartmut ID - 8468 IS - 4 JF - Journal of Biomolecular NMR SN - 0925-2738 TI - Three-dimensional deuterium-carbon correlation experiments for high-resolution solid-state MAS NMR spectroscopy of large proteins VL - 51 ER - TY - JOUR AB - Recent discovery of the Large-billed Reed Warbler (Acrocephalus orinus) in museums and in the wild significantly expanded our knowledge of its morphological traits and genetic variability, and revealed new data on geographical distribution of the breeding grounds, migration routes and wintering locations of this species. It is now certain that A. orinus is breeding in Central Asia; however, the precise area of distribution remains unclear. The difficulty in the further study of this species lies in the small number of known specimens, with only 13 currently available in museums, and in the relative uncertainty of the breeding area and habitat of this species. Following morphological and genetic analyses from Svensson, et al, we describe 14 new A. orinus specimens from collections of Zoological Museums of the former USSR from the territory of Central Asian states. All of these specimens were erroneously labeled as Blyth's Reed Warbler (A. dumetorum), which is thought to be a breeding species in these areas. The 14 new A. orinus specimens were collected during breeding season while most of the 85 A. dumetorum specimens from the same area were collected during the migration period. Our data indicate that the Central Asian territory previously attributed as breeding grounds of A. dumetorum is likely to constitute the breeding territory of A. orinus. This rare case of a re-description of the breeding territory of a lost species emphasizes the importance of maintenance of museum collections around the world. If the present data on the breeding grounds of A. orinus are confirmed with field observations and collections, the literature on the biology of A. dumetorum from the southern part of its range may have to be reconsidered. AU - Koblik, Evgeniy A AU - Red'Kin, Yaroslav A AU - Meer, Margarita S AU - Derelle, Romain AU - Golenkina, Sofia A AU - Fyodor Kondrashov AU - Arkhipov, Vladimir Y ID - 890 IS - 4 JF - PLoS One TI - Acrocephalus orinus: A case of Mistaken identity VL - 6 ER - TY - JOUR AB - A popular method for generating micron-sized aerosols is to submerge ultrasonic (ω ∼ MHz) piezoelectric oscillators in a water bath. The submerged oscillator atomizes the fluid, creating droplets with radii proportional to the wavelength of the standing wave at the fluid surface. Classical theory for the Faraday instability predicts a parametric instability driving a capillary wave at the subharmonic (ω / 2) frequency. For many applications it is desirable to reduce the size of the droplets; however, using higher frequency oscillators becomes impractical beyond a few MHz. Observations are presented that demonstrate that smaller droplets may also be created by increasing the driving amplitude of the oscillator, and that this effect becomes more pronounced for large driving frequencies. It is shown that these observations are consistent with a transition from droplets associated with subharmonic (ω/2) capillary waves to harmonic (ω) capillary waves induced by larger driving frequencies and amplitudes, as predicted by a stability analysis of the capillary waves. AU - Higginbotham, Andrew P AU - Guillen, A AU - Jones, Nick AU - Donnelly, Tom AU - Bernoff, Andrew ID - 90 IS - 5 JF - Journal of the Acoustical Society of America TI - Evidence of the harmonic Faraday instability in ultrasonic atomization experiments with a deep, inviscid fluid VL - 130 ER - TY - JOUR AB - A cloud-resolving model is used to investigate the effect of warming on high percentiles of precipitation (precipitation extremes) in the idealized setting of radiative-convective equilibrium. While this idealized setting does not allow for several factors that influence precipitation in the tropics, it does allow for an evaluation of the response of precipitation extremes to warming in simulations with resolved rather than parameterized convection. The methodology developed should also be applicable to less idealized simulations. Modeled precipitation extremes are found to increase in magnitude in response to an increase in sea surface temperature. A dry static energy budget is used to relate the changes in precipitation extremes to changes in atmospheric temperature, vertical velocity, and precipitation efficiency. To first order, the changes in precipitation extremes are captured by changes in the mean temperature structure of the atmosphere. Changes in vertical velocities play a secondary role and tend to weaken the strength of precipitation extremes, despite an intensification of updraft velocities in the upper troposphere. The influence of changes in condensate transports on precipitation extremes is quantified in terms of a precipitation efficiency; it does not change greatly with warming. Tropical precipitation extremes have previously been found to increase at a greater fractional rate than the amount of atmospheric water vapor in observations of present-day variability and in some climate model simulations with parameterized convection. But the fractional increases in precipitation extremes in the cloud-resolving simulations are comparable in magnitude to those in surface water vapor concentrations (owing to a partial cancellation between dynamical and thermodynamical changes), and are substantially less than the fractional increases in column water vapor. AU - Muller, Caroline J AU - O’Gorman, Paul A. AU - Back, Larissa E. ID - 9144 IS - 11 JF - Journal of Climate KW - Atmospheric Science SN - 0894-8755 TI - Intensification of precipitation extremes with warming in a cloud-resolving model VL - 24 ER - TY - JOUR AB - Understanding and predicting the response of the hydrological cycle to climate change is a major challenge with important societal implications. Much progress has been made in understanding the response of global average precipitation by considering the energy balances of the atmosphere and the surface1,2,3,4,5,6. This energetic perspective reveals that changes in temperature, greenhouse gases, aerosols, solar forcing and cloud feedbacks can all affect the global average rate of precipitation5,7,8,9,10,11. Local precipitation changes have conventionally been analysed using the water vapour budget, but here we show that the energetic approach can be extended to local changes in precipitation by including changes in horizontal energy transport. In simulations of twenty-first century climate change, this energy transport accounts for much of the spatial variability in precipitation change. We show that changes in radiative and surface sensible heat fluxes are a guide to the local precipitation response over land and at large scales, but not at small scales over the ocean, where cloud and water vapour radiative feedbacks dampen the response. The energetic approach described here helps bridge the gap between our understanding of global and regional precipitation changes. It could be applied to better understand the response of regional precipitation to different radiative forcings, including geo-engineering schemes, as well as to understand the differences between the fast and slow responses of regional precipitation to such forcings. AU - Muller, Caroline J AU - O’Gorman, P. A. ID - 9143 IS - 5 JF - Nature Climate Change SN - 1758-678X TI - An energetic perspective on the regional response of precipitation to climate change VL - 1 ER - TY - JOUR AB - The conserved role of Notch signaling in controlling intestinal cell fate specification and homeostasis has been extensively studied. Nevertheless, the precise identity of the cells in which Notch signaling is active and the role of different Notch receptor paralogues in the intestine remain ambiguous, due to the lack of reliable tools to investigate Notch expression and function in vivo. We generated a new series of transgenic mice that allowed us, by lineage analysis, to formally prove that Notch1 and Notch2 are specifically expressed in crypt stem cells. In addition, a novel Notch reporter mouse, Hes1-EmGFP SAT, demonstrated exclusive Notch activity in crypt stem cells and absorptive progenitors. This roster of knock-in and reporter mice represents a valuable resource to functionally explore the Notch pathway in vivo in virtually all tissues. AU - Fré, Silvia AU - Hannezo, Edouard B AU - Šale, Sanja AU - Huyghe, Mathilde AU - Lafkas, Daniel AU - Kissel, Holger AU - Louvi, Angeliki AU - Greve, Jeffrey AU - Louvard, Daniel AU - Artavanis Tsakonas, Spyros ID - 923 IS - 10 JF - PLoS One TI - Notch lineages and activity in intestinal stem cells determined by a new set of knock in mice VL - 6 ER - TY - JOUR AB - Imprinted genes are expressed primarily or exclusively from either the maternal or paternal allele, a phenomenon that occurs in flowering plants and mammals. Flowering plant imprinted gene expression has been described primarily in endosperm, a terminal nutritive tissue consumed by the embryo during seed development or after germination. Imprinted expression in Arabidopsis thaliana endosperm is orchestrated by differences in cytosine DNA methylation between the paternal and maternal genomes as well as by Polycomb group proteins. Currently, only 11 imprinted A. thaliana genes are known. Here, we use extensive sequencing of cDNA libraries to identify 9 paternally expressed and 34 maternally expressed imprinted genes in A. thaliana endosperm that are regulated by the DNA-demethylating glycosylase DEMETER, the DNA methyltransferase MET1, and/or the core Polycomb group protein FIE. These genes encode transcription factors, proteins involved in hormone signaling, components of the ubiquitin protein degradation pathway, regulators of histone and DNA methylation, and small RNA pathway proteins. We also identify maternally expressed genes that may be regulated by unknown mechanisms or deposited from maternal tissues. We did not detect any imprinted genes in the embryo. Our results show that imprinted gene expression is an extensive mechanistically complex phenomenon that likely affects multiple aspects of seed development. AU - Hsieh, Tzung-Fu AU - Shin, Juhyun AU - Uzawa, Rie AU - Silva, Pedro AU - Cohen, Stephanie AU - Bauer, Matthew J. AU - Hashimoto, Meryl AU - Kirkbride, Ryan C. AU - Harada, John J. AU - Zilberman, Daniel AU - Fischer, Robert L. ID - 9483 IS - 5 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Regulation of imprinted gene expression in Arabidopsis endosperm VL - 108 ER - TY - JOUR AB - Motivated by recent experiments on the material Ba3NiSb 2O9, we consider a spin-one quantum antiferromagnet on a triangular lattice with the Heisenberg bilinear and biquadratic exchange interactions and a single-ion anisotropy. Using a fermionic "triplon" representation for spins, we study the phase diagram within mean-field theory. In addition to a fully gapped spin-liquid ground state, we find a state where one gapless triplon mode with a Fermi surface coexists with d+id topological pairing of the other triplons. Despite the existence of a Fermi surface, this ground state has fully gapped bulk spin excitations. Such a state has linear in-temperature specific heat and constant in-plane spin susceptibility, with an unusually high Wilson ratio. AU - Maksym Serbyn AU - Senthil, Todadri S AU - Lee, Patrick ID - 967 IS - 18 JF - Physical Review B - Condensed Matter and Materials Physics TI - Exotic S=1 spin-liquid state with fermionic excitations on the triangular lattice VL - 84 ER - TY - JOUR AB - We investigate the isotope effect on the London penetration depth of a superconductor which measures n S/m*, the ratio of superfluid density to effective mass. We use a simplified model of electrons weakly coupled to a single phonon frequency ω E, but assume that the energy gap Δ does not have any isotope effect. Nevertheless, we find an isotope effect for n S/m* which is significant if Δ is sufficiently large that it becomes comparable to ω E, a regime of interest to high-T c cuprate superconductors and possibly other families of unconventional superconductors with relatively high T c. Our model is too simple to describe the cuprates and it gives the wrong sign of the isotope effect when compared with experiment, but it is a proof of principle that the isotope effect exists for n S/m* in materials where the pairing gap and T c are not of phonon origin and have no isotope effect. AU - Maksym Serbyn AU - Lee, Patrick ID - 969 IS - 2 JF - Physical Review B - Condensed Matter and Materials Physics TI - Isotope effect on the superfluid density in conventional and high-temperature superconductors VL - 83 ER - TY - JOUR AB - Despite the importance of protein fibrils in the context of conformational diseases, information on their structure is still sparse. Hydrogen/deuterium exchange measurements of backbone amide protons allow the identification hydrogen-bonding patterns and reveal pertinent information on the amyloid β-sheet architecture. However, they provide only little information on the identity of residues exposed to solvent or buried inside the fibril core. NMR spectroscopy is a potent method for identifying solvent-accessible residues in proteins via observation of polarization transfer between chemically exchanging side-chain protons and water protons. We show here that the combined use of highly deuterated samples and fast magic-angle spinning greatly attenuates unwanted spin diffusion and allows identification of polarization exchange with the solvent in a site-specific manner. We apply this measurement protocol to HET-s(218–289) prion fibrils under different conditions (including physiological pH, where protofibrils assemble together into thicker fibrils) and demonstrate that each protofibril of HET-s(218–289), is surrounded by water, thus excluding the existence of extended dry interfibril contacts. We also show that exchangeable side-chain protons inside the hydrophobic core of HET-s(218–289) do not exchange over time intervals of weeks to months. The experiments proposed in this study can provide insight into the detailed structural features of amyloid fibrils in general. AU - Van Melckebeke, Hélène AU - Schanda, Paul AU - Gath, Julia AU - Wasmer, Christian AU - Verel, René AU - Lange, Adam AU - Meier, Beat H. AU - Böckmann, Anja ID - 8471 IS - 3 JF - Journal of Molecular Biology SN - 0022-2836 TI - Probing water accessibility in HET-s(218–289) amyloid fibrils by solid-state NMR VL - 405 ER - TY - JOUR AB - The classical principle of least action says that orbits of mechanical systems extremize action; an important subclass are those orbits that minimize action. In this paper we utilize this principle along with Aubry-Mather theory to construct (Birkhoff) regions of instability for a certain three-body problem, given by a Hamiltonian system of 2 degrees of freedom. We believe that these methods can be applied to construct instability regions for a variety of Hamiltonian systems with 2 degrees of freedom. The Hamiltonian model we consider describes dynamics of a Sun-Jupiter-comet system, and under some simplifying assumptions, we show the existence of instabilities for the orbit of the comet. In particular, we show that a comet which starts close to an orbit in the shape of an ellipse of eccentricity e=0.66 can increase in eccentricity up to e=0.96. In the sequels to this paper, we extend the result to beyond e=1 and show the existence of ejection orbits. Such orbits are initially well within the range of our solar system. This might give an indication of why most objects rotating around the Sun in our solar system have relatively low eccentricity. AU - Galante, Joseph AU - Kaloshin, Vadim ID - 8505 IS - 2 JF - Duke Mathematical Journal KW - General Mathematics SN - 0012-7094 TI - Destruction of invariant curves in the restricted circular planar three-body problem by using comparison of action VL - 159 ER - TY - CHAP AU - Fyodor Kondrashov ID - 881 T2 - Evolution after Gene Duplication TI - Gene Dosage and Duplication ER - TY - JOUR AB - Collective cell migration in tissues occurs throughout embryonic development, during wound healing, and in cancerous tumor invasion, yet most detailed knowledge of cell migration comes from single-cell studies. As single cells migrate, the shape of the cell body fluctuates dramatically through cyclic processes of extension, adhesion, and retraction, accompanied by erratic changes in migration direction. Within confluent cell layers, such subcellular motions must be coupled between neighbors, yet the influence of these subcellular motions on collective migration is not known. Here we study motion within a confluent epithelial cell sheet, simultaneously measuring collective migration and subcellular motions, covering a broad range of length scales, time scales, and cell densities. At large length scales and time scales collective migration slows as cell density rises, yet the fastest cells move in large, multicell groups whose scale grows with increasing cell density. This behavior has an intriguing analogy to dynamic heterogeneities found in particulate systems as they become more crowded and approach a glass transition. In addition we find a diminishing self-diffusivity of short-wavelength motions within the cell layer, and growing peaks in the vibrational density of states associated with cooperative cell-shape fluctuations. Both of these observations are also intriguingly reminiscent of a glass transition. Thus, these results provide a broad and suggestive analogy between cell motion within a confluent layer and the dynamics of supercooled colloidal and molecular fluids approaching a glass transition. AU - Angelini, Thomas AU - Hannezo, Edouard B AU - Trepatc, Xavier AU - Marquez, Manuel AU - Fredberg, Jeffrey AU - Weitz, David ID - 919 IS - 12 JF - Proceedings of the National Academy of Sciences of the United States of America TI - Glass-like dynamics of collective cell migration VL - 108 ER - TY - JOUR AB - We study theoretically the shapes of a dividing epithelial monolayer of cells lying on top of an elastic stroma. The negative tension created by cell division provokes a buckling instability at a finite wave vector leading to the formation of periodic arrays of villi and crypts. The instability is similar to the buckling of a metallic plate under compression. We use the results to rationalize the various structures of the intestinal lining observed in vivo. Taking into account the coupling between cell division and local curvature, we obtain different patterns of villi and crypts, which could explain the different morphologies of the small intestine and the colon. AU - Hannezo, Edouard B AU - Prost, Jacques AU - Joanny, Jean ID - 918 IS - 7 JF - Physical Review Letters TI - Instabilities of monolayered epithelia Shape and structure of villi and crypts VL - 107 ER - TY - GEN AB - Little is known about chromatin remodeling events immediately after fertilization. A recent report by Autran et al. (2011) in Cell now shows that chromatin regulatory pathways that silence transposable elements are responsible for global delayed activation of gene expression in the early Arabidopsis embryo. AU - Zilberman, Daniel ID - 9522 IS - 6 SN - 1534-5807 T2 - Developmental Cell TI - Balancing parental contributions in plant embryonic gene activation VL - 20 ER - TY - CONF AB - In this paper, we establish a correspondence between the incremental algorithm for computing AT-models [8,9] and the one for computing persistent homology [6,14,15]. We also present a decremental algorithm for computing AT-models that allows to extend the persistence computation to a wider setting. Finally, we show how to combine incremental and decremental techniques for persistent homology computation. AU - Gonzalez-Diaz, Rocio AU - Ion, Adrian AU - Jimenez, Maria Jose AU - Poyatos, Regina ID - 9648 SN - 03029743 T2 - Computer Analysis of Images and Patterns TI - Incremental-decremental algorithm for computing AT-models and persistent homology VL - 6854 ER - TY - JOUR AB - A Reply to the Comment by Andrei Sergeev, M. Reizer, and V. Mitin. AU - Maksym Serbyn AU - Skvortsov, Mikhail A AU - Varlamov, Andrei A AU - Galitski, Victor M ID - 968 IS - 13 JF - Physical Review Letters TI - Serbyn et al. Reply: VL - 106 ER - TY - JOUR AB - Defining population structure and genetic diversity levels is of the utmost importance for developing efficient conservation strategies. Overfishing has caused mean annual catches of the European spiny lobster (Palinurus elephas) to decrease alarmingly along its distribution area. In this context, there is a need for comprehensive studies aiming to evaluate the genetic health of the exploited populations. The present study is based on a set of ten nuclear markers amplified in 331 individuals from ten different localities covering most of P. elephas distribution area. Samples from Atlantic and Mediterranean basins showed small but significant differences, indicating that P. elephas populations do not behave as a single panmictic unit but form two partially-overlapping groups. Despite intense overfishing, our dataset did not recover a recent bottleneck signal, and instead showed a large and stable historical effective size. This result could be accounted for by specific life-history traits (reproduction and longevity) and the limitations of molecular markers in covering recent timescales for nontemporal samples. The findings of the present study emphasize the need to integrate information on effective population sizes and life-history parameters when evaluating population connectivity levels from genetic data. AU - Palero, Ferran AU - Abello, Pere AU - Macpherson, Enrique AU - Beaumont, Mark AU - Pascual, Marta ID - 3395 IS - 2 JF - Biological Journal of the Linnean Society TI - Effect of oceanographic barriers and overfishing on the population genetic structure of the European spiny lobster Palinurus elephas VL - 104 ER - TY - GEN AB - Defining population structure and genetic diversity levels is of the utmost importance for developing efficient conservation strategies. Overfishing has caused mean annual catches of the European spiny lobster (Palinurus elephas) to decrease alarmingly along its distribution area. In this context, there is a need for comprehensive studies to evaluate the genetic health of the exploited populations. The present work is based on a set of 10 nuclear markers amplified in 331 individuals from 10 different localities covering most of P. elephas distribution area. Samples from Atlantic and Mediterranean basins showed small but significant differences, indicating that P. elephas populations do not behave as a single panmictic unit but form two partially-overlapping groups. Despite intense overfishing, our dataset did not recover a recent bottleneck signal, and showed a large and stable historical effective size instead. This result could be accounted for by specific life history traits (reproduction and longevity) and the limitations of molecular markers in covering very recent timescales for non temporal samples. Our study emphasizes the necessity of integrating information on effective population sizes and life history parameters when evaluating population connectivity levels from genetic data. AU - Palero, Ferran AU - Abello, Pere AU - Macpherson, Enrique AU - Beaumont, Mark AU - Pascual, Marta ID - 9762 TI - Data from: Effect of oceanographic barriers and overfishing on the population genetic structure of the European spiny lobster (Palinurus elephas) ER - TY - CONF AB - Segmentation is the process of partitioning digital images into meaningful regions. The analysis of biological high content images often requires segmentation as a first step. We propose ilastik as an easy-to-use tool which allows the user without expertise in image processing to perform segmentation and classification in a unified way. ilastik learns from labels provided by the user through a convenient mouse interface. Based on these labels, ilastik infers a problem specific segmentation. A random forest classifier is used in the learning step, in which each pixel's neighborhood is characterized by a set of generic (nonlinear) features. ilastik supports up to three spatial plus one spectral dimension and makes use of all dimensions in the feature calculation. ilastik provides realtime feedback that enables the user to interactively refine the segmentation result and hence further fine-tune the classifier. An uncertainty measure guides the user to ambiguous regions in the images. Real time performance is achieved by multi-threading which fully exploits the capabilities of modern multi-core machines. Once a classifier has been trained on a set of representative images, it can be exported and used to automatically process a very large number of images (e.g. using the CellProfiler pipeline). ilastik is an open source project and released under the BSD license at www.ilastik.org. AU - Sommer, Christoph M AU - Straehle, Christoph AU - Köthe, Ullrich AU - Hamprecht, Fred A. ID - 9943 KW - image segmentation KW - biomedical imaging KW - three dimensional displays KW - neurons KW - retina KW - observers KW - image color analysis SN - 1945-7928 T2 - 2011 IEEE International Symposium on Biomedical Imaging: from Nano to Micro TI - Ilastik: Interactive learning and segmentation toolkit ER - TY - CONF AB - This paper presents a method to create a model of an articulated object using the planar motion in an initialization video. The model consists of rigid parts connected by points of articulation. The rigid parts are described by the positions of salient feature-points tracked throughout the video. Following a filtering step that identifies points that belong to different objects, rigid parts are found by a grouping process in a graph pyramid. Valid articulation points are selected by verifying multiple hypotheses for each pair of parts. AU - Artner, Nicole M. AU - Ion, Adrian AU - Kropatsch, Walter G. ED - Jiang, Xiaoyi ED - Ferrer, Miquel ED - Torsello, Andrea ID - 10907 SN - 0302-9743 T2 - Graph-Based Representations in Pattern Recognition TI - Spatio-temporal extraction of articulated models in a graph pyramid VL - 6658 ER - TY - THES AB - Chemokines organize immune cell trafficking by inducing either directed (tactic) or random (kinetic) migration and by activating integrins in order to support surface adhesion (haptic). Beyond that the same chemokines can establish clearly defined functional areas in secondary lymphoid organs. Until now it is unclear how chemokines can fulfill such diverse functions. One decisive prerequisite to explain these capacities is to know how chemokines are presented in tissue. In theory chemokines could occur either soluble or immobilized, and could be distributed either homogenously or as a concentration gradient. To dissect if and how the presenting mode of chemokines influences immune cells, I tested the response of dendritic cells (DCs) to differentially displayed chemokines. DCs are antigen presenting cells that reside in the periphery and migrate into draining lymph nodes (LNs) once exposed to inflammatory stimuli to activate naïve T cells. DCs are guided to and within the LN by the chemokine receptor CCR7, which has two ligands, the chemokines CCL19 and CCL21. Both CCR7 ligands are expressed by fibroblastic reticular cells in the LN, but differ in their ability to bind to heparan sulfate residues. CCL21 has a highly charged C-terminal extension, which mediates binding to anionic surfaces, whereas CCL19 is lacking such residues and likely distributes as a soluble molecule. This study shows that surface-bound CCL21 causes random, haptokinetic DC motility, which is confined to the chemokine coated area by insideout activation of β2 integrins that mediate cell binding to the surface. CCL19 on the other hand forms concentration gradients which trigger directional, chemotactic movement, but no surface adhesion. In addition DCs can actively manipulate this system by recruiting and activating serine proteases on their surfaces, which create - by proteolytically removing the adhesive C-terminus - a solubilized variant of CCL21 that functionally resembles CCL19. By generating a CCL21 concentration gradient DCs establish a positive feedback loop to recruit further DCs from the periphery to the CCL21 coated region. In addition DCs can sense chemotactic gradients as well as immobilized haptokinetic fields at the same time and integrate these signals. The result is chemotactically biased haptokinesis - directional migration confined to a chemokine coated track or area - which could explain the dynamic but spatially tightly controlled swarming leukocyte locomotion patterns that have been observed in lymphatic organs by intravital microscopists. The finding that DCs can approach soluble cues in a non-adhesive manner while they attach to surfaces coated with immobilized cues raises the question how these cells transmit intracellular forces to the environment, especially in the non-adherent migration mode. In order to migrate, cells have to generate and transmit force to the extracellular substrate. Force transmission is the prerequisite to procure an expansion of the leading edge and a forward motion of the whole cell body. In the current conceptions actin polymerization at the leading edge is coupled to extracellular ligands via the integrin family of transmembrane receptors, which allows the transmission of intracellular force. Against the paradigm of force transmission during migration, leukocytes, like DCs, are able to migrate in threedimensional environments without using integrin transmembrane receptors (Lämmermann et al., 2008). This reflects the biological function of leukocytes, as they can invade almost all tissues, whereby their migration has to be independent from the extracellular environment. How the cells can achieve this is unclear. For this study I examined DC migration in a defined threedimensional environment and highlighted actin-dynamics with the probe Lifeact-GFP. The result was that chemotactic DCs can switch between integrin-dependent and integrin- independent locomotion and can thereby adapt to the adhesive properties of their environment. If the cells are able to couple their actin cytoskeleton to the substrate, actin polymerization is entirely converted into protrusion. Without coupling the actin cortex undergoes slippage and retrograde actin flow can be observed. But retrograde actin flow can be completely compensated by higher actin polymerization rate keeping the migration velocity and the shape of the cells unaltered. Mesenchymal cells like fibroblast cannot balance the loss of adhesive interaction, cannot protrude into open space and, therefore, strictly depend on integrinmediated force coupling. This leukocyte specific phenomenon of “adaptive force transmission” endows these cells with the unique ability to transit and invade almost every type of tissue. AU - Schumann, Kathrin ID - 3275 SN - 2663-337X TI - The role of chemotactic gradients in dendritic cell migration ER - TY - THES AU - Maître, Jean-Léon ID - 3273 SN - 2663-337X TI - Mechanics of adhesion and de‐adhesion in zebrafish germ layer progenitors ER - TY - CONF AB - We construct efficient authentication protocols and message-authentication codes (MACs) whose security can be reduced to the learning parity with noise (LPN) problem. Despite a large body of work - starting with the HB protocol of Hopper and Blum in 2001 - until now it was not even known how to construct an efficient authentication protocol from LPN which is secure against man-in-the-middle (MIM) attacks. A MAC implies such a (two-round) protocol. © 2011 International Association for Cryptologic Research AU - Kiltz, Eike AU - Pietrzak, Krzysztof Z AU - Cash, David AU - Jain, Abhishek AU - Venturi, Daniele ID - 3238 TI - Efficient authentication from hard learning problems VL - 6632 ER - TY - JOUR AB - Migrating lymphocytes acquire a polarized phenotype with a leading and a trailing edge, or uropod. Although in vitro experiments in cell lines or activated primary cell cultures have established that Rho-p160 coiled-coil kinase (ROCK)-myosin II-mediated uropod contractility is required for integrin de-adhesion on two-dimensional surfaces and nuclear propulsion through narrow pores in three-dimensional matrices, less is known about the role of these two events during the recirculation of primary, nonactivated lymphocytes. Using pharmacological antagonists of ROCK and myosin II, we report that inhibition of uropod contractility blocked integrin-independent mouse T cell migration through narrow, but not large, pores in vitro. T cell crawling on chemokine-coated endothelial cells under shear was severely impaired by ROCK inhibition, whereas transendothelial migration was only reduced through endothelial cells with high, but not low, barrier properties. Using three-dimensional thick-tissue imaging and dynamic two-photon microscopy of T cell motility in lymphoid tissue, we demonstrated a significant role for uropod contractility in intraluminal crawling and transendothelial migration through lymph node, but not bone marrow, endothelial cells. Finally, we demonstrated that ICAM-1, but not anatomical constraints or integrin-independent interactions, reduced parenchymal motility of inhibitor-treated T cells within the dense lymphoid microenvironment, thus assigning context-dependent roles for uropod contraction during lymphocyte recirculation. AU - Soriano, Silvia AU - Hons, Miroslav AU - Schumann, Kathrin AU - Kumar, Varsha AU - Dennier, Timo AU - Lyck, Ruth AU - Sixt, Michael K AU - Stein, Jens ID - 3392 IS - 5 JF - Journal of Immunology SN - 0022-1767 TI - In vivo analysis of uropod function during physiological T cell trafficking VL - 187 ER - TY - CONF AB - We study multi-label prediction for structured output sets, a problem that occurs, for example, in object detection in images, secondary structure prediction in computational biology, and graph matching with symmetries. Conventional multilabel classification techniques are typically not applicable in this situation, because they require explicit enumeration of the label set, which is infeasible in case of structured outputs. Relying on techniques originally designed for single-label structured prediction, in particular structured support vector machines, results in reduced prediction accuracy, or leads to infeasible optimization problems. In this work we derive a maximum-margin training formulation for multi-label structured prediction that remains computationally tractable while achieving high prediction accuracy. It also shares most beneficial properties with single-label maximum-margin approaches, in particular formulation as a convex optimization problem, efficient working set training, and PAC-Bayesian generalization bounds. AU - Lampert, Christoph ID - 3163 TI - Maximum margin multi-label structured prediction ER - TY - GEN AB - We study multi-label prediction for structured output spaces, a problem that occurs, for example, in object detection in images, secondary structure prediction in computational biology, and graph matching with symmetries. Conventional multi-label classification techniques are typically not applicable in this situation, because they require explicit enumeration of the label space, which is infeasible in case of structured outputs. Relying on techniques originally designed for single- label structured prediction, in particular structured support vector machines, results in reduced prediction accuracy, or leads to infeasible optimization problems. In this work we derive a maximum-margin training formulation for multi-label structured prediction that remains computationally tractable while achieving high prediction accuracy. It also shares most beneficial properties with single-label maximum-margin approaches, in particular a formulation as a convex optimization problem, efficient working set training, and PAC-Bayesian generalization bounds. AU - Lampert, Christoph ID - 3322 T2 - NIPS: Neural Information Processing Systems TI - Maximum margin multi label structured prediction ER - TY - JOUR AB - Powerful statistical models that can be learned efficiently from large amounts of data are currently revolutionizing computer vision. These models possess a rich internal structure reflecting task-specific relations and constraints. This monograph introduces the reader to the most popular classes of structured models in computer vision. Our focus is discrete undirected graphical models which we cover in detail together with a description of algorithms for both probabilistic inference and maximum a posteriori inference. We discuss separately recently successful techniques for prediction in general structured models. In the second part of this monograph we describe methods for parameter learning where we distinguish the classic maximum likelihood based methods from the more recent prediction-based parameter learning methods. We highlight developments to enhance current models and discuss kernelized models and latent variable models. To make the monograph more practical and to provide links to further study we provide examples of successful application of many methods in the computer vision literature. AU - Nowozin, Sebastian AU - Lampert, Christoph ID - 3320 IS - 3-4 JF - Foundations and Trends in Computer Graphics and Vision TI - Structured learning and prediction in computer vision VL - 6 ER - TY - CONF AB - We address the problem of metric learning for multi-view data, namely the construction of embedding projections from data in different representations into a shared feature space, such that the Euclidean distance in this space provides a meaningful within-view as well as between-view similarity. Our motivation stems from the problem of cross-media retrieval tasks, where the availability of a joint Euclidean distance function is a pre-requisite to allow fast, in particular hashing-based, nearest neighbor queries. We formulate an objective function that expresses the intuitive concept that matching samples are mapped closely together in the output space, whereas non-matching samples are pushed apart, no matter in which view they are available. The resulting optimization problem is not convex, but it can be decomposed explicitly into a convex and a concave part, thereby allowing efficient optimization using the convex-concave procedure. Experiments on an image retrieval task show that nearest-neighbor based cross-view retrieval is indeed possible, and the proposed technique improves the retrieval accuracy over baseline techniques. AU - Quadrianto, Novi AU - Lampert, Christoph ID - 3319 TI - Learning multi-view neighborhood preserving projections ER - TY - JOUR AB - The use of optical traps to measure or apply forces on the molecular level requires a precise knowledge of the trapping force field. Close to the trap center, this field is typically approximated as linear in the displacement of the trapped microsphere. However, applications demanding high forces at low laser intensities can probe the light-microsphere interaction beyond the linear regime. Here, we measured the full nonlinear force and displacement response of an optical trap in two dimensions using a dual-beam optical trap setup with back-focal-plane photodetection. We observed a substantial stiffening of the trap beyond the linear regime that depends on microsphere size, in agreement with Mie theory calculations. Surprisingly, we found that the linear detection range for forces exceeds the one for displacement by far. Our approach allows for a complete calibration of an optical trap. AU - Jahnel, Marcus AU - Behrndt, Martin AU - Jannasch, Anita AU - Schaeffer, Erik AU - Grill, Stephan ID - 3373 IS - 7 JF - Optics Letters TI - Measuring the complete force field of an optical trap VL - 36 ER - TY - JOUR AB - By exploiting an analogy between population genetics and statistical mechanics, we study the evolution of a polygenic trait under stabilizing selection, mutation and genetic drift. This requires us to track only four macroscopic variables, instead of the distribution of all the allele frequencies that influence the trait. These macroscopic variables are the expectations of: the trait mean and its square, the genetic variance, and of a measure of heterozygosity, and are derived from a generating function that is in turn derived by maximizing an entropy measure. These four macroscopics are enough to accurately describe the dynamics of the trait mean and of its genetic variance (and in principle of any other quantity). Unlike previous approaches that were based on an infinite series of moments or cumulants, which had to be truncated arbitrarily, our calculations provide a well-defined approximation procedure. We apply the framework to abrupt and gradual changes in the optimum, as well as to changes in the strength of stabilizing selection. Our approximations are surprisingly accurate, even for systems with as few as five loci. We find that when the effects of drift are included, the expected genetic variance is hardly altered by directional selection, even though it fluctuates in any particular instance. We also find hysteresis, showing that even after averaging over the microscopic variables, the macroscopic trajectories retain a memory of the underlying genetic states. AU - de Vladar, Harold AU - Barton, Nicholas H ID - 3375 IS - 58 JF - Journal of the Royal Society Interface TI - The statistical mechanics of a polygenic character under stabilizing selection mutation and drift VL - 8 ER - TY - JOUR AB - Unlike unconditionally advantageous “Fisherian” variants that tend to spread throughout a species range once introduced anywhere, “bistable” variants, such as chromosome translocations, have two alternative stable frequencies, absence and (near) fixation. Analogous to populations with Allee effects, bistable variants tend to increase locally only once they become sufficiently common, and their spread depends on their rate of increase averaged over all frequencies. Several proposed manipulations of insect populations, such as using Wolbachia or “engineered underdominance” to suppress vector-borne diseases, produce bistable rather than Fisherian dynamics. We synthesize and extend theoretical analyses concerning three features of their spatial behavior: rate of spread, conditions to initiate spread from a localized introduction, and wave stopping caused by variation in population densities or dispersal rates. Unlike Fisherian variants, bistable variants tend to spread spatially only for particular parameter combinations and initial conditions. Wave initiation requires introduction over an extended region, while subsequent spatial spread is slower than for Fisherian waves and can easily be halted by local spatial inhomogeneities. We present several new results, including robust sufficient conditions to initiate (and stop) spread, using a one-parameter cubic approximation applicable to several models. The results have both basic and applied implications. AU - Barton, Nicholas H AU - Turelli, Michael ID - 3393 IS - 3 JF - American Naturalist SN - 0003-0147 TI - Spatial waves of advance with bistable dynamics: Cytoplasmic and genetic analogues of Allee effects VL - 178 ER - TY - JOUR AB - Understanding the mechanism of protein folding requires a detailed knowledge of the structural properties of the barriers separating unfolded from native conformations. The S-peptide from ribonuclease S forms its α-helical structure only upon binding to the folded S-protein. We characterized the transition state for this binding-induced folding reaction at high resolution by determining the effect of site-specific backbone thioxylation and side-chain modifications on the kinetics and thermodynamics of the reaction, which allows us to monitor formation of backbone hydrogen bonds and side-chain interactions in the transition state. The experiments reveal that α-helical structure in the S-peptide is absent in the transition state of binding. Recognition between the unfolded S-peptide and the S-protein is mediated by loosely packed hydrophobic side-chain interactions in two well defined regions on the S-peptide. Close packing and helix formation occurs rapidly after binding. Introducing hydrophobic residues at positions outside the recognition region can drastically slow down association. AU - Bachmann, Annett AU - Wildemann, Dirk AU - Praetorius, Florian M AU - Fischer, Gunter AU - Kiefhaber, Thomas ID - 14305 IS - 10 JF - PNAS KW - Multidisciplinary SN - 0027-8424 TI - Mapping backbone and side-chain interactions in the transition state of a coupled protein folding and binding reaction VL - 108 ER - TY - JOUR AB - During assembly of the Drosophila olfactory circuit, projection neuron (PN) dendrites prepattern the developing antennal lobe before the arrival of axons from their presynaptic partners, the adult olfactory receptor neurons (ORNs). We previously found that levels of transmembrane Semaphorin-1a, which acts as a receptor, instruct PN dendrite targeting along the dorsolateral-ventromedial axis. Here we show that two secreted semaphorins, Sema-2a and Sema-2b, provide spatial cues for PN dendrite targeting. Sema-2a and Sema-2b proteins are distributed in gradients opposing the Sema-1a protein gradient, and Sema-1a binds to Sema-2a-expressing cells. In Sema-2a and Sema-2b double mutants, PN dendrites that normally target dorsolaterally in the antennal lobe mistarget ventromedially, phenocopying cell-autonomous Sema-1a removal from these PNs. Cell ablation, cell-specific knockdown, and rescue experiments indicate that secreted semaphorins from degenerating larval ORN axons direct dendrite targeting. Thus, a degenerating brain structure instructs the wiring of a developing circuit through the repulsive action of secreted semaphorins. AU - Sweeney, Lora Beatrice Jaeger AU - Chou, Ya-Hui AU - Wu, Zhuhao AU - Joo, William AU - Komiyama, Takaki AU - Potter, Christopher J. AU - Kolodkin, Alex L. AU - Garcia, K. Christopher AU - Luo, Liqun ID - 7701 IS - 5 JF - Neuron SN - 0896-6273 TI - Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting VL - 72 ER - TY - JOUR AB - Longitudinal axon fascicles within the Drosophila embryonic CNS provide connections between body segments and are required for coordinated neural signaling along the anterior-posterior axis. We show here that establishment of select CNS longitudinal tracts and formation of precise mechanosensory afferent innervation to the same CNS region are coordinately regulated by the secreted semaphorins Sema-2a and Sema-2b. Both Sema-2a and Sema-2b utilize the same neuronal receptor, plexin B (PlexB), but serve distinct guidance functions. Localized Sema-2b attraction promotes the initial assembly of a subset of CNS longitudinal projections and subsequent targeting of chordotonal sensory afferent axons to these same longitudinal connectives, whereas broader Sema-2a repulsion serves to prevent aberrant innervation. In the absence of Sema-2b or PlexB, chordotonal afferent connectivity within the CNS is severely disrupted, resulting in specific larval behavioral deficits. These results reveal that distinct semaphorin-mediated guidance functions converge at PlexB and are critical for functional neural circuit assembly. AU - Wu, Zhuhao AU - Sweeney, Lora Beatrice Jaeger AU - Ayoob, Joseph C. AU - Chak, Kayam AU - Andreone, Benjamin J. AU - Ohyama, Tomoko AU - Kerr, Rex AU - Luo, Liqun AU - Zlatic, Marta AU - Kolodkin, Alex L. ID - 7702 IS - 2 JF - Neuron SN - 0896-6273 TI - A combinatorial semaphorin code instructs the initial steps of sensory circuit assembly in the Drosophila CNS VL - 70 ER -