Ring-like Oligomers of Synaptotagmins and Related C2 Domain Proteins

We recently reported that the C2AB portion of Synaptotagmin 1 (Syt1) could self-assemble into Ca2+-sensitive ring-like oligomers on membranes, which could potentially regulate neurotransmitter release. Here we report that analogous ring-like oligomers assemble from the C2AB domains of other Syt isoforms (Syt2, Syt7, Syt9) as well as related C2 domain containing protein, Doc2B and extended Synaptotagmins (E-Syts). Evidently, circular oligomerization is a general and conserved structural aspect of many C2 domain proteins, including Synaptotagmins. Further, using electron microscopy combined with targeted mutations, we show that under physiologically relevant conditions, both the Syt1 ring assembly and its rapid disruption by Ca2+ involve the well-established functional surfaces on the C2B domain that are important for synaptic transmission. Our data suggests that ring formation may be triggered at an early step in synaptic vesicle docking and positions Syt1 to synchronize neurotransmitter release to Ca2+ influx

Synaptotagmin-1 membrane binding is driven by the C2B domain and assisted cooperatively by the C2A domain

Synaptotagmin interaction with anionic lipid (phosphatidylserine/phosphatidylinositol) containing membranes, both in the absence and presence of calcium ions (Ca2+), is critical to its central role in orchestrating neurotransmitter release. The molecular surfaces involved, namely the conserved polylysine motif in the C2B domain and Ca2+-binding aliphatic loops on both C2A and C2B domains, are known. Here we use surface force apparatus combined with systematic mutational analysis of the functional surfaces to directly measure Syt1-membrane interaction and fully map the site-binding energetics of Syt1 both in the absence and presence of Ca2+. By correlating energetics data with the molecular rearrangements measured during confinement, we find that both C2 domains cooperate in membrane binding, with the C2B domain functioning as the main energetic driver, and the C2A domain acting as a facilitator

M-Branes and Metastable States

We study a supersymmetry breaking deformation of the M-theory background found in arXiv:hep-th/0012011. The supersymmetric solution is a warped product of R^{2,1} and the 8-dimensional Stenzel space, which is a higher dimensional generalization of the deformed conifold. At the bottom of the warped throat there is a 4-sphere threaded by \tilde{M} units of 4-form flux. The dual (2+1)-dimensional theory has a discrete spectrum of bound states. We add p anti-M2 branes at a point on the 4-sphere, and show that they blow up into an M5-brane wrapping a 3-sphere at a fixed azimuthal angle on the 4-sphere. This supersymmetry breaking state turns out to be metastable for p / \tilde{M} < 0.054. We find a smooth O(3)-symmetric Euclidean bounce solution in the M5-brane world volume theory that describes the decay of the false vacuum. Calculation of the Euclidean action shows that the metastable state is extremely long-lived. We also describe the corresponding metastable states and their decay in the type IIA background obtained by reduction along one of the spatial directions of R^{2,1}.Comment: 33 pages, 5 figures; v2 note adde

Field-induced quantum fluctuations in the heavy fermion superconductor CeCu2Ge2

Quantum-mechanical fluctuations in strongly correlated electron systems cause unconventional phenomena such as non-Fermi liquid behavior, and arguably high temperature superconductivity. Here we report the discovery of a field-tuned quantum critical phenomenon in stoichiometric CeCu2Ge2, a spin density wave ordered heavy fermion metal that exhibits unconventional superconductivity under ~ 10 GPa of applied pressure. Our finding of the associated quantum critical spin fluctuations of the antiferromagnetic spin density wave order, dominating the local fluctuations due to single-site Kondo effect, provide new information about the underlying mechanism that can be important in understanding superconductivity in this novel compound.Comment: Heavy Fermion, Quantum Critical Phenomeno

Holographic Symmetry-Breaking Phases in AdS3_3/CFT2_2

In this note we study the symmetry-breaking phases of 3D gravity coupled to matter. In particular, we consider black holes with scalar hair as a model of symmetry-breaking phases of a strongly coupled 1+1 dimensional CFT. In the case of a discrete symmetry, we show that these theories admit metastable phases of broken symmetry and study the thermodynamics of these phases. We also demonstrate that the 3D Einstein-Maxwell theory shows continuous symmetry breaking at low temperature. The apparent contradiction with the Coleman-Mermin-Wagner theorem is discussed.Comment: 15 pages, 7 figur

Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly

Synaptic vesicle fusion is mediated by SNARE proteins—VAMP2 on the vesicle and Syntaxin‐1/SNAP25 on the presynaptic membrane. Chaperones Munc18‐1 and Munc13‐1 cooperatively catalyze SNARE assembly via an intermediate ‘template’ complex containing Syntaxin‐1 and VAMP2. How SNAP25 enters this reaction remains a mystery. Here, we report that Munc13‐1 recruits SNAP25 to initiate the ternary SNARE complex assembly by direct binding, as judged by bulk FRET spectroscopy and single‐molecule optical tweezer studies. Detailed structure–function analyses show that the binding is mediated by the Munc13‐1 MUN domain and is specific for the SNAP25 ‘linker’ region that connects the two SNARE motifs. Consequently, freely diffusing SNAP25 molecules on phospholipid bilayers are concentrated and bound in ~ 1 : 1 stoichiometry by the self‐assembled Munc13‐1 nanoclusters

Changing and pivoting the business model in software startups

In a company, its business strategy and business model undergo changes throughout its life. These changes can be induced or forced externally or they can result from a deliberate strategy to improve the business performance and to achieve success. Certain changes can lead to a major change in the business model of the company (i.e., a pivot). Such change or innovation in the business model can occur in various of its dimensions. According to Osterwalder and Pigneur, there are four epicenters of change and innovation to be taken into consideration. In this manuscript, fifteen Portuguese software startups were studied using essentially semi-structured interviews to gather the information. The data was processed with a software application for qualitative data analysis. The main results are related to a dynamic process of evolution and change of the business model in software startups. In particular, we have identified that the changes in the business elements that support the production of the value proposition (left-hand side of the Business Model Canvas) affect the elements that explain the strategy of delivering the value proposition to customers (right-hand side of the Business Model Canvas).This work was supported by COMPETE: POCI-01-0145-FEDER-007043 and FCT Fundação para a Ciência e a Tecnologia within the Project Scope: UID/CEC/00319/2013

Weinberg like sum rules revisited

The generalized Weinberg sum rules containing the difference of isovector vector and axial-vector spectral functions saturated by both finite and infinite number of narrow resonances are considered. We summarize the status of these sum rules and analyze their overall agreement with phenomenological Lagrangians, low-energy relations, parity doubling, hadron string models, and experimental data.Comment: 31 pages, noticed misprints are corrected, references are added, and other minor corrections are mad

MICRO-Foundations in Strategic Management: Squaring Coleman's Diagram

Abell, Felin and Foss argue that "macro-explanations" in strategic management, explanations in which organizational routines figure prominently and in which both the explanandum and explanans are at the macro-level, are necessarily incomplete. They take a diagram (which has the form of a trapezoid) from Coleman, Foundations of Social Theory, The Belknap Press of Harvard University Press, Cambridge (Mass.)/London, (1990) to task to show that causal chains connecting two macro-phenomena always involve "macro-to-micro" and "micro-to-macro" links, links that macro-explanations allegedly fail to recognize. Their plea for micro-foundations in strategic management is meant to shed light on these "missing links". The paper argues that while there are good reasons for providing micro-foundations, Abell, Felin and Foss's causal incompleteness argument is not one of them. Their argument does not sufficiently distinguish between causal and constitutive relations. Once these relations are carefully distinguished, it follows that Coleman's diagram has to be squared. This in turn allows us to see that macro-explanations need not be incomplete

The Radiative Corrections to the Mass of the Kink Using an Alternative Renormalization Program

In this paper we compute the radiative correction to the mass of the kink in $\phi^4$ theory in 1+1 dimensions, using an alternative renormalization program. In this newly proposed renormalization program the breaking of the translational invariance and the topological nature of the problem, due to the presence of the kink, is automatically taken into account. This will naturally lead to uniquely defined position dependent counterterms. We use the mode number cutoff in conjunction with the above program to compute the mass of the kink up to and including the next to the leading order quantum correction. We discuss the differences between the results of this procedure and the previously reported ones.Comment: 8 pages, 2 figures. arXiv admin note: substantial text overlap with arXiv:0806.036