@inproceedings{8339,
abstract = {Discrete Gaussian distributions over lattices are central to lattice-based cryptography, and to the computational and mathematical aspects of lattices more broadly. The literature contains a wealth of useful theorems about the behavior of discrete Gaussians under convolutions and related operations. Yet despite their structural similarities, most of these theorems are formally incomparable, and their proofs tend to be monolithic and written nearly “from scratch,” making them unnecessarily hard to verify, understand, and extend.
In this work we present a modular framework for analyzing linear operations on discrete Gaussian distributions. The framework abstracts away the particulars of Gaussians, and usually reduces proofs to the choice of appropriate linear transformations and elementary linear algebra. To showcase the approach, we establish several general properties of discrete Gaussians, and show how to obtain all prior convolution theorems (along with some new ones) as straightforward corollaries. As another application, we describe a self-reduction for Learning With Errors (LWE) that uses a fixed number of samples to generate an unlimited number of additional ones (having somewhat larger error). The distinguishing features of our reduction are its simple analysis in our framework, and its exclusive use of discrete Gaussians without any loss in parameters relative to a prior mixed discrete-and-continuous approach.
As a contribution of independent interest, for subgaussian random matrices we prove a singular value concentration bound with explicitly stated constants, and we give tighter heuristics for specific distributions that are commonly used for generating lattice trapdoors. These bounds yield improvements in the concrete bit-security estimates for trapdoor lattice cryptosystems.},
author = {Genise, Nicholas and Micciancio, Daniele and Peikert, Chris and Walter, Michael},
booktitle = {23rd IACR International Conference on the Practice and Theory of Public-Key Cryptography},
isbn = {9783030453732},
issn = {16113349},
location = {Edinburgh, United Kingdom},
pages = {623--651},
publisher = {Springer Nature},
title = {{Improved discrete Gaussian and subgaussian analysis for lattice cryptography}},
doi = {10.1007/978-3-030-45374-9_21},
volume = {12110},
year = {2020},
}
@phdthesis{8340,
abstract = {Mitochondria are sites of oxidative phosphorylation in eukaryotic cells. Oxidative phosphorylation operates by a chemiosmotic mechanism made possible by redox-driven proton pumping machines which establish a proton motive force across the inner mitochondrial membrane. This electrochemical proton gradient is used to drive ATP synthesis, which powers the majority of cellular processes such as protein synthesis, locomotion and signalling. In this thesis I investigate the structures and molecular mechanisms of two inner mitochondrial proton pumping enzymes, respiratory complex I and transhydrogenase. I present the first high-resolution structure of the full transhydrogenase from any species, and a significantly improved structure of complex I. Improving the resolution from 3.3 Å available previously to up to 2.3 Å in this thesis allowed us to model bound water molecules, crucial in the proton pumping mechanism. For both enzymes, up to five cryo-EM datasets with different substrates and inhibitors bound were solved to delineate the catalytic cycle and understand the proton pumping mechanism. In transhydrogenase, the proton channel is gated by reversible detachment of the NADP(H)-binding domain which opens the proton channel to the opposite sites of the membrane. In complex I, the proton channels are gated by reversible protonation of key glutamate and lysine residues and breaking of the water wire connecting the proton pumps with the quinone reduction site. The tight coupling between the redox and the proton pumping reactions in transhydrogenase is achieved by controlling the NADP(H) exchange which can only happen when the NADP(H)-binding domain interacts with the membrane domain. In complex I, coupling is achieved by cycling of the whole complex between the closed state, in which quinone can get reduced, and the open state, in which NADH can induce quinol ejection from the binding pocket. On the basis of these results I propose detailed mechanisms for catalytic cycles of transhydrogenase and complex I that are consistent with a large amount of previous work. In both enzymes, conformational and electrostatic mechanisms contribute to the overall catalytic process. Results presented here could be used for better understanding of the human pathologies arising from deficiencies of complex I or transhydrogenase and could be used to develop novel therapies.},
author = {Kampjut, Domen},
isbn = {978-3-99078-008-4},
issn = {2663-337X},
pages = {242},
publisher = {Institute of Science and Technology Austria},
title = {{Molecular mechanisms of mitochondrial redox-coupled proton pumping enzymes}},
doi = {10.15479/AT:ISTA:8340},
year = {2020},
}
@phdthesis{8341,
abstract = {One of the most striking hallmarks of the eukaryotic cell is the presence of intracellular vesicles and organelles. Each of these membrane-enclosed compartments has a distinct composition of lipids and proteins, which is essential for accurate membrane traffic and homeostasis. Interestingly, their biochemical identities are achieved with the help
of small GTPases of the Rab family, which cycle between GDP- and GTP-bound forms on the selected membrane surface. While this activity switch is well understood for an individual protein, how Rab GTPases collectively transition between states to generate decisive signal propagation in space and time is unclear. In my PhD thesis, I present
in vitro reconstitution experiments with theoretical modeling to systematically study a minimal Rab5 activation network from bottom-up. We find that positive feedback based on known molecular interactions gives rise to bistable GTPase activity switching on system’s scale. Furthermore, we determine that collective transition near the critical
point is intrinsically stochastic and provide evidence that the inactive Rab5 abundance on the membrane can shape the network response. Finally, we demonstrate that collective switching can spread on the lipid bilayer as a traveling activation wave, representing a possible emergent activity pattern in endosomal maturation. Together, our
findings reveal new insights into the self-organization properties of signaling networks away from chemical equilibrium. Our work highlights the importance of systematic characterization of biochemical systems in well-defined physiological conditions. This way, we were able to answer long-standing open questions in the field and close the gap between regulatory processes on a molecular scale and emergent responses on system’s level.},
author = {Bezeljak, Urban},
issn = {2663-337X},
pages = {215},
publisher = {Institute of Science and Technology Austria},
title = {{In vitro reconstitution of a Rab activation switch}},
doi = {10.15479/AT:ISTA:8341},
year = {2020},
}
@phdthesis{8350,
abstract = {Cytoplasm is a gel-like crowded environment composed of tens of thousands of macromolecules, organelles, cytoskeletal networks and cytosol. The structure of the cytoplasm is thought to be highly organized and heterogeneous due to the crowding of its constituents and their effective compartmentalization. In such an environment, the diffusive dynamics of the molecules is very restricted, an effect that is further amplified by clustering and anchoring of molecules. Despite the jammed nature of the cytoplasm at the microscopic scale, large-scale reorganization of cytoplasm is essential for important cellular functions, such as nuclear positioning and cell division. How such mesoscale reorganization of the cytoplasm is achieved, especially for very large cells such as oocytes or syncytial tissues that can span hundreds of micrometers in size, has only begun to be understood.
In this thesis, I focus on the recent advances in elucidating the molecular, cellular and biophysical principles underlying cytoplasmic organization across different scales, structures and species. First, I outline which of these principles have been identified by reductionist approaches, such as in vitro reconstitution assays, where boundary conditions and components can be modulated at ease. I then describe how the theoretical and experimental framework established in these reduced systems have been applied to their more complex in vivo counterparts, in particular oocytes and embryonic syncytial structures, and discuss how such complex biological systems can initiate symmetry breaking and establish patterning.
Specifically, I examine an example of large-scale reorganizations taking place in zebrafish embryos, where extensive cytoplasmic streaming leads to the segregation of cytoplasm from yolk granules along the animal-vegetal axis of the embryo. Using biophysical experimentation and theory, I investigate the forces underlying this process, to show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the embryo. This wave functions in segregation by both pulling cytoplasm animally and pushing yolk granules vegetally. Cytoplasm pulling is mediated by bulk actin network flows exerting friction forces on the cytoplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. This study defines a novel role of bulk actin polymerization waves in embryo polarization via cytoplasmic segregation. Lastly, I describe the cytoplasmic reorganizations taking place during zebrafish oocyte maturation, where the initial segregation of the cytoplasm and yolk granules occurs. Here, I demonstrate a previously uncharacterized wave of microtubule aster formation, traveling the oocyte along the animal-vegetal axis. Further research is required to determine the role of such microtubule structures in cytoplasmic reorganizations therein.
Collectively, these studies provide further evidence for the coupling between cell cytoskeleton and cell cycle machinery, which can underlie a core self-organizing mechanism for orchestrating large-scale reorganizations in a cell-cycle-tunable manner, where the modulations of the force-generating machinery and cytoplasmic mechanics can be harbored to fulfill cellular functions.},
author = {Shamipour, Shayan},
issn = {2663-337X},
pages = {107},
publisher = {Institute of Science and Technology Austria},
title = {{Bulk actin dynamics drive phase segregation in zebrafish oocytes }},
doi = {10.15479/AT:ISTA:8350},
year = {2020},
}
@phdthesis{8353,
abstract = {Mrp (Multi resistance and pH adaptation) are broadly distributed secondary active antiporters that catalyze the transport of monovalent ions such as sodium and potassium outside of the cell coupled to the inward translocation of protons. Mrp antiporters are unique in a way that they are composed of seven subunits (MrpABCDEFG) encoded in a single operon, whereas other antiporters catalyzing the same reaction are mostly encoded by a single gene. Mrp exchangers are crucial for intracellular pH homeostasis and Na+ efflux, essential mechanisms for H+ uptake under alkaline environments and for reduction of the intracellular concentration of toxic cations. Mrp displays no homology to any other monovalent Na+(K+)/H+ antiporters but Mrp subunits have primary sequence similarity to essential redox-driven proton pumps, such as respiratory complex I and membrane-bound hydrogenases. This similarity reinforces the hypothesis that these present day redox-driven proton pumps are descended from the Mrp antiporter. The Mrp structure serves as a model to understand the yet obscure coupling mechanism between ion or electron transfer and proton translocation in this large group of proteins. In the thesis, I am presenting the purification, biochemical analysis, cryo-EM analysis and molecular structure of the Mrp complex from Anoxybacillus flavithermus solved by cryo-EM at 3.0 Å resolution. Numerous conditions were screened to purify Mrp to high homogeneity and to obtain an appropriate distribution of single particles on cryo-EM grids covered with a continuous layer of ultrathin carbon. A preferred particle orientation problem was solved by performing a tilted data collection. The activity assays showed the specific pH-dependent
profile of secondary active antiporters. The molecular structure shows that Mrp is a dimer of seven-subunit protomers with 50 trans-membrane helices each. The dimer interface is built by many short and tilted transmembrane helices, probably causing a thinning of the bacterial membrane. The surface charge distribution shows an extraordinary asymmetry within each monomer, revealing presumable proton and sodium translocation pathways. The two largest
and homologous Mrp subunits MrpA and MrpD probably translocate one proton each into the cell. The sodium ion is likely being translocated in the opposite direction within the small subunits along a ladder of charged and conserved residues. Based on the structure, we propose a mechanism were the antiport activity is accomplished via electrostatic interactions between the charged cations and key charged residues. The flexible key TM helices coordinate these
electrostatic interactions, while the membrane thinning between the monomers enables the translocation of sodium across the charged membrane. The entire family of redox-driven proton pumps is likely to perform their mechanism in a likewise manner.},
author = {Steiner, Julia},
issn = {2663-337X},
pages = {191},
publisher = {Institute of Science and Technology Austria},
title = {{Biochemical and structural investigation of the Mrp antiporter, an ancestor of complex I}},
doi = {10.15479/AT:ISTA:8353},
year = {2020},
}
@phdthesis{8358,
abstract = {During bacterial cell division, the tubulin-homolog FtsZ forms a ring-like structure at the center of the cell. This so-called Z-ring acts as a scaffold recruiting several division-related proteins to mid-cell and plays a key role in distributing proteins at the division site, a feature driven by the treadmilling motion of FtsZ filaments around the septum. What regulates the architecture, dynamics and stability of the Z-ring is still poorly understood, but FtsZ-associated proteins (Zaps) are known to play an important role.
Advances in fluorescence microscopy and in vitro reconstitution experiments have helped to shed light into some of the dynamic properties of these complex systems, but methods that allow to collect and analyze large quantitative data sets of the underlying polymer dynamics are still missing.
Here, using an in vitro reconstitution approach, we studied how different Zaps affect FtsZ filament dynamics and organization into large-scale patterns, giving special emphasis to the role of the well-conserved protein ZapA. For this purpose, we use high-resolution fluorescence microscopy combined with novel image analysis workfows to study pattern organization and polymerization dynamics of active filaments. We quantified the influence of Zaps on FtsZ on three diferent spatial scales: the large-scale organization of the membrane-bound filament network, the underlying
polymerization dynamics and the behavior of single molecules.
We found that ZapA cooperatively increases the spatial order of the filament network, binds only transiently to FtsZ filaments and has no effect on filament length and treadmilling velocity. Our data provides a model for how FtsZ-associated proteins can increase the precision and stability of the bacterial cell division machinery in a
switch-like manner, without compromising filament dynamics. Furthermore, we believe that our automated quantitative methods can be used to analyze a large variety of dynamic cytoskeletal systems, using standard time-lapse
movies of homogeneously labeled proteins obtained from experiments in vitro or even inside the living cell.
},
author = {Dos Santos Caldas, Paulo R},
isbn = {978-3-99078-009-1},
issn = {2663-337X},
pages = {135},
publisher = {Institute of Science and Technology Austria},
title = {{Organization and dynamics of treadmilling filaments in cytoskeletal networks of FtsZ and its crosslinkers}},
doi = {10.15479/AT:ISTA:8358},
year = {2020},
}
@article{8361,
abstract = {With the lithium-ion technology approaching its intrinsic limit with graphite-based anodes, Li metal is recently receiving renewed interest from the battery community as potential high capacity anode for next-generation rechargeable batteries. In this focus paper, we review the main advances in this field since the first attempts in the mid-1970s. Strategies for enabling reversible cycling and avoiding dendrite growth are thoroughly discussed, including specific applications in all-solid-state (inorganic and polymeric), Lithium–Sulfur (Li–S) and Lithium-O2 (air) batteries. A particular attention is paid to recent developments of these battery technologies and their current state with respect to the 2030 targets of the EU Integrated Strategic Energy Technology Plan (SET-Plan) Action 7.},
author = {Varzi, Alberto and Thanner, Katharina and Scipioni, Roberto and Di Lecce, Daniele and Hassoun, Jusef and Dörfler, Susanne and Altheus, Holger and Kaskel, Stefan and Prehal, Christian and Freunberger, Stefan Alexander},
issn = {0378-7753},
journal = {Journal of Power Sources},
number = {12},
publisher = {Elsevier},
title = {{Current status and future perspectives of lithium metal batteries}},
doi = {10.1016/j.jpowsour.2020.228803},
volume = {480},
year = {2020},
}
@phdthesis{8366,
abstract = {Fabrication of curved shells plays an important role in modern design, industry, and science. Among their remarkable properties are, for example, aesthetics of organic shapes, ability to evenly distribute loads, or efficient flow separation. They find applications across vast length scales ranging from sky-scraper architecture to microscopic devices. But, at
the same time, the design of curved shells and their manufacturing process pose a variety of challenges. In this thesis, they are addressed from several perspectives. In particular, this thesis presents approaches based on the transformation of initially flat sheets into the target curved surfaces. This involves problems of interactive design of shells with nontrivial mechanical constraints, inverse design of complex structural materials, and data-driven modeling of delicate and time-dependent physical properties. At the same time, two newly-developed self-morphing mechanisms targeting flat-to-curved transformation are presented.
In architecture, doubly curved surfaces can be realized as cold bent glass panelizations. Originally flat glass panels are bent into frames and remain stressed. This is a cost-efficient fabrication approach compared to hot bending, when glass panels are shaped plastically. However such constructions are prone to breaking during bending, and it is highly
nontrivial to navigate the design space, keeping the panels fabricable and aesthetically pleasing at the same time. We introduce an interactive design system for cold bent glass façades, while previously even offline optimization for such scenarios has not been sufficiently developed. Our method is based on a deep learning approach providing quick
and high precision estimation of glass panel shape and stress while handling the shape
multimodality.
Fabrication of smaller objects of scales below 1 m, can also greatly benefit from shaping originally flat sheets. In this respect, we designed new self-morphing shell mechanisms transforming from an initial flat state to a doubly curved state with high precision and detail. Our so-called CurveUps demonstrate the encodement of the geometric information
into the shell. Furthermore, we explored the frontiers of programmable materials and showed how temporal information can additionally be encoded into a flat shell. This allows prescribing deformation sequences for doubly curved surfaces and, thus, facilitates self-collision avoidance enabling complex shapes and functionalities otherwise impossible.
Both of these methods include inverse design tools keeping the user in the design loop.},
author = {Guseinov, Ruslan},
isbn = {978-3-99078-010-7},
issn = {2663-337X},
keywords = {computer-aided design, shape modeling, self-morphing, mechanical engineering},
pages = {118},
publisher = {Institute of Science and Technology Austria},
title = {{Computational design of curved thin shells: From glass façades to programmable matter}},
doi = {10.15479/AT:ISTA:8366},
year = {2020},
}
@misc{8375,
abstract = {Supplementary movies showing the following sequences for spatio-temporarily programmed shells: input geometry and actuation time landscape; comparison of morphing processes from a camera recording and a simulation; final actuated shape.},
author = {Guseinov, Ruslan},
publisher = {Institute of Science and Technology Austria},
title = {{Supplementary data for "Computational design of curved thin shells: from glass façades to programmable matter"}},
doi = {10.15479/AT:ISTA:8375},
year = {2020},
}
@inproceedings{8382,
abstract = {We present the first deterministic wait-free long-lived snapshot algorithm, using only read and write operations, that guarantees polylogarithmic amortized step complexity in all executions. This is the first non-blocking snapshot algorithm, using reads and writes only, that has sub-linear amortized step complexity in executions of arbitrary length. The key to our construction is a novel implementation of a 2-component max array object which may be of independent interest.},
author = {Baig, Mirza Ahad and Hendler, Danny and Milani, Alessia and Travers, Corentin},
booktitle = {Proceedings of the 39th Symposium on Principles of Distributed Computing},
isbn = {9781450375825},
location = {Virtual, Italy},
pages = {31--40},
publisher = {Association for Computing Machinery},
title = {{Long-lived snapshots with polylogarithmic amortized step complexity}},
doi = {10.1145/3382734.3406005},
year = {2020},
}
@inproceedings{8383,
abstract = {We introduce extension-based proofs, a class of impossibility proofs that includes valency arguments. They are modelled as an interaction between a prover and a protocol. Using proofs based on combinatorial topology, it has been shown that it is impossible to deterministically solve k-set agreement among n > k ≥ 2 processes in a wait-free manner. However, it was unknown whether proofs based on simpler techniques were possible. We explain why this impossibility result cannot be obtained by an extension-based proof and, hence, extension-based proofs are limited in power.},
author = {Alistarh, Dan-Adrian and Aspnes, James and Ellen, Faith and Gelashvili, Rati and Zhu, Leqi},
booktitle = {Proceedings of the 39th Symposium on Principles of Distributed Computing},
isbn = {9781450375825},
location = {Virtual, Italy},
pages = {54--56},
publisher = {Association for Computing Machinery},
title = {{Brief Announcement: Why Extension-Based Proofs Fail}},
doi = {10.1145/3382734.3405743},
year = {2020},
}
@article{8384,
abstract = {Previous research on animations of soap bubbles, films, and foams largely focuses on the motion and geometric shape of the bubble surface. These works neglect the evolution of the bubble’s thickness, which is normally responsible for visual phenomena like surface vortices, Newton’s interference patterns, capillary waves, and deformation-dependent rupturing of films in a foam. In this paper, we model these natural phenomena by introducing the film thickness as a reduced degree of freedom in the Navier-Stokes equations and deriving their equations of motion. We discretize the equations on a nonmanifold triangle mesh surface and couple it to an existing bubble solver. In doing so, we also introduce an incompressible fluid solver for 2.5D films and a novel advection algorithm for convecting fields across non-manifold surface junctions. Our simulations enhance state-of-the-art bubble solvers with additional effects caused by convection, rippling, draining, and evaporation of the thin film.},
author = {Ishida, Sadashige and Synak, Peter and Narita, Fumiya and Hachisuka, Toshiya and Wojtan, Christopher J},
issn = {15577368},
journal = {ACM Transactions on Graphics},
number = {4},
publisher = {Association for Computing Machinery},
title = {{A model for soap film dynamics with evolving thickness}},
doi = {10.1145/3386569.3392405},
volume = {39},
year = {2020},
}
@article{8385,
abstract = {We present a method for animating yarn-level cloth effects using a thin-shell solver. We accomplish this through numerical homogenization: we first use a large number of yarn-level simulations to build a model of the potential energy density of the cloth, and then use this energy density function to compute forces in a thin shell simulator. We model several yarn-based materials, including both woven and knitted fabrics. Our model faithfully reproduces expected effects like the stiffness of woven fabrics, and the highly deformable nature and anisotropy of knitted fabrics. Our approach does not require any real-world experiments nor measurements; because the method is based entirely on simulations, it can generate entirely new material models quickly, without the need for testing apparatuses or human intervention. We provide data-driven models of several woven and knitted fabrics, which can be used for efficient simulation with an off-the-shelf cloth solver.},
author = {Sperl, Georg and Narain, Rahul and Wojtan, Christopher J},
issn = {15577368},
journal = {ACM Transactions on Graphics},
number = {4},
publisher = {Association for Computing Machinery},
title = {{Homogenized yarn-level cloth}},
doi = {10.1145/3386569.3392412},
volume = {39},
year = {2020},
}
@phdthesis{8386,
abstract = {Form versus function is a long-standing debate in various design-related fields, such as architecture as well as graphic and industrial design. A good design that balances form and function often requires considerable human effort and collaboration among experts from different professional fields. Computational design tools provide a new paradigm for designing functional objects. In computational design, form and function are represented as mathematical
quantities, with the help of numerical and combinatorial algorithms, they can assist even novice users in designing versatile models that exhibit their desired functionality. This thesis presents three disparate research studies on the computational design of functional objects: The appearance of 3d print—we optimize the volumetric material distribution for faithfully replicating colored surface texture in 3d printing; the dynamic motion of mechanical structures—
our design system helps the novice user to retarget various mechanical templates with different functionality to complex 3d shapes; and a more abstract functionality, multistability—our algorithm automatically generates models that exhibit multiple stable target poses. For each of these cases, our computational design tools not only ensure the functionality of the results but also permit the user aesthetic freedom over the form. Moreover, fabrication constraints
were taken into account, which allow for the immediate creation of physical realization via 3D printing or laser cutting.},
author = {Zhang, Ran},
issn = {2663-337X},
pages = {148},
publisher = {Institute of Science and Technology Austria},
title = {{Structure-aware computational design and its application to 3D printable volume scattering, mechanism, and multistability}},
doi = {10.15479/AT:ISTA:8386},
year = {2020},
}
@phdthesis{8390,
abstract = {Deep neural networks have established a new standard for data-dependent feature extraction pipelines in the Computer Vision literature. Despite their remarkable performance in the standard supervised learning scenario, i.e. when models are trained with labeled data and tested on samples that follow a similar distribution, neural networks have been shown to struggle with more advanced generalization abilities, such as transferring knowledge across visually different domains, or generalizing to new unseen combinations of known concepts. In this thesis we argue that, in contrast to the usual black-box behavior of neural networks, leveraging more structured internal representations is a promising direction
for tackling such problems. In particular, we focus on two forms of structure. First, we tackle modularity: We show that (i) compositional architectures are a natural tool for modeling reasoning tasks, in that they efficiently capture their combinatorial nature, which is key for generalizing beyond the compositions seen during training. We investigate how to to learn such models, both formally and experimentally, for the task of abstract visual reasoning. Then, we show that (ii) in some settings, modularity allows us to efficiently break down complex tasks into smaller, easier, modules, thereby improving computational efficiency; We study this behavior in the context of generative models for colorization, as well as for small objects detection. Secondly, we investigate the inherently layered structure of representations learned by neural networks, and analyze its role in the context of transfer learning and domain adaptation across visually
dissimilar domains. },
author = {Royer, Amélie},
isbn = {978-3-99078-007-7},
issn = {2663-337X},
pages = {197},
publisher = {Institute of Science and Technology Austria},
title = {{Leveraging structure in Computer Vision tasks for flexible Deep Learning models}},
doi = {10.15479/AT:ISTA:8390},
year = {2020},
}
@article{8402,
abstract = {Background: The mitochondrial pyruvate carrier (MPC) plays a central role in energy metabolism by transporting pyruvate across the inner mitochondrial membrane. Its heterodimeric composition and homology to SWEET and semiSWEET transporters set the MPC apart from the canonical mitochondrial carrier family (named MCF or SLC25). The import of the canonical carriers is mediated by the carrier translocase of the inner membrane (TIM22) pathway and is dependent on their structure, which features an even number of transmembrane segments and both termini in the intermembrane space. The import pathway of MPC proteins has not been elucidated. The odd number of transmembrane segments and positioning of the N-terminus in the matrix argues against an import via the TIM22 carrier pathway but favors an import via the flexible presequence pathway.
Results: Here, we systematically analyzed the import pathways of Mpc2 and Mpc3 and report that, contrary to an expected import via the flexible presequence pathway, yeast MPC proteins with an odd number of transmembrane segments and matrix-exposed N-terminus are imported by the carrier pathway, using the receptor Tom70, small TIM chaperones, and the TIM22 complex. The TIM9·10 complex chaperones MPC proteins through the mitochondrial intermembrane space using conserved hydrophobic motifs that are also required for the interaction with canonical carrier proteins.
Conclusions: The carrier pathway can import paired and non-paired transmembrane helices and translocate N-termini to either side of the mitochondrial inner membrane, revealing an unexpected versatility of the mitochondrial import pathway for non-cleavable inner membrane proteins.},
author = {Rampelt, Heike and Sucec, Iva and Bersch, Beate and Horten, Patrick and Perschil, Inge and Martinou, Jean-Claude and van der Laan, Martin and Wiedemann, Nils and Schanda, Paul and Pfanner, Nikolaus},
issn = {1741-7007},
journal = {BMC Biology},
keywords = {Biotechnology, Plant Science, General Biochemistry, Genetics and Molecular Biology, Developmental Biology, Cell Biology, Physiology, Ecology, Evolution, Behavior and Systematics, Structural Biology, General Agricultural and Biological Sciences},
publisher = {Springer Nature},
title = {{The mitochondrial carrier pathway transports non-canonical substrates with an odd number of transmembrane segments}},
doi = {10.1186/s12915-019-0733-6},
volume = {18},
year = {2020},
}
@unpublished{8403,
abstract = {Chaperones are essential for assisting protein folding, and for transferring poorly soluble proteins to their functional locations within cells. Hydrophobic interactions drive promiscuous chaperone–client binding, but our understanding of how additional interactions enable client specificity is sparse. Here we decipher what determines binding of two chaperones (TIM8·13, TIM9·10) to different integral membrane proteins, the all-transmembrane mitochondrial carrier Ggc1, and Tim23 which has an additional disordered hydrophilic domain. Combining NMR, SAXS and molecular dynamics simulations, we determine the structures of Tim23/TIM8·13 and Tim23/TIM9·10 complexes. TIM8·13 uses transient salt bridges to interact with the hydrophilic part of its client, but its interactions to the transmembrane part are weaker than in TIM9·10. Consequently, TIM9·10 outcompetes TIM8·13 in binding hydrophobic clients, while TIM8·13 is tuned to few clients with both hydrophilic and hydrophobic parts. Our study exemplifies how chaperones fine-tune the balance of promiscuity vs. specificity.},
author = {Sučec, Iva and Wang, Yong and Dakhlaoui, Ons and Weinhäupl, Katharina and Jores, Tobias and Costa, Doriane and Hessel, Audrey and Brennich, Martha and Rapaport, Doron and Lindorff-Larsen, Kresten and Bersch, Beate and Schanda, Paul},
booktitle = {bioRxiv},
publisher = {Cold Spring Harbor Laboratory},
title = {{Structural basis of client specificity in mitochondrial membrane-protein chaperones}},
doi = {10.1101/2020.06.08.140772},
year = {2020},
}
@unpublished{8404,
abstract = {The mitochondrial Tim chaperones are responsible for the transport of membrane proteins across the inter-membrane space to the inner and outer mitochondrial membranes. TIM9·10, a hexameric 70 kDa protein complex formed by 3 copies of Tim9 and Tim10, guides its clients across the aqueous compartment. The TIM9·10·12 complex is the anchor point at the inner-membrane insertase complex TIM22. The mechanism of client transport by TIM9·10 has been resolved recently, but the structure and subunit composition of the TIM9·10·12 complex remains largely unresolved. Furthermore, the assembly process of the hexameric TIM chaperones from its subunits remained elusive. We investigate the structural and dynamical properties of the Tim subunits, and show that they are highly dynamic. In their non-assembled form, the subunits behave as intrinsically disordered proteins; when the conserved cysteines of the CX3C-Xn-CX3C motifs are formed, short marginally stable α-helices are formed, which are only fully stabilized upon hexamer formation to the mature chaperone. Subunits are in equilibrium between their hexamer-embedded and a free form, with exchange kinetics on a minutes time scale. Joint NMR, small-angle X-ray scattering and MD simulation data allow us to derive a structural model of the TIM9·10·12 assembly, which has a 2:3:1 stoichiometry (Tim9:Tim10:Tim12) with a conserved hydrophobic client-binding groove and flexible N- and C-terminal tentacles.},
author = {Weinhäupl, Katharina and Wang, Yong and Hessel, Audrey and Brennich, Martha and Lindorff-Larsen, Kresten and Schanda, Paul},
booktitle = {bioRxiv},
publisher = {Cold Spring Harbor Laboratory},
title = {{Architecture and subunit dynamics of the mitochondrial TIM9·10·12 chaperone}},
doi = {10.1101/2020.03.13.990150},
year = {2020},
}
@book{8414,
abstract = {Arnold diffusion, which concerns the appearance of chaos in classical mechanics, is one of the most important problems in the fields of dynamical systems and mathematical physics. Since it was discovered by Vladimir Arnold in 1963, it has attracted the efforts of some of the most prominent researchers in mathematics. The question is whether a typical perturbation of a particular system will result in chaotic or unstable dynamical phenomena. In this groundbreaking book, Vadim Kaloshin and Ke Zhang provide the first complete proof of Arnold diffusion, demonstrating that that there is topological instability for typical perturbations of five-dimensional integrable systems (two and a half degrees of freedom).
This proof realizes a plan John Mather announced in 2003 but was unable to complete before his death. Kaloshin and Zhang follow Mather’s strategy but emphasize a more Hamiltonian approach, tying together normal forms theory, hyperbolic theory, Mather theory, and weak KAM theory. Offering a complete, clean, and modern explanation of the steps involved in the proof, and a clear account of background material, this book is designed to be accessible to students as well as researchers. The result is a critical contribution to mathematical physics and dynamical systems, especially Hamiltonian systems.},
author = {Kaloshin, Vadim and Zhang, Ke},
isbn = {9-780-6912-0253-2},
pages = {224},
publisher = {Princeton University Press},
title = {{Arnold Diffusion for Smooth Systems of Two and a Half Degrees of Freedom}},
doi = {10.1515/9780691204932},
volume = {208},
year = {2020},
}
@article{8434,
abstract = {Efficient migration on adhesive surfaces involves the protrusion of lamellipodial actin networks and their subsequent stabilization by nascent adhesions. The actin-binding protein lamellipodin (Lpd) is thought to play a critical role in lamellipodium protrusion, by delivering Ena/VASP proteins onto the growing plus ends of actin filaments and by interacting with the WAVE regulatory complex, an activator of the Arp2/3 complex, at the leading edge. Using B16-F1 melanoma cell lines, we demonstrate that genetic ablation of Lpd compromises protrusion efficiency and coincident cell migration without altering essential parameters of lamellipodia, including their maximal rate of forward advancement and actin polymerization. We also confirmed lamellipodia and migration phenotypes with CRISPR/Cas9-mediated Lpd knockout Rat2 fibroblasts, excluding cell type-specific effects. Moreover, computer-aided analysis of cell-edge morphodynamics on B16-F1 cell lamellipodia revealed that loss of Lpd correlates with reduced temporal protrusion maintenance as a prerequisite of nascent adhesion formation. We conclude that Lpd optimizes protrusion and nascent adhesion formation by counteracting frequent, chaotic retraction and membrane ruffling.This article has an associated First Person interview with the first author of the paper. },
author = {Dimchev, Georgi A and Amiri, Behnam and Humphries, Ashley C. and Schaks, Matthias and Dimchev, Vanessa and Stradal, Theresia E. B. and Faix, Jan and Krause, Matthias and Way, Michael and Falcke, Martin and Rottner, Klemens},
issn = {1477-9137},
journal = {Journal of Cell Science},
keywords = {Cell Biology},
number = {7},
publisher = {The Company of Biologists},
title = {{Lamellipodin tunes cell migration by stabilizing protrusions and promoting adhesion formation}},
doi = {10.1242/jcs.239020},
volume = {133},
year = {2020},
}