@article{786, abstract = {Lock-free concurrent algorithms guarantee that some concurrent operation will always make progress in a finite number of steps. Yet programmers prefer to treat concurrent code as if it were wait-free, guaranteeing that all operations always make progress. Unfortunately, designing wait-free algorithms is generally a very complex task, and the resulting algorithms are not always efficient. Although obtaining efficient wait-free algorithms has been a long-time goal for the theory community, most nonblocking commercial code is only lock-free. This article suggests a simple solution to this problem.We show that for a large class of lock-free algorithms, under scheduling conditions that approximate those found in commercial hardware architectures, lock-free algorithms behave as if they are wait-free. In other words, programmers can continue to design simple lock-free algorithms instead of complex wait-free ones, and in practice, they will get wait-free progress. Our main contribution is a new way of analyzing a general class of lock-free algorithms under a stochastic scheduler. Our analysis relates the individual performance of processes to the global performance of the system using Markov chain lifting between a complex per-process chain and a simpler system progress chain. We show that lock-free algorithms are not only wait-free with probability 1 but that in fact a general subset of lock-free algorithms can be closely bounded in terms of the average number of steps required until an operation completes. To the best of our knowledge, this is the first attempt to analyze progress conditions, typically stated in relation to a worst-case adversary, in a stochastic model capturing their expected asymptotic behavior.}, author = {Alistarh, Dan-Adrian and Censor Hillel, Keren and Shavit, Nir}, journal = {Journal of the ACM}, number = {4}, publisher = {ACM}, title = {{Are lock free concurrent algorithms practically wait free }}, doi = {10.1145/2903136}, volume = {63}, year = {2016}, } @article{8020, abstract = {Balance of cortical excitation and inhibition (EI) is thought to be disrupted in several neuropsychiatric conditions, yet it is not clear how it is maintained in the healthy human brain. When EI balance is disturbed during learning and memory in animal models, it can be restabilized via formation of inhibitory replicas of newly formed excitatory connections. Here we assess evidence for such selective inhibitory rebalancing in humans. Using fMRI repetition suppression we measure newly formed cortical associations in the human brain. We show that expression of these associations reduces over time despite persistence in behavior, consistent with inhibitory rebalancing. To test this, we modulated excitation/inhibition balance with transcranial direct current stimulation (tDCS). Using ultra-high-field (7T) MRI and spectroscopy, we show that reducing GABA allows cortical associations to be re-expressed. This suggests that in humans associative memories are stored in balanced excitatory-inhibitory ensembles that lie dormant unless latent inhibitory connections are unmasked.}, author = {Barron, H.C. and Vogels, Tim P and Emir, U.E. and Makin, T.R. and O’Shea, J. and Clare, S. and Jbabdi, S. and Dolan, R.J. and Behrens, T.E.J.}, issn = {0896-6273}, journal = {Neuron}, number = {1}, pages = {191--203}, publisher = {Elsevier}, title = {{Unmasking latent inhibitory connections in human cortex to reveal dormant cortical memories}}, doi = {10.1016/j.neuron.2016.02.031}, volume = {90}, year = {2016}, } @inproceedings{8094, abstract = {With the accelerated development of robot technologies, optimal control becomes one of the central themes of research. In traditional approaches, the controller, by its internal functionality, finds appropriate actions on the basis of the history of sensor values, guided by the goals, intentions, objectives, learning schemes, and so forth. The idea is that the controller controls the world---the body plus its environment---as reliably as possible. This paper focuses on new lines of self-organization for developmental robotics. We apply the recently developed differential extrinsic synaptic plasticity to a muscle-tendon driven arm-shoulder system from the Myorobotics toolkit. In the experiments, we observe a vast variety of self-organized behavior patterns: when left alone, the arm realizes pseudo-random sequences of different poses. By applying physical forces, the system can be entrained into definite motion patterns like wiping a table. Most interestingly, after attaching an object, the controller gets in a functional resonance with the object's internal dynamics, starting to shake spontaneously bottles half-filled with water or sensitively driving an attached pendulum into a circular mode. When attached to the crank of a wheel the neural system independently discovers how to rotate it. In this way, the robot discovers affordances of objects its body is interacting with.}, author = {Martius, Georg S and Hostettler, Rafael and Knoll, Alois and Der, Ralf}, booktitle = {Proceedings of the Artificial Life Conference 2016}, isbn = {9780262339360}, location = {Cancun, Mexico}, pages = {142--143}, publisher = {MIT Press}, title = {{Self-organized control of an tendon driven arm by differential extrinsic plasticity}}, doi = {10.7551/978-0-262-33936-0-ch029}, volume = {28}, year = {2016}, } @unpublished{8128, abstract = {The stimulus selectivity of synaptic currents in cortical neurons often shows a co-tuning of excitation and inhibition, but the mechanisms that underlie the emergence and plasticity of this co-tuning are not fully understood. Using a computational model, we show that an interaction of excitatory and inhibitory synaptic plasticity reproduces both the developmental and – when combined with a disinhibitory gate – the adult plasticity of excitatory and inhibitory receptive fields in auditory cortex. The co-tuning arises from inhibitory plasticity that balances excitation and inhibition, while excitatory stimulus selectivity can result from two different mechanisms. Inhibitory inputs with a broad stimulus tuning introduce a sliding threshold as in Bienenstock-Cooper-Munro rules, introducing an excitatory stimulus selectivity at the cost of a broader inhibitory receptive field. Alternatively, input asymmetries can be amplified by synaptic competition. The latter leaves any receptive field plasticity transient, a prediction we verify in recordings in auditory cortex.}, author = {Clopath, Claudia and Vogels, Tim P and Froemke, Robert C. and Sprekeler, Henning}, booktitle = {bioRxiv}, pages = {43}, publisher = {Cold Spring Harbor Laboratory}, title = {{Receptive field formation by interacting excitatory and inhibitory synaptic plasticity}}, year = {2016}, } @article{813, abstract = {The Gag polyprotein of retroviruses drives immature virus assembly by forming hexameric protein lattices. The assembly is primarily mediated by protein-protein interactions between capsid (CA) domains and by interactions between nucleocapsid (NC) domains and RNA. Specific interactions between NC and the viral RNA are required for genome packaging. Previously reported cryoelectron microscopy analysis of immature Mason-Pfizer monkey virus (M-PMV) particles suggested that a basic region (residues RKK) in CA may serve as an additional binding site for nucleic acids. Here, we have introduced mutations into the RKK region in both bacterial and proviral M-PMV vectors and have assessed their impact on M-PMV assembly, structure, RNA binding, budding/release, nuclear trafficking, and infectivity using in vitro and in vivo systems. Our data indicate that the RKK region binds and structures nucleic acid that serves to promote virus particle assembly in the cytoplasm. Moreover, the RKK region appears to be important for recruitment of viral genomic RNA into Gag particles, and this function could be linked to changes in nuclear trafficking. Together these observations suggest that in M-PMV, direct interactions between CA and nucleic acid play important functions in the late stages of the viral life cycle.}, author = {Füzik, Tibor and Píchalová, Růžena and Florian Schur and Strohalmová, Karolína and Křížová, Ivana and Hadravová, Romana and Rumlová, Michaela and Briggs, John A and Ulbrich, Pavel and Ruml, Tomáš}, journal = {Journal of Virology}, number = {9}, pages = {4593 -- 4603}, publisher = {ASM}, title = {{Nucleic acid binding by Mason-Pfizer monkey virus CA promotes virus assembly and genome packaging}}, doi = {10.1128/JVI.03197-15}, volume = {90}, year = {2016}, } @article{816, abstract = {Immature HIV-1 assembles at and buds from the plasma membrane before proteolytic cleavage of the viral Gag polyprotein induces structural maturation. Maturation can be blocked by maturation inhibitors (MIs), thereby abolishing infectivity. The CA (capsid) and SP1 (spacer peptide 1) region of Gag is the key regulator of assembly and maturation and is the target of MIs.We applied optimized cryo-electron tomography and subtomogram averaging to resolve this region within assembled immature HIV-1 particles at 3.9 angstrom resolution and built an atomic model. The structure reveals a network of intra- And intermolecular interactions mediating immature HIV-1 assembly. The proteolytic cleavage site between CA and SP1 is inaccessible to protease.We suggest that MIs prevent CA-SP1 cleavage by stabilizing the structure, and MI resistance develops by destabilizing CA-SP1.}, author = {Florian Schur and Martin Obr and Hagen, Wim J and Wan, William and Jakobi, Arjen J and Kirkpatrick, Joanna M and Sachse, Carsten and Kraüsslich, Hans Georg and Briggs, John A}, journal = {Science}, number = {6298}, pages = {506 -- 508}, publisher = {American Association for the Advancement of Science}, title = {{An atomic model of HIV-1 capsid-SP1 reveals structures regulating assembly and maturation}}, doi = {10.1126/science.aaf9620}, volume = {353}, year = {2016}, } @article{8241, abstract = {Background: Anticancer vaccines could represent a valuable complementary strategy to established therapies, especially in settings of early stage and minimal residual disease. HER-2 is an important target for immunotherapy and addressed by the monoclonal antibody trastuzumab. We have previously generated HER-2 mimotope peptides from phage display libraries. The synthesized peptides were coupled to carriers and applied for epitope-specific induction of trastuzumab-like IgG. For simplification and to avoid methodological limitations of synthesis and coupling chemistry, we herewith present a novel and optimized approach by using adeno-associated viruses (AAV) as effective and high-density mimotope-display system, which can be directly used for vaccination. Methods: An AAV capsid display library was constructed by genetically incorporating random peptides in a plasmid encoding the wild-type AAV2 capsid protein. AAV clones, expressing peptides specifically reactive to trastuzumab, were employed to immunize BALB/c mice. Antibody titers against human HER-2 were determined, and the isotype composition and functional properties of these were tested. Finally, prophylactically immunized mice were challenged with human HER-2 transfected mouse D2F2/E2 cells. Results: HER-2 mimotope AAV-vaccines induced antibodies specific to human HER-2. Two clones were selected for immunization of mice, which were subsequently grafted D2F2/E2 cells. Both mimotope AAV clones delayed the growth of tumors significantly, as compared to controls. Conclusion: In this study, a novel mimotope AAV-based platform was created allowing the isolation of mimotopes, which can be directly used as anticancer vaccines. The example of trastuzumab AAV-mimotopes demonstrates that this vaccine strategy could help to establish active immunotherapy for breast-cancer patients.}, author = {Singer, Josef and Manzano-Szalai, Krisztina and Fazekas, Judit and Thell, Kathrin and Bentley-Lukschal, Anna and Stremnitzer, Caroline and Roth-Walter, Franziska and Weghofer, Margit and Ritter, Mirko and Pino Tossi, Kerstin and Hörer, Markus and Michaelis, Uwe and Jensen-Jarolim, Erika}, issn = {2162-402X}, journal = {OncoImmunology}, number = {7}, publisher = {Taylor & Francis}, title = {{Proof of concept study with an HER-2 mimotope anticancer vaccine deduced from a novel AAV-mimotope library platform}}, doi = {10.1080/2162402x.2016.1171446}, volume = {5}, year = {2016}, } @inproceedings{8300, abstract = {The integration of social networking concepts into Internet of Things systems is a burgeoning topic of research that promises to support novel and more powerful applications. In this paper we focus on the design and implementation of a highly scalable Trust and Reputation Model for the Internet of Things based on the social approach that the COSMOS project introduces, as part of its final results. We create our model by combining popular solutions proposed for Peer-to-Peer and mobile ad-hoc networks and adapting them on the Internet of Things concept. Each Thing can compute the Trust index of another Thing based on its own experiences, while it has the capability of determining its Reputation Index either by consulting its other “friends” (Followees) or referring to the Platform, a management system used in COSMOS. The model is tested through simulations of the proposed social system, demonstrating the ability of TRM-SIoT to achieve the Social Exclusion of malicious nodes and collectives from the network, with low computational overhead and high scalability. Furthermore, due to the adaptive nature of the system, Social Reintegration of these nodes is also possible.}, author = {Kokoris Kogias, Eleftherios and Voutyras, Orfefs and Varvarigou, Theodora}, booktitle = {2016 IEEE 21st International Conference on Emerging Technologies and Factory Automation}, isbn = {9781509013142}, location = {Berlin, Germany}, publisher = {IEEE}, title = {{TRM-SIoT: A scalable hybrid trust & reputation model for the social Internet of Things}}, doi = {10.1109/etfa.2016.7733612}, year = {2016}, } @inproceedings{8302, abstract = {While showing great promise, Bitcoin requires users to wait tens of minutes for transactions to commit, and even then, offering only probabilistic guarantees. This paper introduces ByzCoin, a novel Byzantine consensus protocol that leverages scalable collective signing to commit Bitcoin transactions irreversibly within seconds. ByzCoin achieves Byzantine consensus while preserving Bitcoin’s open membership by dynamically forming hash power-proportionate consensus groups that represent recently-successful block miners. ByzCoin employs communication trees to optimize transaction commitment and verification under normal operation while guaranteeing safety and liveness under Byzantine faults, up to a near-optimal tolerance of f faulty group members among 3f + 2 total. ByzCoin mitigates double spending and selfish mining attacks by producing collectively signed transaction blocks within one minute of transaction submission. Tree-structured communication further reduces this latency to less than 30 seconds. Due to these optimizations, ByzCoin achieves a throughput higher than Paypal currently handles, with a confirmation latency of 15-20 seconds.}, author = {Kokoris Kogias, Eleftherios and Jovanovic, Philipp and Gailly, Nicolas and Khoffi, Ismail and Gasser, Linus and Ford, Bryan}, booktitle = {Proceedings of the 25th USENIX Conference on Security Symposium}, isbn = {9781931971324}, location = {Austin, TX, United States}, pages = {279–296}, publisher = {USENIX Association}, title = {{Enhancing bitcoin security and performance with strong consistency via collective signing}}, year = {2016}, } @article{8452, abstract = {During spore formation in Bacillus subtilis a transenvelope complex is assembled across the double membrane that separates the mother cell and forespore. This complex (called the “A–Q complex”) is required to maintain forespore development and is composed of proteins with remote homology to components of type II, III, and IV secretion systems found in Gram-negative bacteria. Here, we show that one of these proteins, SpoIIIAG, which has remote homology to ring-forming proteins found in type III secretion systems, assembles into an oligomeric ring in the periplasmic-like space between the two membranes. Three-dimensional reconstruction of images generated by cryo-electron microscopy indicates that the SpoIIIAG ring has a cup-and-saucer architecture with a 6-nm central pore. Structural modeling of SpoIIIAG generated a 24-member ring with dimensions similar to those of the EM-derived saucer. Point mutations in the predicted oligomeric interface disrupted ring formation in vitro and impaired forespore gene expression and efficient spore formation in vivo. Taken together, our data provide strong support for the model in which the A–Q transenvelope complex contains a conduit that connects the mother cell and forespore. We propose that a set of stacked rings spans the intermembrane space, as has been found for type III secretion systems.}, author = {Rodrigues, Christopher D. A. and Henry, Xavier and Neumann, Emmanuelle and Kurauskas, Vilius and Bellard, Laure and Fichou, Yann and Schanda, Paul and Schoehn, Guy and Rudner, David Z. and Morlot, Cecile}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {41}, pages = {11585--11590}, publisher = {National Academy of Sciences}, title = {{A ring-shaped conduit connects the mother cell and forespore during sporulation in Bacillus subtilis}}, doi = {10.1073/pnas.1609604113}, volume = {113}, year = {2016}, } @article{8453, abstract = {Transverse relaxation rate measurements in magic-angle spinning solid-state nuclear magnetic resonance provide information about molecular motions occurring on nanosecond-to-millisecond (ns–ms) time scales. The measurement of heteronuclear (13C, 15N) relaxation rate constants in the presence of a spin-lock radiofrequency field (R1ρ relaxation) provides access to such motions, and an increasing number of studies involving R1ρ relaxation in proteins have been reported. However, two factors that influence the observed relaxation rate constants have so far been neglected, namely, (1) the role of CSA/dipolar cross-correlated relaxation (CCR) and (2) the impact of fast proton spin flips (i.e., proton spin diffusion and relaxation). We show that CSA/D CCR in R1ρ experiments is measurable and that the CCR rate constant depends on ns–ms motions; it can thus provide insight into dynamics. We find that proton spin diffusion attenuates this CCR due to its decoupling effect on the doublet components. For measurements of dynamics, the use of R1ρ rate constants has practical advantages over the use of CCR rates, and this article reveals factors that have so far been disregarded and which are important for accurate measurements and interpretation.}, author = {Kurauskas, Vilius and Weber, Emmanuelle and Hessel, Audrey and Ayala, Isabel and Marion, Dominique and Schanda, Paul}, issn = {1520-6106}, journal = {The Journal of Physical Chemistry B}, keywords = {Physical and Theoretical Chemistry, Materials Chemistry, Surfaces, Coatings and Films}, number = {34}, pages = {8905--8913}, publisher = {American Chemical Society}, title = {{Cross-correlated relaxation of dipolar coupling and chemical-shift anisotropy in magic-angle spinning R1ρ NMR measurements: Application to protein backbone dynamics measurements}}, doi = {10.1021/acs.jpcb.6b06129}, volume = {120}, year = {2016}, } @article{8454, abstract = {Magic-angle spinning solid-state NMR spectroscopy is an important technique to study molecular structure, dynamics and interactions, and is rapidly gaining importance in biomolecular sciences. Here we provide an overview of experimental approaches to study molecular dynamics by MAS solid-state NMR, with an emphasis on the underlying theoretical concepts and differences of MAS solid-state NMR compared to solution-state NMR. The theoretical foundations of nuclear spin relaxation are revisited, focusing on the particularities of spin relaxation in solid samples under magic-angle spinning. We discuss the range of validity of Redfield theory, as well as the inherent multi-exponential behavior of relaxation in solids. Experimental challenges for measuring relaxation parameters in MAS solid-state NMR and a few recently proposed relaxation approaches are discussed, which provide information about time scales and amplitudes of motions ranging from picoseconds to milliseconds. We also discuss the theoretical basis and experimental measurements of anisotropic interactions (chemical-shift anisotropies, dipolar and quadrupolar couplings), which give direct information about the amplitude of motions. The potential of combining relaxation data with such measurements of dynamically-averaged anisotropic interactions is discussed. Although the focus of this review is on the theoretical foundations of dynamics studies rather than their application, we close by discussing a small number of recent dynamics studies, where the dynamic properties of proteins in crystals are compared to those in solution.}, author = {Schanda, Paul and Ernst, Matthias}, issn = {0079-6565}, journal = {Progress in Nuclear Magnetic Resonance Spectroscopy}, number = {8}, pages = {1--46}, publisher = {Elsevier}, title = {{Studying dynamics by magic-angle spinning solid-state NMR spectroscopy: Principles and applications to biomolecules}}, doi = {10.1016/j.pnmrs.2016.02.001}, volume = {96}, year = {2016}, } @article{8455, abstract = {Solid-state NMR spectroscopy allows the characterization of the structure, interactions and dynamics of insoluble and/or very large proteins. Sensitivity and resolution are often major challenges for obtaining atomic-resolution information, in particular for very large protein complexes. Here we show that the use of deuterated, specifically CH3-labelled proteins result in significant sensitivity gains compared to previously employed CHD2 labelling, while line widths increase only marginally. We apply this labelling strategy to a 468 kDa-large dodecameric aminopeptidase, TET2, and the 1.6 MDa-large 50S ribosome subunit of Thermus thermophilus.}, author = {Kurauskas, Vilius and Crublet, Elodie and Macek, Pavel and Kerfah, Rime and Gauto, Diego F. and Boisbouvier, Jérôme and Schanda, Paul}, issn = {1359-7345}, journal = {Chemical Communications}, keywords = {Materials Chemistry, Electronic, Optical and Magnetic Materials, General Chemistry, Surfaces, Coatings and Films, Metals and Alloys, Ceramics and Composites, Catalysis}, number = {61}, pages = {9558--9561}, publisher = {Royal Society of Chemistry}, title = {{Sensitive proton-detected solid-state NMR spectroscopy of large proteins with selective CH3labelling: Application to the 50S ribosome subunit}}, doi = {10.1039/c6cc04484k}, volume = {52}, year = {2016}, } @article{849, abstract = {Understanding the principles that led to the current complexity of the genetic code is a central question in evolution. Expansion of the genetic code required the selection of new transfer RNAs (tRNAs) with specific recognition signals that allowed them to be matured, modified, aminoacylated, and processed by the ribosome without compromising the fidelity or efficiency of protein synthesis. We show that saturation of recognition signals blocks the emergence of new tRNA identities and that the rate of nucleotide substitutions in tRNAs is higher in species with fewer tRNA genes. We propose that the growth of the genetic code stalled because a limit was reached in the number of identity elements that can be effectively used in the tRNA structure.}, author = {Saint-Léger, Adélaïde and Bello, Carla and Dans, Pablo D and Torres, Adrian G and Novoa, Eva M and Camacho, Noelia and Orozco, Modesto and Fyodor Kondrashov and Ribas De Pouplana, Lluís}, journal = {Science advances}, number = {4}, pages = {e1501860 -- e1501860}, publisher = {American Association for the Advancement of Science}, title = {{Saturation of recognition elements blocks evolution of new tRNA identities}}, doi = {10.1126/sciadv.1501860}, volume = {2}, year = {2016}, } @article{8493, abstract = {In this paper we study a so-called separatrix map introduced by Zaslavskii–Filonenko (Sov Phys JETP 27:851–857, 1968) and studied by Treschev (Physica D 116(1–2):21–43, 1998; J Nonlinear Sci 12(1):27–58, 2002), Piftankin (Nonlinearity (19):2617–2644, 2006) Piftankin and Treshchëv (Uspekhi Mat Nauk 62(2(374)):3–108, 2007). We derive a second order expansion of this map for trigonometric perturbations. In Castejon et al. (Random iteration of maps of a cylinder and diffusive behavior. Preprint available at arXiv:1501.03319, 2015), Guardia and Kaloshin (Stochastic diffusive behavior through big gaps in a priori unstable systems (in preparation), 2015), and Kaloshin et al. (Normally Hyperbolic Invariant Laminations and diffusive behavior for the generalized Arnold example away from resonances. Preprint available at http://www.terpconnect.umd.edu/vkaloshi/, 2015), applying the results of the present paper, we describe a class of nearly integrable deterministic systems with stochastic diffusive behavior.}, author = {Guardia, M. and Kaloshin, Vadim and Zhang, J.}, issn = {0010-3616}, journal = {Communications in Mathematical Physics}, pages = {321--361}, publisher = {Springer Nature}, title = {{A second order expansion of the separatrix map for trigonometric perturbations of a priori unstable systems}}, doi = {10.1007/s00220-016-2705-9}, volume = {348}, year = {2016}, } @article{8494, abstract = {We prove a form of Arnold diffusion in the a-priori stable case. Let H0(p)+ϵH1(θ,p,t),θ∈Tn,p∈Bn,t∈T=R/T, be a nearly integrable system of arbitrary degrees of freedom n⩾2 with a strictly convex H0. We show that for a “generic” ϵH1, there exists an orbit (θ,p) satisfying ∥p(t)−p(0)∥>l(H1)>0, where l(H1) is independent of ϵ. The diffusion orbit travels along a codimension-1 resonance, and the only obstruction to our construction is a finite set of additional resonances. For the proof we use a combination of geometric and variational methods, and manage to adapt tools which have recently been developed in the a-priori unstable case.}, author = {Bernard, Patrick and Kaloshin, Vadim and Zhang, Ke}, issn = {0001-5962}, journal = {Acta Mathematica}, number = {1}, pages = {1--79}, publisher = {Institut Mittag-Leffler}, title = {{Arnold diffusion in arbitrary degrees of freedom and normally hyperbolic invariant cylinders}}, doi = {10.1007/s11511-016-0141-5}, volume = {217}, year = {2016}, } @article{8496, author = {Avila, Artur and De Simoi, Jacopo and Kaloshin, Vadim}, issn = {0003-486X}, journal = {Annals of Mathematics}, number = {2}, pages = {527--558}, publisher = {Princeton University Press}, title = {{An integrable deformation of an ellipse of small eccentricity is an ellipse}}, doi = {10.4007/annals.2016.184.2.5}, volume = {184}, year = {2016}, } @article{8497, abstract = {We study the dynamics of the restricted planar three-body problem near mean motion resonances, i.e. a resonance involving the Keplerian periods of the two lighter bodies revolving around the most massive one. This problem is often used to model Sun–Jupiter–asteroid systems. For the primaries (Sun and Jupiter), we pick a realistic mass ratio μ=10−3 and a small eccentricity e0>0. The main result is a construction of a variety of non local diffusing orbits which show a drastic change of the osculating (instant) eccentricity of the asteroid, while the osculating semi major axis is kept almost constant. The proof relies on the careful analysis of the circular problem, which has a hyperbolic structure, but for which diffusion is prevented by KAM tori. In the proof we verify certain non-degeneracy conditions numerically. Based on the work of Treschev, it is natural to conjecture that the time of diffusion for this problem is ∼−ln(μe0)μ3/2e0. We expect our instability mechanism to apply to realistic values of e0 and we give heuristic arguments in its favor. If so, the applicability of Nekhoroshev theory to the three-body problem as well as the long time stability become questionable. It is well known that, in the Asteroid Belt, located between the orbits of Mars and Jupiter, the distribution of asteroids has the so-called Kirkwood gaps exactly at mean motion resonances of low order. Our mechanism gives a possible explanation of their existence. To relate the existence of Kirkwood gaps with Arnol'd diffusion, we also state a conjecture on its existence for a typical ϵ-perturbation of the product of the pendulum and the rotator. Namely, we predict that a positive conditional measure of initial conditions concentrated in the main resonance exhibits Arnol’d diffusion on time scales −lnϵϵ2.}, author = {Féjoz, Jacques and Guàrdia, Marcel and Kaloshin, Vadim and Roldán, Pablo}, issn = {1435-9855}, journal = {Journal of the European Mathematical Society}, number = {10}, pages = {2315--2403}, publisher = {European Mathematical Society Publishing House}, title = {{Kirkwood gaps and diffusion along mean motion resonances in the restricted planar three-body problem}}, doi = {10.4171/jems/642}, volume = {18}, year = {2016}, } @article{850, abstract = {Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. However, systematic high-throughput studies of the local fitness landscape of an entire protein have not yet been reported. Here we visualize an extensive region of the local fitness landscape of the green fluorescent protein from Aequorea Victoria (avGFP) by measuring the native function (fluorescence) of tens of thousands of derivative genotypes of avGFP. We show that the fitness landscape of avGFP is narrow, with 3/4 of the derivatives with a single mutation showing reduced fluorescence and half of the derivatives with four mutations being completely non-fluorescent. The narrowness is enhanced by epistasis, which was detected in up to 30% of genotypes with multiple mutations and mostly occurred through the cumulative effect of slightly deleterious mutations causing a threshold-like decrease in protein stability and a concomitant loss of fluorescence. A model of orthologous sequence divergence spanning hundreds of millions of years predicted the extent of epistasis in our data, indicating congruence between the fitness landscape properties at the local and global scales. The characterization of the local fitness landscape of avGFP has important implications for several fields including molecular evolution, population genetics and protein design.}, author = {Karen Sarkisyan and Bolotin, Dmitry A and Meer, Margarita V and Usmanova, Dinara R and Mishin, Alexander S and Sharonov, George V and Ivankov, Dmitry N and Bozhanova, Nina G and Baranov, Mikhail S and Soylemez, Onuralp and Bogatyreva, Natalya S and Vlasov, Peter K and Egorov, Evgeny S and Logacheva, Maria D and Kondrashov, Alexey S and Chudakov, Dmitriy M and Putintseva, Ekaterina V and Mamedov, Ilgar Z and Tawfik, Dan S and Lukyanov, Konstantin A and Fyodor Kondrashov}, journal = {Nature}, pages = {397 -- 401}, publisher = {Nature Publishing Group}, title = {{Local fitness landscape of the green fluorescent protein}}, doi = {10.1038/nature17995}, volume = {533}, year = {2016}, } @article{853, abstract = {A comparative analysis of the metagenomes from two 30 000-year-old permafrost samples, one of lake-alluvial origin and the other from late Pleistocene Ice Complex sediments, revealed significant differences within microbial communities. The late Pleistocene Ice Complex sediments (which have been characterized by the absence of methane with lower values of redox potential and Fe2+ content) showed a low abundance of methanogenic archaea and enzymes from both the carbon and nitrogen cycles, but a higher abundance of enzymes associated with the sulfur cycle. The metagenomic and geochemical analyses described in the paper provide evidence that the formation of the sampled late Pleistocene Ice Complex sediments likely took place under much more aerobic conditions than lake-alluvial sediments.}, author = {Rivkina, Elizaveta and Petrovskaya, Lada E and Vishnivetskaya, Tatiana A and Krivushin, Kirill V and Shmakova, Lyubov A and Tutukina, Maria and Meyers, Arthur J and Fyodor Kondrashov}, journal = {Biogeosciences}, number = {7}, pages = {2207 -- 2219}, publisher = {European Geosciences Union}, title = {{Metagenomic analyses of the late Pleistocene permafrost - Additional tools for reconstruction of environmental conditions}}, doi = {10.5194/bg-13-2207-2016}, volume = {13}, year = {2016}, }