0 there exists a large subset of a ∈ F×p such that for kl a,1,p : x → e((ax+x) / p) we have M(kla,1,p) ≥ (1−ε/√2π + o(1)) log log p, as p→∞. Finally, we prove a result on the growth of the moments of {M (kla,1,p)}a∈F×p. 2020 Mathematics Subject Classification: 11L03, 11T23 (Primary); 14F20, 60F10 (Secondary). AU - Bonolis, Dante ID - 9364 IS - 3 JF - Mathematical Proceedings of the Cambridge Philosophical Society SN - 0305-0041 TI - On the size of the maximum of incomplete Kloosterman sums VL - 172 ER - TY - JOUR AB - Tin selenide (SnSe) is considered a robust candidate for thermoelectric applications due to its very high thermoelectric figure of merit, ZT, with values of 2.6 in p-type and 2.8 in n-type single crystals. Sn has been replaced with various lower group dopants to achieve successful p-type doping in SnSe with high ZT values. A known, facile, and powerful alternative way to introduce a hole carrier is to use a natural single Sn vacancy, VSn. Through transport and scanning tunneling microscopy studies, we discovered that VSn are dominant in high-quality (slow cooling rate) SnSe single crystals, while multiple vacancies, Vmulti, are dominant in low-quality (high cooling rate) single crystals. Surprisingly, both VSn and Vmulti help to increase the power factors of SnSe, whereas samples with dominant VSn have superior thermoelectric properties in SnSe single crystals. Additionally, the observation that Vmulti are good p-type sources observed in relatively low-quality single crystals is useful in thermoelectric applications because polycrystalline SnSe can be used due to its mechanical strength; this substance is usually fabricated at very high cooling speeds. AU - Nguyen, Van Quang AU - Trinh, Thi Ly AU - Chang, Cheng AU - Zhao, Li Dong AU - Nguyen, Thi Huong AU - Duong, Van Thiet AU - Duong, Anh Tuan AU - Park, Jong Ho AU - Park, Sudong AU - Kim, Jungdae AU - Cho, Sunglae ID - 11401 JF - NPG Asia Materials SN - 1884-4049 TI - Unidentified major p-type source in SnSe: Multivacancies VL - 14 ER - TY - JOUR AB - By varying the concentration of molecules in the cytoplasm or on the membrane, cells can induce the formation of condensates and liquid droplets, similar to phase separation. Their thermodynamics, much studied, depends on the mutual interactions between microscopic constituents. Here, we focus on the kinetics and size control of 2D clusters, forming on membranes. Using molecular dynamics of patchy colloids, we model a system of two species of proteins, giving origin to specific heterotypic bonds. We find that concentrations, together with valence and bond strength, control both the size and the growth time rate of the clusters. In particular, if one species is in large excess, it gradually saturates the binding sites of the other species; the system then becomes kinetically arrested and cluster coarsening slows down or stops, thus yielding effective size selection. This phenomenology is observed both in solid and fluid clusters, which feature additional generic homotypic interactions and are reminiscent of the ones observed on biological membranes. AU - Palaia, Ivan AU - Šarić, Anđela ID - 11400 IS - 19 JF - The Journal of Chemical Physics KW - Physical and Theoretical Chemistry KW - General Physics and Astronomy SN - 0021-9606 TI - Controlling cluster size in 2D phase-separating binary mixtures with specific interactions VL - 156 ER - TY - JOUR AB - Fixed-horizon planning considers a weighted graph and asks to construct a path that maximizes the sum of weights for a given time horizon T. However, in many scenarios, the time horizon is not fixed, but the stopping time is chosen according to some distribution such that the expected stopping time is T. If the stopping-time distribution is not known, then to ensure robustness, the distribution is chosen by an adversary as the worst-case scenario. A stationary plan for every vertex always chooses the same outgoing edge. For fixed horizon or fixed stopping-time distribution, stationary plans are not sufficient for optimality. Quite surprisingly we show that when an adversary chooses the stopping-time distribution with expected stopping-time T, then stationary plans are sufficient. While computing optimal stationary plans for fixed horizon is NP-complete, we show that computing optimal stationary plans under adversarial stopping-time distribution can be achieved in polynomial time. AU - Chatterjee, Krishnendu AU - Doyen, Laurent ID - 11402 JF - Journal of Computer and System Sciences SN - 0022-0000 TI - Graph planning with expected finite horizon VL - 129 ER - TY - JOUR AB - Understanding the properties of neural networks trained via stochastic gradient descent (SGD) is at the heart of the theory of deep learning. In this work, we take a mean-field view, and consider a two-layer ReLU network trained via noisy-SGD for a univariate regularized regression problem. Our main result is that SGD with vanishingly small noise injected in the gradients is biased towards a simple solution: at convergence, the ReLU network implements a piecewise linear map of the inputs, and the number of “knot” points -- i.e., points where the tangent of the ReLU network estimator changes -- between two consecutive training inputs is at most three. In particular, as the number of neurons of the network grows, the SGD dynamics is captured by the solution of a gradient flow and, at convergence, the distribution of the weights approaches the unique minimizer of a related free energy, which has a Gibbs form. Our key technical contribution consists in the analysis of the estimator resulting from this minimizer: we show that its second derivative vanishes everywhere, except at some specific locations which represent the “knot” points. We also provide empirical evidence that knots at locations distinct from the data points might occur, as predicted by our theory. AU - Shevchenko, Aleksandr AU - Kungurtsev, Vyacheslav AU - Mondelli, Marco ID - 11420 IS - 130 JF - Journal of Machine Learning Research SN - 1532-4435 TI - Mean-field analysis of piecewise linear solutions for wide ReLU networks VL - 23 ER - TY - JOUR AB - Elevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer’s disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in slices from mice brainstem. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10–20 µM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased MT-bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin 1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission. AU - Hori, Tetsuya AU - Eguchi, Kohgaku AU - Wang, Han Ying AU - Miyasaka, Tomohiro AU - Guillaud, Laurent AU - Taoufiq, Zacharie AU - Mahapatra, Satyajit AU - Yamada, Hiroshi AU - Takei, Kohji AU - Takahashi, Tomoyuki ID - 11419 JF - eLife TI - Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer's disease synapse model VL - 11 ER - TY - JOUR AB - We consider the quadratic form of a general high-rank deterministic matrix on the eigenvectors of an N×N Wigner matrix and prove that it has Gaussian fluctuation for each bulk eigenvector in the large N limit. The proof is a combination of the energy method for the Dyson Brownian motion inspired by Marcinek and Yau (2021) and our recent multiresolvent local laws (Comm. Math. Phys. 388 (2021) 1005–1048). AU - Cipolloni, Giorgio AU - Erdös, László AU - Schröder, Dominik J ID - 11418 IS - 3 JF - Annals of Probability SN - 0091-1798 TI - Normal fluctuation in quantum ergodicity for Wigner matrices VL - 50 ER - TY - JOUR AB - Over the past few years, the field of quantum information science has seen tremendous progress toward realizing large-scale quantum computers. With demonstrations of quantum computers outperforming classical computers for a select range of problems,1–3 we have finally entered the noisy, intermediate-scale quantum (NISQ) computing era. While the quantum computers of today are technological marvels, they are not yet error corrected, and it is unclear whether any system will scale beyond a few hundred logical qubits without significant changes to architecture and control schemes. Today's quantum systems are analogous to the ENIAC (Electronic Numerical Integrator And Computer) and EDVAC (Electronic Discrete Variable Automatic Computer) systems of the 1940s, which ran on vacuum tubes. These machines were built on a solid, nominally scalable architecture and when they were developed, nobody could have predicted the development of the transistor and the impact of the resulting semiconductor industry. Simply put, the computers of today are nothing like the early computers of the 1940s. We believe that the qubits of future fault-tolerant quantum systems will look quite different from the qubits of the NISQ machines in operation today. This Special Topic issue is devoted to new and emerging quantum systems with a focus on enabling technologies that can eventually lead to the quantum analog to the transistor. We have solicited both research4–18 and perspective articles19–21 to discuss new and emerging qubit systems with a focus on novel materials, encodings, and architectures. We are proud to present a collection that touches on a wide range of technologies including superconductors,7–13,21 semiconductors,15–17,19 and individual atomic qubits.18 AU - Sigillito, Anthony J. AU - Covey, Jacob P. AU - Fink, Johannes M AU - Petersson, Karl AU - Preble, Stefan ID - 11417 IS - 19 JF - Applied Physics Letters SN - 0003-6951 TI - Emerging qubit systems: Guest editorial VL - 120 ER - TY - JOUR AB - We study structural rigidity for assemblies with mechanical joints. Existing methods identify whether an assembly is structurally rigid by assuming parts are perfectly rigid. Yet, an assembly identified as rigid may not be that “rigid” in practice, and existing methods cannot quantify how rigid an assembly is. We address this limitation by developing a new measure, worst-case rigidity, to quantify the rigidity of an assembly as the largest possible deformation that the assembly undergoes for arbitrary external loads of fixed magnitude. Computing worst-case rigidity is non-trivial due to non-rigid parts and different joint types. We thus formulate a new computational approach by encoding parts and their connections into a stiffness matrix, in which parts are modeled as deformable objects and joints as soft constraints. Based on this, we formulate worst-case rigidity analysis as an optimization that seeks the worst-case deformation of an assembly for arbitrary external loads, and solve the optimization problem via an eigenanalysis. Furthermore, we present methods to optimize the geometry and topology of various assemblies to enhance their rigidity, as guided by our rigidity measure. In the end, we validate our method on a variety of assembly structures with physical experiments and demonstrate its effectiveness by designing and fabricating several structurally rigid assemblies. AU - Liu, Zhenyuan AU - Hu, Jingyu AU - Xu, Hao AU - Song, Peng AU - Zhang, Ran AU - Bickel, Bernd AU - Fu, Chi-Wing ID - 10922 IS - 2 JF - Computer Graphics Forum SN - 0167-7055 TI - Worst-case rigidity analysis and optimization for assemblies with mechanical joints VL - 41 ER - TY - JOUR AB - This paper proposes a method for simulating liquids in large bodies of water by coupling together a water surface wave simulator with a 3D Navier-Stokes simulator. The surface wave simulation uses the equivalent sources method (ESM) to efficiently animate large bodies of water with precisely controllable wave propagation behavior. The 3D liquid simulator animates complex non-linear fluid behaviors like splashes and breaking waves using off-the-shelf simulators using FLIP or the level set method with semi-Lagrangian advection. We combine the two approaches by using the 3D solver to animate localized non-linear behaviors, and the 2D wave solver to animate larger regions with linear surface physics. We use the surface motion from the 3D solver as boundary conditions for 2D surface wave simulator, and we use the velocity and surface heights from the 2D surface wave simulator as boundary conditions for the 3D fluid simulation. We also introduce a novel technique for removing visual artifacts caused by numerical errors in 3D fluid solvers: we use experimental data to estimate the artificial dispersion caused by the 3D solver and we then carefully tune the wave speeds of the 2D solver to match it, effectively eliminating any differences in wave behavior across the boundary. To the best of our knowledge, this is the first time such a empirically driven error compensation approach has been used to remove coupling errors from a physics simulator. Our coupled simulation approach leverages the strengths of each simulation technique, animating large environments with seamless transitions between 2D and 3D physics. AU - Schreck, Camille AU - Wojtan, Christopher J ID - 11432 IS - 2 JF - Computer Graphics Forum SN - 0167-7055 TI - Coupling 3D liquid simulation with 2D wave propagation for large scale water surface animation using the equivalent sources method VL - 41 ER - TY - JOUR AB - We introduce a new variant of quantitative Helly-type theorems: the minimal homothetic distance of the intersection of a family of convex sets to the intersection of a subfamily of a fixed size. As an application, we establish the following quantitative Helly-type result for the diameter. If $K$ is the intersection of finitely many convex bodies in $\mathbb{R}^d$, then one can select $2d$ of these bodies whose intersection is of diameter at most $(2d)^3{diam}(K)$. The best previously known estimate, due to Brazitikos [Bull. Hellenic Math. Soc., 62 (2018), pp. 19--25], is $c d^{11/2}$. Moreover, we confirm that the multiplicative factor $c d^{1/2}$ conjectured by Bárány, Katchalski, and Pach [Proc. Amer. Math. Soc., 86 (1982), pp. 109--114] cannot be improved. The bounds above follow from our key result that concerns sparse approximation of a convex polytope by the convex hull of a well-chosen subset of its vertices: Assume that $Q \subset {\mathbb R}^d$ is a polytope whose centroid is the origin. Then there exist at most 2d vertices of $Q$ whose convex hull $Q^{\prime \prime}$ satisfies $Q \subset - 8d^3 Q^{\prime \prime}.$ AU - Ivanov, Grigory AU - Naszodi, Marton ID - 11435 IS - 2 JF - SIAM Journal on Discrete Mathematics SN - 08954801 TI - A quantitative Helly-type theorem: Containment in a homothet VL - 36 ER - TY - JOUR AB - Van der Holst and Pendavingh introduced a graph parameter σ, which coincides with the more famous Colin de Verdière graph parameter μ for small values. However, the definition of a is much more geometric/topological directly reflecting embeddability properties of the graph. They proved μ(G) ≤ σ(G) + 2 and conjectured σ(G) ≤ σ(G) for any graph G. We confirm this conjecture. As far as we know, this is the first topological upper bound on σ(G) which is, in general, tight. Equality between μ and σ does not hold in general as van der Holst and Pendavingh showed that there is a graph G with μ(G) ≤ 18 and σ(G) ≥ 20. We show that the gap appears at much smaller values, namely, we exhibit a graph H for which μ(H) ≥ 7 and σ(H) ≥ 8. We also prove that, in general, the gap can be large: The incidence graphs Hq of finite projective planes of order q satisfy μ(Hq) ∈ O(q3/2) and σ(Hq) ≥ q2. AU - Kaluza, Vojtech AU - Tancer, Martin ID - 10335 JF - Combinatorica SN - 0209-9683 TI - Even maps, the Colin de Verdière number and representations of graphs ER - TY - CHAP AB - To compute the persistent homology of a grayscale digital image one needs to build a simplicial or cubical complex from it. For cubical complexes, the two commonly used constructions (corresponding to direct and indirect digital adjacencies) can give different results for the same image. The two constructions are almost dual to each other, and we use this relationship to extend and modify the cubical complexes to become dual filtered cell complexes. We derive a general relationship between the persistent homology of two dual filtered cell complexes, and also establish how various modifications to a filtered complex change the persistence diagram. Applying these results to images, we derive a method to transform the persistence diagram computed using one type of cubical complex into a persistence diagram for the other construction. This means software for computing persistent homology from images can now be easily adapted to produce results for either of the two cubical complex constructions without additional low-level code implementation. AU - Bleile, Bea AU - Garin, Adélie AU - Heiss, Teresa AU - Maggs, Kelly AU - Robins, Vanessa ED - Gasparovic, Ellen ED - Robins, Vanessa ED - Turner, Katharine ID - 11440 SN - 9783030955182 T2 - Research in Computational Topology 2 TI - The persistent homology of dual digital image constructions VL - 30 ER - TY - JOUR AB - This article investigates library-related documents written by Gerard van Swieten (1700–72) during his tenure as Library Prefect in the Imperial Library of Vienna (1745–72). Van Swieten’s time as Library Prefect is considered through a textual analysis. Handwritten letters were deconstructed in terms of their appearance, layout, and tone in order to mine them for meaning. Furthermore, the contents were examined for library matters such as censorship, catalogues, and collection development. The Imperial Court Library held a prominent role as a repository for rare and valuable works, later becoming the National Library of Austria. Gerard van Swieten’s work as a librarian tends to be overlooked, perhaps because he is better known as the private physician of Maria Theresia, as well as a medical reformer. Nevertheless, he was a hard-working chief librarian deeply involved in all aspects of librarianship. Van Swieten endorsed modern scientific works, which were otherwise banned officially by the censorship commission, for the use of scholars in the library, expanded the collection by acquiring books through his network of scholars and publishers, and reissued library catalogues. He also provided for the comfort of users in the library reading room, at a time when such considerations were unusual. In conclusion, a proposal is made that van Swieten viewed his role as librarian with some importance and pride. AU - Chlebak, Clara A AU - Reid, Peter H. ID - 11444 IS - 1 JF - Library and Information History SN - 1758-3489 TI - From the prefect’s desk: Gerard van Swieten’s library correspondence VL - 38 ER - TY - JOUR AB - Lasers with well-controlled relative frequencies are indispensable for many applications in science and technology. We present a frequency-offset locking method for lasers based on beat-frequency discrimination utilizing hybrid electronic LC filters. The method is specifically designed for decoupling the tightness of the lock from the broadness of its capture range. The presented demonstration locks two free-running diode lasers at 780 nm with a 5.5-GHz offset. It displays an offset frequency instability below 55 Hz for time scales in excess of 1000 s and a minimum of 12 Hz at 10-s averaging. The performance is complemented with a 190-MHz lock-capture range, a tuning range of up to 1 GHz, and a frequency ramp agility of 200kHz/μs. AU - Li, Vyacheslav AU - Diorico, Fritz R AU - Hosten, Onur ID - 11438 IS - 5 JF - Physical Review Applied KW - General Physics and Astronomy SN - 2331-7019 TI - Laser frequency-offset locking at 10-Hz-level instability using hybrid electronic filters VL - 17 ER - TY - JOUR AB - In eukaryotes, clathrin-coated vesicles (CCVs) facilitate the internalization of material from the cell surface as well as the movement of cargo in post-Golgi trafficking pathways. This diversity of functions is partially provided by multiple monomeric and multimeric clathrin adaptor complexes that provide compartment and cargo selectivity. The adaptor-protein assembly polypeptide-1 (AP-1) complex operates as part of the secretory pathway at the trans-Golgi network (TGN), while the AP-2 complex and the TPLATE complex jointly operate at the plasma membrane to execute clathrin-mediated endocytosis. Key to our further understanding of clathrin-mediated trafficking in plants will be the comprehensive identification and characterization of the network of evolutionarily conserved and plant-specific core and accessory machinery involved in the formation and targeting of CCVs. To facilitate these studies, we have analyzed the proteome of enriched TGN/early endosome-derived and endocytic CCVs isolated from dividing and expanding suspension-cultured Arabidopsis (Arabidopsis thaliana) cells. Tandem mass spectrometry analysis results were validated by differential chemical labeling experiments to identify proteins co-enriching with CCVs. Proteins enriched in CCVs included previously characterized CCV components and cargos such as the vacuolar sorting receptors in addition to conserved and plant-specific components whose function in clathrin-mediated trafficking has not been previously defined. Notably, in addition to AP-1 and AP-2, all subunits of the AP-4 complex, but not AP-3 or AP-5, were found to be in high abundance in the CCV proteome. The association of AP-4 with suspension-cultured Arabidopsis CCVs is further supported via additional biochemical data. AU - Dahhan, DA AU - Reynolds, GD AU - Cárdenas, JJ AU - Eeckhout, D AU - Johnson, Alexander J AU - Yperman, K AU - Kaufmann, Walter AU - Vang, N AU - Yan, X AU - Hwang, I AU - Heese, A AU - De Jaeger, G AU - Friml, Jiří AU - Van Damme, D AU - Pan, J AU - Bednarek, SY ID - 10841 IS - 6 JF - Plant Cell SN - 1040-4651 TI - Proteomic characterization of isolated Arabidopsis clathrin-coated vesicles reveals evolutionarily conserved and plant-specific components VL - 34 ER - TY - JOUR AB - Auxin has always been at the forefront of research in plant physiology and development. Since the earliest contemplations by Julius von Sachs and Charles Darwin, more than a century-long struggle has been waged to understand its function. This largely reflects the failures, successes, and inevitable progress in the entire field of plant signaling and development. Here I present 14 stations on our long and sometimes mystical journey to understand auxin. These highlights were selected to give a flavor of the field and to show the scope and limits of our current knowledge. A special focus is put on features that make auxin unique among phytohormones, such as its dynamic, directional transport network, which integrates external and internal signals, including self-organizing feedback. Accented are persistent mysteries and controversies. The unexpected discoveries related to rapid auxin responses and growth regulation recently disturbed our contentment regarding understanding of the auxin signaling mechanism. These new revelations, along with advances in technology, usher us into a new, exciting era in auxin research. AU - Friml, Jiří ID - 10016 IS - 5 JF - Cold Spring Harbor Perspectives in Biology SN - 1943-0264 TI - Fourteen stations of auxin VL - 14 ER - TY - JOUR AB - Consider a linear elliptic partial differential equation in divergence form with a random coefficient field. The solution operator displays fluctuations around its expectation. The recently developed pathwise theory of fluctuations in stochastic homogenization reduces the characterization of these fluctuations to those of the so-called standard homogenization commutator. In this contribution, we investigate the scaling limit of this key quantity: starting from a Gaussian-like coefficient field with possibly strong correlations, we establish the convergence of the rescaled commutator to a fractional Gaussian field, depending on the decay of correlations of the coefficient field, and we investigate the (non)degeneracy of the limit. This extends to general dimension $d\ge1$ previous results so far limited to dimension $d=1$, and to the continuum setting with strong correlations recent results in the discrete iid case. AU - Duerinckx, Mitia AU - Fischer, Julian L AU - Gloria, Antoine ID - 10548 IS - 2 JF - Annals of applied probability SN - 1050-5164 TI - Scaling limit of the homogenization commutator for Gaussian coefficient fields VL - 32 ER - TY - JOUR AB - Studies of protein fitness landscapes reveal biophysical constraints guiding protein evolution and empower prediction of functional proteins. However, generalisation of these findings is limited due to scarceness of systematic data on fitness landscapes of proteins with a defined evolutionary relationship. We characterized the fitness peaks of four orthologous fluorescent proteins with a broad range of sequence divergence. While two of the four studied fitness peaks were sharp, the other two were considerably flatter, being almost entirely free of epistatic interactions. Mutationally robust proteins, characterized by a flat fitness peak, were not optimal templates for machine-learning-driven protein design – instead, predictions were more accurate for fragile proteins with epistatic landscapes. Our work paves insights for practical application of fitness landscape heterogeneity in protein engineering. AU - Gonzalez Somermeyer, Louisa AU - Fleiss, Aubin AU - Mishin, Alexander S AU - Bozhanova, Nina G AU - Igolkina, Anna A AU - Meiler, Jens AU - Alaball Pujol, Maria-Elisenda AU - Putintseva, Ekaterina V AU - Sarkisyan, Karen S AU - Kondrashov, Fyodor ID - 11448 JF - eLife KW - General Immunology and Microbiology KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Medicine KW - General Neuroscience SN - 2050-084X TI - Heterogeneity of the GFP fitness landscape and data-driven protein design VL - 11 ER - TY - JOUR AB - Background: Proper cerebral cortical development depends on the tightly orchestrated migration of newly born neurons from the inner ventricular and subventricular zones to the outer cortical plate. Any disturbance in this process during prenatal stages may lead to neuronal migration disorders (NMDs), which can vary in extent from focal to global. Furthermore, NMDs show a substantial comorbidity with other neurodevelopmental disorders, notably autism spectrum disorders (ASDs). Our previous work demonstrated focal neuronal migration defects in mice carrying loss-of-function alleles of the recognized autism risk gene WDFY3. However, the cellular origins of these defects in Wdfy3 mutant mice remain elusive and uncovering it will provide critical insight into WDFY3-dependent disease pathology. Methods: Here, in an effort to untangle the origins of NMDs in Wdfy3lacZ mice, we employed mosaic analysis with double markers (MADM). MADM technology enabled us to genetically distinctly track and phenotypically analyze mutant and wild-type cells concomitantly in vivo using immunofluorescent techniques. Results: We revealed a cell autonomous requirement of WDFY3 for accurate laminar positioning of cortical projection neurons and elimination of mispositioned cells during early postnatal life. In addition, we identified significant deviations in dendritic arborization, as well as synaptic density and morphology between wild type, heterozygous, and homozygous Wdfy3 mutant neurons in Wdfy3-MADM reporter mice at postnatal stages. Limitations: While Wdfy3 mutant mice have provided valuable insight into prenatal aspects of ASD pathology that remain inaccessible to investigation in humans, like most animal models, they do not a perfectly replicate all aspects of human ASD biology. The lack of human data makes it indeterminate whether morphological deviations described here apply to ASD patients or some of the other neurodevelopmental conditions associated with WDFY3 mutation. Conclusions: Our genetic approach revealed several cell autonomous requirements of WDFY3 in neuronal development that could underlie the pathogenic mechanisms of WDFY3-related neurodevelopmental conditions. The results are also consistent with findings in other ASD animal models and patients and suggest an important role for WDFY3 in regulating neuronal function and interconnectivity in postnatal life. AU - Schaaf, Zachary A. AU - Tat, Lyvin AU - Cannizzaro, Noemi AU - Green, Ralph AU - Rülicke, Thomas AU - Hippenmeyer, Simon AU - Zarbalis, Konstantinos S. ID - 11460 JF - Molecular Autism KW - Psychiatry and Mental health KW - Developmental Biology KW - Developmental Neuroscience KW - Molecular Biology SN - 2040-2392 TI - WDFY3 mutation alters laminar position and morphology of cortical neurons VL - 13 ER - TY - CONF AB - We present a novel approach to differential cost analysis that, given a program revision, attempts to statically bound the difference in resource usage, or cost, between the two program versions. Differential cost analysis is particularly interesting because of the many compelling applications for it, such as detecting resource-use regressions at code-review time or proving the absence of certain side-channel vulnerabilities. One prior approach to differential cost analysis is to apply relational reasoning that conceptually constructs a product program on which one can over-approximate the difference in costs between the two program versions. However, a significant challenge in any relational approach is effectively aligning the program versions to get precise results. In this paper, our key insight is that we can avoid the need for and the limitations of program alignment if, instead, we bound the difference of two cost-bound summaries rather than directly bounding the concrete cost difference. In particular, our method computes a threshold value for the maximal difference in cost between two program versions simultaneously using two kinds of cost-bound summaries---a potential function that evaluates to an upper bound for the cost incurred in the first program and an anti-potential function that evaluates to a lower bound for the cost incurred in the second. Our method has a number of desirable properties: it can be fully automated, it allows optimizing the threshold value on relative cost, it is suitable for programs that are not syntactically similar, and it supports non-determinism. We have evaluated an implementation of our approach on a number of program pairs collected from the literature, and we find that our method computes tight threshold values on relative cost in most examples. AU - Zikelic, Dorde AU - Chang, Bor-Yuh Evan AU - Bolignano, Pauline AU - Raimondi, Franco ID - 11459 SN - 9781450392655 T2 - Proceedings of the 43rd ACM SIGPLAN International Conference on Programming Language Design and Implementation TI - Differential cost analysis with simultaneous potentials and anti-potentials ER - TY - JOUR AB - Variational quantum algorithms are promising algorithms for achieving quantum advantage on nearterm devices. The quantum hardware is used to implement a variational wave function and measure observables, whereas the classical computer is used to store and update the variational parameters. The optimization landscape of expressive variational ansätze is however dominated by large regions in parameter space, known as barren plateaus, with vanishing gradients, which prevents efficient optimization. In this work we propose a general algorithm to avoid barren plateaus in the initialization and throughout the optimization. To this end we define a notion of weak barren plateaus (WBPs) based on the entropies of local reduced density matrices. The presence of WBPs can be efficiently quantified using recently introduced shadow tomography of the quantum state with a classical computer. We demonstrate that avoidance of WBPs suffices to ensure sizable gradients in the initialization. In addition, we demonstrate that decreasing the gradient step size, guided by the entropies allows WBPs to be avoided during the optimization process. This paves the way for efficient barren plateau-free optimization on near-term devices. AU - Sack, Stefan AU - Medina Ramos, Raimel A AU - Michailidis, Alexios AU - Kueng, Richard AU - Serbyn, Maksym ID - 11471 IS - 2 JF - PRX Quantum KW - General Medicine SN - 2691-3399 TI - Avoiding barren plateaus using classical shadows VL - 3 ER - TY - JOUR AB - Thermalizing and localized many-body quantum systems present two distinct dynamical phases of matter. Recently the fate of a localized system coupled to a thermalizing system viewed as a quantum bath received significant theoretical and experimental attention. In this work, we study a mobile impurity, representing a small quantum bath, that interacts locally with an Anderson insulator with a finite density of localized particles. Using static Hartree approximation to obtain an effective disorder strength, we formulate an analytic criterion for the perturbative stability of the localization. Next, we use an approximate dynamical Hartree method and the quasi-exact time-evolved block decimation (TEBD) algorithm to study the dynamics of the system. We find that the dynamical Hartree approach which completely ignores entanglement between the impurity and localized particles predicts the delocalization of the system. In contrast, the full numerical simulation of the unitary dynamics with TEBD suggests the stability of localization on numerically accessible timescales. Finally, using an extension of the density matrix renormalization group algorithm to excited states (DMRG-X), we approximate the highly excited eigenstates of the system. We find that the impurity remains localized in the eigenstates and entanglement is enhanced in a finite region around the position of the impurity, confirming the dynamical predictions. Dynamics and the DMRG-X results provide compelling evidence for the stability of localization. AU - Brighi, Pietro AU - Michailidis, Alexios AU - Kirova, Kristina AU - Abanin, Dmitry A. AU - Serbyn, Maksym ID - 11469 IS - 22 JF - Physical Review B SN - 2469-9950 TI - Localization of a mobile impurity interacting with an Anderson insulator VL - 105 ER - TY - JOUR AB - Many-body localization (MBL) is an example of a dynamical phase of matter that avoids thermalization. While the MBL phase is robust to weak local perturbations, the fate of an MBL system coupled to a thermalizing quantum system that represents a “heat bath” is an open question that is actively investigated theoretically and experimentally. In this work, we consider the stability of an Anderson insulator with a finite density of particles interacting with a single mobile impurity—a small quantum bath. We give perturbative arguments that support the stability of localization in the strong interaction regime. Large-scale tensor network simulations of dynamics are employed to corroborate the presence of the localized phase and give quantitative predictions in the thermodynamic limit. We develop a phenomenological description of the dynamics in the strong interaction regime, and we demonstrate that the impurity effectively turns the Anderson insulator into an MBL phase, giving rise to nontrivial entanglement dynamics well captured by our phenomenology. AU - Brighi, Pietro AU - Michailidis, Alexios A. AU - Abanin, Dmitry A. AU - Serbyn, Maksym ID - 11470 IS - 22 JF - Physical Review B SN - 2469-9950 TI - Propagation of many-body localization in an Anderson insulator VL - 105 ER - TY - CONF AB - Messaging platforms like Signal are widely deployed and provide strong security in an asynchronous setting. It is a challenging problem to construct a protocol with similar security guarantees that can efficiently scale to large groups. A major bottleneck are the frequent key rotations users need to perform to achieve post compromise forward security. In current proposals – most notably in TreeKEM (which is part of the IETF’s Messaging Layer Security (MLS) protocol draft) – for users in a group of size n to rotate their keys, they must each craft a message of size log(n) to be broadcast to the group using an (untrusted) delivery server. In larger groups, having users sequentially rotate their keys requires too much bandwidth (or takes too long), so variants allowing any T≤n users to simultaneously rotate their keys in just 2 communication rounds have been suggested (e.g. “Propose and Commit” by MLS). Unfortunately, 2-round concurrent updates are either damaging or expensive (or both); i.e. they either result in future operations being more costly (e.g. via “blanking” or “tainting”) or are costly themselves requiring Ω(T) communication for each user [Bienstock et al., TCC’20]. In this paper we propose CoCoA; a new scheme that allows for T concurrent updates that are neither damaging nor costly. That is, they add no cost to future operations yet they only require Ω(log2(n)) communication per user. To circumvent the [Bienstock et al.] lower bound, CoCoA increases the number of rounds needed to complete all updates from 2 up to (at most) log(n); though typically fewer rounds are needed. The key insight of our protocol is the following: in the (non-concurrent version of) TreeKEM, a delivery server which gets T concurrent update requests will approve one and reject the remaining T−1. In contrast, our server attempts to apply all of them. If more than one user requests to rotate the same key during a round, the server arbitrarily picks a winner. Surprisingly, we prove that regardless of how the server chooses the winners, all previously compromised users will recover after at most log(n) such update rounds. To keep the communication complexity low, CoCoA is a server-aided CGKA. That is, the delivery server no longer blindly forwards packets, but instead actively computes individualized packets tailored to each user. As the server is untrusted, this change requires us to develop new mechanisms ensuring robustness of the protocol. AU - Alwen, Joël AU - Auerbach, Benedikt AU - Cueto Noval, Miguel AU - Klein, Karen AU - Pascual Perez, Guillermo AU - Pietrzak, Krzysztof Z AU - Walter, Michael ID - 11476 SN - 0302-9743 T2 - Advances in Cryptology – EUROCRYPT 2022 TI - CoCoA: Concurrent continuous group key agreement VL - 13276 ER - TY - JOUR AB - Understanding population divergence that eventually leads to speciation is essential for evolutionary biology. High species diversity in the sea was regarded as a paradox when strict allopatry was considered necessary for most speciation events because geographical barriers seemed largely absent in the sea, and many marine species have high dispersal capacities. Combining genome-wide data with demographic modelling to infer the demographic history of divergence has introduced new ways to address this classical issue. These models assume an ancestral population that splits into two subpopulations diverging according to different scenarios that allow tests for periods of gene flow. Models can also test for heterogeneities in population sizes and migration rates along the genome to account, respectively, for background selection and selection against introgressed ancestry. To investigate how barriers to gene flow arise in the sea, we compiled studies modelling the demographic history of divergence in marine organisms and extracted preferred demographic scenarios together with estimates of demographic parameters. These studies show that geographical barriers to gene flow do exist in the sea but that divergence can also occur without strict isolation. Heterogeneity of gene flow was detected in most population pairs suggesting the predominance of semipermeable barriers during divergence. We found a weak positive relationship between the fraction of the genome experiencing reduced gene flow and levels of genome-wide differentiation. Furthermore, we found that the upper bound of the ‘grey zone of speciation’ for our dataset extended beyond that found before, implying that gene flow between diverging taxa is possible at higher levels of divergence than previously thought. Finally, we list recommendations for further strengthening the use of demographic modelling in speciation research. These include a more balanced representation of taxa, more consistent and comprehensive modelling, clear reporting of results and simulation studies to rule out nonbiological explanations for general results. AU - De Jode, Aurélien AU - Le Moan, Alan AU - Johannesson, Kerstin AU - Faria, Rui AU - Stankowski, Sean AU - Westram, Anja M AU - Butlin, Roger K. AU - Rafajlović, Marina AU - Fraisse, Christelle ID - 11479 JF - Evolutionary Applications TI - Ten years of demographic modelling of divergence and speciation in the sea VL - 00 ER - TY - JOUR AB - Cerebral organoids differentiated from human-induced pluripotent stem cells (hiPSC) provide a unique opportunity to investigate brain development. However, organoids usually lack microglia, brain-resident immune cells, which are present in the early embryonic brain and participate in neuronal circuit development. Here, we find IBA1+ microglia-like cells alongside retinal cups between week 3 and 4 in 2.5D culture with an unguided retinal organoid differentiation protocol. Microglia do not infiltrate the neuroectoderm and instead enrich within non-pigmented, 3D-cystic compartments that develop in parallel to the 3D-retinal organoids. When we guide the retinal organoid differentiation with low-dosed BMP4, we prevent cup development and enhance microglia and 3D-cysts formation. Mass spectrometry identifies these 3D-cysts to express mesenchymal and epithelial markers. We confirmed this microglia-preferred environment also within the unguided protocol, providing insight into microglial behavior and migration and offer a model to study how they enter and distribute within the human brain. AU - Bartalska, Katarina AU - Hübschmann, Verena AU - Korkut, Medina AU - Cubero, Ryan John A. AU - Venturino, Alessandro AU - Rössler, Karl AU - Czech, Thomas AU - Siegert, Sandra ID - 11478 IS - 7 JF - iScience TI - A systematic characterization of microglia-like cell occurrence during retinal organoid differentiation VL - 25 ER - TY - JOUR AB - Much of plant development depends on cell-to-cell redistribution of the plant hormone auxin, which is facilitated by the plasma membrane (PM) localized PIN FORMED (PIN) proteins. Auxin export activity, developmental roles, subcellular trafficking, and polarity of PINs have been well studied, but their structure remains elusive besides a rough outline that they contain two groups of 5 alpha-helices connected by a large hydrophilic loop (HL). Here, we focus on the PIN1 HL as we could produce it in sufficient quantities for biochemical investigations to provide insights into its secondary structure. Circular dichroism (CD) studies revealed its nature as an intrinsically disordered protein (IDP), manifested by the increase of structure content upon thermal melting. Consistent with IDPs serving as interaction platforms, PIN1 loops homodimerize. PIN1 HL cytoplasmic overexpression in Arabidopsis disrupts early endocytic trafficking of PIN1 and PIN2 and causes defects in the cotyledon vasculature formation. In summary, we demonstrate that PIN1 HL has an intrinsically disordered nature, which must be considered to gain further structural insights. Some secondary structures may form transiently during pairing with known and yet-to-be-discovered interactors. AU - Bilanovičová, V AU - Rýdza, N AU - Koczka, L AU - Hess, M AU - Feraru, E AU - Friml, Jiří AU - Nodzyński, T ID - 11489 IS - 11 JF - International Journal of Molecular Sciences SN - 1422-0067 TI - The hydrophilic loop of Arabidopsis PIN1 auxin efflux carrier harbors hallmarks of an intrinsically disordered protein VL - 23 ER - TY - THES AB - The polaron model is a basic model of quantum field theory describing a single particle interacting with a bosonic field. It arises in many physical contexts. We are mostly concerned with models applicable in the context of an impurity atom in a Bose-Einstein condensate as well as the problem of electrons moving in polar crystals. The model has a simple structure in which the interaction of the particle with the field is given by a term linear in the field’s creation and annihilation operators. In this work, we investigate the properties of this model by providing rigorous estimates on various energies relevant to the problem. The estimates are obtained, for the most part, by suitable operator techniques which constitute the principal mathematical substance of the thesis. The first application of these techniques is to derive the polaron model rigorously from first principles, i.e., from a full microscopic quantum-mechanical many-body problem involving an impurity in an otherwise homogeneous system. We accomplish this for the N + 1 Bose gas in the mean-field regime by showing that a suitable polaron-type Hamiltonian arises at weak interactions as a low-energy effective theory for this problem. In the second part, we investigate rigorously the ground state of the model at fixed momentum and for large values of the coupling constant. Qualitatively, the system is expected to display a transition from the quasi-particle behavior at small momenta, where the dispersion relation is parabolic and the particle moves through the medium dragging along a cloud of phonons, to the radiative behavior at larger momenta where the polaron decelerates and emits free phonons. At the same time, in the strong coupling regime, the bosonic field is expected to behave purely classically. Accordingly, the effective mass of the polaron at strong coupling is conjectured to be asymptotically equal to the one obtained from the semiclassical counterpart of the problem, first studied by Landau and Pekar in the 1940s. For polaron models with regularized form factors and phonon dispersion relations of superfluid type, i.e., bounded below by a linear function of the wavenumbers for all phonon momenta as in the interacting Bose gas, we prove that for a large window of momenta below the radiation threshold, the energy-momentum relation at strong coupling is indeed essentially a parabola with semi-latus rectum equal to the Landau–Pekar effective mass, as expected. For the Fröhlich polaron describing electrons in polar crystals where the dispersion relation is of the optical type and the form factor is formally UV–singular due to the nature of the point charge-dipole interaction, we are able to give the corresponding upper bound. In contrast to the regular case, this requires the inclusion of the quantum fluctuations of the phonon field, which makes the problem considerably more difficult. The results are supplemented by studies on the absolute ground-state energy at strong coupling, a proof of the divergence of the effective mass with the coupling constant for a wide class of polaron models, as well as the discussion of the apparent UV singularity of the Fröhlich model and the application of the techniques used for its removal for the energy estimates. AU - Mysliwy, Krzysztof ID - 11473 SN - 2663-337X TI - Polarons in Bose gases and polar crystals: Some rigorous energy estimates ER - TY - JOUR AB - We study a class of polaron-type Hamiltonians with sufficiently regular form factor in the interaction term. We investigate the strong-coupling limit of the model, and prove suitable bounds on the ground state energy as a function of the total momentum of the system. These bounds agree with the semiclassical approximation to leading order. The latter corresponds here to the situation when the particle undergoes harmonic motion in a potential well whose frequency is determined by the corresponding Pekar functional. We show that for all such models the effective mass diverges in the strong coupling limit, in all spatial dimensions. Moreover, for the case when the phonon dispersion relation grows at least linearly with momentum, the bounds result in an asymptotic formula for the effective mass quotient, a quantity generalizing the usual notion of the effective mass. This asymptotic form agrees with the semiclassical Landau–Pekar formula and can be regarded as the first rigorous confirmation, in a slightly weaker sense than usually considered, of the validity of the semiclassical formula for the effective mass. AU - Mysliwy, Krzysztof AU - Seiringer, Robert ID - 10564 IS - 1 JF - Journal of Statistical Physics SN - 0022-4715 TI - Polaron models with regular interactions at strong coupling VL - 186 ER - TY - THES AB - Because of the increasing popularity of machine learning methods, it is becoming important to understand the impact of learned components on automated decision-making systems and to guarantee that their consequences are beneficial to society. In other words, it is necessary to ensure that machine learning is sufficiently trustworthy to be used in real-world applications. This thesis studies two properties of machine learning models that are highly desirable for the sake of reliability: robustness and fairness. In the first part of the thesis we study the robustness of learning algorithms to training data corruption. Previous work has shown that machine learning models are vulnerable to a range of training set issues, varying from label noise through systematic biases to worst-case data manipulations. This is an especially relevant problem from a present perspective, since modern machine learning methods are particularly data hungry and therefore practitioners often have to rely on data collected from various external sources, e.g. from the Internet, from app users or via crowdsourcing. Naturally, such sources vary greatly in the quality and reliability of the data they provide. With these considerations in mind, we study the problem of designing machine learning algorithms that are robust to corruptions in data coming from multiple sources. We show that, in contrast to the case of a single dataset with outliers, successful learning within this model is possible both theoretically and practically, even under worst-case data corruptions. The second part of this thesis deals with fairness-aware machine learning. There are multiple areas where machine learning models have shown promising results, but where careful considerations are required, in order to avoid discrimanative decisions taken by such learned components. Ensuring fairness can be particularly challenging, because real-world training datasets are expected to contain various forms of historical bias that may affect the learning process. In this thesis we show that data corruption can indeed render the problem of achieving fairness impossible, by tightly characterizing the theoretical limits of fair learning under worst-case data manipulations. However, assuming access to clean data, we also show how fairness-aware learning can be made practical in contexts beyond binary classification, in particular in the challenging learning to rank setting. AU - Konstantinov, Nikola H ID - 10799 KW - robustness KW - fairness KW - machine learning KW - PAC learning KW - adversarial learning SN - 978-3-99078-015-2 TI - Robustness and fairness in machine learning ER - TY - JOUR AB - Addressing fairness concerns about machine learning models is a crucial step towards their long-term adoption in real-world automated systems. While many approaches have been developed for training fair models from data, little is known about the robustness of these methods to data corruption. In this work we consider fairness-aware learning under worst-case data manipulations. We show that an adversary can in some situations force any learner to return an overly biased classifier, regardless of the sample size and with or without degrading accuracy, and that the strength of the excess bias increases for learning problems with underrepresented protected groups in the data. We also prove that our hardness results are tight up to constant factors. To this end, we study two natural learning algorithms that optimize for both accuracy and fairness and show that these algorithms enjoy guarantees that are order-optimal in terms of the corruption ratio and the protected groups frequencies in the large data limit. AU - Konstantinov, Nikola H AU - Lampert, Christoph ID - 10802 JF - Journal of Machine Learning Research KW - Fairness KW - robustness KW - data poisoning KW - trustworthy machine learning KW - PAC learning SN - 15324435 TI - Fairness-aware PAC learning from corrupted data VL - 23 ER - TY - JOUR AB - Imbalanced mitochondrial dNTP pools are known players in the pathogenesis of multiple human diseases. Here we show that, even under physiological conditions, dGTP is largely overrepresented among other dNTPs in mitochondria of mouse tissues and human cultured cells. In addition, a vast majority of mitochondrial dGTP is tightly bound to NDUFA10, an accessory subunit of complex I of the mitochondrial respiratory chain. NDUFA10 shares a deoxyribonucleoside kinase (dNK) domain with deoxyribonucleoside kinases in the nucleotide salvage pathway, though no specific function beyond stabilizing the complex I holoenzyme has been described for this subunit. We mutated the dNK domain of NDUFA10 in human HEK-293T cells while preserving complex I assembly and activity. The NDUFA10E160A/R161A shows reduced dGTP binding capacity in vitro and leads to a 50% reduction in mitochondrial dGTP content, proving that most dGTP is directly bound to the dNK domain of NDUFA10. This interaction may represent a hitherto unknown mechanism regulating mitochondrial dNTP availability and linking oxidative metabolism to DNA maintenance. AU - Molina-Granada, David AU - González-Vioque, Emiliano AU - Dibley, Marris G. AU - Cabrera-Pérez, Raquel AU - Vallbona-Garcia, Antoni AU - Torres-Torronteras, Javier AU - Sazanov, Leonid A AU - Ryan, Michael T. AU - Cámara, Yolanda AU - Martí, Ramon ID - 11551 IS - 1 JF - Communications Biology TI - Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit VL - 5 ER - TY - JOUR AB - Large oligomeric enzymes control a myriad of cellular processes, from protein synthesis and degradation to metabolism. The 0.5 MDa large TET2 aminopeptidase, a prototypical protease important for cellular homeostasis, degrades peptides within a ca. 60 Å wide tetrahedral chamber with four lateral openings. The mechanisms of substrate trafficking and processing remain debated. Here, we integrate magic-angle spinning (MAS) NMR, mutagenesis, co-evolution analysis and molecular dynamics simulations and reveal that a loop in the catalytic chamber is a key element for enzymatic function. The loop is able to stabilize ligands in the active site and may additionally have a direct role in activating the catalytic water molecule whereby a conserved histidine plays a key role. Our data provide a strong case for the functional importance of highly dynamic - and often overlooked - parts of an enzyme, and the potential of MAS NMR to investigate their dynamics at atomic resolution. AU - Gauto, Diego F. AU - Macek, Pavel AU - Malinverni, Duccio AU - Fraga, Hugo AU - Paloni, Matteo AU - Sučec, Iva AU - Hessel, Audrey AU - Bustamante, Juan Pablo AU - Barducci, Alessandro AU - Schanda, Paul ID - 11179 JF - Nature Communications TI - Functional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR VL - 13 ER - TY - JOUR AB - Rotational dynamics of D2 molecules inside helium nanodroplets is induced by a moderately intense femtosecond pump pulse and measured as a function of time by recording the yield of HeD+ ions, created through strong-field dissociative ionization with a delayed femtosecond probe pulse. The yield oscillates with a period of 185 fs, reflecting field-free rotational wave packet dynamics, and the oscillation persists for more than 500 periods. Within the experimental uncertainty, the rotational constant BHe of the in-droplet D2 molecule, determined by Fourier analysis, is the same as Bgas for an isolated D2 molecule. Our observations show that the D2 molecules inside helium nanodroplets essentially rotate as free D2 molecules. AU - Qiang, Junjie AU - Zhou, Lianrong AU - Lu, Peifen AU - Lin, Kang AU - Ma, Yongzhe AU - Pan, Shengzhe AU - Lu, Chenxu AU - Jiang, Wenyu AU - Sun, Fenghao AU - Zhang, Wenbin AU - Li, Hui AU - Gong, Xiaochun AU - Averbukh, Ilya Sh AU - Prior, Yehiam AU - Schouder, Constant A. AU - Stapelfeldt, Henrik AU - Cherepanov, Igor AU - Lemeshko, Mikhail AU - Jäger, Wolfgang AU - Wu, Jian ID - 11552 IS - 24 JF - Physical Review Letters SN - 00319007 TI - Femtosecond rotational dynamics of D2 molecules in superfluid helium nanodroplets VL - 128 ER - TY - JOUR AB - Local adaptation leads to differences between populations within a species. In many systems, similar environmental contrasts occur repeatedly, sometimes driving parallel phenotypic evolution. Understanding the genomic basis of local adaptation and parallel evolution is a major goal of evolutionary genomics. It is now known that by preventing the break-up of favourable combinations of alleles across multiple loci, genetic architectures that reduce recombination, like chromosomal inversions, can make an important contribution to local adaptation. However, little is known about whether inversions also contribute disproportionately to parallel evolution. Our aim here is to highlight this knowledge gap, to showcase existing studies, and to illustrate the differences between genomic architectures with and without inversions using simple models. We predict that by generating stronger effective selection, inversions can sometimes speed up the parallel adaptive process or enable parallel adaptation where it would be impossible otherwise, but this is highly dependent on the spatial setting. We highlight that further empirical work is needed, in particular to cover a broader taxonomic range and to understand the relative importance of inversions compared to genomic regions without inversions. AU - Westram, Anja M AU - Faria, Rui AU - Johannesson, Kerstin AU - Butlin, Roger AU - Barton, Nicholas H ID - 11546 IS - 1856 JF - Philosophical Transactions of the Royal Society B: Biological Sciences KW - General Agricultural and Biological Sciences KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0962-8436 TI - Inversions and parallel evolution VL - 377 ER - TY - JOUR AB - We revisit two basic Direct Simulation Monte Carlo Methods to model aggregation kinetics and extend them for aggregation processes with collisional fragmentation (shattering). We test the performance and accuracy of the extended methods and compare their performance with efficient deterministic finite-difference method applied to the same model. We validate the stochastic methods on the test problems and apply them to verify the existence of oscillating regimes in the aggregation-fragmentation kinetics recently detected in deterministic simulations. We confirm the emergence of steady oscillations of densities in such systems and prove the stability of the oscillations with respect to fluctuations and noise. AU - Kalinov, Aleksei AU - Osinskiy, A.I. AU - Matveev, S.A. AU - Otieno, W. AU - Brilliantov, N.V. ID - 11556 JF - Journal of Computational Physics KW - Computer Science Applications KW - Physics and Astronomy (miscellaneous) KW - Applied Mathematics KW - Computational Mathematics KW - Modeling and Simulation KW - Numerical Analysis SN - 0021-9991 TI - Direct simulation Monte Carlo for new regimes in aggregation-fragmentation kinetics VL - 467 ER - TY - JOUR AB - We classify contravariant pairings between standard Whittaker modules and Verma modules over a complex semisimple Lie algebra. These contravariant pairings are useful in extending several classical techniques for category O to the Miličić–Soergel category N . We introduce a class of costandard modules which generalize dual Verma modules, and describe canonical maps from standard to costandard modules in terms of contravariant pairings. We show that costandard modules have unique irreducible submodules and share the same composition factors as the corresponding standard Whittaker modules. We show that costandard modules give an algebraic characterization of the global sections of costandard twisted Harish-Chandra sheaves on the associated flag variety, which are defined using holonomic duality of D-modules. We prove that with these costandard modules, blocks of category N have the structure of highest weight categories and we establish a BGG reciprocity theorem for N . AU - Brown, Adam AU - Romanov, Anna ID - 11545 JF - Journal of Algebra KW - Algebra and Number Theory SN - 0021-8693 TI - Contravariant pairings between standard Whittaker modules and Verma modules VL - 609 ER - TY - JOUR AB - Visualizing cell behavior and effector function on a single cell level has been crucial for understanding key aspects of mammalian biology. Due to their small size, large number and rapid recruitment into thrombi, there is a lack of data on fate and behavior of individual platelets in thrombosis and hemostasis. Here we report the use of platelet lineage restricted multi-color reporter mouse strains to delineate platelet function on a single cell level. We show that genetic labeling allows for single platelet and megakaryocyte (MK) tracking and morphological analysis in vivo and in vitro, while not affecting lineage functions. Using Cre-driven Confetti expression, we provide insights into temporal gene expression patterns as well as spatial clustering of MK in the bone marrow. In the vasculature, shape analysis of activated platelets recruited to thrombi identifies ubiquitous filopodia formation with no evidence of lamellipodia formation. Single cell tracking in complex thrombi reveals prominent myosin-dependent motility of platelets and highlights thrombus formation as a highly dynamic process amenable to modification and intervention of the acto-myosin cytoskeleton. Platelet function assays combining flow cytrometry, as well as in vivo, ex vivo and in vitro imaging show unaltered platelet functions of multicolor reporter mice compared to wild-type controls. In conclusion, platelet lineage multicolor reporter mice prove useful in furthering our understanding of platelet and MK biology on a single cell level. AU - Nicolai, Leo AU - Kaiser, Rainer AU - Escaig, Raphael AU - Hoffknecht, Marie Louise AU - Anjum, Afra AU - Leunig, Alexander AU - Pircher, Joachim AU - Ehrlich, Andreas AU - Lorenz, Michael AU - Ishikawa-Ankerhold, Hellen AU - Aird, William C. AU - Massberg, Steffen AU - Gärtner, Florian R ID - 11588 IS - 7 JF - Haematologica SN - 0390-6078 TI - Single platelet and megakaryocyte morpho-dynamics uncovered by multicolor reporter mouse strains in vitro and in vivo VL - 107 ER -