@article{158, abstract = {The angiosperm seed is composed of three genetically distinct tissues: the diploid embryo that originates from the fertilized egg cell, the triploid endosperm that is produced from the fertilized central cell, and the maternal sporophytic integuments that develop into the seed coat1. At the onset of embryo development in Arabidopsis thaliana, the zygote divides asymmetrically, producing a small apical embryonic cell and a larger basal cell that connects the embryo to the maternal tissue2. The coordinated and synchronous development of the embryo and the surrounding integuments, and the alignment of their growth axes, suggest communication between maternal tissues and the embryo. In contrast to animals, however, where a network of maternal factors that direct embryo patterning have been identified3,4, only a few maternal mutations have been described to affect embryo development in plants5–7. Early embryo patterning in Arabidopsis requires accumulation of the phytohormone auxin in the apical cell by directed transport from the suspensor8–10. However, the origin of this auxin has remained obscure. Here we investigate the source of auxin for early embryogenesis and provide evidence that the mother plant coordinates seed development by supplying auxin to the early embryo from the integuments of the ovule. We show that auxin response increases in ovules after fertilization, due to upregulated auxin biosynthesis in the integuments, and this maternally produced auxin is required for correct embryo development.}, author = {Robert, Hélène and Park, Chulmin and Gutièrrez, Carla and Wójcikowska, Barbara and Pěnčík, Aleš and Novák, Ondřej and Chen, Junyi and Grunewald, Wim and Dresselhaus, Thomas and Friml, Jirí and Laux, Thomas}, journal = {Nature Plants}, number = {8}, pages = {548 -- 553}, publisher = {Nature Publishing Group}, title = {{Maternal auxin supply contributes to early embryo patterning in Arabidopsis}}, doi = {10.1038/s41477-018-0204-z}, volume = {4}, year = {2018}, } @article{159, abstract = {L-type Ca2+ channels (LTCCs) play a crucial role in excitation-contraction coupling and release of hormones from secretory cells. They are targets of antihypertensive and antiarrhythmic drugs such as diltiazem. Here, we present a photoswitchable diltiazem, FHU-779, which can be used to reversibly block endogenous LTCCs by light. FHU-779 is as potent as diltiazem and can be used to place pancreatic β-cell function and cardiac activity under optical control.}, author = {Fehrentz, Timm and Huber, Florian and Hartrampf, Nina and Bruegmann, Tobias and Frank, James and Fine, Nicholas and Malan, Daniela and Danzl, Johann G and Tikhonov, Denis and Sumser, Maritn and Sasse, Philipp and Hodson, David and Zhorov, Boris and Klocker, Nikolaj and Trauner, Dirk}, journal = {Nature Chemical Biology}, number = {8}, pages = {764 -- 767}, publisher = {Nature Publishing Group}, title = {{Optical control of L-type Ca2+ channels using a diltiazem photoswitch}}, doi = {10.1038/s41589-018-0090-8}, volume = {14}, year = {2018}, } @article{16, abstract = {We report quantitative evidence of mixing-layer elastic instability in a viscoelastic fluid flow between two widely spaced obstacles hindering a channel flow at Re 1 and Wi 1. Two mixing layers with nonuniform shear velocity profiles are formed in the region between the obstacles. The mixing-layer instability arises in the vicinity of an inflection point on the shear velocity profile with a steep variation in the elastic stress. The instability results in an intermittent appearance of small vortices in the mixing layers and an amplification of spatiotemporal averaged vorticity in the elastic turbulence regime. The latter is characterized through scaling of friction factor with Wi and both pressure and velocity spectra. Furthermore, the observations reported provide improved understanding of the stability of the mixing layer in a viscoelastic fluid at large elasticity, i.e., Wi 1 and Re 1 and oppose the current view of suppression of vorticity solely by polymer additives.}, author = {Varshney, Atul and Steinberg, Victor}, journal = {Physical Review Fluids}, number = {10}, publisher = {American Physical Society}, title = {{Mixing layer instability and vorticity amplification in a creeping viscoelastic flow}}, doi = {10.1103/PhysRevFluids.3.103303}, volume = {3}, year = {2018}, } @inproceedings{160, abstract = {We present layered concurrent programs, a compact and expressive notation for specifying refinement proofs of concurrent programs. A layered concurrent program specifies a sequence of connected concurrent programs, from most concrete to most abstract, such that common parts of different programs are written exactly once. These programs are expressed in the ordinary syntax of imperative concurrent programs using gated atomic actions, sequencing, choice, and (recursive) procedure calls. Each concurrent program is automatically extracted from the layered program. We reduce refinement to the safety of a sequence of concurrent checker programs, one each to justify the connection between every two consecutive concurrent programs. These checker programs are also automatically extracted from the layered program. Layered concurrent programs have been implemented in the CIVL verifier which has been successfully used for the verification of several complex concurrent programs.}, author = {Kragl, Bernhard and Qadeer, Shaz}, location = {Oxford, UK}, pages = {79 -- 102}, publisher = {Springer}, title = {{Layered Concurrent Programs}}, doi = {10.1007/978-3-319-96145-3_5}, volume = {10981}, year = {2018}, } @article{161, abstract = {Which properties of metabolic networks can be derived solely from stoichiometry? Predictive results have been obtained by flux balance analysis (FBA), by postulating that cells set metabolic fluxes to maximize growth rate. Here we consider a generalization of FBA to single-cell level using maximum entropy modeling, which we extend and test experimentally. Specifically, we define for Escherichia coli metabolism a flux distribution that yields the experimental growth rate: the model, containing FBA as a limit, provides a better match to measured fluxes and it makes a wide range of predictions: on flux variability, regulation, and correlations; on the relative importance of stoichiometry vs. optimization; on scaling relations for growth rate distributions. We validate the latter here with single-cell data at different sub-inhibitory antibiotic concentrations. The model quantifies growth optimization as emerging from the interplay of competitive dynamics in the population and regulation of metabolism at the level of single cells.}, author = {De Martino, Daniele and Mc, Andersson Anna and Bergmiller, Tobias and Guet, Calin C and Tkacik, Gasper}, journal = {Nature Communications}, number = {1}, publisher = {Springer Nature}, title = {{Statistical mechanics for metabolic networks during steady state growth}}, doi = {10.1038/s41467-018-05417-9}, volume = {9}, year = {2018}, } @article{162, abstract = {Facial shape is the basis for facial recognition and categorization. Facial features reflect the underlying geometry of the skeletal structures. Here, we reveal that cartilaginous nasal capsule (corresponding to upper jaw and face) is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived Sonic Hedgehog (SHH) enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Unexpectedly, the cartilage of the nasal capsule turned out to be important for shaping membranous facial bones during development. This suggests that conserved neurosensory structures could benefit from protection and have evolved signals inducing cranial cartilages encasing them. Experiments with mutant mice revealed that the genomic regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts.}, author = {Kaucka, Marketa and Petersen, Julian and Tesarova, Marketa and Szarowska, Bara and Kastriti, Maria and Xie, Meng and Kicheva, Anna and Annusver, Karl and Kasper, Maria and Symmons, Orsolya and Pan, Leslie and Spitz, Francois and Kaiser, Jozef and Hovorakova, Maria and Zikmund, Tomas and Sunadome, Kazunori and Matise, Michael P and Wang, Hui and Marklund, Ulrika and Abdo, Hind and Ernfors, Patrik and Maire, Pascal and Wurmser, Maud and Chagin, Andrei S and Fried, Kaj and Adameyko, Igor}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage}}, doi = {10.7554/eLife.34465}, volume = {7}, year = {2018}, } @article{163, abstract = {For ultrafast fixation of biological samples to avoid artifacts, high-pressure freezing (HPF) followed by freeze substitution (FS) is preferred over chemical fixation at room temperature. After HPF, samples are maintained at low temperature during dehydration and fixation, while avoiding damaging recrystallization. This is a notoriously slow process. McDonald and Webb demonstrated, in 2011, that sample agitation during FS dramatically reduces the necessary time. Then, in 2015, we (H.G. and S.R.) introduced an agitation module into the cryochamber of an automated FS unit and demonstrated that the preparation of algae could be shortened from days to a couple of hours. We argued that variability in the processing, reproducibility, and safety issues are better addressed using automated FS units. For dissemination, we started low-cost manufacturing of agitation modules for two of the most widely used FS units, the Automatic Freeze Substitution Systems, AFS(1) and AFS2, from Leica Microsystems, using three dimensional (3D)-printing of the major components. To test them, several labs independently used the modules on a wide variety of specimens that had previously been processed by manual agitation, or without agitation. We demonstrate that automated processing with sample agitation saves time, increases flexibility with respect to sample requirements and protocols, and produces data of at least as good quality as other approaches.}, author = {Reipert, Siegfried and Goldammer, Helmuth and Richardson, Christine and Goldberg, Martin and Hawkins, Timothy and Hollergschwandtner, Elena and Kaufmann, Walter and Antreich, Sebastian and Stierhof, York}, issn = {0022-1554}, journal = {Journal of Histochemistry and Cytochemistry}, number = {12}, pages = {903--921}, publisher = {SAGE Publications}, title = {{Agitation modules: Flexible means to accelerate automated freeze substitution}}, doi = {10.1369/0022155418786698}, volume = {66}, year = {2018}, } @article{17, abstract = {Creeping flow of polymeric fluid without inertia exhibits elastic instabilities and elastic turbulence accompanied by drag enhancement due to elastic stress produced by flow-stretched polymers. However, in inertia-dominated flow at high Re and low fluid elasticity El, a reduction in turbulent frictional drag is caused by an intricate competition between inertial and elastic stresses. Here we explore the effect of inertia on the stability of viscoelastic flow in a broad range of control parameters El and (Re,Wi). We present the stability diagram of observed flow regimes in Wi-Re coordinates and find that the instabilities' onsets show an unexpectedly nonmonotonic dependence on El. Further, three distinct regions in the diagram are identified based on El. Strikingly, for high-elasticity fluids we discover a complete relaminarization of flow at Reynolds number in the range of 1 to 10, different from a well-known turbulent drag reduction. These counterintuitive effects may be explained by a finite polymer extensibility and a suppression of vorticity at high Wi. Our results call for further theoretical and numerical development to uncover the role of inertial effect on elastic turbulence in a viscoelastic flow.}, author = {Varshney, Atul and Steinberg, Victor}, journal = {Physical Review Fluids}, number = {10}, publisher = {American Physical Society}, title = {{Drag enhancement and drag reduction in viscoelastic flow}}, doi = {10.1103/PhysRevFluids.3.103302}, volume = {3}, year = {2018}, } @inproceedings{185, abstract = {We resolve in the affirmative conjectures of A. Skopenkov and Repovš (1998), and M. Skopenkov (2003) generalizing the classical Hanani-Tutte theorem to the setting of approximating maps of graphs on 2-dimensional surfaces by embeddings. Our proof of this result is constructive and almost immediately implies an efficient algorithm for testing whether a given piecewise linear map of a graph in a surface is approximable by an embedding. More precisely, an instance of this problem consists of (i) a graph G whose vertices are partitioned into clusters and whose inter-cluster edges are partitioned into bundles, and (ii) a region R of a 2-dimensional compact surface M given as the union of a set of pairwise disjoint discs corresponding to the clusters and a set of pairwise disjoint "pipes" corresponding to the bundles, connecting certain pairs of these discs. We are to decide whether G can be embedded inside M so that the vertices in every cluster are drawn in the corresponding disc, the edges in every bundle pass only through its corresponding pipe, and every edge crosses the boundary of each disc at most once.}, author = {Fulek, Radoslav and Kynčl, Jan}, isbn = {978-3-95977-066-8}, location = {Budapest, Hungary}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Hanani-Tutte for approximating maps of graphs}}, doi = {10.4230/LIPIcs.SoCG.2018.39}, volume = {99}, year = {2018}, } @inproceedings{186, abstract = {A drawing of a graph on a surface is independently even if every pair of nonadjacent edges in the drawing crosses an even number of times. The ℤ2-genus of a graph G is the minimum g such that G has an independently even drawing on the orientable surface of genus g. An unpublished result by Robertson and Seymour implies that for every t, every graph of sufficiently large genus contains as a minor a projective t × t grid or one of the following so-called t-Kuratowski graphs: K3, t, or t copies of K5 or K3,3 sharing at most 2 common vertices. We show that the ℤ2-genus of graphs in these families is unbounded in t; in fact, equal to their genus. Together, this implies that the genus of a graph is bounded from above by a function of its ℤ2-genus, solving a problem posed by Schaefer and Štefankovič, and giving an approximate version of the Hanani-Tutte theorem on orientable surfaces.}, author = {Fulek, Radoslav and Kynčl, Jan}, location = {Budapest, Hungary}, pages = {40.1 -- 40.14}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{The ℤ2-Genus of Kuratowski minors}}, doi = {10.4230/LIPIcs.SoCG.2018.40}, volume = {99}, year = {2018}, } @inproceedings{187, abstract = {Given a locally finite X ⊆ ℝd and a radius r ≥ 0, the k-fold cover of X and r consists of all points in ℝd that have k or more points of X within distance r. We consider two filtrations - one in scale obtained by fixing k and increasing r, and the other in depth obtained by fixing r and decreasing k - and we compute the persistence diagrams of both. While standard methods suffice for the filtration in scale, we need novel geometric and topological concepts for the filtration in depth. In particular, we introduce a rhomboid tiling in ℝd+1 whose horizontal integer slices are the order-k Delaunay mosaics of X, and construct a zigzag module from Delaunay mosaics that is isomorphic to the persistence module of the multi-covers. }, author = {Edelsbrunner, Herbert and Osang, Georg F}, location = {Budapest, Hungary}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{The multi-cover persistence of Euclidean balls}}, doi = {10.4230/LIPIcs.SoCG.2018.34}, volume = {99}, year = {2018}, } @inproceedings{188, abstract = {Smallest enclosing spheres of finite point sets are central to methods in topological data analysis. Focusing on Bregman divergences to measure dissimilarity, we prove bounds on the location of the center of a smallest enclosing sphere. These bounds depend on the range of radii for which Bregman balls are convex.}, author = {Edelsbrunner, Herbert and Virk, Ziga and Wagner, Hubert}, location = {Budapest, Hungary}, pages = {35:1 -- 35:13}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Smallest enclosing spheres and Chernoff points in Bregman geometry}}, doi = {10.4230/LIPIcs.SoCG.2018.35}, volume = {99}, year = {2018}, } @article{19, abstract = {Bacteria regulate genes to survive antibiotic stress, but regulation can be far from perfect. When regulation is not optimal, mutations that change gene expression can contribute to antibiotic resistance. It is not systematically understood to what extent natural gene regulation is or is not optimal for distinct antibiotics, and how changes in expression of specific genes quantitatively affect antibiotic resistance. Here we discover a simple quantitative relation between fitness, gene expression, and antibiotic potency, which rationalizes our observation that a multitude of genes and even innate antibiotic defense mechanisms have expression that is critically nonoptimal under antibiotic treatment. First, we developed a pooled-strain drug-diffusion assay and screened Escherichia coli overexpression and knockout libraries, finding that resistance to a range of 31 antibiotics could result from changing expression of a large and functionally diverse set of genes, in a primarily but not exclusively drug-specific manner. Second, by synthetically controlling the expression of single-drug and multidrug resistance genes, we observed that their fitness-expression functions changed dramatically under antibiotic treatment in accordance with a log-sensitivity relation. Thus, because many genes are nonoptimally expressed under antibiotic treatment, many regulatory mutations can contribute to resistance by altering expression and by activating latent defenses.}, author = {Palmer, Adam and Chait, Remy P and Kishony, Roy}, issn = {0737-4038}, journal = {Molecular Biology and Evolution}, number = {11}, pages = {2669 -- 2684}, publisher = {Oxford University Press}, title = {{Nonoptimal gene expression creates latent potential for antibiotic resistance}}, doi = {10.1093/molbev/msy163}, volume = {35}, year = {2018}, } @article{190, abstract = {The German cockroach, Blattella germanica, is a worldwide pest that infests buildings, including homes, restaurants, and hospitals, often living in unsanitary conditions. As a disease vector and producer of allergens, this species has major health and economic impacts on humans. Factors contributing to the success of the German cockroach include its resistance to a broad range of insecticides, immunity to many pathogens, and its ability, as an extreme generalist omnivore, to survive on most food sources. The recently published genome shows that B. germanica has an exceptionally high number of protein coding genes. In this study, we investigate the functions of the 93 significantly expanded gene families with the aim to better understand the success of B. germanica as a major pest despite such inhospitable conditions. We find major expansions in gene families with functions related to the detoxification of insecticides and allelochemicals, defense against pathogens, digestion, sensory perception, and gene regulation. These expansions might have allowed B. germanica to develop multiple resistance mechanisms to insecticides and pathogens, and enabled a broad, flexible diet, thus explaining its success in unsanitary conditions and under recurrent chemical control. The findings and resources presented here provide insights for better understanding molecular mechanisms that will facilitate more effective cockroach control.}, author = {Harrison, Mark and Arning, Nicolas and Kremer, Lucas and Ylla, Guillem and Belles, Xavier and Bornberg Bauer, Erich and Huylmans, Ann K and Jongepier, Evelien and Puilachs, Maria and Richards, Stephen and Schal, Coby}, journal = {Journal of Experimental Zoology Part B: Molecular and Developmental Evolution}, pages = {254--264}, publisher = {Wiley}, title = {{Expansions of key protein families in the German cockroach highlight the molecular basis of its remarkable success as a global indoor pest}}, doi = {10.1002/jez.b.22824}, volume = {330}, year = {2018}, } @article{192, abstract = {The phytohormone auxin is the information carrier in a plethora of developmental and physiological processes in plants(1). It has been firmly established that canonical, nuclear auxin signalling acts through regulation of gene transcription(2). Here, we combined microfluidics, live imaging, genetic engineering and computational modelling to reanalyse the classical case of root growth inhibition(3) by auxin. We show that Arabidopsis roots react to addition and removal of auxin by extremely rapid adaptation of growth rate. This process requires intracellular auxin perception but not transcriptional reprogramming. The formation of the canonical TIR1/AFB-Aux/IAA co-receptor complex is required for the growth regulation, hinting to a novel, non-transcriptional branch of this signalling pathway. Our results challenge the current understanding of root growth regulation by auxin and suggest another, presumably non-transcriptional, signalling output of the canonical auxin pathway.}, author = {Fendrych, Matyas and Akhmanova, Maria and Merrin, Jack and Glanc, Matous and Hagihara, Shinya and Takahashi, Koji and Uchida, Naoyuki and Torii, Keiko U and Friml, Jirí}, journal = {Nature Plants}, number = {7}, pages = {453 -- 459}, publisher = {Springer Nature}, title = {{Rapid and reversible root growth inhibition by TIR1 auxin signalling}}, doi = {10.1038/s41477-018-0190-1}, volume = {4}, year = {2018}, } @inproceedings{193, abstract = {We show attacks on five data-independent memory-hard functions (iMHF) that were submitted to the password hashing competition (PHC). Informally, an MHF is a function which cannot be evaluated on dedicated hardware, like ASICs, at significantly lower hardware and/or energy cost than evaluating a single instance on a standard single-core architecture. Data-independent means the memory access pattern of the function is independent of the input; this makes iMHFs harder to construct than data-dependent ones, but the latter can be attacked by various side-channel attacks. Following [Alwen-Blocki'16], we capture the evaluation of an iMHF as a directed acyclic graph (DAG). The cumulative parallel pebbling complexity of this DAG is a measure for the hardware cost of evaluating the iMHF on an ASIC. Ideally, one would like the complexity of a DAG underlying an iMHF to be as close to quadratic in the number of nodes of the graph as possible. Instead, we show that (the DAGs underlying) the following iMHFs are far from this bound: Rig.v2, TwoCats and Gambit each having an exponent no more than 1.75. Moreover, we show that the complexity of the iMHF modes of the PHC finalists Pomelo and Lyra2 have exponents at most 1.83 and 1.67 respectively. To show this we investigate a combinatorial property of each underlying DAG (called its depth-robustness. By establishing upper bounds on this property we are then able to apply the general technique of [Alwen-Block'16] for analyzing the hardware costs of an iMHF.}, author = {Alwen, Joel F and Gazi, Peter and Kamath Hosdurg, Chethan and Klein, Karen and Osang, Georg F and Pietrzak, Krzysztof Z and Reyzin, Lenoid and Rolinek, Michal and Rybar, Michal}, booktitle = {Proceedings of the 2018 on Asia Conference on Computer and Communication Security}, location = {Incheon, Republic of Korea}, pages = {51 -- 65}, publisher = {ACM}, title = {{On the memory hardness of data independent password hashing functions}}, doi = {10.1145/3196494.3196534}, year = {2018}, } @article{194, abstract = {Ants are emerging model systems to study cellular signaling because distinct castes possess different physiologic phenotypes within the same colony. Here we studied the functionality of inotocin signaling, an insect ortholog of mammalian oxytocin (OT), which was recently discovered in ants. In Lasius ants, we determined that specialization within the colony, seasonal factors, and physiologic conditions down-regulated the expression of the OT-like signaling system. Given this natural variation, we interrogated its function using RNAi knockdowns. Next-generation RNA sequencing of OT-like precursor knock-down ants highlighted its role in the regulation of genes involved in metabolism. Knock-down ants exhibited higher walking activity and increased self-grooming in the brood chamber. We propose that OT-like signaling in ants is important for regulating metabolic processes and locomotion.}, author = {Liutkeviciute, Zita and Gil Mansilla, Esther and Eder, Thomas and Casillas Perez, Barbara E and Giulia Di Giglio, Maria and Muratspahić, Edin and Grebien, Florian and Rattei, Thomas and Muttenthaler, Markus and Cremer, Sylvia and Gruber, Christian}, issn = {0892-6638}, journal = {The FASEB Journal}, number = {12}, pages = {6808--6821}, publisher = {FASEB}, title = {{Oxytocin-like signaling in ants influences metabolic gene expression and locomotor activity}}, doi = {10.1096/fj.201800443}, volume = {32}, year = {2018}, } @article{19494, abstract = {Starting from any given rational-sided, right triangle, for example, the (3,4,5)-triangle with area 6, we use Euclidean geometry to show that there are infinitely many other rational-sided, right triangles of the same area. We show further that the set of all such triangles of a given area is finitely generated under our geometric construction. Such areas are known as “congruent numbers” and have a rich history in which all the results in this article have been proved and far more. Yet, as far as we can tell, this seems to be the first exploration using this kind of geometric technique.}, author = {Chan, Yik Tung}, issn = {1930-0972}, journal = {The American Mathematical Monthly}, number = {8}, pages = {689--703}, publisher = {Taylor & Francis}, title = {{Rational right triangles of a given area}}, doi = {10.1080/00029890.2018.1495491}, volume = {125}, year = {2018}, } @article{195, abstract = {We demonstrate that identical impurities immersed in a two-dimensional many-particle bath can be viewed as flux-tube-charged-particle composites described by fractional statistics. In particular, we find that the bath manifests itself as an external magnetic flux tube with respect to the impurities, and hence the time-reversal symmetry is broken for the effective Hamiltonian describing the impurities. The emerging flux tube acts as a statistical gauge field after a certain critical coupling. This critical coupling corresponds to the intersection point between the quasiparticle state and the phonon wing, where the angular momentum is transferred from the impurity to the bath. This amounts to a novel configuration with emerging anyons. The proposed setup paves the way to realizing anyons using electrons interacting with superfluid helium or lattice phonons, as well as using atomic impurities in ultracold gases.}, author = {Yakaboylu, Enderalp and Lemeshko, Mikhail}, journal = {Physical Review B - Condensed Matter and Materials Physics}, number = {4}, publisher = {American Physical Society}, title = {{Anyonic statistics of quantum impurities in two dimensions}}, doi = {10.1103/PhysRevB.98.045402}, volume = {98}, year = {2018}, } @article{19544, abstract = {Medicinal bioinorganic chemistry is a thriving field of drug research for cancer treatment. Transition metal complexes coordinated to essential biological scaffolds represent a highly promising class of compounds for design of novel target-specific therapeutics. We report here the biological evaluation of a novel Isatin-Schiff base derivative and its Cu(II) complex in several tumor cell lines by assessing their effects on cellular metabolism, real-time cell proliferation and induction of apoptosis. Further, the impact of compounds on the p53 protein and expression of its target genes, including MDM2, p21/CDKN1A, and PUMA was evaluated. Results obtained in this study provide further evidence in support of our prior data suggesting the p53-mediated mechanism of action for Isatin-Schiff base derivatives and their complexes and also shed light on potential use of these compounds for stimulation of apoptosis in breast cancer cells via activation of the pro-apoptotic PUMA gene.}, author = {Bulatov, Emil and Sayarova, Regina and Mingaleeva, Rimma and Miftakhova, Regina and Gomzikova, Marina and Ignatev, Iurii and Petukhov, Alexey and Davidovich, Pavel and Rizvanov, Albert and Barlev, Nickolai A.}, issn = {2058-7716}, journal = {Cell Death Discovery}, publisher = {Springer Nature}, title = {{Isatin-Schiff base-copper (II) complex induces cell death in p53-positive tumors}}, doi = {10.1038/s41420-018-0120-z}, volume = {4}, year = {2018}, }