TY - JOUR AB - Mosaic Analysis with Double Markers (MADM) is a method for generating genetically mosaic mice, in which sibling mutant and wild-type cells are labeled with different fluorescent markers. It is a powerful tool that enables analysis of gene function at the single cell level in vivo. It requires transgenic cassettes to be located between the centromere and the mutation in the gene of interest on the same chromosome. Here we compare procedures for introduction of MADM cassettes into new loci in the mouse genome, and describe new approaches for expanding the utility of MADM. We show that: 1) Targeted homologous recombination outperforms random transgenesis in generation of reliably expressed MADM cassettes, 2) MADM cassettes in new genomic loci need to be validated for biallelic and ubiquitous expression, 3) Recombination between MADM cassettes on different chromosomes can be used to study reciprocal chromosomal deletions/duplications, and 4) MADM can be modified to permit transgene expression by combining it with a binary expression system. The advances described in this study expand current, and enable new and more versatile applications of MADM. AU - Tasic, Bosiljka AU - Miyamichi, Kazunari AU - Simon Hippenmeyer AU - Dani, Vardhan S. AU - Zeng, H. AU - Joo, William AU - Zong, Hui AU - Chen-Tsai, Yanru AU - Luo, Liqun ID - 2262 IS - 3 JF - PLoS One TI - Extensions of MADM (Mosaic Analysis with Double Markers) in Mice VL - 7 ER - TY - CONF AB - This paper presents an analytic formulation for anti-aliased sampling of 2D polygons and 3D polyhedra. Our framework allows the exact evaluation of the convolution integral with a linear function defined on the polytopes. The filter is a spherically symmetric polynomial of any order, supporting approximations to refined variants such as the Mitchell-Netravali filter family. This enables high-quality rasterization of triangles and tetrahedra with linearly interpolated vertex values to regular and non-regular grids. A closed form solution of the convolution is presented and an efficient implementation on the GPU using DirectX and CUDA C is described. AU - Thomas Auzinger AU - Guthe, Michael AU - Stefan Jeschke ID - 2268 IS - 121 TI - Analytic anti-aliasing of linear functions on polytopes VL - 31 ER - TY - JOUR AB - We introduce propagation models (PMs), a formalism able to express several kinds of equations that describe the behavior of biochemical reaction networks. Furthermore, we introduce the propagation abstract data type (PADT), which separates concerns regarding different numerical algorithms for the transient analysis of biochemical reaction networks from concerns regarding their implementation, thus allowing for portable and efficient solutions. The state of a propagation abstract data type is given by a vector that assigns mass values to a set of nodes, and its (next) operator propagates mass values through this set of nodes. We propose an approximate implementation of the (next) operator, based on threshold abstraction, which propagates only "significant" mass values and thus achieves a compromise between efficiency and accuracy. Finally, we give three use cases for propagation models: the chemical master equation (CME), the reaction rate equation (RRE), and a hybrid method that combines these two equations. These three applications use propagation models in order to propagate probabilities and/or expected values and variances of the model's variables. AU - Henzinger, Thomas A AU - Mateescu, Maria ID - 2302 IS - 2 JF - IEEE ACM Transactions on Computational Biology and Bioinformatics TI - The propagation approach for computing biochemical reaction networks VL - 10 ER - TY - JOUR AB - The translation of "next-generation" sequencing directly to the clinic is still being assessed but has the potential for genetic diseases to reduce costs, advance accuracy, and point to unsuspected yet treatable conditions. To study its capability in the clinic, we performed whole-exome sequencing in 118 probands with a diagnosis of a pediatric-onset neurodevelopmental disease in which most known causes had been excluded. Twenty-two genes not previously identified as disease-causing were identified in this study (19% of cohort), further establishing exome sequencing as a useful tool for gene discovery. New genes identified included EXOC8 in Joubert syndrome and GFM2 in a patient with microcephaly, simplified gyral pattern, and insulin-dependent diabetes. Exome sequencing uncovered 10 probands (8% of cohort) with mutations in genes known to cause a disease different from the initial diagnosis. Upon further medical evaluation, these mutations were found to account for each proband's disease, leading to a change in diagnosis, some of which led to changes in patient management. Our data provide proof of principle that genomic strategies are useful in clarifying diagnosis in a proportion of patients with neurodevelopmental disorders. AU - Dixon-Salazar, Tracy J AU - Silhavy, Jennifer L AU - Udpa, Nitin AU - Schroth, Jana AU - Bielas, Stephanie L AU - Schaffer, Ashleigh E AU - Olvera, Jesus AU - Bafna, Vineet K AU - Zaki, Maha S AU - Abdel-Salam, Ghada M AU - Mansour, Lobna A AU - Selim, Laila A AU - Abdel-Hadi, Sawsan S AU - Marzouki, Naima AU - Ben-Omran, Tawfeg I AU - Al-Saana, Nouriya A AU - Sönmez, Fatma M AU - Celep, Figen AU - Azam, Matloob AU - Hill, Kiley J AU - Collazo, Adrienne AU - Fenstermaker, Ali G AU - Gaia Novarino AU - Akizu, Naiara AU - Garimella, Kiran V AU - Sougnez, Carrie L AU - Russ, Carsten AU - Gabriel, Stacey B AU - Gleeson, Joseph G ID - 2313 IS - 138 JF - Science Translational Medicine TI - Exome sequencing can improve diagnosis and alter patient management VL - 4 ER - TY - JOUR AB - Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome. AU - Gaia Novarino AU - El-Fishawy, Paul AU - Kayserili, Hülya AU - Meguid, Nagwa A AU - Scott, Eric M AU - Schroth, Jana AU - Silhavy, Jennifer L AU - Kara, Majdi AU - Khalil, Rehab O AU - Ben-Omran, Tawfeg I AU - Ercan-Sencicek, Adife G AU - Hashish, Adel F AU - Sanders, Stephan J AU - Gupta, Abha R AU - Hashem, Hebatalla S AU - Matern, Dietrich AU - Gabriel, Stacey B AU - Sweetman, Lawrence AU - Rahimi, Yasmeen AU - Harris, Robert A AU - State, Matthew W AU - Gleeson, Joseph G ID - 2314 IS - 6105 JF - Science TI - Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy VL - 338 ER - TY - JOUR AB - We show that bosons interacting via pair potentials with negative scattering length form bound states for a suitable number of particles. In other words, the absence of many-particle bound states of any kind implies the non-negativity of the scattering length of the interaction potential. AU - Seiringer, Robert ID - 2318 IS - 3 JF - Journal of Spectral Theory TI - Absence of bound states implies non-negativity of the scattering length VL - 2 ER - TY - CONF AB - We present a summary of our recent rigorous derivation of the celebrated Ginzburg-Landau (GL) theory, starting from the microscopic Bardeen-Cooper-Schrieffer (BCS) model. Close to the critical temperature, GL arises as an effective theory on the macroscopic scale. The relevant scaling limit is semiclassical in nature, and semiclassical analysis, with minimal regularity assumptions, plays an important part in our proof. AU - Frank, Rupert L AU - Hainzl, Christian AU - Robert Seiringer AU - Solovej, Jan P ID - 2317 TI - Microscopic derivation of the Ginzburg-Landau model ER - TY - CONF AB - We summarize our recent results on the ground state energy of multi-polaron systems. In particular, we discuss stability and existence of the thermodynamic limit, and we discuss the absence of binding in the case of large Coulomb repulsion and the corresponding binding-unbinding transition. We also consider the Pekar-Tomasevich approximation to the ground state energy and we study radial symmetry of the ground state density. AU - Frank, Rupert L AU - Lieb, Élliott H AU - Robert Seiringer AU - Thomas, Lawrence E ID - 2316 TI - Ground state properties of multi-polaron systems ER - TY - JOUR AB - The Manin conjecture is established for Châtelet surfaces over Q aris-ing as minimal proper smooth models of the surface Y 2 + Z 2 = f(X) in A 3 Q, where f ∈ Z[X] is a totally reducible polynomial of degree 3 without repeated roots. These surfaces do not satisfy weak approximation. AU - de la Bretèche, Régis AU - Timothy Browning AU - Peyre, Emmanuel ID - 237 IS - 1 JF - Annals of Mathematics TI - On Manin's conjecture for a family of Châtelet surfaces VL - 175 ER - TY - JOUR AB - For given positive integers a, b, q we investigate the density of solutions (x, y) ∈ Z2 to congruences ax + by2 ≡ 0 mod q. AU - Baier, Stephan AU - Timothy Browning ID - 238 IS - 2 JF - Functiones et Approximatio, Commentarii Mathematici TI - Inhomogeneous quadratic congruences VL - 47 ER -