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We report the frequency, positive rate, and type of mutations in 14 genes (PMP22, GJB1, MPZ, MFN2, SH3TC2, GDAP1, NEFL, LITAF, GARS, HSPB1, FIG4, EGR2, PRX, and RAB7A) associated with Charcot–Marie–Tooth disease (CMT) in a cohort of 17,880 individuals referred to a commercial genetic testing laboratory. Deidentified results from sequencing assays and multiplex ligation‐dependent probe amplification (MLPA) were analyzed including 100,102 Sanger sequencing, 2338 next‐generation sequencing (NGS), and 21,990 MLPA assays. Genetic abnormalities were identified in 18.5% (n = 3312) of all individuals. Testing by Sanger and MLPA (n = 3216) showed that duplications (dup) (56.7%) or deletions (del) (21.9%) in the PMP22 gene accounted for the majority of positive findings followed by mutations in the GJB1 (6.7%), MPZ (5.3%), and MFN2 (4.3%) genes. GJB1 del and mutations in the remaining genes explained 5.3% of the abnormalities. Pathogenic mutations were distributed as follows: missense (70.6%), nonsense (14.3%), frameshift (8.7%), splicing (3.3%), in‐frame deletions/insertions (1.8%), initiator methionine mutations (0.8%), and nonstop changes (0.5%). Mutation frequencies, positive rates, and the types of mutations were similar between tests performed by either Sanger (n = 17,377) or NGS (n = 503). Among patients with a positive genetic finding in a CMT‐related gene, 94.9% were positive in one of four genes (PMP22, GJB1, MPZ, or MFN2). In a testing cohort of 17,880 individuals, we report that duplications (dup) (56.7%) or deletions (del) (21.9%) in the PMP22 gene accounted for the majority of positive findings followed by mutations in the GJB1 (6.7%), MPZ (5.3%), and MFN2 (4.3%) genes.

Experimental evidence suggests the existence of a negative feedback pathway between horizontal cells and cone photoreceptors in the outer plexiform layer of the retina that modulates the flow of calcium ions into the synaptic terminals of cones. However, the underlying mechanism for this feedback is controversial and there are currently three competing hypotheses: the ephaptic hypothesis, the pH hypothesis, and the GABA hypothesis. The goal of this investigation is to demonstrate the ephaptic hypothesis by means of detailed numerical simulations. The drift-diffusion (Poisson-Nernst-Planck) model with membrane boundary current equations is applied to a realistic two-dimensional cross-section of the triad synapse in the goldfish retina to verify the existence of strictly electrical feedback, as predicted by the ephaptic hypothesis. The effect on electrical feedback from the behavior of the bipolar cell membrane potential is also explored. The computed steady-state cone calcium transmembrane current-voltage curves for several cases are presented and compared with experimental data on goldfish. The results provide convincing evidence that an ephaptic mechanism can produce the feedback effect seen in experiments. The model and numerical methods presented here can be applied to any neuronal circuit where dendritic spines are invaginated in presynaptic terminals or boutons.

The drift-diffusion (Poisson—Nernst—Planck) model—including a numerical model for cell membranes that resolves surface-charge boundary layers—is applied to the cone—horizontal cell synapse in the outer plexiform layer of the retina. Numerical simulations reproduce the experimental calcium current-voltage (IV) curves for the goldfish retina in response to a bright spot, with and without an illuminated background. The ephaptic (electrical) effect is demonstrated by computing the shift in the IV curve for background off versus background on for increasingly narrower openings between the sides of the cone and the horizontal cell.

Synopsis We discuss the implementation (https://commons.lbl.gov/display/csd/LBNL-AMO-MCTDHF) of Multiconfiguration Time-Dependent Hartree-Fock for polyatomic molecules using a Cartesian product grid of sinc basis functions, and present absorption cross sections and other results calculated with it.

Numerical simulations are performed using the WENO method of the SVS 13 micro-jet and bow shock bubble which reproduce the main features and dynamics of Keck Telescope/OSIRIS velocity-resolved integral field spectrograph data: an expanding cooler bow shock bubble, with the bubble center moving at approximately 50 km/s with a radial expansion velocity of 11 km/s, surrounding the fast hotter jet, which is propagating at 156 km/s. Contact and bow shock waves are visible in the simulations from both the initial short jet pulse which creates the nearly spherical bow shock bubble and from the fast micro-jet, while a terminal Mach disk shock is visible near the tip of the continuous micro-jet, which reduces the jet gas velocity down to the flow velocity of the contact discontinuity at the leading edge of the jet. At 21.1 yr after the launch of the initial bubble pulse, the jet has caught up with and penetrated almost all the way across the bow shock bubble of the slower initial pulse. At times later than about 22 yr, the jet has penetrated through the bubble and thereafter begins to subsume its spherical form. Emission maps from the simulations of the jet---traced by the emission of the shock excited 1.644 micron [Fe II] line---and bow shock bubble---traced in the lower excitation 2.122 micron H_2 1--0 S(1) line---projected onto the plane of the sky are presented, and are in good agreement with the Keck observations.

Recent Hubble Space Telescope (HST) observations of the extragalactic radio source Centaurus A (Cen A) display a young stellar population around the southwest tip of the inner filament 8.5 kpc from the Cen A galactic center, with ages in the range of 1-3 Myr. Crockett et al. (2012) argue that the transverse bow shock of the Cen A jet triggered this star formation as it impacted dense molecular cores of clouds in the filament. To test this hypothesis, we perform three-dimensional numerical simulations of induced star formation by the jet bow shock in the inner filament of Cen A, using a positivity preserving WENO method to solve the equations of gas dynamics with radiative cooling. We find that star clusters form inside a bow-shocked molecular cloud when the maximum initial density of the cloud is > 40 H2 molecules/cm^3. In a typical molecular cloud of mass 10^6 M_sun and diameter 200 pc, approximately 20 star clusters of mass 10^4 M_sun are formed, matching the HST images.

We outline a general procedure for simulating the surface brightness of astrophysical jets (and other astronomical objects) by post-processing gas dynamical simulations of densities and temperatures using spectral line emission data from the astrophysical spectral synthesis package {\\em Cloudy}. Then we validate the procedure by comparing the simulated surface brightness of the HH~30 astrophysical jet in the forbidden [O~I], [N~II], and [S~II] doublets with {\\em Hubble Space Telescope}\\/ observations of Hartigan and Morse and multiple-ion magnetohydrodynamic simulations of Tesileanu et al. The general trend of our simulated surface brightness in each doublet using the gas dynamical/{\\em Cloudy}\\/ approach is in excellent agreement with the observational data.

The method of McCurdy, Baertschy, and Rescigno, J. Phys. B, 37, R137 (2004) is generalized to obtain a straightforward, surprisingly accurate, and scalable numerical representation for calculating the electronic wave functions of molecules. It uses a basis set of product sinc functions arrayed on a Cartesian grid, and yields 1 kcal/mol precision for valence transition energies with a grid resolution of approximately 0.1 bohr. The Coulomb matrix elements are replaced with matrix elements obtained from the kinetic energy operator. A resolution-of-the-identity approximation renders the primitive one- and two-electron matrix elements diagonal; in other words, the Coulomb operator is local with respect to the grid indices. The calculation of contracted two-electron matrix elements among orbitals requires only O(N log(N)) multiplication operations, not O(N^4), where N is the number of basis functions; N = n^3 on cubic grids. The representation not only is numerically expedient, but also produces energies and properties superior to those calculated variationally. Absolute energies, absorption cross sections, transition energies, and ionization potentials are reported for one- (He^+, H_2^+ ), two- (H_2, He), ten- (CH_4) and 56-electron (C_8H_8) systems.

Dog breeds, old and new The development of the domestic dog is a fascinating example of a dramatic radiation in form and function that has occurred rapidly in association with the expansion of human civilization. An extensive genome-wide survey of over 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf, reveals striking patterns of genetic subdivision. Two clearly divergent clusters emerge, one of ancient breeds and the other of modern breeds created in the nineteenth century. An analysis of haplotype sharing suggests that the dog has a dominant Middle Eastern or European origin, consistent with recent archaeological finds, rather than one in East Asia as suggested previously by mitochondrial DNA data. An extensive genome-wide survey of over 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf, was conducted to shed light on the process of dog diversification. The results reveal that much of genome diversity came from Middle Eastern progenitors, combined with interbreeding with local wolf populations, and that recent evolution involved limited genetic variation to create the phenotypic diversity of modern dogs. Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication 1 , 2 . To understand the process of dog diversification better, we conducted an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf. Here we show that dog breeds share a higher proportion of multi-locus haplotypes unique to grey wolves from the Middle East, indicating that they are a dominant source of genetic diversity for dogs rather than wolves from east Asia, as suggested by mitochondrial DNA sequence data 3 . Furthermore, we find a surprising correspondence between genetic and phenotypic/functional breed groupings but there are exceptions that suggest phenotypic diversification depended in part on the repeated crossing of individuals with novel phenotypes. Our results show that Middle Eastern wolves were a critical source of genome diversity, although interbreeding with local wolf populations clearly occurred elsewhere in the early history of specific lineages. More recently, the evolution of modern dog breeds seems to have been an iterative process that drew on a limited genetic toolkit to create remarkable phenotypic diversity.

High genetic diversity of East Asian village dogs has recently been used to argue for an East Asian origin of the domestic dog. However, global village dog genetic diversity and the extent to which semiferal village dogs represent distinct, indigenous populations instead of admixtures of various dog breeds has not been quantified. Understanding these issues is critical to properly reconstructing the timing, number, and locations of dog domestication. To address these questions, we sampled 318 village dogs from 7 regions in Egypt, Uganda, and Namibia, measuring genetic diversity >680 bp of the mitochondrial D-loop, 300 SNPs, and 89 microsatellite markers. We also analyzed breed dogs, including putatively African breeds (Afghan hounds, Basenjis, Pharaoh hounds, Rhodesian ridgebacks, and Salukis), Puerto Rican street dogs, and mixed breed dogs from the United States. Village dogs from most African regions appear genetically distinct from non-native breed and mixed-breed dogs, although some individuals cluster genetically with Puerto Rican dogs or United States breed mixes instead of with neighboring village dogs. Thus, African village dogs are a mosaic of indigenous dogs descended from early migrants to Africa, and non-native, breed-admixed individuals. Among putatively African breeds, Pharaoh hounds, and Rhodesian ridgebacks clustered with non-native rather than indigenous African dogs, suggesting they have predominantly non-African origins. Surprisingly, we find similar mtDNA haplotype diversity in African and East Asian village dogs, potentially calling into question the hypothesis of an East Asian origin for dog domestication.