A crust and upper mantle model of Eurasia and North Africa for Pn travel time calculation

We develop a Regional Seismic Travel Time (RSTT) model and methods to account for the first-order effect of the three-dimensional crust and upper mantle on travel times. The model parameterization is a global tessellation of nodes with a velocity profile at each node. Interpolation of the velocity profiles generates a 3-dimensional crust and laterally variable upper mantle velocity. The upper mantle velocity profile at each node is represented as a linear velocity gradient, which enables travel time computation in approximately 1 millisecond. This computational speed allows the model to be used in routine analyses in operational monitoring systems. We refine the model using a tomographic formulation that adjusts the average crustal velocity, mantle velocity at the Moho, and the mantle velocity gradient at each node. While the RSTT model is inherently global and our ultimate goal is to produce a model that provides accurate travel time predictions over the globe, our first RSTT tomography effort covers Eurasia and North Africa, where we have compiled a data set of approximately 600,000 Pn arrivals that provide path coverage over this vast area. Ten percent of the tomography data are randomly selected and set aside for testing purposes. Travel time residual variance for the validation data is reduced by 32%. Based on a geographically distributed set of validation events with epicenter accuracy of 5 km or better, epicenter error using 16 Pn arrivals is reduced by 46% from 17.3 km (ak135 model) to 9.3 km after tomography. Relative to the ak135 model, the median uncertainty ellipse area is reduced by 68% from 3070 km{sup 2} to 994 km{sup 2}, and the number of ellipses with area less than 1000 km{sup 2}, which is the area allowed for onsite inspection under the Comprehensive Nuclear Test Ban Treaty, is increased from 0% to 51%

Tomography and Methods of Travel-Time Calculation for Regional Seismic Location

We are developing a laterally variable velocity model of the crust and upper mantle across Eurasia and North Africa to reduce event location error by improving regional travel-time prediction accuracy. The model includes both P and S velocities and we describe methods to compute travel-times for Pn, Sn, Pg, and Lg phases. For crustal phases Pg and Lg we assume that the waves travel laterally at mid-crustal depths, with added ray segments from the event and station to the mid crustal layer. Our work on Pn and Sn travel-times extends the methods described by Zhao and Xie (1993). With consideration for a continent scale model and application to seismic location, we extend the model parameterization of Zhao and Xie (1993) by allowing the upper-mantle velocity gradient to vary laterally. This extension is needed to accommodate the large variation in gradient that is known to exist across Eurasia and North African. Further, we extend the linear travel-time calculation method to mantle-depth events, which is needed for seismic locators that test many epicenters and depths. Using these methods, regional travel times are computed on-the-fly from the velocity model in milliseconds, forming the basis of a flexible travel time facility that may be implemented in an interactive locator. We use a tomographic technique to improve upon a laterally variable starting velocity model that is based on Lawrence Livermore and Los Alamos National Laboratory model compilation efforts. Our tomographic data set consists of approximately 50 million regional arrivals from events that meet the ground truth (GT) criteria of Bondar et al. (2004) and other non-seismic constraints. Each datum is tested to meet strict quality control standards that include comparison with established distance-dependent travel-time residual populations relative to the IASPIE91 model. In addition to bulletin measurements, nearly 50 thousand arrival measurements were made at the national laboratories. The tomographic method adjusts Pn velocity, mantle gradient, and a node-specific crustal slowness correction for optimized travel-time prediction

The emergence of functional microcircuits in visual cortex.

Sensory processing occurs in neocortical microcircuits in which synaptic connectivity is highly structured and excitatory neurons form subnetworks that process related sensory information. However, the developmental mechanisms underlying the formation of functionally organized connectivity in cortical microcircuits remain unknown. Here we directly relate patterns of excitatory synaptic connectivity to visual response properties of neighbouring layer 2/3 pyramidal neurons in mouse visual cortex at different postnatal ages, using two-photon calcium imaging in vivo and multiple whole-cell recordings in vitro. Although neural responses were already highly selective for visual stimuli at eye opening, neurons responding to similar visual features were not yet preferentially connected, indicating that the emergence of feature selectivity does not depend on the precise arrangement of local synaptic connections. After eye opening, local connectivity reorganized extensively: more connections formed selectively between neurons with similar visual responses and connections were eliminated between visually unresponsive neurons, but the overall connectivity rate did not change. We propose a sequential model of cortical microcircuit development based on activity-dependent mechanisms of plasticity whereby neurons first acquire feature preference by selecting feedforward inputs before the onset of sensory experience--a process that may be facilitated by early electrical coupling between neuronal subsets--and then patterned input drives the formation of functional subnetworks through a redistribution of recurrent synaptic connections

Motor Unit Abnormalities in Dystonia musculorum Mice

Dystonia musculorum (dt) is a mouse inherited sensory neuropathy caused by mutations in the dystonin gene. While the primary pathology lies in the sensory neurons of dt mice, the overt movement disorder suggests motor neurons may also be affected. Here, we report on the contribution of motor neurons to the pathology in dt27J mice. Phenotypic dt27J mice display reduced alpha motor neuron cell number and eccentric alpha motor nuclei in the ventral horn of the lumbar L1 spinal cord region. A dramatic reduction in the total number of motor axons in the ventral root of postnatal day 15 dt27J mice was also evident. Moreover, analysis of the trigeminal nerve of the brainstem showed a 2.4 fold increase in number of degenerating neurons coupled with a decrease in motor neuron number relative to wild type. Aberrant phosphorylation of neurofilaments in the perikaryon region and axonal swellings within the pre-synaptic terminal region of motor neurons were observed. Furthermore, neuromuscular junction staining of dt27J mouse extensor digitorum longus and tibialis anterior muscle fibers showed immature endplates and a significant decrease in axon branching compared to wild type littermates. Muscle atrophy was also observed in dt27J muscle. Ultrastructure analysis revealed amyelinated motor axons in the ventral root of the spinal nerve, suggesting a possible defect in Schwann cells. Finally, behavioral analysis identified defective motor function in dt27J mice. This study reveals neuromuscular defects that likely contribute to the dt27J pathology and identifies a critical role for dystonin outside of sensory neurons

ASEAN's unchanged melody? The theory and practice of 'non-interference' in Southeast Asia

This is an Author's Accepted Manuscript of an article published as Jones, Lee. (2010). ASEAN's unchanged melody? The theory and practice of 'non-interference' in Southeast Asia. Pacific Review 23:4, 479-502 as published in PACIFIC REVIEW 2010 © Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/09512748.2010.49599

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

The impact of salamander predation on Collembola abundance

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Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome

© 2017 The Author(s).Background: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. Results: We sequenc

Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome

© 2017 The Author(s).Background: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. Results: We sequenc

Harmonizing the collection of clinical data on genetic testing requisition forms to enhance variant interpretation in hypertrophic cardiomyopathy (HCM): a study from the ClinGen Cardiomyopathy Variant Curation Expert Panel

Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal data set. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50-case pilot showed that although demographics and assertion of a clinical diagnosis of HCM had 86% to 98% completion, specific phenotypic features, such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease, were completed only 24% to 44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group, such as the ClinGen Program, to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care