Mice Hemizygous for a Pathogenic Mitofusin-2 Allele Exhibit Hind Limb/Foot Gait Deficits and Phenotypic Perturbations in Nerve and Muscle.

Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of hereditary sensory motor neuropathy, is caused by mutations of mitofusin-2 (MFN2). Mitofusin-2 is a GTPase required for fusion of mitochondrial outer membranes, repair of damaged mitochondria, efficient mitochondrial energetics, regulation of mitochondrial-endoplasmic reticulum calcium coupling and axonal transport of mitochondria. We knocked T105M MFN2 preceded by a loxP-flanked STOP sequence into the mouse Rosa26 locus to permit cell type-specific expression of this pathogenic allele. Crossing these mice with nestin-Cre transgenic mice elicited T105M MFN2 expression in neuroectoderm, and resulted in diminished numbers of mitochondria in peripheral nerve axons, an alteration in skeletal muscle fiber type distribution, and a gait abnormality

Non-specific filtering of beta-distributed data.

BackgroundNon-specific feature selection is a dimension reduction procedure performed prior to cluster analysis of high dimensional molecular data. Not all measured features are expected to show biological variation, so only the most varying are selected for analysis. In DNA methylation studies, DNA methylation is measured as a proportion, bounded between 0 and 1, with variance a function of the mean. Filtering on standard deviation biases the selection of probes to those with mean values near 0.5. We explore the effect this has on clustering, and develop alternate filter methods that utilize a variance stabilizing transformation for Beta distributed data and do not share this bias.ResultsWe compared results for 11 different non-specific filters on eight Infinium HumanMethylation data sets, selected to span a variety of biological conditions. We found that for data sets having a small fraction of samples showing abnormal methylation of a subset of normally unmethylated CpGs, a characteristic of the CpG island methylator phenotype in cancer, a novel filter statistic that utilized a variance-stabilizing transformation for Beta distributed data outperformed the common filter of using standard deviation of the DNA methylation proportion, or its log-transformed M-value, in its ability to detect the cancer subtype in a cluster analysis. However, the standard deviation filter always performed among the best for distinguishing subgroups of normal tissue. The novel filter and standard deviation filter tended to favour features in different genome contexts; for the same data set, the novel filter always selected more features from CpG island promoters and the standard deviation filter always selected more features from non-CpG island intergenic regions. Interestingly, despite selecting largely non-overlapping sets of features, the two filters did find sample subsets that overlapped for some real data sets.ConclusionsWe found two different filter statistics that tended to prioritize features with different characteristics, each performed well for identifying clusters of cancer and non-cancer tissue, and identifying a cancer CpG island hypermethylation phenotype. Since cluster analysis is for discovery, we would suggest trying both filters on any new data sets, evaluating the overlap of features selected and clusters discovered

Interplay between the Cancer Genome and Epigenome

Cancer arises as a consequence of cumulative disruptions to cellular growth control with Darwinian selection for those heritable changes that provide the greatest clonal advantage. These traits can be acquired and stably maintained by either genetic or epigenetic means. Here, we explore the ways in which alterations in the genome and epigenome influence each other and cooperate to promote oncogenic transformation. Disruption of epigenomic control is pervasive in malignancy and can be classified as an enabling characteristic of cancer cells, akin to genome instability and mutation

Vertex embeddings of regular polytopes

AbstractThe question of when one regular polytope (finite, convex) embedds in the vertices of another, of the same dimension, leads to a fascinating interplay of geometry, combinatorics, and matrix theory, with further relations to number theory and algebraic topology. This mainly expository paper is an account of this subject, its history, and the principal results together with an outline of their proofs. The relationships with other branches of mathematics are also explained

Glows Co Automated Chemical Etching Machine for Fiber Optic Cable

This report summarizes the conceptualization and development of an automated machine designed for a fiber optic cable stripping process used by Lumentum LLC. This process is currently manually operated by Lumentum’s technicians and involves unavoidable handling of corrosive chemicals. To increase technician safety, the process will be automated to reduce chemical - operator interactions. Improving safety conditions for technicians is the primary motivation for automating this process. Automation will also decrease process variation and increase product quality. GLOWS CO was tasked with creating this automated solution, leading to the design of the Automatic Chemical Etching Machine (or A-CHEM) for the fiber etching process for Lumentum LLC. At the conclusion of this project, the A-CHEM successfully fulfilled all of the requirements set out by Lumentum, namely improving technician safety and making the process more ergonomic

Not Alone: Tracing the Origins of Very Low Mass Stars and Brown Dwarfs Through Multiplicity Studies

The properties of multiple stellar systems have long provided important empirical constraints for star formation theories, enabling (along with several other lines of evidence) a concrete, qualitative picture of the birth and early evolution of normal stars. At very low masses (VLM; M <~ 0.1 M_sun), down to and below the hydrogen burning minimum mass, our understanding of formation processes is not as clear, with several competing theories now under consideration. One means of testing these theories is through the empirical characterization of VLM multiple systems. Here, we review the results of various VLM multiplicity studies to date. These systems can be generally characterized as closely separated (93% have projected separations Delta < 20 AU) and near equal-mass (77% have M_2/M_1 >= 0.8) occurring infrequently (perhaps 10-30%). Both the frequency and maximum separation of stellar and brown dwarf binaries steadily decrease for lower system masses, suggesting that VLM binary formation and/or evolution may be a mass-dependent process. There is evidence for a fairly rapid decline in the number of loosely-bound systems below ~0.3 M_sun, corresponding to a factor of 10-20 increase in the minimum binding energy of VLM binaries as compared to more massive stellar binaries. This wide-separation ``desert'' is present among both field (~1-5 Gyr) and older (> 100 Myr) cluster systems, while the youngest (<~10 Myr) VLM binaries, particularly those in nearby, low-density star forming regions, appear to have somewhat different systemic properties. We compare these empirical trends to predictions laid out by current formation theories, and outline future observational studies needed to probe the full parameter space of the lowest mass multiple systems.Comment: 16 pages, 7 figures, contributed chapter for Planets and Protostars V meeting (October 2005); full table of VLM binaries can be obtained at http://paperclip.as.arizona.edu/~nsiegler/VLM_binarie

Spatial aggregation error and agglomeration benefits from transport improvements

Aggregating data to other spatial resolutions can result in spatial aggregation errors, which can affect the data and subsequent analyses. This paper investigates the nature of spatial aggregation errors in the calculation of agglomeration benefits. The finding shows that inappropriate aggregation can result in significant errors in the monetised benefits used in transport appraisals. The error is analysed using both a stylised model and four case studies. Using arithmetic employment-weighted averages for transport costs when calculating the access to economic mass (ATEM) of the aggregated zones resulted in an error of +/-70%. An arithmetic trip-weighted average reduces errors. The error is further reduced using a harmonic employment-weighted average in the ATEM calculation, but it is not eliminated. The remaining error stems from the altered structure of the data stemming from the aggregation process, which is called the modifiable area unit problem (MAUP). Our findings, which concur with the broader MAUP literature, indicate that this error is unavoidable. Our policy recommendation is to calculate the agglomeration benefits as disaggregated as possible, but if aggregation is necessary, use the harmonic employment-weighted average for transport costs. Keywords: wider economic impacts, spatial aggregation, agglomeration benefits, transport appraisalpublishedVersio

Variations during ageing in the three-dimensional anatomical arrangement of fascicles within the equine superficial digital flexor tendon

Tendons are constructed from collagenous fascicles separated by endotenon/interfascicular matrix (IFM). Tendons may be specialised for precision movement or to store energy during locomotion and for the latter the elasticity of the endotenon/IFM is particularly important. The equine superficial digital flexor tendon (SDFT) is a dedicated energy-storing tendon with a similar function to the human Achilles tendon. Classical anatomical descriptions portray fascicles as longitudinally arranged distinct anatomical structures. In the present study, using three-dimensional reconstruction from whole tissue slices and histological sections, the fascicles of the equine SDFT were found to adopt a complex interweaved arrangement. Fascicles were found to fully and partially converge and diverge within the tendon and fascicle bundles were observed. Fascicle morphology was not homogenous with narrowing, broadening and twisted fascicles observed in addition to relatively straight fascicles. The number of fascicle bundles observed in cross-section increased from the proximal to the distal end of the tendon, whilst the number of fascicles decreased with age in the proximal region. Fascicular patterns were not similar between the left and right limbs, across different regions or at different ages. A decrease in thickness of the endotenon/IFM between fascicles with age was found in the distal tendon region. The results provide a rationale for considering fascicular organisation when diagnosing and treating tendon injuries, for bioengineering tendon and when modelling tendon function