Hair cells in the inner ear of the pirouette and shaker 2 mutant mice

The shaker 2 ( sh2 ) and pirouette ( pi ) mouse mutants display severe inner ear dysfunction that involves both auditory and vestibular manifestation. Pathology of the stereocilia of hair cells has been found in both mutants. This study was designed to further our knowledge of the pathological characteristics of the inner ear sensory epithelia in both the sh2 and pi strains. Measurements of auditory brainstem responses indicated that both mutants were profoundly deaf. The morphological assays were specifically designed to characterize a pathological actin bundle that is found in both the inner hair cells and the vestibular hair cells in all five vestibular organs in these two mutants. Using light microscope analysis of phalloidin-stained specimens, these actin bundles could first be detected on postnatal day 3. As the cochleae matured, each inner hair cell and type I vestibular hair cell contained a bundle that spans from the region of the cuticular plate to the basal end of the cell, then extends along with cytoplasm and membrane, towards the basement membrane. Abnormal contact with the basement membrane was found in vestibular hair cells. Based on the shape of the cellular extension and the actin bundle that supports it, we propose to name these extensions “cytocauds.” The data suggest that the cytocauds in type I vestibular hair cells and inner hair cells are associated with a failure to differentiate and detach from the basement membrane.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47461/1/11068_2004_Article_278960.pd

South Ridgeline habitat study : Final report

177 pp. Bookmarks supplied by UO. Includes maps and figures. Published August, 2007. Captured January 23, 2008.This report contains documentation of a five-month inventory and assessment of over 2600 acres of upland habitats on public and private land in the South Ridgeline area of Eugene, Oregon. The South Ridgeline Habitat Study (SRHS) was undertaken to document the location, quantity, and quality of upland habitat, and suitability of habitat for uncommon and rare species in the area, and to do so in a way that meets the inventory standards contained in the administrative rules for Statewide Planning Goal 5.... This report contains: 1) background information about the study area, including ecological history; 2) methodology for inventory and assessment ratings; and 3) a summary of results. [From the Document

Domestic abuse: predicting, assessing and responding to risk in the Criminal Justice System and beyond

This chapter brings together early findings from three PhD projects on domestic abuse, each taking a different approach. The first explores the issues of underreporting and the predictors of risk; the second focuses on the police response to domestic abuse, highlighting gaps in service provision to victims; and the final project looks at specialist courts and the work of independent domestic violence advisors. This chapter cannot do justice to all three of the projects here; however, it is worth noting that, together, they form a body of research with the potential to make a significant contribution to the field. Indeed, the motivation for each of the projects is to add to current efforts to improve responses to domestic abuse within the criminal justice system and beyond. This chapter will focus on the ways in which practitioners might predict, assess, and respond to risk in relation to domestic abuse

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Contains fulltext : 158967.pdf (publisher's version ) (Open Access)Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine

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