Development of the Continuously Variable Volume Reactor for Use in Flow Injection Analysis

Recognizing a need for an improved mixer/reactor, the continuously variable volume reactor (CVVR) was developed to address the need for remote unattended FIA manifold operation and the issue of manifold optimization. Development of the CVVR allows fully automated FIA analysis, and through its design allows the volume of the mixing coil to be changed dynamically as the sample bolus travels through the mixing coil to the detector. This is the first time this approach has been demonstrated in the literature

Autosomal Dominant Familial Dyskinesia and Facial Myokymia Single Exome Sequencing Identifies a Mutation in Adenylyl Cyclase 5

Background: Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a 5-generation family of German ancestry, we previously mapped FDFM to chromosome band 3p21-3q21. The 72.5-Mb linkage region was too large for traditional positional mutation identification. Objective: To identify the gene responsible for FDFM by exome resequencing of a single affected individual. Participants: We performed whole exome sequencing in 1 affected individual and used a series of bioinformatic filters, including functional significance and presence in dbSNP or the 1000 Genomes Project, to reduce the number of candidate variants. Co-segregation analysis was performed in 15 additional individuals in 3 generations. Main Outcome Measures: Unique DNA variants in the linkage region that co-segregate with FDFM. Results: The exome contained 23 428 single-nucleotide variants, of which 9391 were missense, nonsense, or splice site alterations. The critical region contained 323 variants, 5 of which were not present in 1 of the sequence databases. Adenylyl cyclase 5 (ADCY5) was the only gene in which the variant (c.2176G>A) was co-transmitted perfectly with disease status and was not present in 3510 control white exomes. This residue is highly conserved, and the change is nonconservative and predicted to be damaging. Conclusions: ADCY5 is highly expressed in striatum. Mice deficient in Adcy5 develop a movement disorder that is worsened by stress. We conclude that FDFM likely results from a missense mutation in ADCY5. This study demonstrates the power of a single exome sequence combined with linkage information to identify causative genes for rare autosomal dominant mendelian diseases

Further localization of a gene for paroxysmal dystonic choreoathetosis to a 5-cM region on chromosome 2q34

Paroxysmal dystonic choreoathetosis (PDC) is a rare neurological disorder characterized by episodes of involuntary movement, involving the extremities and face, which may occur spontaneously or be precipitated by caffeine, alcohol, anxiety, and fatigue. PDC is transmitted as an autosomal dominant trait with incomplete penetrance. A gene implicated in this paroxysmal disorder has been mapped to a 10–15 cM region on chromosome 2q31–36 in two families. We describe a third family with PDC. Two-point linkage analyses with markers linked to the candidate PDC locus were performed. A maximum two-point LOD score of 4.20 at a recombination fraction of zero was obtained for marker D2S120, confirming linkage to the distal portion of chromosome 2q. The anion exchanger gene, SLC2C, maps to this region, but the family was poorly informative for polymorphic markers within and flanking this candidate gene. Haplotype analysis revealed a critical recombination event that confines the PDC gene to a 5-cM region bounded by the markers D2S164 and D2S377. We compared the haplotype in our family with that in another chromosome 2-linked PDC family, but did not detect a region of shared genotypes. However, identifying a third family whose disease maps to the same region and narrowing the critical region will facilitate identification of the 2q-linked PDC gene.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42259/1/439-102-1-93_81020093.pd

The expressive role of performance measurement systems: a field study of a mental health development project

The management control systems (MCS) literature has long recognized the importance of values and beliefs (e.g., Ouchi, 1979; Simons, 1995). However, in this literature, values and beliefs are typically presented in the context of mission statements or company slogans that can play little substantive role in shaping actions and behaviours. In this paper we focus on how MCS can play a more active role in values expression, and examine the potential for performance measurement systems (PMS) to be used within organizations to express the values and beliefs of organizational members. This use of PMS, which we term its expressive role, is important as pluralistic and expressive forms of organizing are becoming more prevalent. Furthermore, prior research indicates that enabling the expression of values and beliefs by organizational members can generate energy and commitment that are important to the achievement of organizational objectives. In a field study of a mental health development project in a non-government organization, we examine the design and operational characteristics that are important for the expressive role of PMS. We also examine the interplay between the expressive role and the instrumental role of PMS and identify circumstances in which these roles can clash and/or be complementary

Proposals for a Practical System of Significance Evaluation in Archaeological Heritage Management

World Heritage & Archaeological Resource Managemen

Full Spectrum Archaeology

Full Spectrum Archaeology (FSA) is an aspiration stemming from the convergence of archaeology’s fundamental principles with international heritage policies and community preferences. FSA encompasses study and stewardship of the full range of heritage resources in accord with the full range of associated values and through the application of treatments selected from the full range of appropriate options. Late modern states, including British Columbia, Canada, nominally embrace de jure heritage policies consonant with international standards yet also resist de facto heritage management practice grounded in professional ethics and local values and preferences. In response, inheritor communities and their allies in archaeology are demonstrating the benefits of FSA and reclaiming control over cultural heritage. Archaeology and heritage management driven by altruistic articulation of communal, educational, scientific and other values further expose shortcomings and vulnerabilities of late modern states as well as public goods in and from FSA

Lipoprotein Lipase Links Dietary Fat to Solid Tumor Cell Proliferation

Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain pre-formed, diet-derived fatty acids by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further demonstrate that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or fatty acid uptake will be necessary to target the requirement of cancer cells for FA

Disease-Toxicant Interactions in Manganese Exposed Huntington Disease Mice: Early Changes in Striatal Neuron Morphology and Dopamine Metabolism

YAC128 Huntington's disease (HD) transgenic mice accumulate less manganese (Mn) in the striatum relative to wild-type (WT) littermates. We hypothesized that Mn and mutant Huntingtin (HTT) would exhibit gene-environment interactions at the level of neurochemistry and neuronal morphology. Twelve-week-old WT and YAC128 mice were exposed to MnCl2-4H2O (50 mg/kg) on days 0, 3 and 6. Striatal medium spiny neuron (MSN) morphology, as well as levels of dopamine (DA) and its metabolites (which are known to be sensitive to Mn-exposure), were analyzed at 13 weeks (7 days from initial exposure) and 16 weeks (28 days from initial exposure). No genotype-dependent differences in MSN morphology were apparent at 13 weeks. But at 16 weeks, a genotype effect was observed in YAC128 mice, manifested by an absence of the wild-type age-dependent increase in dendritic length and branching complexity. In addition, genotype-exposure interaction effects were observed for dendritic complexity measures as a function of distance from the soma, where only YAC128 mice were sensitive to Mn exposure. Furthermore, striatal DA levels were unaltered at 13 weeks by genotype or Mn exposure, but at 16 weeks, both Mn exposure and the HD genotype were associated with quantitatively similar reductions in DA and its metabolites. Interestingly, Mn exposure of YAC128 mice did not further decrease DA or its metabolites versus YAC128 vehicle exposed or Mn exposed WT mice. Taken together, these results demonstrate Mn-HD disease-toxicant interactions at the onset of striatal dendritic neuropathology in YAC128 mice. Our results identify the earliest pathological change in striatum of YAC128 mice as being between 13 to 16 weeks. Finally, we show that mutant HTT suppresses some Mn-dependent changes, such as decreased DA levels, while it exacerbates others, such as dendritic pathology