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

Development of the Continuously Variable Volume Reactor for Flow Injection AnalysisDesign, Capabilities and Testing

A new apparatus for mixing sample and reagent in flow injection analysis is described. The continuously variable volume reactor (CVVR) replaces the conventional mixing coil in a flow injection manifold to provide mixing and dilution. A linear actuator motor allows control of the chamber volume via Lab VIEW software. The chamber volume can be incremented in steps of 1 uL over the range 68-1704 uL. In addition, the chamber has an integral variable-speed stirring unit that is also under computer control. Experiments were performed to evaluate the dispersion characteristics of this new device, evaluate the volume reproducibility, and understand the mixing characteristics. Use of the chamber is shown in the determination of iron (II) in pond water, and in NIST SRM 1643d with excellent results and a detection limit of 3.7 ug/L iron(II). Advantages of the CVVR and future research activities using the device are discussed

Earnings Management: The Effect of Ex Ante Earnings Expectations

Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Trends in the Management of Headache Disorders in US Emergency Departments: Analysis of 2007–2018 National Hospital Ambulatory Medical Care Survey Data

We examined trends in management of headache disorders in United States (US) emergency department (ED) visits. We conducted a cross-sectional study using 2007–2018 National Hospital Ambulatory Medical Care Survey data. We included adult patient visits (≥18 years) with a primary ED discharge diagnosis of headache. We classified headache medications by pharmacological group: opioids, butalbital, ergot alkaloids/triptans, acetaminophen/nonsteroidal anti-inflammatory drugs (NSAIDs), antiemetics, diphenhydramine, corticosteroids, and intravenous fluids. To obtain reliable estimates, we aggregated data into three time periods: 2007–2010, 2011–2014, and 2015–2018. Using multivariable logistic regression, we examined medication, neuroimaging, and outpatient referral trends, separately. Among headache-related ED visits, opioid use decreased from 54.1% in 2007–2010 to 28.3% in 2015–2018 (Ptrend < 0.001). There were statistically significant increasing trends in acetaminophen/NSAIDs, diphenhydramine, and corticosteroids use (all Ptrend < 0.001). Changes in butalbital (6.4%), ergot alkaloid/triptan (4.7%), antiemetic (59.2% in 2015–2018), and neuroimaging (37.3%) use over time were insignificant. Headache-related ED visits with outpatient referral for follow-up increased slightly from 73.3% in 2007–2010 to 79.7% in 2015–2018 (Ptrend = 0.02). Reflecting evidence-based guideline recommendations for headache management, opioid use substantially decreased from 2007 to 2018 among US headache-related ED visits. Future studies are warranted to identify strategies to promote evidence-based treatment for headaches (e.g., sumatriptan, dexamethasone) and appropriate outpatient referral and reduce unnecessary neuroimaging orders in EDs

Anticipated impact of the 2009 Four Corners raid and arrests

Archaeological looting on United States federal land has been illegal for over a century. Regardless, the activity has continued in the Four Corners region. This paper discusses how the 1979 Archaeological Resources Protection Act (ARPA) can be viewed as sumptuary law, and within a sumptuary context, subversion can be anticipated. An analysis of 1986 and June 2009 federal raids in the Four Corners will exemplify this point by identifying local discourses found in newspapers both before and after each raid, which demonstrate a sumptuary effect. Ultimately, this paper concludes that looting just adapted, rather than halted, after each federal raid and that understanding this social context of continued local justification and validation of illegal digging is a potential asset for cultural resource protection

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

Early Warning Signals of Social Transformation: A Case Study from the US Southwest

abstract: Recent research in ecology suggests that generic indicators, referred to as early warning signals (EWS), may occur before significant transformations, both critical and non-critical, in complex systems. Up to this point, research on EWS has largely focused on simple models and controlled experiments in ecology and climate science. When humans are considered in these arenas they are invariably seen as external sources of disturbance or management. In this article we explore ways to include societal components of socio-ecological systems directly in EWS analysis. Given the growing archaeological literature on ‘collapses,’ or transformations, in social systems, we investigate whether any early warning signals are apparent in the archaeological records of the build-up to two contemporaneous cases of social transformation in the prehistoric US Southwest, Mesa Verde and Zuni. The social transformations in these two cases differ in scope and severity, thus allowing us to explore the contexts under which warning signals may (or may not) emerge. In both cases our results show increasing variance in settlement size before the transformation, but increasing variance in social institutions only before the critical transformation in Mesa Verde. In the Zuni case, social institutions appear to have managed the process of significant social change. We conclude that variance is of broad relevance in anticipating social change, and the capacity of social institutions to mitigate transformation is critical to consider in EWS research on socio-ecological systems.The article is published at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.016368

Circadian regulation of hormone signaling and plant physiology

The survival and reproduction of plants depend on their ability to cope with a wide range of daily and seasonal environmental fluctuations during their life cycle. Phytohormones are plant growth regulators that are involved in almost every aspect of growth and development as well as plant adaptation to myriad abiotic and biotic conditions. The circadian clock, an endogenous and cell-autonomous biological timekeeper that produces rhythmic outputs with close to 24-h rhythms, provides an adaptive advantage by synchronizing plant physiological and metabolic processes to the external environment. The circadian clock regulates phytohormone biosynthesis and signaling pathways to generate daily rhythms in hormone activity that fine-tune a range of plant processes, enhancing adaptation to local conditions. This review explores our current understanding of the interplay between the circadian clock and hormone signaling pathways