A Silicon-Bridged Bis(substituted Cp) Yttrium Complex

rac-Bis(tetrahydrofuran)lithium [bis(2-trimethylsilyl-4-tert-butyl-η^5-cyclopentadienyl)dimethylsilane] dichloroyttrate, [Li(C_4H_80)_2][Y(C_(26)H_(48)-Si_3)Cl_2], M_r= 755.87, triclinic, Pl, ɑ = 13.110 (8), b = 17.163 (15), c = 20.623 (14) Å, ɑ= 104.02 (7), β = 99.38 (5), y = 100.24 (6)º, V = 4326 (6) Å^3, z = 4, D_x = 1.16 g cm^(-3), λ(Mo Kɑ)= 0.71073 Å, μ = 15.86 cm^(-1), F(000) = 1608, room temperature, R = 0.056 for 6136 reflections with F_o^2 > 3σ(F_o^2). There are two virtually identical molecules in the asymmetric unit. In each, the Y atom is tetrahedrally coordinated to a substituted Si-bridged bis(cyclopentadienyl) ligand and to two Cl ions in the cleft. The Li atom is 2.35 Å from each Cl ion, and two molecules of tetrahydrofuran are connected to the Li, completing its tetrahedral coordination

Impact of acamprosate on plasma amyloid-β precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker

BACKGROUND: Understanding of the pathophysiology of autism spectrum disorder (ASD) remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-β precursor protein (APP), secreted APPα (sAPPα), has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPPα holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and deficient GABAergic neurotransmission in the disorder. With this in mind, acamprosate, a novel modulator of glutamate and GABA function, has been studied in ASD. No data is available on the impact of glutamate or GABA modulation on sAPPα function. METHODS: Plasma APP derivative levels pre- and post-treatment with acamprosate were determined in two pilot studies involving youth with idiopathic and fragile X syndrome (FXS)-associated ASD. We additionally compared baseline APP derivative levels between youth with FXS-associated or idiopathic ASD. RESULTS: Acamprosate use was associated with a significant reduction in plasma sAPP(total) and sAPPα levels but no change occurred in Aβ40 or Aβ42 levels in 15 youth with ASD (mean age: 11.1 years). Youth with FXS-associated ASD (n = 12) showed increased sAPPα processing compared to age-, gender- and IQ-match youth with idiopathic ASD (n = 11). CONCLUSIONS: Plasma APP derivative analysis holds promise as a potential biomarker for use in ASD targeted treatment. Reduction in sAPP (total) and sAPPα may be a novel pharmacodynamic property of acamprosate. Future study is required to address limitations of the current study to determine if baseline APP derivative analysis may predict subgroups of persons with idiopathic or FXS-associated ASD who may respond best to acamprosate or to potentially other modulators of glutamate and/or GABA neurotransmission

A Silicon-Bridged Bis(substituted Cp) Yttrium Complex

rac-Bis(tetrahydrofuran)lithium [bis(2-trimethylsilyl-4-tert-butyl-η^5-cyclopentadienyl)dimethylsilane] dichloroyttrate, [Li(C_4H_80)_2][Y(C_(26)H_(48)-Si_3)Cl_2], M_r= 755.87, triclinic, Pl, ɑ = 13.110 (8), b = 17.163 (15), c = 20.623 (14) Å, ɑ= 104.02 (7), β = 99.38 (5), y = 100.24 (6)º, V = 4326 (6) Å^3, z = 4, D_x = 1.16 g cm^(-3), λ(Mo Kɑ)= 0.71073 Å, μ = 15.86 cm^(-1), F(000) = 1608, room temperature, R = 0.056 for 6136 reflections with F_o^2 > 3σ(F_o^2). There are two virtually identical molecules in the asymmetric unit. In each, the Y atom is tetrahedrally coordinated to a substituted Si-bridged bis(cyclopentadienyl) ligand and to two Cl ions in the cleft. The Li atom is 2.35 Å from each Cl ion, and two molecules of tetrahydrofuran are connected to the Li, completing its tetrahedral coordination

Metagenomic analysis of DNA viruses with targeted sequence capture of canine lobular orbital adenomas and normal conjunctiva

Our study aims are: (1) to evaluate phenotypically normal canine conjunctival and orbital tissue and tissue from canine lobular orbital adenomas (CLOAs) for the presence of viral genomic material and (2) phylogenetically classify detected DNA viruses to determine if a DNA virus is associated with CLOAs. A total of 31 formalin fixed paraffin embedded CLOA tissue samples, 4 papillomas or sarcoid, and 10 fresh clinically normal conjunctival tissues were included in this study. Genomic DNA was isolated from all samples and sequencing libraries were prepared. The libraries were molecularly indexed and pooled and viral DNA was enriched via targeted sequence capture utilizing ViroCap. The libraries were sequenced on the Illumina HiSeq platform and compared to known viral DNA reference genomes to identify viral DNA. Carnivore parvovirus was identified in 6.4% and 20% of CLOA tissue and normal conjunctival samples, respectively. This study showed that conjunctival tissue from healthy dogs and CLOAs uncommonly harbor DNA viruses, and no DNA virus was associated with these tumors. Further studies are needed to evaluate the etiologic cause of CLOAs

Papillomavirus DNA not detected in canine lobular orbital adenoma and normal conjunctival tissue

Background: Canine lobular orbital adenomas are benign tumors that arise from orbital glandular tissue and extend into the orbit, conjunctiva, and third eyelid. Surgical excision is challenging and recurrence rates are high following excision alone. Enucleation and exenteration reduces the likelihood of recurrence, but is a radical therapeutic option for an otherwise visual and comfortable eye. Human papillomavirus causes 4.5 percent of worldwide cancers in people and has been identified in up to 23 percent of benign salivary gland tumors. To date, the etiology of canine lobular orbital adenomas has not been established and it is reasonable to consider canine papillomaviruses as an associative agent with benign glandular tumors in dogs. Identification of the underlying etiology of these tumors may help establish treatment or preventative measures. The purpose of this study was to evaluate conjunctival and orbital tissue of phenotypically normal dogs and tissue from canine lobular orbital adenomas for the presence of papillomavirus DNA. Results: Thirty seven canine lobular orbital adenoma samples (36 formalin fixed paraffin embedded (FFPE) tissue samples from 33 dogs and one freshly collected sample) were evaluated via polymerase chain reaction for the presence of papillomavirus DNA. Conjunctival tissue samples, from 10 dogs with normal ocular examinations, excised immediately following euthanasia, were used as phenotypically normal controls. Three FFPE and one freshly collected tissue samples previously confirmed to be positive for papillomavirus DNA were used as positive controls. PCR products verified positive controls. Papillomavirus DNA was not detected in fresh conjunctival tissue of the phenotypically normal control dogs or in samples of fresh or FFPE canine lobular orbital adenoma tissue. Conclusions: An association between papillomavirus and the development of canine lobular orbital adenomas is unlikely. Further research is needed to evaluate if other viruses play a role in the pathogenesis of canine lobular orbital adenomas

Improving the Effectiveness of Health Care Innovation Implementation: Middle Managers as Change Agents

The rate of successful health care innovation implementation is dismal. Middle managers have a potentially important yet poorly understood role in health care innovation implementation. This study used self-administered surveys and interviews of middle managers in health centers that implemented an innovation to reduce health disparities to address the questions: Does middle managers’ commitment to health care innovation implementation influence implementation effectiveness? If so, in what ways does their commitment influence implementation effectiveness? Although quantitative survey data analysis results suggest a weak relationship, qualitative interview data analysis results indicate that middle managers’ commitment influences implementation effectiveness when middle managers are proactive. Scholars should account for middle managers’ influence in implementation research, and health care executives may promote implementation effectiveness by hiring proactive middle managers and creating climates in which proactivity is rewarded, supported, and expected

Disturbed neuronal ER-Golgi sorting of unassembled glycine receptors suggests altered subcellular processing is a cause of human hyperekplexia.

Recent studies on the pathogenic mechanisms of recessive hyperekplexia indicate disturbances in glycine receptor (GlyR) α1 biogenesis. Here, we examine the properties of a range of novel glycine receptor mutants identified in human hyperekplexia patients using expression in transfected cell lines and primary neurons. All of the novel mutants localized in the large extracellular domain of the GlyR α1 have reduced cell surface expression with a high proportion of receptors being retained in the ER, although there is forward trafficking of glycosylated subpopulations into the ER-Golgi intermediate compartment and cis-Golgi compartment. CD spectroscopy revealed that the mutant receptors have proportions of secondary structural elements similar to wild-type receptors. Two mutants in loop B (G160R, T162M) were functional, but none of those in loop D/β2-3 were. One nonfunctional truncated mutant (R316X) could be rescued by coexpression with the lacking C-terminal domain. We conclude that a proportion of GlyR α1 mutants can be transported to the plasma membrane but do not necessarily form functional ion channels. We suggest that loop D/β2-3 is an important determinant for GlyR trafficking and functionality, whereas alterations to loop B alter agonist potencies, indicating that residues here are critical elements in ligand binding.This work was supported by the Deutsche Forschungsgemeinschaft (Grant DFG VI586 to C.V.) and the European Union (FP7 project Neurocypres to C.J.K., K.L.P., and S.C.R.L.). N. Schaefer and G.L. are supported by the GSLS Wuerzburg. S.C.R.L. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Research.This is the author accepted manuscript. The final version is available from the Society of Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.1509-14.201

From strategy to action: How top managers’ support increases middle managers’ commitment to innovation implementation in health care organizations

Evidence suggests that top managers’ support influences middle managers’ commitment to innovation implementation. What remains unclear is how top managers’ support influences middle managers’ commitment. Results may be used to improve dismal rates of innovation implementation

Development of Type 1 Diabetes in Wild Bank Voles Associated With Islet Autoantibodies and the Novel Ljungan Virus

Wild bank voles (Clethrionomys glareolus) may develop diabetes in laboratory captivity. The aim of this study was to test whether bank voles develop type 1 diabetes in association with Ljungan virus. Two groups of bank voles were analyzed for diabetes, pancreas histology, autoantibodies to glutamic acid decarboxylase (GAD65), IA-2, and insulin by standardized radioligand-binding assays as well as antibodies to in vitro transcribed and translated Ljungan virus antigens. Group A represented 101 trapped bank voles, which were screened for diabetes when euthanized within 24 hours of capture. Group B represented 67 bank voles, which were trapped and kept in the laboratory for 1 month before being euthanized. Group A bank voles did not have diabetes. Bank voles in group B (22/67; 33%) developed diabetes due to specific lysis of pancreatic islet beta cells. Compared to nondiabetic group B bank voles, diabetic animals had increased levels of GAD65 (P < .0001), IA-2 (P < .0001), and insulin (P = .03) autoantibodies. Affected islets stained positive for Ljungan virus, a novel picorna virus isolated from bank voles. Ljungan virus inoculation of nondiabetic wild bank voles induced beta-cell lysis. Compared to group A bank voles, Ljungan virus antibodies were increased in both nondiabetic (P < .0001) and diabetic (P = .0015) group B bank voles. Levels of Ljungan virus antibodies were also increased in young age at onset of newly diagnosed type 1 diabetes in children (P < .01). These findings support the hypothesis that the development of type 1 diabetes in captured wild bank voles is associated with Ljungan virus. It is speculated that bank voles may have a possible zoonotic role as a reservoir and vector for virus that may contribute to the incidence of type 1 diabetes in humans