86 research outputs found

    Preface

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    Oregon Natural Resources Council v. Thomas; Another Meritorious Timber Lawsuit Fails: Do Substantive Riders Warrant an Exception to the Plain Language Rule?

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    This note provides a brief background to the Rescissions Act, outlines the Act\u27s provisions and examines the Ninth Circuit Court\u27s decisions interpreting these provisions prior to Oregon Natural Resources Council v. Thomas. Section III sets forth the facts and procedural history of ONRC II, the most recent meritorious lawsuit to fall victim to the provisions of the Rescissions Act. Section IV examines the Ninth Circuit Court\u27s analysis and holding in ONRC II. Section V argues that although the Ninth Circuit\u27s decision in ONRC II was correct under current standards, the result was fundamentally wrong. Section V also examines the rules prohibiting the attachment of substantive riders to appropriations bills, the effect of such riders on public participation, and the multiple misrepresentations made by sponsors in the course of soliciting support for the salvage rider. Finally, section V proposes a new standard to be applied by the courts when interpreting the provisions of a substantive rider attached to an appropriations bill in violation of House and Senate rules. Section VI concludes that the congressional rules prohibiting the attachment of riders to appropriations bills should not be waivable. Alternatively, if those rules are waived, the courts must look beyond the plain language of the subsequently enacted statute when interpreting its provisions. Section VII then briefly summarizes three additional cases decided by the Ninth Circuit subsequent to ONRC II

    The First Developments of Bellingham Washington: Understanding the Plat Maps of Bellingham Washington in the Late 1800s Following the Oregon Land Law of 1850

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    This paper explores the impact of the Donation Land Claim Act of 1850 on the development of Bellingham, Washington, focusing on the transformation of land use and platting over time. The Act provided 320 acres to married white settlers and 160 acres to single white males. This was one of the most important federal acts in settling what would become Washington State. This research focuses on using historical plat maps to identify which Donation Land Claim recipients developed their land into Bellingham, Washington. Using historical documents, maps, and plats, the research traces the land\u27s transition from large rural plots to urban subdivisions. Key findings include the significant influence of original grantee families such as the Eldridges, Roeders, and Peabodys, who played pivotal roles in early Bellingham’s development. The paper also discusses how many of the original families had little effect on this part of the development and left the area before it began its development. The research mapped historical land claims against modern Bellingham, showing how original allocations were subdivided and developed over time. Much of this platting still exists today and this paper explores how decisions made over 140 years ago still affect Bellingham’s physical shape

    AAV9-mediated central nervous system-targeted gene delivery via cisterna magna route in mice

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    Current barriers to the use of adeno-associated virus serotype 9 (AAV9) in clinical trials for treating neurological disorders are its high expression in many off-target tissues such as liver and heart, and lack of cell specificity within the central nervous system (CNS) when using ubiquitous promoters such as human cytomegalovirus (CMV) or chicken-β-actin hybrid (CAG). To enhance targeting the transgene expression in CNS cells, self-complementary (sc) AAV9 vectors, scAAV9-GFP vectors carrying neuronal Hb9 and synapsin 1, and nonspecific CMV and CAG promoters were constructed. We demonstrate that synapsin 1 and Hb9 promoters exclusively targeted neurons in vitro, although their strengths were up to 10-fold lower than that of CMV. In vivo analyses of mouse tissue after scAAV9-GFP vector delivery via the cisterna magna revealed a significant advantage of synapsin 1 promoter over both Hb9 variants in targeting neurons throughout the brain, since Hb9 promoters were driving gene expression mainly within the motor-related areas of the brain stem. In summary, this study demonstrates that cisterna magna administration is a safe alternative to intracranial or intracerebroventricular vector delivery route using scAAV9, and introduces a novel utility of the Hb9 promoter for the targeted gene expression for both in vivo and in vitro applications

    Fiber optic Raman spectroscopy for the evaluation of disease state in Duchenne muscular dystrophy:An assessment using the mdx model and human muscle

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    INTRODUCTION/AIMS: Raman spectroscopy is an emerging technique for the evaluation of muscle disease. In this study we evaluate the ability of in vivo intramuscular Raman spectroscopy to detect the effects of voluntary running in the mdx model of Duchenne muscular dystrophy (DMD). We also compare mdx data with muscle spectra from human DMD patients. METHODS: Thirty 90‐day‐old mdx mice were randomly allocated to an exercised group (48‐hour access to a running wheel) and an unexercised group (n = 15 per group). In vivo Raman spectra were collected from both gastrocnemius muscles and histopathological assessment subsequently performed. Raman data were analyzed using principal component analysis–fed linear discriminant analysis (PCA‐LDA). Exercised and unexercised mdx muscle spectra were compared with human DMD samples using cosine similarity. RESULTS: Exercised mice ran an average of 6.5 km over 48 hours, which induced a significant increase in muscle necrosis (P = .03). PCA‐LDA scores were significantly different between the exercised and unexercised groups (P < .0001) and correlated significantly with distance run (P = .01). Raman spectra from exercised mice more closely resembled human spectra than those from unexercised mice. DISCUSSION: Raman spectroscopy provides a readout of the biochemical alterations in muscle in both the mdx mouse and human DMD muscle

    Ap4b1-knockout mouse model of hereditary spastic paraplegia type 47 displays motor dysfunction, aberrant brain morphology and ATG9A mislocalization

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    Mutations in any one of the four subunits (ɛ4, β4, μ4 and σ4) comprising the adaptor protein Complex 4 results in a complex form of hereditary spastic paraplegia, often termed adaptor protein Complex 4 deficiency syndrome. Deficits in adaptor protein Complex 4 complex function have been shown to disrupt intracellular trafficking, resulting in a broad phenotypic spectrum encompassing severe intellectual disability and progressive spastic paraplegia of the lower limbs in patients. Here we report the presence of neuropathological hallmarks of adaptor protein Complex 4 deficiency syndrome in a clustered regularly interspaced short palindromic repeats-mediated Ap4b1-knockout mouse model. Mice lacking the β4 subunit, and therefore lacking functional adaptor protein Complex 4, have a thin corpus callosum, enlarged lateral ventricles, motor co-ordination deficits, hyperactivity, a hindlimb clasping phenotype associated with neurodegeneration, and an abnormal gait. Analysis of autophagy-related protein 9A (a known cargo of the adaptor protein Complex 4 in these mice shows both upregulation of autophagy-related protein 9A protein levels across multiple tissues, as well as a striking mislocalization of autophagy-related protein 9A from a generalized cytoplasmic distribution to a marked accumulation in the trans-Golgi network within cells. This mislocalization is present in mature animals but is also in E15.5 embryonic cortical neurons. Histological examination of brain regions also shows an accumulation of calbindin-positive spheroid aggregates in the deep cerebellar nuclei of adaptor protein Complex 4-deficient mice, at the site of Purkinje cell axonal projections. Taken together, these findings show a definitive link between loss-of-function mutations in murine Ap4b1 and the development of symptoms consistent with adaptor protein Complex 4 deficiency disease in humans. Furthermore, this study provides strong evidence for the use of this model for further research into the aetiology of adaptor protein Complex 4 deficiency in humans, as well as its use for the development and testing of new therapeutic modalities

    In vivo fiber optic raman spectroscopy of muscle in preclinical models of amyotrophic lateral sclerosis and Duchenne muscular dystrophy

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    Neuromuscular diseases result in muscle weakness, disability, and, in many instances, death. Preclinical models form the bedrock of research into these disorders, and the development of in vivo and potentially translational biomarkers for the accurate identification of disease is crucial. Spontaneous Raman spectroscopy can provide a rapid, label-free, and highly specific molecular fingerprint of tissue, making it an attractive potential biomarker. In this study, we have developed and tested an in vivo intramuscular fiber optic Raman technique in two mouse models of devastating human neuromuscular diseases, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy (SOD1G93A and mdx, respectively). The method identified diseased and healthy muscle with high classification accuracies (area under the receiver operating characteristic curves (AUROC): 0.76–0.92). In addition, changes in diseased muscle over time were also identified (AUROCs 0.89–0.97). Key spectral changes related to proteins and the loss of α-helix protein structure. Importantly, in vivo recording did not cause functional motor impairment and only a limited, resolving tissue injury was seen on high-resolution magnetic resonance imaging. Lastly, we demonstrate that ex vivo muscle from human patients with these conditions produced similar spectra to those observed in mice. We conclude that spontaneous Raman spectroscopy of muscle shows promise as a translational research tool

    Translating SOD1 gene silencing towards the clinic: A highly efficacious, off-target free and biomarker-supported strategy for familial ALS

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    Twenty per cent of familial amyotrophic lateral sclerosis (fALS) cases are caused by mutations in the gene encoding human cytosolic Cu/Zn superoxide dismutase (hSOD1). Efficient translation of the therapeutic potential of interfering RNA (RNAi) for the treatment of SOD1-ALS patients requires the development of vectors that are free of significant off-target effects and with reliable biomarkers to discern sufficient target engagement and correct dosing. Using adeno-associated virus serotype 9 to deliver RNAi against hSOD1 in the SOD1G93A mouse model, we found that intrathecal injection of the therapeutic vector via the cisterna magna delayed onset of disease, decreased motor neuron death at end stage by up to 88% and prolonged the median survival of SOD1G93A mice by up to 42%. To our knowledge this is the first report to demonstrate no significant off-target effects linked to hSOD1 silencing, providing further confidence in the specificity of this approach. We also report the measurement of cerebrospinal fluid (CSF) hSOD1 protein levels as a biomarker of effective dosing and efficacy of hSOD1 knockdown. Together, these data provide further confidence in the safety of the clinical therapeutic vector. The CSF biomarker will be a useful measure of biological activity for translation into human clinical trials
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