Howard Florey Institute

Howard, United States

Howard Florey Institute

Howard, United States
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Davey C.E.,University of Melbourne | Davey C.E.,Howard Florey Institute | Davey C.E.,NICTA | Grayden D.B.,University of Melbourne | And 5 more authors.
NeuroImage | Year: 2013

Correlation-based functional MRI connectivity methods typically impose a temporal sample independence assumption on the data. However, the conventional use of temporal filtering to address the high noise content of fMRI data may introduce sample dependence. Violation of the independence assumption has ramifications for the distribution of sample correlation which, if unaccounted for, may invalidate connectivity results. To enable the use of temporal filtering for noise suppression while maintaining the integrity of connectivity results, we derive the distribution of sample correlation between filtered timeseries as a function of the filter frequency response. Corrected distributions are also derived for statistical inference tests of sample correlation between filtered timeseries, including Fisher's z-transformation and the Student's t-test. Crucially, the proposed corrections are valid for any unknown true correlation and arbitrary filter specifications. Empirical simulations demonstrate the potential for temporal filtering to artificially induce connectivity by introducing sample dependence, and verify the utility of the proposed corrections in mitigating this effect. The importance of our corrections is exemplified in a resting state fMRI connectivity analysis: seed-voxel correlation maps generated from filtered data using uncorrected test variates yield an unfeasible number of connections to the left primary motor cortex, suggesting artificially induced connectivity, while maps acquired from filtered data using corrected test variates exhibit bilateral connectivity in the primary motor cortex, in conformance with expected results as seen in the literature. © 2012 Elsevier Inc.


Bohanna I.,Howard Florey Institute | Bohanna I.,University of Melbourne | Georgiou-Karistianis N.,Monash University | Egan G.F.,Howard Florey Institute | Egan G.F.,University of Melbourne
Neurobiology of Disease | Year: 2011

The striatum, the primary site of degeneration in Huntington's disease (HD), connects to the cerebral cortex via topographically organized circuits subserving unique motor, associative and limbic functions. Currently, it is not known whether all cortico-striatal circuits are equally affected in HD. We aimed to study the selective vulnerability of individual cortico-striatal circuits within the striatum in HD, and hypothesized that motor cortico-striatal pathways would be most affected, consistent with HD being a primarily motor disorder. Diffusion Tensor Imaging (DTI) tractography was used to identify connections between the striatum and seven major cortical regions in 12 HD patients and 14 matched controls. The striatum of both groups was parcellated into subregions based on connectivity with the cerebral cortex. Volumetric and DTI microstructural measures of Fractional Anisotropy (FA) and Mean Diffusivity (MD) were obtained within each subregion and compared statistically between groups. Tractography demonstrated the topographic organization of cortical connections in the striatum of both controls and HD patients. In HD patients, the greatest difference from controls in volume, FA and MD was observed in M1 and S1 subregions of the caudate and putamen. Motor symptoms correlated with volume and MD in sensorimotor striatal subregions, suggesting that sensorimotor striatal degeneration is closely related to motor dysfunction. DTI tractography provides a novel approach to sensitively examine circuit-specific abnormalities in HD and has identified that the motor cortico-striatal circuit is selectively vulnerable in HD. © 2011 Elsevier Inc.


Vihinen M.,University of Tampere | den Dunnen J.T.,Leiden University | Dalgleish R.,University of Leicester | Cotton R.G.H.,Howard Florey Institute
Human Mutation | Year: 2012

Information about genetic variation has been collected for some 20 years into registries, known as locus specific databases (LSDBs), which nowadays often contain information in addition to the actual genetic variation. Several issues have to be taken into account when considering establishing and maintaining LSDBs and these have been discussed previously in a number of articles describing guidelines and recommendations. This information is widely scattered and, for a newcomer, it would be difficult to obtain the latest information and guidance. Here, a sequence of steps essential for establishing an LSDB is discussed together with guidelines for each step. Curators need to collect information from various sources, code it in systematic way, and distribute to the research and clinical communities. In doing this, ethical issues have to be taken into account. To facilitate integration of information to, for example, analyze genotype-phenotype correlations, systematic data representation using established nomenclatures, data models, and ontologies is essential. LSDB curation and maintenance comprises a number of tasks that can be managed by following logical steps. These resources are becoming ever more important and new curators are essential to ensure that we will have expertly curated databases for all disease-related genes in the near future. © 2011 Wiley Periodicals, Inc.


Patent
St. Vincent's Institute and Howard Florey Institute | Date: 2012-08-09

The present invention relates to inhibitors of insulin-regulated aminopeptidase (IRAP) and methods for inhibiting same, as well as compositions comprising said inhibitors. In particular, the inhibitors of the present invention may be useful in therapeutic applications including enhancing memory and learning functions.


Patent
St. Vincent's Institute and Howard Florey Institute | Date: 2013-02-06

The present invention relates to inhibitors of insulin-regulated aminopeptidase (IRAP) and methods for inhibiting same, as well as compositions comprising said inhibitors. In particular, the inhibitors of the present invention may be useful in therapeutic applications including enhancing memory and learning functions.


Tae H.,Howard Florey Institute
Channels (Austin, Tex.) | Year: 2011

The second of three SPRY domains (SPRY2, S1085 -V1208) located in the skeletal muscle ryanodine receptor (RyR1) is contained within regions of RyR1 that influence EC coupling and bind to imperatoxin A, a toxin probe of RyR1 channel gating. We examined the binding of the F loop (P1107-A1121) in SPRY2 to the ASI/basic region in RyR1 (T3471-G3500, containing both alternatively spliced (ASI) residues and neighboring basic amino acids). We then investigated the possible influence of this interaction on excitation contraction (EC) coupling. A peptide with the F loop sequence and an antibody to the SPRY2 domain each enhanced RyR1 activity at low concentrations and inhibited at higher concentrations. A peptide containing the ASI/basic sequence bound to SPRY2 and binding decreased ~10-fold following mutation or structural disruption of the basic residues. Binding was abolished by mutation of three critical acidic F loop residues. Together these results suggest that the ASI/basic and SPRY2 domains interact in an F loop regulatory module. Although a region that includes the SPRY2 domain influences EC coupling, as does the ASI/basic region, Ca2+ release during ligand- and depolarization-induced RyR1 activation were not altered by mutation of the three critical F loop residues following expression of mutant RyR1 in RyR1-null myotubes. Therefore the electrostatic regulatory interaction between the SPRY2 F loop residues (that bind to imperatoxin A) and the ASI/basic residues of RyR1 does not influence bi-directional DHPR-RyR1 signaling during skeletal EC coupling, possibly because the interaction is interrupted by the influence of factors present in intact muscle cells.


Patent
University of Melbourne and Howard Florey Institute | Date: 2010-12-15

The specification relates to methods for treating a neurodegenerative disease such as multiple sclerosis by administering to a subject in need an EphA4 antagonist or an EphA4 ligand antagonist. The antagonist may be a soluble EphA4 or EphA4-binding ephrin or a functional variant thereof such as an EphA4-Fc or an ephrin A5-Fc. The antagonist may be an antibody or an antigen binding fragment, a nucleic acid, polypeptide, peptide, or organic molecule that binds to EphA4 or an EphA4-ligand or a nucleic acid encoding same and downregulates its activity. Combination therapies are also disclosed.


Methods, compositions and kits based on TAM receptors, or TAM receptor ligands or agonists are for detection of neuropathological diseases or determination of their progression. The neural diseases include multiple sclerosis or other inflammatory neural disorders that are characterized by demyelination, oligodendrocyte cytotoxicity and microglial activation. These methods include screening cells of a subject where identification of an elevation of expression of a TAM receptor or a change in expression of a TAM receptor ligand indicates the presence of the disease presence or progression. In addition, subjects with such neuropathological diseases can be treated by administering TAM receptor ligands (such as GAS 6 or Protein S) or by administering agonists such as antibodies specific for the TAM receptors; Axl, Mer or Tyro3.


Patent
Howard Florey Institute | Date: 2014-03-24

The present invention relates generally to the field of therapeutic treatment and compounds having utility therefor, in particular the therapy or management of conditions associated with excessive, unwanted or undesirable sodium ion passage through cellular membranes via voltage-gated sodium channels. In one embodiment the invention is concerned with the treatment of neuropathic pain. The invention contemplates to aryloxy-substituted amines, as sodium channel blockers or modulators. In further embodiments, the invention also relates to compounds which may advantageously have dual sodium channel blocker/modulating and antioxidative (free-radical scavenging) effects. Methods for their manufacture and compositions containing the compounds are also contemplated.


The present disclosure relates to the use of TAM receptor ligands, metabolites, precursor and binding partners thereof in the field of inflammatory neuropathology. This includes the early diagnosis and monitoring of an inflammatory neuropathology as well as screening for medicaments used in the treatment and prophylaxis of such a condition. The method comprises screening blood fluid from a subject for a TAM receptor ligand, or metabolite, or precursor thereof wherein an altered level of the ligand or its metabolite or precursor relative to a control is indicative of the presence of an inflammatory neuropathological disease or condition or a likelihood of developing the same. Diagnostic kits, high throughput screening assays and therapeutic compositions for inflammatory neuropathies are also taught herein.

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