Fat mass and obesity-related (FTO) shuttles between the nucleus and cytoplasm.

SNPs (single nucleotide polymorphisms) on a chromosome 16 locus encompassing FTO, as well as IRX3, 5, 6, FTM and FTL are robustly associated with human obesity. FTO catalyses the Fe(II)- and 2OG-dependent demethylation of RNA and is an AA (amino acid) sensor that couples AA levels to mTORC1 (mammalian target of rapamycin complex 1) signalling, thereby playing a key role in regulating growth and translation. However, the cellular compartment in which FTO primarily resides to perform its biochemical role is unclear. Here, we undertake live cell imaging of GFP (green fluorescent protein)-FTO, and demonstrate that FTO resides in both the nucleus and cytoplasm. We show using 'FLIP' (fluorescence loss in photobleaching) that a mobile FTO fraction shuttles between both compartments. We performed a proteomic study and identified XPO2 (Exportin 2), one of a family of proteins that mediates the shuttling of proteins between the nucleus and the cytoplasm, as a binding partner of FTO. Finally, using deletion studies, we show that the N-terminus of FTO is required for its ability to shuttle between the nucleus and cytoplasm. In conclusion, FTO is present in both the nucleus and cytoplasm, with a mobile fraction that shuttles between both cellular compartments, possibly by interaction with XPO2.This is the final published version. It first appeared at http://www.bioscirep.org/bsr/034/bsr034e144.htm

Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

SummaryLow energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell nonautonomously by CRTC-1 in the nervous system. Neuronal CRTC-1/CREB regulates peripheral metabolism antagonistically with the functional PPARα ortholog, NHR-49, drives mitochondrial fragmentation in distal tissues, and suppresses the effects of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that while both local and distal mechanisms combine to modulate aging, distal regulation overrides local contribution. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging

Proceedings of the 2015 WA Chapter of MSA Symposium on Music Performance and Analysis

This publication, entitled Proceedings of the 2015 WA Chapter MSA Symposium on Music Performance and Analysis, is a double-blind peer-reviewed conference proceedings published by the Western Australian Chapter of the Musicological Society of Australia, in conjunction with the Western Australian Academy of Performing Arts, Edith Cowan University, edited by Jonathan Paget, Victoria Rogers, and Nicholas Bannan. The original symposium was held at the University of Western Australia, School of Music, on 12 December 2015. With the advent of performer-scholars within Australian Universities, the intersections between analytical knowledge and performance are constantly being re-evaluated and reinvented. This collection of papers presents several strands of analytical discourse, including: (1) the analysis of music recordings, particularly in terms of historical performance practices; (2) reinventions of the \u27page-to-stage\u27 paradigm, employing new analytical methods; (3) analytical knowledge applied to pedagogy, particularly concerning improvisation; and (4) so-called \u27practice-led\u27 research.https://ro.ecu.edu.au/ecubooks/1005/thumbnail.jp

Anthelmintic activity of selected ethno-medicinal plant extracts on parasitic stages of Haemonchus contortus

Background: Parasitic roundworms (nematodes) cause substantial morbidity and mortality in livestock animals globally, and considerable productivity losses to farmers. The control of these nematodes has relied largely on the use of a limited number of anthelmintics. However, resistance to many of these these anthelmintics is now widespread, and, therefore, there is a need to find new drugs to ensure sustained and effective treatment and control into the future. Methods: Recently, we developed a screening assay to test natural, plant extracts with known inhibitory effects against the free-living worm Caenorhabditis elegans. Using this assay, we assessed here the effects of the extracts on motility and development of parasitic larval stages of Haemonchus contortus, one of the most important nematodes of small ruminants worldwide. Results: The study showed that two of five extracts from Picria fel-terrae Lour. have a significant inhibitory effect (at concentrations of 3-5 mg/ml) on the motility and development of H. contortus larvae. Although the two extracts originated from the same plant, they displayed different levels of inhibition on motility and development, which might relate to the presence of various active constituents in these extracts, or the same constituents at different concentrations in distinct parts of the plant. Conclusions: These results suggest that extracts from P. fel-terrae Lour. have promising anthelmintic activity and that more broadly, plant extracts are a potential rich source of anthelmintics to combat helminthic diseases. © 2016 Kumarasingha et al

Functional Identification of Valerena-1,10-diene Synthase, a Terpene Synthase Catalyzing a Unique Chemical Cascade in the Biosynthesis of Biologically Active Sesquiterpenes in Valeriana officinalis

Valerian is an herbal preparation from the roots of Valeriana officinalis used as an anxiolytic and sedative and in the treatment of insomnia. The biological activities of valerian are attributed to valerenic acid and its putative biosynthetic precursor valerenadiene, sesquiterpenes, found in V. officinalis roots. These sesquiterpenes retain an isobutenyl side chain whose origin has been long recognized as enigmatic because a chemical rationalization for their biosynthesis has not been obvious. Using recently developed metabolomic and transcriptomic resources, we identified seven V. officinalis terpene synthase genes (VoTPSs), two that were functionally characterized as monoterpene synthases and three that preferred farnesyl diphosphate, the substrate for sesquiterpene synthases. The reaction products for two of the sesquiterpene synthases exhibiting root-specific expression were characterized by a combination of GC-MS and NMR in comparison to the terpenes accumulating in planta. VoTPS7 encodes for a synthase that biosynthesizes predominately germacrene C, whereas VoTPS1 catalyzes the conversion of farnesyl diphosphate to valerena-1,10-diene. Using a yeast expression system, specific labeled [13C]acetate, and NMR, we investigated the catalytic mechanism for VoTPS1 and provide evidence for the involvement of a caryophyllenyl carbocation, a cyclobutyl intermediate, in the biosynthesis of valerena-1,10-diene. We suggest a similar mechanism for the biosynthesis of several other biologically related isobutenyl-containing sesquiterpenes

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria

P2Y12 inhibitors for the neurointerventionalist.

The use of antiplatelets is widespread in clinical practice. However, for neurointerventional procedures, protocols for antiplatelet use are scarce and practice varies between individuals and institutions. This is further complicated by the quantity of antiplatelet agents which differ in route of administration, dosage, onset of action, efficacy and ischemic and hemorrhagic complications. Clarifying the individual characteristics for each antiplatelet agent, and their associated risks, will increasingly become relevant as the practice of mechanical thrombectomy, stenting, coiling and flow diversion procedures grows. The aim of this review is to summarize the existing literature for the use of P2Y12 inhibitors in neurointerventional procedures, examine the quality of the evidence, and highlight areas in need of further research

Technical note: development of a 3D printed subresolution sandwich phantom for validation of brain SPECT analysis

Purpose: To make an adaptable, head shaped radionuclide phantom to simulate molecular imaging of the brain using clinical acquisition and reconstruction protocols. This will allow the characterization and correction of scanner characteristics, and improve the accuracy of clinical image analysis, including the application of databases of normal subjects. Methods: A fused deposition modeling 3D printer was used to create a head shaped phantom made up of transaxial slabs, derived from a simulated MRI dataset. The attenuation of the printed polylactide (PLA), measured by means of the Hounsfield unit on CT scanning, was set to match that of the brain by adjusting the proportion of plastic filament and air (fill ratio). Transmission measurements were made to verify the attenuation of the printed slabs. The radionuclide distribution within the phantom was created by adding 99mTc pertechnetate to the ink cartridge of a paper printer and printing images of gray and white matter anatomy, segmented from the same MRI data. The complete subresolution sandwich phantom was assembled from alternate 3D printed slabs and radioactive paper sheets, and then imaged on a dual headed gamma camera to simulate an HMPAO SPECT scan. Results: Reconstructions of phantom scans successfully used automated ellipse fitting to apply attenuation correction. This removed the variability inherent in manual application of attenuation correction and registration inherent in existing cylindrical phantom designs. The resulting images were assessed visually and by count profiles and found to be similar to those from an existing elliptical PMMA phantom. Conclusions: The authors have demonstrated the ability to create physically realistic HMPAO SPECT simulations using a novel head-shaped 3D printed subresolution sandwich method phantom. The phantom can be used to validate all neurological SPECT imaging applications. A simple modification of the phantom design to use thinner slabs would make it suitable for use in PET

Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting

This manuscript provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward