Randomized trial of inosine for urate elevation in amyotrophic lateral sclerosis.

Introduction/aims: Higher urate levels are associated with improved ALS survival in retrospective studies, however whether raising urate levels confers a survival advantage is unknown. In the Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (SURE-ALS) trial, inosine raised serum urate and was safe and well-tolerated. The SURE-ALS2 trial was designed to assess longer term safety.

Methods for living guidelines: early guidance based on practical experience. Paper 2: consumer engagement in living guidelines.

Objectives: To describe and reflect on the consumer engagement approaches used in five living guidelines from the perspectives of consumers (i.e., patients, carers, the public, and their representatives) and guideline developers.

A trauma-informed substance use disorder prevention program for transracially adopted children and adolescents.

The prevalence of substance use among transracial and international adoptees is higher than that of non-adopted persons, and yet no specialized treatment modalities exist for this underserved population. Our purpose is to propose a substance use disorder (SUD) prevention program for transracial adoptive families that addresses the specific issues that face this community. There are several pre- and post-adoption factors which position transracial and international adoptees (TRIAs) to be at higher risk to develop SUDs.

Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization.

Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-β signaling that is rapidly degraded upon ligand stimulation.

Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo.

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

Background: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.

Methods: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months.

Lived experience researchers partnering with consumers and carers to improve mental health research: Reflections from an Australian initiative.

Unlabelled: Consumer and carer involvement in mental health research is a growing and developing field. Whilst there has been policy and in-principle support for such involvement from governments around the world, lived experience researchers conducting academic research in partnership with other consumers and carers remains uncommon.

Acacia: The Australian Capital Territory Consumer and Carer Mental Health Research Unit is based at The Australian National University and employs academic researchers with lived experience to undertake research directly relevant to the needs of mental health consumers and carers with the aim of influencing policy and practice.

Conformational dependence of through-space tellurium-tellurium spin-spin coupling in peri-substituted bis(tellurides).

Three related series of peri-substituted bis(tellurides) bearing naphthalene, acenaphthene and acenaphthylene backbones (Nap/Acenap/Aceyl(TeY)2 (Nap = naphthalene-1,8-diyl N; Acenap = acenaphthene-5,6-diyl A; Aceyl = acenaphthylene-5,6-diyl Ay; Y = Ph 1; Fp 2; Tol 3; An-p- 4; An-o- 5; Tp 6; Mes 7; Tip 8) have been synthesised and their solid-state structures determined by X-ray crystallography. Molecular conformations were classified as a function of the two C9-C-Te-C(Y) dihedral angles (θ); in the solid all members adopt AB or CCt configurations, with larger Te(aryl) moieties exclusively imposing the CCt variant. Exceptionally large J((125)Te,(125)Te) spin-spin coupling constants between 3289-3848 Hz were obtained for compounds substituted by bulky Te(aryl) groups, implying these species are locked in a CCt-type conformation.

A BMP regulatory network controls ectodermal cell fate decisions at the neural plate border.

During ectodermal patterning the neural crest and preplacodal ectoderm are specified in adjacent domains at the neural plate border. BMP signalling is required for specification of both tissues, but how it is spatially and temporally regulated to achieve this is not understood. Here, using a transgenic zebrafish BMP reporter line in conjunction with double-fluorescent in situ hybridisation, we show that, at the beginning of neurulation, the ventral-to-dorsal gradient of BMP activity evolves into two distinct domains at the neural plate border: one coinciding with the neural crest and the other abutting the epidermis.

Electrochemically informed synthesis: oxidation versus coordination of 5,6-bis(phenylchalcogeno)acenaphthenes.

Chalcogen dications: Facile synthesis of E--E bonded dications can be readily achieved. Radical cations are identified as the intermediates.

A Pilot Study of Fluorodeoxyglucose Positron Emission Tomography Findings in Patients with Phenylketonuria before and during Sapropterin Supplementation.

Background And Purpose: PET scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate. Phenylalanine (Phe) and its metabolites appear to impair several aspects of brain energy metabolism. 1) To evaluate brain glucose metabolism with FDG-PET imaging in phenylketonuria (PKU) patients before and 4 months after sapropterin therapy; 2) to evaluate neurodevelopmental changes, blood Phe levels and dietary Phe tolerance before and after sapropterin therapy; 3) to generate pilot data to assess the feasibility of evaluating brain glucose metabolism with FDG-PET imaging and to explore potential trends resulting from the administration of sapropterin therapy.

Synthetic, structural, NMR, and computational study of a geminally bis(peri-substituted) tridentate phosphine and its chalcogenides and transition-metal complexes.

Coupling of two acenaphthene backbones through a phosphorus atom in a geminal fashion gives the first geminally bis(peri-substituted) tridentate phosphine 1. The rigid nature of the aromatic backbone and overall crowding of the molecule result in a rather inflexible ligand, with the three phosphorus atoms forming a relatively compact triangular cluster. Phosphine 1 displays restricted dynamics on an NMR time scale, which leads to the anisochronicity of all three phosphorus nuclei at low temperatures.

An efficient route for the synthesis of phosphorus-selenium macro-heterocycles.

Four-membered ring [PhP(Se)(μ-Se)]2 (Woollins' reagent, WR) reacts with disodium alkenyl-diols followed by in situ ring-closure reaction with appropriate dibromoalkanes affording a series of unusual nine- to fifteen-membered organoselenophosphorus macrocycles bearing the O-P-Se-Cn-Se-P-O or O-P-Se-Cn-O-P-Se linkage.

Dihydropteridine reductase deficiency and treatment with tetrahydrobiopterin: a case report.

Dihydropteridine reductase (DHPR) deficiency is a genetic disorder of tetrahydrobiopterin (BH4) regeneration and may present with hyperphenylalaninemia, microcephaly, hypotonia, mental retardation, and convulsions. BH4 is an essential cofactor for the hydroxylation of aromatic amino acids and a deficiency of BH4 results in decreased synthesis of dopamine and serotonin. We present a 27-month-old female patient with DHPR deficiency who was treated with L-dopa/carbidopa (2 mg/kg, four times per day), 5-hydroxytryptophan (2 mg/kg, four times per day), folinic acid (10 mg/day), and BH4 supplementation (20 mg/kg, twice a day).

Weak Te,Te interactions through the looking glass of NMR spin-spin coupling.

Across the bay: J((125)Te, (125)Te) spin-spin coupling is a highly sensitive probe into the electronic and geometric structure of 1,8-peri-substituted naphthalene tellurium derivatives. The coupling is related to the onset of multicenter bonding in these systems.

Synthetic and computational study of geminally bis(supermesityl) substituted phosphorus compounds.

Reaction chemistry of an extremely sterically encumbered phosphinic chloride (Mes*)(2)P(=O)Cl (Mes* = 2,4,6-tri-t-butylphenyl, supermesityl) was investigated. This compound, as well as other compounds bearing two supermesityl groups placed geminally at the central phosphorus atom, shows extremely low reactivity at the phosphorus centre. Nevertheless, some synthetically significant transformations were possible.

Investigating silver coordination to mixed chalcogen ligands.

Six silver(I) coordination complexes have been prepared and structurally characterised. Mixed chalcogen-donor acenaphthene ligands L1-L3 [Acenap(EPh)(E'Ph)] (Acenap = acenaphthene-5,6-diyl; E/E' = S, Se, Te) were independently treated with silver(I) salts (AgBF₄/AgOTf). In order to keep the number of variables to a minimum, all reactions were carried out using a 1:1 ratio of Ag/L and run in dichloromethane.

Silver(I) coordination complexes and extended networks assembled from S, Se, Te substituted acenaphthenes.

Six related organo–chalconium silver(I) coordination complexes, including two examples of rare organotellurium-silver coordination, have been prepared and structurally characterised by X-ray crystallography. The series of 5-bromo-6-(phenylchalcogeno)acenaphthene ligands L1–L3 [Acenap(Br)(EPh)] (Acenap = acenaphthene-5,6-diyl; E = S, Se, Te) were independently treated with silver(I) salts (AgBF4, AgOTf). In order to keep the number of variables to a minimum, all reactions were carried out using a 1:1 ratio of Ag/L and run in dichloromethane.

Noncovalent interactions in peri-substituted chalconium acenaphthene and naphthalene salts: a combined experimental, crystallographic, computational, and solid-state NMR study.

Twelve related monocation chalconium salts [{Nap(EPh)(E'Ph)Me}(+){CF(3)SO(3)}(-)] 2-4, [{Acenap(Br)(EPh)Me}{CF(3)SO(3)}(-)] 5-7, and [{Acenap(EPh)(E'Ph)Me}(+){CF(3)SO(3)}(-)] 8-13 have been prepared and structurally characterized. For their synthesis naphthalene compounds [Nap(EPh)(E'Ph)] (Nap = naphthalene-1,8-diyl; E/E' = S, Se, Te) N2-N4 and associated acenaphthene derivatives [Acenap(X)(EPh)]/[Acenap(EPh)(E'Ph)] (Acenap = acenaphthene-5,6-diyl; E/E' = S, Se, Te; X = Br) A5-A13 were independently treated with a single molar equivalent of methyl trifluoromethanesulfonate (MeOTf). In addition, reaction of bis-tellurium compound A10 with 2 equiv of MeOTf afforded the doubly methylated dication salt [{Acenap(TePhMe)(2)}(2+){(CF(3)SO(3))(2)}(2-)}] 14.

Transforming growth factor β inhibits bone morphogenetic protein-induced transcription through novel phosphorylated Smad1/5-Smad3 complexes.

In vivo cells receive simultaneous signals from multiple extracellular ligands and must integrate and interpret them to respond appropriately. Here we investigate the interplay between pathways downstream of two transforming growth factor β (TGF-β) superfamily members, bone morphogenetic protein (BMP) and TGF-β. We show that in multiple cell lines, TGF-β potently inhibits BMP-induced transcription at the level of both BMP-responsive reporter genes and endogenous BMP target genes.

Exploring hypervalency and three-centre, four-electron bonding interactions: reactions of acenaphthene chalcogen donors and dihalogen acceptors.

Sterically crowded peri-substituted selenium and tellurium acenaphthene donors D1-D7 [Acenap(EPh)(Br) E = Se, Te; Acenap(SePh)(EPh) E = Se, S; Acenap(TePh)(EPh) E = S, Se, Te] react with dibromine and diiodine acceptors to afford a group of structurally diverse addition products 1-12, comparable in some cases to previously reported naphthalene analogues. Tellurium donors D4-D6 react conventionally with the dihalogens to afford insertion adducts 6-11 (X-R(2)Te-X) exhibiting molecular see-saw geometries, characterised by hypervalent X-Te-X quasi-linear fragments. The reactions of selenium donors D1-D3 with diiodine afford expected neutral charge-transfer (CT) spoke adducts 1, 4 and 5 (R(2)Se-I-I) containing quasi-linear Se-I-I alignments.

Onset of three-centre, four-electron bonding in peri-substituted acenaphthenes: a structural and computational investigation.

Two series of sterically crowded peri-substituted acenaphthenes have been prepared, containing mixed halogen-chalcogen functionalities at the 5,6-positions in A1-A6 (Acenap[X][EPh] (Acenap = acenaphthene-5,6-diyl; X = Br, I; E = S, Se, Te) and chalcogen-chalcogen moieties in A7-A12 (Acenap[EPh][E'Ph] (Acenap = acenaphthene-5,6-diyl; E/E' = S, Se, Te). The related dihalide compounds A13-A16 Acenap[XX'] (XX' = BrBr, II, IBr, ClCl) have also been prepared. Distortion of the acenaphthene framework away from the ideal was studied as a function of the steric bulk of the interacting halogen and chalcogen atoms occupying the peri-positions.