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Contains fulltext : 88858.pdf (publisher's version ) (Closed access), We identified a member of the BTB/Kelch protein family that is mutated in nemaline myopathy type 6 (NEM6), an autosomal-dominant neuromuscular disorder characterized by the presence of nemaline rods and core lesions in the skeletal myofibers. Analysis of affected families allowed narrowing of the candidate region on chromosome 15q22.31, and mutation screening led to the identification of a previously uncharacterized gene, KBTBD13, coding for a hypothetical protein and containing missense mutations that perfectly cosegregate with nemaline myopathy in the studied families. KBTBD13 contains a BTB/POZ domain and five Kelch repeats and is expressed primarily in skeletal and cardiac muscle. The identified disease-associated mutations, C.742C>A (p.Arg248Ser), c.1170G>C (p.Lys390Asn), and c.1222C>T (p.Arg408Cys), located in conserved domains of Kelch repeats, are predicted to disrupt the molecule's beta-propeller blades. Previously identified BTB/POZ/Kelch-domain-containing proteins have been implicated in a broad variety of biological processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, and myofibril assembly. The functional role of KBTBD13 in skeletal muscle and the pathogenesis of NEM6 are subjects for further studies.

Out of three mutations in the dystrophin gene that cause Duchenne muscular dystrophy (DMD), the most common, serious childhood muscle wasting disease, two are genomic deletions of one or more exons that disrupt the reading frame. Specific removal of an exon flanking a genomic deletion using antisense oligonucleotide intervention during pre-RNA processing can restore the reading frame and could potentially reduce disease severity. We describe a rare dystrophin gene rearrangement; inversion of ∼28 kb, flanked by a 10-bp duplication and an 11-kb deletion, which led to the omission of exons 49 and 50 from the mature mRNA and the variable inclusion of several pseudoexons. In vitro transfection of cultured patient cells with antisense oligonucleotides directed at exon 51 induced efficient removal of that exon, as well as one of the more commonly included pseudoexons, suggesting closely coordinated splicing of these exons. Surprisingly, several antisense oligonucleotides (AOs) directed at this pseudoexon had no detectable effect on the splicing pattern, while all AOs directed at the other predominant pseudoexon efficiently excised that target. Antisense oligomers targeting dystrophin exon 51 for removal are currently undergoing clinical trials. Despite the unique nature of the dystrophin gene rearrangement described here, a personalized multiexon skipping treatment is applicable and includes one compound entering clinical trials for DMD.

The effects of radiata pine (Pinus radiata D. Don) seedlings and ryegrass (Lolium perenne L.) on the mineralisation of orthophosphate monoesters in 7 grassland soils were assessed in a 10-month pot trial using NaOH–EDTA extraction and solution 31P NMR spectroscopy. Extraction with NaOH–EDTA recovered 46–86% of the total soil P, and NaOH–EDTA-extractable organic P determined by molybdate colourimetry ranged between 194 and 715 mg/kg soil, representing 34–85% of the total soil organic P. Orthophosphate monoesters were the predominant species of the extracted organic P in all soils, with much smaller concentrations of orthophosphate diesters, and traces of phosphonates. Concentrations of orthophosphate monoesters were consistently lower in soils under pine (103–480 mg P/kg soil) compared with the initial soils (142–598 mg P/kg soil) and most soils under grass (122–679 mg/kg soil). Mineralisation of myo-inositol hexakisphosphate accounted for 18–100% of the total mineralisation of orthophosphate monoesters in most soils under radiata pine. This suggests that supposedly recalcitrant inositol phosphates are available for uptake by radiata pine, although the extent of this varies among soils.

The potential for replacing activated carbon with AuRIX 100 for the recovery of gold and silver from pregnant leach solutions typical of heap leach operations is evaluated. Two operating points representing the extremes in solution flow and grade generally experienced in heap leach operations were selected as the basis for the carbon-in-solution (CIS) and resin-in-solution (RIS) circuit designs. Synthetic and real leach solutions, from an operation in Sonora, Mexico, were used in bench-scale testwork to provide process design parameters for the RIS circuit; industry standard design data and operating data from existing CIS operations were used as a basis for comparison. Cost comparisons indicate that the RIS circuit would save 16-17% in terms of capital and 27-40% in terms of operating costs compared with a conventional CIS circuit. Dore produced by the RIS pilot plant assayed 90.01% Au, 9.37% Ag and 0.62% Cu compared with 68.7% Au, 25.9% Ag and 5.5% Cu produced in the CIS production plant., The potential for replacing activated carbon with AuRIX 100 for the recovery of gold and silver from pregnant leach solutions typical of heap leach operations is evaluated. Two operating points representing the extremes in solution flow and grade generally experienced in heap leach operations were selected as the basis for the carbon-in-solution (CIS) and resin-in-solution (RIS) circuit designs. Synthetic and real leach solutions, from an operation in Sonora, Mexico, were used in bench-scale testwork to provide process design parameters for the RIS circuit; industry standard design data and operating data from existing CIS operations were used as a basis for comparison. Cost comparisons indicate that the RIS circuit would save 16-17% in terms of capital and 27-40% in terms of operating costs compared with a conventional CIS circuit. Dore produced by the RIS pilot plant assayed 90.01% Au, 9.37% Ag and 0.62% Cu compared with 68.7% Au, 25.9% Ag and 5.5% Cu produced in the CIS production plant.

The nemaline myopathies are muscle disorders of variable severity and age of onset, with characteristic nemaline bodies in the sarcoplasm. Genes for dominant (NEM1) and recessive (NEM2A) nemaline myopathy have been localised to chromosomes one and two, respectively. A missense mutation in the alpha-tropomyosin gene (TPM3) has been associated with NEM1 in one family. Probands from 76 other nemaline myopathy families have now been screened for TPM3 mutations. One proband, who was not noted to have any weakness neonatally, but who died at 21 months of age, was shown to be homozygous for a single strand conformation polymorphism (SSCP) in skeletal-muscle-specific exon 1 of TPM3. Sequencing revealed homozygosity for a nonsense mutation at codon 31 (CAG to TAG). The patient should have no functioning alpha-tropomyosin slow protein. The nemaline bodies in this patient were exclusively in type one fibres, consistent with the expression of TPM3 only in type one fibres.

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OBJECTIVE: To determine the relationship between the apolipoprotein E epsilon 4 allele and autopsy-verified Alzheimer's disease (AD) in an Australian population. DESIGN: Retrospective case-control study. SETTING: Royal Perth Hospital, Perth, Western Australia (a tertiary referral hospital). SUBJECTS: 50 subjects with "definite" AD (according to the histological and clinical criteria of the Consortium to Establish a Registry for Alzheimer's Disease [CERAD]) and 30 control subjects who had died from a non-neurological disease were randomly selected from the hospital's neuropathology register. OUTCOME MEASURES: Histological grading of brain sections stained with the modified Bielschowsky stain according to the criteria of CERAD; number (burden) of neuritic plaques; apolipoprotein E genotype (APOE). RESULTS: Frequency of the epsilon 4 allele was significantly higher in the AD group (37%) than in the control group (2%) (chi 2 = 25.8; P < 0.00001). In the AD group, 50% of subjects were heterozygous for the epsilon 4 allele and 12% were homozygous, while in the control group one subject was heterozygous for the allele and none were homozygous. No association was seen between the epsilon 4 allele and neuritic plaque burden in the hippocampus, entorhinal cortex, middle frontal gyrus or inferior parietal lobule in subjects with AD. CONCLUSIONS: Our findings confirm an association between the epsilon 4 allele and autopsy-verified AD. The epsilon 4 allele may be an important risk factor for susceptibility to AD in the general Australian population.

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