The IFITM5 mutation c.-14C > T results in an elongated transcript expressed in human bone; And causes varying phenotypic severity of osteogenesis imperfecta type V

Background The genetic mutation resulting in osteogenesis imperfecta (OI) type V was recently characterised as a single point mutation (c.-14C > T) in the 5' untranslated region (UTR) of IFITM5, a gene encoding a transmembrane protein with expression restricted to skeletal tissue. This mutation creates an alternative start codon and has been shown in a eukaryotic cell line to result in a longer variant of IFITM5, but its expression has not previously been demonstrated in bone from a patient with OI type V. Methods Sanger sequencing of the IFITM5 5' UTR was performed in our cohort of subjects with a clinical diagnosis of OI type V. Clinical data was collated from referring clinicians. RNA was extracted from a bone sample from one patient and Sanger sequenced to determine expression of wild-type and mutant IFITM5. Results: All nine subjects with OI type V were heterozygous for the c.-14C > T IFITM5 mutation. Clinically, there was heterogeneity in phenotype, particularly in the manifestation of bone fragility amongst subjects. Both wild-type and mutant IFITM5 mRNA transcripts were present in bone. Conclusions The c.-14C > T IFITM5 mutation does not result in an RNA-null allele but is expressed in bone. Individuals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family.

Statutory protections from forfeiture of a leasehold estate following Apriaden Pty Ltd v Seacrest Pty Ltd

In Apriaden Pty Ltd v Seacrest Pty Ltd the Victorian Court of Appeal decided that termination of a lease under common law contractual principles following repudiation is an alternative to reliance upon an express forfeiture provision in the lease and that it is outside the sphere of statutory protections given against the enforcing of a forfeiture. The balance of authority supports the first aspect of the decision. This article focuses on the second aspect of it, which is a significant development in the law of leases. The article considers the implications of this decision for essential terms of clauses in leases, argues that common law termination for breach of essential terms should be subject to compliance with these statutory requirements and, as an alternative, suggests a way forward through appropriate law reform, considering whether the recent Victorian reform goes far enough.

Enhancement of DNA repair using topical T4 endonuclease V does not inhibit melanoma formation in Cdk4R24C/R24C/Tyr-NrasQ61K mice following neonatal UVR

To further investigate the use of DNA repair-enhancing agents for skin cancer prevention, we treated Cdk4R24C/R24C/NrasQ61K mice topically with the T4 endonuclease V DNA repair enzyme (known as Dimericine) immediately prior to neonatal ultraviolet radiation (UVR) exposure, which has a powerful effect in exacerbating melanoma development in the mouse model. Dimericine has been shown to reduce the incidence of basal-cell and squamous cell carcinoma. Unexpectedly, we saw no difference in penetrance or age of onset of melanoma after neonatal UVR between Dimericine-treated and control animals, although the drug reduced DNA damage and cellular proliferation in the skin. Interestingly, epidermal melanocytes removed cyclobutane pyrimidine dimers (CPDs) more efficiently than surrounding keratinocytes. Our study indicates that neonatal UVR-initiated melanomas may be driven by mechanisms other than solely that of a large CPD load and/or their inefficient repair. This is further suggestive of different mechanisms by which UVR may enhance the transformation of keratinocytes and melanocytes.

Influence of all-out and fast start of 5-min cycling time trial performance

Purpose: To examine the influence of two different fast-start pacing strategies on performance and oxygen consumption (V˙O2) during cycle ergometer time trials lasting ∼5 min. Methods: Eight trained male cyclists performed four cycle ergometer time trials whereby the total work completed (113 ± 11.5 kJ; mean ± SD) was identical to the better of two 5-min self-paced familiarization trials. During the performance trials, initial power output was manipulated to induce either an all-out or a fast start. Power output during the first 60 s of the fast-start trial was maintained at 471.0 ± 48.0 W, whereas the all-out start approximated a maximal starting effort for the first 15 s (mean power: 753.6 ± 76.5 W) followed by 45 s at a constant power output (376.8 ± 38.5 W). Irrespective of starting strategy, power output was controlled so that participants would complete the first quarter of the trial (28.3 ± 2.9 kJ) in 60 s. Participants performed two trials using each condition, with their fastest time trial compared. Results: Performance time was significantly faster when cyclists adopted the all-out start (4 min 48 s ± 8 s) compared with the fast start (4 min 51 s ± 8 s; P < 0.05). The first-quarter V˙O2 during the all-out start trial (3.4 ± 0.4 L·min-1) was significantly higher than during the fast-start trial (3.1 ± 0.4 L·min-1; P < 0.05). After removal of an outlier, the percentage increase in first-quarter V˙O2 was significantly correlated (r = -0.86, P < 0.05) with the relative difference in finishing time. Conclusions: An all-out start produces superior middle distance cycling performance when compared with a fast start. The improvement in performance may be due to a faster V˙O2 response rather than time saved due to a rapid acceleration.

Artful determination : "state of the art" and PCME Ltd v. Goyen COntrols Co. UK Ltd

In a recent decision by Mr Justice Laddie, a patent was held anticipated by, inter alia, prior use of a device which fell within the claims of the patent in suit, even though its circuitry was enclosed in resin. The anticipating invention had been "made available to the public" within the terms of section 2 (2) of the Patents Act 1977 because its essential integers would have been revealed by an interesting character, the "skilled forensic engineer".

Locking away the mysteries of fair basis : Lockwood v Doric in the High Court

This article updates a previous article on the Lockwood v Doric fair basing case in the Full Court of the Federal Court which was recently appealed to the High Court. The High Court's decision provides a new and welcome level of clarity in this difficult area of patent law. With this new clarity we can finally lock away some of the mysteries that have plagued the area for some time. Already, indications are that Lockwood's guidelines are being usefully applied in the Patent Office and Federal Court.

Recent developments : loss of chance in medical litigation : Tabet v Gett [2010] HCA 12.

Following the judgement of the High Court in Tabet v Gett [2010]HCA 12 handed down on 21 April 2010 it appears that in Australia there is now very limited scope for recovery in negligence for the loss of a chance of a better medical outcome.

Oxford Companion to Australian Gardens [contributions: entries S-V]

Shelton, Edward Mason; p.548 Sherwood Arboretum; p.550 Soutter, William; pp.563-564 Styles or gardens and designed landscapes; pp.575-576 Summer-house; pp.579-580 Trapnell, Walter George; p.602 Tropical Gardens; pp.604-605 Wickham Park; p.642 Wijaya, Made; p.642 Williams, George; p.644 Williams, Keith A.W.; p.644 Verandah Garadening; p.614

A myosin from a higher plant has structural similarities to class V myosins

In plant cells, myosin is believed to be the molecular motor responsible for actin-based motility processes such as cytoplasmic streaming and directed vesicle transport. In an effort to characterize plant myosin, a cDNA encoding a myosin heavy chain was isolated from Arabidopsis thaliana. The predicted product of the MYA1 gene is 173 kDa and is structurally similar to the class V myosins. It is composed of the highly-conserved NH2-terminal "head" domain, a putative calmodulin-binding "neck" domain an alpha-helical coiled-coil domain, and a COOH-terminal domain. Northern blot analysis shows that the Arabidopsis MYA1 gene is expressed in all the major plant tissues (flower, leaf, root, and stem). We suggest that the MYA1 myosin may be involved in a general intracellular transport process in plant cells.

Contribution of transmembrane domain V amino acids to β1l-adrenoceptor activity and affinity

Introduction. There are two binding sites on the β1-adrenoceptor (AR), β1H and β1L corresponding to high and low affinity binding sites respectively, which can be activated to cause cardiostimulation. Some β-blockers that block β1AR and β2ARs can activate β1LARs at higher concentrations than those required to cause blockade. The β2AR does not form a corresponding low affinity binding site and therefore we postulated that heterologous amino acids are responsible for the formation of β1LAR. Aim. To investigate whether heterologous amino acids of transmembrane domain V (TMDV) of β1AR and β2ARs contribute to β1LAR. Methods. β1ARs, β2ARs and mutant β1ARs containing all (β1(β2TMDV)AR) or single amino acids of TMDV of the β2AR were prepared and stably expressed in Chinese Hamster Ovary cells. Concentration-effect curves for cyclicAMP accumulation were carried out for (-)-CGP12177 in the absence or presence of (-)-bupranolol. Results. The potencies (pEC50) of (-)-CGP12177 were β2AR (9.24 ± 0.14, n = 5), β1(V230I)AR (9.07 ± 0.07, n = 10), β1(β2TMDV)AR (8.86 ± 0.10, n = 15), β1(R222Q)AR (8.09 ± 0.29, n = 6), β1AR (8.00 ± 0.11, n = 11). The affinities (pKB) of (-)-bupranolol were β2AR (9.82 ± 0.52, n = 5), β1(V230I)AR (7.64 ± 0.12, n = 8), β1(β2TMV)AR (8.06 ± 0.17, n = 8), β1(R222Q)AR (7.33 ± 0.23, n = 5), β1AR (7.23 ± 0.23, n = 5). Discussion. The potency of (-)-CGP12177 was higher at β2AR than at β1AR consistent with activation through a low affinity site at the β1AR (β1LAR). The presence of V230 in β1AR accounted for the lower potency of (-)-CGP 12177. The affinity of (-)-bupranolol was lower at β1AR compared to β2AR. The presence of V230 in β1AR accounted in part for the lower affinity. In conclusion TMDV of the β1AR contributes in part to the low affinity binding site of β1AR.

Contribution of transmembrane domain V amino acids to β1l-adrenoceptor activity and affinity

There are two binding sites on the β1-adrenoceptor (AR), β1H and β1L corresponding to high and low affinity binding sites respectively, which can be activated to cause cardiostimulation (reviewed Kaumann and Molenaar, 2008). Some β-blockers that block β1AR and β2ARs can activate β1LARs at higher concentrations than those required to cause blockade. The β2AR does not form a corresponding low affinity binding site (Baker et al 2002) and therefore we postulated that heterologous amino acids are responsible for the formation of β1LAR. Our aim was to investigate whether heterologous amino acids of transmembrane domain V (TMDV) of β1AR and β2ARs contribute to β1LAR. β1ARs, β2ARs and mutant β1ARs containing all (β1(β2TMDV)AR) or single amino acids of TMDV of the β2AR were prepared and stably expressed in Chinese Hamster Ovary cells. Concentration-effect curves for cyclicAMP accumulation were carried out for (-)-CGP12177 or (-)-isoprenaline in the absence or presence of (-)-bupranolol. _______________________________________________________________________ (-)-CGP 12177 (-)-Bupranolol affinity (pKB) pEC50 vs (-)-CGP 12177 vs (-)-isoprenaline _______________________________________________________________________ β1AR 8.00 ± 0.11 (11) 7.23 ± 0.23 (5) 9.52 ± 0.28 (5) β2AR (high density) 9.24 ± 0.14 (5) 9.82 ± 0.52 (8) xPaulxxxxxxx β2AR (low density) no effect β1(β2TMV)AR 8.86 ± 0.10 (15) 8.06 ± 0.17 (8) 9.08 ± 0.22 (6) β1(V230I)AR 9.07 ± 0.07 (10) 7.64 ± 0.12 (8) 9.36 ± 0.28 (9) β1(R222Q)AR 8.09 ± 0.29 (6) 7.33 ± 0.23 (5) 9.36 ± 0.08 (6) β1(V230A)AR 7.59 ± 0.09 (6) 7.32 ± 0.24 (4) 8.62 ± 0.18 (5) _______________________________________________________________________ The potency of (-)-CGP12177 was higher at β2AR than at β1AR consistent with activation through a low affinity site at the β1AR (β1LAR) but not β2AR. The presence of V230 in β1AR accounted for the lower potency of (-)-CGP 12177. The affinity of (-)-bupranolol at β1AR and mutants was higher when determined with (-)-isoprenaline than with (-)-CGP 12177. The affinity of (-)-bupranolol determined against (-)-CGP 12177 was lower at β1AR compared to β2AR. The presence of V230 in β1AR accounted in part for the lower affinity. In conclusion V230 of the β1AR contributes in part to the low affinity binding site of β1AR. Baker JG, Hall IP, Hill SJ (2002). Pharmacological characterization of CGP12177 at the human β2-adrenoceptor. Br J Pharmacol 137, 400−408 Kaumann AJ, Molenaar P (2008) The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology. Pharmacol Ther 118, 303-336

Channel plasmon-polariton modes in V grooves filled with dielectric

We investigated the effect of dielectric filling in a V groove on the propagation parameters of channel plasmon-polariton (CPP) modes. In particular, existence conditions and critical groove angles, mode localization, field structure, dispersion, and propagation distances of CPP modes are analyzed as functions of dielectric permittivity inside the groove. It is demonstrated that increasing dielectric permittivity in the groove results in a rapid increase of mode localization near the tip of the groove and increase of both the critical angles that determine a range of groove angles for which CPP modes can exist. Detailed analysis of the field structure has demonstrated that the maximum of the field in a CPP mode is typically reached at a small distance from the tip of the groove. The effect of rounded tip is also investigated.

Access to medicine and the dangers of patent linkage : lessons from Bayer Corp v. Union of India

In February 2010, the Delhi High Court delivered its decision in Bayer Corp v Union of India in which Bayer had appealed against an August 2009 decision of the same court. Both decisions prevented Bayer from introducing the concept of patent linkage into India’s drug regulatory regime. Bayer appealed to the Indian Supreme Court, the highest court in India, which agreed on 2 March 2010 to hear the appeal. Given that India is regarded as a global pharmaceutical manufacturer of generic medications, how its judiciary and government perceive their international obligations has a significant impact on the global access to medicines regime. In rejecting the application of patent linkage, the case provides an opportunity for India to further acknowledge its international human rights obligations.