Country of Origin and Internet Publication: Applying the Berne Convention in the Digital Age

Historically, determining the country of origin of a published work presented few challenges, because works were generally published physically – whether in print or otherwise – in a distinct location or few locations. However, publishing opportunities presented by new technologies mean that we now live in a world of simultaneous publication – works that are first published online are published simultaneously to every country in world in which there is Internet connectivity. While this is certainly advantageous for the dissemination and impact of information and creative works, it creates potential complications under the Berne Convention for the Protection of Literary and Artistic Works (“Berne Convention”), an international intellectual property agreement to which most countries in the world now subscribe. Under the Berne Convention’s national treatment provisions, rights accorded to foreign copyright works may not be subject to any formality, such as registration requirements (although member countries are free to impose formalities in relation to domestic copyright works). In Kernel Records Oy v. Timothy Mosley p/k/a Timbaland, et al. however, the Florida Southern District Court of the United States ruled that first publication of a work on the Internet via an Australian website constituted “simultaneous publication all over the world,” and therefore rendered the work a “United States work” under the definition in section 101 of the U.S. Copyright Act, subjecting the work to registration formality under section 411. This ruling is in sharp contrast with an earlier decision delivered by the Delaware District Court in Håkan Moberg v. 33T LLC, et al. which arrived at an opposite conclusion. The conflicting rulings of the U.S. courts reveal the problems posed by new forms of publishing online and demonstrate a compelling need for further harmonization between the Berne Convention, domestic laws and the practical realities of digital publishing. In this chapter, we argue that even if a work first published online can be considered to be simultaneously published all over the world it does not follow that any country can assert itself as the “country of origin” of the work for the purpose of imposing domestic copyright formalities. More specifically, we argue that the meaning of “United States work” under the U.S. Copyright Act should be interpreted in line with the presumption against extraterritorial application of domestic law to limit its application to only those works with a real and substantial connection to the United States. There are gaps in the Berne Convention’s articulation of “country of origin” which provide scope for judicial interpretation, at a national level, of the most pragmatic way forward in reconciling the goals of the Berne Convention with the practical requirements of domestic law. We believe that the uncertainties arising under the Berne Convention created by new forms of online publishing can be resolved at a national level by the sensible application of principles of statutory interpretation by the courts. While at the international level we may need a clearer consensus on what amounts to “simultaneous publication” in the digital age, state practice may mean that we do not yet need to explore textual changes to the Berne Convention.

Determining and quantifying components of an aquaculture soundscape.

Recirculating aquaculture systems have a unique anthropogenic-based soundscape which is characterized by the type of equipment utilized, the structural configuration of walls, tanks, equipment, the substrate the tanks are situated on and even the activities of the personnel operating the facility. The soundscape of recirculation facilities is inadequately understood and remains poorly characterized, although it is generally accepted that the dominant sounds found in such facilities are within the hearing range of fish. The objective of this study was to evaluate the soundscape in a recirculating aquaculture facility from an intra-tank perspective and determine how the soundscape is shaped by a range of characteristics within the facility. Sounds were recorded across an operating aquaculture facility including different tank designs. The sounds recorded fell within previously measured pressure level ranges for recirculating systems, with the highest maximum sound pressure level (SPL) recorded at 124 dB re 1 mu Pa-2/Hz (with an FFT bin width of 46.9 Hz, centered at 187.5 Hz). The soundscape within the tanks was stratified and positively correlated with depth, the highest sound pressure occurring at the base of the tanks. Each recording of the soundscape was dominated by a frequency component of 187.5 Hz (corresponding centre of the 4th 46.9 Hz FFT analysis bin) that produced the highest observed SPL Analysis of sound recordings revealed that this peak SPL was associated with the acoustic signature of the pump. The soundscape was also evaluated for impacts of tank hood position, time of day, transient sounds and airstone particle size types, all of which were found to appreciably influence sound levels and structure within the tank environment. This study further discusses the distinctiveness of the soundscape, how it is shaped by the various operating components and considers the aquaculture soundscape in relation to natural soundscapes found within aquatic tropical environments.

Effect of position on precision within the recording field of a markerless motion capture system

Introduction Markerless motion capture systems are relatively new devices that can significantly speed up capturing full body motion. A precision of the assessment of the finger’s position with this type of equipment was evaluated at 17.30 ± 9.56 mm when compare to an active marker system [1]. The Microsoft Kinect was proposed to standardized and enhanced clinical evaluation of patients with hemiplegic cerebral palsy [2]. Markerless motion capture systems have the potential to be used in a clinical setting for movement analysis, as well as for large cohort research. However, the precision of such system needs to be characterized. Global objectives • To assess the precision within the recording field of the markerless motion capture system Openstage 2 (Organic Motion, NY). • To compare the markerless motion capture system with an optoelectric motion capture system with active markers. Specific objectives • To assess the noise of a static body at 13 different location within the recording field of the markerless motion capture system. • To assess the smallest oscillation detected by the markerless motion capture system. • To assess the difference between both systems regarding the body joint angle measurement. Methods Equipment • OpenStage® 2 (Organic Motion, NY) o Markerless motion capture system o 16 video cameras (acquisition rate : 60Hz) o Recording zone : 4m * 5m * 2.4m (depth * width * height) o Provide position and angle of 23 different body segments • VisualeyezTM VZ4000 (PhoeniX Technologies Incorporated, BC) o Optoelectric motion capture system with active markers o 4 trackers system (total of 12 cameras) o Accuracy : 0.5~0.7mm Protocol & Analysis • Static noise: o Motion recording of an humanoid mannequin was done in 13 different locations o RMSE was calculated for each segment in each location • Smallest oscillation detected: o Small oscillations were induced to the humanoid mannequin and motion was recorded until it stopped. o Correlation between the displacement of the head recorded by both systems was measured. A corresponding magnitude was also measured. • Body joints angle: o Body motion was recorded simultaneously with both systems (left side only). o 6 participants (3 females; 32.7 ± 9.4 years old) • Tasks: Walk, Squat, Shoulder flexion & abduction, Elbow flexion, Wrist extension, Pronation / supination (not in results), Head flexion & rotation (not in results), Leg rotation (not in results), Trunk rotation (not in results) o Several body joint angles were measured with both systems. o RMSE was calculated between signals of both systems. Results Conclusion Results show that the Organic Motion markerless system has the potential to be used for assessment of clinical motor symptoms or motor performances However, the following points should be considered: • Precision of the Openstage system varied within the recording field. • Precision is not constant between limb segments. • The error seems to be higher close to the range of motion extremities.

Principles to guide sustainable implementation of extended-scope-of-practice physiotherapy workforce redesign initiatives in Australia: Stakeholder perspectives, barriers, supports, and incentives

Sustainable implementation of new workforce redesign initiatives requires strategies that minimize barriers and optimize supports. Such strategies could be provided by a set of guiding principles. A broad understanding of the concerns of all the key stakeholder groups is required before effective strategies and initiatives are developed. Many new workforce redesign initiatives are not underpinned by prior planning, and this threatens their uptake and sustainability. This study reports on a cross-sectional qualitative study that sought the perspectives of representatives of key stakeholders in a new workforce redesign initiative (extended-scope-of-practice physiotherapy) in one Australian tertiary hospital. The key stakeholder groups were those that had been involved in some way in the development, management, training, funding, and/or delivery of the initiative. Data were collected using semistructured questions, answered individually by interview or in writing. Responses were themed collaboratively, using descriptive analysis. Key identified themes comprised: the importance of service marketing; proactively addressing barriers; using readily understood nomenclature; demonstrating service quality and safety, monitoring adverse events, measuring health and cost outcomes; legislative issues; registration; promoting viable career pathways; developing, accrediting, and delivering a curriculum supporting physiotherapists to work outside of the usual scope; and progression from "a good idea" to established service. Health care facilities planning to implement new workforce initiatives that extend scope of usual practice should consider these issues before instigating workforce/model of care changes. © 2014 Morris et al.

Electron-Energy Loss Spectroscopy (Eels) Of Organic-Molecules In Vapor-Phase - Design And Fabrication Of An Indigenous Eel Spectrometer

An indigenous electron energy loss spectrometer has been designed and fabricated for the study of free molecules. The spectrometer enables the recording of low-resolution electronic spectra of molecules inthe vapour phase with ready access to the vacuum ultraviolet region. Electron energy loss spectra of aliphatic alcohols and carbonyl compounds as wellas of benzene derivatives have been recorded with the indigenous spectrometer and the electronic transitions in these molecules discussed.

Multi-trait assessment of early-in-life female, male and genomic measures for use in genetic selection to improve female reproductive performance of Brahman cattle

Early-in-life female and male measures with potential to be practical genetic indicators were chosen from earlier analyses and examined together with genomic measures for multi-trait use to improve female reproduction of Brahman cattle. Combinations of measures were evaluated on the genetic gains expected from selection of sires and dams for each of age at puberty (AGECL, i.e. first observation of a corpus luteum), lactation anoestrous interval in 3-year-old cows (LAI), and lifetime annual weaning rate (LAWR, i.e. the weaning rate of cows based on the number of annual matings they experienced over six possible matings). Selection was on an index of comparable records for each combination. Selection intensities were less than theoretically possible but assumed a concerted selection effort was able to be made across the Brahman breed. The results suggested that substantial genetic gains could be possible but need to be confirmed in other data. The estimated increase in LAWR in 10 years, for combinations without or with genomic measures, ranged from 8 to 12 calves weaned per 100 cows from selection of sires, and from 12 to 15 calves weaned per 100 cows from selection of sires and dams. Corresponding reductions in LAI were 60-103 days or 94-136 days, and those for AGECL were 95-125 or 141-176 days, respectively. Coat score (a measure of the sleekness or wooliness of the coat) and hip height in females, and preputial eversion and liveweight in males, were measures that may warrant wider recording for Brahman female reproduction genetic evaluation. Pregnancy-test outcomes from Matings 1 and 2 also should be recorded. Percentage normal sperm may be important to record for reducing LAI and scrotal size and serum insulin-like growth factor-I concentration in heifers at 18 months for reducing AGECL. Use of a genomic estimated breeding value (EBV) in combination with other measures added to genetic gains, especially at genomic EBV accuracies of 40%. Accuracies of genomic EBVs needed to approach 60% for the genomic EBV to be the most important contributor to gains in the combinations of measures studied.

Geospatial environmental data modelling applications using remote sensing, GIS and spatial statistics

This thesis presents novel modelling applications for environmental geospatial data using remote sensing, GIS and statistical modelling techniques. The studied themes can be classified into four main themes: (i) to develop advanced geospatial databases. Paper (I) demonstrates the creation of a geospatial database for the Glanville fritillary butterfly (Melitaea cinxia) in the Åland Islands, south-western Finland; (ii) to analyse species diversity and distribution using GIS techniques. Paper (II) presents a diversity and geographical distribution analysis for Scopulini moths at a world-wide scale; (iii) to study spatiotemporal forest cover change. Paper (III) presents a study of exotic and indigenous tree cover change detection in Taita Hills Kenya using airborne imagery and GIS analysis techniques; (iv) to explore predictive modelling techniques using geospatial data. In Paper (IV) human population occurrence and abundance in the Taita Hills highlands was predicted using the generalized additive modelling (GAM) technique. Paper (V) presents techniques to enhance fire prediction and burned area estimation at a regional scale in East Caprivi Namibia. Paper (VI) compares eight state-of-the-art predictive modelling methods to improve fire prediction, burned area estimation and fire risk mapping in East Caprivi Namibia. The results in Paper (I) showed that geospatial data can be managed effectively using advanced relational database management systems. Metapopulation data for Melitaea cinxia butterfly was successfully combined with GPS-delimited habitat patch information and climatic data. Using the geospatial database, spatial analyses were successfully conducted at habitat patch level or at more coarse analysis scales. Moreover, this study showed it appears evident that at a large-scale spatially correlated weather conditions are one of the primary causes of spatially correlated changes in Melitaea cinxia population sizes. In Paper (II) spatiotemporal characteristics of Socupulini moths description, diversity and distribution were analysed at a world-wide scale and for the first time GIS techniques were used for Scopulini moth geographical distribution analysis. This study revealed that Scopulini moths have a cosmopolitan distribution. The majority of the species have been described from the low latitudes, sub-Saharan Africa being the hot spot of species diversity. However, the taxonomical effort has been uneven among biogeographical regions. Paper III showed that forest cover change can be analysed in great detail using modern airborne imagery techniques and historical aerial photographs. However, when spatiotemporal forest cover change is studied care has to be taken in co-registration and image interpretation when historical black and white aerial photography is used. In Paper (IV) human population distribution and abundance could be modelled with fairly good results using geospatial predictors and non-Gaussian predictive modelling techniques. Moreover, land cover layer is not necessary needed as a predictor because first and second-order image texture measurements derived from satellite imagery had more power to explain the variation in dwelling unit occurrence and abundance. Paper V showed that generalized linear model (GLM) is a suitable technique for fire occurrence prediction and for burned area estimation. GLM based burned area estimations were found to be more superior than the existing MODIS burned area product (MCD45A1). However, spatial autocorrelation of fires has to be taken into account when using the GLM technique for fire occurrence prediction. Paper VI showed that novel statistical predictive modelling techniques can be used to improve fire prediction, burned area estimation and fire risk mapping at a regional scale. However, some noticeable variation between different predictive modelling techniques for fire occurrence prediction and burned area estimation existed.

Measurement of sensitivities for the thermal recording of laser beams

A simple technique for determining the energy sensitivities for the thermographic recording of laser beams is described. The principle behind this technique is that, if a laser beam with a known spatial distribution such as a Gaussian profile is used for imaging, the radius of the thermal image formed depends uniquely on the intensity of the impinging beam. Thus by measuring the radii of the images produced for different incident beam intensities the minimum intensity necessary (that is, the threshold) for thermographic imaging is found. The diameter of the laser beam can also be found from this measurement. A simple analysis based on the temperature distribution in the laser heated material shows that there is an inverse square root dependence on pulse duration or period of exposure for the energy fluence of the laser beam required, both for the threshold and the subsequent increase in the size of the recording. It has also been shown that except for low intensity, long duration exposure on very low conductivity materials, heat losses are not very significant.

A shift in priority in diabetic foot care and research: 75% of foot ulcers are preventable

Diabetic foot ulceration poses a heavy burden on the patient and the healthcare system, but prevention thereof receives little attention. For every euro spent on ulcer prevention, ten are spent on ulcer healing, and for every randomized controlled trial conducted on prevention, ten are conducted on healing. In this article, we argue that a shift in priorities is needed. For the prevention of a first foot ulcer, we need more insight into the effect of interventions and practices already applied globally in many settings. This requires systematic recording of interventions and outcomes, and well-designed randomized controlled trials that include analysis of cost-effectiveness. After healing of a foot ulcer, the risk of recurrence is high. For the prevention of a recurrent foot ulcer, home monitoring of foot temperature, pressure-relieving therapeutic footwear, and certain surgical interventions prove to be effective. The median effect size found in a total of 23 studies on these interventions is large, over 60%, and further increases when patients are adherent to treatment. These interventions should be investigated for efficacy as a state-of-the-art integrated foot care approach, where attempts are made to assure treatment adherence. Effect sizes of 75-80% may be expected. If such state-of-the-art integrated foot care is implemented, the majority of problems with foot ulcer recurrence in diabetes can be resolved. It is therefore time to act and to set a new target in diabetic foot care. This target is to reduce foot ulcer incidence with at least 75%.

Rethinking connectedness: improving access to professional learning for regional and remote teachers

Transformation of Australian education is occurring at a rapid rate through the implementation of a number of initiatives. These initiatives include the Digital Education Revolution, the move to a National Curriculum and the implementation of a National Framework for Professional Standards for Teachers and Principals. As these initiatives are rolled out to schools across Australia, the equitable access to professional learning to support all teachers, regardless of their geographical location, is in question. A number of studies have been conducted in Australia that highlight the importance of professional learning and the difficulty faced by regional and remote teachers with regard to access (Gerard Daniels, 2007; Lysons, Cooksey, Panizzon, Parnell & Pegg 2006; Ministerial Review of Schooling, 1994, Rural and Remote Education Advisory Council, 2000; Vinson, 2002). Along with access to professional learning, has been the discussion of effective modes of delivery. Face to face professional learning, in regional and metropolitan areas, is offered in isolation, or in some cases, is complimented with virtual learning environments. The need for a more sustainable approach to professional learning is highly necessary. A mixed method research approach was utilised in order to answer the primary research question "In what ways might technology be used to support professional learning of regional and remote teachers in Western Australia?" This research paper outlines the findings from the study including the significance of travel time; impact of limited relief teachers; implications for promotion and teacher registration; professional learning communities being valued but often limited by small staff numbers; professional learning conducted in the local context being preferred; professional learning established at the teacher and school level being desirable; teachers being confident in using technology and accessing PD online if required; and social cohesiveness being valued and often limited by isolation. Further, this research has culminated in the development of a "model of rethinking connectedness" that would facilitate improving the amount and variety of professional learning available to regional and remote teachers.

Complimentary collaborations: Teachers and researchers co-developing best practices in art education

Australia is currently experiencing a huge cultural shift as it moves from a State-based curriculum, to a national education system. The Australian State-based bodies that currently manage teacher registration, teacher education course accreditation, curriculum frameworks and syllabi are often complex organisations that hold conflicting ideologies about education and teaching. The development of a centralised system, complete with a single accreditation body and a national curriculum can be seen as a reaction to this complexity. At the time of writing, the Australian Curriculum is being rolled out in staggered phases across the states and territories of Australia. Phase one has been implemented, introducing English, Mathematics, History and Science. Subsequent phases (Humanities and Social Sciences, the Arts, Technologies, Health and Physical Education, Languages, and year 9-10 work studies) are intended to follow. Forcing an educational shift of this magnitude is no simple task; not least because the States and Territories have and continue to demonstrate varying levels of resistance to winding down their own curricula in favour of new content with its unfamiliar expectations and organisations. The full implementation process is currently far from over, and far from being fully resolved. The Federal Government has initiated a number of strategies to progress the implementation, such as the development of the Australian Institute for Teaching and School Leadership (AITSL) to aid professional educators to implement the new curriculum. AITSL worked with professional and peak specialist bodies to develop Illustrations of Practice (hereafter IoP) for teachers to access and utilise. This paper tells of the building of one IoP, where a graduate teacher and a university lecturer collaborated to construct ideas and strategies to deliver visual arts lessons to early childhood students in a low Socio- Economic Status [SES] regional setting and discusses the experience in terms of its potential for professional learning in art education.

Structuring time and questioning to achieve tactical awareness in games lessons

Background: A paradigm shift in educational policy to create problem solvers and critical thinkers produced the games concept approach (GCA) in Singapore's Revised Syllabus for Physical Education (1999). A pilot study (2001) conducted on 11 primary school student teachers (STs) using this approach identified time management and questioning as two of the major challenges faced by novice teachers. Purpose: To examine the GCA from three perspectives: structure—lesson form in terms of teacher-time and pupil-time; product—how STs used those time fractions; and process—the nature of their questioning (type, timing, and target). Participants and setting: Forty-nine STs from three different PETE cohorts (two-year diploma, four-year degree, two-year post-graduate diploma) volunteered to participate in the study conducted during the penultimate week of their final practicum in public primary and secondary schools. Intervention: Based on the findings of the pilot study, PETE increased the emphasis on GCA content specific knowledge and pedagogical procedures. To further support STs learning to actualise the GCA, authentic micro-teaching experiences that were closely monitored by faculty were provided in schools nearby. Research design: This is a descriptive study of time-management and questioning strategies implemented by STs on practicum. Each lesson was segmented into a number of sub-categories of teacher-time (organisation, demonstration and closure) and pupil-time (practice time and game time). Questions were categorised as knowledge, technical, tactical or affective. Data collection: Each ST was video-taped teaching a GCA lesson towards the end of their final practicum. The STs individually determined the timing of the data collection and the lesson to be observed. Data analysis: Each lesson was segmented into a number of sub-categories of both teacher- and pupil-time. Duration recording using Noldus software (Observer 4.0) segmented the time management of different lesson components. Questioning was coded in terms of type, timing and target. Separate MANOVAs were used to measure the difference between programmes and levels (primary and secondary) in relation to time-management procedures and questioning strategies. Findings: No differences emerged between the programmes or levels in their time-management or questioning strategies. Using the GCA, STs generated more pupil time (53%) than teacher time (47%). STs at the primary level provided more technical practice, and those in secondary schools more small-sided game play. Most questions (58%) were asked during play or practice but were substantially low-order involving knowledge or recall (76%) and only 6.7% were open-ended or divergent and capable of developing tactical awareness. Conclusions: Although STs are delivering more pupil time (practice and game) than teacher-time, the lesson structure requires further fine-tuning to extend the practice task beyond technical drills. Many questions are being asked to generate knowledge about games but lack sufficient quality to enhance critical thinking and tactical awareness, as the GCA intends.

Molecular Tuning of Rhodopsins for High Visual Sensitivity in Different Light Environments : Variation in Absorbance Spectrum and Opsin Sequence within and between Species

Visual pigments of different animal species must have evolved at some stage to match the prevailing light environments, since all visual functions depend on their ability to absorb available photons and transduce the event into a reliable neural signal. There is a large literature on correlation between the light environment and spectral sensitivity between different fish species. However, little work has been done on evolutionary adaptation between separated populations within species. More generally, little is known about the rate of evolutionary adaptation to changing spectral environments. The objective of this thesis is to illuminate the constraints under which the evolutionary tuning of visual pigments works as evident in: scope, tempo, available molecular routes, and signal/noise trade-offs. Aquatic environments offer Nature s own laboratories for research on visual pigment properties, as naturally occurring light environments offer an enormous range of variation in both spectral composition and intensity. The present thesis focuses on the visual pigments that serve dim-light vision in two groups of model species, teleost fishes and mysid crustaceans. The geographical emphasis is in the brackish Baltic Sea area with its well-known postglacial isolation history and its aquatic fauna of both marine and fresh-water origin. The absorbance spectrum of the (single) dim-light visual pigment were recorded by microspectrophotometry (MSP) in single rods of 26 fish species and single rhabdoms of 8 opossum shrimp populations of the genus Mysis inhabiting marine, brackish or freshwater environments. Additionally, spectral sensitivity was determined from six Mysis populations by electroretinogram (ERG) recording. The rod opsin gene was sequenced in individuals of four allopatric populations of the sand goby (Pomatoschistus minutus). Rod opsins of two other goby species were investigated as outgroups for comparison. Rod absorbance spectra of the Baltic subspecies or populations of the primarily marine species herring (Clupea harengus membras), sand goby (P. minutus), and flounder (Platichthys flesus) were long-wavelength-shifted compared to their marine populations. The spectral shifts are consistent with adaptation for improved quantum catch (QC) as well as improved signal-to-noise ratio (SNR) of vision in the Baltic light environment. Since the chromophore of the pigment was pure A1 in all cases, this has apparently been achieved by evolutionary tuning of the opsin visual pigment. By contrast, no opsin-based differences were evident between lake and sea populations of species of fresh-water origin, which can tune their pigment by varying chromophore ratios. A more detailed analysis of differences in absorbance spectra and opsin sequence between and within populations was conducted using the sand goby as model species. Four allopatric populations from the Baltic Sea (B), Swedish west coast (S), English Channel (E), and Adriatic Sea (A) were examined. Rod absorbance spectra, characterized by the wavelength of maximum absorbance (λmax), differed between populations and correlated with differences in the spectral light transmission of the respective water bodies. The greatest λmax shift as well as the greatest opsin sequence difference was between the Baltic and the Adriatic populations. The significant within-population variation of the Baltic λmax values (506-511 nm) was analyzed on the level of individuals and was shown to correlate well with opsin sequence substitutions. The sequences of individuals with λmax at shorter wavelengths were identical to that of the Swedish population, whereas those with λmax at longer wavelengths additionally had substitution F261F/Y in the sixth transmembrane helix of the protein. This substitution (Y261) was also present in the Baltic common gobies and is known to redshift spectra. The tuning mechanism of the long-wavelength type Baltic sand gobies is assumed to be the co-expression of F261 and Y261 in all rods to produce ≈ 5 nm redshift. The polymorphism of the Baltic sand goby population possibly indicates ambiguous selection pressures in the Baltic Sea. The visual pigments of all lake populations of the opossum shrimp (Mysis relicta) were red-shifted by 25 nm compared with all Baltic Sea populations. This is calculated to confer a significant advantage in both QC and SNR in many humus-rich lakes with reddish water. Since only A2 chromophore was present, the differences obviously reflect evolutionary tuning of the visual protein, the opsin. The changes have occurred within the ca. 9000 years that the lakes have been isolated from the Sea after the most recent glaciation. At present, it seems that the mechanism explaining the spectral differences between lake and sea populations is not an amino acid substitution at any other conventional tuning site, but the mechanism is yet to be found.

Synthesis and Evaluation of a Novel Class of G-Quadruplex-Stabilizing Small Molecules Based on the 1,3-Phenylene-Bis(piperazinyl benzimidazole) System

Achieving stabilization of telomeric DNA in G-quadruplex conformation by Various organic compounds has been an important goal for the medicinal chemists seeking to develop new anticancer agents. Several compounds are known to stabilize G-quadruplexes. However, relatively few are known to induce their formation and/or alter the topology, of the preformed quadruplex DNA. Herein, four compounds having the 1,3-phenylene-bis(piperazinyl benzimidazole) unit as a basic skeleton have been synthesized, and their interactions with the 24-mer telomeric DNA sequences from Tetrahymena thermophilia d(T(2)G(4))(4) have been investigated using high-resolution techniques Such as circular dichroism (CD) spectropolarimetry, CD melting, emission spectroscopy, and polyacrylamide gel electrophoresis. The data obtained, in the presence of one of three ions (Li+, Na+, or K+), indicate that all the new compounds have a high affinity for G-quadruplex DNA, and the strength of the binding with G-quadruplex depends on (1) phenyl ring substitution, (ii) the piperazinyl side chain, and (iii) the type of monovalent cation present in the buffer. Results further Suggest that these compounds are able to abet the conversion of the Intramolecular quadruplex into parallel stranded intermolecular G-quadruplex DNA. Notably, these compounds are also capable of inducing and stabilizing the parallel stranded quadruplex from randomly structured DNA in the absence of any stabilizing cation. The kinetics of the structural changes Induced by these compounds could be followed by recording the changes in the CD signal as a function of time. The implications of the findings mentioned above are discussed in this paper.

The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with chronic kidney disease: A randomised controlled trial

BACKGROUND Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation. METHODS/DESIGN This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study. DISCUSSION To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.