Exploring human resource development: a level of analysis approach.

Levels of analysis perform an important function in framing research and practice in human resource development (HRD). The purpose of this paper is to examine the concept of HRD from the individual, organizational and community/societal levels of analysis. The paper highlights both the distinctiveness and usefulness of each level of analysis, identifies tensions within and between them, and outlines differences in underpinning assumptions, characteristics of HRD provision and delivery of HRD interventions. By adopting this approach, the paper draws attention to variations in meaning, intent, content and practice with implications for developing both the theory and practice of HRD.

Moodle on the Move.

Recent shifts in technology have seen some writers question the value of tablet computers as phones becomes bigger, more powerful and their battery life improves: (http://www.wired.com/2015/01/nobody-knows-ipad-good-anymore/ In trying to encourage greater student engagement with their studies, lecturers can be caught unsure of how to proceed. Moodle has improved since its introduction and now it adjusts the content to match the screen size. Does that matter? Results from a recent module survey suggests that 75% of students access Moodle from their phone which would suggest that when we design our Moodle pages we may need to think about the placement of information. What works on a 21" HD monitor in our office may not give the same result on a laptop, tablet or phone.

Interactive support effects on career agency and occupational engagement among young adults.

The PIC model by Gati and Asher describes three career decision making stages: pre-screening, in-depth exploration, and choice of career options. We consider the role that three different forms of support (general career support by parents, emotional/instrumental support, and informational support) may play for young adults in each of these three decision-making stages. The authors further propose that different forms of support may predict career agency and occupational engagement, which are important career decision precedents. In addition, we consider the role of personality traits and perceptions (decision-making window) on these two outcomes. Using an online survey sample (N = 281), we found that general career support was important for career agency and occupational engagement. However, it was the combination of higher general career support with either emotional/instrumental support or informational support that was found to lead to both greater career agency and higher occupational engagement. Personality also played a role: Greater proactivity also led to greater occupational engagement, even when there was little urgency for participants to make decisions (window of decision-making was wide open and not restricted). In practical terms, the findings suggest that the learning required in each of the three PIC processes (pre-screening, in-depth exploration, choice of career options may benefit when the learner has access to the three support measures.

The Rpf/DSF system and the regulation of virulence in the plant pathogen Xanthomonas campestris

The full virulence of Xanthomonas campestris pv. campestris (Xcc) to plants depends upon cell-to-cell signalling mediated by the signal molecule DSF (for diffusible signal factor), that has been characterised as cis-11-methyl-2-dodecenoic acid. DSF-mediated signalling regulates motility, biofilm dynamics and the synthesis of particular virulence determinants. The synthesis and perception of the DSF signal molecule involves products of the rpf (regulation of pathogenicity factors) gene cluster. DSF synthesis is fully dependent on RpfF, which encodes a putative enoyl-CoA hydratase. A two-component system, comprising the complex sensor histidine kinase RpfC and the HD-GYP domain regulator RpfG, is implicated in DSF perception. The HD-GYP domain of RpfG is a phosphodiesterase working on cyclic di-GMP; DSF perception is thereby linked to the turnover of this intracellular second messenger. The full range of regulatory influences of the Rpf/DSF system and of cyclic di-GMP in Xcc has yet to be established. In order to further characterise the Rpf/DSF regulatory network in Xcc, a proteomic approach was used to compare protein expression in the wildtype and defined rpf mutants. This work shows that the Rpf/DSF system regulates a range of biological functions that are associated with virulence and biofilm formation but also reveals new functions mediated by DSF regulation. These functions include antibiotic resistance, detoxification and stress tolerance. Mutational analysis showed that several of these regulated protein functions contribute to virulence in Chinese radish. Interestingly, it was demonstrated that different patterns of protein expression are associated with mutations of rpfF, rpfC and rpfG. This suggests that RpfG and RpfC have broader roles in regulation other than perception and transduction of DSF. Taken together, this analysis indicates the broad and complex regulatory role of Rpf/DSF system and identifies a number of new functions under Rpf/DSF control, which were shown to play a role in virulence.

Modified cyclodextrins as novel non-viral vectors for neuronal siRNA delivery: focus on Huntington’s disease

Huntington’s Disease (HD) is a rare autosomal dominant neurodegenerative disease caused by the expression of a mutant Huntingtin (muHTT) protein. Therefore, preventing the expression of muHTT by harnessing the specificity of the RNA interference (RNAi) pathway is a key research avenue for developing novel therapies for HD. However, the biggest caveat in the RNAi approach is the delivery of short interfering RNA (siRNAs) to neurons, which are notoriously difficult to transfect. Indeed, despite the great advances in the field of nanotechnology, there remains a great need to develop more effective and less toxic carriers for siRNA delivery to the Central Nervous System (CNS). Thus, the aim of this thesis was to investigate the utility of modified amphiphilic β-cyclodextrins (CDs), oligosaccharide-based molecules, as non-viral vectors for siRNA delivery for HD. Modified CDs were able to bind and complex siRNAs forming nanoparticles capable of delivering siRNAs to ST14A-HTT120Q cells and to human HD fibroblasts, and reducing the expression of the HTT gene in these in vitro models of HD. Moreover, direct administration of CD.siRNA nanoparticles into the R6/2 mouse brain resulted in significant HTT gene expression knockdown and selective alleviation of rotarod motor deficits in this mouse model of HD. In contrast to widely used transfection reagents, CD.siRNA nanoparticles only induced limited cytotoxic and neuroinflammatory responses in multiple brain-derived cell-lines, and also in vivo after single direct injections into the mouse brain. Alternatively, we have also described a PEGylation-based formulation approach to further stabilise CD.siRNA nanoparticles and progress towards a systemic delivery nanosystem. Resulting PEGylated CD.siRNA nanoparticles showed increased stability in physiological saltconditions and, to some extent, reduced protein-induced aggregation. Taken together, the work outlined in this thesis identifies modified CDs as effective, safe and versatile siRNA delivery systems that hold great potential for the treatment of CNS disorders, such as HD.

Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated skin and skin-structure infection (cSSSI). Increasing antimicrobial resistance in cSSSI has led to a need for new safe and effective therapies. Ceftaroline was evaluated as treatment for cSSSI in 2 identical phase 3 clinical trials, the pooled analysis of which is presented here. The primary objective of each trial was to determine the noninferiority of the clinical cure rate achieved with ceftaroline monotherapy, compared with that achieved with vancomycin plus aztreonam combination therapy, in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations. METHODS: Adult patients with cSSSI requiring intravenous therapy received ceftaroline (600 mg every 12 h) or vancomycin plus aztreonam (1 g each every 12 h) for 5-14 days. RESULTS: Of 1378 patients enrolled in both trials, 693 received ceftaroline and 685 received vancomycin plus aztreonam. Baseline characteristics of the treatment groups were comparable. Clinical cure rates were similar for ceftaroline and vancomycin plus aztreonam in the CE (91.6% vs 92.7%) and MITT (85.9% vs 85.5%) populations, respectively, as well as in patients infected with MRSA (93.4% vs 94.3%). The rates of adverse events, discontinuations because of an adverse event, serious adverse events, and death also were similar between treatment groups. CONCLUSIONS: Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and other common cSSSI pathogens, and was well tolerated, with a safety profile consistent with the cephalosporin class. Ceftaroline has the potential to provide a monotherapy alternative for the treatment of cSSSI. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2.

The toxicology of climate change: environmental contaminants in a warming world.

Climate change induced by anthropogenic warming of the earth's atmosphere is a daunting problem. This review examines one of the consequences of climate change that has only recently attracted attention: namely, the effects of climate change on the environmental distribution and toxicity of chemical pollutants. A review was undertaken of the scientific literature (original research articles, reviews, government and intergovernmental reports) focusing on the interactions of toxicants with the environmental parameters, temperature, precipitation, and salinity, as altered by climate change. Three broad classes of chemical toxicants of global significance were the focus: air pollutants, persistent organic pollutants (POPs), including some organochlorine pesticides, and other classes of pesticides. Generally, increases in temperature will enhance the toxicity of contaminants and increase concentrations of tropospheric ozone regionally, but will also likely increase rates of chemical degradation. While further research is needed, climate change coupled with air pollutant exposures may have potentially serious adverse consequences for human health in urban and polluted regions. Climate change producing alterations in: food webs, lipid dynamics, ice and snow melt, and organic carbon cycling could result in increased POP levels in water, soil, and biota. There is also compelling evidence that increasing temperatures could be deleterious to pollutant-exposed wildlife. For example, elevated water temperatures may alter the biotransformation of contaminants to more bioactive metabolites and impair homeostasis. The complex interactions between climate change and pollutants may be particularly problematic for species living at the edge of their physiological tolerance range where acclimation capacity may be limited. In addition to temperature increases, regional precipitation patterns are projected to be altered with climate change. Regions subject to decreases in precipitation may experience enhanced volatilization of POPs and pesticides to the atmosphere. Reduced precipitation will also increase air pollution in urbanized regions resulting in negative health effects, which may be exacerbated by temperature increases. Regions subject to increased precipitation will have lower levels of air pollution, but will likely experience enhanced surface deposition of airborne POPs and increased run-off of pesticides. Moreover, increases in the intensity and frequency of storm events linked to climate change could lead to more severe episodes of chemical contamination of water bodies and surrounding watersheds. Changes in salinity may affect aquatic organisms as an independent stressor as well as by altering the bioavailability and in some instances increasing the toxicity of chemicals. A paramount issue will be to identify species and populations especially vulnerable to climate-pollutant interactions, in the context of the many other physical, chemical, and biological stressors that will be altered with climate change. Moreover, it will be important to predict tipping points that might trigger or accelerate synergistic interactions between climate change and contaminant exposures.

Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits.

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a poly-glutamine (poly-Q) stretch in the huntingtin (Htt) protein. Gain-of-function effects of mutant Htt have been extensively investigated as the major driver of neurodegeneration in HD. However, loss-of-function effects of poly-Q mutations recently emerged as potential drivers of disease pathophysiology. Early synaptic problems in the excitatory cortical and striatal connections have been reported in HD, but the role of Htt protein in synaptic connectivity was unknown. Therefore, we investigated the role of Htt in synaptic connectivity in vivo by conditionally silencing Htt in the developing mouse cortex. When cortical Htt function was silenced, cortical and striatal excitatory synapses formed and matured at an accelerated pace through postnatal day 21 (P21). This exuberant synaptic connectivity was lost over time in the cortex, resulting in the deterioration of synapses by 5 weeks. Synaptic decline in the cortex was accompanied with layer- and region-specific reactive gliosis without cell loss. To determine whether the disease-causing poly-Q mutation in Htt affects synapse development, we next investigated the synaptic connectivity in a full-length knock-in mouse model of HD, the zQ175 mouse. Similar to the cortical conditional knock-outs, we found excessive excitatory synapse formation and maturation in the cortices of P21 zQ175, which was lost by 5 weeks. Together, our findings reveal that cortical Htt is required for the correct establishment of cortical and striatal excitatory circuits, and this function of Htt is lost when the mutant Htt is present.

Flexible self-adjustment of task deployment in dynamic environments

This paper presents an investigation into dynamic self-adjustment of task deployment and other aspects of self-management, through the embedding of multiple policies. Non-dedicated loosely-coupled computing environments, such as clusters and grids are increasingly popular platforms for parallel processing. These abundant systems are highly dynamic environments in which many sources of variability affect the run-time efficiency of tasks. The dynamism is exacerbated by the incorporation of mobile devices and wireless communication. This paper proposes an adaptive strategy for the flexible run-time deployment of tasks; to continuously maintain efficiency despite the environmental variability. The strategy centres on policy-based scheduling which is informed by contextual and environmental inputs such as variance in the round-trip communication time between a client and its workers and the effective processing performance of each worker. A self-management framework has been implemented for evaluation purposes. The framework integrates several policy-controlled, adaptive services with the application code, enabling the run-time behaviour to be adapted to contextual and environmental conditions. Using this framework, an exemplar self-managing parallel application is implemented and used to investigate the extent of the benefits of the strategy

Constructive trusts, illegal purpose and locus poenitentiae

Analyses the Family Division decision in Q v Q on the competing claims of a father and son to beneficial ownership of a house in which the father sought to on a secret agreement entered into with his sons when transferring the property into their joint names, intended to subvert the inheritance tax rules on lifetime gifts by retaining the right to have the property transferred back to him, and the son relied on a later agreement with his brother to transfer the house into his sole name, in reliance on which he and his wife had acted to their detriment by paying for its upkeep and renovation.

Contractual termination of leases: lessons from the Commonwealth: Pt. 1

This, the first part of a three-part article on contractual termination of leases, considers the extent to which determination of a lease in accordance with the contract law principles of frustration and acceptance of a repudiatory breach has been accepted by Commonwealth courts. Reviews the approaches adopted by the courts in Canada, the US and Australia to the application of contractual principles to landlord and tenant disputes.

Options to renew leases: time for legislative relief?

Argues that England should follow the example of Australia and New Zealand and give the courts statutory power to grant a tenant relief against forfeiture of the right to exercise an option to renew a lease by reason of the tenant being in breach of covenant. Suggests the legislative provision introducing this power should adopt wording mirroring that in the Law of Property Act 1925 s.146(2).

Meaning of "residing with" and succession rights

Reviews case law on the meaning of the phrase "residing with" as used in the Housing Act 1985 s.87 to identify one of the qualifying requirements for the right to succeed to a secure tenancy. Focuses on the Court of Appeal decision in Freeman v Islington LBC on whether a daughter intended to have her settled home with her father where, in the year preceding her father's death she lived with him full time in order to care for him whilst retaining her own flat and using it as her correspondence address for everything but her credit card. Lists conclusions that can be drawn from the case law.

The promised land

Examines the House of Lords ruling in Thorner v Curtis on whether the claimant could rely on proprietary estoppel against the estate of the deceased, who had died intestate, based on an assurance given by the deceased that the claimant would inherit the deceased's farm. Reviews case law on proprietary estoppel and testamentary promises, and considers the possible application of constructive trust doctrine in similar cases.