BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell cycle arrest and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here we report that estrogen and estrogen metabolites can cause DNA double strand breaks (DSB) in estrogen receptor-α negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolising enzymes, such as CYP1A1, in breast cells. Lastly, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumours in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.

Some major problems with existing models and terminology associated with kimberlite pipes from a volcanological perspective, and some suggestions

Five significant problems hinder advances in understanding of the volcanology of kimberlites: (1) kimberlite geology is very model driven; (2) a highly genetic terminology drives deposit or facies interpretation; (3) the effects of alteration on preserved depositional textures have been grossly underestimated; (4) the level of understanding of the physical process significance of preserved textures is limited; and, (5) some inferred processes and deposits are not based on actual, modern volcanological processes. These issues need to be addressed in order to advance understanding of kimberlite volcanological pipe forming processes and deposits. The traditional, steep-sided southern African pipe model (Class I) consists of a steep tapering pipe with a deep root zone, a middle diatreme zone and an upper crater zone (if preserved). Each zone is thought to be dominated by distinctive facies, respectively: hypabyssal kimberlite (HK, descriptively called here massive coherent porphyritic kimberlite), tuffisitic kimberlite breccia (TKB, descriptively here called massive, poorly sorted lapilli tuff) and crater zone facies, which include variably bedded pyroclastic kimberlite and resedimented and reworked volcaniclastic kimberlite (RVK). Porphyritic coherent kimberlite may, however, also be emplaced at different levels in the pipe, as later stage intrusions, as well as dykes in the surrounding country rock. The relationship between HK and TKB is not always clear. Sub-terranean fluidisation as an emplacement process is a largely unsubstantiated hypothesis; modern in-vent volcanological processes should initially be considered to explain observed deposits. Crater zone volcaniclastic deposits can occur within the diatreme zone of some pipes, indicating that the pipe was largely empty at the end of the eruption, and subsequently began to fill-in largely through resedimentation and sourcing of pyroclastic deposits from nearby vents. Classes II and III Canadian kimberlite models have a more factual, descriptive basis, but are still inadequately documented given the recency of their discovery. The diversity amongst kimberlite bodies suggests that a three-model classification is an over-simplification. Every kimberlite is altered to varying degrees, which is an intrinsic consequence of the ultrabasic composition of kimberlite and the in-vent context; few preserve original textures. The effects of syn- to post-emplacement alteration on original textures have not been adequately considered to date, and should be back-stripped to identify original textural elements and configurations. Applying sedimentological textural configurations as a guide to emplacement processes would be useful. The traditional terminology has many connotations about spatial position in pipe and of process. Perhaps the traditional terminology can be retained in the industrial situation as a general lithofacies-mining terminological scheme because it is so entrenched. However, for research purposes a more descriptive lithofacies terminology should be adopted to facilitate detailed understanding of deposit characteristics, important variations in these, and the process origins. For example every deposit of TKB is different in componentry, texture, or depositional structure. However, because so many deposits in many different pipes are called TKB, there is an implication that they are all similar and that similar processes were involved, which is far from clear.

Is comfort important for optimal use of child restraints?

Suboptimal restraint use, particularly the incorrect use of restraints, is a significant and widespread problem among child vehicle occupants, and increases the risk of injury. Previous research has identified comfort as a potential factor influencing suboptimal restraint use. Both the real comfort experienced by the child and the parent’s perception of the child’s comfort are reported to influence the optimal use of restraints. Problems with real comfort may lead the child to misuse the restraint in their attempt to achieve better comfort whilst parent-perceived discomfort has been reported as a driver for premature graduation and inappropriate restraint choice. However, this work has largely been qualitative. There has been no research that objectively studies either the association between real and parental perceived comfort, or any association between comfort and suboptimal restraint use. One barrier to such studies is the absence of validated tools for quantifying real comfort in children. We aimed to develop methods to examine both real and parent-perceived comfort and examine their effects on suboptimal restraint use. We conducted online parent surveys (n=470) to explore what drives parental perceptions of their child’s comfort in restraint systems (study 1) and used data from field observation studies (n=497) to examine parent-perceived comfort and its relationship with observed restraint use (study 2). We developed methods to measure comfort in children in a laboratory setting (n=14) using video analysis to estimate a Discomfort Avoidance Behaviour (DAB) score, pressure mapping and adapted survey tools to differentiate between comfortable and induced discomfort conditions (study 3). Preliminary analysis of our recent online survey of Australian parents (study 1) indicates that 23% of parents report comfort as a consideration when making a decision to change restraints. Logistic regression modelling of data collected during the field observation study (study 2) revealed that parent-perceived discomfort was not significantly associated with premature graduation. Contrary to expectation, children of parents who reported that their child was comfortable were almost twice as likely to have been incorrectly restrained (p<0.01, 95% CI 1.24 - 2.77). In the laboratory study (study 3) we found our adapted survey tools did not provide a reliable measurement of real comfort among children. However our DAB score was able to differentiate between comfortable and induced discomfort conditions and correlated well with pressure mapping. Our results suggest that while some parents report concern about their child’s comfort, parent-reported comfort levels were not associated with restraint choice. If comfort is important for optimal restraint use, it is likely to be the real comfort of the child rather than that reported by the parent. The method we have developed for studying real comfort can be used in naturalistic studies involving child occupants to further understand this relationship. This work will be of interest to vehicle and child restraint manufacturers interested in improving restraint design for young occupants as well as researchers and other stakeholders interested in reducing the incidence of restraint misuse among children.

Adoption dynamics of increasing-return technologies in systemic contexts

Many systemic, complex technologies have been suggested to exhibit increasing returns to adoption, whereby the initial increase in adoption leads to increasing experience with the technology, which drives technological improvements and use, subsequently leading to further adoption. In addition, in the systemic context, mimetic behavior may lend support to increasing returns as technology adoption is witnessed among other agents in the systemic context. Finally, inter-dependencies in the systemic context also sensitize the adoption behavior to fundamental changes in technology provisioning, and this may lend support for the increasing returns type of dynamics in adoption. Our empirical study examines the dynamics of organizational technology adoption when technology is provisioned by organizations in another sub-system in a systemic context. We hypothesize that innovation, imitation, and technological change effects are present in creating increasing returns in the systemic context. Our empirical setting considers 24 technologies represented by 2282 data points in the computer industry. Our results provide support for our prediction that imitation effects are present in creating increasing returns to adoption. We further discuss the managerial and research implications of our results.

Modelling milling train performance

This paper describes recent updates to a milling train extraction model used to assess and predict the performance of a milling train. An extension was made to the milling unit model for the bagasse mills to replace the imbibition coefficient with crushing factor and mixing efficiency. New empirical relationships for reabsorption factor, imbibition coefficient, crushing factor, mixing efficiency and purity ratio were developed. The new empirical relationships were tested against factory measurements and previous model predictions. The updated model has been implemented in the SysCAD process modelling software. New additions to the model implementation include: a shredder model to assess or predict cane preparation, mill and shredder drives for power consumption and an updated imbibition control system to add allow water to be added to intermediate mills.

Client learning and the performance of collaborative infrastructure projects

Australia is a leading user of collaborative procurement methods, which are used to deliver large and complex infrastructure projects. Project alliances, Early Contractor Involvement (ECI), and partnering are typical examples of collaborative procurement models. In order to increase procurement effectiveness and value for money (VfM), clients have adopted various learning strategies for new contract development. However client learning strategies and behaviours have not been systematically analysed before. Therefore, the current paper undertakes a literature review addressing the research question “How can client learning capabilities be effectively understood?”. From the resource-based and dynamic capability perspectives, this paper proposes that the collaborative learning capability (CLC) of clients drives procurement model evolution. Learning routines underpinning CLC carry out exploratory, transformative and exploitative learning phases associated with collaborative project delivery. This learning improves operating routines, and ultimately performance. The conceptualization of CLC and the three sequential learning phases is used to analyse the evidence in the construction management literature. The main contribution of this study is the presentation of a theoretical foundation for future empirical studies to unveil effective learning strategies, which help clients to improve the performance of collaborative projects in the dynamic infrastructure market.

Interleukin-23 mediates the intestinal response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in SKG mice

Objective Spondyloarthritides (SpA) occur in 1% of the population and include ankylosing spondylitis (AS) and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis, and IBD. Genetic studies implicate interleukin-23 (IL-23) receptor signaling in the development of SpA and IBD, and IL-23 overexpression in mice is sufficient for enthesitis, driven by entheseal-resident T cells. However, in genetically prone individuals, it is not clear where IL-23 is produced and how it drives the SpA syndrome, including IBD or subclinical gut inflammation of AS. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We undertook this study to determine the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP-70W163C-mutant (SKG) mice injected intraperitoneally with β-1,3-glucan (curdlan). Methods Eight weeks after curdlan injection in wild-type or IL-17A-/- SKG or BALB/c mice, pathology was scored in tissue sections. Mice were treated with anti-IL-23 or anti-IL-22. Cytokine production and endoplasmic reticulum (ER) stress were determined in affected organs. Results In curdlan-treated SKG mice, arthritis, enthesitis, and ileitis were IL-23 dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-23 was induced in the ileum, where it amplified ER stress, goblet cell dysfunction, and proinflammatory cytokine production. IL-17A was pathogenic, while IL-22 was protective against ileitis. IL-22+CD3- innate-like cells were increased in lamina propria mononuclear cells of ileitis-resistant BALB/c mice, which developed ileitis after curdlan injection and anti-IL-22. Conclusion In response to systemic β-1,3-glucan, intestinal IL-23 provokes local mucosal dysregulation and cytokines driving the SpA syndrome, including IL-17/IL-22-dependent enthesitis. Innate IL-22 production promotes ileal tolerance.

Milling innovations at Rocky Point

This paper reviews the innovations that have been introduced in the milling train at Rocky Point mill since 2001 and provides some operational, performance and maintenance comparisons of the technologies in use. The decision to install BHEM mills in the #2 and #3 mill positions to complement the six-roll mills in the #1 and #4 mill positions has proven a good one. Satisfactory performance is being obtained by these mills while maintenance costs are significantly less. Very good #1 mill extraction and final bagasse moisture content are being achieved. The innovation of using Hägglunds hydraulic drives at higher speed…

Particle emissions from biodiesels with different physical properties and chemical composition

Biodiesels produced from different feedstocks usually have wide variations in their fatty acid methyl ester (FAME) so that their physical properties and chemical composition are also different. The aim of this study is to investigate the effect of the physical properties and chemical composition of biodiesels on engine exhaust particle emissions. Alongside with neat diesel, four biodiesels with variations in carbon chain length and degree of unsaturation have been used at three blending ratios (B100, B50, B20) in a common rail engine. It is found that particle emission increased with the increase of carbon chain length. However, for similar carbon chain length, particle emissions from biodiesel having relatively high average unsaturation are found to be slightly less than that of low average unsaturation. Particle size is also found to be dependent on fuel type. The fuel or fuel mix responsible for higher particle mass (PM) and particle number (PN) emissions is also found responsible for larger particle median size. Particle emissions reduced consistently with fuel oxygen content regardless of the proportion of biodiesel in the blends, whereas it increased with fuel viscosity and surface tension only for higher diesel–biodiesel blend percentages (B100, B50). However, since fuel oxygen content increases with the decreasing carbon chain length, it is not clear which of these factors drives the lower particle emission. Overall, it is evident from the results presented here that chemical composition of biodiesel is more important than its physical properties in controlling exhaust particle emissions.

Thermal evolution of the submonolayer near-surface alloy of ZnPd on Pd (111)

We have performed a high-resolution synchrotron radiation photoelectron spectroscopy study of the initial growth stages of the ZnPd near-surface alloy on Pd(111), complemented by scanning tunnelling microscopy data. We show that the chemical environment for surfaces containing less than half of one monolayer of Zn is chemically distinct from subsequent layers. Surfaces where the deposition is performed at room temperature contain ZnPd islands surrounded by a substrate with dilute Zn substitutions. Annealing these surfaces drives the Zn towards the substrate top-layer, and favours the completion of the first 1 : 1 monolayer before the onset of growth in the next layer.

Catalytic transformation of aliphatic alcohols to corresponding esters in O2 under neutral conditions using visible-light irradiation

Selective oxidation of aliphatic alcohols under mild and base-free conditions is a challenging process for organic synthesis. Herein, we report a one-pot process for the direct oxidative esterification of aliphatic alcohols that is significantly enhanced by visible-light irradiation at ambient temperatures. The new methodology uses heterogenerous photocatalysts of gold–palladium alloy nanoparticles on a phosphate-modified hydrotalcite support and molecular oxygen as a benign oxidant. The alloy photocatalysts can absorb incident light, and the light-excited metal electrons on the surface of metal nanoparticles can activate the adsorbed reactant molecules. Tuning the light intensity and wavelength of the irradiation can remarkably change the reaction activity. Shorter wavelength light (<550 nm) drives the reaction more efficiently than light of longer wavelength (e.g., 620 nm), especially at low temperatures. The phosphate-exchanged hydrotalcite support provides sufficient basicity (and buffer) for the catalytic reactions; thus, the addition of base is not required. The photocatalysts are efficient and readily recyclable. The findings reveal the first example of using “green” oxidants and light energy to drive direct oxidative esterification of aliphatic alcohols under base-free, mild conditions.

The role of comfort in child restraint use practices

Suboptimal restraint use, particularly the incorrect use of restraints, is a significant and widespread problem among child vehicle occupants, and increases the risk of injury. Previous research has identified comfort as a potential factor influencing suboptimal restraint use. Both the real comfort experienced by the child and the parent’s perception of the child’s comfort are reported to influence the optimal use of restraints. Problems with real comfort may lead the child to misuse the restraint in their attempt to achieve better comfort whilst parent-perceived discomfort has been reported as a driver for premature graduation and inappropriate restraint choice. However, this work has largely been qualitative. There has been no research that objectively studies either the association between real and parent-perceived comfort, or any association between comfort and suboptimal restraint use. One barrier to such studies is the absence of validated tools for quantifying real comfort in children. We aimed to develop methods to examine both real and parent-perceived comfort and examine their effects on suboptimal restraint use. We conducted online parent surveys (n=470) to explore what drives parental perceptions of their child’s comfort in restraint systems (study 1) and used data from field observation studies (n=497) to examine parent-perceived comfort and its relationship with observed restraint use (study 2). We developed methods to measure comfort in children in a laboratory setting (n=14) using video analysis to estimate a Discomfort Avoidance Behaviour (DAB) score, pressure mapping and adapted survey tools to differentiate between comfortable and induced discomfort conditions (study 3). The DAB rate was then used to compare an integrated booster with an add-on booster (study 4) Preliminary analysis of our recent online survey of Australian parents (study 1) indicates that 23% of parents report comfort as a consideration when making a decision to change restraints. Logistic regression modelling of data collected during the field observation study (study 2) revealed that parent-perceived discomfort was not significantly associated with premature graduation. Contrary to expectation, children of parents who reported that their child was comfortable were almost twice as likely to have been incorrectly restrained (p<0.01, 95% CI 1.24 - 2.77).In the laboratory study (study 3) we found our adapted survey tools did not provide a reliable measurement of real comfort among children. However our DAB score was able to differentiate between comfortable and induced discomfort conditions and correlated well with pressure mapping. Preliminary results from the laboratory comparison study (study 4) indicate a positive correlation between DAB rate and use errors. In experiments conducted to date, we have seen a significantly higher DAB rate in the integrated booster compared to the add-on booster (p < 0.01). However, this needs to be confirmed in a naturalistic setting and in further experiments that take length of time under observation into account. Our results suggest that while some parents report concern about their child’s comfort, parent-reported comfort levels were not associated with restraint choice. If comfort is important for optimal restraint use, it is likely to be the real comfort of the child rather than that reported by the parent. The method we have developed for studying real comfort can be used in naturalistic studies involving child occupants to further understand this relationship. This work will be of interest to vehicle and child restraint manufacturers interested in improving restraint design for young occupants as well as researchers and other stakeholders interested in reducing the incidence of restraint misuse among children.

The mechanisms of human renal epithelial cell modulation of autologous dendritic cell phenotype and function

Proximal tubule epithelial cells (PTEC) of the kidney line the proximal tubule downstream of the glomerulus and play a major role in the re-absorption of small molecular weight proteins that may pass through the glomerular filtration process. In the perturbed disease state PTEC also contribute to the inflammatory disease process via both positive and negative mechanisms via the production of inflammatory cytokines which chemo-attract leukocytes and the subsequent down-modulation of these cells to prevent uncontrolled inflammatory responses. It is well established that dendritic cells are responsible for the initiation and direction of adaptive immune responses. Both resident and infiltrating dendritic cells are localised within the tubulointerstitium of the renal cortex, in close apposition to PTEC, in inflammatory disease states. We previously demonstrated that inflammatory PTEC are able to modulate autologous human dendritic cell phenotype and functional responses. Here we extend these findings to characterise the mechanisms of this PTEC immune-modulation using primary human PTEC and autologous monocyte-derived dendritic cells (MoDC) as the model system. We demonstrate that PTEC express three inhibitory molecules: (i) cell surface PD-L1 that induces MoDC expression of PD-L1; (ii) intracellular IDO that maintains the expression of MoDC CD14, drives the expression of CD80, PD-L1 and IL-10 by MoDC and inhibits T cell stimulatory capacity; and (iii) soluble HLA-G (sHLA-G) that inhibits HLA-DR and induces IL-10 expression by MoDC. Collectively the results demonstrate that primary human PTEC are able to modulate autologous DC phenotype and function via multiple complex pathways. Further dissection of these pathways is essential to target therapeutic strategies in the treatment of inflammatory kidney disorders.

Internet marketing capabilities and international market growth

The Internet has been shown to facilitate elements of internationalisation such as information accumulation and network opportunities. However, there is limited understanding of how the Internet combined with marketing capabilities drives international market growth. This study, based on a sample of 224 Australian firms, develops and tests, using structural equation modelling (SEM), a conceptual model of Internet marketing capabilities and international market growth. Results indicate that firms deploying Internet marketing capabilities will benefit due to the reduction of information uncertainty and increased capacity to develop international network capabilities. Moreover, Internet marketing capabilities indirectly lead to international market growth when the firm has a high level of international strategic orientation and international network capabilities. Overall, Internet marketing capabilities enhance the firm's ability to generate other internal capabilities within the firm, which in turn have a positive impact on the international market growth of the firm.

Online learning an effective means for developing small business owner-managers’ capabilities?

Purpose If owner-managers engage in management development activities then chances of success may be improved for small businesses. But small business owner-managers (SBOMs) are a difficult group to engage in management development activities. While practitioners worry about timing, content and location of development activities, the purpose of this paper is to examine what drives SBOMs to participate in an online discussion forum (ODF) as a form of management development. An ODF was run with SBOMs and the factors affecting their participation are reported from this exploratory study. Design/methodology/approach A qualitative methodology was used where data gathered from three sources, the ODF posts, in-depth interviews with participants and a focus group with non-participants. These were analysed to evaluate factors affecting participation of SBOMs in an ODF. Findings The findings point to the importance of owner-managers’ attitudes. Attitudes that positively affected SBOMs participation in the ODF included; appreciating that learning leads to business success; positive self-efficacy developed through prior online experience; and an occupational identity as a business manager. Research limitations/implications Few SBOMs participated in the ODF, which is consistent with research finding that they are a difficult group to engage in management development learning activities. Three forms of data were analysed to strengthen results. Practical implications Caution should be exercised when considering investment in e-learning to develop the managerial capabilities of SBOMs. Originality/value Evidence of the factors important for participation in an informal voluntary ODF. The findings suggest greater emphasis should be placed on changing attitudes if SBOMs are to be encouraged to participate in management development activities.