Regulation of ROCK1 via Notch1 during breast cancer cell migration into dense matrices

Background The behaviour of tumour cells depends on factors such as genetics and the tumour microenvironment. The latter plays a crucial role in normal mammary gland development and also in breast cancer initiation and progression. Breast cancer tissues tend to be highly desmoplastic and dense matrix as a pre-existing condition poses one of the highest risk factors for cancer development. However, matrix influence on tumour cell gene expression and behaviour such as cell migration is not fully elucidated. Results We generated high-density (HD) matrices that mimicked tumour collagen content of 20 mg/cm3 that were ~14-fold stiffer than low-density (LD) matrix of 1 mg/cm3. Live-cell imaging showed breast cancer cells utilizing cytoplasmic streaming and cell body contractility for migration within HD matrix. Cell migration was blocked in the presence of both the ROCK inhibitor, Y-27632, and the MMP inhibitor, GM6001, but not by the drugs individually. This suggests roles for ROCK1 and MMP in cell migration are complicated by compensatory mechanisms. ROCK1 expression and protein activity, were significantly upregulated in HD matrix but these were blocked by treatment with a histone deacetylase (HDAC) inhibitor, MS-275. In HD matrix, the inhibition of ROCK1 by MS-275 was indirect and relied upon protein synthesis and Notch1. Inhibition of Notch1 using pooled siRNA or DAPT abrogated the inhibition of ROCK1 by MS-275. Conclusion Increased matrix density elevates ROCK1 activity, which aids in cell migration via cell contractility. The upregulation of ROCK1 is epigenetically regulated in an indirect manner involving the repression of Notch1. This is demonstrated from inhibition of HDACs by MS-275, which caused an upregulation of Notch1 levels leading to blockade of ROCK1 expression.

The impact of fuser roller temperature on laser printer particle emission

The emission of particles in the ultrafine range (<100 nm) from laser printers has not been reported until recently (Uhde et al., 2006; He et al., 2007; Morawska et al., 2009). The research reported to date has provided a body of information about printer emissions and shed light on particle formation mechanisms. However, until now, the effect of fuser roller temperature on particle emissions had not been comprehensively investigated...

Heat strain evaluation of overt and covert body armour in a hot and humid environment

The aim of this study was to elucidate the thermophysiological effects of wearing lightweight non-military overt and covert personal body armour (PBA) in a hot and humid environment. Eight healthy males walked on a treadmill for 120 min at 22% of their heart rate reserve in a climate chamber simulating 31 °C (60%RH) wearing either no armour (control), overt or covert PBA in addition to a security guard uniform, in a randomised controlled crossover design. No significant difference between conditions at the end of each trial was observed in core temperature, heart rate or skin temperature (P > 0.05). Covert PBA produced a significantly greater amount of body mass change (−1.81 ± 0.44%) compared to control (−1.07 ± 0.38%, P = 0.009) and overt conditions (−1.27 ± 0.44%, P = 0.025). Although a greater change in body mass was observed after the covert PBA trial; based on the physiological outcome measures recorded, the heat strain encountered while wearing lightweight, non-military overt or covert PBA was negligible compared to no PBA. Practitioner summary The wearing of bullet proof vests or body armour is a requirement of personnel engaged in a wide range of occupations including police, security, customs and even journalists in theatres of war. This randomised controlled crossover study is the first to examine the thermophysiological effects of wearing lightweight non-military overt and covert personal body armour (PBA) in a hot and humid environment. We conclude that the heat strain encountered while wearing both overt and covert lightweight, non-military PBA was negligible compared to no PBA.

F9 fimbriae of uropathogenic Escherichia coli are expressed at low temperature and recognise Galβ1-3GlcNAc-containing glycans

Uropathogenic Escherichia coli (UPEC) is the leading causative agent of urinary tract infections (UTI) in the developed world. Among the major virulence factors of UPEC, surface expressed adhesins mediate attachment and tissue tropism. UPEC strains typically possess a range of adhesins, with type 1 fimbriae and P fimbriae of the chaperone-usher class the best characterised. We previously identified and characterised F9 as a new chaperone-usher fimbrial type that mediates biofilm formation. However, the regulation and specific role of F9 fimbriae remained to be determined in the context of wild-type clinical UPEC strains. In this study we have assessed the distribution and genetic context of the f9 operon among diverse E. coli lineages and pathotypes and demonstrated that f9 genes are significantly more conserved in a UPEC strain collection in comparison to the well-defined E. coli reference (ECOR) collection. In the prototypic UPEC strain CFT073, the global regulator protein H-NS was identified as a transcriptional repressor of f9 gene expression at 37°C through its ability to bind directly to the f9 promoter region. F9 fimbriae expression was demonstrated at 20°C, representing the first evidence of functional F9 fimbriae expression by wild-type E. coli. Finally, glycan array analysis demonstrated that F9 fimbriae recognise and bind to terminal Galβ1-3GlcNAc structures.

Supply chain regulation to protect the occupational health and safety of vulnerable workers

The last two decades have witnessed a fragmentation of previously integrated systems of production and service delivery with the advent of boundary-less, networked and porous organisational forms. This trend has been associated with the growth of outsourcing and increased use of contingent workers. One consequence of these changes is the development of production/service delivery systems based on complex national and international networks of multi-tiered subcontracting increasingly labelled as supply chains. A growing body of research indicates that subcontracting and contingent work arrangements affect design and decision-making processes in ways that can seriously undermine occupational health and safety (OHS). Elaborate supply chains also present a regulatory challenge because legal responsibility for OHS is diffused amongst a wider array of parties, targeting key decision-makers is more difficult, and government agencies encounter greater logistical difficulties trying to safeguard contingent workers. In a number of industries these problems have prompted new forms of regulatory intervention, including mechanisms for sheeting legal responsibility to the top of supply chains, contractual tracking devices and increasing industry, union and community involvement in enforcement. After describing the problems just alluded to this paper examines recent efforts to regulate supply chains to safeguard OHS in the United Kingdom and Australia.

Stochastic ranking method for thermostatically controllable appliances to provide regulation services

Demand response can be used for providing regulation services in the electricity markets. The retailers can bid in a day-ahead market and respond to real-time regulation signal by load control. This paper proposes a new stochastic ranking method to provide regulation services via demand response. A pool of thermostatically controllable appliances (TCAs) such as air conditioners and water heaters are adjusted using direct load control method. The selection of appliances is based on a probabilistic ranking technique utilizing attributes such as temperature variation and statuses of TCAs. These attributes are stochastically forecasted for the next time step using day-ahead information. System performance is analyzed with a sample regulation signal. Network capability to provide regulation services under various seasons is analyzed. The effect of network size on the regulation services is also investigated.

Book review - Richard Goldberg, Medicinal Product Liability and Regulation (Hart Publishing, Oxford, 2013) 214pp

In December 2013, settlement was reached between approximately 100 Australian and New Zealand Thalidomide victims and the company which had acted as the Australian distributor of the infamous drug, thus putting to rest the possibility of litigation. Around the same time, Thalidomide victims in the United Kingdom (UK) launched a similar bid for compensation against the manufacturer and distributor. It is clear that despite a lengthy amount of time having passed ever since the thalidomide disaster commenced in 1962, the controversy over compensation continues. Indeed, the author of Medicinal Product Liability and Regulation (published before the announcement of the British legal claim), Professor Goldberg, notes that claims for resulting birth defects continue to emerge right into the present day. His prescient insight into the contemporary relevance of compensation for pharmaceutical injuries thus makes Medicinal Product Liability and Regulation a very relevant addition to the small body of scholarship that is available on this rather specific and complex issue.

Influence of habitual physical activity on gastric emptying in healthy males and relationships with body composition and energy expenditure

Although a number of studies have examined the role of gastric emptying (GE) in obesity, the influences of habitual physical activity level, body composition and energy expenditure (EE) on GE have received very little consideration. In this study, we have compared GE in active and inactive males, and we have characterised relationships with body composition (fat and fat free mass) and EE. Forty-four males (Active: n=22, Inactive: n=22; range BMI 21-36kg/m2; range percent fat mass 9-42%) were studied, with GE of a standardised (1676 kJ) pancake meal being assessed by 13C-octanoic acid breath test, body composition by air displacement plethysmography, resting metabolic rate (RMR) by indirect calorimetry and activity EE (AEE) by accelerometry. Results showed that GE was faster in active compared to inactive males (mean ±SD half time (t1/2): Active: 157±18 and Inactive: 179±21 min, p<0.001). When data from both groups were pooled, GE t1/2 was associated with percent fat mass (r=0.39, p<0.01) and AEE (r =-0.46, p<0.01). After controlling for habitual physical activity status, the association between AEE and GE remained, but not that for percent fat mass and GE. BMI and RMR were not associated with GE. In summary, faster GE is considered to be a marker of a habitually active lifestyle in males, and is associated with a higher AEE and lower percent fat mass. The possibility that GE contributes to a gross physiological regulation (or dysregulation) of food intake with physical activity level deserves further investigation.

Whole-body cryotherapy (extreme cold air exposure) for preventing and treating muscle soreness after exercise in adults

Background Recovery strategies are often usedwith the intention of preventing orminimisingmuscle soreness after exercise. Whole-body cryotherapy, which involves a single or repeated exposure(s) to extremely cold dry air (below -100 °C) in a specialised chamber or cabin for two to four minutes per exposure, is currently being advocated as an effective intervention to reduce muscle soreness after exercise. Objectives To assess the effects (benefits and harms) of whole-body cryotherapy (extreme cold air exposure) for preventing and treating muscle soreness after exercise in adults. Search methods We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, the British Nursing Index and the Physiotherapy Evidence Database. We also searched the reference lists of articles, trial registers and conference proceedings, handsearched journals and contacted experts. The searches were run in August 2015. Selection criteria We aimed to include randomised and quasi-randomised trials that compared the use of whole-body cryotherapy (WBC) versus a passive or control intervention (rest, no treatment or placebo treatment) or active interventions including cold or contrast water immersion, active recovery and infrared therapy for preventing or treating muscle soreness after exercise in adults. We also aimed to include randomised trials that compared different durations or dosages of WBC. Our prespecified primary outcomes were muscle soreness, subjective recovery (e.g. tiredness, well-being) and adverse effects. Data collection and analysis Two review authors independently screened search results, selected studies, assessed risk of bias and extracted and cross-checked data. Where appropriate, we pooled results of comparable trials. The random-effects model was used for pooling where there was substantial heterogeneity.We assessed the quality of the evidence using GRADE. Main results Four laboratory-based randomised controlled trials were included. These reported results for 64 physically active predominantly young adults (mean age 23 years). All but four participants were male. Two trials were parallel group trials (44 participants) and two were cross-over trials (20 participants). The trials were heterogeneous, including the type, temperature, duration and frequency of WBC, and the type of preceding exercise. None of the trials reported active surveillance of predefined adverse events. All four trials had design features that carried a high risk of bias, potentially limiting the reliability of their findings. The evidence for all outcomes was classified as ’very low’ quality based on the GRADE criteria. Two comparisons were tested: WBC versus control (rest or no WBC), tested in four studies; and WBC versus far-infrared therapy, also tested in one study. No studies compared WBC with other active interventions, such as cold water immersion, or different types and applications of WBC. All four trials compared WBC with rest or no WBC. There was very low quality evidence for lower self-reported muscle soreness (pain at rest) scores after WBC at 1 hour (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -1.42 to -0.12; 20 participants, 2 cross-over trials); 24 hours (SMD -0.57, 95%CI -1.48 to 0.33) and 48 hours (SMD -0.58, 95% CI -1.37 to 0.21), both with 38 participants, 2 cross-over studies, 1 parallel group study; and 72 hours (SMD -0.65, 95% CI -2.54 to 1.24; 29 participants, 1 cross-over study, 1 parallel group study). Of note is that the 95% CIs also included either no between-group differences or a benefit in favour of the control group. One small cross-over trial (9 participants) found no difference in tiredness but better well-being after WBC at 24 hours post exercise. There was no report of adverse events. One small cross-over trial involving nine well-trained runners provided very low quality evidence of lower levels of muscle soreness after WBC, when compared with infrared therapy, at 1 hour follow-up, but not at 24 or 48 hours. The same trial found no difference in well-being but less tiredness after WBC at 24 hours post exercise. There was no report of adverse events. Authors’ conclusions There is insufficient evidence to determine whether whole-body cryotherapy (WBC) reduces self-reportedmuscle soreness, or improves subjective recovery, after exercise compared with passive rest or no WBC in physically active young adult males. There is no evidence on the use of this intervention in females or elite athletes. The lack of evidence on adverse events is important given that the exposure to extreme temperature presents a potential hazard. Further high-quality, well-reported research in this area is required and must provide detailed reporting of adverse events.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10−8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of approximately 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Book Review: "Safe Design and Construction of Machinery – Regulation, Practice and Performance [First edition]"

With Safe Design and Construction of Machinery, the author presents the results of empirical studies into this significant aspect of safety science in a very readable, well-structured format. The book contains 436 references, 17 tables, one figure and a comprehensive index. Liz Bluff addresses a complex and important, but often neglected domain in OHS – the safety of machinery – in a holistic and profound, yet evidence based analysis; with many applied cases from her studies, which make the book accessible and a pleasant lecture. Although research that led to this remarkable publication might have been primarily focused on the regulators, this book can be highly recommended to all OHS academics and practitioners. It provides an important contribution to the body of knowledge in OHS, and establishes one of the few Australian in-depth insights into the significance of machinery producers, rather than machinery users in the wider framework of risk management. The author bases this fresh perspective on the well-established European Machinery Safety guidelines, and grounds her mixed-methods research predominantly in qualitative analysis of motivation and knowledge, which eventually leads to specific safety outcomes. It should be noted that both European and Australian legal aspects are investigated and considered, as both equally apply to many machinery exporters. A detailed description of the research design and methods can be found in an appendix. Overall, the unique combination of quantitative safety performance data and qualitative analysis of safety behaviours form a valuable addition to the understanding of machinery safety. The author must be congratulated on making these complex relationships transparent to the reader through her meticulous inquiry.