CCL2 is transcriptionally controlled by the lysosomal protease cathepsin S in a CD74-dependent manner

Cathepsins S (CatS) has been implicated in numerous tumourigenic processes and here we document for the first time its involvement in CCL2 regulation within the tumour microenvironment. Analysis of syngeneic tumours highlighted reduced infiltrating macrophages in CatS depleted tumours. Interrogation of tumours and serum revealed genetic ablation of CatS leads to the depletion of several pro-inflammatory chemokines, most notably, CCL2. This observation was validated in vitro, where shRNA depletion of CatS resulted in reduced CCL2 expression. This regulation is transcriptionally mediated, as evident from RT-PCR analysis and CCL2 promoter studies. We revealed that CatS regulation of CCL2 is modulated through CD74 (also known as the invariant chain), a known substrate of CatS and a mediator of NFkB activity. Furthermore, CatS and CCL2 show a strong clinical correlation in brain, breast and colon tumours. In summary, these results highlight a novel mechanism by which CatS controls CCL2, which may present a useful pharmacodynamic marker for CatS inhibition.

Mining Money: the generative capacities of scientific and legal knowledge practices in the making of resource economies

In 1997 a scandal associated with Bre-X, a junior mining firm, and its prospecting activities in Indonesia, exposed to public scrutiny the ways in which mineral exploration firms acquire, assess and report on scientific claims about the natural environment. At stake here was not just how investors understood the provisional nature of scientific knowledge, but also evidence of fraud. Contemporaneous mining scandals not only included the salting of cores, but also unreliable proprietary sample preparation and assay methods, mis-representations of visual field estimates as drilling results and ‘overly optimistic’ geological reports. This paper reports on initiatives taken in the wake of these scandals and prompted by the Mining Standards Task Force (TSE/OSC 1999). For regulators, mandated to increase investor confidence in Canada’s leading role within the global mining industry, efforts focused first and foremost upon identifying and removing sources of error and wilfulness within the production and circulation of scientific knowledge claims. A common goal cross-cutting these initiatives was ‘a faithful representation of nature’ (Daston and Galison 2010), however, as the paper argues, this was manifest in an assemblage of practices governed by distinct and rival regulative visions of science and the making of markets in claims about ‘nature’. These ‘practices of fidelity’, it is argued, can be consequential in shaping the spatial and temporal dynamics of the marketization of nature.

Adiposity as a cause of cardiovascular disease: a Mendelian randomization study

Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.

Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.

Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12–1.28, P = 1.9·10−7), heart failure (HR = 1.47, 95% CI, 1.35–1.60, P = 9·10−19) and ischaemic stroke (HR = 1.15, 95% CI, 1.06–1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028–0.033, P = 3·10−107). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12–3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05–3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.

Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.

Scotland’s Curriculum for Excellence: a defence of autonomy and personhood.

Curriculum for Excellence, Scotland’s 3-18 curriculum, has been described as ‘the most significant curricular change in Scotland for a generation’ (McAra, Broadley and McLauchlan, 2013:223). The purpose of the curriculum is ‘encapsulated’ in four capacities in order that learners become i) successful learners, ii) confident individuals, iii) responsible citizens, and iv) effective contributors. With particular reference to these capacities, we explore the principle of autonomy as it pertains to both individual and collective flourishing seeking to disarm commonplace criticisms of autonomy by arguing that it might be put to work in CfE as a potentially multi-dimensional, context-sensitive concept that is relational as well as individual. We conclude that the four capacities lend themselves to re-consideration and re-mapping in pursuit of autonomy and flourishing premised on the principles of liberal personhood.

Debating Darwin at the Cape

This paper focuses attention on the fortunes of Darwin's theory among the English-speaking community in Cape Colony during the latter part of the nineteenth century. The paper begins with a review of early encounters with Darwin dwelling particularly on the response of figures like Roderick Noble - professor and editor of the Cape Monthly Magazine, the geologist John Shaw, and Sir Henry Barkly, governor of the colony. Besides these more theoretical responses, Darwin's ideas were also mobilised in a range of scientific inquiries on such subjects as birds and butterflies. But most conspicuous was the use of evolutionary thought-forms in the work of the eminent philologist Wilhelm Bleek, cousin of Darwin's leading German apologist, Ernst Haeckel. The prevailing sense is of a liberal intelligentsia calmly interacting with a novel theory with all due deference. During the 1870s, an address by Langham Dale at the South African Public Library injected new energy into the Darwin discussion. Dale expressed disquiet over some of the anthropological implications of evolution as well as its apparent reductionism, and this stimulated a range of reactions. Several anonymous commentators responded but the most sustained evaluation of Dale's position emanated from the Queenstown physician and later politician, Sir William Bisset Berry. Then, in 1874, copious extracts from John Tyndall's infamous 'Belfast Address' were printed in the Cape Monthly and this added yet further impetus to the debate. Tyndall's seeming materialism bothered a number of readers, not least Hon William Porter, former attorney-general of Cape Colony. To figures like these the materialist extrapolations of radical Darwinians such as Haeckel were deeply disturbing, not just for religious reasons, but because they seemed to destabilise the moral and pedagogic progressivism that lay at the heart of their civilising credo. While reservations about Darwin's proposals were certainly audible, taken in the round Darwinian conversations among the English-speaking literati at the Cape were conducted with liberal sentiments, not least when evolutionary science approached questions of race. For Darwin's writings were seen to confirm a monogenetic account of the origin and unity of the human race, and could readily be called upon to justify the paternalistic ideology that governed colonial affairs.

Effects of tobacco products on the attachment and growth of periodontal ligament fibroblasts

BACKGROUND: Cigarette smoking is one of the most significant risk factors in the development and further advancement of inflammatory periodontal disease, however, the role of either nicotine or its primary metabolite cotinine in the progression of periodontitis is unclear. This study aimed to investigate the effects of nicotine and cotinine on the attachment and growth of fibroblasts derived from human periodontal ligament (PDL).

METHODS: Primary cultures were prepared from the roots of extracted premolar teeth. Cells were used at both low (P3 to P5) and high (P11 to P13) passage. Cell numbers were determined over 14 days using either the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay or with a Coulter counter. Cultures were exposed to culture medium supplemented with 1) 15% fetal calf serum (FCS) only; 2) 1% FCS only; 3) 1% FCS and nicotine (concentration range 5 ng/ml to 10 mg/ml); or 4) 1% FCS and cotinine (concentration range 0.5 ng/ml to 10 microg/ml).

RESULTS: Nicotine significantly (P <0.05, by ANOVA) inhibits attachment and growth of low passage cells at concentrations >1 mg/ml and high passage PDL fibroblasts at concentrations >0.5 mg/ml. Cotinine, at the highest concentration used (10 microg/ml), appeared to inhibit attachment and growth of both low and high passage fibroblasts but this was not statistically significant (P >0.05, by ANOVA).

CONCLUSIONS: Tobacco products inhibit attachment and growth of human PDL fibroblasts. This may partly explain the role of these substances in the progression of periodontitis.

Prevalence and determinants of spectacle nonwear among rural Chinese secondary schoolchildren: the Xichang Pediatric Refractive Error Study Report 3.

OBJECTIVE: To study spectacle wear among rural Chinese children. METHODS: Visual acuity, refraction, spectacle wear, and visual function were measured. RESULTS: Among 1892 subjects (84.7% of the sample), the mean (SD) age was 14.7 (0.8) years. Among 948 children (50.1%) potentially benefiting from spectacle wear, 368 (38.8%) did not own them. Among 580 children owning spectacles, 17.9% did not wear them at school. Among 476 children wearing spectacles, 25.0% had prescriptions that could not improve their visual acuity to better than 6/12. Therefore, 62.3% (591 of 948) of children needing spectacles did not benefit from appropriate correction. Children not owning and not wearing spectacles had better self-reported visual function but worse visual acuity at initial examination than children wearing spectacles and had a mean (SD) refractive error of -2.06 (1.15) diopter (D) and -2.78 (1.32) D, respectively. Girls (P < .001) and older children (P = .03) were more likely to be wearing their spectacles. A common reason for nonwear (17.0%) was the belief that spectacles weaken the eyes. Among children without spectacles, 79.3% said their families would pay for them (mean, US $15). CONCLUSIONS: Although half of the children could benefit from spectacle wear, 62.3% were not wearing appropriate correction. These children have significant uncorrected refractive errors. There is potential to support programs through spectacle sales.