Synthesis of empty bacterial microcompartments, directed organelle protein incorporation, and evidence of filament-associated organelle movement

Compartmentalization is an important process, since it allows the segregation of metabolic activities and, in the era of synthetic biology, represents an important tool by which defined microenvironments can be created for specific metabolic functions. Indeed, some bacteria make specialized proteinaceous metabolic compartments called bacterial microcompartments (BMCs) or metabolosomes. Here we demonstrate that the shell of the metabolosome (representing an empty BMC) can be produced within E. coil cells by the coordinated expression of genes encoding structural proteins. A plethora of diverse structures can be generated by changing the expression profile of these genes, including the formation of large axial filaments that interfere with septation. Fusing GFP to PduC, PduD, or PduV, none of which are shell proteins, allows regiospecific targeting of the reporter group to the empty BMC. Live cell imaging provides unexpected evidence of filament-associated BMC movement within the cell in the presence of Pdu

The pore structure and water absorption in Portland/slag blended hardened cement paste determined by synchrotron X-ray microtomography and neutron radiography

The pore structures of hardened Portland/slag cement pastes (>75 wt% slag content), and the initial capillary absorption of moisture through these pores, were monitored using ex situ synchrotron X-ray computerised microtomography and in situ quantitative neutron radiography. The pore structure becomes more constricted as the cement hydrates and its microstructure develops. This mechanism was effective even at a slag content as high as 90 wt% in the cementitious blend, where the lowest total porosity and a significant pore refinement were identified at extended curing ages (360 d). By combining this information with neutron radiographic imaging, and directly quantifying both depth and mass of water uptake, it was observed that 90 wt% slag cement outperformed the 75 wt% slag blend at 90 days in terms of resistance to capillary water uptake, although the higher-slag blend had not yet developed such a refined microstructure at 28 days of curing. The assumptions associated with the “sharp front model” for water ingress do not hold true for highly substituted slag cement pastes. Testing transport properties at 28 days may not give a true indication of the performance of these materials in service in the long term

Phase evolution of slag-rich cementitious grouts for immobilisation of nuclear wastes

An updated calcium silicate hydrate (C–S–H) model incorporating aluminium-containing end-members was used for thermodynamic modelling of blended cements using blast-furnace slag and Portland cement (BFS:PC) with ratios of 1:1, 3:1 and 9:1, using GEMSelektor. Selective dissolution and magic angle spinning nuclear magnetic resonance (MAS NMR) studies were performed to determine the degree of hydration (DoH) of the anhydrous material as an input parameter for the modelling work. Both techniques showed similar results for determining the DoH of the BFS within each sample. Characterisation of the hardened cement pastes over 360 days, using X-ray diffraction analysis and MAS NMR, demonstrated that the use of the updated C–S–H model can highlight the effect of different blend ratios and curing ages on the phase assemblages in these cements. Validation using this modelling approach was performed on 20 year old specimens from the literature to highlight its applicability for modelling later-age blended cements

The pore structure and water absorption in Portland/slag blended hardened cement paste determined by synchrotron X-ray microtomography and neutron radiography

The pore structures of hardened Portland/slag cement pastes (>75 wt% slag content), and the initial capillary absorption of moisture through these pores, were monitored using ex situ synchrotron X-ray computerised microtomography and in situ quantitative neutron radiography. The pore structure becomes more constricted as the cement hydrates and its microstructure develops. This mechanism was effective even at a slag content as high as 90 wt% in the cementitious blend, where the lowest total porosity and a significant pore refinement were identified at extended curing ages (360 d). By combining this information with neutron radiographic imaging, and directly quantifying both depth and mass of water uptake, it was observed that 90 wt% slag cement outperformed the 75 wt% slag blend at 90 days in terms of resistance to capillary water uptake, although the higher-slag blend had not yet developed such a refined microstructure at 28 days of curing. The assumptions associated with the “sharp front model” for water ingress do not hold true for highly substituted slag cement pastes. Testing transport properties at 28 days may not give a true indication of the performance of these materials in service in the long term

Thermodynamic modelling of BFS-PC cements under temperature conditions relevant to the geological disposal of nuclear wastes

Intermediate level waste produced in UK nuclear power generation is encapsulated or immobilised in blended cements comprising blast furnace slag (BFS) and Portland cement (PC), to be emplaced in a proposed geological disposal facility (GDF). The wasteforms are expected to be exposed to temperatures from 35 to 80 °C during the initial 150 years of GDF operation. Thermodynamic modelling is applied here to describe the phase assemblages of hydrated 1:1, 3:1 and 9:1 BFS-PC blends, with the participation of hydrogarnet as an important phase above 60 °C. The chemical composition of the main phase forming in these systems, an aluminium rich calcium silicate hydrate (C-A-S-H), was well described by a solid-solution model with explicit Al incorporation, although the Al/Si ratio was systematically slightly under-predicted. The developed thermodynamic model predicts the correct phase assemblage across varying temperature regimes, making it a valuable tool to assess the effects of temperature on cements

Gender norms and social norms: differences, similarities and why they matter in prevention science.

Two streams of theory and practice on gender equity have begun to elide. The first is work conducted to change social norms, particularly using theory that emerged from studies in social psychology. The second is work done on gender norms, emerging historically from feminist scholars working to counter gender inequality. As these two streams of work intersect, conceptual clarity is needed to understand differences and similarities between these two traditions. Increased clarity will improve efforts to address harmful norms and practices. In this article, we review similarities and differences between social and gender norms, reviewing the history of the concepts and identifying key tension points of contrast. We identified six areas of comparison that might be helpful for practitioners working for the promotion of global health as they make sense of social and gender norms. We then offer a definition of gender norms for practitioners and researchers working at the intersection between these two theories. Our definition draws from the two different streams of thought of how norms influence people's actions, acknowledging the double nature of gender norms: beliefs nested in people's minds and embedded in institutions that profoundly affect health-related behaviours and shape differential access to health services

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.NovartisEli Lilly and CompanyAstraZenecaAbbViePfizer UKCelgeneEisaiGenentechMerck Sharp and DohmeRocheCancer Research UKGovernment of CanadaArray BioPharmaGenome CanadaNational Institutes of HealthEuropean CommissionMinistère de l'Économie, de l’Innovation et des Exportations du QuébecSeventh Framework ProgrammeCanadian Institutes of Health Researc

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92–0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88–0.94). Conclusions Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer

Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

BACKGROUND: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. METHODS: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. RESULTS: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. CONCLUSIONS: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer

Paleoseismology and hystorical seismicity for seismic hazard assessment in Italy: examples from the Fucino and Pollino tectonic structures.

Marshall, California, U.S.A., U.S.G.S