Site and gender specificity of inheritance of bone mineral density

Differences in genetic control of BMD by skeletal sites and genders were examined by complex segregation analysis in 816 members of 147 families with probands with extreme low BMD. Spine BMD correlated more strongly in male-male comparisons and hip BMD in female-female comparisons, consistent with gender- and site-specificity of BMD heritability. Introduction: Evidence from studies in animals and humans suggests that the genetic control of bone mineral density (BMD) may differ at different skeletal sites and between genders. This question has important implications for the design and interpretation of genetic studies of osteoporosis. Methods: We examined the genetic profile of 147 families with 816 individuals recruited through probands with extreme low BMD (T-score < −2.5, Z-score < −2.0). Complex segregation analysis was performed using the Pedigree Analysis Package. BMD was measured by DXA at both lumbar spine (L1-L4) and femoral neck. Results: Complex segregation analysis excluded purely monogenic and environmental models of segregation of lumbar spine and femoral neck BMD in these families. Pure polygenic models were excluded at the lumbar spine when menopausal status was considered as a covariate, but not at the femoral neck. Mendelian models with a residual polygenic component were not excluded. These models were consistent with the presence of a rare Mendelian genotype of prevalence 3–19 %, causing high BMD at the hip and spine in these families, with additional polygenic effects. Total heritability range at the lumbar spine was 61–67 % and at the femoral neck was 44–67 %. Significant differences in correlation of femoral neck and lumbar spine BMD were observed between male and female relative pairs, with male-male comparisons exhibiting stronger lumbar spine BMD correlation than femoral neck, and female-female comparisons having greater femoral neck BMD correlation than lumbar spine. These findings remained true for parent-offspring correlations when menopausal status was taken into account. The recurrence risk ratio for siblings of probands of a Z-score < −2.0 was 5.4 at the lumbar spine and 5.9 at the femoral neck. Conclusions: These findings support gender- and site-specificity of the inheritance of BMD. These results should be considered in the design and interpretation of genetic studies of osteoporosis.

Reduced graphene oxide growth on 316L stainless steel for medical applications

We report a new method for the growth of reduced graphene oxide (rGO) on the 316L alloy of stainless steel (SS) and its relevance for biomedical applications. We demonstrate that electrochemical etching increases the concentration of metallic species on the surface and enables the growth of rGO. This result is supported through a combination of Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), scanning electron microscopy (SEM), density functional theory (DFT) calculations and static water contact angle measurements. Raman spectroscopy identifies the G and D bands for oxidized species of graphene at 1595 cm(-1) and 1350 cm(-1), respectively, and gives an ID/IG ratio of 1.2, indicating a moderate degree of oxidation. XPS shows -OH and -COOH groups in the rGO stoichiometry and static contact angle measurements confirm the wettability of rGO. SEM and AFM measurements were performed on different substrates before and after coronene treatment to confirm rGO growth. Cell viability studies reveal that these rGO coatings do not have toxic effects on mammalian cells, making this material suitable for biomedical and biotechnological applications.

Effects of fish density distribution and effort distribution on catchability

The effects of fish density distribution and effort distribution on the overall catchability coefficient are examined. Emphasis is also on how aggregation and effort distribution interact to affect overall catch rate [catch per unit effort (cpue)]. In particular, it is proposed to evaluate three indices, the catchability index, the knowledge parameter, and the aggregation index, to describe the effectiveness of targeting and the effects on overall catchability in the stock area. Analytical expressions are provided so that these indices can easily be calculated. The average of the cpue calculated from small units where fishing is random is a better index for measuring the stock abundance. The overall cpue, the ratio of lumped catch and effort, together with the average cpue, can be used to assess the effectiveness of targeting. The proposed methods are applied to the commercial catch and effort data from the Australian northern prawn fishery. The indices are obtained assuming a power law for the effort distribution as an approximation of targeting during the fishing operation. Targeting increased catchability in some areas by 10%, which may have important implications on management advice.

High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19

OBJECTIVE To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis. DESIGN Case-control study. SETTING Academic research. PATIENT(S) Cases=3,223 women with surgically confirmed endometriosis; controls=1,190 women without endometriosis and 7,060 population samples. INTERVENTION(S) Analysis of 11,984 single nucleotide polymorphisms on chromosome 10. MAIN OUTCOME MEASURE(S) Allele frequency differences between cases and controls. RESULT(S) Linkage analyses on families grouped by endometriosis symptoms (primarily subfertility) provided increased evidence for linkage (logarithm of odds score=3.62) near a previously reported linkage peak. Three independent association signals were found at 96.59 Mb (rs11592737), 105.63 Mb (rs1253130), and 124.25 Mb (rs2250804). Analyses including only samples from linkage families supported the association at all three regions. However, only rs11592737 in the cytochrome P450 subfamily C (CYP2C19) gene was replicated in an independent sample of 2,079 cases and 7,060 population controls. CONCLUSION(S) The role of the CYP2C19 gene in conferring risk for endometriosis warrants further investigation.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Aqueous colloidal stability evaluated by zeta potential measurement and resultant TiO2 for superior photovoltaic performance

Controlling the morphological structure of titanium dioxide (TiO 2) is crucial for obtaining superior power conversion efficiency for dye-sensitized solar cells. Although the sol-gel-based process has been developed for this purpose, there has been limited success in resisting the aggregation of nanostructured TiO2, which could act as an obstacle for mass production. Herein, we report a simple approach to improve the efficiency of dye-sensitized solar cells (DSSC) by controlling the degree of aggregation and particle surface charge through zeta potential analysis. We found that different aqueous colloidal conditions, i.e., potential of hydrogen (pH), water/titanium alkoxide (titanium isopropoxide) ratio, and surface charge, obviously led to different particle sizes in the range of 10-500 nm. We have also shown that particles prepared under acidic conditions are more effective for DSSC application regarding the modification of surface charges to improve dye loading and electron injection rate properties. Power conversion efficiency of 6.54%, open-circuit voltage of 0.73 V, short-circuit current density of 15.32 mA/cm2, and fill factor of 0.73 were obtained using anatase TiO 2 optimized to 10-20 nm in size, as well as by the use of a compact TiO2 blocking layer.

Correlative fluorescence and transmission electron microscopy: An elegant tool to study the actin cytoskeleton of whole-mount (breast) cancer cells

Elucidating the structure and dynamics of lamellipodia and filopodia in response to different stimuli is a topic of continuing interest in cancer cells as these structures may be attractive targets for therapeutic purposes. Interestingly, a close functional relationship between these actin-rich protrusions and specialized membrane domains has been recently demonstrated. The aim of this study was therefore to investigate the fine organization of these actin-rich structures and examine how they structurally may relate to detergent-resistant membrane (DRM) domains in the MTLn3 EGF/serum starvation model. For this reason, we designed a straightforward and alternative method to study cytoskeleton arrays and their associated structures by means of correlative fluorescence (/laser)- and electron microscopy (CFEM). CFEM on whole mounted breast cancer cells revealed that a lamellipodium is composed of an intricate filamentous actin web organized in various patterns after different treatments. Both actin dots and DRM's were resolved, and were closely interconnected with the surrounding cytoskeleton. Long actin filaments were repeatedly observed extending beyond the leading edge and their density and length varied after different treatments. Furthermore, CFEM also allowed us to demonstrate the close structural association of DRMs with the cytoskeleton in general and the filamentous/dot-like structural complexes in particular, suggesting that they are all functionally linked and consequently may regulate the cell's fingertip dynamics. Finally, electron tomographic modelling on the same CFEM samples confirmed that these extensions are clearly embedded within the cytoskeletal matrix of the lamellipodium.