Atypical subtrochanteric femoral shaft fractures: role for mechanics and bone quality

Bisphosphonates are highly effective agents for reducing osteoporotic fractures in women and men, decreasing fracture incidence at the hip and spine up to 50%. In a small subset of patients, however, these agents have recently been associated with ''atypical femoral fractures'' (AFFs) in the subtrochanteric region or the diaphysis. These fractures have several atypical characteristics, including occurrence with minimal trauma; younger age than typical osteoporotic fractures; occurrence at cortical, rather than cancellous sites; early radiographic appearance similar to that of a stress fracture; transverse fracture pattern rather than the familiar spiral or transverse-oblique morphologies; initiation on the lateral cortex; and high risk of fracture on the contralateral side, at the same location as the initial fracture. Fracture is a mechanical phenomenon that occurs when the loads applied to a structure such as a long bone exceed its load-bearing capacity, either due to a single catastrophic overload (traumatic failure) or as a result of accumulated damage and crack propagation at sub-failure loads (fatigue failure). The association of AFFs with no or minimal trauma suggests a fatigue-based mechanism that depends on cortical cross-sectional geometry and tissue material properties. In the case of AFFs, bisphosphonate treatment may alter cortical tissue properties, as these agents are known to alter bone remodeling. This review discusses the use of bisphosphonates, their effects on bone remodeling, mechanics and tissue composition, their significance as an effective therapy for osteoporosis, and why these agents may increase fracture risk in a small population of patients.     

From Markovian to pairwise epidemic models and the performance of moment closure approximations

Many if not all models of disease transmission on networks can be linked to the exact state-based Markovian formulation. However the large number of equations for any system of realistic size limits their applicability to small populations. As a result, most modelling work relies on simulation and pairwise models. In this paper, for a simple SIS dynamics on an arbitrary network, we formalise the link between a well known pairwise model and the exact Markovian formulation. This involves the rigorous derivation of the exact ODE model at the level of pairs in terms of the expected number of pairs and triples. The exact system is then closed using two different closures, one well established and one that has been recently proposed. A new interpretation of both closures is presented, which explains several of their previously observed properties. The closed dynamical systems are solved numerically and the results are compared to output from individual-based stochastic simulations. This is done for a range of networks with the same average degree and clustering coefficient but generated using different algorithms. It is shown that the ability of the pairwise system to accurately model an epidemic is fundamentally dependent on the underlying large-scale network structure. We show that the existing pairwise models are a good fit for certain types of network but have to be used with caution as higher-order network structures may compromise their effectiveness.     

Aluminium, iron and copper in human brain tissues donated to the Medical Research Council's Cognitive Function and Ageing Study

Aluminium, iron and copper are all implicated in the aetiology of neurodegenerative diseases including Alzheimer's disease. However, there are very few large cohort studies of the content of these metals in aged human brains. We have used microwave digestion and TH GFAAS to measure aluminium, iron and copper in the temporal, frontal, occipital and parietal lobes of 60 brains donated to the Cognitive Function and Ageing Study. Every precaution was taken to reduce contamination of samples and acid digests to a minimum. Actual contamination was estimated by preparing a large number of (170+) method blanks which were interspersed within the full set of 700+ tissue digests. Subtraction of method blank values (MBV) from tissue digest values resulted in metal contents in all tissues in the range, MBV to 33 μg g(-1) dry wt. for aluminium, 112 to 8305 μg g(-1) dry wt. for iron and MBV to 384 μg g(-1) dry wt. for copper. While the median aluminium content for all tissues was 1.02 μg g(-1) dry wt. it was informative that 41 brains out of 60 included at least one tissue with an aluminium content which could be considered as potentially pathological (> 3.50 μg g(-1) dry wt.). The median content for iron was 286.16 μg g(-1) dry wt. and overall tissue iron contents were generally high which possibly reflected increased brain iron in ageing and in neurodegenerative disease. The median content for copper was 17.41 μg g(-1) dry wt. and overall tissue copper contents were lower than expected for aged brains but they were commensurate with aged brains showing signs of neurodegenerative disease. In this study we have shown, in particular, the value of carrying out significant numbers of method blanks to identify unknown sources of contamination. When these values are subtracted from tissue digest values the absolute metal contents could be considered as conservative and yet they may still reflect aspects of ageing and neurodegenerative disease in individual brains.     

High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs

Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients. Our genome-wide association study (GWAS) found several significant and suggestive associations. We prioritized consistent associations for functional follow-up using gene-expression analyses. The NAD(P)H quinone dehydrogenase 1 (NQO1) gene was found to be associated with the dose-response of arsenic trioxide, erlotinib, trametinib, and a combination treatment of paclitaxel + epirubicin. NQO1 has previously been shown as a biomarker of epirubicin response, but our results reveal novel associations with these additional treatments. Baseline gene expression of NQO1 was positively correlated with response for 43 of the 44 treatments surveyed. By interrogating the functional mechanisms of this association, the results demonstrate differences in both baseline and drug-exposed induction.     

Methyl Sulfide Production by a Novel Carbon Monoxide Metabolism in Methanosarcina acetivorans

We observed dimethyl sulfide and methanthiol production in pure incubations of the methanogen Methanosarcina acetivorans when carbon monoxide (CO) served as the only electron donor. Energy conservation likely uses sodium ion gradients for ATP synthesis. This novel metabolism permits utilization of CO by the methanogen, resulting in quantitative sulfide methylation.     

High-resolution crystal structure and in vivo function of a kinesin-2 homologue in Giardia intestinalis

A critical component of flagellar assembly, the kinesin-2 heterotrimeric complex powers the anterograde movement of proteinaceous rafts along the outer doublet of axonemes in intraflagellar transport (IFT). We present the first high-resolution structures of a kinesin-2 motor domain and an ATP hydrolysis-deficient motor domain mutant from the parasitic protist Giardia intestinalis. The high-resolution crystal structures of G. intestinalis wild-type kinesin-2 (GiKIN2a) motor domain, with its docked neck linker and the hydrolysis-deficient mutant GiKIN2aT104N were solved in a complex with ADP and Mg(2+) at 1.6 and 1.8 A resolutions, respectively. These high-resolution structures provide unique insight into the nucleotide coordination within the active site. G. intestinalis has eight flagella, and we demonstrate that both kinesin-2 homologues and IFT proteins localize to both cytoplasmic and membrane-bound regions of axonemes, with foci at cell body exit points and the distal flagellar tips. We demonstrate that the T104N mutation causes GiKIN2a to act as a rigor mutant in vitro. Overexpression of GiKIN2aT104N results in significant inhibition of flagellar assembly in the caudal, ventral, and posterolateral flagellar pairs. Thus we confirm the conserved evolutionary structure and functional role of kinesin-2 as the anterograde IFT motor in G. intestinalis.     

C/EBPbeta represses p53 to promote cell survival downstream of DNA damage independent of oncogenic Ras and p19(Arf)

CCAAT/enhancer-binding protein-beta (C/EBPbeta) is a mediator of cell survival and tumorigenesis. When C/EBPbeta(-/-) mice are treated with carcinogens that produce oncogenic Ras mutations in keratinocytes, they respond with abnormally elevated keratinocyte apoptosis and a block in skin tumorigenesis. Although this aberrant carcinogen-induced apoptosis results from abnormal upregulation of p53, it is not known whether upregulated p53 results from oncogenic Ras and its ability to induce p19(Arf) and/or activate DNA-damage response pathways or from direct carcinogen-induced DNA damage. We report that p19(Arf) is dramatically elevated in C/EBPbeta(-/-) epidermis and that C/EBPbeta represses a p19(Arf) promoter reporter. To determine whether p19(Arf) is responsible for the proapoptotic phenotype in C/EBPbeta(-/-) mice, C/EBPbeta(-/-);p19(Arf-/-) mice were generated. C/EBPbeta(-/-);p19(Arf-/-) mice responded to carcinogen treatment with increased p53 and apoptosis, indicating p19(Arf) is not essential. To ascertain whether oncogenic Ras activation induces aberrant p53 and apoptosis in C/EBPbeta(-/-) epidermis, we generated K14-ER:Ras;C/EBPbeta(-/-) mice. Oncogenic Ras activation induced by 4-hydroxytamoxifen did not produce increased p53 or apoptosis. Finally, when C/EBPbeta(-/-) mice were treated with differing types of DNA-damaging agents, including alkylating chemotherapeutic agents, they displayed aberrant levels of p53 and apoptosis. These results indicate that C/EBPbeta represses p53 to promote cell survival downstream of DNA damage and suggest that inhibition of C/EBPbeta may be a target for cancer cotherapy to increase the efficacy of alkylating chemotherapeutic agents.