Towards an improvement of optically stimulated luminescence (OSL) age uncertainties: modelling OSL ages with systematic errors, stratigraphic constraints and radiocarbon ages using the R package BayLum

Statistical analysis has become increasingly important in optically stimulated luminescence (OSL) dating since it has become possible to measure signals at the single-grain scale. The accuracy of large chronological datasets can benefit from the inclusion, in chronological modelling, of stratigraphic constraints and shared systematic errors. Recently, a number of Bayesian models have been developed for OSL age calculation; the R package “BayLum” presented herein allows different models of this type to be implemented, particularly for samples in stratigraphic order which share systematic errors. We first show how to introduce stratigraphic constraints in BayLum; then, we focus on the construction, based on measurement uncertainties, of dose covariance matrices to account for systematic errors specific to OSL dating. The nature (systematic versus random) of errors affecting OSL ages is discussed, based – as an example – on the dose rate determination procedure at the IRAMAT-CRP2A laboratory (Bordeaux). The effects of the stratigraphic constraints and dose covariance matrices are illustrated on example datasets. In particular, the benefit of combining the modelling of systematic errors with independent ages, unaffected by these errors, is demonstrated. Finally, we discuss other common ways of estimating dose rates and how they may be taken into account in the covariance matrix by other potential users and laboratories. Test datasets are provided as a Supplement to the reader, together with an R markdown tutorial allowing the reproduction of all calculations and figures presented in this study.</p

Prostate cancer cells modulate osteoblast mineralisation and osteoclast differentiation through Id-1

Background: Id-1 is overexpressed in and correlated with metastatic potential of prostate cancer. The role of Id-1 in this metastatic process was further analysed. Methods: Conditioned media from prostate cancer cells, expressing various levels of Id-1, were used to stimulate pre-osteoclast differentiation and osteoblast mineralisation. Downstream effectors of Id-1 were identified. Expressions of Id-1 and its downstream effectors in prostate cancers were studied using immunohistochemistry in a prostate cancer patient cohort (N110). Results: We found that conditioned media from LNCaP prostate cancer cells overexpressing Id-1 had a higher ability to drive osteoclast differentiation and a lower ability to stimulate osteoblast mineralisation than control, whereas conditioned media from PC3 prostate cancer cells with Id-1 knockdown were less able to stimulate osteoclast differentiation. Id-1 was found to negatively regulate TNF-Β and this correlation was confirmed in human prostate cancer specimens (P0.03). Furthermore, addition of recombinant TNF-Β to LNCaP Id-1 cell-derived media blocked the effect of Id-1 overexpression on osteoblast mineralisation. Conclusion: In prostate cancer cells, the ability of Id-1 to modulate bone cell differentiation favouring metastatic bone disease is partially mediated by TNF-Β, and Id-1 could be a potential therapeutic target for prostate cancer to bone metastasis. © 2010 Cancer Research UK. All rights reserved.link_to_OA_fulltex

One origin for metallo-β-lactamase activity, or two? An investigation assessing a diverse set of reconstructed ancestral sequences based on a sample of phylogenetic trees

This work was supported by BBSRC (grant BB/F016778/1)Bacteria use metallo-β-lactamase enzymes to hydrolyse lactam rings found in many antibiotics, rendering them ineffective. Metallo-β-lactamase activity is thought to be polyphyletic, having arisen on more than one occasion within a single functionally diverse homologous superfamily. Since discovery of multiple origins of enzymatic activity conferring antibiotic resistance has broad implications for the continued clinical use of antibiotics, we test the hypothesis of polyphyly further; if lactamase function has arisen twice independently, the most recent common ancestor (MRCA) is not expected to possess lactam-hydrolysing activity. Two major problems present themselves. Firstly, even with a perfectly known phylogeny, ancestral sequence reconstruction is error prone. Secondly, the phylogeny is not known, and in fact reconstructing a single, unambiguous phylogeny for the superfamily has proven impossible. To obtain a more statistical view of the strength of evidence for or against MRCA lactamase function, we reconstructed a sample of 98 MRCAs of the metallo-β-lactamases, each based on a different tree in a bootstrap sample of reconstructed phylogenies. InterPro sequence signatures and homology modelling were then used to assess our sample of MRCAs for lactamase functionality. Only 5 % of these models conform to our criteria for metallo-β-lactamase functionality, suggesting that the ancestor was unlikely to have been a metallo-β-lactamase. On the other hand, given that ancestral proteins may have had metallo-β-lactamase functionality with variation in sequence and structural properties compared with extant enzymes, our criteria are conservative, estimating a lower bound of evidence for metallo-β-lactamase functionality but not an upper bound.Publisher PDFPeer reviewe

Identifying sources and estimating glandular output of salivary TIMP-1

Objective. Tissue inhibitor of metalloproteinases 1 (TIMP-1) has been identified as a potential biomarker in diseases such as cancer, cardiovascular diseases and diabetes. Since TIMP-1 resides in most tissues and bodily fluids, we evaluated the potential of using saliva to obtain reproducible TIMP-1 measurements in a non-invasive manner. Material and methods. Samples of unstimulated and stimulated whole saliva and saliva collected from individual glands were analysed for TIMP-1 content. A TIMP-1 ELISA was validated for use in saliva testing and the most optimal sampling and handling procedures for reproducible measurements identified. Western blotting and MALDI-TOF mass spectrometry were used for confirmatory analyses. Results. The TIMP-1 ELISA was found suitable for saliva measurements. All saliva secretions contained TIMP-1, but in different concentrations ranging from 2.81 ng/mL in submandibular/ sublingual saliva to 173.88 ng/mL in parotid saliva. TIMP-1 concentrations were influenced to a varying degree by fluctuations in flow. We found the lowest output in submandibular/sublingual saliva stimulated with 0.5 % citric acid (3.56 ng/min) and highest output in chewing-stimulated whole saliva (267.01 ng/min). Conclusion. This study shows that saliva contains authentic TIMP-1, the concentration of which was found to depend on gland type and salivary flow. Stimulated whole saliva is suggested as a reliable and easily accessible source for TIMP-1 determinations in bodily fluids.7 page(s