Variable Mutation Rates as an Adaptive Strategy in Replicator Populations

For evolving populations of replicators, there is much evidence that the effect of mutations on fitness depends on the degree of adaptation to the selective pressures at play. In optimized populations, most mutations have deleterious effects, such that low mutation rates are favoured. In contrast to this, in populations thriving in changing environments a larger fraction of mutations have beneficial effects, providing the diversity necessary to adapt to new conditions. What is more, non-adapted populations occasionally benefit from an increase in the mutation rate. Therefore, there is no optimal universal value of the mutation rate and species attempt to adjust it to their momentary adaptive needs. In this work we have used stationary populations of RNA molecules evolving in silico to investigate the relationship between the degree of adaptation of an optimized population and the value of the mutation rate promoting maximal adaptation in a short time to a new selective pressure. Our results show that this value can significantly differ from the optimal value at mutation-selection equilibrium, being strongly influenced by the structure of the population when the adaptive process begins. In the short-term, highly optimized populations containing little variability respond better to environmental changes upon an increase of the mutation rate, whereas populations with a lower degree of optimization but higher variability benefit from reducing the mutation rate to adapt rapidly. These findings show a good agreement with the behaviour exhibited by actual organisms that replicate their genomes under broadly different mutation rates

Mineral Preservatives in the Wood of Stradivari and Guarneri

Following the futile efforts of generations to reach the high standard of excellence achieved by the luthiers in Cremona, Italy, by variations of design and plate tuning, current interest is being focused on differences in material properties. The long-standing question whether the wood of Stradivari and Guarneri were treated with wood preservative materials could be answered only by the examination of wood specimens from the precious antique instruments. In a recent communication (Nature, 2006), we reported about the degradation of the wood polymers in instruments of Stradivari and Guarneri, which could be explained only by chemical manipulations, possibly by preservatives. The aim of the current work was to identify the minerals from the small samples of the maple wood which were available to us from the antique instruments. The ashes of wood from one violin and one cello by Stradivari, two violins by Guarneri, one viola by H. Jay, one violin by Gand-Bernardel were analyzed and compared with a variety of commercial tone woods. The methods of analysis were the following: back-scattered electron imaging, X-ray fluorescence maps for individual elements, wave-length dispersive spectroscopy, energy dispersive X-ray spectroscopy and quantitative microprobe analysis. All four Cremonese instruments showed the unmistakable signs of chemical treatments in the form of chemicals which are not present in natural woods, such as BaSO4, CaF2, borate, and ZrSiO4. In addition to these, there were also changes in the common wood minerals. Statistical evaluation of 12 minerals by discriminant analysis revealed: a. a difference among all four Cremona instruments, b. the difference of the Cremonese instruments from the French and English antiques, and c. only the Cremonese instruments differed from all commercial woods. These findings may provide the answer why all attempts to recreate the Stradivarius from natural wood have failed. There are many obvious implications with regard to how the green tone wood should be treated, which chould lead to changes in the practice of violin-making. This research should inspire others to analyze more antique violins for their chemical contents

Autocatalytic Activation of the Furin Zymogen Requires Removal of the Emerging Enzyme's N-Terminus from the Active Site

Before furin can act on protein substrates, it must go through an ordered process of activation. Similar to many other proteinases, furin is synthesized as a zymogen (profurin) which becomes active only after the autocatalytic removal of its auto-inhibitory prodomain. We hypothesized that to activate profurin its prodomain had to be removed and, in addition, the emerging enzyme's N-terminus had to be ejected from the catalytic cleft.We constructed and analyzed the profurin mutants in which the egress of the emerging enzyme's N-terminus from the catalytic cleft was restricted. Mutants were autocatalytically processed at only the primary cleavage site Arg-Thr-Lys-Arg(107) downward arrowAsp(108), but not at both the primary and the secondary (Arg-Gly-Val-Thr-Lys-Arg(75) downward arrowSer(76)) cleavage sites, yielding, as a result, the full-length prodomain and mature furins commencing from the N-terminal Asp108. These correctly processed furin mutants, however, remained self-inhibited by the constrained N-terminal sequence which continuously occupied the S' sub-sites of the catalytic cleft and interfered with the functional activity. Further, using the in vitro cleavage of the purified prodomain and the analyses of colon carcinoma LoVo cells with the reconstituted expression of the wild-type and mutant furins, we demonstrated that a three-step autocatalytic processing including the cleavage of the prodomain at the previously unidentified Arg-Leu-Gln-Arg(89) downward arrowGlu(90) site, is required for the efficient activation of furin.Collectively, our results show the restrictive role of the enzyme's N-terminal region in the autocatalytic activation mechanisms. In a conceptual form, our data apply not only to profurin alone but also to a range of self-activated proteinases

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10-9) and 3145 (P < 1 × 10-5) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness

Abundance and Diversity of Dockerin-Containing Proteins in the Fiber-Degrading Rumen Bacterium, Ruminococcus flavefaciens FD-1

Peer reviewedPublisher PD

Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma

Epidermal growth factor receptor (EGFR) mutations are a potential predictor of the effectiveness of EGFR inhibitors for the treatment of lung cancer. Although EGFR mutations were reported to occur with high frequency in nonsmoking Japanese adenocarcinoma patients, the exact nature has not been fully elucidated. We examined EGFR gene mutations within exons 18–21 and their correlations to clinico-pathological factors and other genetic alterations in tumour specimens from 154 patients who underwent resection for lung cancer at Kyoto University Hospital. Epidermal growth factor receptor mutations were observed in 60 tumours (39.0%), all of which were adenocarcinoma. Among the patients with adenocarcinoma (n=108), EGFR mutations were more frequently observed in nonsmokers than former smokers or current smokers (83.0, 50.0, 15.2%, respectively), in women than men (76.3 vs 34.0%), in tumours with bronchio-alveolar component than those without bronchio-alveolar component (78.9 vs 42.9%), and in well or moderately differentiated tumours than poorly differentiated tumours (72.0, 64.4, 34.2%). No tumours with EGFR mutations had any K-ras codon 12 mutations, which were well-known smoking-related gene mutations. In conclusion, adenocarcinomas with EGFR mutation had a distinctive clinico-pathological feature unrelated to smoking. Epidermal growth factor receptor mutations may play a key role in the development of smoking-independent adenocarcinoma

The present and future of serum diagnostic tests for testicular germ cell tumours.

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371-373 and miR-302-367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17

Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1

Introduction We have previously reported that induction of epidermal growth factor receptor and ErbB2 in response to antihormonal agents may provide an early mechanism to allow breast cancer cells to evade the growth-inhibitory action of such therapies and ultimately drive resistant cell growth. More recently, the other two members of the ErbB receptor family, ErbB3 and ErbB4, have been implicated in antihormone resistance in breast cancer. In the present study, we have investigated whether induction of ErbB3 and/or ErbB4 may provide an alternative resistance mechanism to antihormonal action in a panel of four oestrogen receptor (ER)-positive breast cancer cell lines. Methods MCF-7, T47D, BT474 and MDAMB361 cell lines were exposed to fulvestrant (100 nM) for seven days, and effects on ErbB3/4 expression and signalling, as well as on cell growth, were assessed. Effects of heregulin β1 (HRGβ1) were also examined in the absence and presence of fulvestrant to determine the impact of ER blockade on the capacity of this ErbB3/4 ligand to promote signalling and cell proliferation. Results Fulvestrant potently reduced ER expression and transcriptional activity and significantly inhibited growth in MCF-7, T47D, BT474 and MDAMB361 cells. However, alongside this inhibitory activity, fulvestrant also consistently induced protein expression and activity of ErbB3 in MCF-7 and T47D cells and ErbB4 in BT474 and MDAMB361 cell lines. Consequently, fulvestrant treatment sensitised all cell lines to the actions of the ErbB3/4 ligand HRGβ1 with enhanced ErbB3/4-driven signalling activity, reexpression of cyclin D1 and significant increases in cell proliferation being observed when compared to untreated cells. Indeed, in T47D and MDAMB361 HRGβ1 was converted from a ligand having negligible or suppressive growth activity into one that potently promoted cell proliferation. Consequently, fulvestrant-mediated growth inhibition was completely overridden by HRGβ1 in all four cell lines. Conclusions These findings suggest that although antihormones such as fulvestrant may have potent acute growth-inhibitory activity in ER-positive breast cancer cells, their ability to induce and sensitise cells to growth factors may serve to reduce and ultimately limit their inhibitory activity