Finding the right molecule - knowledge-driven enzyme discovery

Activity based screening of microbial strain or expression libraries from metagenomic sampling is still the strongest approach for discovery of unknown enzyme functionalities. However, the abundance of genomic and/or protein sequences suggests easy access to new, uncharacterized enzymes of known function, having the required physical properties for industrial use simply by extracting the right sequence from databases, ordering the gene and express it for application. This sequence based enzyme discovery is unfortunately hampered by two key factors: The functional classification is not of a quality that guarantees a correct functional prediction (see e.g. Furnham N et al., 2009, Walsh, JR et al., 2016) As of today it is almost impossible to unambiguously predict physical parameters of enzyme function based on amino acid sequence alone As a consequence numerous tools have to be employed to come at least to a correct functional prediction (Alderson, RG, 2012) using the available resources, which the scientific community has developed. Resources for sequence based enzyme discovery span from (meta-)genomic databases, a plethora of genome data, amino acid sequence databases (Schomburg and Schomburg, 2010), via the RCSB protein structure database (Rose PW et al., 2017) to enzyme property databases like BRENDA (Chang, A et al. 2015). A huge set of bioinformatics tools enables access to this databases, evaluation and classification of search results (e.g. Kuiper, RK et al. 2010). A streamlined enzyme discovery process is most likely achieved by setting it up as a multidisciplinary effort. Alderson et al. remark that biologists and chemists have different view, interests and interpretation of enzyme data and functionality. That professional bias in looking at molecules offers a chance to develop methods for speeding up the search for new enzymes. In the presentation, we will discuss, using examples, the exploitation of various databases and bioinformatics tools to enhance sequence based enzyme discovery processes. We will also look at the applicability of these technologies for protein engineering projects, which have evolved into an integral part of enzyme discovery and development. Literature: Alderson RG et al. (2012) Curr Top Med Chem. 2012 Sep 1; 12(17): 1911–1923 Chang A et al. (2015), Nucleic Acids Res. 2015 43 (D1): D439-46 Furnham N et al. (2009), Nature Chemical Biology 5, 521 - 525 Kuipers RK et al. (2010), Proteins. 2010 Jul;78(9):2101-13. Rose PW et al. (2017), Nucleic Acids Res 2017, 45 (D1): D271-D281. Schomburg D and Schomburg I (2010), Methods Mol Biol. 2010;609:113-28 Walsh JR et al. (2016), BMC Syst Biol. 2016; 10: 12

Tyrol Prostate Cancer Demonstration Project : early detection, treatment, outcome, incidence and mortality

This study aimed to evaluate the effectiveness of a well-controlled programme of early detection and treatment of prostate cancer in the population of Tyrol, Austria, where such a programme of early detection and treatment was initiated in 1988 and where prostate-specific antigen (PSA) testing was offered for free to all men aged 45-75 years from 1993. Comparison of prostate cancer mortality rates in Tyrol and the rest of Austria was accomplished through a generalized additive model. A piecewise linear change-point Poisson regression model was used to compare mortality rates in Tyrol and the rest of Austria. Standardized mortality ratios were calculated with reference to the mortality rates in 1986-1990. In all, 86.6% of eligible men have been tested at least once since 1993. Cancer deaths in Tyrol in 2005 were 54% (95% confidence interval [CI] 34-69%) lower than expected compared with 29% (95% CI 22-35%) in the rest of Austria. The decreasing trend in prostate cancer mortality was significantly greater in Tyrol compared with the rest of Austria (P = 0.001). A significant migration to lower stage disease occurred and radical prostatectomy was associated with low morbidity. In the Tyrol region where treatment is freely available to all patients, where widespread PSA testing and treatment with curative intent occurs, there was a reduction in prostate cancer mortality rates which was significantly greater than the reduction in the rest of Austria. This reduction in prostate cancer mortality is most probably due to early detection, consequent down-staging and effective treatment of prostate cancer

Prostate-specific antigen testing in Tyrol, Austria: prostate cancer mortality reduction was supported by an update with mortality data up to 2008

Objectives: The objective of this study was to update an in-depth analysis of the time trend for prostate cancer (PCA) mortality in the population of Tyrol by 5 years, namely to 2008. In Tyrol, prostate-specific antigen (PSA) tests were introduced in 1988/89; more than three-quarters of all men in the age group 45–74 had at least one PSA test in the past decade. Methods: We applied the same model as in a previous publication, i.e., an age-period-cohort model using Poisson regression, to the mortality data covering more than three decades from 1970 to 2008. Results: For Tyrol from 2004 to 2008 in the age group 60+ period terms show a significant reduction in prostate cancer mortality with a risk ratio of 0.70 (95% confidence interval 0.57, 0.87) for Tyrol, and for Austria excluding Tyrol a moderate reduction with a risk ratio of 0.92 (95% confidence interval 0.87, 0.97), each compared to the mortality rate in the period 1989–1993. Conclusions: This update strengthens our previously published results, namely that PSA testing offered to a population at no charge can reduce prostate cancer mortality. The extent of mortality reduction is in line with that reported in the other recent publications. However, our data do not permit us to fully assess the harms associated with PCA screening, and no recommendation for PSA screening can be made without a careful evaluation of overdiagnosis and overtreatment

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements