A mass spectrometry-guided genome mining approach for natural product peptidogenomics.

Peptide natural products show broad biological properties and are commonly produced by orthogonal ribosomal and nonribosomal pathways in prokaryotes and eukaryotes. To harvest this large and diverse resource of bioactive molecules, we introduce here natural product peptidogenomics (NPP), a new MS-guided genome-mining method that connects the chemotypes of peptide natural products to their biosynthetic gene clusters by iteratively matching de novo tandem MS (MS(n)) structures to genomics-based structures following biosynthetic logic. In this study, we show that NPP enabled the rapid characterization of over ten chemically diverse ribosomal and nonribosomal peptide natural products of previously unidentified composition from Streptomycete bacteria as a proof of concept to begin automating the genome-mining process. We show the identification of lantipeptides, lasso peptides, linardins, formylated peptides and lipopeptides, many of which are from well-characterized model Streptomycetes, highlighting the power of NPP in the discovery of new peptide natural products from even intensely studied organisms

Simultaneous non-negative matrix factorization for multiple large scale gene expression datasets in toxicology

Non-negative matrix factorization is a useful tool for reducing the dimension of large datasets. This work considers simultaneous non-negative matrix factorization of multiple sources of data. In particular, we perform the first study that involves more than two datasets. We discuss the algorithmic issues required to convert the approach into a practical computational tool and apply the technique to new gene expression data quantifying the molecular changes in four tissue types due to different dosages of an experimental panPPAR agonist in mouse. This study is of interest in toxicology because, whilst PPARs form potential therapeutic targets for diabetes, it is known that they can induce serious side-effects. Our results show that the practical simultaneous non-negative matrix factorization developed here can add value to the data analysis. In particular, we find that factorizing the data as a single object allows us to distinguish between the four tissue types, but does not correctly reproduce the known dosage level groups. Applying our new approach, which treats the four tissue types as providing distinct, but related, datasets, we find that the dosage level groups are respected. The new algorithm then provides separate gene list orderings that can be studied for each tissue type, and compared with the ordering arising from the single factorization. We find that many of our conclusions can be corroborated with known biological behaviour, and others offer new insights into the toxicological effects. Overall, the algorithm shows promise for early detection of toxicity in the drug discovery process

HypoRiPPAtlas as an Atlas of hypothetical natural products for mass spectrometry database search

Recent analyses of public microbial genomes have found over a million biosynthetic gene clusters, the natural products of the majority of which remain unknown. Additionally, GNPS harbors billions of mass spectra of natural products without known structures and biosynthetic genes. We bridge the gap between large-scale genome mining and mass spectral datasets for natural product discovery by developing HypoRiPPAtlas, an Atlas of hypothetical natural product structures, which is ready-to-use for in silico database search of tandem mass spectra. HypoRiPPAtlas is constructed by mining genomes using seq2ripp, a machine-learning tool for the prediction of ribosomally synthesized and post-translationally modified peptides (RiPPs). In HypoRiPPAtlas, we identify RiPPs in microbes and plants. HypoRiPPAtlas could be extended to other natural product classes in the future by implementing corresponding biosynthetic logic. This study paves the way for large-scale explorations of biosynthetic pathways and chemical structures of microbial and plant RiPP classes

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Canadian physiotherapists' views on certification, specialisation, extended role practice, and entry-level training in rheumatology

<p>Abstract</p> <p>Background</p> <p>Since the last decade there has been a gradual change of boundaries of health professions in providing arthritis care. In Canada, some facilities have begun to adopt new arthritis care models, some of which involve physiotherapists (PT) working in extended roles. However, little is known about PTs' interests in these new roles. The primary objective of this survey was to determine the interests among orthopaedic physiotherapists (PTs) in being a certified arthritis therapist, a PT specialized in arthritis, or an extended scope practitioner in rheumatology, and to explore the associated factors, including the coverage of arthritis content in the entry-level physiotherapy training.</p> <p>Methods</p> <p>Six hundred PTs practicing in orthopaedics in Canada were randomly selected to receive a postal survey. The questionnaire covered areas related to clinical practice, perceptions of rheumatology training received, and attitudes toward PT roles in arthritis care. Logistic regression models were developed to explore the associations between PTs' interests in pursuing each of the three extended scope practice designations and the personal/professional/attitudinal variables.</p> <p>Results</p> <p>We received 286 questionnaires (response rate = 47.7%); 258 contained usable data. The average length of time in practice was 15.4 years (SD = 10.4). About 1 in 4 PTs agreed that they were interested in assuming advanced practice roles (being a certified arthritis therapist = 28.9%, being a PT specialized in rheumatology = 23.3%, being a PT practitioner = 20.9%). Having a caseload of ≥ 40% in arthritis, having a positive attitude toward advanced practice roles in arthritis care and toward the formal credentialing process, and recognizing the difference between certification and specialisation were associated with an interest in pursing advanced practice roles.</p> <p>Conclusion</p> <p>Orthopaedic PTs in Canada indicated a fair level of interest in pursuing certification, specialisation and extended scope practice roles in arthritis care. Future research should focus on the effectiveness and cost-effectiveness of the emerging health service delivery models involving certified, specialized or extended scope practice PTs in the management of arthritis.</p

Correlated long-range mixed-harmonic fluctuations measured in pp, p+Pb and low-multiplicity Pb+Pb collisions with the ATLAS detector

For abstract see published article

Measurements of inclusive and differential fiducial cross-sections of tt production with additional heavy-flavour jets in proton-proton collisions at √ s= 13 TeV with the ATLAS detector

This paper presents measurements of tt production in association with additional b-jets in pp collisions at the LHC at a centre-of-mass energy of 13 TeV. The data were recorded with the ATLAS detector and correspond to an integrated luminosity of 36.1 fb−1. Fiducial cross-section measurements are performed in the dilepton and lepton-plus-jets tt decay channels. Results are presented at particle level in the form of inclusive cross-sections of tt final states with three and four b-jets as well as differential cross-sections as a function of global event properties and properties of b-jet pairs. The measured inclusive fiducial cross-sections generally exceed the ttbb predictions from various next-to-leading-order matrix element calculations matched to a parton shower but are compatible within the total uncertainties. The experimental uncertainties are smaller than the uncertainties in the predictions. Comparisons of state-of-the-art theoretical predictions with the differential measurements are shown and good agreement with data is found for most of them

Search for Higgs bosons produced via vector-boson fusion and decaying into bottom quark pairs in √s =13 TeV pp collisions with the ATLAS detector

A search for the bb ¯ decay of the Standard Model Higgs boson produced through vector-boson fusion is presented. Three mutually exclusive channels are considered: two all-hadronic channels and a photon-associated channel. Results are reported from the analysis of up to 30.6 fb −1 of pp data at s √ =13 TeV collected with the ATLAS detector at the LHC. The measured signal strength relative to the Standard Model prediction from the combined analysis is 2.5 +1.4 −1.3 for inclusive Higgs boson production and 3.0 +1.7 −1.6 for vector-boson fusion production only