Plus ça change - evolutionary sequence divergence predicts protein subcellular localization signals

Background: Protein subcellular localization is a central problem in understanding cell biology and has been the focus of intense research. In order to predict localization from amino acid sequence a myriad of features have been tried: including amino acid composition, sequence similarity, the presence of certain motifs or domains, and many others. Surprisingly, sequence conservation of sorting motifs has not yet been employed, despite its extensive use for tasks such as the prediction of transcription factor binding sites.Results: Here, we flip the problem around, and present a proof of concept for the idea that the lack of sequence conservation can be a novel feature for localization prediction. We show that for yeast, mammal and plant datasets, evolutionary sequence divergence alone has significant power to identify sequences with N-terminal sorting sequences. Moreover sequence divergence is nearly as effective when computed on automatically defined ortholog sets as on hand curated ones. Unfortunately, sequence divergence did not necessarily increase classification performance when combined with some traditional sequence features such as amino acid composition. However a post-hoc analysis of the proteins in which sequence divergence changes the prediction yielded some proteins with atypical (i.e. not MPP-cleaved) matrix targeting signals as well as a few misannotations.Conclusion: We report the results of the first quantitative study of the effectiveness of evolutionary sequence divergence as a feature for protein subcellular localization prediction. We show that divergence is indeed useful for prediction, but it is not trivial to improve overall accuracy simply by adding this feature to classical sequence features. Nevertheless we argue that sequence divergence is a promising feature and show anecdotal examples in which it succeeds where other features fail. © 2014 Fukasawa et al.; licensee BioMed Central Ltd.Link_to_subscribed_fulltex

Estimating daily and diurnal variations of illicit drug use in Hong Kong: A pilot study of using wastewater analysis in an Asian metropolitan city

The measurement of illicit drug metabolites in raw wastewater is increasingly being adopted as an approach to objectively monitor population-level drug use, and is an effective complement to traditional epidemiological methods. As such, it has been widely applied in western countries. In this study, we utilised this approach to assess drug use patterns over nine days during April 2011 in Hong Kong. Raw wastewater samples were collected from the largest wastewater treatment plant serving a community of approximately 3.5 million people and analysed for excreted drug residues including cocaine, ketamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and key metabolites using liquid chromatography coupled with tandem mass spectrometry. The overall drug use pattern determined by wastewater analysis was consistent with that have seen amongst people coming into contact with services in relation to substance use; among our target drugs, ketamine (estimated consumption: 1400-1600. mg/day/1000 people) was the predominant drug followed by methamphetamine (180-200. mg/day/1000 people), cocaine (160-180. mg/day/1000 people) and MDMA (not detected). The levels of these drugs were relatively steady throughout the monitoring period. Analysing samples at higher temporal resolution provided data on diurnal variations of drug residue loads. Elevated ratios of cocaine to benzoylecgonine were identified unexpectedly in three samples during the evening and night, providing evidence for potential dumping events of cocaine. This study provides the first application of wastewater analysis to quantitatively evaluate daily drug use in an Asian metropolitan community. Our data reinforces the benefit of wastewater monitoring to health and law enforcement authorities for strategic planning and evaluation of drug intervention strategies

Effects of genuine dimension-six Higgs operators

We systematically discuss the consequences of genuine dimension-six Higgs operators. These operators are not subject to stringent constraints from electroweak precision data. However, they can modify the couplings of the Higgs boson to electroweak gauge bosons and, in particular, the Higgs self-interactions. We study the sensitivity to which those couplings can be probed at future \ee linear colliders in the sub-TeV and in the multi-TeV range. We find that for $\sqrt s=500$ GeV with a luminosity of 1 ab$^{-1}$ the anomalous $WWH$ and $ZZH$ couplings may be probed to about the 0.01 level, and the anomalous $HHH$ coupling to about the 0.1 level.Comment: 21 pages, 17 figures; typos corrected and references adde

Spin liquid ground state in a two dimensional non-frustrated spin model

We consider an exchange model describing two isotropic spin-1/2 Heisenberg antiferromagnets coupled by a quartic term on the square lattice. The model is relevant for systems with orbital degeneracy and strong electron-vibron coupling in the large Hubbard repulsion limit, and is known to show a spin-Peierls-like dimerization in one dimension. In two dimensions we calculate energy gaps, susceptibilities, and correlation functions with a Green's Function Monte Carlo. We find a finite spin gap and no evidence of any kind of order. We conclude that the ground state is, most likely, a spin liquid of resonating valence bonds.Comment: 4 pages, 4 figures, Revte

Total and Active Rabbit Antithymocyte Globulin (rATG;Thymoglobulin®) Pharmacokinetics in Pediatric Patients Undergoing Unrelated Donor Bone Marrow Transplantation

AbstractRabbit antithymocyte globulin (rATG; Thymoglobulin®) is currently used to prevent or treat graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation (HSCT). The dose and schedule of rATG as part of the preparative regimen for unrelated donor (URD) bone marrow transplantation (BMT) have not been optimized in pediatric patients. We conducted a prospective study of 13 pediatric patients with hematologic malignancies undergoing URD BMT at St. Jude Children's Research Hospital from October 2003 to March 2005, to determine the pharmacokinetics and toxicities of active and total rATG. The conditioning regimen comprised total body irradiation (TBI), thiotepa, and cyclophosphamide (Cy); cyclosporine (CsA) and methotrexate (MTX) were administered as GVHD prophylaxis. Patients received a total dose of 10 mg/kg rATG, and serial blood samples were assayed for total rATG by enzyme linked immunosorbent assay (ELISA) and active rATG by florescein activated cell sorting (FACS). We found that our weight-based dosing regimen for rATG was effective and well tolerated by patients. The half-lives of total and active rATG were comparable to those from previous studies, and despite high doses our patients had low maximum concentrations of active and total rATG. There were no occurrences of grade iii-iv GVHD even in patients having low peak rATG levels, and the overall incidence of grade II GVHD was only 15%. None of the patients had serious infections following transplantation. These data support the use of a 10 mg/kg dose of rATG in children with hematologic malignancies because it can be administered without increasing the risk of graft rejection, or serious infection in pediatric patients with a low rate of GVHD. These conclusions may not apply to patients with nonmalignant disorders

Neutral Dissociation of Hydrogen Following Photoexcitation of HCl at the Chlorine K Edge

Time-of-flight mass spectroscopy was used to study the relaxation dynamics of HCl following photoexcitation in the vicinity of the Cl K edge (~2.8 keV) using monochromatic synchrotron radiation. At the lowest resonant excitation to the 6ơ* antibonding orbital, almost half of the excited molecules decay by emission of a neutral H atom, mostly in coincidence with a highly charged Cln1 ion. The present work demonstrates that neutral-atom emission can be a significant decay channel for excited states with very short lifetimes (1 fs). [S1050-2947(98)03604-X