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The tuberculosis drug candidate SQ109 targets the trehalose monomycolate transporter MmpL3 in Mycobacterium tuberculosis and also has activity against other pathogens. We found related proteins in 22 protozoa, including Trypanosoma cruzi and Entamoeba histolytica, as well as in archaea and other bacteria, including the fatty acid transporter, FarE. We show these proteins, alpha-MMPL proteins, adopt similar structures to that of MsMmpL3 having two sets (P1 and P2) of conserved active site/H+-transporter Asp, Tyr and Phe residues in “pentad” motifs (DYxxF) that can bind to the SQ109 ethylenediamine and adamantyl moieties. Based on structural comparisons with MsMmpL3, we find that there are superimposable transmembrane and H+-transporter structures in much larger proteins, beta-MMPLs, found in apicomplexan parasites, fungi, plants and animals. They also contain double “pentad” motifs in which the P1 Asp is totally conserved, but the P2 Asp may also be a Glu, and the P2 Phe seen in the alpha-MMPLs is a His that H-bonds to the P1 and P2 Asp/Glu residues. There are also 5 conserved Ser/Thr residues that extend the H-bond/H+-transporter network with 2 interacting directly with the P1 Asp, and the His. We propose that all MMPL proteins are involved in proton motive force-mediated lipid (phospholipid, glycolipid, sterol, fatty acid) transport, and that SQ109 may target some pathogens directly, by binding to the P1/P2 motifs. Overall, the results are of general interest since they indicate that there are two major classes of lipid transporters: alpha-MMPL proteins found in many bacteria and protozoa, and much larger, beta-MMPL proteins, found in fungi, apicomplexa, plants and animals and, in some cases, they are potential drug targets.

The capacity to flexibly respond to contextual changes is crucial to adapting to a dynamic environment. Compulsivity, or behavioural inflexibility, consists of heterogeneous subtypes with overlapping yet discrete neural substrates. The subthalamic nucleus (STN) mediates the switch from automatic to controlled processing to slow, break or stop behaviour when necessary. Rodent STN lesions or inactivation are linked with perseveration or repetitive, compulsive responding. However, there are few studies examining the role of latent STN-centric neural networks and compulsive behaviour in healthy individuals. We therefore aimed to characterize the relationship between measures of compulsivity (goal-directed and habit learning, perseveration, and self-reported obsessive - compulsive symptoms) and the intrinsic resting state network of the STN. We scanned 77 healthy controls using a multi-echo resting state functional MRI sequence analyzed using independent components analysis (ME-ICA) with enhanced signal-to-noise ratio to examine small subcortical structures. Goal directed model-based behaviour was associated with higher connectivity of STN with medial orbitofrontal cortex (mOFC) and ventral striatum (VS) and more habitual model-free learning was associated with STN connectivity with hippocampus and dorsal anterior cingulate cortex (ACC). Perseveration was associated with reduced connectivity between STN and premotor cortex and finally, higher obsessive -compulsive inventory scores were associated with reduced STN connectivity with dorsolateral prefrontal cortex (PF). We highlight unique contributions of diffuse cortico-striatal functional connections with STN in dissociable measures of compulsivity. These findings are relevant to the development of potential biomarkers of treatment response in neurosurgical procedures targeting the STN for neurological and psychiatric disorders.

Lipoteichoic acid is an essential component of the Staphylococcus aureus cell envelope and an attractive target for the development of vaccines and antimicrobials directed against antibiotic-resistant Gram-positive bacteria such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. In this study, we showed that the lipoteichoic acid polymer is essential for growth of S. aureus only as long as the ClpX chaperone is present in the cell. Our results indicate that lipoteichoic acid and ClpX play opposite roles in a pathway that controls two key cell division processes in S. aureus, namely, septum formation and autolytic activity. The discovery of a novel functional connection in the genetic network that controls cell division in S. aureus may expand the repertoire of possible strategies to identify compounds or compound combinations that kill antibiotic-resistant S. aureus.

We searched for the $CP$-violating rare decay of neutral kaon, $K_{L} \to ��^0 ��\overline��$, in data from the first 100 hours of physics running in 2013 of the J-PARC KOTO experiment. One candidate event was observed while $0.34\pm0.16$ background events were expected. We set an upper limit of $5.1\times10^{-8}$ for the branching fraction at the 90\% confidence level (C.L.). An upper limit of $3.7\times10^{-8}$ at the 90\% C.L. for the $K_{L} \to ��^{0} X^{0}$decay was also set for the first time, where $X^{0}$ is an invisible particle with a mass of 135 MeV/$c^{2}$., 11 pages, 5 figures, to be published in PTEP

Presence, sources and food web biomagnification of cyclic volatile methylsiloxanes (cVMS) was investigated in three Norwegian lakes (Mjøsa, Randsfjorden, Femunden). The high levels and food web biomagnification of the cVMS D5 in Mjøsa reported in 2010 was confirmed. The cVMS levels in lakes with discharge from waste water treatment plants were higher than in the reference lake with minor human impact (Femunden), suggesting that local sources are the major input of cVMS, rather than long range transport. The cVMS analysed for (D4, D5, D6) were found in effluent water from the investigated waste water treatment plants in Mjøsa and Randsfjorden. D5 and D6 biomagnified in the pelagic food web with trophic magnification factors above 1 in both Mjøsa and Randsfjorden. Results indicated that D4 is subject to trophic dilution, with decreasing concentrations with increasing trophic level. Klif

Denne screening prosjekt undersøkt forekomsten av nonylfenol og nonylfenol monoethoksylat, oktylfenol og oktylfenol monnoethoksylat, og bisfenol A i marin og ferskvanns akvatiske miljøer, bunnstoffet Zineb og dens nedbrytnings produkt ethylenethiourea i småbåthavner, det soppmiddel transformasjon produktet N,N-dimethylsulfamid, valgt annensgenerasjons antikoagulant rottegift i leveren hos utvalgte rovfugl, og nonylfenol og nonylfenol monoethoksylat, oktylfenol og oktylfenol monnoethoksylat og valgte nåværende bruk plantevernmidler i Arktis biota. Klif

An evaluation of the performance of a range of techniques for the measurement of the concentration of trace level organic contaminants was undertaken in the River Glomma during the period August-November 2010. This work focussed on further evaluating two techniques that have the potential to substantially improve the reliability and limits of detection of such measurements. Passive sampling devices, namely low density polyethylene membranes and silicone strips, were deployed over three consecutive 28 day periods to measure dissolved concentrations of polycyclic aromatic hydrocarbons, polychlorinated biphenyls and brominated flame retardants. Continuous flow centrifugation was used to measure these contaminants associated with the particulate phase. Contaminant limits of detection were in the low pg L-1 range or below. These methods have the potential to become a vital part of the Riverine Input and Discharge (RID) monitoring programme for the evaluation of riverine fluxes of contaminants to the North Sea and to help with responding to the challenges set by the EU Water Framework Directive (WFD). A set of recommendations for the use of these techniques for such monitoring tasks is given. Klima- og forurensningsdirektoratet (Klif)

This report investigated concentrations of silver, arsenic, chromium, nickel, brominated compounds including PBDEs and HBCDD, perfluorinated organic compounds including PFOS and PFOSA, organochlorines including trichloroethylene, endosulfan, trichlrorbenzene and HCBD, cyclodiene pesticides, selected phenols and chlorophenols, isoproturon and DEHP. Analyses were done on samples from sediment from the period 2004 - 2008, and blue mussel and cod from 2008 collected under the Coordinated Environmental Monitoring Programme (CEMP). The report is a contribution implementation of the EU Water Framework Directive with respect to gaining more knowledge about some hazardous substances that are not routinely monitored. Statens Forurensningstilsyn

parameter extraction method (zero-gm method), based on the measured S-parameters, are proposed for microwave applications of submicron (Lg=0.6 m) Si-MOSFET’s. The ambiguity between the channel charging resistance Rgsi and the transconductance delay in conventional models (gm=gmoe j ) are also claried. Without a conventional de-embedding process, which uses additional test patterns with exactly the same geometrical structures as the device under test, extrinsic parameters, including contact pads and interconnection lines of the DUT, are uniquely extracted at zero-gm bias condition (VGS jgm=0= 0.25 V, VDS=0 V) from 45 MHz to 30 GHz. For a simple and accurate smallsignal model for microwave applications, a nonlinear curve tting of an analytical 2-port network parameter equation is employed.

Semantic wikis have been regarded as an important collaboration tool among a number of experts from multiple domains. This wiki platform can play a role of collaborative knowledge management system which can provide an efficient framework to raise social interactions between remote people synchronously. However, as these semantic wiki systems allow users to exploit their own semantics and backgrounds for describing their knowledge and skills, there are often semantic conflicts between knowledge (or information) published and provided by the users. Thereby, the main aims of this work are i) to automatically detect such conflicts by keeping track on the user semantics, and ii) to reasonably select consensus choice by analyzing social collaborations. In this paper, we want to note major patterns of knowledge dynamics through the social interactions on semantic wikis, and the semantic conflicts caused by the knowledge dynamics. The consensus choice has been effectively selected to be recommended for better understandability about the knowledge conflicts.