Determination of anthelmintic drug residues in milk using ultra high performance liquid chromatography-tandem mass spectrometry with rapid polarity switching

Whelan, M.,Kinsella, B.,Furey, A.,Moloney, M.,Cantwell, H.,Lehotay, S.J.,Danaher, M. Elsevier 2010 Journal of chromatography Vol.1217 No.27

A new UHPLC-MS/MS (ultra high performance liquid chromatography coupled to tandem mass spectrometry) method was developed and validated to detect 38 anthelmintic drug residues, consisting of benzimidazoles, avermectins and flukicides. A modified QuEChERS-type extraction method was developed with an added concentration step to detect most of the analytes at <1μgkg<SUP>-1</SUP> levels in milk. Anthelmintic residues were extracted into acetonitrile using magnesium sulphate and sodium chloride to induce liquid-liquid partitioning followed by dispersive solid phase extraction for cleanup. The extract was concentrated into dimethyl sulphoxide, which was used as a keeper to ensure analytes remain in solution. Using rapid polarity switching in electrospray ionisation, a single injection was capable of detecting both positively and negatively charged ions in a 13min run time. The method was validated at two levels: the unapproved use level and at the maximum residue level (MRL) according to Commission Decision (CD) 2002/657/EC criteria. The decision limit (CCα) of the method was in the range of 0.14-1.9 and 11-123μgkg<SUP>-1</SUP> for drugs validated at unapproved and MRL levels, respectively. The performance of the method was successfully verified for benzimidazoles and levamisole by participating in a proficiency study.

A study of the pH dependence of electronically excited guanosine compounds by picosecond time-resolved infrared spectroscopy

McGovern, David A.,Doorley, Gerard W.,Whelan, Aine M.,Parker, Anthony W.,Towrie, Michael,Kelly, John M.,Quinn, Susan J. Korean Society of Photoscience 2009 Photochemical & photobiological sciences Vol.8 No.4

The photophysical properties of 5'-guanosine monophosphate (5'-GMP) and polyguanylic acid {poly(G)} in $D_2O$ solutions of varying pH have been studied using picosecond transient infrared absorption spectroscopy. Whereas in neutral or weakly alkaline solution only the vibrationally excited electronic ground state of 5'-GMP is observed, in acidic solution the relatively long-lived ($229{\pm}20\;ps$) electronic excited state of protonated 5'-GMP, which possesses strong absorptions at 1517 and $1634\;cm^{-1}$, could be detected. The picosecond transient behaviour of polyguanylic acid in acidic solution is also very different from that of the polynucleotide in neutral solution due not only to the protonation of guanine moieties yielding the protonated excited state but because of the disruption of the guanine stacks which are present in the species in neutral solution.

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

Guadalupe, Tulio,Mathias, Samuel R.,vanErp, Theo G. M.,Whelan, Christopher D.,Zwiers, Marcel P.,Abe, Yoshinari,Abramovic, Lucija,Agartz, Ingrid,Andreassen, Ole A.,Arias-Vá,squez, Alejandro,Aribi Springer US 2017 Brain imaging and behavior Vol.11 No.5

<P>The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s11682-016-9629-z) contains supplementary material, which is available to authorized users.</P>

Two chemically similar stellar overdensities on opposite sides of the plane of the Galactic disk

Bergemann, Maria,Sesar, Branimir,Cohen, Judith G.,Serenelli, Aldo M.,Sheffield, Allyson,Li, Ting S.,Casagrande, Luca,Johnston, Kathryn V.,Laporte, Chervin F. P.,Price-Whelan, Adrian M.,Schö,nrich, Macmillan Publishers Limited, part of Springer Nat 2018 Nature Vol.555 No.7696

Our Galaxy is thought to have an active evolutionary history, dominated over the past ten billion years or so by star formation, the accretion of cold gas and, in particular, the merging of clumps of baryonic and dark matter. The stellar halo—the faint, roughly spherical component of the Galaxy—reveals rich ‘fossil’ evidence of these interactions, in the form of stellar streams, substructures and chemically distinct stellar components. The effects of interactions with dwarf galaxies on the content and morphology of the Galactic disk are still being explored. Recent studies have identified kinematically distinct stellar substructures and moving groups of stars in our Galaxy, which may have extragalactic origins. There is also mounting evidence that stellar overdensities (regions with greater-than-average stellar density) at the interface between the outer disk and the halo could have been caused by the interaction of a dwarf galaxy with the disk. Here we report a spectroscopic analysis of 14 stars from two stellar overdensities, each lying about five kiloparsecs above or below the Galactic plane—locations suggestive of an association with the stellar halo. We find that the chemical compositions of these two groups of stars are almost identical, both within and between these overdensities, and closely match the abundance patterns of stars in the Galactic disk. We conclude that these stars came from the disk, and that the overdensities that they are part of were created by tidal interactions of the disk with passing or merging dwarf galaxies.

Metabolomics Approach in the Study of the Well-Defined Polyherbal Preparation Zyflamend

Eric D. Tague,Allen K. Bourdon,Amber MacDonald,Maggie S. Lookadoo,Edward D. Kim,Wesley M. White,Paul D. Terry,Shawn R. Campagna,Brynn H. Voy,Jay Whelan 한국식품영양과학회 2018 Journal of medicinal food Vol.21 No.3

Zyflamend is a highly controlled blend of 10 herbal extracts that synergistically impact multiple cell signaling pathways with anticancer and anti-inflammatory properties. More recently, its effects were shown to also modify cellular energetics, for example, activation of fatty acid oxidation and inhibition of lipogenesis. However, its general metabolic effects in vivo have yet to be explored. The objective of this study was to characterize the tissue specific metabolomes in response to supplementation of Zyflamend in mice, with a comparison of equivalent metabolomics data generated in plasma from humans supplemented with Zyflamend. Because Zyflamend has been shown to activate AMPK, the “energy sensor” of the cell, in vitro, the effects of Zyflamend on adiposity were also tested in the murine model. C57BL/6 mice were fed diets that mimicked the macro- and micronutrient composition of the U.S. diet with and without Zyflamend supplementation at human equivalent doses. Untargeted metabolomics was performed in liver, skeletal muscle, adipose, and plasma from mice consuming Zyflamend and in plasma from humans supplemented with Zyflamend at an equivalent dose. Adiposity in mice was significantly reduced in the Zyflamend-treated animals (compared with controls) without affecting body weight or weight gain. Based on KEGG pathway enrichment, purine and pyrimidine metabolism (potential regulators of AMPK) were particularly responsive to Zyflamend across all tissues, but only in mice. Consistent with the metabolomics data, Zyflamend activated AMPK and inhibited acetyl CoA-carboxylase in adipose tissue, key regulators of lipogenesis. Zyflamend reduces adipose tissue in mice through a mechanism that likely involves the activation of AMPK.

International regulatory requirements for skin sensitization testing

Daniel, Amber B.,Strickland, Judy,Allen, David,Casati, Silvia,Zuang, Valé,rie,Barroso, Joã,o,Whelan, Maurice,Ré,gimbald-Krnel, M.J.,Kojima, Hajime,Nishikawa, Akiyoshi,Park, Hye-Kyung Elsevier 2018 Regulatory toxicology and pharmacology Vol.95 No.-

<P><B>Abstract</B></P> <P>Skin sensitization test data are required or considered by chemical regulation authorities around the world. These data are used to develop product hazard labeling for the protection of consumers or workers and to assess risks from exposure to skin-sensitizing chemicals. To identify opportunities for regulatory uses of non-animal replacements for skin sensitization tests, the needs and uses for skin sensitization test data must first be clarified. Thus, we reviewed skin sensitization testing requirements for seven countries or regions that are represented in the International Cooperation on Alternative Test Methods (ICATM). We noted the type of skin sensitization data required for each chemical sector and whether these data were used in a hazard classification, potency classification, or risk assessment context; the preferred tests; and whether alternative non-animal tests were acceptable. An understanding of national and regional regulatory requirements for skin sensitization testing will inform the development of ICATM's international strategy for the acceptance and implementation of non-animal alternatives to assess the health hazards and risks associated with potential skin sensitizers.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We reviewed regulatory requirements for skin sensitization testing, by chemical sector, of seven countries or regions. </LI> <LI> This review summarizes data needs for hazard classification, potency classification, and risk assessment. </LI> <LI> We identify preferred test methods and note whether non-animal alternative test methods are acceptable. </LI> <LI> This effort will inform an international strategy for implementing non-animal approaches for skin sensitization assessment. </LI> </UL> </P>

Immune evasion in cancer: Mechanistic basis and therapeutic strategies

Vinay, D.S.,Ryan, E.P.,Pawelec, G.,Talib, W.H.,Stagg, J.,Elkord, E.,Lichtor, T.,Decker, W.K.,Whelan, R.L.,Kumara, H.M.C.S.,Signori, E.,Honoki, K.,Georgakilas, A.G.,Amin, A.,Helferich, W.G.,Boosani, C. Saunders Scientific Publications ; Academic Press 2015 SEMINARS IN CANCER BIOLOGY Vol.35 No.suppl

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through ''equilibrium'' and ''senescence'' before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.

Standardisation of defined approaches for skin sensitisation testing to support regulatory use and international adoption: position of the International Cooperation on Alternative Test Methods

Casati, S.,Aschberger, K.,Barroso, J.,Casey, W.,Delgado, I.,Kim, T. S.,Kleinstreuer, N.,Kojima, H.,Lee, J. K.,Lowit, A.,Park, H. K.,Ré,gimbald-Krnel, M. J.,Strickland, J.,Whelan, M.,Yang, Y.,Zua Springer Berlin Heidelberg 2018 Archives of toxicology Vol.92 No.2

<P>Skin sensitisation is the regulatory endpoint that has been at the centre of concerted efforts to replace animal testing in recent years, as demonstrated by the Organisation for Economic Co-operation and Development (OECD) adoption of five non-animal methods addressing mechanisms under the first three key events of the skin sensitisation adverse outcome pathway. Nevertheless, the currently adopted methods, when used in isolation, are not sufficient to fulfil regulatory requirements on the skin sensitisation potential and potency of chemicals comparable to that provided by the regulatory animal tests. For this reason, a number of defined approaches integrating data from these methods with other relevant information have been proposed and documented by the OECD. With the aim to further enhance regulatory consideration and adoption of defined approaches, the European Union Reference Laboratory for Alternatives to Animal testing in collaboration with the International Cooperation on Alternative Test Methods hosted, on 4–5 October 2016, a workshop on the international regulatory applicability and acceptance of alternative non-animal approaches, i.e., defined approaches, to skin sensitisation assessment of chemicals used in a variety of sectors. The workshop convened representatives from more than 20 regulatory authorities from the European Union, United States, Canada, Japan, South Korea, Brazil and China. There was a general consensus among the workshop participants that to maximise global regulatory acceptance of data generated with defined approaches, international harmonisation and standardisation are needed. Potential assessment criteria were defined for a systematic evaluation of existing defined approaches that would facilitate their translation into international standards, e.g., into a performance-based Test Guideline. Informed by the discussions at the workshop, the ICATM members propose practical ways to further promote the regulatory use and facilitate adoption of defined approaches for skin sensitisation assessments.</P>