bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacists on the front line in providing support for nicotine replacement therapy and bupropion purchasers
Authors: PAUL CHRISTINE L. , TZELEPIS FLORA , WALSH RAOUL A. , TURNER RICHARD
Published: June 2007

Introduction and Aims. Increased access for smokers to pharmacotherapies for smoking cessation suggests that pharmacists have a potential role in influencing how these pharmacotherapies are used in the community. This study aimed to identify the extent and type of advice provided by pharmacists to customers purchasing nicotine replacement therapy (NRT) or bupropion and to identify pharmacists' perceptions about the desirability and feasibility of providing such advice. Design and Methods. A sample of 700 pharmacies was selected at random from the NSW Electronic Yellow Pages and a questionnaire was sent by mail, fax or e‐mail to the pharmacist in charge. Results. From 665 eligible pharmacies, 375 pharmacists returned completed questionnaires, giving a response rate of 56.4%. Participants reported providing a mean of 5 minutes of advice to both bupropion and NRT purchasers, with 59.5% reporting the provision of behavioural advice to NRT purchasers. Although over 70% of pharmacists perceived the provision of a brochure about NRT or bupropion as desirable and feasible, brochures were provided to less than one‐third of NRT purchasers. Discussion and Conclusions. Pharmacists report providing a sizeable amount of advice to purchasers of NRT and bupropion. Recommendations for enhancing the role of pharmacists in influencing the use of cessation pharmacotherapies are discussed briefly. [Paul CL, Tzelepis F, Walsh RA, Turner R. Pharmacists on the front line in providing support for nicotine replacement therapy and bupropion purchasers. Drug Alcohol Rev 2007;26:429–433]
Suitability of the Limit Dose in Evaluating Reproductive Toxicity of Substances and Preparations
Authors: Schneider Klaus , Oltmanns Jan , Van Gelder Rainer , Gebel Thomas
Published: June 2007

An oral dose of 1000 mg/kg body weight/day is mentioned in Organisation for Economic Cooperation and Development (OECD) and European Union (EU) guidelines as a default maximum dose in limit tests for studies on reproductive toxicity. This paper investigated whether upper range human exposure data from the workplace are supportive of this limit dose as an upper limit of possible human exposure. To this end, published exposure data as well as data from the database MEGA of the German “Berufsgenossenschaften” were evaluated. These data indicate that exposure concentrations in the range of 500 to 2000 mg/m3 (time-weighted averages) can be considered high human exposures to volatile compounds. Inhalation exposure to aerosols and dermal exposure result in lower dose levels. By applying suitable extrapolation factors, it was concluded that occupational exposures up to 325 mg/m3 can reliably be assessed with limit tests using a dose level of 1000 mg/kg/day. The limit dose has been proposed for use in the EU as a starting point to derive specific concentration limits for hazard classification of preparations containing reproductive toxicants, with the objective to consider the potency of the substances. This analysis shows that for some groups of chemicals, instead of the limit dose, the putative maximum levels of human exposure should be taken into account when deriving concentration limits for the classification of preparations. Furthermore, possible deviations from a linear correlation between concentration in the preparation and exposure should be considered.
Effects of Phalloidin on Hepatic Gene Expression in Mice
Authors: Lim Jung-Sun , Jeong Sun-Young , Hwang Ji-Yoon , Park Han-Jin , Kim Yong-Bum , Rana Suresh V. S. , Yoon Seokjoo
Published: June 2007

An attempt has been made to identify molecular markers of intrahepatic cholestasis in mice employing phalloidin as a cholestatic agent. Phalloidin was administered to BALB/c mice at three predetermined dose: 250 μg/kg, 500 μg/kg, and 1 mg/kg for 1, 3, and 7 days. Liver function was estimated to confirm cholestasis. Histopathological observations on liver were also made to confirm liver injury. Phalloidin at 1 mg/kg for 7 days was found to induce cholestasis. Therefore gene expression studies were confined to this group only. A total of 88 genes were found to be affected by phalloidin. These were the genes associated with cytoskeleton regulation as well as tight junction, focal adhesion, and ATP-binding cassette transporters. Such proteins obstruct the removal of bile components from hepatocytes to the bile canaliculus or blood. Phalloidin treatment did not affect the proteins responsible for cell maintenance or death. The authors show that phalloidin-induced intrahepatic cholestasis is manifested by disturbing the cytoskeleton. The set of genes up-regulated by phalloidin can be considered as molecular markers of intrahepatic cholestasis. The observations are further expected to be helpful in the management of cholestatic pharmaceuticals and associated problems of liver diseases in humans.
Transplacental Transfer of Monomethyl Phthalate and Mono(2-ethylhexyl) Phthalate in a Human Placenta Perfusion System
Authors: Mose Tina , Knudsen Lisbeth E. , Hedegaard Morten , Mortensen Gerda K.
Published: June 2007

The transplacental passage of monomethylphtalate (mMP) and mono (2-ethylhexyl) phthalate (mEHP) was studied using an ex vivo placental perfusion model with simultaneous perfusion of fetal and maternal circulation in a single cotyledon. Umbilical cord blood and placental tissue collected both before and after perfusion were also analyzed. Placentas were obtained immediately after elective cesarean section and dually perfused in a recirculation system. mMP or mEHP was added to maternal perfusion medium to obtain concentrations at 10 and 25 μg/L, respectively. The placental transfer was followed analyzing samples from fetal and maternal perfusion media by liquid chromatography–mass spectrometry–mass spectrometry (LC-MS-MS). Four perfusions with mMP indicated a slow transplacental transfer, with a fetomaternal ratio (FM ratio) of 0.30 ± 0.03 after 150 min of perfusion. Four perfusions with mEHP indicated a very slow or nonexisting placental transfer. mEHP was only detected in fetal perfusion media from two perfusions, giving rise to FM ratios of 0.088 and 0.20 after 150 min of perfusion. Detectable levels of mMP, mEHP, monoethylphthalate (mEP), and monobutylphthalate were found in tissue. Higher tissue levels of mMP after perfusions with mMP compared to perfusions with mEHP suggest an accumulation of mMP during perfusion. No tendency for accumulation of mEHP was observed during perfusions with mEHP compared to perfusions with mMP. Detectable levels of mEHP and mEP were found in umbilical cord plasma samples. mMP and possibly other short-chained phthalate monoesters in maternal blood can cross the placenta by slow transfer, whereas the results indicate no placental transfer of mEHP. Further studies are recommended.
Gestational Age Dependency in the Prenatal Toxicity and in the Disposition Kinetics of the Novel Anticonvulsant HEPP (D,L-3-Hydroxy-3-ethyl-3-phenylpropionamide) after Subcutaneous Administration in Pregnant Rats
Authors: Gómez-Martínez Lisbeth E.
Published: June 2007

HEPP (D,L-3-hydroxy-3-ethyl-3-phenylpropionamide) is a novel anticonvulsant with promising anticonvulsant profile, which is being actively researched. The potential maternal and embryo/fetal toxicities of HEPP were evaluated in pregnant rats following subcutaneous (s.c.) administration during organogenesis (gestation days 6 through 14, GDs 6–14) and the fetal period (GDs 14–21). Single- and multiple-dose pharmacokinetics were also evaluated at the same periods in order to establish possible correlations with some maternal or embryo/fetal toxicity end points. Embryotoxicity was mainly indicated by a significant dose-concentration dependency in the increase in resorptions, high percentage of fully resorbed litters, and decrease in embryo body weights during the GD6–14 dosing period. No gross external alterations were observed in live fetuses. There was no indication of maternal toxicity; but a marked increase in maternal body weight was evident following dosing from GD14 to GD21. The maternal plasma profile following single subcutaneous dose of 50 mg/kg on both GD14 and GD21 showed a monoexponential elimination pattern. Statistically significant differences between treatments (GD14 versus GD21) were observed in elimination ( kel = 0.12 versus 0.15 h−1), absorption ( ka = 2.01 versus 3.14 h−1), maximum plasma concentration time points ( Tmax = 1.49 versus 1.01 h); maximum plasma concentration ( Cmax = 40.23 versus 36.31 μg/ml) and areas under the concentration-time curve (AUCs0– ∞ = 421.88 versus 274 μg h/ml. Based on comparisons of Cmax, Tmax, and AUCs0– ∞ between the actual data and single intraperitoneal (i.p.) data previously published, the s.c. administration exhibited slower disposition and higher absorbed amount. After multiple-dose administrations of 50 and 100 mg/kg every 12 h (07:00 and 19:00 h), steady-state plasma levels were lower than the computer prediction, and only slight accumulation was observed. In both dosing periods HEPP levels were similar in mothers and offspring at steady-state conditions. The high incidence of embryo death and reduced embryo weight at GD6–14 dosing compared to GD14–21 dosing suggest that embryos are more sensitive to the deleterious effects of HEPP than fetuses; however, the faster elimination observed at late gestation could also contribute to the lower toxicity observed during the fetal period. Because the maternal HEPP plasma levels and the AUC values were positively correlated with embryo/fetal toxicity end points, both pharmacokinetic parameters could be reliable indicators of offspring exposure and consequently of potential toxicity. These data suggest that the length of time that HEPP is present in the maternal plasma at a sufficiently high concentration could be determinant of adverse effects in the offspring.
Acute Oral Toxicity Study of Asiasari radix Extract in Mice
Authors: Ramesh T. , Lee K. , Lee H. W. , Kim S. J.
Published: June 2007

Acute oral toxicity of methanol extract of Asiasari radix was evaluated in ICR mice of both sexes. In this study, mice were administrated orally with dosages of 1000, 3000, and 5000 mg/kg body weight of Asiasari radix extract. Mortality, signs of toxicity, body weight, food consumption, and gross findings were observed for 14 days post treatment of Asiasari radix extract. No mortality, signs of toxicity, and abnormalities in gross findings were observed. In addition, no significant differences were noticed in the body and organ weights between the control and treated groups of both sexes. These results show that the methanol extract of Asiasari radix is toxicologically safe by oral administration.
Evaluation of the Developmental Toxicity of Alpha-iso-methylionone in Rats
Authors: Politano Valerie T. , Lewis Elise M. , Hoberman Alan M. , Christian Mildred S. , Diener Robert M. , Api Anne Marie
Published: June 2007

Alpha-iso-methylionone, a widely used fragrance ingredient, was evaluated for developmental toxicity in presumed pregnant Sprague-Dawley rats (25/group). Oral dosages of 0, 3, 10, or 30 mg/kg/day alpha-iso-methylionone in corn oil were administered by gavage on gestational days 7 to 17. The presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day. Rats were observed for viability, clinical signs, body weights, and feed consumption. Caesarean sectioning and necropsy occurred on gestational day 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. Numbers of corpora lutea were also recorded. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. No maternal or fetal deaths occurred. No fragrance ingredient–related clinical signs were observed. Feed consumption, body weight gains, gross tissue changes at necropsy, and caesarean section or litter parameters, as well as fetal developmental morphology, were unaffected by dosages of alpha-iso-methylionone as high as 30 mg/kg/day. Based on these data, maternal and developmental no observed adverse effect levels of equal to or greater than 30 mg/kg/day were established for alpha-iso-methylionone. It is concluded that alpha-iso-methylionone is not a developmental toxicant in rats at maternal doses of up to 30 mg/kg/day.
The Localization of Inner Centromeric Protein (INCENP) at the Cleavage Furrow Is Dependent on Kif12 and Involves Interactions of the N Terminus of INCENP with the Actin Cytoskeleton
Authors: Chen Qian , Lakshmikanth Gandikota S. , Spudich James A. , De Lozanne Arturo
Published: June 2007

The inner centromeric protein (INCENP) and other chromosomal passenger proteins are known to localize on the cleavage furrow and to play a role in cytokinesis. However, it is not known how INCENP localizes on the furrow or whether this localization is separable from that at the midbody. Here, we show that the association of Dictyostelium INCENP (DdINCENP) with the cortex of the cleavage furrow involves interactions with the actin cytoskeleton and depends on the presence of the kinesin-6–related protein Kif12. We found that Kif12 is found on the central spindle and the cleavage furrow during cytokinesis. Kif12 is not required for the redistribution of DdINCENP from centromeres to the central spindle. However, in the absence of Kif12, DdINCENP fails to localize on the cleavage furrow. Domain analysis indicates that the N terminus of DdINCENP is necessary and sufficient for furrow localization and that it binds directly to the actin cytoskeleton. Our data suggest that INCENP moves from the central spindle to the furrow of a dividing cell by a Kif12-dependent pathway. Once INCENP reaches the equatorial cortex, it associates with the actin cytoskeleton where it then concentrates toward the end of cytokinesis.
Regulation of RasGRP1 by B Cell Antigen Receptor Requires Cooperativity between Three Domains Controlling Translocation to the Plasma Membrane
Authors: Beaulieu Nadine , Zahedi Bari , Goulding Rebecca E. , Tazmini Ghazaleh , Anthony Kira V. , Omeis Stephanie L. , de Jong Danielle R. , Kay Robert J.
Published: June 2007

RasGRP1 is a Ras-activating exchange factor that is positively regulated by translocation to membranes. RasGRP1 contains a diacylglycerol-binding C1 domain, and it has been assumed that this domain is entirely responsible for RasGRP1 translocation. We found that the C1 domain can contribute to plasma membrane-targeted translocation of RasGRP1 induced by ligation of the B cell antigen receptor (BCR). However, this reflects cooperativity of the C1 domain with the previously unrecognized Plasma membrane Targeter (PT) domain, which is sufficient and essential for plasma membrane targeting of RasGRP1. The adjacent suppressor of PT (SuPT) domain attenuates the plasma membrane-targeting activity of the PT domain, thus preventing constitutive plasma membrane localization of RasGRP1. By binding to diacylglycerol generated by BCR-coupled phospholipase Cγ2, the C1 domain counteracts the SuPT domain and enables efficient RasGRP1 translocation to the plasma membrane. In fibroblasts, the PT domain is inactive as a plasma membrane targeter, and the C1 domain specifies constitutive targeting of RasGRP1 to internal membranes where it can be activated and trigger oncogenic transformation. Selective use of the C1, PT, and SuPT domains may contribute to the differential targeting of RasGRP1 to the plasma membrane versus internal membranes, which has been observed in lymphocytes and other cell types.
Myosin-IIA Heavy-Chain Phosphorylation Regulates the Motility of MDA-MB-231 Carcinoma Cells
Authors: Dulyaninova Natalya G. , House Reniqua P. , Betapudi Venkaiah , Bresnick Anne R.
Published: June 2007

In mammalian nonmuscle cells, the mechanisms controlling the localized formation of myosin-II filaments are not well defined. To investigate the mechanisms mediating filament assembly and disassembly during generalized motility and chemotaxis, we examined the EGF-dependent phosphorylation of the myosin-IIA heavy chain in human breast cancer cells. EGF stimulation of MDA-MB-231 cells resulted in transient increases in both the assembly and phosphorylation of the myosin-IIA heavy chains. In EGF-stimulated cells, the myosin-IIA heavy chain is phosphorylated on the casein kinase 2 site (S1943). Cells expressing green fluorescent protein-myosin-IIA heavy-chain S1943E and S1943D mutants displayed increased migration into a wound and enhanced EGF-stimulated lamellipod extension compared with cells expressing wild-type myosin-IIA. In contrast, cells expressing the S1943A mutant exhibited reduced migration and lamellipod extension. These observations support a direct role for myosin-IIA heavy-chain phosphorylation in mediating motility and chemotaxis.
Centrin1 Is Required for Organelle Segregation and Cytokinesis inTrypanosoma brucei
Authors: Selvapandiyan Angamuthu , Kumar Praveen , Morris James C. , Salisbury Jeffrey L. , Wang Ching C. , Nakhasi Hira L.
Published: June 2007

Centrin is a calcium-binding centrosome/basal body–associated protein involved in duplication and segregation of these organelles in eukaryotes. We had shown that disruption of one of the centrin genes (centrin1) in Leishmania amastigotes resulted in failure of both basal body duplication and cytokinesis. Here, we undertook to define the role of centrin1 (TbCen1) in the duplication and segregation of basal body and its associated organelles kinetoplast and Golgi, as well as its role in cytokinesis of the procyclic form of Trypanosoma brucei by depleting its protein using RNA inhibition methodology. TbCen1-depleted cells showed significant reduction in growth compared with control cells. Morphological analysis of these cells showed they were large and pleomorphic with multiple detached flagella. Both immunofluorescence assays using organelle-specific antibodies and electron microscopic analysis showed that TbCen1-deficient cells contained multiple basal bodies, kinetoplasts, Golgi, and nuclei. These multiple organelles were, however, closely clustered together, indicating duplication without segregation in the absence of centrin. This failure in organelle segregation may be the likely cause of inhibition of cytokinesis, suggesting for the first time a new and unique role for centrin in the segregation of organelles without affecting their multiplication in the procyclic form of T. brucei.
Dynein Light Chain Association Sequences Can Facilitate Nuclear Protein Import
Authors: Moseley Gregory W. , Roth Daniela Martino , DeJesus Michelle A. , Leyton Denisse L. , Filmer Richard P. , Pouton Colin W. , Jans David A.
Published: June 2007

Nuclear localization sequence (NLS)-dependent nuclear protein import is not conventionally held to require interaction with microtubules (MTs) or components of the MT motor, dynein. Here we report for the first time the role of sequences conferring association with dynein light chains (DLCs) in NLS-dependent nuclear accumulation of the rabies virus P-protein. We find that P-protein nuclear accumulation is significantly enhanced by its dynein light chain association sequence (DLC-AS), dependent on MT integrity and association with DLCs, and that P-protein-DLC complexes can associate with MT cytoskeletal structures. We also find that P-protein DLC-AS, as well as analogous sequences from other proteins, acts as an independent module that can confer enhancement of nuclear accumulation to proteins carrying the P-protein NLS, as well as several heterologous NLSs. Photobleaching experiments in live cells demonstrate that the MT-dependent enhancement of NLS-mediated nuclear accumulation by the P-protein DLC-AS involves an increased rate of nuclear import. This is the first report of DLC-AS enhancement of NLS function, identifying a novel mechanism regulating nuclear transport with relevance to viral and cellular protein biology. Importantly, this data indicates that DLC-ASs represent versatile modules to enhance nuclear delivery with potential therapeutic application.
Two Alternative Mechanisms That Regulate the Presentation of Apoptotic Cell Engulfment Signal inCaenorhabditis elegans
Authors: Venegas Victor , Zhou Zheng
Published: June 2007

Phosphatidylserine exposed on the surface of apoptotic mammalian cells is considered an “eat-me” signal that attracts phagocytes. The generality of using phosphatidylserine as a clearance signal for apoptotic cells in animals and the regulation of this event remain uncertain. Using ectopically expressed mouse MFG-E8, a secreted phosphatidylserine-binding protein, we detected specific exposure of phosphatidylserine on the surface of apoptotic cells in Caenorhabditis elegans. Masking the surface phosphatidylserine inhibits apoptotic cell engulfment. CED-7, an ATP-binding cassette (ABC) transporter, is necessary for the efficient exposure of phosphatidylserine on apoptotic somatic cells, and for the recognition of these cells by phagocytic receptor CED-1. Alternatively, phosphatidylserine exposure on apoptotic germ cells is not CED-7 dependent, but instead requires phospholipid scramblase PLSC-1, a homologue of mammalian phospholipid scramblases. Moreover, deleting plsc-1 results in the accumulation of apoptotic germ cells but not apoptotic somatic cells. These observations suggest that phosphatidylserine might be recognized by CED-1 and act as a conserved eat-me signal from nematodes to mammals. Furthermore, the two different biochemical activities used in somatic cells (ABC transporter) and germ cells (phospholipid scramblase) suggest an increased complexity in the regulation of phosphatidylserine presentation in response to apoptotic signals in different tissues and during different developmental stages.
Modulation of Proteinase K-resistant Prion Protein in Cells and Infectious Brain Homogenate by Redox Iron: Implications for Prion Replication and Disease Pathogenesis
Authors: Basu Subhabrata , Mohan Maradumane L. , Luo Xiu , Kundu Bishwajit , Kong Qingzhong , Singh Neena
Published: June 2007

The principal infectious and pathogenic agent in all prion disorders is a β-sheet–rich isoform of the cellular prion protein (PrPC) termed PrP-scrapie (PrPSc). Once initiated, PrPSc is self-replicating and toxic to neuronal cells, but the underlying mechanisms remain unclear. In this report, we demonstrate that PrPC binds iron and transforms to a PrPSc-like form (*PrPSc) when human neuroblastoma cells are exposed to an inorganic source of redox iron. The *PrPSc thus generated is itself redox active, and it induces the transformation of additional PrPC, simulating *PrPSc propagation in the absence of brain-derived PrPSc. Moreover, limited depletion of iron from prion disease-affected human and mouse brain homogenates and scrapie-infected mouse neuroblastoma cells results in 4- to 10-fold reduction in proteinase K (PK)-resistant PrPSc, implicating redox iron in the generation, propagation, and stability of PK-resistant PrPSc. Furthermore, we demonstrate increased redox-active ferrous iron levels in prion disease-affected brains, suggesting that accumulation of PrPSc is modulated by the combined effect of imbalance in brain iron homeostasis and the redox-active nature of PrPSc. These data provide information on the mechanism of replication and toxicity by PrPSc, and they evoke predictable and therapeutically amenable ways of modulating PrPSc load.
Diacylglycerol Is Required for the Formation of COPI Vesicles in the Golgi-to-ER Transport Pathway
Authors: Fernández-Ulibarri Inés , Vilella Montserrat , Lázaro-Diéguez Francisco , Sarri Elisabet , Martínez Susana E. , Jiménez Nuria , Claro Enrique , Mérida Isabel , Burger Koert N.J. , Egea Gustavo
Published: June 2007

Diacylglycerol is necessary for trans-Golgi network (TGN) to cell surface transport, but its functional relevance in the early secretory pathway is unclear. Although depletion of diacylglycerol did not affect ER-to-Golgi transport, it led to a redistribution of the KDEL receptor to the Golgi, indicating that Golgi-to-ER transport was perturbed. Electron microscopy revealed an accumulation of COPI-coated membrane profiles close to the Golgi cisternae. Electron tomography showed that the majority of these membrane profiles originate from coated buds, indicating a block in membrane fission. Under these conditions the Golgi-associated pool of ARFGAP1 was reduced, but there was no effect on the binding of coatomer or the membrane fission protein CtBP3/BARS to the Golgi. The addition of 1,2-dioctanoyl-sn-glycerol or the diacylglycerol analogue phorbol 12,13-dibutyrate reversed the effects of endogenous diacylglycerol depletion. Our findings implicate diacylglycerol in the retrograde transport of proteins from Golgi to the ER and suggest that it plays a critical role at a late stage of COPI vesicle formation.
A Comparative Analysis of Diagnostic Protocols for Detection of the Asian Soybean Rust Pathogen, Phakopsora pachyrhizi
Authors: Jurick Wayne M. , Harmon Carrie L. , Marois Jim , Wright David L. , Lamour Kurt , Vitoreli Anne , Creswell Tom , Hershman Don , Estevez Consuelo , Kemerait Bob , Balbalian Clarissa , Harmon Philip F.
Published: June 2007

Plant diagnosticians routinely process soybean rust samples with one or more of the following diagnostic protocols: visual assessment using a dissecting microscope, an enzyme-linked immunosorbant assay (ELISA), and pathogen-specific PCR (conventional and real-time). Results of these three diagnostic protocols and time requirements for diagnosis were collected for samples with signs (sporulation) of soybean rust (presumed positive) and samples without sporulating rust pustules (presumed negative). Data were collected for samples processed in triplicate at six university plant disease clinics. The effects of sample treatment and storage on results of two diagnostic protocols also were examined. Visual diagnosis required the least amount of time (4 min), ELISA and PCR took approximately six-and-a-half times longer per sample (multiple samples being processed at one time) than a visual diagnosis. ELISA could not detect the pathogen in positive samples after desiccation followed by long-term storage at room temperature and following one or more autoclave treatments for 30 min. However, conventional PCR was capable of detecting P. pachyrhizi-infected plant material following all sample storage regimes.

Accepted for publication 9 February 2007. Published 31 May 2007.
Sir James William Longman Beament. 17 November 1921 — 10 March 2005
Authors: Green John T.
Published: June 2007

There were two dominant scientific passions in Jimmie Beament's life: insect physiology and the mechanism of hearing (and psychoacoustics). These accompanied his other passions – his family, music, and Queen's College, Cambridge. Throughout his career, Jimmie's research field remained very much his own, covering permeability and respiration in insects, orientation of lipids, the resistance of insect eggs to desiccation and to insecticides; and latterly the surface adhesion of pollen and the interaction of plant surfaces with rain. Jimmie never had time for research that needed the newest, biggest or most expensive bits of kit. Rather he preferred to choose problems that had never been solved because the
means
of attacking the problem did not exist. Thus Jimmie (with collaborators such as R. H. J. Brown & K. E. Machin) designed and built innovative, specialized equipment – he was a precision engineer as well as a scientist. Every strand of his life reflected his extraordinary energy and his desire always to move onwards. As in his science, so in his artistic life: from acting to music, first writing revues then as a performer; followed by serious composition and significant works on the theory of hearing and instruments.

Above all Jimmie was a polymath – one of an increasingly rare breed of scientists who have a broad understanding of science … and more.
Harold Scott MacDonald Coxeter. 9 February 1907 — 31 March 2003
Authors: Roberts Siobhan , Ivić Weiss Asia
Published: June 2007

Donald Coxeter was the twentieth century's greatest classical geometer and the leading authority on polytopes. His Coxeter groups, deepening the investigation of symmetries, have found wide application in the sciences.
Sir John Vivian Dacie. 20 July 1912 — 12 February 2005
Authors: Lewis Mitchell , Mollison Patrick , Weatherall David
Published: June 2007

John Dacie was the leading figure in haematology in this country during its period of major expansion after World War II. By his meticulous approach to the study of patients with haematological disorders in the laboratory he was able accurately to define many new diseases, particularly haemolytic anaemias, so laying a firm foundation for their further definition by the tools of the protein chemistry and molecular biology eras. And by establishing the haematology laboratory at the Royal Postgraduate Medical School as an international centre of excellence, where many future leaders of the field were trained, he had a critical role in the development of the clinical and laboratory aspects of haematology, both in the UK and internationally.
Thomas Gold. 22 May 1920 — 22 June 2004
Authors: Bondi Hermann
Published: June 2007

Tommy (as he was invariably called by his numerous friends) Gold was a most unusual scientist in several respects. One of these is that at school and even as an undergraduate it never crossed his mind that he might become a professional scientist. Only a remarkable chain of events brought this about. He came from a very well–to–do family in Vienna. His father (who was Jewish, while his mother was not) was a hard–working senior director in a major industrial firm. Tommy admired him greatly. It seemed natural to Tommy that he would follow his father in business.
Jean Leray. 7 November 1906 — 10 November 1998
Authors: Andler Martin
Published: June 2007

Jean Leray was one of the major mathematicians of the twentieth century. His primary focus in mathematics came from applications; indeed, a majority of his contributions were in the theory of partial differential equations arising in physics, notably his 1934 paper on the Navier–Stokes equation. World War II, during which he was a prisoner–of–war in Austria for five years, induced him to turn to pure mathematics to avoid helping the German war effort. There he worked in topology, developing two radically new ideas: sheaf theory and spectral sequences. After 1950 he came back to partial differential equations and became interested in complex analysis, writing a remarkable series of papers on the Cauchy problem. Leray remained mathematically active until the end of his life; in the course of his career he wrote 132 papers. His influence on present mathematics is tremendous. On the one hand, sheaf theory and spectral sequences became essential tools in contemporary pure mathematics, reaching far beyond their initial scope in topology. On the other hand, Leray can rightly be considered the intellectual guide of the distinguished French school of applied mathematics.
Hugh Christopher Longuet–Higgins. 11 April 1923 — 27 March 2004
Authors: Gregory Richard L. , Murrell John N.
Published: June 2007

Hugh Christopher Longuet–Higgins, always known as Christopher, was an exceptional scholar and teacher who made important scientific advances in two quite different disciplines, chemistry and cognitive science. He was also a talented amateur musician, both as performer and composer, and was keen to advance the scientific understanding of this art.
Ernst Walter Mayr. 5 July 1904 — 3 February 2005
Authors: Bock Walter J.
Published: June 2007

Ernst Walter Mayr was a person of the twentieth century, having missed only a few years at the beginning of that century and lived into a few years of the twenty–first. He was a naturalist all of his life which established the foundation for his career as an evolutionary biologist. Often called the ‘Darwin of the twentieth century’, Ernst Mayr was clearly one of the best–known evolutionary biologists of his time, being one of the major architects of the modern evolutionary synthesis of 1937–48 and serving as the major founder of the Society for the Study of Evolution and of its journal
Evolution
. Although he was born and educated in Germany, Ernst was an American scientist, having worked at the American Museum of Natural History (AMNH) and the Museum of Comparative Zoology, Harvard University, for 74 of his 100 years. Almost all of his publications were in the area of evolutionary biology; he published very few papers in functional biology. The most technical tool that he used was a Dictaphone. Ernst was truly a non–technical person and complained in his later years about libraries putting their catalogues in an electronic form because he did not know how to type – he did not even know the location of the keys on the keyboard – which delayed him greatly finding books he did not know. Computers were out of the question. He was outgoing, sought out interesting people whether they were important or not, talked to them, listened to what they said, read intensively, and thought deeply about what he took in. He had an amazing memory, but more importantly he could readily put the bits of knowledge together into new and significant ideas. He was a real teacher and simply could not allow someone to someone to leave with wrong ideas. Ernst had strongly held ideas and was firm in them; hence many people considered him to be overly dogmatic. He was interested in what was correct and not necessarily who was correct. He would argue strongly for his ideas, but he would change his position readily if he was convinced of the opposing stance. One had to be certain of one's facts and logic in any discussion with Ernst, which prevented many students and co–workers from discussing controversial ideas with him, something that made him sad. I can recall clearly his statement that ‘My bark is worse than my bite.’
Patrick Anthony Merton. 8 October 1920 — 13 June 2000
Authors: Rothwell John , Glynn Ian
Published: June 2007

Over a period of 35 years Pat Merton was responsible for a succession of elegant experiments, nearly all on human muscle, which elucidated the nervous mechanisms responsible for the control of movement, and the nature of muscle fatigue.
Joseph Arthur Colin Nicol. 5 December 1915 — 20 December 2004
Authors: Maddock Linda
Published: June 2007

Colin Nicol was a Canadian citizen but spent most of his working life based in the UK, at the Marine Biological Association in Plymouth, and in the USA, at the University of Texas Marine Science Institute at Port Aransas. His most important work was on the physiology of marine organisms, in particular their relationship to light, both natural and biologically produced. He was the first to show that bioluminescence is under nervous control and he made an extensive study of the tapetum lucidum, the reflective layer at the back of the eye of a wide range of animals, particularly those living in dim light. Many other subjects caught his interest and resulted in some 145 publications spanning 50 years.
Rendel Sebastian Pease. 2 November 1922 — 17 October 2004
Authors: Watson Christopher
Published: June 2007

Rendel Sebastian Pease, universally known to his friends and colleagues as Bas Pease, came from good political, scientific and Quaker stock. On his father's side he was descended from a long line of distinguished Quakers with an interest in social issues, including his grandfather Edward Pease, who was a co–founder and first secretary of the Fabian Society. On his mother's side his forebears included Josiah Wedgwood FRS, the founder of the Wedgwood pottery dynasty, whose descendents included no less than 10 Fellows of the Royal Society, including Charles Darwin and Francis Galton. The fourth generation of this remarkable family included Josiah Clement Wedgwood MP, First Lord Wedgwood of Barlaston, who became a Cabinet Minister under Ramsay McDonald in 1924. Bas's father, Michael Pease, a Cambridge geneticist, married Helen Wedgwood in 1920, and Bas was born on 2 November 1922.
Sir John Anthony Pople. 31 October 1925 — 15 March 2004
Authors: Buckingham A.D.
Published: June 2007

John Pople was one of the founders of modern computational chemistry. During his career in Cambridge University, the National Physical Laboratory, Carnegie–Mellon University and Northwestern University he made many major contributions to chemistry. In 1998 the Royal Swedish Academy of Sciences awarded the Nobel prize for chemistry ‘to Walter Kohn for his development of the density–functional theory and to John Pople for his development of computational methods in quantum chemistry’. The award was widely acclaimed.
Dame Miriam Louisa Rothschild. 5 August 1908 — 20 January 2005
Authors: van Emden Helmut F. , Gurdon John
Published: June 2007

Miriam Louisa Rothschild was born at Ashton Wold, Northampton, on 5 August 1908 and died there on 20 January 2005, at the age of 96. She had no traditional education, but was tutored in natural history by her father and her uncle. Her first scientific studies were on parasites of marine snails and seabirds, but one of her principal achievements was the six–volume work cataloguing the Rothschild flea collection over a 30–year period. Her other main area of research was the chemical ecology of insects, particularly in mimicry, and the sequestering of toxic compounds from plants, in which she was a pioneer. She was still actively working in this area at the time of her death. Parts of her house and glasshouses were modified for research, but much of her chemical ecological work was performed in collaboration with some of the best natural–product chemists in the world. Nature conservation was dear to her heart and she developed the production of wildflower seeds on her farm and techniques for their establishment; she also lobbied energetically on behalf of nature reserves. She combined all this with the management of a large estate including a profitable farm, and was much loved by her tenants.
Sir Frederick Henry Stewart. 16 January 1916 — 9 December 2001
Authors: O'Hara M.J.
Published: June 2007

‘Fred Stewart was charming, canny, perceptive, patient, incisive, highly intelligent, ever so stubborn and completely laid-back’, was the opening assessment of Gordon Craig, his friend and close associate for several decades, in his obituary for
The Scotsman
on 14 December 2001. All that and a keen sense of humour came into play on an occasion during a game of chess on the London–Edinburgh express when for once I had the upper hand and launched a sacrificial attack. hI can take that rook’, said Fred, engrossed over the board. ‘Are you
sure
that you can afford to lose it?’ After a few more rounds of this, Fred gave in, looked up with a mischievous grin and was duly checkmated – but his philosophy was that there was no point in giving in until you are quite certain that your opponent knows that he has won and, moreover, is absolutely sure that he has won. I was a junior lecturer at the time, but learning fast. Fred was Regius Professor of Geology but maintained an informal relationship with staff that was unfamiliar but very welcome after my previous institution.
Arthur Geoffrey Walker. 17 July 1909 — 31 March 2001
Authors: Hitchin Nigel J.
Published: June 2007

Arthur Geoffrey Walker was born in Watford, Hertfordshire, on 17 July 1909, and attended Watford Grammar School, from where he won in 1928 an Open Mathematical Scholarship to Balliol College, Oxford. There, his tutor was John William Nicholson FRS, who had been a professor at King's College, London, and was one of the first mathematical physicists to relate quantum theory to atomic spectra. However, in the late 1920s he was suffering from a psychiatric illness and in 1930 was hospitalized, so that Walker had to study on his own a great deal. This perhaps influenced his subsequent method of working on mathematics, which he normally did in the privacy of his room rather than in active consultation with others. He obtained a Second in Moderations, but in 1930 won a Junior Mathematical Exhibition and in 1931 took a First with a Distinction in the special subject of differential geometry, which was to become his life's work. Eisenhart's book
Riemannian geometry
(Eisenhart 1926) became his bible and he continually referred to it in many of his papers.
George Patrick Leonard Walker. 2 March 1926 — 17 January 2005
Authors: Self S. , Sparks R.S.J.
Published: June 2007

George Walker was one of the most creative, inspirational and influential volcanologists of the twentieth century. Born in Harlesden, London, on 2 March 1926 in a respectable working–class neighbourhood, he was the first member of his family to take an interest in science and to attend university. His father, Leonard Walker, an insurance salesman, was badly wounded at Passchendaele in World War I as a sergeant bomber and never fully recovered. He died in 1932, when George was six years old. His mother, Evelyn Frances (
née
McConkey), was a nurse. George had no siblings. He attended Acton Lane Elementary School and recollected a lesson on the making of iron as being memorable. Other influences included natural history, adventure books and visits to the South Kensington Museum and London Zoo. He did well at school and in 1937 won a scholarship to Willesden Secondary School.
Maurice Hugh Frederick Wilkins. 15 December 1916 — 5 October 2004
Authors: Arnott Struther , Kibble T.W.B. , Shallice Tim
Published: June 2007

Maurice Hugh Frederick Wilkins was the ‘Third man of the double helix’ according to the publishers who were allowed to foist this title on his late–written autobiography. Certainly it is for his role in the discovery of the duplex secondary structure of DNA that he will be remembered. It might be argued that he was the first man, rather than the third, for it was his successful revival of X–ray diffraction studies of DNA and their earliest product in 1950, a pattern of a well–oriented and polycrystalline DNA of unprecedented quality, that allowed him to conclude almost immediately that the basic framework of the genetic material was simple and symmetrical, and that the symmetrical structure took the form of a helix. This same pattern, displayed at a conference in Naples six months later, was the major inspiration for the involvement of J. D. Watson (ForMemRS 1981) in modelling DNA structure in collaboration with F. H. C. Crick (FRS 1959). Crick was a personal friend of Maurice's and was more involved with studies of proteins until the progress of Maurice's research programme and Watson's enthusiastic presence in Cambridge convinced him to put nucleic acids first. The carefully crafted citation for the 1960 Lasker Award, which these three men shared in 1960, put Maurice's name first and accurately referred to ‘… the painstaking x–ray diffraction studies of Wilkins that provided a most important clue that was pursued in an ingenious fashion and to a logical conclusion by Crick and Watson…’. Maurice's diffraction studies of DNA were not only the alpha but also the omega of the double helix because it was left to him to remedy a major flaw in the original (1953) Watson–Crick conjecture.
John Michael Ziman. 16 May 1925 — 2 January 2005
Authors: Berry Michael , Nye John F.
Published: June 2007

John Ziman was a theoretical physicist whose work was characterized by its clarity and simplicity and was always firmly grounded in experimental reality. He developed and refined the application of quantum mechanics to the transport properties of crystalline solids, and pioneered the quantum theory of disordered solids and liquid metals. He served as Head of the Physics Department at Bristol University, and created the theoretical physics group there. In many influential books and articles he broke fresh ground in his studies of science as a collective human enterprise.
Pan-S replication patterns and chromosomal domains defined by genome-tiling arrays of ENCODE genomic areas
Authors: Karnani Neerja , Taylor Christopher , Malhotra Ankit , Dutta Anindya
Published: June 2007

In eukaryotes, accurate control of replication time is required for the efficient completion of S phase and maintenance of genome stability. We present a high-resolution genome-tiling array-based profile of replication timing for ∼1% of the human genome studied by The ENCODE Project Consortium. Twenty percent of the investigated segments replicate asynchronously (pan-S). These areas are rich in genes and CpG islands, features they share with early-replicating loci. Interphase FISH showed that pan-S replication is a consequence of interallelic variation in replication time and is not an artifact derived from a specific cell cycle synchronization method or from aneuploidy. The interallelic variation in replication time is likely due to interallelic variation in chromatin environment, because while the early- or late-replicating areas were exclusively enriched in activating or repressing histone modifications, respectively, the pan-S areas had both types of histone modification. The replication profile of the chromosomes identified contiguous chromosomal segments of hundreds of kilobases separated by smaller segments where the replication time underwent an acute transition. Close examination of one such segment demonstrated that the delay of replication time was accompanied by a decrease in level of gene expression and appearance of repressive chromatin marks, suggesting that the transition segments are boundary elements separating chromosomal domains with different chromatin environments.
Butyrate mediates decrease of histone acetylation centered on transcription start sites and down-regulation of associated genes
Authors: Rada-Iglesias Alvaro , Enroth Stefan , Ameur Adam , Koch Christoph M. , Clelland Gayle K. , Respuela-Alonso Patricia , Wilcox Sarah , Dovey Oliver M. , Ellis Peter D. , Langford Cordelia F. , Dunham Ian , Komorowski Jan , Wadelius Claes
Published: June 2007

Butyrate is a histone deacetylase inhibitor (HDACi) with anti-neoplastic properties, which theoretically reactivates epigenetically silenced genes by increasing global histone acetylation. However, recent studies indicate that a similar number or even more genes are down-regulated than up-regulated by this drug. We treated hepatocarcinoma HepG2 cells with butyrate and characterized the levels of acetylation at DNA-bound histones H3 and H4 by ChIP-chip along the ENCODE regions. In contrast to the global increases of histone acetylation, many genomic regions close to transcription start sites were deacetylated after butyrate exposure. In order to validate these findings, we found that both butyrate and trichostatin A treatment resulted in histone deacetylation at selected regions, while nucleosome loss or changes in histone H3 lysine 4 trimethylation (H3K4me3) did not occur in such locations. Furthermore, similar histone deacetylation events were observed when colon adenocarcinoma HT-29 cells were treated with butyrate. In addition, genes with deacetylated promoters were down-regulated by butyrate, and this was mediated at the transcriptional level by affecting RNA polymerase II (POLR2A) initiation/elongation. Finally, the global increase in acetylated histones was preferentially localized to the nuclear periphery, indicating that it might not be associated to euchromatin. Our results are significant for the evaluation of HDACi as anti-tumourogenic drugs, suggesting that previous models of action might need to be revised, and provides an explanation for the frequently observed repression of many genes during HDACi treatment.