De Beer Research Articles

The neomuran origin of archaebacteria, the negibacterial root of the universal tree and bacterial megaclassification.

Prokaryotes constitute a single kingdom, Bacteria, here divided into two new subkingdoms: Negibacteria, with a cell envelope of two distinct genetic membranes, and Unibacteria, comprising the new phyla Archaebacteria and Posibacteria, with only one. Other new bacterial taxa are established in a revised higher-level classification that recognizes only eight phyla and 29 classes. Morphological, palaeontological and molecular data are integrated into a unified picture of large-scale bacterial cell evolution despite occasional lateral gene transfers. Archaebacteria and eukaryotes comprise the clade neomura, with many common characters, notably obligately co-translational secretion of N-linked glycoproteins, signal recognition particle with 7S RNA and translation-arrest domain, protein-spliced tRNA introns, eight-subunit chaperonin, prefoldin, core histones, small nucleolar ribonucleoproteins (snoRNPs), exosomes and similar replication, repair, transcription and translation machinery. Eubacteria (posibacteria and negibacteria) are paraphyletic, neomura having arisen from Posibacteria within the new subphylum Actinobacteria (possibly from the new class Arabobacteria, from which eukaryotic cholesterol biosynthesis probably came). Replacement of eubacterial peptidoglycan by glycoproteins and adaptation to thermophily are the keys to neomuran origins. All 19 common neomuran character suites probably arose essentially simultaneously during the radical modification of an actinobacterium. At least 11 were arguably adaptations to thermophily. Most unique archaebacterial characters (prenyl ether lipids; flagellar shaft of glycoprotein, not flagellin; DNA-binding protein lob; specially modified tRNA; absence of Hsp90) were subsequent secondary adaptations to hyperthermophily and/or hyperacidity. The insertional origin of protein-spliced tRNA introns and an insertion in proton-pumping ATPase also support the origin of neomura from eubacteria. Molecular co-evolution between histones and DNA-handling proteins, and in novel protein initiation and secretion machineries, caused quantum evolutionary shifts in their properties in stem neomura. Proteasomes probably arose in the immediate common ancestor of neomura and Actinobacteria. Major gene losses (e.g. peptidoglycan synthesis, hsp90, secA) and genomic reduction were central to the origin of archaebacteria. Ancestral archaebacteria were probably heterotrophic, anaerobic, sulphur-dependent hyperthermoacidophiles; methanogenesis and halophily are secondarily derived. Multiple lateral gene transfers from eubacteria helped secondary archaebacterial adaptations to mesophily and genome re-expansion. The origin from a drastically altered actinobacterium of neomura, and the immediately subsequent simultaneous origins of archaebacteria and eukaryotes, are the most extreme and important cases of quantum evolution since cells began. All three strikingly exemplify De Beer's principle of mosaic evolution: the fact that, during major evolutionary transformations, some organismal characters are highly innovative and change remarkably swiftly, whereas others are largely static, remaining conservatively ancestral in nature. This phenotypic mosaicism creates character distributions among taxa that are puzzling to those mistakenly expecting uniform evolutionary rates among characters and lineages. The mixture of novel (neomuran or archaebacterial) and ancestral eubacteria-like characters in archaebacteria primarily reflects such vertical mosaic evolution, not chimaeric evolution by lateral gene transfer. No symbiogenesis occurred. Quantum evolution of the basic neomuran characters, and between sister paralogues in gene duplication trees, makes many sequence trees exaggerate greatly the apparent age of archaebacteria. Fossil evidence is compelling for the extreme antiquity of eubacteria [over 3500 million years (My)] but, like their eukaryote sisters, archaebacteria probably arose only 850 My ago. Negibacteria are the most ancient, radiating rapidly into six phyla. Evidence from molecular sequences, ultrastructure, evolution of photosynthesis, envelope structure and chemistry and motility mechanisms fits the view that the cenancestral cell was a photosynthetic negibacterium, specifically an anaerobic green non-sulphur bacterium, and that the universal tree is rooted at the divergence between sulphur and non-sulphur green bacteria. The negibacterial outer membrane was lost once only in the history of life, when Posibacteria arose about 2800 My ago after their ancestors diverged from Cyanobacteria.

Of Judgement and Cunning Work

Ian Smillie is an Ottawa-based writer and consultant. He was co-author of PAC's Sierra Leone diamond study, The Heart of the Matter, and is research co-ordinator on PAC's Diamonds and Human Security Project. He served on the United Nations Expert Panel on Sierra Leone in 2000 and is a member of the Kimberley Process Task Force. His latest book is Partnership or Patronage: Local Capacity Building in Humanitarian Crises. And thous shalt make the breastplate of judgement with cunning work... and the second row shall be an emerald, a sapphire and a diamond. Exodus 28:15, 18FOR YEARS, THERE HAVE BEEN TWO DIRTY LITTLE SECRETS in the world's diamond industry. The first is that diamonds, symbols of love, purity, and devotion, have become the currency of war in several parts of Africa. The second is that the entire industry has become infected by illegal activity. This is bad news for Canada because one of the richest diamond finds of the past four decades has just come on stream in the Northwest Territories, pitching us headlong into an old industry where all that glisters is not good. This paper will outline the nature of the industry, its problems, the implications for Canada, and what is being done to bring a partially corrupted and totally secretive industry into the twentieth century, if not the twenty-first.As a coveted, high-priced consumer product, diamonds are in fact largely a creation of the twentieth century, and the structure of the diamond trade as it exists today is a hangover from the swashbuckling pre-World War I days of cartels and monopolies. But the story is already getting ahead of itself. Reference to diamonds can be found in the Bible, in Pliny and in other early sources. The world's first known diamonds were mined in India, finding their way to ancient Rome, the far east, and later to renaissance Europe. Before 1850, as many as 30 million carats may have been produced in India. The world's second source of diamonds was Brazil, although its industry peaked in the eighteenth century, and the country is now regarded as a minor producer. The modern diamond era begins with a 15-year-old South African boy named Erasmus Jacobs, out one day in 1867 looking for sticks. Instead, he found a 21 carat diamond, and the rush was on. One of the best early South African sites was on a farm near Kimberley, owned by two brothers named De Beer. They had bought the farm for [Symbol Not Transcribed]50 and must have thought they were turning a handsome profit when they sold it to a consortium of diggers for [Symbol Not Transcribed]6300. They disappeared into history, but they left their name behind with one of the most fabled companies of all time.South African diamonds remain a force to contend with, but diamonds were subsequently discovered in the German Protectorate of Southwest Africa, now Namibia, in 1908, and at about the same time in the Belgian Congo, now the Democratic Republic of Congo (DRC). Diamonds were found in Angola in 1912, and in the 1930s there were important finds in West Africa. Minor deposits were discovered in Guinea, Liberia, and Cote d'Ivoire, but the best quality gem diamonds were found in Kono District of Sierra Leone. Diamonds had been found in Russia in the nineteenth century, but it was not until the 1950s that the major Yakutia diamond deposits were uncovered, half of them north of the Arctic Circle. Australia has in recent years become a major producer of industrial diamonds, and there are smaller production sites in China, Venezuela, Tanzania, and elsewhere. The Canadian finds in 1991 - 300 kilometres northeast of Yellowknife - took the industry by surprise, and they promised to be important. As late as 1998, however, Canadian diamonds were still not on the production radar: by weight, 32 per cent of world production came out of Australia, 20 per cent more or less from the DRC (which will be explained later), 16 per cent each came from Botswana and Russia, nine per cent from Angola, and five per cent from all the other countries combined. …

Role of the FYVE finger and the RUN domain for the subcellular localization of Rabip4.

Rabip4 is a Rab4 effector, which possesses a RUN domain, two coiled-coil domains, and a FYVE finger. It is associated with the early endosomes and leads, in concert with Rab4, to the enlargement of endosomes, resulting in the fusion of sorting and recycling endosomes. Our goal was to characterize the role of these various domains in Rabip4 subcellular localization and their function in Chinese hamster ovary cells. Although the FYVE finger domain specifically bound phosphatidylinositol 3-phosphate and was necessary for the function of Rabip4, it was not sufficient for the protein association with membranes. Indeed a protein containing the FYVE finger and the Rab4-binding site was cytosolic, whereas the total protein was mostly associated to the membrane fraction, whether or not cells were pretreated with wortmannin. By contrast, a construct corresponding to the N-terminal end, Rabip4-(1-212), and containing the RUN domain was membrane-associated. The complete protein partitioned between the Triton X-100-insoluble and -soluble fractions and a wortmannin treatment increased the amount of the protein in the Triton X-100 fraction. Rabip4-(1-212) was totally Triton X-100-insoluble, and confocal microscopic examination showed that it labeled not only the endosomes, positive for Rabip4, but also a filamentous network with a honeycomb appearance. The Triton X-100-insoluble fraction that contains Rabip4 did not correspond to the caveolin or glycosylphosphatidylinositol-enriched lipid rafts. Rabip4 did not appear directly linked to actin but seemed associated to the actin network. We propose that the subcellular localization of the protein is primarily driven by the RUN domain to endosomal microdomains characterized by Triton X-100 insolubility and that the FYVE domain and the Rab4-binding domain then allow for the recruitment of the protein to lipophilic microdomains enriched in phosphatidylinositol 3-phosphate.

CD36 does not play a direct role in HDL or LDL metabolism

CD36 and scavenger receptor class B, type I (SR-BI) are both class B scavenger receptors that recognize a broad variety of ligands, including oxidized low density lipoprotein (oxLDL), HDL, anionic phospholipids, and apoptotic cells. In this study we investigated the role of mouse CD36 (mCD36) as a physiological lipoprotein receptor. We compared the association of various lipoprotein particles with mCD36 and mSR-BI expressed in COS cells by adenovirus-mediated gene transfer. mCD36 bound human oxLDL and mouse HDL with high affinity. Human LDL bound poorly to mCD36, indicating that mCD36 is unlikely to play a significant role in LDL metabolism. The ability of mCD36 to mediate the selective uptake of cholesteryl esters (CE) from receptor-bound HDL was assessed. In comparison with mSR-BI, mCD36 inefficiently mediated the selective uptake of CE. Hepatic overexpression of mCD36 in C57BL/6 mice by adenovirus-mediated gene transfer did not result in significant alterations in plasma LDL and HDL levels. We conclude that mCD36, while able to bind HDL with high affinity, does not contribute significantly to HDL or LDL metabolism. —de Villiers, W. J. S., L. Cai, N. R. Webb, M. C. de Beer, D. R. van der Westhuyzen, and F. C. de Beer. CD36 does not play a direct role in HDL or LDL metabolism.

PI3P Attracts PX Domains

Four papers this week (Kanai et al. , Ellson et al. , Cheever et al. , and Xu et al. ) show that the PX (phox homology) domain binds to inositol lipids phosphorylated on the 3 position [(phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol-3,4-bisphophate (PI3,4P 2 )], the products of phosphatidylinositol 3-kinase (PI3K). In neutrophils and other phagocytic cells, two subunits of NADPH oxidase (p40phox and p47phox) are kept in the cytosol until cells are activated. Upon activation, which involves activation of PI3K, these two subunits are recruited to secretory vesicles and granules where the remaining subunits are located. These vesicles then fuse with the plasma membrane and phagosomes leading to production of reactive oxygen species (ROS). Kanai et al. show that p40phox binds preferentially to PI3P and p47phox binds preferentially to PI3,4P 2 and that binding to the endosomal membranes depends on PI3P production and an intact PX domain. Ellson et al. used ROS assays to determine that PI3P was essential for activation of ROS. Furthermore, the component binding PI3P was identified as p40phox by surface plasmon resonance assays, and the PX domain was sufficient to target a reporter protein to endosomes. The identification of this phospholipid-binding motif provides an essential missing piece in the puzzle of why PI3K is important for regulating neutrophil function and inflammatory processes. The remaining two papers address this motif in proteins involved in targeting proteins to the vacuole in yeast (Cheever et al. ) and in sorting proteins in the endosomal system (Xu et al. ). Thus, the PX domain is a common motif that allows protein trafficking to be controlled by the activity of PI3K and the production of PI3P species. F. Kanai, H. Liu, S. J. Field, H. Akbary, T. Matsuo, G. E. Brown, L. C. Cantley, M. B. Yaffe, The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nature Cell Biol. 3 , 675-678 (2001). [Online Journal] C. D. Ellson, S. Gobert-Gosse, K. E. Anderson, K. Davidson, H. Erdjument-Bromage, P. Tempst, J. W. Thuring, M. A. Cooper, Z.-Y. Lim, A. B. Holmes, P. T. J. Gaffney, J. Coadwell, E. R. Chilvers, P. T. Hawkins, L. R. Stephins, PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40 phox . Nature Cell Biol. 3 , 679-682 (2001). [Online Journal] M. L. Cheever, T. K Sato, T. de Beer, T. G. Kutateladze, S. D. Emr, M. Overduin, Phox domain interaction with PdtIns(3)P targets the Vam7 t-SNARE to vacuole membranes. Nature Cell Biol. 3 , 613-618 (2001). [Online Journal] Y. Xu, H. Hortsman, L. Seet, S. H. Wong, W. Hong, SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nature Cell Biol. 3 , 658-666 (2001). [Online Journal]

SHORT REVIEWS

Books reviewed in this article: Martin Carnoy, Sustaining the New Economy: Work, Family, and Community in the Information Age Joop Garssen, Joop De Beer, Lieneke Hoeksma, Kees Prins, And Rolf Verhoef (Eds.), Vital Events: Past, Present and Future of the Dutch Population International Fund for Agricultural Development, Rural Poverty Report 2001: The Challenge of Ending Rural Poverty Andrew Mason and Georges Tapinos (Eds.), Sharing the Wealth: Demographic Change and Economic Transfers between Generations Phil Mullan, The Imaginary Time Bomb: Why An Ageing Problem Is Not a Social Problem National Research Council, Board on Sustainable Development, Our Common Journey: A Transition toward Sustainability National Research Council, Forum on Biodiversity Committee, Nature and Human Society: The Quest for a Sustainable World Ronald E. Seavoy, Subsistence and Economic Development United Nations Children's Fund, A League Table of Child Deaths by Injury in Rich Nations

Apolipoprotein A-I conformation markedly influences HDL interaction with scavenger receptor BI

Apolipoprotein A-I (apoA-I) is an important ligand for the high density lipoprotein (HDL) scavenger receptor class B type I (SR-BI). SR-BI binds both free and lipoprotein-associated apoA-I, but the effects of particle size, composition, and apolipoprotein conformation on HDL binding to SR-BI are not understood. We have studied the effect of apoA-I conformation on particle binding using native HDL and reconstituted HDL particles of defined composition and size. SR-BI expressed in transfected Chinese hamster ovary cells was shown to bind human HDL2 with greater affinity than HDL3, suggesting that HDL size, composition, and possibly apolipoprotein conformation influence HDL binding to SR-BI. To discriminate between these factors, SR-BI binding was studied further using reconstituted l-α-palmitoyloleoyl-phosphatidylcholine-containing HDL particles having identical components and equal amounts of apoA-I, but differing in size (7.8 vs. 9.6 nm in diameter) and apoA-I conformation. The affinity of binding to SR-BI was significantly greater (50-fold) for the larger (9.6-nm) particle than for the 7.8-nm particle. We conclude that differences in apoA-I conformation in different-sized particles markedly influence apoA-I recognition by SR-BI. Preferential binding of larger HDL particles to SR-BI would promote productive selective cholesteryl ester uptake from larger cholesteryl ester-rich HDL over lipid-poor HDL. —de Beer, M. C., D. M. Durbin, L. Cai, A. Jonas, F. C. de Beer, and D. R. van der Westhuyzen. Apolipoprotein A-I conformation markedly influences HDL interaction with scavenger receptor BI.

Biophysical Characterization of the DNA Binding Domain of gpNu1, a Viral DNA Packaging Protein

Terminase enzymes are common to double-stranded DNA viruses. These enzymes "package" the viral genome into a pre-formed capsid. Terminase from bacteriophage lambda is composed of gpA (72.4 kDa) and gpNu1 (20.4 kDa) subunits. We have described the expression and biochemical characterization of gpNu1DeltaK100, a construct comprising the N-terminal 100 amino acids of gpNu1 (Yang, Q., de Beer, T., Woods, L., Meyer, J., Manning, M., Overduin, M., and Catalano, C. E. (1999) Biochemistry 38, 465-477). Here we present a biophysical characterization of this construct. Thermally induced loss of secondary and tertiary structures is fully reversible. Surprisingly, although loss of tertiary structure is cooperative, loss of secondary structure is non-cooperative. NMR and limited proteolysis data suggest that approximately 30 amino acids of gpNu1DeltaK100 are solvent-exposed and highly flexible. We therefore constructed gpNu1DeltaE68, a protein consisting of the N-terminal 68 residues of gpNu1. gpNu1DeltaE68 is a dimer with no evidence of dissociation or further aggregation. Thermally induced unfolding of gpNu1DeltaE68 is reversible, with concomitant loss of both secondary and tertiary structure. The melting temperature increases with increasing protein concentration, suggesting that dimerization and folding are, at least in part, coupled. The data suggest that gpNu1DeltaE68 represents the minimal DNA binding domain of gpNu1. We further suggest that the C-terminal approximately 30 residues in gpNu1DeltaK100 adopt a pseudo-stable alpha-helix that extends from the folded core of the protein. A model describing the role of this helix in the assembly of the packaging apparatus is discussed.

HDL modification by secretory phospholipase A2 promotes scavenger receptor class B type I interaction and accelerates HDL catabolism

During inflammatory states plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) are reduced. Secretory group IIa phospholipase A2 (sPLA2) is a cytokine-induced acute-phase enzyme associated with HDL. Transgenic mice overexpressing sPLA2 have reduced HDL levels. Studies were performed to define the mechanism for the HDL reduction in these mice. HDL isolated from sPLA2 transgenic mice have a significantly lower phospholipid content and greater triglyceride content. In autologous clearance studies, 125I-labeled HDL from sPLA2 transgenic mice was catabolized significantly faster than HDL from control mice (4.24 ± 1.16 vs. 2.84 ± 0.1 pools per day, P < 0.008). In both sPLA2 transgenic and control mice, the cholesteryl ester component of HDL was more rapidly catabolized than the protein component, indicating a selective uptake mechanism. In vitro studies using CHO cells transfected with scavenger receptor class B type I (SR-BI) showed that sPLA2-modified HDL was nearly twice as efficient as a substrate for cholesteryl ester transfer. These data were confirmed in in vivo selective uptake experiments using adenoviral vector overexpression of SR-BI. In these studies, increased hepatic selective uptake was associated with increased 125I-labeled apolipoprotein uptake in the kidney. We conclude that during inflammation sPLA2 hydrolysis of HDL phospholipids alters the lipid composition of the particle, allowing for more efficient SR-BI-mediated selective cholesteryl ester uptake. This enhanced SR-BI activity generates HDL remnants that are preferentially catabolized in the kidney.—de Beer, F. C., P. M. Connell, J. Yu, M. C. de Beer, N. R. Webb, and D. R. van der Westhuyzen. HDL modification by secretory phospholipase A2 promotes scavenger receptor class B type I interaction and accelerates HDL catabolism. J. Lipid Res. 2000. 41: 1849–1857.

Balfour, Garstang and de Beer: The First Century of Evolutionary Embryology

Evolution has been integrated with embryology during two great periods: the latter half of the 19th C as evolutionary morphology/embryology, and the latter third of the 20th C as evolutionary developmental biology. My mandate was to use the contributions of three embryologists/morphologists: Francis (Frank) Balfour (1851–1882), Walter Garstang (1868–1949) and Gavin de Beer (1899–1972) to discuss the foundations of evolutionary embryology in the UK from 1870 (when “every aspiring zoologist was an embryologist, and the one topic of professional conversation was evolution,” Bateson, 1922, p. 56), through the 1920s (“ontogeny does not recapitulate phylogeny, it creates it,” Garstang, 1922, p. 81) to the 1970s (“homology of phenotypes does not imply similarity in genotypes,” de Beer, 1971, p. 15). Evolutionary embryology was driven by a comparative embryological approach that sought homology of adult structures in germ layers and ancestry in embryos, and sought to differentiate larval adaptations from retained ancestral characters. An initial emphasis on a phylogenetic mechanism (recapitulation) slowly gave way to more mechanistic approaches that included heterochrony and the integration of embryology with physiological genetics. Germ layers, homology, larval evolution, larval origins of the vertebrates, paedomorphosis and heterochrony underpinned the origins of evolutionary embryology, and so I discuss each of these topics.

Balfour, Garstang and de Beer: The First Century of Evolutionary Embryology1

Evolution has been integrated with embryology during two great periods: the latter half of the 19th C as evolutionary morphology/embryology, and the latter third of the 20th C as evolutionary developmental biology. My mandate was to use the contributions of three embryologists/morphologists: Francis (Frank) Balfour (1851–1882), Walter Garstang (1868–1949) and Gavin de Beer (1899–1972) to discuss the foundations of evolutionary embryology in the UK from 1870 (when “every aspiring zoologist was an embryologist, and the one topic of professional conversation was evolution,” Bateson, 1922, p. 56), through the 1920s (“ontogeny does not recapitulate phylogeny, it creates it,” Garstang, 1922, p. 81) to the 1970s (“homology of phenotypes does not imply similarity in genotypes,” de Beer, 1971, p. 15). Evolutionary embryology was driven by a comparative embryological approach that sought homology of adult structures in germ layers and ancestry in embryos, and sought to differentiate larval adaptations from retained ancestral characters. An initial emphasis on a phylogenetic mechanism (recapitulation) slowly gave way to more mechanistic approaches that included heterochrony and the integration of embryology with physiological genetics. Germ layers, homology, larval evolution, larval origins of the vertebrates, paedomorphosis and heterochrony underpinned the origins of evolutionary embryology, and so I discuss each of these topics.

Description of a new taxon brookei of Levaillant's Cisticola Cisticola tinniens from the Western Cape, South Africa

Herremans, M., Philogene, D., Underhill, G.D., Raijmakers, J.M.H., Underhill, L.G., Johnson, D., Bemitz, H., Bernitz, Z., Bowker, M.B. & De Beer, S.J. 1999. Description of a new taxon brookei of Levaillant's Cisticola Cisticola tinniens from the Western Cape, South Africa. Ostrich 70(3&4): 164- 172. All Levaillant's Cisticolas south of the Limpopo River are currently considered to be of the nominate race. Atlas data indicate a distinct discontinuity in the distribution, separating birds in the winter rainfall region of the Western Cape from those in the summer rainfall zone of South Africa. Western Cape birds breed and moult earlier, are smaller in wing and tail length, but heavier in weight, and lack the distinctive summer plumage of a pale rufous, unstreaked crown in nominate tinniens. Both taxa undergo a partial body moult in spring, but in Western Cape birds this is not a pre- but a peri-breeding moult during which they develop a new nonbreeding plumage. Evidence for early territorial settlement and pairing in juvenile plumage, which is similar to the nonbreeding plumage, was obtained, indicating that the summer plumage may not be a key factor in species recognition. Western Cape birds are described as a new subspecies brookei. A sample of museum specimens contained too many apparently incorrectly sexed birds to reveal sexual bimodality in biometry, and they indicated differences in biometry between taxa in the opposite direction of that found in larger samples of live birds.

Tryptophan glycoconjugates in food and human urine

Evaluating the formation of tryptophan glycoconjugates other than well-established Amadori rearrangement products, HPLC-tandem MS (MS/MS) analysis of human urine collected from several healthy individuals proved the presence of one distinct tryptophan C-glycosyl compound [Horiuchi, Yonekawa, Iwahara, Kanno, Kurihara and Fujise (1994) J. Biochem. (Tokyo) 115, 362-366]. After isolation, unambiguous identification of this novel tryptophan metabolite as 2-(alpha-mannopyranosyl)-l-tryptophan was achieved by tandem MS combined with NMR spectroscopy including homonuclear COSY, heteronuclear multiple-bond connectivity and (1)H-detected heteronuclear multiple-quantum coherence experiments. Remarkably, a thorough evaluation of vicinal proton-proton coupling constants in different solvents and nuclear Overhauser effect experiments demonstrate the predominant axial orientation of the hydroxymethyl group of the hexopyranosyl residue. Likewise this spatial arrangement indicates that the respective alpha-anomeric C-mannosylhexopyranose is preferentially adopting a (1)C(4) conformation in acidic methanol. Whereas only one distinct tryptophan mannoconjugate could be observed in human urine, HPLC-MS/MS analysis of food samples for the first time led to the identification of numerous N(1)-(beta-d-hexopyranosyl)-l-tryptophan, 2-(beta-d-hexopyranosyl)-l-tryptophan and 1-(1,2,3,4,5-pentahyd- roxypent-1-yl)-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid derivatives derived from the condensation of tryptophan with aldohexoses. Taking into consideration the significant differences between profiles and configurations of tryptophan glycoconjugates originating from dietary sources and human urine, C-2 mannosylation of tryptophan residues [de Beer, Vliegenthart, Loeffler and Hofsteenge (1995) Biochemistry 34, 11785-11789] represents a novel enzymic pathway in tryptophan metabolism in humans.

'Varnish the business for the ladies': Edward Gibbon's decline and fall.

Edward Gibbon (1737-1794) aroused strong feelings. Samuel Taylor Coleridgel said '[his] style is detestable, but his style is not the worst thing about him'. But his works, the multivolume Decline and Fall of the Roman Empire2 and the Autobiography3 published in the year after his death by his friend and literary executor J B Holroyd (Lord Sheffield), have not been out of print for over 200 years and are fun to read, especially the shorter Autobiography, which was expanded by Lord Sheffield with extracts from Gibbon's letters and his own observations. It is rich in data about Gibbon's health and death; and there have been comprehensive later publications of Gibbon's diaries and letters4. Gibbon has attracted many excellent biographers (including Leslie Stephen7, J B Bury3, D M Low8, G M Young9, J W Burrow10) but only the biologist Sir Gavin de Beer11'12 has discussed Gibbon's longstanding, and ultimately fatal, affliction. Sir Geoffrey Keynes'3 work on Gibbon was confined to his library, and Roy Porter's14 to literary and historical criticism. Recent transatlantic students15'16 have indulged, like de Beer, in 'psycho-biography', but Gibbon himself had written stylishly and explicitly about his feelings and inclinations, as he had done about his 'organic' symptoms3 4. Gibbon was the first born of a wealthy City of London family:

Huxley's bulldog: the battles of E. Ray Lankester (1846-1929).

Huxley's bulldog: the battles of E. Ray Lankester (1846-1929).

Evolution, development and complexity in Pere Alberch (1954–1998)

Evolution, development and complexity in Pere Alberch (1954–1998)

Expression of serum amyloid A protein in the absence of the acute phase response does not reduce HDL cholesterol or apoA-I levels in human apoA-I transgenic mice

Plasma concentrations of high density lipoprotein (HDL) cholesterol and its major apolipoprotein (apo)A-I are significantly decreased in inflammatory states. Plasma levels of the serum amyloid A (SAA) protein increase markedly during the acute phase response and are elevated in many chronic inflammatory states. Because SAA is associated with HDL and has been shown to be capable of displacing apoA-I from HDL in vitro, it is believed that expression of SAA is the primary cause of the reduced HDL cholesterol and apoA-I in inflammatory states. In order to directly test this hypothesis, we constructed recombinant adenoviruses expressing the murine SAA and human SAA1 genes (the major acute phase SAA proteins in both species). These recombinant adenoviruses were injected intravenously into wild-type and human apoA-I transgenic mice and the effects of SAA expression on HDL cholesterol and apoA-I were compared with mice injected with a control adenovirus. Plasma levels of SAA were comparable to those seen in the acute phase response in mice and humans. However, despite high plasma levels of murine or human SAA, no significant changes in HDL cholesterol or apoA-I levels were observed. SAA was found associated with HDL but did not specifically alter the cholesterol or human apoA-I distribution among lipoproteins. In summary, high plasma levels of SAA in the absence of a generalized acute phase response did not result in reduction of HDL cholesterol or apoA-I in mice, suggesting that there are components of the acute phase response other than SAA expression that may directly influence HDL metabolism.—Hosoai, H., N. R. Webb, J. M. Glick, U. J. F. Tietge, M. S. Purdom, F. C. de Beer, and D. J. Rader. Expression of serum amyloid A protein in the absence of the acute phase response does not reduce HDL cholesterol or apoA-I levels in human apoA-I transgenic mice. J. Lipid Res. 1999. 40: 648–653.

Letters from the President: the correspondence of Sir Joseph Banks 1

Nothing gives so just an idea of an age as genuine letters; nay, history waits for its last seal from them.Horace Walpole 2 Many scientific ideas have been described in works that have deeply affected the way we regard ourselves and the world. Even when a scientist has not been so influential, his writings might still be a rewarding source of interest. Indeed, they might have artistic worth and broad historical relevance of a kind that is rarely appreciated. Nothing could be more true of the 18th century, when the literary nature of science made the spread of knowledge and enquiry possible. At this time some men made voyages of discovery to distant lands. They collected, described and classified, imposing scientific order on the ‘New World’ as they went. The reports that were sent back excited readers in Europe eager to hear more of remote places, and not least those considering the form an imperial order might take. Meanwhile, other men crowded into societies dedicated to learning, or gathered their fellows together in correspondence. The mass of information available for scientists increased with their ability to draw on such web-like networks. A few became powerful through them, even manipulating the course of history. This combination of science and literature as a means of shaping events drew Sir Gavin de Beer's attention to one man: ‘It is curious that Banks should not yet have been recognized as one of the greatest letter-writers in the English language, but such he clearly was.’. 3

Influence of Tire-Pavement Contact Stress Distribution on Development of Distress Mechanisms in Pavements

It is demonstrated that accurate characterization of tire-pavement contact stress distribution is important for the correct prediction of distress evolution in flexible pavements. First, an analysis of tire imprints and measured tire-pavement contact stress distribution leads to the conclusion that the shape of the contact area depends on the load and tire pressure and that the contact stress distribution is nonuniform. Second, software for a linear-layered elastic medium contrasts the stress distribution in a pavement due to two loads: a uniformly distributed pressure on a circular area and a distribution reported earlier by de Beer and Fisher. The analysis herein demonstrates that nonuniform contact stress distribution leads to considerably larger stresses in the pavement relative to the uniform stress distribution case. Consequently, both rut and crack evolution prediction would be different if they were based on true distribution rather than on the uniform distribution assumption. It is also shown that for overloaded tires, the contact area is rectangular, where the width of the contact is a tire property independent of the applied load. Therefore, approximating the load as a uniformly distributed stress over a circular area may lead to erroneous prediction regarding the transverse or longitudinal orientation of cracks.

Investment‐led entrepreneurship development

Spatial development initiatives are characterised by intensive intervention in an identified area in order to fast‐track investment. The key objectives of SDIs are the generation of growth and development through private sector investment, the stimulation of small, medium and microenterprises (SMMEs) and the empowerment of local communities. This report is part of a series of guiding papers which contribute towards understanding and achieving the principles of the Spatial Development Initiatives (SDIs) programme as operating in South and southern Africa (De Beer & Arkwright, 1997; De Beer & Elliffe, 1997; De Beer & Wheeler, 1997; De Beer et al, 1997; Elliffe et al, 1997). The article builds on the foundations provided by these earlier studies and specifically focuses on the stimulation of SMMEs and the associated empowerment of local communities as principles that underlie all SDI interventions.