Mammalian Origin Research Articles

Synchrotron FTIR reveals lipid around and within amyloid plaques in transgenic mice and Alzheimer's disease brain

While the basis of neuronal degeneration in Alzheimer's disease (AD) continues to be debated, the amyloid cascade hypothesis remains central. Amyloid plaques are a required pathological marker for post mortem diagnosis, and Aβ peptide is regarded by most as a critical trigger at the very least. We present spectrochemical image analysis of brain tissue sections obtained with the mid-infrared beamline IRENI (InfraRed ENvironmental Imaging, Synchrotron Radiation Center, U Wisconsin-Madison), where the pixel resolution of 0.54 × 0.54 µm(2) permits analysis at sub-cellular dimensions. Spectrochemical images of dense core plaque found in hippocampus and cortex sections of two transgenic mouse models of AD (TgCRND8 and 3×Tg) are compared with plaque images from a 91 year old apoE43 human AD case. Spectral analysis was done in conjunction with histochemical stains of serial sections. A lipid membrane-like spectral signature surrounded and infiltrated the dense core plaques in all cases. Remarkable compositional similarities in early stage plaques suggest similar routes to plaque formation, regardless of genetic predisposition or mammalian origin.

Novel Models of Avian Leucosis Virus-induced CarcinogenesisNovel Models of Avian Leucosis Virus-induced Carcinogenesis

The LSCC-SF-MC29 cell culture model system was further characterized by studies on the provirus content of the cells, the host range and the subgroup specificity of the produced virus. The transforming potential of the Mc29 virus was evaluated by the focus-forming and colony-forming assays on primary cell cultures and continuous cell lines of avian and mammalian origin. The in ovo effects of the myelocytomatosis virus Mc29 on 15I line White Leghorn chicken embryos were studied by routine histopathological methods. Six avian leucosis virus-specific proviral sequences were detected by PCR analysis in the genome of LSCC-SF-MC29 cells. The presence of a Mc29 provirus-specific sequence located in the gag-myc region was confirmed. Using primers designed to differentiate ALV subgroups, amplification product was obtained with subgroup B/D-specific PCR primers. As it was expected, the subgroup E-specific PCR primers amplified the endogenous ALV sequences. In vitro studies on the host range of Mc29 virus showed that the primary cultures of chicken and hamster cells and a continuous hamster cell line were susceptible, while the cultures of primary quail cells and of a permanent line of duck embryo cells were resistant to the transforming effect of the virus. In ovo, the inoculated Mc29 virus induced hyperplasic and preneoplastic lesions in the embryonal liver and pancreas and myxomas of the neck.

Replication of swine and human influenza viruses in juvenile and layer turkey hens

Since the first reported isolation of swine influenza viruses (SIVs) in turkeys in the 1980s, transmission of SIVs to turkeys was frequently documented. Recently, the 2009 pandemic H1N1 virus, that was thought to be of swine origin, was detected in turkeys with a severe drop in egg production. In this study, we assessed the infectivity of different mammalian influenza viruses including swine, pandemic H1N1 and seasonal human influenza viruses in both juvenile and layer turkeys. In addition, we investigated the potential influenza virus dissemination in the semen of experimentally infected turkey toms. Results showed that all mammalian origin influenza viruses tested can infect turkeys. SIVs were detected in respiratory and digestive tracts of both juvenile and layer turkeys. Variations in replication efficiencies among SIVs were observed especially in the reproductive tract of layer turkeys. Compared to SIVs, limited replication of seasonal human H1N1 and no detectable replication of recent human-like swine H1N2, pandemic H1N1 and seasonal human H3N2 viruses was noticed. All birds seroconverted to all tested viruses regardless of their replication level. In turkey toms, we were able to detect swine H3N2 virus in semen and reproductive tract of infected toms by real-time RT-PCR although virus isolation was not successful. These data suggest that turkey hens could be affected by diverse influenza strains especially SIVs. Moreover, the differences in the replication efficiency we demonstrated among SIVs and between SIV and human influenza viruses in layer turkeys suggest a possible use of turkeys as an animal model to study host tropism and pathogenesis of influenza viruses. Our results also indicate a potential risk of venereal transmission of influenza viruses in turkeys.

Snake Venom Phospholipases A2: A Novel Tool Against Bacterial Diseases

The majority of snake venom phospholipases A(2) (svPLA(2)s) are toxic and induce a wide spectrum of biological effects. They are cysteine-rich proteins that contain 119-134 amino acids and share similar structures and functions. About 50% of the residues are incorporated into α-helices, whereas only 10% are in β-sheets. Fourteen conserved cysteines form a network of seven disulfide bridges that stabilize the tertiary structure. They show a high degree of sequence and structural similarity, and are believed to have a common calcium- dependent catalytic mechanism. Additionally, svPLA(2)s display an array of biological actions that are either dependent or independent of catalysis. The PLA(2)s of mammalian origin also exert potent bactericidal activity by binding to anionic surfaces and enzymatic degradation of phospholipids in the target membranes, preferentially of Gram-positive species. The bactericidal activity against Gram-negatives by svPLA(2) requires a synergistic action with bactericidal/permeability-increasing protein (BPI), but is equally dependent on enzymatic- based membrane degradation. Several hypotheses account for the bactericidal properties of svPLA(2)s, which include "fatal depolarization" of the bacterial membrane, creation of physical holes in the membrane, scrambling of normal distribution of lipids between the bilayer leaflets, and damage of critical intracellular targets after internalization of the peptide. The present review discusses several svPLA(2)s and derived peptides that exhibit strong bactericidal activity. The reports demonstrate that svPLA(2)-derived peptides have the potential to counteract microbial infections. In fact, the C-terminal cationic/hydrophobic segment (residues 115-129) of svPLA(2)s is bactericidal. Thus identification of the bactericidal sites in svPLA(2)s has potential for developing novel antimicrobials.

Snake Venom Phospholipases A2: A Novel Tool Against Bacterial Diseases

The majority of snake venom phospholipases A2 (svPLA2s) are toxic and induce a wide spectrum of biological effects. They are cysteine-rich proteins that contain 119-134 amino acids and share similar structures and functions. About 50% of the residues are incorporated into α-helices, whereas only 10% are in β-sheets. Fourteen conserved cysteines form a network of seven disulfide bridges that stabilize the tertiary structure. They show a high degree of sequence and structural similarity, and are believed to have a common calcium- dependent catalytic mechanism. Additionally, svPLA2s display an array of biological actions that are either dependent or independent of catalysis. The PLA2s of mammalian origin also exert potent bactericidal activity by binding to anionic surfaces and enzymatic degradation of phospholipids in the target membranes, preferentially of Gram-positive species. The bactericidal activity against Gramnegatives by svPLA2 requires a synergistic action with bactericidal/permeability-increasing protein (BPI), but is equally dependent on enzymatic- based membrane degradation. Several hypotheses account for the bactericidal properties of svPLA2s, which include “fatal depolarization” of the bacterial membrane, creation of physical holes in the membrane, scrambling of normal distribution of lipids between the bilayer leaflets, and damage of critical intracellular targets after internalization of the peptide. The present review discusses several svPLA2s and derived peptides that exhibit strong bactericidal activity. The reports demonstrate that svPLA2-derived peptides have the potential to counteract microbial infections. In fact, the C-terminal cationic/hydrophobic segment (residues 115-129) of svPLA2s is bactericidal. Thus identification of the bactericidal sites in svPLA2s has potential for developing novel antimicrobials.

Human viruses: discovery and emergence

There are 219 virus species that are known to be able to infect humans. The first of these to be discovered was yellow fever virus in 1901, and three to four new species are still being found every year. Extrapolation of the discovery curve suggests that there is still a substantial pool of undiscovered human virus species, although an apparent slow-down in the rate of discovery of species from different families may indicate bounds to the potential range of diversity. More than two-thirds of human viruses can also infect non-human hosts, mainly mammals, and sometimes birds. Many specialist human viruses also have mammalian or avian origins. Indeed, a substantial proportion of mammalian viruses may be capable of crossing the species barrier into humans, although only around half of these are capable of being transmitted by humans and around half again of transmitting well enough to cause major outbreaks. A few possible predictors of species jumps can be identified, including the use of phylogenetically conserved cell receptors. It seems almost inevitable that new human viruses will continue to emerge, mainly from other mammals and birds, for the foreseeable future. For this reason, an effective global surveillance system for novel viruses is needed.

Darwin's two competing phylogenetic trees: marsupials as ancestors or sister taxa?

Studies of the origin and diversification of major groups of plants and animals are contentious topics in current evolutionary biology. This includes the study of the timing and relationships of the two major clades of extant mammals – marsupials and placentals. Molecular studies concerned with marsupial and placental origin and diversification can be at odds with the fossil record. Such studies are, however, not a recent phenomenon. Over 150 years ago Charles Darwin weighed two alternative views on the origin of marsupials and placentals. Less than a year after the publication of On the origin of species, Darwin outlined these in a letter to Charles Lyell dated 23 September 1860. The letter concluded with two competing phylogenetic diagrams. One showed marsupials as ancestral to both living marsupials and placentals, whereas the other showed a non-marsupial, non-placental as being ancestral to both living marsupials and placentals. These two diagrams are published here for the first time. These are the only such competing phylogenetic diagrams that Darwin is known to have produced. In addition to examining the question of mammalian origins in this letter and in other manuscript notes discussed here, Darwin confronted the broader issue as to whether major groups of animals had a single origin (monophyly) or were the result of “continuous creation” as advocated for some groups by Richard Owen. Charles Lyell had held similar views to those of Owen, but it is clear from correspondence with Darwin that he was beginning to accept the idea of monophyly of major groups.

Genomic Evidence for Large, Long-Lived Ancestors to Placental Mammals

It is widely assumed that our mammalian ancestors, which lived in the Cretaceous era, were tiny animals that survived massive asteroid impacts in shelters and evolved into modern forms after dinosaurs went extinct, 65 Ma. The small size of most Mesozoic mammalian fossils essentially supports this view. Paleontology, however, is not conclusive regarding the ancestry of extant mammals, because Cretaceous and Paleocene fossils are not easily linked to modern lineages. Here, we use full-genome data to estimate the longevity and body mass of early placental mammals. Analyzing 36 fully sequenced mammalian genomes, we reconstruct two aspects of the ancestral genome dynamics, namely GC-content evolution and nonsynonymous over synonymous rate ratio. Linking these molecular evolutionary processes to life-history traits in modern species, we estimate that early placental mammals had a life span above 25 years and a body mass above 1 kg. This is similar to current primates, cetartiodactyls, or carnivores, but markedly different from mice or shrews, challenging the dominant view about mammalian origin and evolution. Our results imply that long-lived mammals existed in the Cretaceous era and were the most successful in evolution, opening new perspectives about the conditions for survival to the Cretaceous-Tertiary crisis.

Experimental and computational study of inter- and intra- species specificity of gonadotropins for various gonadotropin receptors

The gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and their receptors play critical roles in vertebrate reproduction. In order to study intra- and interspecies ligand promiscuity of gonadotropins, COS-7 cells were transiently transfected with one of the gonadotropin receptor genes, FSHR or LHR, and tested for activation by gonadotropins from representative fish orders: Aquilliformes (eel; e), Salmoniformes (trout; tr), and Perciformes (tilapia; ta), and of mammalian origin: porcine (p), bovine (b) and human (h).The study reveals complex relations between the gonadotropin hormones and their receptors. Each gonadotropin activated its own cognate receptor. However, taLHR was also activated by hCG and eLHR was activated by hFSH, hCG, and trFSH. For FSHR, the only cross-reactivity detected was for hFSHR, which was activated by pFSH and bFSH. These findings are of great interest and applicability in the context of activation of various GTHRs by their ligands and by ligands from other vertebrates. Analysis of the three-dimensional models of the structures highlights the importance of residues outside of the currently established hormone-receptor interface region. In addition, the interface residues in taFSHR and the effect of exon duplication, which causes an insert in the LRR domain, are suggested to affect the interaction and binding of taFSH.

“Lost sugars” — reality of their biological and medical applications

Abstract The glycan chains attached to cell surfaces or to single proteins are highly dynamic structures with various functions. The glycan chains of mammals and of some microorganisms often terminate in sialic acids or α-1,3-galactose. Although these two sugars are completely distinct, there are several similarities in their biological and medical importance. First, one type of sialic acid, N-glycolylneuraminic acid, and the galactose bound by an α-1,3-linkage to LacNAc, that forms an α-gal epitope, were both eliminated in human evolution, resulting in the production of antibodies to these sugars. Both of these evolutionary events have consequences connected with the consumption of foods of mammalian origin, causing medical complications of varying severity. In terms of ageing, sialic acids prevent the clearance of glycoproteins and circulating blood cells, whereas cryptic α-gal epitopes on senescent red blood cells contribute to their removal from circulation. The efficiency of therapeutic proteins can be increased by sialylation. Another common feature is the connection with microorganisms since sialic acids and α-gal epitopes serve as receptors on host cells and can also be expressed on the surfaces of some microorganisms. Whereas, the sialylation of IgG antibodies may help to treat inflammation, the expression of the α-gal epitope on microbial antigens increases the immunogenicity of the corresponding vaccines. Finally, sialic acids and the α-gal epitope have applications in cancer immunotherapy. N-glycolylneuraminic acid is a powerful target for cancer immunotherapy, and the α-gal epitope increases the efficiency of cancer vaccines. The final section of this article contains a brief overview of the methods for oligosaccharide chain synthesis and the characteristics of sialyltransferases and α-1,3-galactosyltransferase.

Fluorescent In Situ Folding Control for Rapid Optimization of Cell-Free Membrane Protein Synthesis

Cell-free synthesis is an open and powerful tool for high-yield protein production in small reaction volumes predestined for high-throughput structural and functional analysis. Membrane proteins require addition of detergents for solubilization, liposomes, or nanodiscs. Hence, the number of parameters to be tested is significantly higher than with soluble proteins. Optimization is commonly done with respect to protein yield, yet without knowledge of the protein folding status. This approach contains a large inherent risk of ending up with non-functional protein. We show that fluorophore formation in C-terminal fusions with green fluorescent protein (GFP) indicates the folding state of a membrane protein in situ, i.e. within the cell-free reaction mixture, as confirmed by circular dichroism (CD), proteoliposome reconstitution and functional assays. Quantification of protein yield and in-gel fluorescence intensity imply suitability of the method for membrane proteins of bacterial, protozoan, plant, and mammalian origin, representing vacuolar and plasma membrane localization, as well as intra- and extracellular positioning of the C-terminus. We conclude that GFP-fusions provide an extension to cell-free protein synthesis systems eliminating the need for experimental folding control and, thus, enabling rapid optimization towards membrane protein quality.

Different intracellular distribution of avian reovirus core protein sigmaA in cells of avian and mammalian origin

A comparative analysis of the intracellular distribution of avian reovirus (ARV) core protein sigmaA in cells of avian and mammalian origin revealed that, whereas the viral protein accumulates in the cytoplasm and nucleolus of avian cells, most sigmaA concentrates in the nucleoplasm of mammalian cells in tight association with the insoluble nuclear matrix fraction. Our results further showed that sigmaA becomes arrested in the nucleoplasm of mammalian cells via association with mammalian cell-specific factors and that this association prevents nucleolar targeting. Inhibition of RNA polymerase II activity, but not of RNA polymerase I activity, in infected mammalian cells induces nucleus-to-cytoplasm sigmaA translocation through a CRM1- and RanGTP-dependent mechanism, yet a heterokaryon assay suggests that sigmaA does not shuttle between the nucleus and cytoplasm. The scarcity of sigmaA in cytoplasmic viral factories of infected mammalian cells could be one of the factors contributing to limited ARV replication in mammalian cells.

Highly bright avidin-based affinity probes carrying multiple lanthanide chelates

Lanthanide ion luminescence has a long lifetime enabling highly sensitive detection in time-gated mode. The sensitivity can be further increased by using multiple luminescent labels attached to a carrier molecule, which can be conjugated to an object of interest. We found that up to 30 lanthanide chelates can be attached to avidin creating highly bright constructs. These constructs with Eu3+ chelates display synergistic effect that enhance the brightness of heavily modified samples, while the opposite effect was observed for Tb3+ chelates thereby significantly reducing their light emission. This undesirable quenching of Tb3+ luminophores was completely suppressed by the introduction of an aromatic spacer between the chelate and the protein attachment site. The estimated detection limit for the conjugates is in the 10−14–10−15 M range. We demonstrated a high sensitivity for the new probes by using them to label living cells of bacterial and mammalian origin.

The epigenetic control of E-box and Myc-dependent chromatin modifications regulate the licensing of lamin B2 origin during cell cycle

Recent genome-wide mapping of the mammalian replication origins has suggested the role of transcriptional regulatory elements in origin activation. However, the nature of chromatin modifications associated with such trans-factors or epigenetic marks imprinted on cis-elements during the spatio-temporal regulation of replication initiation remains enigmatic. To unveil the molecular underpinnings, we studied the human lamin B2 origin that spatially overlaps with TIMM 13 promoter. We observed an early G1-specific occupancy of c-Myc that facilitated the loading of mini chromosome maintenance protein (MCM) complex during subsequent mid-G1 phase rather stimulating TIMM 13 gene expression. Investigations on the Myc-induced downstream events suggested a direct interaction between c-Myc and histone methyltransferase mixed-lineage leukemia 1 that imparted histone H3K4me3 mark essential for both recruitment of acetylase complex HBO1 and hyperacetylation of histone H4. Contemporaneously, the nucleosome remodeling promoted the loading of MCM proteins at the origin. These chromatin modifications were under the tight control of active demethylation of E-box as evident from methylation profiling. The active demethylation was mediated by the Ten-eleven translocation (TET)-thymine DNA glycosylase-base excision repair (BER) pathway, which facilitated spatio-temporal occupancy of Myc. Intriguingly, the genome-wide 43% occurrence of E-box among the human origins could support our hypothesis that epigenetic control of E-box could be a molecular switch for the licensing of early replicating origins.

Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice

ObjectiveEmerging evidence suggests a link between innate immunity and development of type 2 diabetes mellitus (T2D); however, the molecular mechanisms linking them are not fully understood. Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that recognizes the double-stranded RNA of microbial or mammalian origin and contributes to immune responses in the context of infections and chronic inflammation. The objective of this study was to determine whether TLR3 activity impacts insulin sensitivity and lipid metabolism. Materials and MethodsWild type (WT) and TLR3 knock-out (TLR3−/−) mice were fed a high fat diet (HFD) and submitted to glucose tolerance tests (GTTs) over a period of 33weeks. In another study, the same group of mice was treated with a neutralizing monoclonal antibody (mAb) against mouse TLR3. ResultsTLR3−/− mice fed an HFD developed obesity, although they exhibited improved glucose tolerance and lipid profiles compared with WT obese mice. In addition, the increase in liver weight and lipid content normally observed in WT mice on an HFD was significantly ameliorated in TLR3−/− mice. These changes were accompanied by up-regulation of genes involved in cholesterol efflux such as PPARδ, LXRα, and LXRα-targeting genes and down-regulation of pro-inflammatory cytokine and chemokine genes in obese TLR3−/− mice. Furthermore, global gene expression profiling in liver demonstrated TLR3-specific changes in both lipid biosynthesis and innate immune response pathways. ConclusionsTLR3 affects glucose and lipid metabolism as well as inflammatory mediators, and findings in this study reveal a new role for TLR3 in metabolic homeostasis. This suggests antagonizing TLR3 may be a beneficial therapeutic approach for the treatment of metabolic diseases.

Pattern recognition receptor SRA/CD204 restricts T cell activation and antitumor immunity (52.13)

Abstract Scavenger receptor A (SRA), also termed CD204, is an innate immune receptor primarily expressed in dendritic cells (DCs) and macrophages, and displays a broad ligand-binding specificity. SRA/CD204 has been implicated in multiple physiological and pathological processes, including atherosclerosis, Alzheimer's disease, and host defense against pathogen infection. Although initial studies identified SRA/CD204 as a binding receptor for large heat shock proteins (HSPs), our subsequent studies revealed an unexpected feature of SRA/CD204 in attenuating antitumor immune response generated by vaccines formulated with adjuvants of mammalian and foreign origins. SRA/CD204 is capable of dampening both Th1 and CTL responses by limiting the intrinsic immunogenicity of DCs during interactions with T cells. SRA/CD204 may also serve as a molecule bridging antigen-presenting cells (APCs) and activated T cells for immune regulation. Dual effects-mediated by SRA/CD204 indicate pleiotropic functions of this molecule in regulating immune homeostasis and host defense. Furthermore, genetic manipulation of SRA/CD204 expression markedly enhances the immunostimulatory activities of DCs in driving antigen-specific T cell immunity, leading to profoundly improved control of tumor and metastases in preclinical models. Therefore, our studies also provide a rationale for improving vaccine potency and cancer immunotherapy through SRA/CD204-targeting approaches.

Attempts to Express the A1-GMCSF Immunotoxin in the Baculovirus Expression Vector System

Immunotoxins are fusion proteins consisting of two elements, a targeting and a toxin moiety, and are designed for specific elimination of tumor cells. Previously we expressed a recombinant fusion protein consisting of the toxic fragment of Shiga toxin (A1) and GMCSF (A1-GMCSF) in Escherichia coli, and evaluated its cytotoxic properties in acute myeloid leukemia and colon carcinoma cell lines. In view of the specific cytotoxic effects of this immunotoxin, further detailed in-vitro and preclinical studies were undertaken. Large amounts of the recombinant protein of high purity and free of unwanted side products, such as lipopolysaccharides (LPS), were required. Since GMCSF is of mammalian origin and it requires proper disulfide bond formation, we intended to use the baculovirus expression vector system (BEVS) for the expression of the recombinant fusion protein. However, despite previous reports on the expression of several other immunotoxins by this system, the A1 derived fusion proteins revealed an inhibitory effect on baculoviral particle formation and even caused cell death in insect cells. This observation was further pursued and confirmed by the use of other baculoviral specific promoters. The salient features of this finding are described below.

Expression screening of membrane proteins with cell-free protein synthesis

Detailed biophysical studies of integral membrane proteins are often hampered by sample preparation difficulties. Membrane proteins are typically difficult to express in sufficient amounts to enable the use of demanding techniques such as nuclear magnetic resonance and X-ray crystallography for structural biology. Here, we show that an inexpensive batch-based cell-free expression system can be a viable alternative for production of a wide range of different membrane proteins, both of prokaryotic and eukaryotic origin. Out of 38 tested protein constructs, 37 express at levels suitable for structural biology, i.e. enough to produce several milligrams of protein routinely and without excessive costs. This success rate was not anticipated and is even more impressive considering that more than half of the expressed proteins where of mammalian origin. A detergent screen identified Brij-58 as the, in general, most successful choice for co-translational solubilization of the expressed proteins.

What Piece of Work is Man? Frans de Waal and Pragmatist Naturalism

Frans de Waal has questioned the liberal notion that humans are primarily defined by selfishness. De Waal claims that primates are gregarious and guided by empathy. Hence, he argues we should return to Adam Smith's focus on empathy. We believe a return to pragmatism would be more appropriate. Pragmatism largely conforms to the view of human nature that De Waal's research now supports and can provide a more sophisticated framework to integrate recent insights about primate sociality into political and legal theory.The intelligent acknowledgment of the continuity of nature, and society will alone secure a growth of morals which will be serious without being fanatical, aspiring without sentimentality, adapted to reality without conventionality, sensible without taking the form of calculation of profits, idealistic without being romantic.-John Dewey, 1922 (1983, 13)1. IntroductionAt the core of much present-day, liberal, legal and political theory there is a notion of human nature defined in terms of individualism, rationality and selfinterest.1 This definition is central to most forms of contract theory. People are assumed to be calculating and self-regarding loners, reluctant to join the bonds of social union. An autonomous individual can only be asked to suffer the burdens of community, many legal and political theorists suggest, if certain preconditions are met and individual freedoms are guaranteed.Primatologist Frans de Waal has become increasingly vocal in his criticism of these presuppositions of modem liberal thought and the bleak view of human nature implicit in them. Liberal theory, De Waal believes, would benefit from a better understanding of the gregarious and intensely social nature of human beings. Nature has an undeserved bad name in political and legal theory. What is central in the life of our nearest cousins, the social primates, is not individualism and self interest, but sympathy and empathy. To accommodate this insight, De Waal suggests a return to Adam Smith's theory of moral sentiments. Adam Smith intuited the central importance of sympathy and emotion for the development of morality, according to De Waal, and managed to construct a moral theory that is much more in tune with the embryonic morality that can be observed among primates.There is much to be said for this return to Smith. Smith is a highly original thinker who can still suggest new directions for legal and political theory.2 Yet, in this article we will argue that for the reconstruction of legal and political theory that De Waal proposes, pragmatism would be a more suitable framework than Smith's moral sentimentalism. For the project that De Waal wants to pursue, i.e. the reconnection of political and legal theory with their moral roots in primate sociality, there seems to be a great deal more overlap with the classical pragmatists than with Smith. Smith's theory of moral sentiments predates Darwin and eschews many of the central premises of evolutionary theory. In the end, it is a theory primarily inspired on classical virtue ethics, not on a naturalistic recognition of the mammalian origins of our morality. The pragmatists, on the other hand, fully integrated the implications of evolutionary theory into their philosophical thought and drew on the best scholarship of their day to ground their perspective on a scientifically mature understanding of man in nature.3 In an earlier work De Waal argued for the development of a Darwistotelian view; a view which fused the evolutionary insights of Darwin with the virtue ethics of Aristotle - in many ways a precursor of Adam Smith (2001, 81-82). Our suggestion would be to develop not a Darwistotelian, but a Darweyan perspective, which fuses Darwin's insights with the philosophical and moral theories of John Dewey and other pragmatists.There are a number of reasons why an association with philosophical pragmatism would be more fitting than a return to Smith and Aristotle. …

Glycosides of hydroxyproline: Some recent, unusual discoveries

Glycosides of hydroxyproline (Hyp) in the plant cell wall matrix were discovered by Lamport and co-workers in the 1960s. Since then, much has been learned about these Hyp-rich glycoproteins. The intent of this review was to compare and contrast some less common structural motifs, in nontraditional roles, to uncover themes. Arabinosylation of short-peptide plant hormones is essential for growth, cell differentiation and defense. In a very recent development, prolyl hydroxylase and arabinosyltransferase activity has been shown to have a direct impact on the growth of root hairs in Arabidopsis thaliana. Pollen allergens of mugwort and ragweed contain proline-rich domains that are hydroxylated and glycosylated and play a structural role. In the case of mugwort, this domain also presents a significant immunogenic epitope. Major crops, including tobacco and maize, have been used to express and produce recombinant proteins of mammalian origin. The risks of plant-imposed glycosylation are discussed. In unicellular eukaryotes, Skp1 (a subunit of the E3(SCF) ubiquitin ligase complex) harbors a key Hyp residue that is modified by a linear pentasaccharide. These modifications may be involved in sensing oxygen levels. A few studies have probed the impact of glycosylation on the structure of Hyp-containing peptides. These have necessarily looked at small, synthetic molecules, since natural peptides and proteins are often isolable in only minuscule amounts and/or are heterogeneous in nature. The characterization of native structural motifs, together with the determination of glycopeptide conformation and properties, holds the key to rationalizing nature's architectural design.