Marr and Reductionism

David Marr's three-level method for completely understanding a cognitive system and the importance he attaches to the computational level are so familiar as to scarcely need repeating. Fewer seem to recognize that Marr defends his famous method by criticizing the “reductionistic approach.” This sets up a more interesting relationship between Marr and reductionism than is usually acknowledged. I argue that Marr was correct in his criticism of the reductionists of his time—they were only describing (cellular activity), not explaining (cognitive functions). But a careful metascientific account of reductionistic neuroscience over the past two decades reveals that Marr's criticisms no longer have force. Contemporary neuroscience now explains cognition directly, although in a fashion—causal-mechanistically—quite different than Marr recommended. So while Marr was correct to reject the reductionism of his day and offer an alternative method for genuinely explaining cognition, contemporary cognitive scientists now owe us a new defense of Marr's famous method and the advantages of its explanations over the type now pursued successfully in current reductionist neuroscience. There are familiar reasons for thinking that this debt will not be paid easily.     

Adult schistosome cDNA libraries as a source of antigens for the study of experimental and human schistosomiasis

Protective immunity has been demonstrated in experimental schistosomiasis and is also believed to occur in man. It can be mediated by antibodies from infected animals or animals immunized with attenuated organisms. Recombinant Escherichia coli synthesizing antigenic polypeptides from the three principal species of schistosome that infect man, Schistosoma mansoni, S. japonicum and S. haematobium, have been constructed. Libraries of adult worm cDNA were prepared from each species in the expression vector lambda gt 11 and directly screened with antibodies from animals experimentally immunized with S. mansoni and S. japonicum and from humans infected with S. haematobium. The S. mansoni clones have been analysed in greatest detail. At least four different types of clones were identified. All the detected recombinant polypeptide antigens were recognised by antibodies from chronically infected mice and most were also recognised by antibodies from mice immunized with attenuated cercariae and anti-surface membrane antibodies. Clones synthesizing species-specific antigens for both S. mansoni and S. japonicum were identified by simultaneous screening of both libraries. At least three types of S. haematobium clones were identified by screening with human infection serum, most of which were species-specific. All the antigens were in the form of fusion peptides with E. coli beta-galactosidase and their expression was induced by isopropylthiogalactopyranoside. Since known protective monoclonal antibodies recognise highly glycosylated membrane proteins which cannot be identified in the form of nascent polypeptides, the direct identification of polypeptide antigens defined by their reactivity, as reported here, is an essential step in producing reagents by recombinant DNA technology, suitable for vaccination and diagnosis.     

The role of antibody affinity and titre in immunity to Schistosoma mansoni following vaccination with highly irradiated cercariae.

Sera from rabbits and rats vaccinated with highly irradiated cercariae of Schistosoma mansoni (VRabS, VRatS) were found to be of substantially higher affinity than sera from CBA mice vaccinated four times (4 X CVMS), single sex sera (SSS) or chronic infection sera (CIS). In contrast, VRabS and SSS appeared to possess the highest titres of antibody, followed by CIS and VRatS, with 4 X CVMS displaying the lowest titre. Two mouse strains selectively bred for high-affinity (HA) or low-affinity (LA) antibody following vaccination were tested for their ability to resist a challenge infection. LA mice, which produce high titres of low-affinity antibody, manifested significantly more resistance than HA mice, which produce low titres of high-affinity antibody. Immunoprecipitation studies demonstrated that sera from vaccinated LA mice (LVMS) recognized 125I-labelled schistosomular surface antigens more intensely than sera from vaccinated HA mice (HVMS). However, peritoneal macrophages from HA and LA mice in the presence of HVMS, LVMS or 4 X CVMS, and naive macrophages activated in vitro with interferon-gamma (IFN-gamma)/lipopolysaccharide (LPS) mediated comparable levels of schistosomula killing in vitro. The experiments described here provide evidence that the titre of antibody rather than its affinity may be a more critical factor in the development of optimal immunity to S. mansoni.     

A novel mis-sense mutation (G1381A) in the G6PD gene identified in a Chinese man

Objective　To detect new mutations among 29 glucose-6-phosphate dehydrogenase (G6PD) deficient individuals from Yunnan province. Methods　The nitroblue tetrazolium (NBT) method was used to screen G6PD deficient individuals. Mutation was identified by single strand conformation polymorphism (SSCP), amplification created restriction site (ACRS), amplification refractory mutation system (ARMS) and DNA sequencing. Results　Among 29 cases, 18 cases of G1388A, 1 case of C1004A, and 1 case of G1381A were identified. Nine cases remained to be defined. The G1381A mutation is a novel mis-sense mutation, with a substitution of threonine for alanine (A461T). The resultant G6PD had reduced enzymatic activity. In addition, G1381A caused a restriction site of Stu I to disappear, providing a rapid method for the detection of this mutation. Conclusion　A novel mis-sense mutation G1381A was found. This mutation results in a substitution of threonine for alanine, producing enzyme with reduced activity. The loss of the Stu I restriction site offers a rapid method for the detection of this mutation.     

Global silicate weathering flux overestimated because of sediment–water cation exchange

Rivers carry the dissolved and solid products of silicate mineral weathering, a process that removes CO2 from the atmosphere and provides a key negative climate feedback over geological timescales. Here we show that, in some river systems, a reactive exchange pool on river suspended particulate matter, bonded weakly to mineral surfaces, increases the mobile cation flux by 50%. The chemistry of both river waters and the exchange pool demonstrates exchange equilibrium, confirmed by Sr isotopes. Global silicate weathering fluxes are calculated based on riverine dissolved sodium (Na⁺) from silicate minerals. The large exchange pool supplies Na⁺ of nonsilicate origin to the dissolved load, especially in catchments with widespread marine sediments, or where rocks have equilibrated with saline basement fluids. We quantify this by comparing the riverine sediment exchange pool and river water chemistry. In some basins, cation exchange could account for the majority of sodium in the river water, significantly reducing estimates of silicate weathering. At a global scale, we demonstrate that silicate weathering fluxes are overestimated by 12 to 28%. This overestimation is greatest in regions of high erosion and high sediment loads where the negative climate feedback has a maximum sensitivity to chemical weathering reactions. In the context of other recent findings that reduce the net CO2 consumption through chemical weathering, the magnitude of the continental silicate weathering fluxes and its implications for solid Earth CO2 degassing fluxes need to be further investigated.

For decades, silicate weathering has been postulated to provide the negative climate feedback on Earth that prevents a runaway greenhouse climate like on Venus (1). Silicate mineral dissolution with carbonic acid converts atmospheric CO2 into carbonate, and releases essential nutrients to the terrestrial and marine biosphere (2). There have been many attempts to quantify the silicate weathering flux (3), mostly assuming that riverine dissolved sodium (Na+) is derived only from silicate minerals and rock salt. Here we show that there is a major addition of nonsilicate Na+ to the critical zone from ancient seawater, weakly bonded to sedimentary rocks and supplied to waters via the cation exchange process. The implication is not only that the silicate weathering flux is overestimated at a global scale, but that this nonsilicate Na+ is most important in regions previously thought to have the highest silicate weathering fluxes (so called weathering-limited regions) and greatest climate sensitivity.Cation exchange is a rapid chemical reaction between cations in the dissolved phase and mineral surfaces, particularly clays (4). Major and trace cations such as calcium (Ca2+), magnesium (Mg2+), sodium (Na+), potassium (K+), and strontium (Sr2+) form the cation exchange pool, which balances negative charges on river-borne clay particle surfaces. This exchange takes place on interlayer sites, between the tetrahedral and octahedral layers, or on exposed surfaces (4). The importance of the cation exchange pool is well recognized in soils and aquifers (4, 5), has significant implications for enhanced weathering (6), and has been proposed as an important mechanism for buffering the composition of river waters (7–9). However, data on the riverine exchange pool are only available for two large river systems [Amazon and Ganges-Brahmaputra (10, 11)], despite its significance in providing a source of elements that are immediately bioavailable (12), and their potential for biasing the quantification of silicate weathering (9).It is increasingly recognized that rapidly reactive phases have a strong influence on the chemistry of river waters (13, 14). Cation exchange is a rapid reaction occurring continuously in soils, as riverine freshwaters evolve downstream interacting with particulate matter, and when they mix with seawater (15, 16). Important examples of cation exchange are the “swapping” of divalent cations Ca2+ and Mg2+ with Na+, in particular when there is a major change in water composition such as when fluvial clays reach the ocean,Caclay2++2Nawater+⇋2Naclay++Cawater2+.[1]As a result, marine sediments have an exchange pool that is dominated by Na+ (17). Subsequently, these marine sediments are uplifted and emplaced on the continents where Na+ in the exchange pool is released by cation exchange with Ca-rich fresh waters (9). This has major implications for estimates of silicate weathering fluxes and associated CO2 consumption, because they are calculated using the Na+ content of rivers (3). Cerling et al. (9) proposed that the Na+-rich exchange pool exerts an important control on natural waters, based on charge balance arguments from river water chemistry, but this hypothesis has never been rigorously tested (18) by determining the flux and composition of the exchange pool of rivers around the world.In this contribution, we present a large dataset of fluvial sediment cation exchange capacity (CEC) and composition in several of the world’s largest river basins. By comparing with the concomitant dissolved load chemistry, we demonstrate that 1) the exchange pool in river sediments is in equilibrium with the river water; 2) the fraction of mobile elements in the exchange pool relative to the dissolved pool can be significant, particularly in rapidly eroding, weathering-limited catchments; and 3) given reasonable inferences on the composition of old marine sedimentary rocks, modern-day silicate weathering has been overestimated and carbonate weathering has been underestimated. The results reduce the estimated magnitude of the silicate weathering flux, but increase the supply of base cations (e.g., Ca2+, which can be a limiting nutrient) to the biosphere, suggesting a greater role of organic carbon burial compared with silicate weathering for the long-term atmospheric CO2 sink.     

Spatial Arrangement of Ribosomal Proteins: Reaction of the Escherichia coli 30S Subunit with bis-Imidoesters

The 30S ribosomal subunit of E. coli was treated with the bifunctional reagent bis-(methyl)suberimidate. Crosslinked ribosomal proteins were identified as bands with increased molecular weight after electrophoresis in polyacrylamide gels containing sodium dodecyl sulphate. The pattern of crosslinked products was altered when unfolded subunits were used. Free ribosomal protein was not crosslinked. Several of the crosslinked products were cleaved by ammonolysis to form the original monomeric protein constituents. The low yields of the reactions necessitated the use of radioactive proteins and auto-radiographic procedures. The crosslinked proteins were tentatively identified by coelectrophoresis of the radioactive ammonolysis products with carrier 30S protein in sodium dodecyl sulphate, and coelectrophoresis at pH 4.5 in buffers containing urea.     

Immunity to Schistosoma mansoni in vivo: contradiction or clarification?

In recent years controversy and contradiction have hindered the elucidation of the immune effector mechanisms that are most effective against Schistosoma mansoni - an essential goal for the development of an effective vaccine. However, recent in-vivo studies have clarified the relative contributions of such mechanisms to protection. Here, Dario Vignali and colleagues summarize current evidence that suggests that both antibody and CD4+ T cells, in cooperation with macrophages, are crucial for the development of an effective response. In addition, a model is presented that may account for some of the discrepancies observed and which could be used as a basis for future research.     

Immunogenicity of plasmid DNA encoding the 62 kDa fragment of Schistosoma japonicum myosin

The recombinant Schistosoma mansoni 62 kDa myosin fragment, rIrV-5, is highly protective in experimental animals, however, vaccination of mice and rats with the recombinant Schistosoma japonicum homologue, rSj62, did not induce significant resistance against S. japonicum infection. To explore alternative ways of presenting this antigen, we further constructed a plasmid (VRSj62) which encodes Sj62 using the VR1020 vector and tested it in vaccination experiments. Four immunisations with 10 microg VRSj62 DNA alone were sufficient to induce high and progressively increasing levels of IgG antibodies against rSj62 with increasing numbers of injections in CBA/Ca mice (IgG titre > or =1:25000), and three injections with 50 microg VRSj62 DNA alone induced significant IgG responses in C57Bl/6 mice (IgG titre, 1:1600). However, vaccination with plasmid DNA entrapped in cationic liposomes or together with pUC19 DNA as a source of CpG motifs, both of which have been reported to enhance immune responses, did not enhance specific antibody production. In spite of the stimulation of specific antibodies against rSj62 with the naked DNA construct no resistance to challenge was demonstrated.     

Patterns of helminth infection and relationship to BCG vaccination in Karonga District, northern Malawi

Surveys of enteric and urinary helminth infections were carried out in 1999 among 501 schoolchildren and among 320 adolescents and young adults participating in a study of immune responses to BCG vaccine in Karonga District, northern Malawi. Hookworm, Schistosoma mansoni and S. haematobium infections were detected in 64%, 27% and 20% of schoolchildren and in 55%, 40% and 25% of the immunology study subjects, respectively. Other helminths were appreciably less common. The prevalence of 'at least one' helminth infection was 76% among schoolchildren, ranging from 60% to 92% in the 4 schools, and was 79% in the immunology study participants. There was no evidence for an association between the presence of a BCG scar and presence or intensity of infection with worms in the schoolchildren, nor evidence that BCG vaccination of adolescents and young adults had any effect on the prevalence of helminth infections 1 year later.