Showing papers by "Trinity College, Dublin published in 2001"
TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
22,269 citations
TL;DR: In this paper, the authors introduce magnetostatics and magnetism of localized electrons on the atom, and apply it to spin electronics and magnetic recording, as well as applications of hard magnets.
Abstract: 1. Introduction 2. Magnetostatics 3. Magnetism of electrons 4. Magnetism of localized electrons on the atom 5. Ferromagnetism and exchange 6. Antiferromagnetism and other magnetic order 7. Micromagnetism, domains and hysteresis 8. Nanoscale magnetism 9. Magnetic resonance 10. Experimental methods 11. Magnetic materials 12. Applications of soft magnets 13. Applications of hard magnets 14. Spin electronics and magnetic recording 15. Special topics Appendixes Index.
3,137 citations
TL;DR: A protein is described, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome, which is therefore an adapter in TLR-4 signal transduction.
Abstract: The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.
1,250 citations
TL;DR: It is shown that caspase-3 is the primary executioner caspases in this system, necessary for cytochromec/dATP-inducible cleavage of fodrin, gelsolin, U1 small nuclear ribonucleoprotein, DNA fragmentation factor 45, and topoisomerase I, vimentin, Rb, and lamin B.
1,061 citations
TL;DR: There has been an outpouring of research on open-economy dynamic general equilibrium models that incorporate imperfect competition and nominal rigidities as discussed by the authors, and an interim survey of this recent literature can be found here.
675 citations
TL;DR: New data from exceptionally well preserved foraminifer shells extracted from impermeable clay-rich sediments indicate that for the intervals studied, tropical sea surface temperatures were at least 28–32 °C, more in line with the understanding of the geographical distributions of temperature-sensitive fossil organisms and the results of climate models with increased CO2 levels.
Abstract: Climate models with increased levels of carbon dioxide predict that global warming causes heating in the tropics, but investigations of ancient climates based on palaeodata have generally indicated cool tropical temperatures during supposed greenhouse episodes. For example, in the Late Cretaceous and Eocene epochs there is abundant geological evidence for warm, mostly ice-free poles, but tropical sea surface temperatures are generally estimated to be only 15-23 degrees C, based on oxygen isotope palaeothermometry of surface-dwelling planktonic foraminifer shells. Here we question the validity of most such data on the grounds of poor preservation and diagenetic alteration. We present new data from exceptionally well preserved foraminifer shells extracted from impermeable clay-rich sediments, which indicate that for the intervals studied, tropical sea surface temperatures were at least 28-32 degrees C. These warm temperatures are more in line with our understanding of the geographical distributions of temperature-sensitive fossil organisms and the results of climate models with increased CO2 levels.
651 citations
TL;DR: This article examined mitochondrial DNA control-region sequence variation from 392 extant animals sampled from Europe, Africa and the Near East, and compared this with data from four extinct British wild oxen.
Abstract: The limited ranges of the wild progenitors of many of the primary European domestic species point to their origins further east in Anatolia or the fertile crescent. The wild ox (Bos primigenius), however, ranged widely and it is unknown whether it was domesticated within Europe as one feature of a local contribution to the farming economy. Here we examine mitochondrial DNA control-region sequence variation from 392 extant animals sampled from Europe, Africa and the Near East, and compare this with data from four extinct British wild oxen. The ancient sequences cluster tightly in a phylogenetic analysis and are clearly distinct from modern cattle. Network analysis of modern Bos taurus identifies four star-like clusters of haplotypes, with intra-cluster diversities that approximate to that expected from the time depth of domestic history. Notably, one of these clusters predominates in Europe and is one of three encountered at substantial frequency in the Near East. In contrast, African diversity is almost exclusively composed of a separate haplogroup, which is encountered only rarely elsewhere. These data provide strong support for a derived Near-Eastern origin for European cattle.
582 citations
TL;DR: The caspase family of cysteine proteases have emerged as central regulators of apoptosis, and their role in life and death decisions of cells is discussed.
525 citations
TL;DR: The role of cell-derived SDS-stable oligomers, their blocking of hippocampal long-term potentiation in vivo and the finding that this blocking can be prevented by prior treatment of oligomer-producing cells with gamma-secretase inhibitors are reviewed.
Abstract: Despite extensive genetic and animal modelling data that support a central role for the amyloid beta-protein (A beta) in the genesis of Alzheimer's disease, the specific form(s) of A beta which causes injury to neurons in vivo has not been identified. In the present study, we examine the importance of soluble, pre-fibrillar assemblies of A beta as mediators of neurotoxicity. Specifically, we review the role of cell-derived SDS-stable oligomers, their blocking of hippocampal long-term potentiation in vivo and the finding that this blocking can be prevented by prior treatment of oligomer-producing cells with gamma-secretase inhibitors.
503 citations
TL;DR: In this article, the authors examined the global and dimensional nature of self-esteem and how it relates to children and adolescents who either have been victimised or bullied others, and found that children of both primary and post-primary age who were involved in bullying as victims, bullies, or both had significantly lower global selfesteem than did children who had neither bullied nor been bullied.
Abstract: From the rapidly growing literature on bullying, it is increasingly recognised that peer relationship problems as manifested in being bullied are associated with low self-esteem. However, the literature on self-esteem in relation to children who bully others is controversial. The objective of this paper is to elucidate further our understanding of the relationship between self-concept and bullying behaviour. Data from a nationwide study of bullying behaviour carried out in Ireland during 1993-1994 have been reviewed. The relevant results from 8,249 school children aged 8 to 18 years are presented. The paper examines the global and dimensional nature of self-esteem and how it relates to children and adolescents who either have been victimised or bullied others. A distinction is made between "pure victims," "pure bullies," and children and adolescents who were both bullied and who bullied others. In other words, pure victims were those who had not bullied others, and pure bullies had not themselves been bullied. Those who were both bullied and bullied others were subdivided further into victims who bully occasionally, sometimes, and frequently and bullies who are victimised, occasionally, sometimes, and frequently. The results show that children of both primary and post-primary age who were involved in bullying as victims, bullies, or both had significantly lower global self-esteem than did children who had neither bullied nor been bullied. However, the pure bullies, in contrast to the pure victims, placed the same value on their physical attractiveness and attributes and on their popularity as did their peers who had not bullied others or been bullied. The bully-victims of all ages had the lowest self-esteem of the subgroups in the study. Also, the more frequently children were victimised or bullied others, the lower was their global self-esteem. The typology and frequency of bullying and the age of the children when they were involved in bullying influenced the status of the specific domains of self-esteem. There were, e.g., significant differences in anxiety between the pure bullies of post-primary age and their peers who had not bullied others or been bullied. The postprimary children who bullied most frequently were the least anxious. The results indicate that high self-esteem protects children and adolescents from involvement in bullying. Thus, in view of the strong relationship between self-esteem and bullying that has been found in the present paper, it is recommended that top priority be given by parents and teachers to preventing and reducing feelings of poor self-worth among children and adolescents.
495 citations
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TL;DR: In this article, the authors constructed estimates of foreign assets and liabilities and their equity and debt subcomponents for a sample of 67 industrial and developing countries, and explored the sensitivity of estimated stock positions to the treatment of valuation effects not captured in balance of payments data.
Abstract: Although capital flows are closely monitored, surprisingly little is known about the accumulated stocks of foreign assets and liabilities held by various countries, especially in the developing world. This paper constructs estimates of foreign assets and liabilities and their equity and debt subcomponents for a sample of 67 industrial and developing countries. It characterizes the stylized facts of international balance sheets and asks whether there are trends in net foreign asset positions and shifts in debt-equity ratios over time. Finally, it explores the sensitivity of estimated stock positions to the treatment of valuation effects not captured in balance of payments data.
TL;DR: It is reported that Smac/DIABLO export from mitochondria into the cytosol is provoked by cytotoxic drugs and DNA damage, as well as by ligation of the CD95 death receptor.
Abstract: Smac/DIABLO is a mitochondrial protein that potentiates some forms of apoptosis, possibly by neutralizing one or more members of the IAP family of apoptosis inhibitory proteins. Smac has been shown to exit mitochondria and enter the cytosol during apoptosis triggered by UV- or γ-irradiation. Here, we report that Smac/DIABLO export from mitochondria into the cytosol is provoked by cytotoxic drugs and DNA damage, as well as by ligation of the CD95 death receptor. Mitochondrial efflux of Smac/DIABLO, in response to a variety of pro-apoptotic agents, was profoundly inhibited in Bcl-2-overexpressing cells. Thus, in addition to modulating apoptosis-associated mitochondrial cytochrome c release, Bcl-2 also regulates Smac release, suggesting that both molecules may escape via the same route. However, whereas cell stress-associated mitochondrial cytochrome c release was largely caspase independent, release of Smac/DIABLO in response to the same stimuli was blocked by a broad-spectrum caspase inhibitor. This suggests that apoptosis-associated cytochrome c and Smac/DIABLO release from mitochondria do not occur via the same mechanism. Rather, Smac/DIABLO efflux from mitochondria is a caspase-catalysed event that occurs downstream of cytochrome c release.
TL;DR: Phylogenetic analysis of infA sequences and assessment of transit peptide homology indicate that the four nuclear infA genes are probably derived from four independent gene transfers from chloroplast to nuclear DNA during angiosperm evolution.
Abstract: We used DNA sequencing and gel blot surveys to assess the integrity of the chloroplast gene infA , which codes for translation initiation factor 1, in . 300 diverse angiosperms. Whereas most angiosperms appear to contain an intact chloroplast infA gene, the gene has repeatedly become defunct in z 24 separate lineages of angiosperms, including almost all rosid species. In four species in which chloroplast infA is defunct, transferred and expressed copies of the gene were found in the nucleus, complete with putative chloroplast transit peptide sequences. The transit peptide sequences of the nuclear infA genes from soybean and Arabidopsis were shown to be functional by their ability to target green fluorescent protein to chloroplasts in vivo. Phylogenetic analysis of infA sequences and assessment of transit peptide homology indicate that the four nuclear infA genes are probably derived from four independent gene transfers from chloroplast to nuclear DNA during angiosperm evolution. Considering this and the many separate losses of infA from chloroplast DNA, the gene has probably been transferred many more times, making infA by far the most mobile chloroplast gene known in plants.
TL;DR: In this paper, the authors constructed estimates of foreign assets and liabilities and their equity and debt subcomponents for a sample of 67 industrial and developing countries, and characterised the stylized facts of international balance sheets and asked whether there are trends in net foreign asset positions and shifts in debt-equity ratios over time.
TL;DR: The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indicate that therestricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci.
Abstract: Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogeneity would increase the power to identify genes, the effect on evidence for linkage of restricting a sample of autism-affected relative pairs to those with delayed onset (at age >36 mo) of phrase speech (PSD, for phrase speech delay) was studied. In the second stage of a two-stage genome screen for susceptibility loci involving 95 families with two or more individuals with autism or related disorders, a maximal multipoint heterogeneity LOD score (HLOD) of 1.96 and a maximal multipoint nonparametric linkage (NPL) score of 2.39 was seen on chromosome 2q. Restricting the analysis to the subset of families (n=49) with two or more individuals having a narrow diagnosis of autism and PSD generated a maximal multipoint HLOD score of 2.99 and an NPL score of 3.32. The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indicate that the restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci.
TL;DR: It is suggested that ClfA is a crucial virulence determinant for septic arthritis and an excellent target for the generation of immune therapies directed against S. aureus.
Abstract: The importance of the fibrinogen-binding adhesin clumping factor A (ClfA) in the pathogenesis of Staphylococcus aureus septic arthritis was examined in an animal model. The protective effect of active and passive immunization with ClfA also was investigated in S. aureus infection models. The severity of arthritis was markedly reduced in mice challenged intravenously with a clfA mutant, compared with mice infected with the wild-type strain. Mice immunized with recombinant ClfA and challenged with S. aureus developed less-severe arthritis than did mice immunized with a control antigen. Passive immunization of mice with rat and rabbit anti-ClfA antibodies protected against S. aureus arthritis and sepsis-induced death, indicating that the protection by active immunization is antibody mediated. Taken together, these data strongly suggest that ClfA is a crucial virulence determinant for septic arthritis and an excellent target for the generation of immune therapies directed against S. aureus.
TL;DR: A role for the amygdala in processing emotional stimuli that extends beyond negative and fearful stimuli is demonstrated, and arousal level is clearly demonstrated to modulate the amygdala response.
Abstract: Human lesion and functional imaging data suggest a central role for the amygdala in the processing of negative stimuli. To determine whether the amygdala's role in affective processing extends beyond negative stimuli, subjects viewed pictures that varied in emotional content (positive vs negative valence) and arousal level (high vs low) while undergoing functional magnetic resonance imaging. Amygdala activation, relative to a low arousal and neutral valence picture baseline, was significantly increased for both positively and negatively valenced stimuli and did not differ for the two valences. There were no laterality effects. Whereas arousal level appeared to modulate the amygdala response for negative stimuli, all positively valenced pictures (both high and low in arousal) produced significant amygdala responses. These results clearly demonstrate a role for the amygdala in processing emotional stimuli that extends beyond negative and fearful stimuli.
TL;DR: In vitro bovine Vbeta-specific lymphocyte expansion analysis by culture supernatants of wild-type strains and of tst and sec-bovine allele replacement mutants revealed that TSST stimulates BTB13-specific T cells whereas SEC-bovoine stimulates BT B93- specific T cells, suggesting that the presence of SaPIbov may contribute to modulation of the bovines immune response.
Abstract: Previous studies have demonstrated that a proportion ofStaphylococcus aureus isolates from bovine mastitis coproduce toxic shock syndrome toxin (TSST) and staphylococcal enterotoxin C (SEC). In this study, molecular genetic analysis of one such strain, RF122, revealed the presence of a 15,891-bp putative pathogenicity island (SaPIbov) encoding the genes for TSST (tst), the SEC bovine variant (sec-bovine), and a gene (sel) which encodes an enterotoxin-like protein. The island contains 21 open reading frames specifying hypothetical proteins longer than 60 amino acids including an integrase-like gene. The element is bordered by 74-bp direct repeats at the left and right junctions, and the integration site lies adjacent to the 3′ end of the GMP synthase gene (gmps) in the S. aureuschromosome. SaPIbov contains a central region of sequence identity with the previously characterized tst pathogenicity island SaPI1 (J. A. Lindsay et al., Mol. Microbiol. 29:527–543, 1998). A closely related strain, RF120, of the same multilocus enzyme electrophoretic type, random amplified polymorphic DNA type, and ribotype, does not contain the island, implying that the element is mobile and that a recent insertion/deletion event has taken place. TSST and TSST/SEC-deficient mutants of S. aureus strain RF122 were constructed by allele replacement. In vitro bovine Vβ-specific lymphocyte expansion analysis by culture supernatants of wild-type strains and of tst and sec-bovine allele replacement mutants revealed that TSST stimulates BTB13-specific T cells whereas SEC-bovine stimulates BTB93-specific T cells. This suggests that the presence of SaPIbov may contribute to modulation of the bovine immune response.
01 Jul 2001
TL;DR: This paper demonstrates how composition patterns map to one programming model that provides a solution for separation of cross-cutting requirements in code—aspect-oriented programming, and serves to illustrate that separation of aspects may be maintained throughout the software lifecycle.
Abstract: Requirements such as distribution or tracing have an impact on multiple classes in a system. They are cross-cutting requirements, or aspects. Their support is, by necessity, scattered across those multiple classes. A look at an individual class may also show support for cross-cutting requirements tangled up with the core responsibilities of that class. Scattering and tangling make object-oriented software difficult to understand, extend and reuse. Though design is an important activity within the software lifecycle with well-documented benefits, those benefits are reduced when cross-cutting requirements are present. This paper presents a means to mitigate these problems by separating the design of cross-cutting requirements into composition patterns. Composition patterns require extensions to the UML, and are based on a combination of the subject-oriented model for composing separate, overlapping designs, and UML templates. This paper also demonstrates how composition patterns map to one programming model that provides a solution for separation of cross-cutting requirements in code—aspect-oriented programming. This mapping serves to illustrate that separation of aspects may be maintained throughout the software lifecycle.
TL;DR: In this paper, a hopping transport of spin-polarized electrons through a narrow domain wall pinned at a nanocontact was proposed, leading to the nonlinearity of the magnetoresistance curve.
Abstract: Magnetoresistive effects $(R(0)\ensuremath{-}R(H))/R(H)$ exceeding $500%$ are found at room temperature in a field of 7 mT in nanocontacts between ${\mathrm{Fe}}_{3}{\mathrm{O}}_{4}$ crystallites. The shape of the $I(V)$ curve depends on field and the magnitude of the magnetoresistance is correlated with the resistance, the largest effects occurring when $Rg100\mathrm{k}\ensuremath{\Omega}$. The explanation proposed involves hopping transport of spin-polarized electrons through a narrow domain wall pinned at the nanocontact; spin pressure on the domain wall pushes it out into the electrode, leading to the nonlinearity of the $I(V)$ characteristic. Application of current-induced wall motion in a simple fast-switching magnetic memory element is proposed.
TL;DR: Behavioural results showed a single injection of LPS impaired escape latency in both the acquisition and retention phases of the study, whereas a daily injection ofLPS did not significantly impair acquisition or retention.
TL;DR: In this article, the authors demonstrate that the charge neutral anthracene based fluorescent sensors 1a−c, having an aromatic or aliphatic thiourea moiety as an anion receptor, show ideal PET sensor behavior where the anthracenes fluorescence emission is selectively quenched upon titration with AcO−, H2PO4− and F− but not by Cl− and Br− in DMSO.
TL;DR: Analysis of the human genome sequence and other DNA databases is proceeding at a rapid pace, and immunologists are playing an important role in the effort to ascribe functions to putative gene products.
TL;DR: The origin of electrophosphorescence from a doped polymer light emitting diode (LED) has been investigated in this article, where a luminescent polymer host, poly(9,9-dioctylfluorene) (PFO), was doped with a red phosphorescent dye.
Abstract: The origin of electrophosphorescence from a doped polymer light emitting diode (LED) has been investigated. A luminescent polymer host, poly(9,9-dioctylfluorene) (PFO), was doped with a red phosphorescent dye, 2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphyrin platinum(II) (PtOEP). The maximum external quantum efficiency of 3.5% was obtained at a concentration of 4% PtOEP by weight. Energy transfer mechanisms between PFO and PtOEP were studied by absorption, photoluminescence, and photoinduced absorption spectroscopy. Even though electroluminescence spectra were dominated by PtOEP at a concentration of only 0.2 wt% PtOEP, Forster transfer of singlet excitons was weak and there was no evidence for Dexter transfer of triplet excitons. We conclude that the dominant emission mechanism in doped LED{close_quote}s is charge trapping followed by recombination on PtOEP molecules.
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TL;DR: In this paper, the authors show that a small set of fundamentals, such as the stock of public debt and demographic factors, can explain the evolution of net foreign asset positions and provide evidence that a portfolio balance effect exists: real interest rate differentials are inversely related to net foreign assets positions.
Abstract: International financial integration allows countries to become net creditors or net debtors with respect to the rest of the world. In this Paper, we show that a small set of fundamentals shifts in relative output levels, the stock of public debt and demographic factors can do much to explain the evolution of net foreign asset positions. In addition, we highlight that 'external wealth' plays a critical role in determining the behavior of the trade balance, both through shifts in the desired net foreign asset position and the investment returns generated on the outstanding stock of net foreign assets. Finally, we provide some evidence that a portfolio balance effect exists: real interest rate differentials are inversely related to net foreign asset positions.
TL;DR: The Eu(III) tetraazamacrocyclic complexes and the Tb( III) and Yb(II) complexes, synthesized as luminescent molecular-level devices, exhibit unique dual pH switching behavior in water under ambient conditions.
Abstract: The Eu(III) tetraazamacrocyclic complexes [Eu·1] and [Eu·2], and the Tb(III) and Yb(III) complexes [Tb·1] and [Yb·2], have been synthesized as luminescent molecular-level devices. The Eu complexes exhibit unique dual pH switching behavior in water under ambient conditions. The delayed Eu emission is reversibly switched on in acid, with an enhancement factor of several hundred for [Eu·1]. These observations are consistent with the protonation of the quinoline aryl nitrogen moiety (pKa ≈ 5.9 for [Eu·1]). The fluorescence emission spectra of these complexes are unaffected by acid, but pronounced changes occur in alkaline solution due to the deprotonation of the aryl amide nitrogen (pKa ≈ 9.4 for [Eu·1]). [Tb·1] shows a more intriguing pH dependence; Tb emission is switched “on” only in the presence of H+ and in the absence of molecular oxygen, whereas the fluorescence emission properties are similar to those observed with [Eu·1]. This behavior can be conveniently described as a molecular-level logic gate, co...
TL;DR: A general decline in health-related quality of life over time was observed in the pooled data; however, significant improvements were achieved in patients involved in the pharmaceutical care programme in some countries.
Abstract: Objective: This study aimed to measure the outcomes of a harmonised, structured pharmaceutical care programme provided to elderly patients: (greater than or equal to 65 years of age) by community pharmacists in a multicentre international study performed in 7 European countries. Design and setting: The study was a randomised, controlled. longitudinal, clinical trial with repeated measures performed over an Is-month period. A total of 104 intervention and 86 control pharmacy sites participated in the research and 1290 intervention patients and 1164 control patients were recruited into the study. Main outcome measures and results: A general decline in health-related quality of lift: over time was observed in the pooled data; however, significant improvements were achieved in patients involved in the pharmaceutical care programme in some countries. Intervention patients reported better control of their medical conditions as a result of the study and cost savings associated with pharmaceutical care provision were observed in most countries. The new structured service was well accepted by intervention patients and patient satisfaction with the services improved during the study. The pharmacists involved in providing pharmaceutical care had a positive opinion on the new approach, as did the majority of general practitioners surveyed. The positive effects appear to have been achieved via social and psychosocial aspects of the intervention, such as the increased support provided by community pharmacists, rather than via biomedical mechanisms. Conclusions: This study is the first large-scale, multicentre study to investigate the effects of pharmaceutical care provision by community pharmacists to elderly patients. Future research methodology and implementation will be informed by the experience gained from this challenging trial.
TL;DR: The main aims of the workshop were to seek a consensus on the current models of the intestinal barriers and ways to screen for the movement of drugs across this barrier, and to make useful recommendations for the promotion of the three Rs in this area as discussed by the authors.
Abstract: The principal aims of the workshop were to seek a consensus on the current models of the intestinal barriers and ways to screen for the movement of drugs across this barrier,and to make useful recommendations for the promotion of the three Rs in this area.
TL;DR: It is discovered that β-amyloid peptide and the Aβ-containing C -terminus of β-APP (CT) facilitate the induction of LTD in the CA1 area of the intact rat hippocampus, which will result in a profound disruption of information processing dependent on hippocampal synaptic plasticity.
Abstract: The Alzheimer's disease-related β-amyloid precursor protein (β-APP) is metabolized to a number of potentially amyloidogenic peptides that are believed to be pathogenic. Application of relatively low concentrations of the soluble forms of these peptides has previously been shown to block high-frequency stimulation-induced long-term potentiation (LTP) of glutamatergic transmission in the hippocampus. The present experiments examined how these peptides affect low-frequency stimulation-induced long-term depression (LTD) and the reversal of LTP (depotentiation). We discovered that β-amyloid peptide (Aβ1–42) and the Aβ-containing C -terminus of β-APP (CT) facilitate the induction of LTD in the CA1 area of the intact rat hippocampus. The LTD was frequency- and NMDA receptor-dependent. Thus, although low-frequency stimulation alone was ineffective, after intracerebroventricular injection of Aβ1–42, it induced an LTD that was blocked byd-(−)-2-amino-5-phosphonopentanoic acid. Furthermore, an NMDA receptor-dependent depotentiation was induced in a time-dependent manner, being evoked by injection of CT 10 min, but not 1 hr, after LTP induction. These use- and time-dependent effects of the amyloidogenic peptides on synaptic plasticity promote long-lasting reductions in synaptic strength and oppose activity-dependent strengthening of transmission in the hippocampus. This will result in a profound disruption of information processing dependent on hippocampal synaptic plasticity.
05 Sep 2001
TL;DR: This paper presents a process for producing ensembles of classifiers based on different feature subsets that emphasizes diversity (ambiguity) in the ensemble members and finds that the ensemble based on ambiguity have lower generalization error.
Abstract: It is well known that ensembles of predictors produce better accuracy than a single predictor provided there is diversity in the ensemble. This diversity manifests itself as disagreement or ambiguity among the ensemble members. In this paper we focus on ensembles of classifiers based on different feature subsets and we present a process for producing such ensembles that emphasizes diversity (ambiguity) in the ensemble members. This emphasis on diversity produces ensembles with low generalization errors from ensemble members with comparatively high generalization error. We compare this with ensembles produced focusing only on the error of the ensemble members (without regard to overall diversity) and find that the ensembles based on ambiguity have lower generalization error. Further, we find that the ensemble members produced focusing on ambiguity have less features on average that those based on error only. We suggest that this indicates that these ensemble members are local learners.