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Johnson-Laird, Byrne, and Schaeken (1992) present a theory of propositional reasoning by mental models. The present study provides a comprehensive test of the predictions of that theory for the difficulty of simple disjunctive and conditional inferences. The results are largely consistent with the complex pattern of predictions. They are discussed in the light of recently proposed modifications of the original theory.
Signal-transducing G-proteins are heterotrimers composed of GTP-binding alpha subunits in association with a tightly bound complex of beta and gamma subunits. While the alpha subunits are recognized as a family of diverse structures, beta and gamma subunits have also been found as heterogeneous isoforms. To investigate the diversity and tissue specificity of the beta gamma complexes, we have examined homogeneous oligomeric G-proteins from a variety of sources. The beta and gamma subunits isolated from the major-abundance G-proteins from bovine brain, bovine retina, rabbit liver, human placenta, and human platelets were purified and subjected to biochemical and immunological analysis. Protease mapping and immune recognition revealed an identical profile for each of the two distinctly migrating beta isoforms (beta 36 and beta 35) regardless of tissue or G-protein origin. Digestion with V8 protease revealed four distinct, clearly resolved terminal fragments for beta 36 and two for beta 35. Trypsin and chymotrypsin digestion yielded numerous bands, but again each form had a unique profile with no tissue specificity. Tryptic digestion was found to be conformationally specific with the most resistant structure being the native beta gamma complex. With increasing trypsin, the complex was digested but in a pattern distinct from that for denatured beta. In contrast to the two highly homologous beta structures, examination of this set of proteins revealed at least six distinct gamma peptides. Two unique gamma peptides were found in bovine retinal Gt and three gamma peptides in samples of bovine brain derived Go/Gi. Human placental and platelet Gi samples each contained a unique gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
We present a novel method for the automated detection of fragments showing dissimilar expression in mRNA differential display. The analysis is based on aligning the numerical electrophoretic lane data in respect of a given distance function defined on a set of fragments, or signal peaks in general. We presume that significant dissimilarities between peaks result in extreme score values computed for aligned peak pairs. Whereas in sequence comparison, an overall sequence similarity score is conventionally used, the current method defines a special dissimilarity score for searching the peak pairs showing the largest relative differences between the lanes. The output of the analysis is a highly reduced list of peak pairs, along with a set of associated features extracted from the lanes. Only the peaks of this list need to be visually confirmed instead of the vast amount of peaks in the original electrophoretic results. The results obtained by the algorithm correlate well with results of visual evaluation of the same electropherograms. The current algorithm may be applied to the study of complex expression patterns in multiple lanes and, in general, to automated recognition of variously defined patterns of quantitative electrophoretic data.
The complexities of neurobehavioral assessment of the fetus, which can be neither directly viewed nor manipulated, cannot be understated. Impetus to develop methods for measuring fetal neurobehavioral development has been provided by the recognition that individual differences in neurobehavioral functioning do not originate with birth and acceptance of the key contribution of the antenatal period to postnatal life. Research has centered around four aspects of fetal functioning: heart rate, motor activity, behavioral state, and responsivity to stimulation. Longitudinal studies have revealed that the developmental trajectories of these characteristics parallel the developing nervous system, detected a transitional period between 28 and 32 weeks gestation, and established within-fetal stability during the second half of gestation. Despite the promise of fetal stimulation and habituation paradigms as measures of neural functioning, significant safety and ethical concerns exist. Construction of a unified fetal neurobehavioral scale is premature until a sufficient degree of normative data is available and the predictive validity of specific aspects of fetal neurobehavior to child developmental outcomes is better established.
6A6 is a murine monoclonal antibody raised against the humanized anti-tissue factor antibody D3H44. 6A6 is able to completely neutralize the anticoagulant activity of D3H44 in tissue factor-dependent functional assays, such as endotoxin-induced whole blood clotting, prothrombin time, as well as factor X and factor IX activation. ELISA-type assays further showed that 6A6 binds to an epitope with critical determinants on the V(L) domain of D3H44. The possibility that the anti-idiotypic 6A6 might carry an "internal image" of the original antigen (tissue factor) was examined using the X-ray structure of the 6A6-Fab/D3H44-Fab complex determined at 2.5A resolution. We find that 6A6 structurally mimics tissue factor only so far as it combines with the antigen recognition surface of D3H44. While 6A6 contacts both V(L) and V(H) domains of D3H44, as does tissue factor, there is more contact with the D3H44 V(L) domain and less with the D3H44 V(H) domain relative to the tissue factor contacts on D3H44. Additionally, there is an almost total lack of correspondence between 6A6 and tissue factor at the level of amino acid side-chain functional groups. Despite the fact that both tissue factor and 6A6 are composed largely of beta-sheets, they present fundamentally different elements of secondary structure to D3H44; tissue factor presents beta-sheets edge-on, while 6A6 uses mostly loops. Finally, the finding that 6A6 competes with tissue factor for D3H44 binding raises the possibility of using 6A6 as an antidote for D3H44 anticoagulant therapy. To this end, we constructed a chimeric murine/human 6A6-Fab, which effectively neutralized D3H44 and fully restored tissue factor function in enzymatic assays.
Over the last fifteen years, we have witnessed a rapid expansion in the development of artificial odour sensing systems, or so called 'electronic nose' systems. Whilst the power of this approach to flavour has undoubtedly been demonstrated by its recent application to various complex odours, it will be argued that the original research programme, aimed at developing a comparative model of the biological olfactory pathway, has degenerated into an attempt to obtain an ad hoc workable system, based around readily available sensor and pattern recognition (PARC) technologies. At the time, the first 'model' nose system reflected the limited understanding of sensory information processing carried out within the biological olfactory pathway. We are now presented with an opportunity to evaluate and re-assess the architecture for an electronic nose, in view of the recent advances in understanding the key processing principals exploited by the olfactory bulb and cortex in the identification and characterisation of molecular stimuli. In Part II of this paper, we examine the parallels that exist between the biological olfactory system and the electronic nose. It is shown that the two systems share many similarities in their architectures and other properties, such as odour delivery, nonspecific sensor/receptor response, sensor/receptor preprocessing and content addressable memory (CAM) function. Of particular importance, both systems need to overcome similar operating problems, such as sensor/receptor drift, degeneration and poisoning, limited sensor/receptor sensitivity, discrimination of odour quality invariant of intensity and also the identification of particular odour components within a mixture of background odours. Finally, a number of opportunities for improving the biological plausibility of electronic nose systems are suggested that may yield an improvement in performance.
Over the last fifteen years, we have witnessed a rapid expansion in the development of artificial odour sensing systems, or so called 'electronic nose' systems. Whilst the power of this approach to flavour analysis has undoubtedly been demonstrated by its recent application to various complex odours, it will be argued that the original research programme, aimed at developing a comparative model of the biological olfactory pathway, has degenerated into an attempt to obtain an ad hoc workable system, based around readily available sensor and pattern recognition (PARC) technologies. At the time, the first 'model' nose system reflected the limited understanding of sensory information processing carried out within the biological olfactory pathway. We are now presented with an opportunity to evaluate and re-assess the architecture for an electronic nose, in view of the recent advances in understanding the key processing principals exploited by the olfactory bulb and cortex in the identification and characterisation of molecular stimuli. In Part I of this paper, the rapid developments in the understanding of the information processing performed by the biological olfactory system are critically reviewed, and its relevance to current research in artificial olfaction is considered. Not only have the initial biochemical pathways involved in the transduction of odour stimuli been uncovered, but also computational models of the key synaptic circuits have advanced to the point where network simulations are clearly capable of odour discrimination. The key processing principles exploited in the olfactory pathway for overcoming operating constraints such as sensor drift/degeneration, limited sensitivity, and xenobiotic response are highlighted, so that their integration into the electronic analogue may be explored in Part II.
Triggering new rounds of chromosomal DNA replication during the bacterial cell cycle is exquisitely regulated, ensuring both proper timing and one round per cycle stringency. A critical first step is stable unwinding of oriC, the chromosomal replication origin, by multiprotein orisome complexes comprising the AAA+ initiator DnaA and modulator proteins that bend DNA. Recently identified oriC-DnaA interactions in Escherichia coli raise important questions regarding the molecular mechanisms that regulate origin unwinding in bacteria. We describe staged binding of E. coli origin recognition proteins and suggest an unwinding switch based on interactions between DnaA-ATP and specialized oriC sites that must be filled during orisome assembly. By focusing multiple regulatory pathways on only a few key oriC DNA-protein interactions, this model includes an efficient way to control unwinding followed by orisome inactivation during the cell cycle. Future studies will determine whether this regulatory scheme is correct and whether it is generally applicable to other bacterial types.
The alloresponse can be divided into two components. The first of these is allorecognition, which refers to the recognition of antigens, expressed on the surface of cells of non-self origin, by the host's lymphocytes. The second part is the immune effector mechanisms generated by this recognition process. The molecules recognised have been termed histocompatibility antigens and fall into two categories. The strongest responses are provoked by allogeneic major histocompatibility complex (MHC) antigens. T cells recognise these antigens either directly or after being processed like conventional antigens by antigen-presenting cells, in what has been termed indirect presentation. In the context of MHC identity, responses are observed against the second category of antigens, namely minor histocompatibility antigens (mHAgs). Although weaker, these responses are of clinical importance, particularly in bone marrow transplant recipients. CD4+ T cells play a central role in orchestrating the immune response to alloantigens. They secrete cytokines to attract effector cells, such as macrophages and CD8+ T cells, into the graft and are able to interact with B cells that will secrete highly specific alloreactive antibodies. In clinical terms, the result of the immune response to transplanted allografts can be classified as hyperacute rejection, acute and chronic rejection. The immunological effector mechanisms involved in each of these processes are discussed.
Yeast transcription factor tau interacts with the A and B blocks of the intragenic promoter of tRNA genes. The structure of tau was investigated by identifying the polypeptide chains specifically complexed to the tRNA3Glu gene. Highly purified factor, obtained by an improved purification procedure, contained several polypeptide chains, four of which (Mr = 145,000, 135,000, 100,000 and 65,000) comigrated with tau-DNA complex by polyacrylamide gel electrophoresis. Antibodies raised against the 145- and 100-kDa components altered the migration of tau-DNA complexes in band shift assays and inhibited tRNA synthesis in a reconstituted transcription system. These components are immunologically unrelated proteins. By UV cross-linking to 32P-body-labeled tDNA followed by extensive DNase treatment, two polypeptides of the same size (145 and 100 kDa) were found to be radioactively labeled. Factor tau, therefore, appears to be a multisubunit DNA-binding protein with two distinct polypeptides contributing to DNA recognition. Limited proteolysis of tau generated a protease-resistant tau B (tau B) domain that binds solely to the B block. tau B-tDNA complexes were recognized by anti-145 IgG and contained a 120-kDa polypeptide that could originate from the 145-kDa component by proteolysis. These results strongly suggest that the 145-kDa polypeptide belongs to tau B and is responsible for B block binding.
The interaction between double-stranded RNA (dsRNA) and the third double-stranded domain (dsRBD) from Drosophila Staufen protein represents a paradigm to understand how the dsRBD protein family, one of the most common RNA-binding protein units, binds dsRNA. The nuclear magnetic resonance (NMR) structure of this complex and the x-ray structure of another family member revealed the stereochemical basis for recognition, but also raised new questions. Although the crystallographic studies revealed a highly ordered interface containing numerous water-mediated contacts, NMR suggested extensive residual motion at the interface. To address how interfacial motion contributes to molecular recognition in the dsRBD-dsRNA system, we conducted a 2-ns molecular dynamics simulation of the complex derived from Staufen protein and of the separate protein and RNA components. The results support the observation that a high degree of conformational flexibility is retained upon complex formation and that this involves interfacial residues that are critical for dsRBD-dsRNA binding. The structural origin of this residual flexibility is revealed by the analysis of the trajectory of motion. Individual basic side chains switch continuously from one RNA polar group to another with a residence time seldom exceeding 100 ps, while retaining favorable interaction with RNA throughout much of the simulation. Short-lived water molecules mediate some of these interactions for a large fraction of the trajectory studied here. This result indicates that water molecules are not statically associated with the interface, but continuously exchange with the bulk solvent on a 1-10-ps time scale. This work provides new insight into dsRBD-dsRNA recognition and builds upon a growing body of evidence, suggesting that short-lived dynamic interactions play important roles in protein-nucleic acid interactions.
In prokaryotes, incomplete or misfolded polypeptides emanating from a stalled ribosome are marked for degradation by the addition of an 11 residue peptide (AANDENYALAA) to their C terminus. Substrates containing this conserved degradation signal, the SsrA tag, are targeted to specific proteases including ClpXP and ClpAP. SspB was originally characterized as a stringent starvation protein and has been found to bind specifically to SsrA-tagged proteins and to enhance recognition of these proteins by the ClpXP degradation machine. Here, we report the crystal structures of SspB alone and in complex with an SsrA peptide. Unexpectedly, SspB exhibits a fold found in Sm-family RNA binding proteins. The dimeric SspB structures explain the key determinants for recognition of the SsrA tag and define a hydrophobic channel that may bind unfolded substrates.
The full exploitation of single-molecule spectroscopy in disordered systems is often hampered by spectral diffusion processes of the optical transitions due to structural fluctuations in the local environment of the probe molecule which leads to temporal averaging of the signal. Multivariate statistical pattern recognition techniques, originally developed for single-molecule cryoelectron microscopy, allow us to retrieve detailed information from optical single-molecule spectra. As an example, we present the phonon side band of the B800 excitations of the light-harvesting 2 (LH2) complex from Rhodospirillum molischianum, revealing the electron-phonon coupling strength for these transitions. The measured Debye-Waller factors, ranging from 0.4 to 0.9, fall in the regime of weak electron-phonon coupling.
The overarching goal of human behavioral genetics is to understand genetic influences on behavior while also considering the complementary influence of the environment. This paper highlights the explicit goals of behavioral genetics, including some that are particularly relevant to the study of human development, and some common misunderstandings concerning the field. Examples are given to illustrate specifically the degree of genetic influence in behaviors representing physical, cognitive and emotional development during infancy using the methodology of twin, adoption and parent-offspring designs. The effect sizes in the prediction of complex behaviors are typically modest, and thus there is ample room for multiple predictors from different domains. Moreover, there is a fundamental recognition that distal and proximal causes can be different in kind, and that factors that play a role in the origins of behavioral dispositions are different from those that elicit or maintain actual behavior.
To investigate quantitatively the cooperative binding ability of beta-cyclodextrin dimers, a series of bridged bis(beta-cyclodextrin)s with 2,2'-diselenobis(benzoyl) spacer connected by different lengths of oligo(ethylenediamine)s (2-5) and their platinum(IV) complexes (6-9) have been synthesized and their inclusion complexation behavior with selected substrates, such as Acridine Red, Neutral Red, Brilliant Green, Rhodamine B, ammonium 8-anilino-1-naphthalenesulfonate, and 6-p-toluidino-2-naphthalenesulfonic acid, were investigated by means of ultraviolet, fluorescence, fluorescence lifetime, circular dichroism, and 2D-NMR spectroscopy. The spectral titrations have been performed in aqueous phosphate buffer solution (pH 7.20) at 25 degrees C to give the complex stability constants (K(S)) and Gibbs free energy changes (-DeltaG degrees ) for the inclusion complexation of hosts 2-9 with organic dyes and other thermodynamic parameters (DeltaH degrees and TDeltaS degrees ) for the inclusion complexation of 2-5with fluorescent dyes ANS and TNS. The results obtained indicate that beta-cyclodextrin dimers 2-5 can coordinate with one or two platinum(IV) ions to form 1:1 or 1:2 stoichiometry metallobridged bis(beta-cyclodextrin)s. As compared with parent beta-cyclodextrin (1) and bis(beta-cyclodextrin)s 2-5, metallobridged bis(beta-cyclodextrin)s 6-9 can further switch the original molecular binding ability through the coordinating metal to orientate two beta-cyclodextrin cavities and an additional binding site upon the inclusion complexation with model substrates, giving the enhanced binding constants K(S) for both ANS and TNS. The tether length between two cyclodextrin units plays a crucial role in the molecular recognition with guest dyes. The binding constants for TNS decrease linearly with an increase in the tether length of dimeric beta-cyclodextrins. The Gibbs free energy change (-DeltaG degrees ) for the unit increment per ethylene is 0.32 kJ.mol(-)(1) for TNS. Thermodynamically, the higher complex stabilities of both ANS and TNS upon the inclusion complexation with 2-5 are mainly contributed to the favorable enthalpic gain (-DeltaH degrees ) by the cooperative binding of one guest molecule in the closely located two beta-cyclodextrin cavities as compared with parent beta-cyclodextrin. The molecular binding ability and selectivity of organic dyes by hosts 1-9 are discussed from the viewpoints of the multiple recognition mechanism and the size/shape-fitting relationship between host and guest.
We recorded pattern-reversal visual evoked potentials (P-VEP) from dissociated vertical deviation (DVD) patients to evaluate the sensory system abnormalities in DVD. 91 DVD patients with good visual acuity were studied. Normal subjects and horizontal strabismic patients without DVD were compared for evaluation. Transient and steady state P-VEPs were recorded from three EEG electrodes placed on the posterior scalp. Half-field checker-board reversal stimulation was applied to stimulate monocular temporal retina and responses from right and left hemispheres were also compared for evaluation. Paradoxical lateralization was observed in all normal subjects. Abnormal P-VEPs were observed in 4 of 20 (20%) horizontal strabismic patients without DVD when employing the transient stimulation method and in 2 of 8 (25%) when using steady state stimulation. Abnormal P-VEPs were observed in 31 of 67 (46.3%) DVD patients, with the transient stimulation method and in 20 of 25 (80.0%) DVD patients with the steady state stimulation method. The abnormalities were various and diverse. Our observations indicate that DVD patients frequently have an abnormal sensory system detected by P-VEP, and DVD might be a complex and multi-origin condition involving both sensory and motor systems.
Chiral interaction of helical peptide with chiral molecule, and concomitant induction in its helix sense have been demonstrated in optically inactive nonapeptide (1) possessing Gly at its N-terminus: H-Gly-(Delta(Z)Phe-Aib)(4)-OCH(3) (1: Delta(Z)Phe = Z-dehydrophenylalanine; Aib = alpha-aminoisobutyric acid). Spectroscopic measurements [mainly nuclear magnetic resonance (NMR) and circular diochroism (CD)] as well as theoretical simulation have been carried out for that purpose. Peptide 1 in the 3(10)-helix tends to adopt preferentially a right-handed screw sense by chiral Boc-L-amino acid (Boc: t-butoxycarbonyl). Induction in the helix sense through the noncovalent chiral domino effect should be derived primarily from the complex supported by the three-point coordination on the N-terminal sequence. Thus the 3(10)-helical terminus consisting of only alpha-amino acid residues enables chiral recognition of the Boc-amino acid molecule, leading to modulation of the original chain asymmetry. Dynamics in the helix-sense induction also have been discussed on the basis of a low-temperature NMR study. Furthermore, the inversion of induced helix sense has been achieved through solvent effects.
In previous studies, we identified a Marek's disease virus (MDV) origin-binding protein (OBP) gene that is highly homologous to the herpes simplex virus type 1 UL9 gene that encodes an OBP and functions as an initiator protein for viral DNA replication. In this study, a protein of 95 kDa was produced in coupled in vitro transcription-translation reaction with the plasmid containing the wild type MDV OBP gene. The in vitro synthesized protein was detected by immunoprecipitation with a penta-histidine specific monoclonal antibody. Further characterization of MDV OBP was accomplished using electrophoretic mobility shift assay (EMSA) with the in vitro expressed MDV OBP using a double-stranded (ds) 26-mer oligonucleotide as the probe, which was designed from the putative MDV OBP binding site present in the serotype 1 or 2 MDV replication origin. The EMSA results indicated that MDV OBP could form a protein-DNA complex with the ds 26-mer oligonucleotide designed from serotype 1 or 2 replication origin. A series of 26-mer oligonucleotides with two-base-pair (bp) substitution across the putative MDV OBP binding site were used in competitive EMSA to determine the recognition sequence for the MDV OBP. The results demonstrated that the recognition sequence for MDV OBP was the TTCGCACC that is a subset of a 9-bp element (CGTTCGCAC) conserved in the replication origins of alphaherpesviruses. Furthermore, the results of EMSA with a series of deletion mutants from the N-terminus of MDV OBP indicated that the origin-binding domain was located at the amino acids region 528 to 841 of the wild-type MDV OBP. Taken together, our results suggest that the MDV OBP gene encodes an OBP of MDV.