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H Barlow

Publications and source records attributed to H Barlow.

9 recordsLinked to original sources
PubMed1998

Expression and functional analysis of glycosyl-phosphatidyl inositol-linked CD46 in transgenic mice.

BACKGROUND: Complement activation plays a pivotal role in hyperacute xenograft rejection. In humans, activation of complement is regulated by a number of cell surface regulatory proteins. Membrane cofactor protein (CD46) is one such regulator that protects cells by acting as a cofactor for the factor I-mediated cleavage of C3b and C4b. Transgenic animals expressing human CD46 may provide organs that are resistant to complement attack. However, attempts to generate mice expressing human CD46 using cDNA-based constructs have been largely unsuccessful. METHODS: Transgenic mice expressing a glycosylphosphatidyl inositol (GPI)-linked form of CD46 were generated by microinjection of a hybrid CD46/CD55 cDNA under the control of the human intercellular adhesion molecule-2 promoter. Expression of CD46-GPI on the vascular endothelium was determined by immunohistochemistry. The ability of CD46-GPI to protect mouse tissues from human complement attack was determined using an ex vivo isolated perfused heart model. RESULTS: Three founder animals expressing CD46-GPI were identified. Histological analysis showed strong and uniform expression of CD46-GPI on the vascular endothelium of all organs examined. Ex vivo perfusion of transgenic mouse hearts with human plasma showed a reduction in C3c deposition and a slightly prolonged function compared with controls. CONCLUSIONS: High-level expression of CD46-GPI was achieved in transgenic mice by using a modified cDNA-based construct. The CD46-GPI was functional, providing some protection from complement-mediated damage in the ex vivo model, and may be useful in xenotransplantation if expressed in combination with CD55 and CD59.

Animals↗
PubMed1998

The nested networks of brains and minds.

The reductionist approach to the brain shows promise of revolutionizing our ideas about what single neurons can do. A spine on a cortical pyramidal cell is about the size of a single Escherichia coli, and if the internal machinery of a spine is anything like as well organized as that of E. coli, the whole pyramidal cell with its 5000 spines must be capable of computations an order of magnitude more complex than those demanded of the neurons used for current models of the brain. These computations might enable single neurons to detect spatiotemporal patterns, i.e. Hebb's 'phase sequences'. Reductionism is apparently limited because its drive is to look for explanations at lower levels in the organizational tree. For this purpose it often uses isolated preparations in which such lower levels can be studied but higher levels cannot, because they have been thrown down the sink. Reductionism will never lead us to understand organization and interaction in parts discarded or ignored, and this must include the interactions between individual human minds that are crucial for understanding human society. Our brains possess a 'commentary system', a mechanism that can make reports on the internal status of some parts of the brain. This makes possible networks of minds, and the present meeting is such a network whose interactions are being recorded for posterity. On a grander scale such networking creates a cultural forum where communal goals and purposes are formulated, disseminated, modified, and often perpetuated in lasting form. The resulting group behaviour has obvious survival value, and is perhaps the feature that distinguishes humans most clearly from other species.

Animals↗
PubMed1997

Correspondence noise and signal pooling in the detection of coherent visual motion.

In the random dot kinematograms used to analyze the detection of coherent motion in the middle temporal visual area (MT) and in psychophysical experiments the exact way that dots are paired between successive presentations is not known by the observer. We show how to calculate the limit to coherence threshold caused by this uncertainty, which we call "correspondence noise." We compare ideal thresholds limited only by this noise with those of human observers when dot density, ratio of dot numbers in two fields, area of stimulus, number of fields, and method of generation of the coherent dots are varied. The observed thresholds vary in the same way as the ideal thresholds over wide ranges, but they are much higher. We think this difference is because the ideal detector takes advantage of the high precision with which dots are placed in the kinematograms, whereas the neural motion system can only operate with low precision. When kinematograms are generated with decreased precision of dot placement, the ideal detector no longer has this advantage, and the gap between ideal and actual performance is greatly reduced. Because the signals that result from objects moving in the real world are scattered over broad ranges of direction and velocity, high precision is not needed, and it is advantageous for the motion system to pool information over broad ranges. Other mismatches between kinematograms and the neural motion system, and internal noise, may also elevate human thresholds relative to the ideal detector. The importance of external noise suggests that the neurons of MT form a vast array of optimal filters, each matched to a different combination of parameters in the multidimensional space required to define motion in patches of the visual field.

Adult↗
PubMed1997

Changes in cell surface glycosylation in alpha1,3-galactosyltransferase knockout and alpha1,2-fucosyltransferase transgenic mice.

BACKGROUND: Inactivation of the alpha1,3-galactosyltransferase (GalT) gene by homologous recombination (knockout [KO] mice) and competition for the enzyme's N-acetyllactosamine substrate by transgenically expressed alpha1,2-fucosyltransferase (H-transferase) are two genetic approaches to elimination of the Gal alpha1,3Gal (alphaGal) epitope, which is the major xenoantigen in pigs against which humans have preformed antibodies. Such genetic manipulations often have unpredictable results. METHODS: A panel of 19 selected lectins was used to characterize the changes in cell surface glycosylation in GalT KO and H-transferase transgenic mice, compared with nontransgenic littermate controls. RESULTS: GalT KO mice showed complete elimination of the alphaGal epitope, as reported previously. Surprisingly, however, this was associated with only a modest increase in N-acetyllactosamine residues and had little other effect on the pattern of lectin binding. In contrast, the pattern of lectin binding to H-transferase transgenic mouse cells was more profoundly disturbed and indicated, in addition to the expected expression of H substance and suppression of the alphaGal epitope, that there was a marked reduction in alpha2,3-sialylation and exposure of the normally cryptic antigens, sialylated Tn and Forssman antigens. Similar changes in lectin reactivity with porcine aortic endothelial cells were induced by neuraminidase treatment. CONCLUSIONS: Lectins were able to bind underlying carbohydrate structures (sialylated Tn and Forssman antigens) that are normally cryptic antigens on H-transferase transgenic mouse spleen and cardiac endothelial cells, probably as a consequence of the reduction in the electronegativity of the cell surface due to reduced sialylation. As humans have preformed anti-Tn and anti-Forssman antibodies, it is possible that these structures may become targets of the xenograft rejection process, including hyperacute rejection.

Adsorption↗
PubMed1996

Targeting gene expression to endothelial cells in transgenic mice using the human intercellular adhesion molecule 2 promoter.

Genetic engineering of donor animals in xenotransplantation research has been directed largely toward obtaining expression of various immunoregulatory molecules on vascular endothelium, the initial target of recipient antibody and complement. However, specific high-level expression of transgenes throughout the vascular tree in adult animals has proved difficult to achieve, perhaps because of the inherent heterogeneity of endothelium. Using the promoter of the gene for intercellular adhesion molecule 2 (ICAM-2), which is constitutively expressed on all vascular endothelium, we have developed a system for endothelial cell gene targeting in vivo. A 334-basepair fragment from the 5' flanking region of the human ICAM-2 gene was used to drive the expression of human CD59 in transgenic mice. Strong and uniform expression of CD59 was observed on the endothelial cells of all blood vessels in the heart, kidney, lung, liver, and pancreas in the three lines of mice examined. Little or no expression was seen in other cell types, with the exception of neutrophils and monocytes. These results suggest that this small promoter region contains most of the signals necessary to endow it with endothelial cell specificity, making it a potentially valuable tool in areas ranging from xenotransplantation to gene therapy.

Animals↗
PubMed1990

Conditions for versatile learning, Helmholtz's unconscious inference, and the task of perception.

It is a mistake to consider perception and learning separately because what one learns is strongly constrained by what one perceives, and what one perceives depends on what one has experienced. I shall propose the hypothesis that perception is the computation of a representation that enables us to make reliable and versatile inferences about associations occurring in the world around us--that is, perception prepares the ground for learning. The statistical problem in learning is to determine whether a compound event such as "C followed by U" is a random co-occurrence or a significant association, for if it is the former it would be a mistake to pay any particular attention to C, whereas if it is the latter C is a conditional stimulus for U and a useful predictor for it. Now you cannot decide whether the association is random or not without knowledge of the prior probabilities of C and U: hence on my hypothesis when you perceive an object or event the representation must not only signal "it's there" or "it's happened", but must also make evident (or rapidly accessible) the prior probability of what has been signalled. Furthermore it must do this for all the objects or events that can act as conditional stimuli, and this implies that the representative elements should be statistically independent (or approximately so) in the normal environment. Forms of coding that would do this, and the relationship with Helmholtz's unconscious inference, will be discussed. These considerations imply that the task performed in perception has been overlooked both by learning theorists and by connectionists working on associative and adaptive networks. Coding for independence may be particularly important in understanding the developmental processes during the sensitive period: it may be the operation that leads ontogenetically-timed, activity-dependent, connections to imprint appropriate codes if the animal has experience, but inappropriate codes without experience.

Adaptation, Physiological↗