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Biomedical subjects

K G Johnson

Publications and source records attributed to K G Johnson.

At least 19 recordsLinked to original sources

The ecology of extinction: molluscan feeding and faunal turnover in the Caribbean Neogene.

Molluscan faunal turnover in the Plio-Pleistocene of the tropical western Atlantic has been attributed to drops in temperature or primary productivity, but these competing hypotheses have not been assessed ecologically. To test these alternatives, we compiled data on changing molluscan life habits and trophic composition over 12 million years derived from 463 newly made collections from the southwestern Caribbean. Shelf ecosystems have altered markedly in trophic structure since the Late Pliocene. Predatory gastropods and suspension-feeding bivalves declined significantly in abundance, but not in diversity, and reef-dwellers became common. By contrast, all other ecological life habits remained remarkably stable. Food-web changes strongly support the hypothesis that declining regional nutrient supply had an increasing impact on regional macroecology, culminating in a faunal turnover.

Animals↗

Receptor protein tyrosine phosphatases regulate retinal ganglion cell axon outgrowth in the developing Xenopus visual system.

Receptor protein tyrosine phosphatases (RPTPs) are regulators of axon outgrowth and guidance in a variety of different vertebrate and invertebrate systems. Three RPTPs, CRYP-alpha, PTP-delta, and LAR, are expressed in overlapping but distinct patterns in the developing Xenopus retina, including expression in retinal ganglion cells (RGCs) as they send axons to the tectum (Johnson KG, Holt CE. 2000. Expression of CRYP-alpha, LAR, PTP-delta, and PTP-rho in the developing Xenopus visual system. Mech Dev 92:291-294). In order to examine the role of these RPTPs in visual system development, putative dominant negative RPTP mutants (CS-CRYP-alpha, CS-PTP-delta, and CS-LAR) were expressed either singly or in combination in retinal cells. No effect was found on either retinal cell fate determination or on gross RGC axon guidance to the tectum. However, expression of these CS-RPTP constructs differentially affected the rate of RGC axon outgrowth. In vivo, expression of all three CS-RPTPs or CS-PTP-delta alone inhibited RGC axon outgrowth, while CS-LAR and CS-CRYP-alpha had no significant effect. In vitro, expression of CS-CRYP-alpha enhanced neurite outgrowth, while CS-PTP-delta inhibited neurite outgrowth in a substrate-dependent manner. This study provides the first in vivo evidence that RPTPs regulate retinal axon outgrowth.

Animals↗

Constitutive association of SHP-1 with leukocyte-associated Ig-like receptor-1 in human T cells.

The intracellular Src homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP-1) is a negative regulator of cell signaling and contributes to the establishment of TCR signaling thresholds in both developing and mature T lymphocytes. Although there is much functional data implicating SHP-1 as a regulator of TCR signaling, the molecular basis for SHP-1 activation in T lymphocytes is poorly defined. A modification of the yeast two-hybrid system was employed to identify in T cells phosphotyrosine-containing proteins capable of binding the SH2 domains of SHP-1. From this yeast tri-hybrid screen, the p85beta subunit of phosphatidylinositol 3-kinase and the immunoreceptor tyrosine-based inhibitory motif-containing receptors, leukocyte-associated Ig-like receptor-1 (LAIR-1) and programmed death-1 (PD-1), were identified. Coimmunoprecipitation studies demonstrated that the exclusive phosphotyrosine-containing protein associated with SHP-1 in Jurkat T cells under physiological conditions is LAIR-1. Significantly, this interaction is constitutive and was detected only in the membrane-enriched fraction of cell lysates. Ligand engagement of the SH2 domains of SHP-1 is a prerequisite to activation of the enzyme, and, consistent with an association with LAIR-1, SHP-1 was found to be constitutively active in unstimulated Jurkat T cells. Importantly, a constitutive interaction between LAIR-1 and SHP-1 was also detected in human primary T cells. These results illustrate the sustained recruitment and activation of SHP-1 at the plasma membrane of resting human T cells by an inhibitory receptor. We propose that this mechanism may exert a constitutive negative regulatory role upon T cell signaling.

Amino Acid Motifs↗

Requirement for CD28 co-stimulation is lower in SHP-1-deficient T cells.

This study provides biochemical and functional evidence pertaining to the role of the intracellular protein tyrosine phosphatase, SHP-1, in influencing thresholds for TCR activation. Although the loss of SHP-1 in thymocytes from motheaten mice had minimal effects on the initial rise of cytosolic Ca(2+) concentration following TCR triggering, the post-stimulation equilibrium levels of Ca(2+) were consistently elevated. In keeping with a SHP-1 effect on PLCgamma function, IP3 generation was increased in SHP-1 deficient thymocytes. Importantly, we demonstrate that loss of SHP-1 results in a relaxation of the normally stringent co-stimulatory requirements for IL-2 production. SHP-1 deficient single-positive CD4(+) thymocytes revealed a significantly enhanced capacity to produce IL-2 in response to anti-CD3 stimulation alone. In contrast, the simultaneous triggering of CD3 and CD28 was required for equivalent IL-2 production in control single-positive CD4(+) thymocytes. Furthermore, SHP-1 deficient thymocytes generated an increased and prolonged proliferative response to anti-CD3 stimulation alone. In addition, the simultaneous triggering of CD28 and CD3 resulted in equivalent proliferative responses in SHP-1-deficient and control thymocytes, suggesting that a strong co-stimulatory signal is able to override the effect of SHP-1 loss on TCR hyperresponsiveness. Collectively, these results suggest that SHP-1, rather than acting directly on TCR signaling, may indirectly raise thresholds for TCR triggering by modulating co-stimulatory signals.

Animals↗

The immunological synapse.

The adaptive immune response is initiated by the interaction of T cell antigen receptors with major histocompatibility complex molecule-peptide complexes in the nanometer scale gap between a T cell and an antigen-presenting cell, referred to as an immunological synapse. In this review we focus on the concept of immunological synapse formation as it relates to membrane structure, T cell polarity, signaling pathways, and the antigen-presenting cell. Membrane domains provide an organizational principle for compartmentalization within the immunological synapse. T cell polarization by chemokines increases T cell sensitivity to antigen. The current model is that signaling and formation of the immunological synapse are tightly interwoven in mature T cells. We also extend this model to natural killer cell activation, where the inhibitory NK synapse provides a striking example in which inhibition of signaling leaves the synapse in its nascent, inverted state. The APC may also play an active role in immunological synapse formation, particularly for activation of naïve T cells.

Animals↗

Impact of high transvalvular to subvalvular velocity ratio early after aortic valve replacement with Freestyle stentless aortic bioprosthesis.

Although stentless aortic bioprostheses are associated in general with excellent hemodynamics, a subset of patients exhibit high early postoperative gradients. The present study was performed to evaluate the prevalence and impact of suboptimal hemodynamics early after stentless tissue aortic valve replacement. The early postoperative peak transvalvular to peak left ventricular (LV) outflow tract velocity ratio was > or = 3.0 in 44 (6.7%) of 658 patients in the multicenter, long-term study of the Freestyle stentless aortic valve. Mean gradient, effective orifice area (EOA), and LV mass index were compared between these patients and a control group of 44 patients matched for age, sex, valve size, and implant technique. High velocity ratio was associated with female sex (63.6% v 42.8%, P =.01), smaller valve size (77.3% v 45.3%, < or = 23 mm, P =.0004), and use of the modified subcoronary rather than full root implant technique (90.9% v 70.2% modified subcoronary, P =.01). Mean gradient was significantly higher (P <.05) and EOA lower (P <.05) early postoperative and throughout follow-up among patients with high velocity ratio. LV mass index decreased across time among both groups; patients with high velocity ratio tended to have higher LV mass index with less complete LV mass regression, although the difference did not reach statistical significance. In conclusion, there was a 6.7% incidence of hemodynamics suggestive of significant aortic stenosis early after implantation of a Freestyle stentless aortic valve. Gradients decreased and EOA increased in the first months after surgery, although they remained less favorable. Multiple factors likely play a role in early suboptimal hemodynamics following stentless tissue aortic valve replacement, including factors related to patient population, valve size, implant modality, and implant technique.

Aged↗

A supramolecular basis for CD45 tyrosine phosphatase regulation in sustained T cell activation.

Transmembrane protein tyrosine phosphatases, such as CD45, can act as both positive and negative regulators of cellular signaling. CD45 positively modulates T cell receptor (TCR) signaling by constitutively priming p56lck through the dephosphorylation of the C-terminal negative regulatory phosphotyrosine site. However, CD45 can also exert negative effects on cellular processes, including events triggered by integrin-mediated adhesion. To better understand these opposing actions of tyrosine phosphatases, the subcellular compartmentalization of CD45 was imaged by using laser scanning confocal microscopy during functional TCR signaling of live T lymphocytes. On antigen engagement, CD45 was first excluded from the central region of the interface between the T cell and the antigen-presenting surface where CD45 would inhibit integrin activation. Subsequently, CD45 was recruited back to the center of the contact to an area adjacent to the site of sustained TCR engagement. Thus, CD45 is well positioned within a supramolecular assembly in the vicinity of the engaged TCR, where CD45 would be able to maintain src-kinase activity for the duration of TCR engagement.

Animals↗

Ephrin-B regulates the Ipsilateral routing of retinal axons at the optic chiasm.

In Xenopus tadpoles, all retinal ganglion cells (RGCs) send axons contralaterally across the optic chiasm. At metamorphosis, a subpopulation of EphB-expressing RGCs in the ventrotemporal retina begin to project ipsilaterally. However, when these metamorphic RGCs are grafted into embryos, they project contralaterally, suggesting that the embryonic chiasm lacks signals that guide axons ipsilaterally. Ephrin-B is expressed discretely at the chiasm of metamorphic but not premetamorphic Xenopus. When expressed prematurely in the embryonic chiasm, ephrin-B causes precocious ipsilateral projections from the EphB-expressing RGCs. Ephrin-B is also found in the chiasm of mammals, which have ipsilateral projections, but not in the chiasm of fish and birds, which do not. These results suggest that ephrin-B/EphB interactions play a key role in the sorting of axons at the vertebrate chiasm.

Animals↗

Expression of CRYP-alpha, LAR, PTP-delta, and PTP-rho in the developing Xenopus visual system.

Receptor protein tyrosine phosphatases (RPTPs), are involved in axon outgrowth and guidance not only in the Drosophila visual system (Garrity et al., 1999. Neuron 22, 707-717) but also in the developing vertebrate retina (Ledig et al., 1999a. J. Cell Biol. 147, 375-388). We have cloned a variety of Xenopus RPTPs, including four RPTPs expressed in the developing visual system (LAR, PTP-delta, CRYP-alpha and PTP-rho). These four RPTPs are transcribed in the developing optic vesicle during differentiation and in overlapping but distinct patterns in the developing retina during retinal layer formation. LAR, PTP-delta, and CRYP-alpha are also expressed in retinal ganglion cells during axonogenesis and during axon guidance from the retina to the optic tectum.

Animals↗

TCR signaling thresholds regulating T cell development and activation are dependent upon SHP-1.

An examination of thymocytes and peripheral T cells from SHP-1-deficient motheaten mice possessing a transgenic MHC class I-restricted TCR has implicated SHP-1 in regulating TCR signaling thresholds at three checkpoints in T cell development and activation. First, in the population of CD4-CD8- double negative thymocytes, SHP-1 appears capable of regulating signals from TCR complexes that control the maturation and proliferation of double negative thymocytes. Second, the loss of SHP-1 increased the number of CD4+CD8+ double positive thymocytes capable of maturing as TCRhigh single positive thymocytes. Third, the loss of SHP-1 altered the basal level of activation of naive lymph node T cells. Accordingly, SHP-1-deficient lymph node T cells bearing the transgenic TCR demonstrated a hyperresponsiveness to stimulation with cognate peptide. However, the loss of SHP-1 did not alter the cytolytic ability of mature effector cytotoxic T lymphocytes. Together these results suggest that SHP-1 contributes to establishing thresholds for TCR signaling in thymocytes and naive peripheral T cells.

Animals↗

Cardiovascular risk factors and cardiac surgery outcomes in a multiethnic sample of men and women.

BACKGROUND: Cardiovascular disease is more prevalent in some ethnic groups than in others, as are risk factors stemming from cultural practices and values. Data on the health status of Asians and Pacific Islanders are scarce and sporadic, and data on the 2 groups are usually combined for analysis. OBJECTIVE: To determine ethnic and sex-related differences among white, Japanese, and Pacific Island subjects in cardiovascular risk factors and outcomes after coronary artery bypass graft surgery. METHODS: Data were collected from a random sample of 41 men and 19 women scheduled for nonemergent coronary artery bypass graft surgery: 19 white, 18 Japanese, and 23 Pacific Island/Hawaiian subjects. Subjects were interviewed about risk factors before surgery and were followed up for the first 20 hours after surgery. Problems that occurred during the remainder of the hospital stay were assessed by chart review. Instruments used included the Charlson Comorbidity Index, Acute Physiology and Chronic Health Evaluation II, and the Therapeutic Intervention Scoring System. RESULTS: Pacific Island and Japanese subjects differed significantly in their demographic and clinical characteristics. Pacific Islanders tended to have a more difficult postoperative course than did white subjects, whereas Japanese patients tended to have fewer problems and an easier postoperative course than other subjects. CONCLUSIONS: Further study of ethnic variations in risk factors and surgical outcomes, especially variations in comorbidities, age at the onset of signs and symptoms, and postoperative complications, is needed. Combining data obtained from Japanese and Pacific Island subjects for data analysis most likely will result in a loss of important information.

Aged↗

Behavioural changes in stabled horses given nontherapeutic levels of virginiamycin.

Abnormal behaviour commonly develops in intensively managed horses. A possible cause is the change in diet occurring when the horse is stabled. An experiment was performed to examine this possibility by manipulating the diet with the feed supplement virginiamycin, as Founderguard. During 4 weeks, 18 horses were fed diets ranging from hay alone to concentrate plus hay in the ratio of 3:1. The rations of half the horses given concentrate were supplemented with Founderguard. Horses eating high concentrate rations displayed abnormal oral behaviours at a higher frequency than those eating only hay. The incidence of these behaviours was reduced when diets were supplemented with Founderguard. The drop in faecal pH of animals on concentrate diets was also reduced by Founderguard. Animals on concentrate diets had an average of 21 kg less gut fill post mortem. Dietary supplementation with virginiamycin as Founderguard apparently lessens some behavioural problems associated with management of stabled horses and the intake of grain. It may allow concentrate to be fed at higher levels than customary without adverse behavioural side effects. The suggested mechanism for the improved behaviour due to Founderguard supplementation is reduced fermentative acidosis in the hindgut.

Animal Feed↗

Direct reimbursement.

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American Dental Association↗

Adaptive behaviour of laboratory rats feeding in hot conditions.

1. A group of six rats, living at thermoneutrality, but with access to food only under a high heat load, was compared with a similar group living and eating at thermoneutrality. 2. Animals eating in the heat reduced total food intake, meal duration, total feeding time, and rate of weight gain; they increased frequency of feeding and had higher water intakes. 3. Identifiable behavioral and nutritional responses explained some of the difference in adaptation between the groups through other factors may also have played a role.

Adaptation, Physiological↗

Temperature and humidity of expired air of sheep.

The temperature and humidity of expired air from three adult Merino sheep were measured at air temperatures of 20, 30 and 40 degrees C before and after the animals were shorn. Expired air was apparently always saturated with water vapour. At the higher air temperatures the temperature of expired air was close to deep body temperature; at lower air temperatures, expired air had been significantly cooled, e.g. to 32.3 degrees C in shorn sheep at 20 degrees C air temperature. Expired air was cooler from shorn than from unshorn animals at 20 and 30 degrees C air temperature, possibly due to thermally induced vasomotor changes in the upper respiratory tract. Cooling of expired air would be expected to lead to recovery of some of the water evaporated during inspiration; at 20 degrees C air temperature, this fraction was estimated to be 25% in unshorn sheep and 36% in shorn sheep.

Animals↗