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Biomedical subjects

G Yu

Publications and source records attributed to G Yu.

295 records · Page 17Linked to original sources
PubMedDate not supplied

Normal brain development in PS1 hypomorphic mice with markedly reduced gamma-secretase cleavage of betaAPP.

Presenilin 1-null mice die at birth from brain and skeletal developmental deformities due to disrupted Notch signaling. Presenilin 1-null mice also have severely reduced gamma-secretase cleavage of betaAPP. The assumption has been that facilitation of Notch signaling and betaAPP processing by presenilin 1 are analogous functions. Here we describe a presenilin 1-targetted mouse model that expresses extremely low levels ( approximately 1% of normal) of mutant PS1-M146L. Homozygous mice have significantly reduced viability due to a Notch-like phenotype. The animals that survive have severe axial skeletal deformities and markedly diminished gamma-secretase activity and accumulation of betaAPP-C100, but no obvious abnormalities in brain development. These results suggest that, in mice, a marked reduction of PS1-facilitated gamma-secretase activity is not detrimental to normal brain development.

Amyloid Precursor Protein Secretases↗
PubMedDate not supplied

Presenilin 1 is actively degraded by the 26S proteasome.

The metabolic pathways governing the turnover of presenilin 1 (PS1) have been incompletely worked out. The PS1 holoprotein has low abundance in many cells and appears to undergo endoproteolytic cleavage near residue 298. We provide evidence that one mechanism by which the PS1 holoprotein is degraded is through the action of the 26S proteasome. We also show that the proteasome does not participate in the endoproteolytic cleavage.

Alzheimer Disease↗
PubMedDate not supplied

Impaired arteriolar mechanotransduction in experimental diabetes mellitus.

Decreased arteriolar distensibility in diabetes may impair signal transduction mechanisms that are required for converting a pressure stimulus into smooth muscle contraction. These studies aimed to determine if pressure-induced increases in arteriolar intracellular Ca(2+) are altered in diabetes and whether diabetes is associated with alterations in composition of the extracellular matrix. Studies of mechanical properties used single, isolated, and cannulated cremaster arterioles from streptozotocin (60 mg/kg) diabetic rats and age-matched controls. To measure Ca(2+)(i), arterioles were loaded with Fura 2 (5 microM) after which preparations were examined by fluorescence microscopy and image analysis. Matrix protein (type IV collagen, laminin, fibronectin) deposition was studied by immunohistochemistry. Over a range of 30-120 mm Hg control vessels showed a linear relationship (r = 0.98, p < 0.01) between intraluminal pressure and Ca(2+)(i). Vessels from diabetic animals also showed a linear relationship (r = 0.99, p < 0.01), however, the mean slope was significantly (p < 0.02) less in the diabetic (0.17 +/- 0.05, n = 5) compared to controls (0.51 +/- 0.09, n = 7). Similarly, the slope of the wall tension-Ca(2+)(i) relationship was significantly decreased in vessels from diabetic animals. These differences were ameliorated by treatment of diabetic animals (n = 5) with aminoguanidine. Increased content of type IV collagen, laminin and fibronectin in vessel media was evident after 2 weeks of diabetes and showed a further increase with duration of diabetes. The data suggest that for a given increase in luminal pressure arterioles from diabetic animals response with an attenuated rise in smooth muscle Ca(2+)(i). This mechanotransduction defect may relate to alterations in the composition of the extracellular matrix within the arteriolar wall.

Animals↗
PubMedDate not supplied

Sequential pathological and immunologic analysis of percutaneous microwave coagulation therapy of hepatocellular carcinoma.

PURPOSE: To evaluate sequential pathologic and immunologic changes and their prognostic significance after percutaneous microwave coagulation therapy (PMCT) of hepatocellular carcinoma (HCC). METHODS: Eighty-nine nodules in 82 consecutive patients were studied. The 89 nodules were divided into two groups: a treatment group, with 82 primary nodules (average dimension was 3.4 +/- 1.2 cm) in 82 patients, and a control group, of seven nodules (average dimension was 1.4 +/- 0.6 cm) in seven patients. The criteria for a nodule's inclusion in the control group was that the nodule was one of two nodules in the same patient and that the two nodules were located in different liver lobes. This guarantees that while one nodule is treated by PMCT, the distant one will not be directly affected by the microwave thermal field. The control group nodules were treated after the study was completed. Specimens were taken with ultrasound-guided liver biopsy from the treated nodule and the control nodule, pre- and post-PMCT. Infiltration by T-lymphocytes, B-lymphocytes, NK cells and macrophages in the tumour tissue were observed immunohistochemically using a panel of monoclonal antibodies against CD3, CD45RO, CD20, CD56 and CD68. The extent of immune cell infiltration was compared both before and after PMCT, as well as between the treated and control nodules. The relationship between the prognosis and the extent of immunocyte infiltration was analysed. RESULTS: The patients were followed for 2-26 months (mean 14.6 +/- 6.3) post-treatment. The recurrence rates at 1 and 2 years were 20.4% and 28.1% within the liver in treatment group, respectively. The survival rates at 1 and 2 years were 92.5% and 75.3% for the treatment group. T-cells, NK cells and macrophages increased significantly in both treated and untreated nodules after PMCT, albeit less markedly within untreated nodules when compared to the treated ones. There is a statistically significant correlation between survival outcome and the extent of immunocyte infiltration. CONCLUSIONS: For inoperable HCC patients, PMCT is one of the treatment choices shown to be effective. Apart from its tissue coagulation effect, an increased systemic immune response directed against the tumour may also play an important role in improved survival.

Adult↗
PubMedDate not supplied

Comparative CD4 T-cell responses of reverse transcriptase inhibitor therapy with or without nelfinavir matched for viral exposure.

BACKGROUND: Therapy of HIV infection with protease inhibitors (PIs) may be associated with improvements in CD4 T-cell number via a mechanism that is independent of effects on plasma viral load (VL). PURPOSE: To compare CD4 responses of patients who receive reverse transcriptase inhibitor (RTI) therapies with or without a PI, matched for viral exposure. METHODS: Patient data were analyzed from two prospective randomized trials of antiviral therapy with or without nelfinavir. Total viral exposure over 24 weeks was estimated by viral area under the curve (AUC), which reflects baseline viral load, slope of virologic decay, viral nadir, and duration of suppression. Patients were stratified into quartiles on the basis of viral AUC, and CD4 T-cell responses were evaluated between PI-containing and RTI-only treatment groups within each quartile. RESULTS: In both trials, patients receiving nelfinavir had greater CD4 T-cell increases than patients receiving RTI alone. Analysis of variance modeling revealed increased CD4 T-cell responses in PI-treated groups at all time points after the second week. These differences were significant (p <.05) at weeks 12, 24, 28, 32, 36, 40, and 48 in one study, and weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, and 44 in the other. Within quartiles matched for viral AUC, absolute CD4 T-cell change from baseline was greater in the PI-treated patients at 84% (101/120) of time points analyzed. CONCLUSION: Nelfinavir-containing therapy is associated with enhanced increases in CD4 T-cell number compared to RTI therapy alone with equivalent antiviral effect. These data suggest that PIs influence CD4 T-cell number through a nonvirologic effect.

Anti-HIV Agents↗