Biomedical subjects

J R Braun

Publications and source records attributed to J R Braun.

At least 19 recordsLinked to original sources

PubMed1996

The major subunit of the asialoglycoprotein receptor is expressed on the hepatocellular surface in mice lacking the minor receptor subunit.

The mammalian asialoglycoprotein receptor (ASGPR) is located on the sinusoidal membrane of hepatocytes where it binds and endocytoses galactose-terminated glycoproteins (asialoglycoproteins). ASGPR is composed of two highly homologous subunits, termed hepatic lectin 1 and 2. Despite numerous studies the contribution of both subunits to biosynthesis and functional activity of ASGPR in vivo has remained controversial. Mice lacking the murine hepatic lectin (MHL)-2 subunit are viable and fertile without obvious phenotypic abnormalities. In the absence of MHL-2, knockout mice express MHL-1 protein at reduced levels. Here, we examine the intracellular fate and function of this remaining subunit. The results show that MHL-1 reaches the hepatocellular surface in knockout mice but is unable to effectively remove any one of three different radiolabeled ligands within 30 min. A small but detectable residual ligand clearance in knockout mice at 4 h is apparently not mediated by remaining MHL-1. Serum concentrations of galactose-terminating glycoproteins are not elevated in these ASGPR-deficient mice. However, competitive in vitro degradation experiments suggest that other endogenous ASGPR ligands, the nature of which remain to be determined, accumulate in serum of knockout animals.

Animals↗

PubMed1996

RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors.

The multifunctional low density lipoprotein (LDL) receptor-related protein (LRP) forms a complex with a receptor-associated protein (RAP) within the secretory pathway. RAP inhibits ligand binding to LRP and is required for normal functional expression of LRP in vivo, suggesting a physiological function as a specialized chaperone. We have used RAP-deficient mice, generated by gene targeting, to investigate the role of RAP in the biosynthesis and biological activity of LRP and other members of the LDL receptor gene family in various organs and in embryonic fibroblasts. Our results demonstrate that RAP is required for the proper folding and export of the receptors from the endoplasmic reticulum (ER) by preventing the premature binding of co-expressed ligands. Overexpression of apolipoprotein E (apoE), a high affinity ligand for LRP, results in dramatically reduced cellular LRP expression, an effect that is prevented by co-expression of RAP. RAP thus defines a novel class of molecular chaperones that selectively protect endocytic receptors by binding to newly synthesized receptor polypeptides, thereby preventing ligand-induced aggregation and subsequent degradation in the ER.

Animals↗

PubMed1995

[Application of genetic principles to the causal assessment of atherosclerosis].

The pathophysiological mechanisms responsible for the development of atherosclerosis are complex and influenced by numerous genetic factors [polygenic] as well as environmental factors. Specific disorders caused by single gene mutations [monogenic] may considerably enhance the risk for atherosclerosis. In such cases, other genes or environmental factors are often secondary importance. A detailed family history including a pedigree analysis may lead to the correct diagnosis; molecular genetic methods can confirm the clinical diagnosis. The association between a particular gene [candidate gene] and a disorder characterized by an increased risk for atherosclerosis can be verified indirectly by linkage analysis or directly by the detection of the gene mutation causing the disorder. Both approaches are based on the fact that a polymorphism used as a marker for a gene locus or a mutation responsible for a particular disorder may destroy or create a restriction site [restriction fragment length polymorphism, RFLP] or may modify the electrophoretic mobility of a fragment amplified by the polymerase chain reaction [PCR]. The latter property is the basis of the single-strand conformation polymorphism [SSCP] technique, followed by sequencing for the exact localization of the polymorphism or the mutation. Using these methods, other family members carrying the underlying gene defect can be identified and treated before the manifestation of their atherosclerotic lesions.

Animals↗

PubMed1990

Consistency of seizure frequency estimates across time, methods, and observers.

Assessed the consistency of seizure frequency reports across observers, time, and methods. Thirty-two persons with intractable, partial seizures and 17 observers participated in a two-phase assessment procedure. During the first phase, subjects and observers provided retrospective seizure frequency estimates for two consecutive 30-day intervals. During the second phase, subjects and observers completed a daily seizure diary for 30 days. Patients' and observers' retrospective estimates were highly stable over a 2-month period. Substantial consistency was also found between two different recording methods (recall vs. diary) for subjects with epilepsy. In contrast, the observers' retrospective estimates were only moderately correlated with their prospective diary counts. Agreement between subjects' and observers' retrospective reports was also high. However, no significant association was found between their diary counts. Contrary to expectation, seizure frequency reports of patients with partial epilepsy showed moderately high consistency across time and between patient and observer pairs.

Adult↗

PubMed1973