Prevalence of hepatitis B virus DNA in anti-HBc-positive/HBsAg-negative sera correlates with HCV but not HIV serostatus.

BACKGROUND: Hepatitis B virus (HBV) DNA often remains detectable in serum despite clinical recovery and loss of HBsAg. OBJECTIVE: To study whether coinfection with HIV and HCV influence the chance of detecting HBV DNA in sera with markers of past hepatitis B. STUDY DESIGN AND RESULTS: The test panel included 160 anti-HBc-positive/HBsAg-negative sera collected in the diagnostic setting. The following parameters were determined in the sera: anti-HIV (32% positive), anti-HCV (34% positive), HCV RNA (18% positive), and anti-HBs (37% positive). A highly sensitive PCR (90%-detection limit 100 copies/ml) amplifying the terminal protein (TP) region of HBV was established and HBV DNA was detected in 12.5% of the samples. In 70% of these samples, the HBV DNA concentration was below 500 copies/ml as measured by real-time PCR in the S gene. Logistic regression analysis revealed that the chance of detecting HBV DNA was increased by a positive HCV serostatus (odds ratio 5.0, 95%-CI 1.6-15.7), whereas HIV coinfection (odds ratio 2.0, 95%-CI 0.7-5.8), anti-HBs (odds ratio 0.9, 95%-CI 0.3-2.6), and HCV RNA status (odds ratio 0.4, 95%-CI 0.1-1.7) had no statistically significant influence. In contrast, the chance of detecting HCV RNA in the subgroup of anti-HCV-positive sera was increased by HIV coinfection (odds ratio 4.5, 95%-CI 1.2-17.4). Sequencing of the TP PCR products revealed neither a specific phylogenetic origin of the circulating HBV DNA nor clustering of uncommon mutations in the TP region. CONCLUSIONS: The prevalence of HBV DNA in serum of anti-HBc-positive/HBsAg-negative subjects correlates with HCV rather than HIV serostatus.     

Predicting protein complex membership using probabilistic network reliability

Evidence for specific protein-protein interactions is increasingly available from both small- and large-scale studies, and can be viewed as a network. It has previously been noted that errors are frequent among large-scale studies, and that error frequency depends on the large-scale method used. Despite knowledge of the error-prone nature of interaction evidence, edges (connections) in this network are typically viewed as either present or absent. However, use of a probabilistic network that considers quantity and quality of supporting evidence should improve inference derived from protein networks. Here we demonstrate inference of membership in a partially known protein complex by using a probabilistic network model and an algorithm previously used to evaluate reliability in communication networks.     

Functional interaction between the N- and C-terminal domains of murine leukemia virus surface envelope protein

A series of murine leukemia viruses (MuLVs) with chimeric envelope proteins (Env) was generated to map functional interactions between the N- and the C-terminal domains of surface proteins (SU). All these chimeras have the 4070A amphotropic receptor-binding region flanked by various lengths of Moloney ecotropic N- and C-terminal Env. A charged residue, E49 (E16 on the mature protein), was identified at the N-terminals of Moloney MuLV SU that is important for the interaction with the C-terminal domain of the SU. The region that interacts with E49 was localized between junction 4 (R265 of M-MuLV Env) and junction 6 (L374 of M-MuLV Env) of SU. Sequencing the viable chimeric Env virus populations identified residues within the SU protein that improved the replication kinetics of the input chimeric Env viruses. Mutations in the C-domain of SU (G387E/R, L435I, L442P) were found to improve chimera IV4, which displayed a delayed onset of replication. The replication of AE6, containing a chimeric junction in the SU C-terminus, was improved by mutations in the N-domain (N40H, E80K), the proline-rich region (Q252R), or the transmembrane protein (L538N). Altogether, these observations provide insights into the structural elements required for Env function.     

The PDZ-binding domain is essential for the dendritic targeting of 5-HT2A serotonin receptors in cortical pyramidal neurons in vitro

The 5-HT(2A) serotonin receptor represents an important molecular target for atypical antipsychotic drugs and for most hallucinogens. In the mammalian cerebral cortex, 5-HT(2A) receptors are enriched in pyramidal neurons, within which 5-HT(2A) receptors are preferentially sorted to the apical dendrites. In primary cortical cultures, 5-HT(2A) receptors are sorted to dendrites and not found in the axons of pyramidal neurons. We identified a sorting motif that mediates the preferential targeting of 5-HT(2A) receptors to the dendrites of cortical pyramidal neurons in vitro. We constructed green fluorescent protein-tagged 5-HT(2A) receptors wherein potential sorting motifs were disrupted, and subsequently employed either the Semliki Forest virus or calcium phosphate for the transient expression of recombinant 5-HT(2A) receptors in cultured cortical pyramidal neurons. Using dual-labeling immunofluorescent confocal microscopy, we quantified the axonal and dendritic sorting patterns of endogenous and recombinant 5-HT(2A) receptors. We discovered that disruption of the PDZ-binding domain of the 5-HT(2A) receptor greatly attenuates the dendritic targeting of 5-HT(2A) receptors without inappropriately sorting 5-HT(2A) receptors to axons. The PDZ-binding domain is therefore a necessary signal for the preferential targeting of the 5-HT(2A) receptor to the dendritic compartment of cultured cortical pyramidal neurons, the first such role ascribed to this protein-protein interaction motif of any G protein-coupled receptor.     

Vitamin D receptor FokI genotype influences bone mineral density response to strength training, but not aerobic training

To determine the influence of the vitamin D receptor (VDR) gene FokI and BsmI genotype on bone mineral density response to two exercise training modalities, 206 healthy men and women (50-81 years old) were studied before and after approximately 5-6 months of either aerobic exercise training (AT) or strength training (ST). A totla of 123 subjects completed AT (51 men, 72 women) and 83 subjects completed ST (40 men, 43 women). DNA was extracted from blood samples of all subjects and genotyping was performed at the VDR FokI and BsmI locus to determine its association to training response. Total body, greater trochanter and femoral neck bone mineral density (BMD) were measured before and after both training programmes using dual-energy X-ray absorptiometry. VDR BsmI genotype was not significantly related to BMD at baseline or after ST or AT. However, VDR FokI genotype was significantly related to ST- but not AT-induced changes in femoral neck BMD (P < 0.05). The heterozygotes (Ff) in the ST group approached a significantly greater increase in femoral neck BMD (P = 0.058) compared to f homozygotes. There were no significant genotype relationships in the AT group. These data indicate that VDR FokI genotype may influence femoral neck BMD response to ST, but not AT.     

Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

Background  

Cytokine production is critical in ischemia/reperfusion (IR) injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury.     

Tacrolimus and Mycophenolate Mofetil Regimens in Transplantation

Immunosuppression, although necessary to enable the graft to escape the consequences of immune surveillance, carries some risks for the patient. There is an associated increase in neoplasms, opportunistic infections and end-organ toxicity. In addition, even with excellent patient compliance, rejection (acute and chronic) remains a major limitation that contributes to the loss or decrease in the function of the allograft. New drugs have been added to the armamentarium of immunosuppressive agents to suppress allograft rejection and to rescue grafts from cyclosporin-resistant rejection. With the availability of these immunosuppressive agents, it has become increasingly difficult to choose the appropriate combination of immunosuppressants with a beneficial effect for the patient and for the allograft. We describe 2 new immunosuppressive agents and some of their different uses in solid organ transplantation.     

The honeybee syndrome - implications of the teratogenicity of mannose in rat-embryo culture

Lethal effects of D-mannose in the honeybee have been recognized for more than a half a century. We observed another toxic effect of D- mannose during culture of rat embryos from the early head-fold stage to the 26-to-29-somite stage (Days 9-1/2 through 11-1 of gestation). The addition to culture mediums of 1.5 mg of D-mannose per milliliter caused growth retardation and faulty neural-tube closure in approximately two thirds of the embryos. Mannose effects occurred during the first 24 hours of culture and were attended by modes inhibition of the glycolysis that constitutes the principal energy pathway at this stage of development. Adding more glucose to preserve glycolytic flux or increasing atmospheric oxygen to promote oxidative metabolism offset the mannose teratogenesis. Our findings highlight the metabolic vulnerabilities that exist during early organogenesis, before oxidative flexibility is established. They may serve as a model to explain the teratogenicity of many other seemingly unrelated agents that could act by perturbing glycolysis at this vulnerable stage.