Interaction analyses of hTAAR1 and mTAAR1 with antagonist EPPTB.

Trace amine-associated receptor 1 (TAAR1) plays a critical role in regulating monoaminergic activity. EPPTB is the only known selective potent antagonist of the mouse (m) TAAR1 presently, while it was shown to be weak at antagonizing human (h) TAAR1. The lack of high-resolution structure of TAAR1 hinders the understanding of the differences in the interaction modes between EPPTB and m/hTARR1. The purpose of this study is to probe these interaction modes using homology modeling, molecular docking, molecular dynamics (MD) simulations, and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. Eight populated conformers of hTAAR1-EPPTB complex were observed during the MD simulations and could be used in structure-based virtual screening in future. The MM-GBSA binding energy of hTAAR1-EPPTB complex (-96.5 kcal/mol) is larger than that of mTAAR1-EPPTB complex (-106.7 kcal/mol), which is consistent with the experimental finding that EPPTB has weaker binding affinity to hTAAR1. The several residues in binding site of hTAAR1 (F1544.56, T1945.42 and I2907.39) are different from these of mTAAR1 (Y1534.56, A1935.42 and Y2877.39), which might contribute to the binding affinity difference. Our docking analysis on another hTAAR1 antagonist Compound 3 has found that: 1). this compound binds in different pockets of our mTAAR1 and hTAAR1 homology models with a slightly stronger binding affinity to hTAAR1; 2). both antagonists bind to a very similar pocket of hTAAR1.

A patient with an acute confusional state.

A 49-year-old male presented in an acutely confused state. His examination and basic blood tests were unremarkable. He was started on intravenous aciclovir and an MRI brain scan showed changes consistent with limbic encephalitis. Serum antibodies including para-neoplastic auto-antibodies and cerebrospinal fluid studies were arranged along with a full body CT scan to look for malignancy. All antibody tests returned negative and the CT scan ruled out the presence of malignancy. The patient improved following treatment with intravenous immunoglobulin and was discharged. Follow-up imaging showed significant radiological improvement. He has been able to return to work and repeat CT scans have failed to find evidence of malignancy. A rare and treatable cause for his illness was found. It is worth considering limbic encephalitis when facing a confused patient especially in the young and middle-aged population.

Iron overload in the Asian community.

Hereditary hemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes. Type 1 hemochromatosis is the most common form of the disease and results from mutations in the HFE gene. Juvenile hemochromatosis (JH) is the most severe form, usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP). The autosomal dominant form of the disease, type 4, is due to mutations in the SLC40A1 gene, which encodes for ferroportin (FPN). Hereditary hemochromatosis is commonly found in populations of European origin. By contrast, hemochromatosis in Asia is rare and less well understood and can be masked by the presence of iron deficiency and secondary iron overload from thalassemia. Here, we provide a comprehensive report of hemochromatosis in a group of patients of Asian origin. We have identified novel mutations in HJV, HAMP, and SLC40A1 in countries not normally associated with hereditary hemochromatosis (Pakistan, Bangladesh, Sri Lanka, and Thailand). Our family studies show a high degree of consanguinity, highlighting the increased risk of iron overload in many countries of the developing world and in countries in which there are large immigrant populations from these regions.