Genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP; SLC10A1) and ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2), which greatly contribute to bile acid homeostasis, were extensively explored in the Korean population and functional variants of NTCP were compared among Asian populations. From direct DNA sequencing, six SNPs were identified in the SLC10A1 gene and 14 SNPs in the SLC10A2 gene. Three of seven coding variants were non-synonymous SNPs: two variants from SLC10A1 (A64T, S267F) and one from SLC10A2 (A171S). No linkage was analysed in the SLC10A1 gene because of low frequencies of genetic variants, and the SLC10A2 gene was composed of two separated linkage disequilibrium blocks contrary to the white population. The stably transfected NTCP-A64T variant showed significantly decreased uptakes of taurocholate and rosuvastatin compared with wild-type NTCP. The decreased taurocholate uptake and increased rosuvastatin uptake were shown in the NTCP-S267F variant. The allele frequencies of these functional variants were 1.0% and 3.1%, respectively, in a Korean population. However, NTCP-A64T was not found in Chinese and Vietnamese subjects. The frequency distribution of NTCP-S267F in Koreans was significantly lower than those in Chinese and Vietnamese populations. Our data suggest that NTCP-A64T and -S267F variants cause substrate-dependent functional change in vitro, and show ethnic difference in their allelic frequencies among Asian populations although the clinical relevance of these variants is remained to be evaluated.

Why metalloenzymes often show dramatic changes in their catalytic activity when subjected to chemically similar but non-native metal substitutions is a long-standing puzzle. Here, we report on the catalytic roles of metal ions in a model metalloenzyme system, human carbonic anhydrase II (CA II). Through a comparative study on the intermediate states of the zinc-bound native CA II and non-native metal-substituted CA IIs, we demonstrate that the characteristic metal ion coordination geometries (tetrahedral for Zn2+, tetrahedral to octahedral conversion for Co2+, octahedral for Ni2+, and trigonal bipyramidal for Cu2+) directly modulate the catalytic efficacy. In addition, we reveal that the metal ions have a long-range (~10 Å) electrostatic effect on restructuring water network in the active site. Our study provides evidence that the metal ions in metalloenzymes have a crucial impact on the catalytic mechanism beyond their primary chemical properties.

This study investigates how the balance between wind and mass is treated in data assimilation, and how it affects the quality of the model states in an analysis–forecast cycle. This is done in terms of the dependence of balance on latitude and on the type of variable. The impact of the nonlinear balance equation is compared with regressed wind–mass balance in the 3‐Dimensional Variational data assimilation (3D‐Var) system of the Korea Institute of Atmospheric Prediction Systems (KIAPS). Its impact is significantly positive in temperature rather than in wind, despite the two‐way influence of the cross‐correlation between wind and mass, in terms of the root‐mean‐square difference (RMSD) of 6 h forecasts against the ERA‐Interim reanalysis data. This temperature effect is observed in the southern hemispheric (SH) polar jet of the mid‐troposphere, the SH midlatitudinal jet, and the mid/lower stratosphere in the Tropics, where there is strong zonal mean flow. Although the zonal wind forecast was harmed by application of the nonlinear balance, the temporal consistency of the damage is relatively weak compared to the improvement by the nonlinear balance in the temperature forecasts. In the SH midlatitudinal jet and the mid/lower stratosphere in the Tropics, the nonlinear balance equation, including the advection term, improves the quality of temperature RMSDs in the analysis–forecast cycle by imposing the proper balance in the initial conditions. However, in the SH polar jet of the mid‐troposphere, where the observation density is relatively low, the nonlinear balance equation achieves the same effect by reducing the analysis error (i.e. generating initial conditions more accurately). The nonlinear balance equation contributes to robustly improving the model states of the analysis–forecast cycles, depending on the dynamical activity and the observation density of the corresponding regions.

No abstract

High field magnetic resonance imaging (MRI)-based delineation of the substantia nigra (SN)and visualization of its inner cellular organization are promising methods for the evaluation of morphological changes associated with neurodegenerative diseases; however, corresponding MR contrasts must be matched and validated with quantitative histological information. Slices from two postmortem SN samples were imaged with a 7 Tesla (7T) MRI with T 1 and T 2 * imaging protocols and then stained with Perl's Prussian blue, Kluver-Barrera, tyrosine hydroxylase, and calbindin immunohistochemistry in a serial manner. The association between T 2 * values and quantitative histology was investigated with a co-registration method that accounts for histology slice preparation. The ventral T 2 * hypointense layers between the SNr and the crus cerebri extended anteriorly to the posterior part of the crus cerebri, which demonstrates the difficulty with an MRI-based delineation of the SN. We found that the paramagnetic hypointense areas within the dorsolateral SN corresponded to clusters of neuromelanin (NM). These NM-rich zones were distinct from the hypointense ventromedial regions with high iron pigments. Nigral T 2 * imaging at 7T can reflect the density of NM-containing neurons as the metal-bound NM macromolecules may decrease T 2 * values and cause hypointense signalling in T 2 * imaging at 7T.Identifying and characterizing the anatomic architecture of the substantia nigra (SN) has important clinical implications for the evaluation of structural changes associated with neurodegenerative conditions, such as Parkinson's disease (PD) [1][2][3] . The SN is subdivided into two histologically distinct regions, the ventral pars reticulata (SNr) and the dorsal pars compacta (SNc). The SNc is composed of neuromelanin (NM)-containing dopaminergic neurons, which are affected early in PD [1][2][3] . Numerous attempts have been made to visualize substructure morphology of the SN and to assess the neurodegenerative changes using various magnetic resonance imaging (MRI) signal contrasts 2,3 . For example, iron-sensitive MR sequences have great potential to define the boundaries and shape of the SN 2-4 as the local deposition of iron alters magnetic field inhomogeneities and appears hypointense in T 2 or T 2 * -weighted images (T 2 *WI) due to the shortening of transverse relaxation times 2,5 . By taking advantage of region-specific iron content within the SN, the area of lower T 2 * -weighted signal intensity is assigned to the SNr based on the histological observation of elevated iron concentration in that region 3,5,6 . NM-sensitive T 1 -weighted fast spin echo technique in in vivo 3T MRI studies allows the visualization of the SNc via hyperintense areas 2,3,[7][8][9] . NM within the dopaminergic neurons is speculated to generate paramagnetic T 1 -shortening effects on combining with metals, such as iron and copper 2,3,7,10 . While NM-containing dopaminergic neurons are densely distributed in the SNc, they form clusters of cells that penetra...