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The data suggest that race, sex, and environmental factors are identifiable sources of interindividual variation in the oral clearance of nifedipine, a CYP3A substrate. Our experience also suggests that data from clinical populations may be biased with regard to age, sex, and formulation selection, and covariates may not be independently distributed, which can limit analyses.

During the process of B cell development, transcription factors, such as E2A and Ebf1, have been known to play key roles. Although transcription factors and chromatin regulators work in concert to direct the expression of B lineage-specific genes, little is known about the involvement of regulators for chromatin structure during B lymphopoiesis. In this article, we show that deletion of Srg3/mBaf155, a scaffold subunit of the SWI/SNF-like BAF complex, in the hematopoietic lineage caused defects at both the common lymphoid progenitor stage and the transition from pre–pro-B to early pro-B cells due to failures in the expression of B lineage-specific genes, such as Ebf1 and Il7ra, and their downstream target genes. Moreover, mice that were deficient in the expression of Brg1, a subunit of the complex with ATPase activity, also showed defects in early B cell development. We also found that the expression of Ebf1 and Il7ra is directly regulated by the SWI/SNF-like BAF complex. Thus, our results suggest that the SWI/SNF-like BAF complex facilitates early B cell development by regulating the expression of B lineage-specific genes.

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Key pointsr Cellular stimuli can modulate the ion selectivity of some anion channels, such as CFTR, ANO1 and the glycine receptor (GlyR), by changing pore size.r Ion selectivity of CFTR, ANO1 and GlyR is critically affected by the electric permittivity and diameter of the channel pore.r Pore size change affects the energy barriers of ion dehydration as well as that of size-exclusion of anion permeation.r Pore dilatation increases the bicarbonate permeability (P HCO 3 /Cl ) of CFTR, ANO1 and GlyR. r Dynamic change in P HCO 3 /Cl may mediate many physiological and pathological processes.Abstract Chloride (Cl − ) and bicarbonate (HCO 3 − ) are two major anions and their permeation through anion channels plays essential roles in our body. However, the mechanism of ion selection by the anion channels is largely unknown. Here, we provide evidence that pore dilatation increases the bicarbonate permeability (P HCO 3 /Cl ) of anion channels by reducing energy barriers of size-exclusion and ion dehydration of HCO 3 − permeation. Molecular, physiological and computational analyses of major anion channels, such as cystic fibrosis transmembrane conductance regulator (CFTR), anoctamin-1(ANO1/TMEM16A) and the glycine receptor (GlyR), revealed that the ion selectivity of anion channels is basically determined by the electric permittivity and diameter of the pore. Importantly, cellular stimuli dynamically modulate the anion selectivity of CFTR and ANO1 by changing the pore size. In addition, pore dilatation by a mutation in the pore-lining region alters the anion selectivity of GlyR. Changes in pore size affected not only the energy barriers of size exclusion but that of ion dehydration by altering the electric permittivity of water-filled cavity in the pore. The dynamic increase in P HCO 3 /Cl by pore dilatation may have many physiological and pathophysiological implications ranging from epithelial HCO 3 − secretion to neuronal excitation.I. Jun, M. Cheng and E. Sim contributed equally to this work.

What is already known about this subject • It was found that the genetic polymorphisms of CYP3A5, CYP3A4 and MDR1 could affect the pharmacokinetics of tacrolimus. • This study was conducted to find such a possibility in the Korean population. What this study adds • CYP3A5 polymorphisms are likely to be associated with altered pharmacokinetics of tacrolimus in Koreans. • MDR1 polymorphisms have no important role in the pharmacokinetics of tacrolimus. Aims To determine the frequencies of the genotypes of CYP3A5 and MDR1 and to examine the influence of the polymorphisms of these genes on tacrolimus pharmacokinetics in the Korean population. Methods Twenty‐nine healthy Koreans who participated in the previous tacrolimus pharmacokinetic study were genotyped for CYP3A4*1B, CYP3A5*3, MDR1 c.1236C→T, MDR1 c.2677G→A/T and MDR1 c.3435C→T. The relationship between the genotypes so obtained and tacrolimus pharmacokinetics observed in the previous study was examined. Results No subject in this study had the CYP3A4*1B variant. The observed frequencies of CYP3A5*1/*1, *1/*3, and *3/*3 were 0.069 [confidence interval (CI) −0.023, 0.161], 0.483 (CI 0.301, 0.665) and 0.448 (CI 0.267, 0.629), respectively. AUC0–∞ for the CYP3A5*1/*1 or *1/*3 genotype was 131.5 ± 44.8 ng h ml−1 (CI 109.6, 153.5), which was much lower compared with the CYP3A5*3/*3 genotype of 323.8 ± 129.3 ng h ml−1 (CI 253.5, 394.1) (P = 2.063E−07). Similarly, Cmax for the CYP3A5*1/*1 or *1/*3 genotype was 11.8 ± 3.4 ng ml−1 (CI 10.1, 13.5), which was also much lower compared with the CYP3A5*3/*3 genotype of 24.4 ± 12.3 ng ml−1 (CI 17.8, 31.1) (P = 0.0001). However, there was no significant difference in tacrolimus pharmacokinetics among the MDR1 diplotypes of CGC‐CGC, CGC‐TTT, CGC‐TGC, TTT‐TGC or TTT‐TTT (P = 0.2486). Conclusions This study shows that the CYP3A5*3 genetic polymorphisms may be associated with the individual difference in tacrolimus pharmacokinetics. An individualized dosage regimen design incorporating such genetic information would help increase clinical efficacy of the drug while reducing adverse drug reactions.

In this paper, we report two metal-organic frameworks [Co3(ndc)3(bipyen)(1.5)]H2O (1) and [Co2(ndc)2bipyen)]C6H6.H2O (2) (bipyen=trans-1,2-bis(4-pyridyl)ethylene, H2ndc=2,6-naphthalenedicarboxylic acid). These compounds were both synthesized from identical hydrothermal reaction conditions except that benzene was added to the reaction for 2. Crystal structures show that the two compounds have triply interpenetrated three-dimensional frameworks and these frameworks have the same primary structure of a two-dimensional network of interconnected [Co2(O2CR)(4/2)] (R=naphthalene group) paddle-wheels and bridging bipyen ligands. Both compounds have guest water molecules and, in addition, 2 has guest benzene molecules. Structural transformations of the host accompanied guest removal, which can be monitored by powder X-ray diffraction. N2 adsorption data of 2 show that there are two different types of pores corresponding to the benzene and water pores. Upon exposure to vapors of several organic molecules, the heat-treated sample of 2 adsorbs benzene and cyclohexene, but does not adsorb toluene, (o-, m-, and p-)xylenes, cycloheptatriene, or cyclohexane.

MicroRNAs (miRNAs) have emerged as important regulators of the immune system. However, despite this prominence, our understanding of the function of miRNAs in the early hematopoietic stages is incomplete. In this study, we found that miR-139-5p negatively regulated the proliferation of hematopoietic stem cells and progenitor cells and that downregulation of miR-139-5p expression was associated with hematopoietic malignancy, such as chronic myeloid leukemia (CML). Knockdown of miR-139-5p resulted in myeloid-biased differentiation with expansion of myeloid progenitor cells. In contrast, miR-139-5p expression inhibited the proliferation of hematopoietic progenitors and resulted in the remission of a CML-like disease that is induced by breakpoint cluster region-Abelson (BCR-ABL) transformation. We also found that Brg1 is a functional target of miR-139-5p and that Brg1 is involved in BCR-ABL-induced leukemogenesis. Thus, our results identify miR-139-5p as a key regulator of cellular proliferation during early hematopoiesis and suggest that it is a potent antileukemic molecule.