The atomic-level structure of a representative ternary Cu-Zr-Al bulk metallic glass (BMG) has been resolved. Cu- (and Al-) centered icosahedral clusters are identified as the basic local structural motifs. Compared with the Cu-Zr base binary, a small percentage of Al in the ternary BMG leads to dramatically increased population of full icosahedra and their spatial connectivity. The stabilizing effect of Al is not merely topological, but also has its origin in the electronic interactions and bond shortening.

In the present study, an open-label, three-treatment, threeperiod clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 6 0.21 and 0.15 6 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (C max ) of CP-I and CP-III by 5.7-and 5.4-fold (RIF) or 5.7-and 6.5-fold (RIF1RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC 0-24h ) of CP-I and CP-III with RIF and RSV increased by 4.0-and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, C max and AUC 0-24h of RSV increased by 13.2-and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies.

This white paper addresses current approaches and knowledge gaps concerning methods to assess the role of transport proteins in drug/metabolite disposition in humans. The discussion focuses on in vitro tools to address key questions in drug development, including vesicle-and cell-based systems. How these methods can be used to assess the liability of compounds for transporter-based drug-drug interactions (DDIs) in vivo is also explored. Existing challenges and approaches to examine the involvement of transporters in drug disposition are discussed. This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG is providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6-and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7-and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6-to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b 2/2 ), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1-to 18.4-fold; P , 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.

Solids in nature can be generally classified into crystalline and non-crystalline states [1][2][3][4][5][6][7] , depending on whether long-range lattice periodicity is present in the material. The differentiation of the two states, however, could face fundamental challenges if the degree of long-range order in crystals is significantly reduced. Here we report a unique paracrystalline state of diamond that is distinct from either crystalline or amorphous diamond [8][9][10] . The paracrystalline diamond reported in this work, consisting of sub-nanometersized paracrystals that possess a well-defined crystalline medium-range order up to a few atomic shells 4,5,[11][12][13][14] , was synthesized in high-pressure high-temperature conditions (e.g., 30 GPa, 1600 K) employing fcc-C 60 as a precursor. The structural characteristics of paracrystalline diamond was identified through a combination of X-ray diffraction, highresolution transmission microscopy, and advanced molecular dynamics simulation. The formation of paracrystalline diamond is a result of densely distributed nucleation sites developed in compressed C 60 as well as pronounced second-nearest-neighbor short-range order in amorphous diamond due to strong sp 3 bonding. The discovery of paracrystalline diamond adds a new diamond form to the enriched carbon family 15-17 , which exhibits distinguishing physical properties and can be furthered exploited to develop new materials. Furthermore, this work reveals the missing link in the length-scale between amorphous and crystalline states across the structural landscape, which has profound implications for recognizing complex structures arising from amorphous materials.Amorphous solids refer to materials that do not possess long-range periodicity as exhibited in crystals [1][2][3][4][5][6][7][8][9][10][11] . Consequently, Bragg peaks associated with crystalline arrangements of atoms are absent or obscured in the diffraction signals of amorphous materials, which renders the recognition of their structural organizations notoriously difficult. Due to decades of research effort, it is now understood that structural ordering on the atomic level of amorphous solids is ubiquitous, as manifested by the short-to-medium-range ordering in metallic glasses [5][6][7] and the continuousrandom networks (CRN) of amorphous semiconductors 1-3 . Moving from the short range into the extended length-scale abutting the long-range scale, however, our understanding of the structural arrangements remains much more limited, and it is often complicated by capricious crystalline structural ordering encountered in amorphous materials 14,[18][19][20] . In an attempt to resolve this structural enigma, a paracrystalline structure model was proposed 11,20 , in which nanosized paracrystals, defined as severely distorted crystals, were introduced to the amorphous matrix to account for the crystalline medium range order (MRO). A crucial question to answer is, in the configurational space, are we able to identify a state of matter that is fully packed with...