Evaluation of 14 PFAS for permeability and organic anion transporter interactions: Implications for renal clearance in humans.

Per- and polyfluoroalkyl substances (PFAS) encompass a diverse group of synthetic fluorinated chemicals known to elicit adverse health effects in animals and humans. However, only a few studies investigated the mechanisms underlying clearance of PFAS. Herein, the relevance of human renal transporters and permeability to clearance and bioaccumulation for 14 PFAS containing three to eleven perfluorinated carbon atoms (ηpfc = 3-11) and several functional head-groups was investigated. Apparent permeabilities and interactions with human transporters were measured using in vitro cell-based assays, including the MDCK-LE cell line, and HEK293 stable transfected cell lines expressing organic anion transporter (OAT) 1-4 and organic cation transporter (OCT) 2. The results generated align with the Extended Clearance Classification System (ECCS), affirming that permeability, molecular weight, and ionization serve as robust predictors of clearance and renal transporter engagement. Notably, PFAS with low permeability (ECCS 3A and 3B) exhibited substantial substrate activity for OAT1 and OAT3, indicative of active renal secretion. Furthermore, we highlight the potential contribution of OAT4-mediated reabsorption to the renal clearance of PFAS with short ηpfc, such as perfluorohexane sulfonate (PFHxS). Our data advance our mechanistic understanding of renal clearance of PFAS in humans, provide useful input parameters for toxicokinetic models, and have broad implications for toxicological evaluation and regulatory considerations.

Species-Specific Unbound Fraction Differences in Highly Bound PFAS: A Comparative Study across Human, Rat, and Mouse Plasma and Albumin.

Per- and polyfluoroalkyl substances (PFAS) are a diverse group of fluorinated compounds which have yet to undergo comprehensive investigation regarding potential adverse health effects and bioaccumulative properties. With long half-lives and accumulative properties, PFAS have been linked to several toxic effects in both non-clinical species such as rat and mouse as well as human. Although biological impacts and specific protein binding of PFAS have been examined, there is no study focusing on the species-specific fraction unbound (fu) in plasma and related toxicokinetics. Herein, a presaturation equilibrium dialysis method was used to measure and validate the binding of 14 individual PFAS with carbon chains containing 4 to 12 perfluorinated carbon atoms and several functional head-groups to albumin and plasma of mouse (C57BL/6 and CD-1), rat, and human. Equivalence testing between each species-matrix combination showed positive correlation between rat and human when comparing fu in plasma and binding to albumin. Similar trends in binding were also observed for mouse plasma and albumin. Relatively high Spearman correlations for all combinations indicate high concordance of PFAS binding regardless of matrix. Physiochemical properties of PFAS such as molecular weight, chain length, and lipophilicity were found to have important roles in plasma protein binding of PFAS.

Low molecular weight acids and OATP1B mediated hepatic clearance: In vitro and in vivo evaluation using novel hypoxia-inducible factor prolyl hydroxylase inhibitors (Dustats).

Organic anion transporting polypeptide (OATP1B) plays a key role in the hepatic clearance of a majority of high molecular weight (MW) acids and zwitterions. Here, we evaluated the role of OATP1B-mediated uptake in the clearance of novel hypoxia-inducible factor prolyl hydroxylase inhibitors ("Dustats"), which are typically low MW (300-400 daltons) aliphatic carboxylic acids. Five acid dustats, namely daprodustat, desidustat, enarodustat, roxadustat and vadadustat, showed specific transport by OATP1B1/1B3 in transporter-transfected HEK293 cells. Neutral compound, molidustat, was not a substrate to OATP1B1/1B3. None of the dustats showed transport by other hepatic uptake transporters, including NTCP, OAT2 and OAT7. In the primary human hepatocytes, uptake of all acids was significantly reduced by rifampin (OATP1B inhibitor); with an estimated fraction transported by OATP1B (ft ,OATP1B) of up to >80% (daprodustat). Molidustat uptake was minimally inhibited by rifampin; and low permeability acids (desidustat and enarodustat) also showed biliary efflux in sandwich culture human hepatocytes. In vivo, intravenous pharmacokinetics of all 5 acids was significantly altered by a single-dose rifampin (30 mg/kg) in Cynomolgus monkey. Hepatic clearance (non-renal) was about 4-fold (vadadustat) to >11-fod (daprodustat and roxadustat) higher in control group compared to rifampin-treated subjects. In vivo ft ,OATP1B was estimated to be ~70-90%. In the case of molidustat, rifampin had a minimal effect on overall clearance. Rifampin also considerably reduced volume of distribution of daprodustat and roxadustat. Overall, OATP1B significantly contribute to the hepatic clearance and pharmacokinetics of several dustats, which are low MW carboxylic acids. OATP1B activity should therefore by evaluated in this property space. Significance Statement Our in vitro and in vivo results suggest that OATP1B-mediated hepatic uptake play a significant role in the pharmacokinetics of low MW acidic dustats, which are being developed or approved for the treatment of anemia in chronic kidney disease. Significant active uptake mechanisms are not apparent for the neutral compound, molidustat. Characterization of uptake mechanisms is therefore important in predicting human pharmacokinetics and evaluating drug-drug interactions for low MW acids.

E-prescription: views and acceptance of general practitioners and pharmacists in Greater Sydney.

BACKGROUND: Electronic prescription (e-prescription) was introduced in 2020 in Australia during the COVID-19 pandemic. This research aimed to explore general practitioners (GPs) and community pharmacists' experience with, and facilitators and barriers to, the use of e-prescription. METHODS: This qualitative study used semi-structured interviews with GPs and pharmacists in Greater Sydney to explore their experience with e-prescription. Thematic analysis used descriptive and mixed inductive and deductive approaches. The Technology Acceptance Model (TAM) was used to further interpret and organise the themes. RESULTS: Eleven GPs and nine pharmacists were interviewed. Thirteen themes were elicited, seven of which were categorised as benefits (facilitators) and six were challenges (barriers). Four facilitator themes (convenience for healthcare providers (HCPs) and patients, addressing issues with paper prescriptions, contactless nature reducing access barriers during COVID-19 lockdown, and enabling patients to manage multiple prescriptions) were mapped to the TAM construct of 'perceived usefulness'; and one facilitator (an easier process) and two barrier themes (lack of information during implementation, and technological issues) were mapped to the TAM construct of 'perceived ease of use'. Themes that fell outside these constructs were separately categorised: four barrier themes (reluctance of some patients and HCPs to change, patient expectations of 'instant prescription' and lost opportunities for best-practice care, HCPs' perceptions of inadequate governmental governance, and ongoing costs) were 'other issues with e-prescription', and two facilitator themes (providing training on the use of e-prescription for HCPs and patients, and making e-prescription more streamlined) were 'suggestions to improve'. CONCLUSION: There are many facilitators and barriers to the use of e-prescription. Our findings may inform the future promotion of e-prescription post-COVID-19 pandemic. Further research should focus on consumers' perspectives of e-prescription.

Comparison of Tumor Binding Across Tumor Types and Cell Lines to Support Free Drug Considerations for Oncology Drug Discovery.

Tumor binding is an important parameter to derive unbound tumor concentration to explore pharmacokinetics (PK) and pharmacodynamics (PD) relationships for oncology disease targets. Tumor binding was evaluated using eleven matrices, including various commonly used ex vivo human and mouse xenograft and syngeneic tumors, tumor cell lines and liver as a surrogate tissue. The results showed that tumor binding is highly correlated among the different tumors and tumor cell lines except for the mouse melanoma (B16F10) tumor type. Liver fraction unbound (fu) has a good correlation with B16F10 tumor binding. Liver also demonstrates a two-fold equivalency, on average, with binding of other tumor types when a scaling factor is applied. Predictive models were developed for tumor binding, with correlations established with LogD (acids), predicted muscle fu (neutrals) and measured plasma protein binding (bases) to estimate tumor fu when experimental data are not available. Many approaches can be applied to obtain and estimate tumor binding values. One strategy proposed is to use a surrogate tumor tissue, such as mouse xenograft ovarian cancer (OVCAR3) tumor, as a surrogate for tumor binding (except for B16F10) to provide an early assessment of unbound tumor concentrations for development of PK/PD relationships.

Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and OAT3 Transporter Activity.

PURPOSE: Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. METHODS: In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. RESULTS: In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by ~ 13% and maximum concentration (Cmax) by ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration. CONCLUSION: Ritlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.

Addressing the Accuracy of Plasma Protein Binding Measurement for Highly Bound Compounds Using the Dilution Method.

Currently, regulatory guidelines recommend using 0.01 as the lower limit of plasma fraction unbound (fu) for prediction of drug-drug interactions (DDI) to err on the conservative side. One way to increase experimental fu of highly bound compounds is to dilute the plasma. With the dilution method, a diluted fu, or fu,d, of ≥ 0.01 can be achieved by adjusting the dilution factor. The undiluted fu can be calculated from fu,d and be used for DDI prediction. In this study, the dilution method was evaluated, and the results showed that it gave similar fu values as those determined using the pre-saturation method without plasma dilution. The dilution method enables generation of accurate fu values and alignment with the regulatory recommendation of reportable fu values of ≥ 0.01 for DDI prediction. We recommend using the dilution method to bridge the regulatory recommended fu limit of 0.01 for DDI prediction and the pre-saturation or equivalent methods for definitive plasma protein binding studies. As the pharmaceutical industry continues to generate high quality PPB data, regulatory agencies will gain confidence in the accuracy of fu measurements for highly bound compounds, and the fu lower limit may no longer be needed in the future.

Identification of Organic Anion Transporter 2 Inhibitors: Screening, Structure-Based Analysis, and Clinical Drug Interaction Risk Assessment.

Organic anion transporter 2 (OAT2 or SLC22A7) plays an important role in the hepatic uptake and renal secretion of several endogenous compounds and drugs. The goal of this work is to understand the structure activity of OAT2 inhibition and assess clinical drug interaction risk. A single-point inhibition assay using OAT2-transfected HEK293 cells was employed to screen about 150 compounds; and concentration-dependent inhibition potency (IC50) was measured for the identified "inhibitors". Acids represented about 65% of all inhibitors, and the frequency of bases-plus-zwitterions approximately doubled for "non-inhibitors". Interestingly, 9 of 10 most potent inhibitors (low IC50) are acids (pKa ∼ 3-5). Additionally, inhibitors are significantly larger and lipophilic than non-inhibitors. In silico (binary) models were developed to identify inhibitors and non-inhibitors. Finally, in vivo risk assessed via static drug-drug interaction models identified several inhibitors with potential for renal and hepatic OAT2 inhibition at clinical doses. This is the first study assessing the global pattern of OAT2-ligand interactions.

In Vitro - in Vivo Extrapolation of Hepatic Clearance in Preclinical Species.

Accurate prediction of human clearance is of critical importance in drug discovery. In this study, in vitro - in vivo extrapolation (IVIVE) of hepatic clearance was established using large sets of compounds for four preclinical species (mouse, rat, dog, and non-human primate) to enable better understanding of clearance mechanisms and human translation. In vitro intrinsic clearances were obtained using pooled liver microsomes (LMs) or hepatocytes (HEPs) and scaled to hepatic clearance using the parallel-tube and well-stirred models. Subsequently, IVIVE scaling factors (SFs) were derived to best predict in vivo clearance. The SFs for extended clearance classification system (ECCS) class 2/4 compounds, involving metabolic clearance, were generally small (≤ 2.6) using both LMs and HEPs with parallel-tube model, with the exception of the rodents (~ 2.4-4.6), suggesting in vitro reagents represent in vivo reasonably well. SFs for ECCS class 1A and 1B are generally higher than class 2/4 across the species, likely due to the contribution of transporter-mediated clearance that is under-represented with in vitro reagents. The parallel-tube model offered lower variability in clearance predictions over the well-stirred model. For compounds that likely demonstrate passive permeability-limited clearance in vitro, rat LM predicted in vivo clearance more accurately than HEP. This comprehensive analysis demonstrated reliable IVIVE can be achieved using LMs and HEPs. Evaluation of clearance IVIVE in preclinical species helps to better understand clearance mechanisms, establish more reliable IVIVE in human, and enhance our confidence in human clearance and PK prediction, while considering species differences in drug metabolizing enzymes and transporters.

Replacement per- and polyfluoroalkyl substances (PFAS) are potent modulators of lipogenic and drug metabolizing gene expression signatures in primary human hepatocytes.

Per- and polyfluoroalkyl substances (PFAS) are a class of environmental toxicants, and some, such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), have been associated with hepatic steatosis in rodents and monkeys. It was hypothesized that perfluorosulfonic acids (C4, 6, 8), perfluorocarboxylic acids (C4-14), perfluoro(2-methyl-3-oxahexanoic) acid (HFPO-DA), 1H, 1H, 2H, 2H-perfluorooctanesulfonic acid (6:2 FTS) along with 3 PFOS precursors could induce expression of lipid metabolism genes and lipid deposition in human hepatocytes. Five-donor pooled cryopreserved human hepatocytes were cultured and treated with 0.1% DMSO vehicle or various PFAS (0.25 to 25 µM) in media. After a 48-h treatment, mRNA transcripts related to lipid transport, metabolism, and synthesis were measured using a Quantigene Plex assay. After 72-h treatments, hepatocytes were stained with Nile Red dye to quantify intracellular lipids. Overall, PFAS were transcriptionally active at 25 µM. In this model, lipid accumulation was not observed with C8-C12 treatments. Shorter chain PFAS (C4-C5), 6:2 FTS, and PFOS precursor, metFOSA, induced significant liver lipid accumulation, and gene activation at lower concentrations than legacy PFAS. In summary short chain PFAS and other alternative PFAS were more potent gene inducers, and potential health effects of replacement PFAS should be critically evaluated in humans.

Nucleation and Growth-Controlled Facile Fabrication of Gold Nanoporous Structures for Highly Sensitive Surface-Enhanced Raman Spectroscopy Applications.

The fabrication of porous metal structures usually involves complicated processes such as lithography or etching. In this study, a facile and clean method based on thermal evaporation at high pressure is introduced, by which a highly porous, black colored structure of Au can be formed through the control of homogeneous nucleation and growth during evaporation. The deposited films have different morphologies, from columnar to nanoporous structures, depending on the working pressure. These porous structures consist of Au nanoparticle aggregates, and a large number of nano-gaps are found among the nanoparticles. Thus, these structures indicate a much higher intensity of surface-enhanced Raman spectroscopy (SERS) when compared with commercial SERS substrates. The SERS intensity depends on the working pressure and thickness. Even circumstances that can induce agglomeration of nanoparticle aggregates do not deteriorate the sensitivity of SERS. These nanoporous structures based on high-pressure thermal evaporation are expected to provide a new platform for the development of low-cost and highly sensitive chemical sensors.

Electronic and Structural Transitions of LaAlO3 /SrTiO3 Heterostructure Driven by Polar Field-Assisted Oxygen Vacancy Formation at the Surface.

The origin of 2D electron gas (2DEG) at LaAlO3 /SrTiO3 (LAO/STO) interfaces has remained highly controversial since its discovery. Various models are proposed, which include electronic reconstruction via surface-to-interface charge transfer and defect-mediated doping involving cation intermixing or oxygen vacancy (VO ) formation. It is shown that the polar field-assisted VO formation at the LAO/STO surface plays critical roles in the 2DEG formation and concurrent structural transition. Comprehensive scanning transmission electron microscopy analyses, in conjunction with density functional theory calculations, demonstrate that VO forming at the LAO/STO surface above the critical thickness (tc ) cancels the polar field by doping the interface with 2DEG. The antiferrodistortive (AFD) octahedral rotations in LAO, which are suppressed below the tc , evolve with the formation of VO above the tc . The present study reveals that local symmetry breaking and shallow donor behavior of VO induce the AFD rotations and relieve the electrical field by electron doping the oxide heterointerface.

Cooperative evolution of polar distortion and nonpolar rotation of oxygen octahedra in oxide heterostructures.

Polarity discontinuity across LaAlO3/SrTiO3 (LAO/STO) heterostructures induces electronic reconstruction involving the formation of two-dimensional electron gas (2DEG) and structural distortions characterized by antiferrodistortive (AFD) rotation and ferroelectric (FE) distortion. We show that AFD and FE modes are cooperatively coupled in LAO/STO (111) heterostructures; they coexist below the critical thickness (t c) and disappear simultaneously above t c with the formation of 2DEG. Electron energy-loss spectroscopy and density functional theory (DFT) calculations provide direct evidence of oxygen vacancy (V O) formation at the LAO (111) surface, which acts as the source of 2DEG. Tracing the AFD rotation and FE distortion of LAO reveals that their evolution is strongly correlated with V O distribution. The present study demonstrates that AFD and FE modes in oxide heterostructures emerge as a consequence of interplay between misfit strain and polar field, and further that their combination can be tuned to competitive or cooperative coupling by changing the interface orientation.

Analysis of Local Charges at Hetero-interfaces by Electron Holography - A Comparative Study of Different Techniques.

Interface charges confined within a few nanometers of hetero-interface can be characterized by measuring the phase shift of the transmitted beam using different electron holography techniques. However, reliable measurement of the electrostatic potential arising from the interface charges is challenging as the mean inner potential difference (ΔV0) between two adjoining materials as well as local variation of the sample thickness affect the phase shift. In the present study, we show how electron holography can be used to characterize the confined charges at an oxide hetero-interface and evaluate the applicability of different techniques for this purpose. The model system chosen for this study is a LaAlO3/SrTiO3 (LAO/STO) (111) hetero-interface featuring a two-dimensional electron gas (2DEG), where the ΔV0 between LAO and STO is about 2 eV, which is unignorably large and dominates the net potential variation across the interface. For transmission electron microscopy specimens prepared by focused ion beam we applied three different variants of electron holography techniques: off-axis, inline and hybrid electron holography; and compare the results obtained by these approaches in terms of the information transfer in the spatial frequency domain, and the signal-to-noise ratio of the electric field and charge density maps. To correctly assess the information pertinent to the interface-confined charges, we calculate the electrostatic potential and electric field distribution based on a charge model with taking account of the ΔV0 between LAO and STO and compared the calculated profiles with the experimental results after calibrating the local thickness variation across the LAO/STO interface. The results show that hybrid electron holography recovers the information across a wide range of spatial frequencies, and as a result, delivers the most reliable charge density information, albeit convoluted with the unavoidable effects arising from ΔV0.

Organic Anion-Transporting Polypeptide 1B1/1B3-Mediated Hepatic Uptake Determines the Pharmacokinetics of Large Lipophilic Acids: In Vitro-In Vivo Evaluation in Cynomolgus Monkey.

It is generally presumed that uptake transport mechanisms are of limited significance in hepatic clearance for lipophilic or high passive-permeability drugs. In this study, we evaluated the mechanistic role of the hepato-selective organic anion-transporting polypeptides (OATPs) 1B1/1B3 in the pharmacokinetics of compounds representing large lipophilic acid space. Intravenous pharmacokinetics of 16 compounds with molecular mass ∼400-730 Da, logP ∼3.5-8, and acid pKa <6 were obtained in cynomolgus monkey after dosing without and with a single-dose rifampicin-OATP1B1/1B3 probe inhibitor. Rifampicin (30 mg/kg oral) significantly (P < 0.05) reduced monkey clearance and/or steady-state volume of distribution (VDss) for 15 of 16 acids evaluated. Additionally, clearance of danoprevir was reduced by about 35%, although statistical significance was not reached. A significant linear relationship was noted between the clearance ratio (i.e., ratio of control to treatment groups) and VDss ratio, suggesting hepatic uptake contributes to the systemic clearance and distribution simultaneously. In vitro transport studies using primary monkey and human hepatocytes showed uptake inhibition by rifampicin (100 µM) for compounds with logP ≤6.5 but not for the very lipophilic acids (logP > 6.5), which generally showed high nonspecific binding in hepatocyte incubations. In vitro uptake clearance and fraction transported by OATP1B1/1B3 (ft,OATP1B) were found to be similar in monkey and human hepatocytes. Finally, for compounds with logP ≤6.5, good agreement was noted between in vitro ft,OATP1B and clearance ratio (as well as VDss ratio) in cynomolgus monkey. In conclusion, this study provides mechanistic evidence for the pivotal role of OATP1B-mediated hepatic uptake in the pharmacokinetics across a wide, large lipophilic acid space. SIGNIFICANCE STATEMENT: This study provides mechanistic insight into the pharmacokinetics of a broad range of large lipophilic acids. Organic anion-transporting polypeptides 1B1/1B3-mediated hepatic uptake is of key importance in the pharmacokinetics and drug-drug interactions of almost all drugs and new molecular entities in this space. Diligent in vitro and in vivo transport characterization is needed to avoid the false negatives often noted because of general limitations in the in vitro assays while handling compounds with such physicochemical attributes.

Effect of Human Plasma on Hepatic Uptake of Organic Anion-Transporting Polypeptide 1B Substrates: Studies Using Transfected Cells and Primary Human Hepatocytes.

Current challenges with the in vitro-in vivo extrapolation (IVIVE) of hepatic uptake clearance involving organic anion-transporting polypeptide (OATP) 1B1/1B3 hinder drug design strategies. Here we evaluated the effect of 100% human plasma on the uptake clearance using transfected human embryonic kidney (HEK) 293 cells and primary human hepatocytes and assessed IVIVE. Apparent unbound uptake clearance (PSinf,u) increased significantly (P < 0.05) in the presence of plasma (vs. buffer incubations) for about 50% of compounds in both OATP1B1-transfected and wild-type HEK cells. Thus, plasma showed a minimal effect on the uptake ratios. With cultured human hepatocytes, plasma significantly (P < 0.05) increased PSinf,u for 11 of 19 OATP1B substrates (median change of 2.1-fold). Cell accumulation in HEK cells and hepatocytes was also increased for tolbutamide, which is not an OATP substrate. Plasma-to-buffer ratio of PSinf,u obtained in hepatocytes showed a good correlation with unbound fraction in plasma, and the relationship was best described by a "facilitated-dissociation" model. IVIVE was evaluated for the 19 OATP1B substrates using hepatocyte data in the presence of buffer and plasma. PSinf,u from buffer incubations markedly underpredicted hepatic intrinsic clearance (calculated via well stirred and parallel tube models) with an estimated bias of 0.10-0.13. Predictions improved when using PSinf,u from plasma incubations; however, considerable systemic underprediction was still apparent (0.19-0.26 bias). Plasma data with a global scaling factor of 3.8-5.3 showed good prediction accuracy (95% predictions within 3-fold; average fold error = 1.7, bias = 1). In summary, this study offers insight into the effect of plasma on the uptake clearance and its scope in improving IVIVE. SIGNIFICANCE STATEMENT: Our study using diverse anionic compounds shows that human plasma facilitates organic anion-transporting polypeptide 1B-mediated as well as passive uptake clearance, particularly for the highly bound compounds. Leveraging data from transfected human embryonic kidney 293 cells and primary human hepatocytes, we further evaluated mechanisms involved in the observed plasma-facilitated uptake transport. Enhanced hepatic uptake rate in the presence of plasma could be of relevance, as such mechanisms likely prevail in vivo and emphasize the need to maintain physiologically relevant assay conditions to achieve improved translation of transport data.

Planar Abstraction and Inverse Rendering of 3D Indoor Environments.

Scanning and acquiring a 3D indoor environment suffers from complex occlusions and misalignment errors. The reconstruction obtained from an RGB-D scanner contains holes in geometry and ghosting in texture. These are easily noticeable and cannot be considered as visually compelling VR content without further processing. On the other hand, the well-known Manhattan World priors successfully recreate relatively simple structures. In this article, we would like to push the limit of planar representation in indoor environments. Given an initial 3D reconstruction captured by an RGB-D sensor, we use planes not only to represent the environment geometrically but also to solve an inverse rendering problem considering texture and light. The complex process of shape inference and intrinsic imaging is greatly simplified with the help of detected planes and yet produces a realistic 3D indoor environment. The generated content can adequately represent the spatial arrangements for various AR/VR applications and can be readily composited with virtual objects possessing plausible lighting and texture.

Direct Identification of Antisite Cation Intermixing and Correlation with Electronic Conduction in CuBi2O4 for Photocathodes.

Cu-based p-type semiconducting oxides have been sought for water-reduction photocathodes to enhance the energy-conversion efficiency in photoelectrochemical cells. CuBi2O4 has recently attracted notable attention as a new family of p-type oxides, based on its adequate band gap. Although the identification of a major defect structure should be the first step toward understanding the electronic conduction behavior, no direct experimental analysis has been carried out yet. Using atomic-scale scanning transmission electron microscopy together with chemical probing, we identify a substantial amount of BiCu-CuBi antisite intermixing as a major point-defect type. Our density functional theory calculations also show that antisite BiCu can seriously hinder the hole-polaron hopping between Cu, in agreement with lower conductivity and a larger thermal activation barrier under a higher degree of intermixing. These findings highlight the value of the direct identification of point defects for a better understanding of electronic properties in complex oxides.