We investigate electronic transport across a magnetic domain wall (DW) in a three-dimensional (3D) second-order topological insulator subject to Anderson disorder. In the clean limit, the DW hosts two co-propagating one-dimensional (1D) topological edge states that act as the two arms of an effective Aharonov-Bohm (AB) interferometer, inducing a sinusoidal conductance oscillation. Upon the introduction of disorder, the AB oscillations are suppressed, while a half-quantized plateau of 0.5 e^2/h for the ensemble-averaged conductance emerges. Notably, within this plateau, the conductance fluctuation exhibits a distinctive two-step plateau structure, with values of ∼ 0.35 e^2/h at moderate disorder, followed by a second plateau at ∼0.29 e^2/h under strong disorder. By developing theoretical frameworks that account for the random-phase interference and inter-mode mixing of the two arms, we identify the first fluctuation plateau as a signature of the phase-averaging regime (PAR) and the second as a signature of the mode-mixing regime (MMR). Furthermore, we show that, in the PAR the conductance follows a U-shaped beta distribution, while it evolves into a uniform distribution in the MMR. The Fano factor associated with shot noise is also computed, which exhibits a similar two-step plateau structure at 1/4 and 1/3, corresponding to the PAR and MMR, respectively. Our work provides a clear demonstration of the disorder-induced crossover from PAR to MMR, and highlights the crucial role of second-order conductance cumulants in identifying these transport regimes. The results suggest disorder-engineering as a powerful route for controlling electronic transport across DW-based devices.

Topological valley kink states (VKSs), which are quantum valley Hall states emerging at the interfaces between adjacent domains with opposite valley Chern numbers, have attracted considerable interest in graphene-based systems. In this work, we investigate the quantum transport of VKSs in ABC-stacked rhombohedral multilayer graphene in the presence of Anderson disorder and a perpendicular magnetic field. Two prominent transport characteristics are revealed. First, in the absence of a magnetic field, the kink states exhibit strong layer polarization, with their wave functions predominantly localized and equally distributed on the outermost top and bottom layers. As a result, their transport properties are highly sensitive to the layer-selective disorder distribution. Second, under a perpendicular magnetic field, the layer-symmetric spatial distribution of VKSs is broken, leading to a significant reduction in the wave-function overlap between counter-propagating VKSs from opposite valleys. Consequently, intervalley scattering is suppressed, and the transmission of VKSs through disordered regions is substantially enhanced. Our results provide new insights into multichannel topological valley transport in rhombohedral multilayer graphene and demonstrates disorder-engineering and magnetic fields as effective approaches for manipulating the propagation of VKSs.

In disordered lattices, itinerant electrons typically undergo Anderson localization due to random phase interference, which suppresses their motion. By contrast, in flat-band systems where electrons are intrinsically localized owing to their vanishing group velocity, the role of disorder remains elusive. Twisted bilayer graphene (TBG) at the magic angle similar to 1.1 degrees provides a representative flat-band platform to investigate this problem. Here, we perform an atomistic tight-binding quantum transport calculation on the interplay between disorder and flat bands in TBG devices. This nonphenomenological approach confirms that moderate disorder enhances conductance, whereas stronger disorder restores localization, revealing a disorder-driven delocalization-to-localization transport behavior. The underlying physical mechanism is understood by an effective intermoir & eacute; tunneling strength via spectral flow analysis of a disordered TBG cylinder. Moreover, by comparing magic-angle and large-angle TBG, we demonstrate qualitatively distinct disorder responses tied to the presence of flat bands. Our quantitative results highlight the unconventional role of disorder in flat-band moir & eacute; materials and offer insights into the observation of the fractional quantum anomalous Hall effect in disordered moir & eacute; systems.

The three-dimensional (3D) topological insulators (TIs), hosting topologically protected helical surface states, can be promoted into second-order TIs when a diagonal Zeeman term, typical of magnetic doping, is introduced. The latter hosts exotic chiral one-dimensional (1D) topological hinge states (THSs). In this paper, we investigate the electronic transport of THSs through a magnetic domain wall (DW) in a 3D TI nanowire. Because of the sign reversal of the out-of-plane magnetization across the DW, four 1D topological boundary states, residing on the edge of the DW, arise and form an enclosed loop mediating the counterpropagating THSs. By applying a uniform magnetic field parallel to the nanowire, we obtain a perfect sinusoidal Aharonov-Bohm oscillation in the two-terminal conductance G, formulated by G = e2 2h[1-cos(nct)lct)0)], with ct) the magnetic flux through the DW and ct)0 = hl2e the flux quantum. Applying a phenomenological scattering matrix approach, we explain this Aharonov-Bohm oscillation perfectly, and attribute the constructive (destructive) interference of transmission at ct) = ct)0 (0) to the n-spin rotation of the THSs traveling through the DW. Extending our study to a double-DW junction, where the central region has antiparallel magnetization to the leads, we observe Fabry-P & eacute;rot oscillations, in which the conductance minima are tuned by the magnetic flux. Our findings open an avenue for finely controlling the quantum transport of THSs in magnetic systems using magnetic flux, and provide a faithful way for detecting THSs in experiments.

In disordered lattices, itinerant electrons typically undergo Anderson localization due to random phase interference, which suppresses their motion. By contrast, in flat-band systems where electrons are intrinsically localized owing to their vanishing group velocity, the role of disorder remains elusive. Twisted bilayer graphene (TBG) at the magic angle ∼ 1.1^∘ provides a representative flat-band platform to investigate this problem. Here, we perform an atomistic tight-binding quantum transport calculation on the interplay between disorder and flat-bands in TBG devices. This non-phenomenological approach provides direct evidence that moderate disorder enhances conductance, whereas stronger disorder restores localization, revealing a disorder-driven delocalization-to-localization transport behavior. The underlying physical mechanism is understood by an effective inter-moiré tunneling strength via spectral flow analysis of a disordered TBG cylinder. Moreover, by comparing magic-angle and large-angle TBG, we demonstrate qualitatively distinct disorder responses tied to the presence of flat-bands. Our quantitative results highlight the unconventional role of disorder in flat-band moiré materials and offer insights into the observation of the fractional quantum anomalous Hall effect in disordered moiré systems.

Universal conductance fluctuations (UCF) are a hallmark of quantum interference in mesoscopic devices. According to the Altshuler-Lee-Stone theory, the amplitude of UCF remains independent of system parameters such as Fermi energy and disorder strength. However, recent experiments have demonstrated a significant variation in UCF with respect to Fermi energy in the anisotropic Dirac semimetal Cd_3As_2, suggesting a dependence on band anisotropy. In this work, we reconcile the discrepancy between theoretical predictions and experimental observations through a detailed study of UCF versus Fermi energy using a tight-binding model with tunable anisotropy parameters. Near the band edge, the Hamiltonian is simplified to an anisotropic free electron gas model, recovering the generalized Altshuler-Lee-Stone theory. However, as the Fermi energy shifts toward the band center, where rotational symmetry breaks into C_4 (four-fold rotational) symmetry, the UCF amplitude deviates from the standard theory. Our findings reveal that UCF becomes increasingly sensitive to Fermi energy as the anisotropy grows stronger. Furthermore, using realistic parameters for Cd_3As_2, our calculations demonstrate an increase in UCF away from the Dirac point, in qualitative agreement with experimental results. The enhancement of UCF occurs in two perpendicular transport directions that we have calculated, albeit with quantitative differences in magnitude, which can be tested in future experiments. Given the prevalence of anisotropic materials and technical advances in engineering anisotropy through strain or twist, our results offer a valuable reference for characterizing intrinsic electronic properties via UCF.

Impurities exist inevitably in two-dimensional materials as they spontaneously adsorb onto the surface during fabrication, usually exerting detrimental effects on electronic transport. Here, we focus on a special type of impurities that preferentially adsorb onto the hollow regions of graphene nanoribbons (GNRs), and study how they affect the quantum transport in GNRs. Contrary to previous knowledge that random adatoms should localize electrons, the so-called Anderson localization, noteworthy quantized conductance peaks (QCPs) are observed at specific electron energies. These QCPs are remarkably robust against variations in system size, GNR edge, and adatom properties, and they can reappear at identical energies following an arithmetic sequence of device width. Further investigation of wavefunction reveals a unique transport mode at each QCP energy which transmits through disordered GNRs reflectionlessly, while all the others become fully Anderson localized, indicating the survival of quantum ballistic transport in the localized regime. Our findings highlight the potential utility of hollow adatoms as a powerful tool to manipulate the conductivity of GNRs, and deepen the understanding of the interplay between impurities and graphene.

Minimally twisted bilayer graphene (TBG) with interlayer potential asymmetry host one-dimensional (1D) topological helical states (THSs) at domain walls between AB/BA stacking regions. However, the nature of THS propagation remains elusive. Although it is widely believed that they form a two-dimensional (2D) triangular network, a few argue that they self-organize into 1D topological zigzag modes (TZMs) that propagate independently. In this Letter, we propose a protocol based on a two-terminal TBG nanoflake transport device and resolve this issue. Through rigorous calculations on the differential conductance and the nonequilibrium local density of states, we show that, these THSs indeed self-construct the 1D distorted TZMs, each bypassing the AA-stacking spots and propagating independently. By considering a long TBG nanoflake, we obtain a nearly quantized conductance plateau with its value close to 1, 2, and 3 (in units of $2e^2/h$), which serves as a strong experimental sign for the existence of TZMs. Our work not only clarifies the propagation nature of the THSs, but also realizes an array of 1D conducting channels on a 2D platform. This work provides an unprecedented way to engineering topological states intrinsic in TBG.

We investigate the mesoscopic transport through a twisted bilayer graphene (TBG) consisting of a clean graphene nanoribbon on the bottom and a disordered graphene disk on the top. We show that, with strong top-layer disorder, the transmission through such a device shows a sequence of resonant peaks with respect to the rotation angle 0, where at the resonant angles 0c the disk region contains one giant hexagonal moire supercell. A further investigation shows that the value of 0c shows negligible dependence on the disorder strength, the Fermi energy, and the shape distortion, indicating the resonance is a robust commensuration feature of the moire supercell. We explain this commensuration resonance based on the bound states formed inside TBG disk as a result of the nonuniform interlayer coupling, with their average local density of states dominating at the AA stacking region while minimizing at the AB/BA stacking regions. By increasing the interlayer distance, the peak becomes less pronounced which further confirms the role of interlayer coupling. The results presented here suggest a new mechanism to tune the quantum transport signal through the twist angle in disordered moire systems.

We propose a realization of a quantum Hall effect (QHE) in a second-order topological insulator (SOTI) in three dimensions (3D), which is mediated by hinge states on a torus surface. It results from the nontrivial interplay of the material structure, Zeeman effect, and the surface curvature. In contrast to the conventional 2D- and 3D-QHE, we show that the 3D-SOTI QHE is not affected by orbital effects of the applied magnetic field and exists in the presence of a Zeeman term only, induced e.g. by magnetic doping. To explain the 3D-SOTI QHE, we analyze the boundary charge for a 3D-SOTI and establish its universal dependence on the Aharonov-Bohm flux threading through the torus hole. Exploiting the fundamental relation between the boundary charge and the Hall conductance, we demonstrate the universal quantization of the latter, as well as its stability against random disorder potentials and continuous deformations of the torus surface.

Objective: The aim of this study is to develop a LC-MS/MS method for the quantitation of seven cytochrome P450 (CYP450) enzymes. Methods: A high-performance liquid chromatography-tandem mass spectrometry method was developed using multiple reaction monitoring mode with positive electrospray ionization. The method was validated with selectivity, linearity, stability, accuracy and precious. In addition, the abundance of seven CYP450 enzymes in human liver microsomes and CYP3A4 in placenta were determined using the current method.Results: The linear range for CYP1A2, CYP2B6 and CYP2C8 was 0.036-3.6 nM and for CYP2C9, CYP2C19, CYP2D6 and CYP3A4 was 0.090-9.0 nM. No interference was found between the blank matrix and each specific peptides. The accuracy and precious results were in accord with the requirement of analytical methods for biological samples in Chinese Pharmacopoeia. In addition, the peptides were stable under current stability conditions. The content of CYP3A4 in placenta and the seven CYP450 enzymes in human liver microsomes were accurately quantified.Conclusion: The developed method is sensitive and specific and can be applied to the quantification of enzymes abundance in different human derived samples like placenta and liver microsomes.

We unravel a fundamental connection between supersymmetry and a wide class of two dimensional second-order topological insulators (SOTI). This particular supersymmetry is induced by applying a half-integer Aharonov-Bohm flux f=Φ/Φ_0=1/2 through a hole in the system. Here, three symmetries are essential to establish this fundamental link: chiral symmetry, inversion symmetry, and mirror symmetry. At such a flux of half-integer value the mirror symmetry anticommutes with the inversion symmetry leading to a nontrivial n=1-SUSY representation for the absolute value of the Hamiltonian in each chiral sector, separately. This implies that a unique zero-energy state and an exact twofold degeneracy of all eigenstates with non-zero energy is found even at finite system size. For arbitrary smooth surfaces the link between 2D-SOTI and SUSY can be described within a universal low-energy theory in terms of an effective surface Hamiltonian which encompasses the whole class of supersymmetric periodic Witten models. Applying this general link to the prototypical example of a Bernevig-Hughes-Zhang(BHZ)-model with an in-plane Zeeman field, we analyze the entire phase diagram and identify a gapless Weyl phase separating the topological from the non-topological gapped phase. Surprisingly, we find that topological states localized at the outer surface remain in the Weyl phase, whereas topological hole states move to the outer surface and change their spatial symmetry upon approaching the Weyl phase. Therefore, the topological hole states can be tuned in a versatile manner opening up a route towards magnetic-field-induced topological engineering in multi-hole systems. Finally, we demonstrate the stability of localized states against deviation from half-integer flux, flux penetration into the sample, surface distortions, and random impurities for impurity strengths up to the order of the surface gap.

The aim of this study was to develop a validated liquid chromatography-tandem mass spectrometry method to quantify nine important transporter proteins, so as to support the quantification of transporter proteins abundance in different human tissues and organs. Quantification was performed by targeted proteomics in positive multiple reaction monitoring mode with liquid chromatography-tandem mass spectrometry. The method was validated with respect to specificity, linearity, accuracy, precision, and stability. All the correlation coefficients (r) were larger than 0.99 and the validation ranges of multidrug-resistant transporter 1, breast cancer resistance protein, organic cation transporter 2, and organic anion transporter 1 were 0.036-3.636 nM, organic anion transporter 3 was 0.018-1.818 nM, organic anion transporting polypeptide transporter 1B1 and multidrug and toxin extrusion transporter 1 were 0.091-9.091 nM, organic anion transporting polypeptide transporter 1B3 and multidrug and toxin extrusion transporter 2K were 0.182-18.182 nM. The results of intra-day and inter-day accuracy and precision were all in line with the quantification requirements of biological samples and the stability results indicated that the samples were stable under current processing and storage conditions. The method is sensitive and efficient for the quantification of nine transporters in human tissues.

Olverembatinib (HQP1351) is a third-generation BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) (including T315I-mutant disease), exhibits drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4, CYP2C9, CYP2C19, CYP1A2, and CYP2B6. A physiologically-based pharmacokinetic (PBPK) model was constructed based on physicochemical and in vitro parameters, as well as clinical data to predict 1) potential DDIs between olverembatinib and CYP3A4 and CYP2C9 inhibitors or inducers 2), effects of olverembatinib on the exposure of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 substrates, and 3) pharmacokinetics in patients with liver function injury. The PBPK model successfully described observed plasma concentrations of olverembatinib from healthy subjects and patients with CML after a single administration, and predicted olverembatinib exposure increases when co-administered with itraconazole (strong CYP3A4 inhibitor) and decreases with rifampicin (strong CYP3A4 inducer), which were validated by observed data. The predicted results suggest that 1) strong, moderate, and mild CYP3A4 inhibitors (which have some overlap with CYP2C9 inhibitors) may increase olverembatinib exposure by approximately 2.39-, 1.80- to 2.39-, and 1.08-fold, respectively; strong, and moderate CYP3A4 inducers may decrease olverembatinib exposure by approximately 0.29-, and 0.35- to 0.56-fold, respectively 2); olverembatinib, as a “perpetrator,” would have no or limited impact on CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activity 3); systemic exposure of olverembatinib in liver function injury with Child-Pugh A, B, C may increase by 1.22-, 1.79-, and 2.13-fold, respectively. These simulations inform DDI risk for olverembatinib as either a “victim” or “perpetrator”.

To preliminarily develop physiologically based population models for Chinese renal impairment patients and to evaluate the prediction performance of new population models by renally cleared antibacterial drugs. First, demographic data and physiological parameters of Chinese renal impairment patients were collected, and then the coefficients of the relative demographic and physiological equation were recalibrated to construct the new population models. Second, drug-independent parameters of ceftazidime, cefodizime, vancomycin, and cefuroxime were collected and verified by Chinese healthy volunteers, Caucasian healthy volunteers, and Caucasian renal impairment population models built in Simcyp. Finally, the newly developed population models were applied to predict the plasma concentration of four antibacterial drugs in Chinese renal impairment patients. The new physiologically based pharmacokinetic (PBPK) population models can predict the main pharmacokinetic parameters, including area under the plasma concentration-time curve extrapolated to infinity (AUCinf ), renal clearance (CLr ), and peak concentration (Cmax ), of ceftazidime, cefodizime, vancomycin, and cefuroxime following intravenous administrations with less than twofold error in mild, moderate, and severe Chinese renal impairment patients. The accuracy and precision of the predictions were improved compared with the Chinese healthy volunteers and Caucasian renal impairment population models. The PBPK population models were preliminarily developed and the first-step validation results of four antibacterial drugs following intravenous administration showed acceptable accuracy and precision. The population models still need more systematic validation by using more drugs and scenarios in future studies to support their applications on dosage recommendation for Chinese renal impairment patients.

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (C max ), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children.

Majorana bound states have been predicted to exist in vortices of topological superconductors (SC). A realization of the Fu-Kane model, based on a three-dimensional topological insulator brought into proximity to an s-wave SC, in iron-based SC Fe(Te,Se) has attracted strong interest after pronounced zero-energy bias peaks were observed in several experiments. Here, we show that, by taking into account inhomogeneities of the chemical potential or the presence of potential impurities on the surface of Fe(Te,Se), the emergence of these zero-energy bias peaks can be explained by trivial Andreev bound states (ABSs) whose energies are close to zero. Our numerical simulations reveal that the ABSs behave similarly to Majorana bound states. ABSs are localized only on the, say, top surface and cannot be distinguished from their topological counterparts in transport experiments performed with STM tips. Thus, such ABSs deserve a careful investigation of their own.

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.

Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19).To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens,a PBPK model,with parameterization of drug distribution extrapolated from animal data,was developed to predict human tissue distribution of CQ.The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism.Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships.The model was also validated by clinical data from Chinese patients with COVID-19.The novel PBPK model allows indepth description of the pharmacokinetics of CQ in several key organs (lung,heart,liver,and kidney),and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID,Days 2 -5:500 mg BID,CQ phosphate),patients with moderate COVID-19 (Day 1: 750 mg and 500 mg,Days 2 -3:500 mg BID,Days 4-5:250 mg BID,CQ phosphate),and other vulnerable populations (e.g.,renal and hepatic impairment and elderly patients,Days 1-5:250 mg BID,CQ phosphate).A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.

Nonlocality is an interesting topic in quantum physics and is usually mediated by some unique quantum states. Here we investigate a Weyl semimetal slab and find an exotic nonlocal correlation effect when placing two potential wells merely on the top and bottom surfaces. This correlation arises from the peculiar Weyl orbit in Weyl semimetals and is a consequence of the bulk-boundary correspondence in topological band theory. A giant nonlocal transport signal and a body breakdown by Weyl fermions are further uncovered, which can serve as signatures for verifying this nonlocal correlation effect experimentally. Our results extend a new member in the nonlocality family and have potential applications for designing new electric devices with fancy functions.