Identification of ferroptosis-related gene signature for tuberculosis diagnosis and therapy efficacy.

Diagnosis of tuberculosis remains a challenge when microbiological tests are negative. Immune cell atlas of patients with tuberculosis and healthy controls were established by single-cell transcriptome. Through integrated analysis of scRNA-seq with microarray and bulk RNA sequencing data, a ferroptosis-related gene signature containing ACSL4, CTSB, and TLR4 genes that were associated with tuberculosis disease was identified. Four gene expression datasets from blood samples of patients with tuberculosis, latent tuberculosis infection, and healthy controls were used to assess the diagnostic value of the gene signature. The areas under the ROC curve for the combined gene signature were 1.000, 0.866, 0.912, and 0.786, respectively, in differentiating active tuberculosis from latent infection. During anti-tuberculosis treatment, the expression of the gene signature decreased significantly in cured patients with tuberculosis. In conclusion, the ferroptosis-related gene signature was associated with tuberculosis treatment efficacy and was a promising biomarker for differentiating active tuberculosis from latent infection.

Single-cell profiling identifies T cell subsets associated with control of tuberculosis dissemination.

To identify T cell subsets associated with control of tuberculosis, single-cell transcriptome and T cell receptor sequencing were performed on total T cells from patients with tuberculosis and healthy controls. Fourteen distinct subsets of T cells were identified by unbiased UMAP clustering. A GZMK-expressing CD8+ cytotoxic T cell cluster and a SOX4-expressing CD4+ central memory T cell cluster were depleted, while a MKI67-expressing proliferating CD3+ T cell cluster was expanded in patients with tuberculosis compared with healthy controls. The ratio of Granzyme K-expressing CD8+CD161-Ki-67- and CD8+Ki-67+ T cell subsets was significantly reduced and inversely correlated with the extent of TB lesions in patients with TB. In contrast, ratio of Granzyme B-expressing CD8+Ki-67+ and CD4+CD161+Ki-67- T cells and Granzyme A-expressing CD4+CD161+Ki-67- T cells were correlated with the extent of TB lesions. It is concluded that granzyme K-expressing CD8+ T cell subsets might contribute to protection against tuberculosis dissemination.

Tim-3 expression is induced by mycobacterial antigens and identifies tissue-resident subsets of MAIT cells from patients with tuberculosis.

Tissue-resident MAIT cells in tuberculous pleural effusions, the site of tuberculosis infection, were investigated in the study. Tim-3+CD69+CD103+ and CD39+CD69+CD103+ tissue-resident MAIT cell subsets were identified in tuberculous pleural effusions. Tim-3 expression in MAIT cells was greatly induced and CD39 expression was elevated following ex vivo stimulation with Mycobacterium tuberculosis antigens. Mycobacterial antigen-stimulated Tim-3+CD69+CD103+ tissue-resident MAIT cells had higher frequency of IFN-γ- and granzyme B-producing cells than Tim-3-CD69+CD103+ subset, while CD39+CD69+CD103+ MAIT cells had similar frequency of IFN-γ-positive cells but higher ratio of granzyme B-producing cells than CD39-CD69+CD103+ subset. Blocking of IL-2, IL-12p70 or IL-18 but not IL-15 led to significantly reduced expression of Tim-3 compared with isotype antibody control. In contrast, CD39 expression was not influenced by any of the cytokines tested. Tim-3+ MAIT cells had higher levels of lipid uptake and lipid content than Tim-3- cells. It is concluded that Tim-3+CD69+CD103+ tissue-resident MAIT cells were elevated in tuberculous pleural effusions and had higher capacity to produce effector molecules of IFN-γ and granzyme B.

Evaluation of IFIT3 and ORM1 as Biomarkers for Discriminating Active Tuberculosis from Latent Infection.

OBJECTIVE: Current commercially available immunological tests cannot be used for discriminating active tuberculosis (TB) from latent TB infection. To evaluate the value of biomarker candidates in the diagnosis of active TB, this study aimed to identify differentially expressed genes in peripheral blood mononuclear cells (PBMCs) between patients with active TB and individuals with latent TB infection by transcriptome sequencing. METHODS: The differentially expressed genes in unstimulated PBMCs and in Mycobacterium tuberculosis (Mtb) antigen-stimulated PBMCs from patients with active TB and individuals with latent TB infection were identified by transcriptome sequencing. Selected candidate genes were evaluated in cohorts consisting of 110 patients with TB, 30 individuals with latent TB infections, and 50 healthy controls by quantitative real-time RT-PCR. Receiver operating characteristic (ROC) curve analysis was performed to calculate the diagnostic value of the biomarker candidates. RESULTS: Among the differentially expressed genes in PBMCs without Mtb antigen stimulation, interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) had the highest area under curve (AUC) value (0.918, 95% CI: 0.852-0.984, P<0.0001) in discriminating patients with active TB from individuals with latent TB infection, with a sensitivity of 91.86% and a specificity of 84.00%. In Mtb antigen-stimulated PBMCs, orosomucoid 1 (ORM1) had a high AUC value (0.833, 95% CI: 0.752-0.915, P<0.0001), with a sensitivity of 81.94% and a specificity of 70.00%. CONCLUSION: IFIT3 and ORM1 might be potential biomarkers for discriminating active TB from latent TB infection.

[Expression of CD160 in natural killer (NK) cells from patients with active tuberculosis and its relationship with cell functions].

Objective To investigate the relationship between the CD160 expression and anti-tuberculosis immunity. Methods Fluorescence quantitative real-time PCR was used to detect the expression of CD160 in peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze the expression of CD160 on main subtypes of PBMCs, such as T cells, B cells, NK cells and monocytes. The relationship among CD160 and perforin, granzyme B, granulysin, CD69, CD107 and IFN-γ in NK cells was analyzed by flow cytometry. Results CD160 mRNAs in the PBMCs from patients with active tuberculosis was significantly down-regulated, and the levels of CD160 expression in Mycobacterium tuberculosis (MTB)-positive patients was significantly lower than in MTB-negative patients. The expression of CD160 on B cells and monocytes was lower in patients with active tuberculosis as compared with normal controls, while no significant difference was observed on CD3+ T cells. NK cells from patients with active tuberculosis had significantly lower CD160 expression than those from normal controls. In vitro culture with MTB antigens led to down-regulated expression of CD160 on NK cells. The activation marker CD69 on NK in patients with active tuberculosis was significantly lower than that in normal controls. The expression of perforin, granzyme B, granulysin, CD69 and CD107 in CD160+ NK cells was significantly higher than that of CD160- NK cells. However, the expression of IFN-γ in CD160+ NK cells was significantly lower than that of CD160- NK cells. Conclusion The mRNA and protein expression of CD160 was significantly down-regulated in patients with active tuberculosis. CD160 promotes the activation and degranulation of NK cells associated with tuberculosis antigens, but suppresses the expression of IFN-γ of NK cells. CD160 may become a new target for the diagnosis and treatment of tuberculosis.

High-performance piezoelectric composites via ß phase programming.

Polymer-ceramic piezoelectric composites, combining high piezoelectricity and mechanical flexibility, have attracted increasing interest in both academia and industry. However, their piezoelectric activity is largely limited by intrinsically low crystallinity and weak spontaneous polarization. Here, we propose a Ti3C2Tx MXene anchoring method to manipulate the intermolecular interactions within the all-trans conformation of a polymer matrix. Employing phase-field simulation and molecular dynamics calculations, we show that OH surface terminations on the Ti3C2Tx nanosheets offer hydrogen bonding with the fluoropolymer matrix, leading to dipole alignment and enhanced net spontaneous polarization of the polymer-ceramic composites. We then translated this interfacial bonding strategy into electrospinning to boost the piezoelectric response of samarium doped Pb (Mg1/3Nb2/3)O3-PbTiO3/polyvinylidene fluoride composite nanofibers by 160% via Ti3C2Tx nanosheets inclusion. With excellent piezoelectric and mechanical attributes, the as-electrospun piezoelectric nanofibers can be easily integrated into the conventional shoe insoles to form a foot sensor network for all-around gait patterns monitoring, walking habits identification and Metatarsalgi prognosis. This work utilizes the interfacial coupling mechanism of intermolecular anchoring as a strategy to develop high-performance piezoelectric composites for wearable electronics.

The role of lattice dynamics in ferroelectric switching.

Reducing the switching energy of ferroelectric thin films remains an important goal in the pursuit of ultralow-power ferroelectric memory and logic devices. Here, we elucidate the fundamental role of lattice dynamics in ferroelectric switching by studying both freestanding bismuth ferrite (BiFeO3) membranes and films clamped to a substrate. We observe a distinct evolution of the ferroelectric domain pattern, from striped, 71° ferroelastic domains (spacing of ~100 nm) in clamped BiFeO3 films, to large (10's of micrometers) 180° domains in freestanding films. By removing the constraints imposed by mechanical clamping from the substrate, we can realize a ~40% reduction of the switching voltage and a consequent ~60% improvement in the switching speed. Our findings highlight the importance of a dynamic clamping process occurring during switching, which impacts strain, ferroelectric, and ferrodistortive order parameters and plays a critical role in setting the energetics and dynamics of ferroelectric switching.

Mesenchymal-epithelial Transition Factor Regulates Monocyte Function during Mycobacterial Infection via Indoleamine 2,3-dioxygenase.

OBJECTIVE: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), causes an estimated 1.6 million human deaths annually, but the pathogenesis of TB remains unclear. Immunity plays a critical role in the onset and outcome of TB. This study aimed to uncover the roles of innate and adaptive immunity in TB. METHODS: The gene expression profiles generated by RNA sequencing from human peripheral blood mononuclear cells (PBMCs) stimulated with or without Mtb strain H37Rv antigens were analyzed. A total of 973 differentially expressed mRNAs were identified. RESULTS: The differentially expressed genes were enriched in innate immunity signaling functions. The mesenchymal-epithelial transition factor (MET) gene was significantly upregulated in CD14+ monocytes. A MET inhibitor improved the uptake of the BCG strain by monocytes and macrophages as well as inhibited the expression of indoleamine 2,3-dioxygenase (IDO). The expression of IDO was increased in PBMCs stimulated with Mtb antigens, and the IDO inhibitor promoted the expression of CD40, CD83, and CD86. CONCLUSION: Our results might provide clues regarding the immunomodulatory mechanisms used by Mtb to evade the host defense system.

Flexoelectric Domain Walls Originated from Structural Phase Transition in Epitaxial BiVO4 Films.

Polar domain walls in centrosymmetric ferroelastics induce inhomogeneity that is the origin of advantageous multifunctionality. In particular, polar domain walls promote charge-carrier separation and hence are promising for energy conversion applications that overcome the hurdles of the rate-limiting step in the traditional photoelectrochemical water splitting processes. Yet, while macroscopic studies investigate the materials at the device scale, the origin of this phenomenon in general and the emergence of polar domain walls during the structural phase transition in particular has remained elusive, encumbering the development of this attractive system. Here, it is demonstrated that twin domain walls arise in centrosymmetric BiVO4 films and they exhibit localized piezoelectricity. It is also shown that during the structural phase transition from the tetragonal to monoclinic, the symmetry reduction is accompanied by an emergence of strain gradient, giving rise to flexoelectric effect and the polar domain walls. These results not only expose the emergence of polar domain walls at centrosymmetric systems by means of direct observation, but they also expand the realm of potential application of ferroelastics, especially in photoelectrochemistry and local piezoelectricity.

Phase-Field Simulations of Tunable Polar Topologies in Lead-Free Ferroelectric/Paraelectric Multilayers with Ultrahigh Energy-Storage Performance.

Dielectric capacitors are emerging energy-storage components that require both high energy-storage density and high efficiency. The conventional approach to energy-storage enhancement is polar nanodomain engineering via chemical modification. Here, a new approach of domain engineering is proposed by exploiting the tunable polar topologies that have been observed recently in ferroelectric/paraelectric multilayer films. Using phase-field simulations, it is demonstrated that vortex, spiral, and in-plane polar structures can be stabilized in BiFeO3 /SrTiO3 (BFO/STO) multilayers by tailoring the strain state and layer thickness. Various switching dynamics are realized in these polar topologies, resulting in relaxor-ferroelectric-, antiferroelectric-, and paraelectric-like polarization behaviors, respectively. Ultrahigh energy-storage densities above 170 J cm-3 and efficiencies above 95% are achievable in STO/BFO/STO trilayers. This strategy should be generally implementable in other multilayer dielectrics and offers a new avenue to enhancing energy storage by tuning the polar topology and thus the polarization characteristics.

Phase transition enhanced superior elasticity in freestanding single-crystalline multiferroic BiFeO3 membranes.

The integration of ferroic oxide thin films into advanced flexible electronics will bring multifunctionality beyond organic and metallic materials. However, it is challenging to achieve high flexibility in single-crystalline ferroic oxides that is considerable to organic or metallic materials. Here, we demonstrate the superior flexibility of freestanding single-crystalline BiFeO3 membranes, which are typical multiferroic materials with multifunctionality. They can endure cyclic 180° folding and have good recoverability, with the maximum bending strain up to 5.42% during in situ bending under scanning electron microscopy, far beyond their bulk counterparts. Such superior elasticity mainly originates from reversible rhombohedral-tetragonal phase transition, as revealed by phase-field simulations. This study suggests a general fundamental mechanism for a variety of ferroic oxides to achieve high flexibility and to work as smart materials in flexible electronics.

Unexpected Giant Microwave Conductivity in a Nominally Silent BiFeO3 Domain Wall.

Nanoelectronic devices based on ferroelectric domain walls (DWs), such as memories, transistors, and rectifiers, have been demonstrated in recent years. Practical high-speed electronics, on the other hand, usually demand operation frequencies in the gigahertz (GHz) regime, where the effect of dipolar oscillation is important. Herein, an unexpected giant GHz conductivity on the order of 103 S m-1 is observed in certain BiFeO3 DWs, which is about 100 000 times greater than the carrier-induced direct current (dc) conductivity of the same walls. Surprisingly, the nominal configuration of the DWs precludes the alternating current (ac) conduction under an excitation electric field perpendicular to the surface. Theoretical analysis shows that the inclined DWs are stressed asymmetrically near the film surface, whereas the vertical walls in a control sample are not. The resultant imbalanced polarization profile can then couple to the out-of-plane microwave fields and induce power dissipation, which is confirmed by the phase-field modeling. Since the contributions from mobile-carrier conduction and bound-charge oscillation to the ac conductivity are equivalent in a microwave circuit, the research on local structural dynamics may open a new avenue to implement DW nano-devices for radio-frequency applications.

PD-1-expressing MAIT cells from patients with tuberculosis exhibit elevated production of CXCL13.

To understand functional role of PD-1-expressing MAIT cells during tuberculosis infection in humans, sorted PD-1+ and PD-1- MAIT cells from pleural effusions of patients with pleural tuberculosis were subjected to transcriptome sequencing. PD-1-expressing MAIT cells were analysed by flow cytometry and their phenotypic and functional features were investigated. Transcriptome sequencing identified 144 genes that were differentially expressed between PD-1+ and PD-1- MAIT cells from tuberculous pleural effusions and CXCL13 was the gene with highest fold difference. The level of PD-1-expressing MAIT cells was associated with extent of TB infection in humans. PD-1-expressing MAIT cells had increased production of CXCL13 and IL-21 as determined by flow cytometry. PD-1high CXCR5- MAIT cells were significantly expanded in pleural effusions from patients with pleural tuberculosis as compared with those from peripheral blood of both patients with tuberculosis and healthy controls. Although PD-1high CXCR5- MAIT cells from tuberculous pleural effusions had reduced IFN-γ level and increased expression of Tim-3 and GITR, they showed activated phenotype and had higher glucose uptake and lipid content. It is concluded that PD-1-expressing MAIT cells had reduced IFN-γ level but increased production of both CXCL13 and IL-21.

Observation of Strong Polarization Enhancement in Ferroelectric Tunnel Junctions.

Ferroelectric heterostructures, with capability of storing data at ultrahigh densities, could act as the platform for next-generation memories. The development of new device paradigms has been hampered by the long-standing notion of inevitable ferroelectricity suppression under reduced dimensions. Despite recent experimental observation of stable polarized states in ferroelectric ultrathin films, the out-of-plane polarization components in these films are strongly attenuated compared to thicker films, implying a degradation of device performance in electronic miniaturization processes. Here, in a model system of BiFeO3/La0.7Sr0.3MnO3, we report observation of a dramatic out-of-plane polarization enhancement that occurs with decreasing film thickness. Our electron microscopy analysis coupled with phase-field simulations reveals a polarization-enhancement mechanism that is dominated by the accumulation of oxygen vacancies at interfacial layers. The results shed light on the interplay between polarization and defects in nanoscale ferroelectrics and suggest a route to enhance functionality in oxide devices.

Intrinsic Conductance of Domain Walls in BiFeO3.

Ferroelectric domain walls exhibit a number of new functionalities that are not present in their host material. One of these functional characteristics is electrical conductivity that may lead to future device applications. Although progress has been made, the intrinsic conductivity of BiFeO3 domain walls is still elusive. Here, the intrinsic conductivity of 71° and 109° domain walls is reported by probing the local conductance over a cross section of the BiFeO3 /TbScO3 (001) heterostructure. Through a combination of conductive atomic force microscopy, high-resolution electron energy loss spectroscopy, and phase-field simulations, it is found that the 71° domain wall has an inherently charged nature, while the 109° domain wall is close to neutral. Hence, the intrinsic conductivity of the 71° domain walls is an order of magnitude larger than that of the 109° domain walls associated with bound-charge-induced bandgap lowering. Furthermore, the interaction of adjacent 71° domain walls and domain wall curvature leads to a variation of the charge distribution inside the walls, and causes a discontinuity of potential in the [110]p direction, which results in an alternative conductivity of the neighboring 71° domain walls, and a low conductivity of the 71° domain walls when measurement is taken from the film top surface.

Chronic psychological stress impairs germinal center response by repressing miR-155.

Germinal centers (GC) are vital to adaptive immunity. BCL6 and miR-155 are implicated in control of GC reaction and lymphomagenesis. FBXO11 causes BCL6 degradation through ubiquitination in B-cell lymphomas. Chronic psychological stress is known to drive immunosuppression. Corticosterone (CORT) is an adrenal hormone expressed in response to stress and can similarly impair immune functions. However, whether GC formation is disrupted by chronic psychological stress and its molecular mechanism remain to be elucidated. To address this issue, we established a GC formation model in vivo, and a GC B cell differentiation model in vitro. Comparing Naive B cells to GC B cells in vivo and in vitro, the differences of BCL6 and FBXO11 mRNA do not match the changes at the protein level and miR-155 levels that were observed. Next we demonstrated that CORT increase, induced by chronic psychological stress, reduced GC response, IgG1 antibody production and miR-155 level in vivo. The effect of chronic psychological stress can be blocked by a glucocorticoid receptor (GR) antagonist. Similarly, impaired GC B cell generation and isotope class switching were observed. Furthermore, we found that miR-155 and BCL6 expression were downregulated, but FBXO11 expression was upregulated in GC B cells treated with CORT in vitro. In addition, we demonstrated that miR-155 directly down-regulated FBXO11 expression by binding to its 3́-untranslated region. The subsequent overexpression of miR-155 significantly blocked the stress-induced impairment of GC response, due to changes in FBXO11 and BCL6 expression, as well as increased apoptosis in B cells both in vivo and in vitro. Our findings suggest perturbation of GC reaction may play a role in chronic psychological stress-induced immunosuppression through a glucocorticoid pathway, and miR-155-mediated post-transcriptional regulation of FBXO11 and BCL6 expression may contribute to the impaired GC response.

A subset of CD1c+ dendritic cells is increased in patients with tuberculosis and promotes Th17 cell polarization.

The role of primary subsets of DCs in Mycobacterium tuberculosis infection in humans is incompletely understood. In this study, we identified a CD1c DC subset with phenotype of CD1c+CD11c+CD19-CD11b+ that was significantly increased in tuberculous pleural effusions and in peripheral blood from patients with TB compared with that from healthy controls (p < 0.0001). Sputum smear/culture-positive patients with tuberculosis had significantly higher frequency of CD1c+CD11b+ DC subset than sputum smear/culture-negative patients (p < 0.0001). After effective anti-TB chemotherapy, the frequency of CD1c+CD11b+ DC subset in peripheral blood and tuberculous pleural effusions was decreased. CD1c+CD11b+ DC subset from tuberculous pleural effusions expressed higher levels of TLR2, TLR4, CD172a, CD206 and FcεRⅠ, but lower levels of CD80, CD83 and CD86 compared with CD1c+CD11b- DC subset. Expression of IL-1ß, IL-6, IL-8, IL-23, TNF-α, IFN-γ and TGF-ß mRNA in CD1c+CD11b+ DCs was higher than in CD1c+CD11b- DC subset. Co-culture of autologous naive CD4+ T cells with sorted CD1c+CD11b+ DCs expressed significantly increased levels of IL-17A and RORγt transcripts as compared with those co-cultured with CD11b- subset. In conclusion, a CD1c+CD11b+ DC subset with elevated frequency in patients with tuberculosis was identified and it promoted Th17 cell differentiation.

Genetic polymorphisms of MBL2 and tuberculosis susceptibility: a meta-analysis of 22 case-control studies.

INTRODUCTION: The association of mannose-binding lectin gene (MBL2) polymorphisms with tuberculosis susceptibility was inconclusive. In this study, a meta-analysis of 22 case-control studies was carried out to assess the effect of MBL2 polymorphisms on tuberculosis risk. MATERIAL AND METHODS: A search was performed in Embase, PubMed and Web of Science up to Sep 30, 2015. Odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the association. Statistical analyses were performed using STATA 12.0 software. RESULTS: rs1800451 was associated with a decreased tuberculosis risk in the allele model (C vs. A: OR = 0.93, 95% CI: 0.86-1.00, p = 0.050). In analyses stratified by ethnicity, rs7096206 (C/G: OR = 1.31, 95% CI: 1.10-1.57, p = 0.003; GG vs. GC + CC: OR = 0.69, 95% CI: 0.56-0.85, p < 0.001) and A/O (O/A: OR = 1.34, 95% CI: 1.10-1.64, p = 0.004) were associated with tuberculosis risk in Asians, A/O (AA vs. AO + OO: OR = 0.71, 95% CI: 0.51-0.99, p = 0.041) and rs1800451 (AC vs. AA + CC: OR = 2.70, 95% CI: 1.27-5.74, p = 0.010) were associated with tuberculosis risk in Americans, and rs1800451 (C/A: OR = 0.92, 95% CI: 0.86-0.99, p = 0.035) was associated with tuberculosis risk in Africans. Additionally, rs1800450 (B/A: OR = 0.42, 95% CI: 0.25-0.72, p = 0.001) was associated with tuberculosis risk in Europeans. CONCLUSIONS: The MBL2 rs1800451 polymorphism is associated with decreased TB risk in the general population, and A/O, rs7096206, rs1800450 and rs1800451 are likely to be associated with the risk for some specific ethnic groups.

Publisher Correction: Anisotropic polarization-induced conductance at a ferroelectric-insulator interface.

In the version of this Letter originally published, the right-hand arrow in Fig. 3b was incorrectly labelled; see correction note for details. Also, ref. 29 was incorrectly included in the reference list; it has now been removed.

Anisotropic polarization-induced conductance at a ferroelectric-insulator interface.

Coupling between different degrees of freedom, that is, charge, spin, orbital and lattice, is responsible for emergent phenomena in complex oxide heterostrutures1,2. One example is the formation of a two-dimensional electron gas (2DEG) at the polar/non-polar LaAlO3/SrTiO3 (LAO/STO)3-7 interface. This is caused by the polar discontinuity and counteracts the electrostatic potential build-up across the LAO film3. The ferroelectric polarization at a ferroelectric/insulator interface can also give rise to a polar discontinuity8-10. Depending on the polarization orientation, either electrons or holes are transferred to the interface, to form either a 2DEG or two-dimensional hole gas (2DHG)11-13. While recent first-principles modelling predicts the formation of 2DEGs at the ferroelectric/insulator interfaces9,10,12-14, experimental evidence of a ferroelectrically induced interfacial 2DEG remains elusive. Here, we report the emergence of strongly anisotropic polarization-induced conductivity at a ferroelectric/insulator interface, which shows a strong dependence on the polarization orientation. By probing the local conductance and ferroelectric polarization over a cross-section of a BiFeO3-TbScO3 (BFO/TSO) (001) heterostructure, we demonstrate that this interface is conducting along the 109° domain stripes in BFO, whereas it is insulating in the direction perpendicular to these domain stripes. Electron energy-loss spectroscopy and theoretical modelling suggest that the anisotropy of the interfacial conduction is caused by an alternating polarization associated with the ferroelectric domains, producing either electron or hole doping of the BFO/TSO interface.