Certification of Genuine Multipartite Entanglement with General and Robust Device-Independent Witnesses.

Genuine multipartite entanglement represents the strongest type of entanglement, which is an essential resource for quantum information processing. Standard methods to detect genuine multipartite entanglement, e.g., entanglement witnesses, state tomography, or quantum state verification, require full knowledge of the Hilbert space dimension and precise calibration of measurement devices, which are usually difficult to acquire in an experiment. The most radical way to overcome these problems is to detect entanglement solely based on the Bell-like correlations of measurement outcomes collected in the experiment, namely, device independently. However, it is difficult to certify genuine entanglement of practical multipartite states in this way, and even more difficult to quantify it, due to the difficulty in identifying optimal multipartite Bell inequalities and protocols tolerant to state impurity. In this Letter, we explore a general and robust device-independent method that can be applied to various realistic multipartite quantum states in arbitrary finite dimension, while merely relying on bipartite Bell inequalities. Our method allows us both to certify the presence of genuine multipartite entanglement and to quantify it. Several important classes of entangled states are tested with this method, leading to the detection of genuinely entangled states. We also certify genuine multipartite entanglement in weakly entangled Greenberger-Horne-Zeilinger states, showing that the method applies equally well to less standard states.

Extracting information from single qubits among multiple observers with optimal weak measurements.

In the context of quantum information, major efforts have been made to maximize the mutual information by measuring single copies of signal states. In general, one execution of optimal projective measurement extracts all the accessible mutual information. However, in some scenarios, weak measurements are preferred because of kinds of specific requirements, e.g., to distribute secret keys to multi-observers. In this study, we propose a method to construct optimal weak measurements for multi-party quantum communications. Utilizing the method in [Physical Review Letters 120, 160501 (2018)] to classify the mutual information, the theoretical study shows that by successively performing this optimal weak measurement, all accessible information can be obtained by multiple observers. This conclusion is experimentally verified by a cascaded measurement apparatus that can perform six successive weak measurements on heralded single photons. The experimental results clearly indicate that almost all accessible mutual information is extracted by this sequence of optimal weak measurements; meanwhile, none of the information is destroyed or residual. Thus, this optimal weak measurement is an efficient and reliable tool for performing quantum communication tasks. The consistence between the experimental and theoretical results verifies that the classifying method in [Phys. Rev. Lett.120, 160501 (2018)] can be applied to characterize realistic quantum measurements.

Experimental Optimal Verification of Entangled States Using Local Measurements.

The initialization of a quantum system into a certain state is a crucial aspect of quantum information science. While a variety of measurement strategies have been developed to characterize how well the system is initialized, for a given one, there is in general a trade-off between its efficiency and the accessible information of the quantum state. Conventional quantum state tomography can characterize unknown states while requiring exponentially expensive time-consuming postprocessing. Alternatively, recent theoretical breakthroughs show that quantum state verification provides a technique to quantify the prepared state with significantly fewer samples, especially for multipartite entangled states. In this Letter, we modify the original proposal to be robust to practical imperfections, and experimentally implement a scalable quantum state verification on two-qubit and four-qubit entangled states with nonadaptive local measurements. For all the tested states, the estimated infidelity is inversely proportional to the number of samples, which illustrates the power to characterize a quantum state with a small number of samples. Compared to the globally optimal strategy which requires nonlocal measurements, the efficiency in our experiment is only worse by a small constant factor (<2.5). We compare the performance difference between quantum state verification and quantum state tomography in an experiment to characterize a four-photon Greenberger-Horne-Zeilinger state, and the results indicate the advantage of quantum state verification in both the achieved efficiency and precision.

Experimental Realization of Robust Self-Testing of Bell State Measurements.

Bell state measurements, of which the eigenvectors are in an entangled form, are crucial resources in the construction of quantum networks. Therefore, device-independent certification of a Bell state measurement has significance in the quantum information process because it satisfies the exact demand on security. In this study, we implement a proof-of-concept experiment to certify a Bell state measurement device independently in an entanglement swapping process, namely, self-testing. Instead of preparing a tensor product of two singlets with four photons, multiplex encoding in polarization and spatial modes is utilized to produce two pairs of entangled qubits. As a result, we implement a full Bell state measurement and achieve a high degree of Bell violation on the remaining two qubits, which are required for nontrivial self-testing of a Bell state measurement. Furthermore, our results combine the correlations before and after the swapping; thus, the quality of the performed Bell state measurement can be precisely inferred.

Experimentally Robust Self-testing for Bipartite and Tripartite Entangled States.

Self-testing is a method with which a classical user can certify the state and measurements of quantum systems in a device-independent way. In particular, self-testing of entangled states is of great importance in quantum information processing. An understandable example is that the maximal violation of the Clauser-Horne-Shimony-Holt inequality necessarily implies that the bipartite system shares a singlet. One essential question in self-testing is that, when one observes a nonmaximum violation, how far is the tested state from the target state (which maximally violates a certain Bell inequality)? The answer to this question describes the robustness of the used self-testing criterion, which is highly important in a practical sense. Recently, J. Kaniewski derived two analytic self-testing bounds for bipartite and tripartite systems. In this Letter, we experimentally investigate these two bounds with high-quality two-qubit and three-qubit entanglement sources. The results show that these bounds are valid for various entangled states that we prepared. Thereby, a proof-of-concept demonstration of robust self-testing is achieved, which improves on the previous results significantly.

Achieving Heisenberg-Scaling Precision with Projective Measurement on Single Photons.

It has been suggested that both quantum superpositions and nonlinear interactions are important resources for quantum metrology. However, to date the different roles that these two resources play in the precision enhancement are not well understood. Here, we experimentally demonstrate a Heisenberg-scaling metrology to measure the parameter governing the nonlinear coupling between two different optical modes. The intense mode with n (more than 10^{6} in our work) photons manifests its effect through the nonlinear interaction strength which is proportional to its average photon number. The superposition state of the weak mode, which contains only a single photon, is responsible for both the linear Hamiltonian and the scaling of the measurement precision. By properly preparing the initial state of single photon and making projective photon-counting measurements, the extracted classical Fisher information (FI) can saturate the quantum FI embedded in the combined state after coupling, which is ∼n^{2} and leads to a practical precision ≃1.2/n. Free from the utilization of entanglement, our work paves a way to realize Heisenberg-scaling precision when only a linear Hamiltonian is involved.

Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells.

Imatinib, a breakpoint cluster region (BCR)-Abelson murine leukemia(ABL) tyrosine kinase inhibitor (TKI), has revolutionized the treatment of chronic myelogenous leukemia (CML). However, development of multidrug resistance(MDR) limits the use of imatinib. In the present study, we aimed to investigate the mechanisms of cellular resistance to imatinib in CML. Therefore, we established an imatinib-resistant human CML cell line(K562-imatinib) through a stepwise selection process. While characterizing the phenotype of these cells, we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells. In addition, these cells were cross-resistant to second- and third-generation BCR-ABL TKIs. Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein(P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells. In addition, accumulation of [14C]6-mercaptopurine (6-MP) was decreased, whereas the ATP-dependent efflux of [14C]6-MP and [3H]methotrexate transport were increased in K562-imatinib cells. These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.

Effects of food restriction and sucrose intake on synaptic delivery of AMPA receptors in nucleus accumbens.

Insertion and removal of AMPA receptors from the synaptic membrane underlie dynamic tuning of synaptic transmission and enduring changes in synaptic strength. Preclinical addiction research suggests that AMPA receptor trafficking plays an important role in nucleus accumbens (NAc) neuroplasticity underlying the compulsive and persistent quality of drug-seeking. Considering the parallels between drug addiction and compulsive eating, plus the supranormal reward properties of sucrose, and the role of dieting as a risk factor in development of binge pathology, the present study used a biochemical subcellular fractionation approach to determine whether brief intake of a 10% sucrose solution increases synaptic delivery of AMPA receptors in NAc of chronically food-restricted (FR) relative to ad libitum fed (AL) rats. FR, alone, produced a small but significant increase in synaptic expression of AMPA receptors. This may contribute to NAc integrative mechanisms that mediate the enhanced behavioral responsiveness of FR subjects to phasic reward stimuli, including food and drugs. Brief intake of sucrose increased GluR1 in the PSD, regardless of dietary condition, though the net effect was greater in FR than AL subjects. A marked increase in GluR2 was also observed, but only in FR rats. This set of results suggests that in FR subjects, sucrose may have primarily increased delivery of GluR1/GluR2 heteromers to the PSD, while in AL subjects sucrose increased delivery of GluR2-lacking channels. The functional consequences of these possible differences in subunit composition of trafficked AMPA receptors between diet groups remain to be determined. Nevertheless, the present set of results suggest a promising new avenue to pursue in the effort to understand synaptic plasticity involved in adaptive and pathological food-directed behavior and the mechanistic basis of severe dieting as a risk factor for the latter.

Improving the precision of optical metrology by detecting fewer photons with biased weak measurement.

In optical metrological protocols to measure physical quantities, it is, in principle, always beneficial to increase photon number n to improve measurement precision. However, practical constraints prevent the arbitrary increase of n due to the imperfections of a practical detector, especially when the detector response is dominated by the saturation effect. In this work, we show that a modified weak measurement protocol, namely, biased weak measurement significantly improves the precision of optical metrology in the presence of saturation effect. This method detects an ultra-small fraction of photons while maintains a considerable amount of metrological information. The biased pre-coupling leads to an additional reduction of photons in the post-selection and generates an extinction point in the spectrum distribution, which is extremely sensitive to the estimated parameter and difficult to be saturated. Therefore, the Fisher information can be persistently enhanced by increasing the photon number. In our magnetic-sensing experiment, biased weak measurement achieves precision approximately one order of magnitude better than those of previously used methods. The proposed method can be applied in various optical measurement schemes to remarkably mitigate the detector saturation effect with low-cost apparatuses.

The epidermal growth factor tyrosine kinase inhibitor AG1478 and erlotinib reverse ABCG2-mediated drug resistance.

ABCG2 is an important member of ATP-binding cassette (ABC) transporter shown to confer drug resistance in cancer cells. Recent studies show that an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, is able to modulate the function of ABCG2 and reverse ABCG2-mediated multidrug resistance (MDR) in cancer cells. Additionally, ABCG2 expression has been shown to impact treatment efficacy and development of side-effects in patients receiving gefitinib. However, it is unclear whether other EGFR TKIs interact with ABCG2 in a similar manner. In the present study, we investigated the interaction of two other EGFR TKIs, AG1478 and erlotinib, with ABCG2. Our data show that AG1478 and erlotinib potently sensitized drug-resistant cells overexpressing either wild-type or mutated ABCG2 to the ABCG2 substrate anti-cancer drugs flavopiridol and mitoxantrone. Neither AG1478 nor erlotinib sensitized ABCG2-overexpressing cells to drugs that are not substrates of ABCG2 nor did they impact drug sensitivity of parental cells. Furthermore, AG1478 and erlotinib were able to significantly enhance the intracellular accumulation of mitoxantrone in cells expressing either wild-type or mutated ABCG2. Additionally, they did not alter the protein expression of ABCG2 in the ABCG2-overexpressing cells. Taken together, we conclude that AG1478 and erlotinib potently reverse ABCG2-mediated MDR through directly inhibiting the drug efflux function of ABCG2 in the ABCG2-overexpressing cells. These results will be useful in the development of novel and more effective EGFR TKIs as well as the development of combinational chemotherapeutic strategies.

Up-regulation of MRP4 and down-regulation of influx transporters in human leukemic cells with acquired resistance to 6-mercaptopurine.

To investigate the mechanism of cellular resistance to 6-MP, we established a 6-MP resistant cell line (CEM-MP5) by stepwise selection of the human T-lymphoblastic leukemia cell line (CEM). CEM-MP5 cells were about 100-fold resistant to 6-MP compared with parental CEM cells. Western blot analysis demonstrated that multidrug resistant protein 4 (MRP4) was increased in CEM-MP5 cells, whereas the levels of the nucleoside transporters hENT1, hCNT2 and hCNT3 were decreased compared with those of parental CEM cells. Consistent with the operation of an efflux pump, accumulation of [14C]6-MP and/or its metabolites was reduced, and ATP-dependent efflux was increased in CEM-MP5 cells. Taken together these results showed that up-regulation of MRP4 and down-regulation of influx transporters played a major role in 6-MP resistance of CEM-MP5 cells.

Involvement of nucleus accumbens AMPA receptor trafficking in augmentation of D- amphetamine reward in food-restricted rats.

RATIONALE: Chronic food restriction (FR) increases behavioral responsiveness to drugs of abuse and associated environments. Pre- and postsynaptic neuroadaptations have been identified in the mesoaccumbens dopamine pathway of FR subjects but the mechanistic basis of increased drug reward magnitude remains unclear. OBJECTIVES: Effects of FR on basal and D-amphetamine-induced trafficking of AMPA receptor subunits to the nucleus accumbens (NAc) postsynaptic density (PSD) were examined, and AMPA receptor involvement in augmentation of D-amphetamine reward was tested. MATERIALS AND METHODS: FR and ad libitum fed (AL) rats were injected with D-amphetamine (2.5 mg/kg, i.p.) or vehicle. Brains were harvested and subcellular fractionation and Western analyses were used to assess AMPA receptor abundance in NAc homogenate and PSD fractions. A follow-up experiment used a curve-shift protocol of intracranial self-stimulation to assess the effect of 1-naphthylacetyl spermine (1-NASPM), a blocker of Ca(2+)-permeable AMPA receptors, on rewarding effects of D-amphetamine microinjected in NAc shell. RESULTS: FR increased GluA1 in the PSD, and D-amphetamine increased p-Ser845-GluA1, GluA1, GluA2, but not GluA3, with a greater effect in FR than AL rats. D-amphetamine lowered reward thresholds, with greater effects in FR than AL rats, and 1-NASPM selectively reversed the enhancing effect of FR. CONCLUSIONS: Results suggest that FR leads to increased synaptic incorporation of GluA1 homomers to potentiate rewarding effects of appetitive stimuli and, as a maladaptive byproduct, D-amphetamine. The D-amphetamine-induced increase in synaptic p-Ser845-GluA1, GluA1, and GluA2 may contribute to the rewarding effect of D-amphetamine, but may also be a mechanism of synaptic strengthening and behavior modification.

Effects of protein kinase A inhibitor and activator on rewarding effects of SKF-82958 microinjected into nucleus accumbens shell of ad libitum fed and food-restricted rats.

RATIONALE: Previous studies indicate that the rewarding effect of D-1 dopamine receptor stimulation in nucleus accumbens (NAc) shell is greater in food-restricted (FR) than in ad libitum fed (AL) rats. The D-1 receptor is positively coupled to adenylyl cyclase and activates protein kinase A (PKA). OBJECTIVES: The purpose of this study was to determine whether PKA is involved in the rewarding effect of D-1 receptor stimulation and, if so, whether it is involved in the enhanced response of FR rats. MATERIALS AND METHODS: Rats were stereotaxically implanted with microinjection cannulae in NAc shell and a stimulating electrode in lateral hypothalamus. The rewarding effects of SKF-82958 (1.5 or 3.0 µg, bilaterally) in the presence and absence of PKA inhibitor, Rp-cAMPS (8.9 µg), and PKA activator, Sp-cAMPS (8.9 µg), were assessed using the curve-shift method of intracranial self-stimulation (ICSS). Basal NAc levels of DARPP-32 phosphorylated on Thr34 and Thr75 were measured. RESULTS: Rp-cAMPS increased the rewarding effect of SKF-82958 in AL but not FR rats, doubling the ICSS threshold-lowering effect of the 3.0-µg dose. Sp-cAMPS decreased the rewarding effect of SKF-82958 in FR but not AL rats. Levels of phospho-DARPP-32 (Thr75), which inhibits PKA, were higher in FR than AL rats. CONCLUSIONS: Results indicate that inhibition of PKA enhances the unconditioned rewarding effect of D-1 receptor stimulation and that decreased PKA may be involved in the effect of FR on drug reward. Evidence for involvement of D-2 receptor-expressing neurons in the enhancing effect of PKA inhibition is discussed.

Enhanced cocaine-conditioned place preference and associated brain regional levels of BDNF, p-ERK1/2 and p-Ser845-GluA1 in food-restricted rats.

Previously, a learning-free measure was used to demonstrate that chronic food restriction (FR) increases the reward magnitude of a wide range of abused drugs. Moreover, a variety of striatal neuroadaptations were detected in FR subjects, some of which are known to be involved in synaptic plasticity but have been ruled out as modulators of acute drug reward magnitude. Little is known about effects of FR on drug-conditioned place preference (CPP) and brain regional mechanisms that may enhance CPP in FR subjects. The purpose of the present study was to compare the expression and persistence of a conditioned place preference (CPP) induced by a relatively low dose of cocaine (7.0mg/kg, i.p.) in ad libitum fed (AL) and FR rats and take several brain regional biochemical measures following the first CPP conditioning session to probe candidate mechanisms that may underlie the more robust CPP observed in FR subjects. Behaviorally, AL subjects displayed a CPP upon initial testing which extinguished rapidly over the course of subsequent test sessions while CPP in FR subjects persisted. Despite previous reports of elevated BDNF protein in forebrain regions of FR rats, the FR protocol used in the present study did not alter BDNF levels in dorsal hippocampus, nucleus accumbens or medial prefrontal cortex. On the other hand, FR rats, whether injected with cocaine or vehicle, displayed elevated p-ERK1/2 and p-Ser845-GluA1 in dorsal hippocampus. FR rats also displayed elevated p-ERK1/2 in medial prefrontal cortex and elevated p-ERK1 in nucleus accumbens, with further increases produced by cocaine. The one effect observed exclusively in cocaine-treated FR rats was increased p-Ser845-GluA1 in nucleus accumbens. These findings suggest a number of avenues for continuing investigation with potential translational significance.

Up-regulation of P-glycoprotein confers acquired resistance to 6-mercaptopurine in human chronic myeloid leukemia cells.

To investigate the mechanisms of cellular resistance to 6-mercaptopurine (6-MP) in chronic myeloid leukemia (CML), a 6-MP resistant cell line (K562-MP5) was established by stepwise selection of the CML cell line (K562). The results of the drug sensitivity analysis of the K562-MP5 cell line revealed the cells to be 339-fold more resistant to 6-MP compared with the parental K562 cells. K562-MP5 cells exhibited decreased accumulation and increased efflux of [(14)C]6-MP and its metabolites. In addition, K562-MP5 cells showed increased [(3)H]MTX transport. K562-MP5 cells over-expressed P-glycoprotein (P-gp) and up-regulated MDR1 mRNA levels. Taken together, these results suggest that the up-regulation of P-gp, which contributes to the decreased accumulation by increasing the efflux of 6-MP and its metabolites, underlies the mechanism of 6-MP resistance in K562 cells.

Cepharanthine is a potent reversal agent for MRP7(ABCC10)-mediated multidrug resistance.

Multidrug resistance protein 7 (MRP7; ABCC10) is an ABC transporter that confers resistance to anticancer agents such as the taxanes. We previously reported that several inhibitors of P-gp and MRP1 were able to inhibit the in vitro transport of E(2)17betaG by MRP7 in membrane vesicles transport assays. However, compounds that are able to reverse MRP7-mediated cellular resistance have not been identified. In this study, we examined the effects of cepharanthine (6',12'-dimethoxy-2,2'-dimethyl-6,7-[methylenebis(oxy)]oxyacanthan), an herbal extract isolated from Stephania cepharantha Hayata, to reverse paclitaxel resistance in MRP7-transfected HEK293 cells. Cepharanthine, at 2microM, completely reversed paclitaxel resistance in MRP7-transfected cells. In contrast, the effect of cepharanthine on the parental transfected cells was significantly less than that on the MRP7-transfected cells. In addition, cepharanthine significantly increased the accumulation of paclitaxel in MRP7-transfected cells almost to the level of control cells in the absence of cepharanthine. The efflux of paclitaxel from MRP7-transfected cells was also significantly inhibited by cepharanthine. The ability of cepharanthine to inhibit MRP7 was analyzed in membrane vesicle assays using E(2)17betaG, an established substrate of MRP7, as a probe. E(2)17betaG transport was competitively inhibited by cepharanthine with a K(i) value of 4.86microM. These findings indicate that cepharanthine reverses MRP7-mediated resistance to paclitaxel in a competitive manner.

Sipholenol A, a marine-derived sipholane triterpene, potently reverses P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells.

Through extensive screening of marine sponge compounds, the authors have found that sipholenol A, a sipholane triterpene isolated from the Red Sea sponge, Callyspongia siphonella, potently reversed multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp). In experiments, sipholenol A potentiated the cytotoxicity of several P-gp substrate anticancer drugs, including colchicine, vinblastine, and paclitaxel, but not the non-P-gp substrate cisplatin, and significantly reversed the MDR of cancer cells KB-C2 and KB-V1 in a concentration-dependent manner. Furthermore, sipholenol A had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing MDR protein 1 or breast cancer resistance protein. Sipholenol A (IC(50) > 50 microM) is not toxic to all the cell lines that were used, regardless of their membrane transporter status. Accumulation and efflux studies with the P-gp substrate [(3)H]-paclitaxel demonstrated that sipholenol A time-dependently increased the intracellular accumulation of [(3)H]-paclitaxel by directly inhibiting P-gp-mediated drug efflux. In addition, sipholenol A did not alter the expression of P-gp after treating KB-C2 and KB-V1 cells for 36 h and 72 h. However, it efficaciously stimulated the activity of ATPase of P-gp and inhibited the photolabeling of this transporter with its transport substrate [(125)I]-iodoarylazidoprazosin. Overall, the present results indicate that sipholenol A efficiently inhibits the function of P-gp through direct interactions, and sipholane triterpenes are a new class of potential reversing agents for treatment of MDR in P-gp-overexpressing tumors.

Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance.

It has been reported that gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has the ability to modulate the function of certain ATP-binding cassette (ABC) transporters and to reverse ABC subfamily B member 1 (ABCB1; P-glycoprotein)- and ABC subfamily G member 2 (ABCG2; breast cancer resistance protein/mitoxantrone resistance protein)-mediated multidrug resistance (MDR) in cancer cells. However, it is unknown whether other EGFR TKIs have effects similar to that of gefitinib. In the present study, we have investigated the interaction of another EGFR TKI, erlotinib, with selected ABC drug transporters. Our findings show that erlotinib significantly potentiated the sensitivity of established ABCB1 or ABCG2 substrates and increased the accumulation of paclitaxel or mitoxantrone in ABCB1- or ABCG2-overexpressing cells. Furthermore, erlotinib did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in all cells and was unable to reverse MRP1-mediated MDR and had no effect on the parental cells. However, erlotinib remarkably inhibited the transport of E(2)17 beta G and methotrexate by ABCG2. In addition, the results of ATPase assays show that erlotinib stimulated the ATPase activity of both ABCB1 and ABCG2. Interestingly, erlotinib slightly inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin (IAAP) at high concentration, but it did not inhibit the photolabeling of ABCG2 with IAAP. Overall, we conclude that erlotinib reverses ABCB1- and ABCG2-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1 and ABCG2. These findings may be useful for cancer combinational therapy with erlotinib in the clinic.