The kagome Heisenberg antiferromagnet is a leading candidate in the search for a spin system with a quantum spin liquid ground state. The nature of its ground state remains a matter of great debate. We conducted 17 O single crystal NMR measurements of the spin S = 1 / 2 kagome lattice in herbertsmithite ZnCu 3 (OH) 6 Cl 2 , which is known to exhibit a spinon continuum in the spin excitation spectrum. We demonstrate that the intrinsic local spin susceptibility χ kagome deduced from the 17 O NMR frequency shift asymptotes to zero below temperature T~0.03J , where 200 J K is the Cu-Cu super-exchange interaction. Combined with the magnetic field dependence of χ kagome we observed at low temperatures, these results imply that the kagome Heisenberg antiferromagnet has a spin liquid ground state with a finite gap. 2The realization and characterization of a kagome Heisenberg antiferromagnet (KHA) with a corner-shared triangle structure (Fig.1A) is crucial for the search for a quantum spin liquid ground state (1,2). Spin-liquids consist of entangled pairs of spin-singlets, and do not undergo a magnetic phase transition. The successful synthesis of the structurally ideal kagome lattice of Cu 2+ ions (spin S = 1 / 2 ) in herbertsmithite ZnCu 3 (OH) 6 Cl 2 (Fig.1B-E) (3) was welcomed as a major milestone (4). ZnCu 3 (OH) 6 Cl 2 remains paramagnetic at least down to ~50 mK (5,6).Moreover, inelastic neutron scattering measurements (7) on single crystals (8) demonstrated that the spin excitation spectrum does not exhibit conventional magnons, but rather a spinon continuum. Despite the recent progress, fundamental issues regarding the nature of the ground state of the KHA remain to be understood. For example, the central question on the existence of a gap in the spin excitation spectrum has not been settled. This information is critical to distinguish between the leading theories for the ground state of the S = 1 / 2 KHA: a gapped spin liquid, gapless spin liquid, or valence bond solid (1,2,9-14)In ZnCu 3 (OH) 6 Cl 2, weakly interacting Cu 2+ defects occupy the non-magnetic Zn 2+ sites between the kagome-layers with ~15% probability (15). Their contributions dominate bulkaveraged thermodynamic properties at low temperatures (3,5,8,16,17), making it difficult to measure the intrinsic low energy properties of this material. Similarly, the Cu 2+ impurity moments can contribute to the inelastic neutron scattering, obscuring the response of the intrinsic kagome spins at low energies (< 2meV) (7 A major advantage of using a single crystal for NMR is that we can achieve high resolution by applying an external magnetic field B ext along specific crystallographic directions.In Fig (c) . In addition, the central peak frequency f for the I z = −1 / 2 to +1 / 2 transition is shifted from the bare resonance frequency f o = (γ n / 2π )B ext by the effects of the hyperfine magnetic fields from nearby Cu 2+ sites, and the shift of the peak (marked as Main in Fig. 2A) is proportional to χ kagome . Such a NMR frequency shift may be expressed i...

Ceramide glycosylation, through glucosylceramide synthase (GCS), allows cellular escape from ceramide-induced programmed cell death. This glycosylation event confers cancer cell resistance to cytotoxic anticancer agents [Liu, Y. Y., Han, T. Y., Giuliano, A. E., and M. C. Cabot. (1999) J. Biol. Chem. 274, 1140-1146]. We previously found that glucosylceramide, the glycosylated form of ceramide, accumulates in adriamycin-resistant breast carcinoma cells, in vinblastine-resistant epithelioid carcinoma cells, and in tumor specimens from patients showing poor response to chemotherapy. Here we show that multidrug resistance can be increased over baseline and then totally reversed in human breast cancer cells by GCS gene targeting. In adriamycin-resistant MCF-7-AdrR cells, transfection of GCS upgraded multidrug resistance, whereas transfection of GCS antisense markedly restored cellular sensitivity to anthracyclines, Vinca alkaloids, taxanes, and other anticancer drugs. Sensitivity to the various drugs by GCS antisense transfection increased 7- to 240-fold and was consistent with the resumption of ceramide-caspase-apoptotic signaling. GCS targeting had little influence on cellular sensitivity to either 5-FU or cisplatin, nor did it modify P-glycoprotein expression or rhodamine-123 efflux. GCS antisense transfection did enhance rhodamine-123 uptake compared with parent MCF-7-AdrR cells. This study reveals that GCS is a novel mechanism of multidrug resistance and positions GCS antisense as an innovative force to overcome multidrug resistance in cancer chemotherapy.

No abstract

In this study, we have introduced glucosylceramide synthase (GCS) into wild type MCF-7 breast cancer cells using a retroviral tetracycline-on expression system, and we developed a cell line, MCF-7/GCS. MCF-7/GCS cells expressed an 11-fold higher level of GCS activity compared with the parental cell line. Interestingly, the transfected cells demonstrated strong resistance to adriamycin and to ceramide, whereas both agents were highly cytotoxic to MCF-7 cells. The EC 50 values of adriamycin and ceramide were 11-fold (p < 0.0005) and 5-fold (p < 0.005) higher, respectively, in MCF-7/GCS cells compared with MCF-7 cells. Ceramide resistance displayed by MCF-7/ GCS cells closely paralleled the activity of expressed GCS with a correlation coefficient of 0.99. In turn, cellular resistance and GCS activity were dependent upon the concentration of the expression mediator doxycycline. Adriamycin resistance in MCF-7/GCS cells was related to the hyperglycosylation of ceramide and was not related to shifts in the levels of either P-glycoprotein or Bcl-2. This work demonstrates that overexpression of GCS, which catalyzes ceramide glycosylation, induces resistance to adriamycin and ceramide in MCF-7 breast cancer cells.