Defect chemistry in ferroelectric perovskites: long standing issues and recent advances.

Accurate control of residual defect density is required for reliable investigation and use of ferroelectric materials. After reviewing the long term endeavor to decrease defect contributions in bulk materials, which reached mass production decades ago, recent challenges are underlined. These mostly result from the continuous trend towards integration which has reached the nanometre range. The contribution of solid state chemistry is of key relevance for improving the present processing routes and suggesting alternative ones, for example by controlling a large density of charged defects to reach unprecedented functionalities. Some of these breakthroughs are reviewed.

Systematic tuning of the conduction mechanisms in ferroelectric thin films.

We have investigated the macroscopic and microscopic properties of large sets of Ba0.7Sr0.3TiO3 thin films including several substitution rates of manganese. Thanks to a high degree of control of the processing parameters at each stage we have been able to find a link between the dc leakage current and the low and high frequency dielectric permittivity and losses. We supplemented these macroscopic observations with in depth investigations of the defect states through x-ray photoelectron spectroscopy. We found that both the leakage current and the extrinsic dielectric parameters arise from a large density of charged point defects related to oxygen vacancies. At the outer surfaces of the films, the density of such charged defects is so high that it can raise the Fermi level to close to the conduction band. Such degradation of the films' performance can be relieved by appropriate manganese substitution for the titanium host ions. Such doping is able to move back the Fermi level to close to the center of the bandgap thus changing the conduction process from interfacial Schottky to bulk Poole Frenkel and decreasing the extrinsic losses. This beneficial effect was already inferred in ceramics and thin films but we have established a clear link between the macroscopic parameters and the microscopic defect state. This model can be transferred to many high permittivity oxides.

The transcriptional network controlling pluripotency in ES cells.

Embryonic stem (ES) cells are capable of continuous self-renewal and pluripotential differentiation. A "core" set of transcription factors, Oct4, Sox2, and Nanog, maintains the ES cell state, whereas various combinations of factors, invariably including Oct4 and Sox2, reprogram somatic cells to pluripotency. We have sought to define the transcriptional network controlling pluripotency in mouse ES cells through combined proteomic and genomic approaches. We constructed a protein interaction network surrounding Nanog and determined gene targets of the core and reprogramming factors, plus others. The expanded transcriptional network we have constructed forms the basis for further studies of directed differentiation and lineage reprogramming, and a paradigm for comprehensive elucidation of regulatory pathways in other stem cells.

Lentiviral vector transduction of hematopoietic stem cells that mediate long-term reconstitution of lethally irradiated mice.

Lentiviral vectors efficiently transduce human CD34(+) cells that mediate long-term engraftment of nonobese diabetic/severe combined immunodeficient mice. However, hematopoiesis in these animals is abnormal. Typically, 95% of the human cells in peripheral blood are B lymphocytes. To determine whether lentiviral vectors efficiently transduce stem cells that maintain normal hematopoiesis in vivo, we isolated Sca-1(+)c-Kit(+)Lin(-) bone marrow cells from mice without 5-fluorouracil treatment, and transduced these cells in the absence of cytokine stimulation with a novel lentiviral vector containing a GFP (green flourescent protein) reporter gene. These cells were transplanted into lethally irradiated C57Bl/6 mice. In fully reconstituted animals, GFP expression was observed in 8.0% of peripheral blood mononuclear cells for 20 weeks posttransplantation. Lineage analysis demonstrated that a similar percentage (approximately 8.0%) of GFP-positive cells was detected in peripheral blood B cells, T cells, granulocytes and monocytes, bone marrow erythroid precursor cells, splenic B cells, and thymic T cells. In secondary transplant recipients, up to 20% of some lineages expressed GFP. Our results suggest that quiescent, hematopoietic stem cells are efficiently transduced by lentiviral vectors without impairing self-renewal and normal lineage specification in vivo. Efficient gene delivery into murine stem cells with lentiviral vectors will allow direct tests of genetic therapies in mouse models of hematopoietic diseases such as sickle cell anemia and thalassemia, in which corrected cells may have a selective survival advantage.