Implementation of a stable, high-power optical lattice for quantum gas microscopy.

We describe the design and implementation of a stable high-power 1064 nm laser system to generate optical lattices for experiments with ultracold quantum gases. The system is based on a low-noise laser amplified by an array of four heavily modified, high-power fiber amplifiers. The beam intensity is stabilized and controlled with a nonlinear feedback loop. Using real-time monitoring of the resulting optical lattice, we find the stability of the lattice site positions to be well below the lattice spacing over the course of hours. The position of the harmonic trap produced by the Gaussian envelope of the lattice beams is stable to about one lattice spacing and the long-term (six-month) relative root-mean-square stability of the lattice spacing itself is 0.5%.

Order of magnitude smaller limit on the electric dipole moment of the electron.

The Standard Model of particle physics is known to be incomplete. Extensions to the Standard Model, such as weak-scale supersymmetry, posit the existence of new particles and interactions that are asymmetric under time reversal (T) and nearly always predict a small yet potentially measurable electron electric dipole moment (EDM), d(e), in the range of 10(-27) to 10(-30) e·cm. The EDM is an asymmetric charge distribution along the electron spin (S(→)) that is also asymmetric under T. Using the polar molecule thorium monoxide, we measured d(e) = (-2.1 ± 3.7stat ± 2.5syst) × 10(-29) e·cm. This corresponds to an upper limit of |d(e)| < 8.7 × 10(-29) e·cm with 90% confidence, an order of magnitude improvement in sensitivity relative to the previous best limit. Our result constrains T-violating physics at the TeV energy scale.

The in vivo properties of STX243: a potent angiogenesis inhibitor in breast cancer.

The steroidal-based drug 2-ethyloestradiol-3,17-O,O-bis-sulphamate (STX243) has been developed as a potent antiangiogenic and antitumour compound. The objective of this study was to ascertain whether STX243 is more active in vivo than the clinically relevant drug 2-methoxyoestradiol (2-MeOE2) and the structurally similar compound 2-MeOE2-3,17-O,O-bis-sulphamate (STX140). The tumour growth inhibition efficacy, antiangiogenic potential and pharmacokinetics of STX243 were examined using four in vivo models. Both STX243 and STX140 were capable of retarding the growth of MDA-MB-231 xenograft tumours (72 and 63%, respectively), whereas no inhibition was observed for animals treated with 2-MeOE2. Further tumour inhibition studies showed that STX243 was also active against MCF-7 paclitaxel-resistant tumours. Using a Matrigel plug-based model, in vivo angiogenesis was restricted with STX243 and STX140 (50 and 72%, respectively, using a 10 mg kg(-1) oral dose), thereby showing the antiangiogenic activity of both compounds. The pharmacokinetics of STX243 were examined at two different doses using adult female rats. The compound was orally bioavailable (31% after a single 10 mg kg(-1) dose) and resistant to metabolism. These results show that STX243 is a potent in vivo drug and could be clinically effective at treating a number of oncological conditions.

Inhibition of steroid sulphatase activity via the percutaneous route: a new option for breast cancer therapy.

Steroid sulphatase (STS) inhibitors have been developed primarily for the treatment of hormone-dependent breast cancer, but may also have utility for the treatment of a number of androgen-dependent skin conditions. STS regulates the hydrolysis of steroid sulphates, such as oestrone sulphate (E1S) and dehydroepiandrosterone sulphate, (DHEAS). Liberated oestrone (E1) can be converted to biologically active oestradiol (E2) while dehydroepiandrosterone (DHEA) can undergo reduction to testosterone or aromatisation to E1. In this study the ability of the STS inhibitor STX64 (BN83495) and its N,N-dimethyl analogue (STX289) to inhibit liver and skin STS when applied orally or topically to nude mice was examined. Oral administration at 1 and 10 mg/kg resulted in almost complete inhibition of skin and liver STS. When applied topically to the dorsal neck region at 1.0 and 10 mg/kg not only skin but, unexpectedly, also liver STS was effectively inhibited. An investigation into the metabolism of these two compounds by HepG2 liver carcinoma cells, with high-performance liquid chromatography (HPLC) analysis, was also undertaken. In the presence of HepG2 cells a similar degree of desulphamoylation of STX64 (68%) or de-N, N-dimethylsulphamoylation of STX289 (66%) occurred over a 3h period. In the absence of cells, however, STX289 was resistant to de-N, N-dimethylsulphamoylation whereas STX64 was completely desulphamoylated, demonstrating the more favourable pharmaceutical profile of STX289 for development for topical application. It is concluded that both STX64 and STX289 are not only effective inhibitors of skin STS, but also liver STS when applied topically. These findings suggest that it may be possible to develop a formulation for the percutaneous administration of STS inhibitors, but also that this class of compound may have therapeutic potential for the treatment of a number of skin disorders.

Tibolone and its delta-4, 7alpha-methyl norethisterone metabolite are reversible inhibitors of human aromatase.

Tibolone is used for the treatment of climacteric symptoms and osteoporosis in menopausal women. After ingestion, it is rapidly converted to a number of metabolites including 3alpha- and 3beta-hydroxy derivatives and the delta-4, 7alpha-methylnorethisterone (7alpha-MeNET) metabolite, which is rapidly cleared from circulation. Tibolone and some of its metabolites act in a tissue-selective manner to inhibit steroid sulphatase (STS) and 17beta-hydroxysteroid dehydrogenase Type 1 (17beta-HSD1) activities but also stimulate steroid sulphotransferase and 17beta-HSD2 activities. In the present study we have examined whether the ability of tibolone and its 7alpha-MeNET metabolites to regulate the activities of enzymes involved in oestrogen formation or inactivation extends to another key enzyme involved in oestrogen synthesis, the aromatase, which converts androstenedione to oestrone. Using JEG-3 choriocarcinoma cells, which have a high level of aromatase activity, tibolone and 7alpha-MeNET, but not the 3alpha- or 3beta-hydroxy metabolites, were found to inhibit aromatase activity in intact cells and also lysates prepared from these cells (up to 61% inhibition at 10muM). An investigation into the nature of aromatase inhibition by these compounds revealed that they inhibit aromatase activity by a reversible mechanism. Tibolone and 7alpha-MeNET also inhibited aromatase activity in MCF-7 breast cancer cells, which have a much lower level of aromatase activity than JEG-3 cells. It is concluded that, in addition to inhibiting STS and 17beta-HSD1, tibolone and 7alpha-MeNET may exert some of their tissue-selective effects in regulating oestrogen synthesis by also inhibiting aromatase activity.

Suppression of myelopoiesis and myeloid leukemia cell line proliferation by a novel bone marrow-derived factor, reptimed.

Bone marrow is the major site of hematopoiesis in the adult mammal. Bone marrow contains a highly organized microenvironment for the support of hematopoietic stem and progenitor cells, including the production of growth factors. Bone marrow cells also produce negative regulatory factors which may regulate hematopoiesis and inflammatory responses. In this paper we describe Reptimed, a unique bone marrow-derived factor with inhibitory activity for myelopoiesis and in vitro growth of myeloid cell lines. Reptimed was partially purified from bone marrow supernatants using a combination of solid-phase extraction and size exclusion chromatography. Reptimed is < 1000 Da MW and is water soluble. Reptimed inhibited growth of granulocyte-macrophage and macrophage colonies as well as proliferation of several myeloid leukemia cell lines. Reptimed may be part of a hemoregulatory circuit.

Separation of allostimulatory and natural suppressor/stem cell functions of murine bone marrow--implications for bone marrow transplantation.

Natural suppressor (NS) activity is defined by the ability of a null cell population to inhibit antigenic and mitogenic activation of lymphoid cells. We had previously demonstrated that murine and human bone marrow was a rich source of NS activity and could be enriched in a population of large, low-density cells after counterflow centrifugal elutriation (CCE). In this report we confirm previous findings in the mixed lymphocyte reaction (MLR) that NS activity is an endogenous function of BM and is not present in peripheral immune tissues. Furthermore, suppression by BM NS cells in the MLR is not MHC restricted, which distinguishes NS activity from veto activity also associated with BM. To enrich for NS activity, BM cells were separated into 3 fractions according to size and density by CCE. Fraction (F) 1 contained small, high-density cells; F2 contained cells of intermediate size and density; and F3 comprised large, low-density cells. Addition of CCE-enriched fractions to the MLR revealed potent NS activity associated with F3, consistent with our previous findings in the Ab response. CCE-enriched fractions of BM cells were also used as stimulators in an MLR to determine which fraction, if any, could support alloantigen-induced proliferation. The use of unfractionated C57Bl/6 (H-2b) BM cells as stimulators for BALB/c (H-2d) splenic responders resulted in little detectable proliferation as compared with that induced by C57Bl/6 splenic stimulators. However, when elutriated fractions were used as stimulators, F1 BM cells induced a significant proliferative response, albeit to a lesser magnitude than spleen cells. In order to determine which fraction contained hematopoietic progenitors, CCE-separated cells were assayed for granulocyte/macrophage colony formation (CFU-GM). F3 BM was enriched five-fold for CFU-GM progenitors as compared with unfractionated BM, while progenitors were virtually absent in F1 and F2 BM. The results suggest that CCE may represent an effective way of removing potential alloantigen-presenting cells (F1) from BM, while retaining hematopoietic progenitors and NS activity (F3). The implications of the findings as they relate to allogeneic BM transplantation are discussed.

Direct selection in vitro for herbicide-resistant mutants of Nicotiana tabacum.

Seven cell lines of Nicotiana tabacum resistant to the herbicide picloram were isolated from cell cultures. In crosses of plants regenerated from four cell lines, resistance was inherited as a single dominant Mendelian allele. Plants could not be regenerated from one cell line, and expression of resistance proved unstable in two others.

Isolation of a Glycerol-Utilizing Mutant of NICOTIANA TABACUM.

Although normal tobacco cell cultures cannot grow on glycerol as the sole carbon source, a spontaneous mutant cell line capable of utilizing glycerol has been isolated. Plants have been regenerated from this mutant cell line, and the results of preliminary genetic analyses are reported. The mutation appears to be specific for glycerol in that it does not alter the capability for callus growth on several other sugars tested.

The distribution and metabolism of arachidonic acid in rabbit platelets during aggregation and its modification by drugs.

1 Gas chromatographic and radio-isotope labelling techniques have been used to establish the origin of the arachindonic acid used by the platelet cyclo-oxygenase for the synthesis of pro-aggregatory prostaglandin endoperoxide derivatives. 2 Measurements of total platelet arachidonate content indicated that more than 95% is esterified in the phosphatide fraction of the cells. 3 During aggregation by collagen or thrombin as much as 80% of the total platelet arachidonate may be liberated and transformed by the platelet enzymes into hydroxyacids and other more polar compounds. 4 The phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositol fractions are major sources of the arachidonate thus used. 5 Indomethacin, which prevents platelet aggregation by inhibiting the cyclo-oxygenase, did not affect this release of arachidonate from the phosphatides but did prevent the transformation of arachidonate to endoperoxide derivatives. 6 Mepacrine, a drug which possesses weak anti-phospholipase activity in platelets, also prevents aggregation by collagen or thrombin, but seems to do so by preventing substrate release from the phosphatide fraction. 7 It is suggested that phospholipase A2 plays a key role in the initial events during platelet aggregation induced by collagen.