Positronium Laser Cooling via the 1

We report on laser cooling of a large fraction of positronium (Ps) in free flight by strongly saturating the 1^{3}S-2^{3}P transition with a broadband, long-pulsed 243 nm alexandrite laser. The ground state Ps cloud is produced in a magnetic and electric field-free environment. We observe two different laser-induced effects. The first effect is an increase in the number of atoms in the ground state after the time Ps has spent in the long-lived 2^{3}P states. The second effect is one-dimensional Doppler cooling of Ps, reducing the cloud's temperature from 380(20) to 170(20) K. We demonstrate a 58(9)% increase in the fraction of Ps atoms with v_{1D}<3.7×10^{4} ms^{-1}.

Low divergence cold-wall oven for loading ion traps.

We present a compact cold-wall oven that is simple to build and align for loading miniature ion traps with calcium ions. The cold-wall oven, which is a metal-loaded capillary heated only through a portion of its length by the passage of a current, is described and characterized. An atomic beam with a low divergence of 14 mrad is produced. We perform Doppler-sensitive, resonant fluorescence measurements on the atomic beam to characterize the oven's performance. The emission of atoms from the oven is seen within ∼70 s after turning on the oven at an electric power consumption of <10 W. The flow rate is measured to be 1.5 ± 0.2 × 109 atoms s-1 at a temperature of 702 ± 7 K. The entire oven assembly is mounted on a CF16 feedthrough. This design can be extended to other species for producing a collimated atomic beam.

Lasing by driven atoms-cavity system in collective strong coupling regime.

The interaction of laser cooled atoms with resonant light is determined by the natural linewidth of the excited state. An optical cavity is another optically resonant system where the loss from the cavity determines the resonant optical response of the system. The near resonant combination of an optical Fabry-Pérot cavity with laser cooled and trapped atoms couples two distinct optical resonators via light and has great potential for precision measurements and the creation of versatile quantum optics systems. Here we show how driven magneto-optically trapped atoms in collective strong coupling regime with the cavity leads to lasing at a frequency red detuned from the atomic transition. Lasing is demonstrated experimentally by the observation of a lasing threshold accompanied by polarization and spatial mode purity, and line-narrowing in the outcoupled light. Spontaneous emission into the cavity mode by the driven atoms stimulates lasing action, which is capable of operating as a continuous wave laser in steady state, without a seed laser. The system is modeled theoretically, and qualitative agreement with experimentally observed lasing is seen. Our result opens up a range of new measurement possibilities with this system.

Collisional Cooling of Light Ions by Cotrapped Heavy Atoms.

We experimentally demonstrate cooling of trapped ions by collisions with cotrapped, higher-mass neutral atoms. It is shown that the lighter ^{39}K^{+} ions, created by ionizing ^{39}K atoms in a magneto-optical trap (MOT), when trapped in an ion trap and subsequently allowed to cool by collisions with ultracold, heavier ^{85}Rb atoms in a MOT, exhibit a longer trap lifetime than without the localized ^{85}Rb MOT atoms. A similar cooling of trapped ^{85}Rb^{+} ions by ultracold ^{133}Cs atoms in a MOT is also demonstrated in a different experimental configuration to validate this mechanism of ion cooling by localized and centered ultracold neutral atoms. Our results suggest that the cooling of ions by localized cold atoms holds for any mass ratio, thereby enabling studies on a wider class of atom-ion systems irrespective of their masses.

Photodissociation of Trapped Rb_{2}

The direct photodissociation of trapped ^{85}Rb_{2}^{+} (rubidium) molecular ions by the cooling light for the ^{85}Rb magneto-optical trap (MOT) is studied, both experimentally and theoretically. Vibrationally excited Rb_{2}^{+} ions are created by photoionization of Rb_{2} molecules formed photoassociatively in the Rb MOT and are trapped in a modified spherical Paul trap. The decay rate of the trapped Rb_{2}^{+} ion signal in the presence of the MOT cooling light is measured and agreement with our calculated rates for molecular ion photodissociation is observed. The photodissociation mechanism due to the MOT light is expected to be active and therefore universal for all homonuclear diatomic alkali metal molecular ions.

Cooling and stabilization by collisions in a mixed ion-atom system.

In mixed systems of trapped ions and cold atoms, the ions and atoms can coexist at different temperatures. This is primarily due to their different trapping and cooling mechanisms. The key questions of how ions can cool collisionally with cold atoms and whether the combined system allows stable coexistence, need to be answered. Here we experimentally demonstrate that rubidium ions cool in contact with magneto-optically trapped rubidium atoms, contrary to the general experimental expectation of ion heating. The cooling process is explained theoretically and substantiated with numerical simulations, which include resonant charge exchange collisions. The mechanism of single collision swap cooling of ions with atoms is discussed. Finally, it is experimentally and numerically demonstrated that the combined ion-atom system is intrinsically stable, which is critical for future cold chemistry experiments with such systems.

Roles of the immune system in skin cancer.

Over the past several decades, there has been increasing interest in understanding the roles of the immune system in the development and progression of cancer. The importance of the immune system in human skin cancer has been long recognized based primarily upon the increased incidence of skin cancers in organ transplant recipients and mechanisms of ultraviolet (UV) radiation-mediated immunomodulation. In this review, we integrate multiple lines of evidence highlighting the roles of the immune system in skin cancer. First, we discuss the concepts of cancer immunosurveillance and immunoediting as they might relate to human skin cancers. We then describe the clinical and molecular mechanisms of skin cancer development and progression in the contexts of therapeutic immunosuppression in organ transplant recipients, viral oncogenesis, and UV radiation-induced immunomodulation with a primary focus on basal cell carcinoma and squamous cell carcinoma. The clinical evidence supporting expanding roles for immunotherapy is also described. Finally, we discuss recent research examining the functions of particular immune cell subsets in skin cancer and how they might contribute to both antitumour and protumour effects. A better understanding of the biological mechanisms of cancer immunosurveillance holds the promise of enabling better therapies.

Investigation of antirelaxation coatings for alkali-metal vapor cells using surface science techniques.

Many technologies based on cells containing alkali-metal atomic vapor benefit from the use of antirelaxation surface coatings in order to preserve atomic spin polarization. In particular, paraffin has been used for this purpose for several decades and has been demonstrated to allow an atom to experience up to 10 000 collisions with the walls of its container without depolarizing, but the details of its operation remain poorly understood. We apply modern surface and bulk techniques to the study of paraffin coatings in order to characterize the properties that enable the effective preservation of alkali spin polarization. These methods include Fourier transform infrared spectroscopy, differential scanning calorimetry, atomic force microscopy, near-edge x-ray absorption fine structure spectroscopy, and x-ray photoelectron spectroscopy. We also compare the light-induced atomic desorption yields of several different paraffin materials. Experimental results include the determination that crystallinity of the coating material is unnecessary, and the detection of C[Double Bond]C double bonds present within a particular class of effective paraffin coatings. Further study should lead to the development of more robust paraffin antirelaxation coatings, as well as the design and synthesis of new classes of coating materials.

Absence of estrogen receptor-related-alpha increases osteoblastic differentiation and cancellous bone mineral density.

The nuclear orphan receptor human estrogen receptor-related receptor (ERR)-alpha is implicated in bone metabolism. We studied the effect of ERRalpha silencing in human mesenchymal stem cells (hMSCs) during osteoblastogenesis. We found that ERRalpha silencing led to an increase of bone sialoprotein and a decrease of osteopontin mRNA levels, suggesting enhanced osteoblastic differentiation. This was confirmed by an increased ability of hMSCs to deposit calcium. Concomitantly, knockdown of ERRalpha inhibited adipogenesis, resulting in a decrease in adipocyte number and adipocyte marker gene expression. In line with a negative role of ERRalpha in bone metabolism, we found that adult female and male ERRalpha-deficient mice displayed a moderate increase in femoral cancellous bone volume and density. Osteoblast surface was increased and marrow fat volume decreased in these animals. Furthermore, ERRalpha-deficient osteoblasts displayed increased differentiation properties in vitro in line with our observations in hMSCs. In summary, we identified a role for ERRalpha in bone mass regulation by affecting osteoblastic differentiation.

Trapping of neutral rubidium with a macroscopic three-phase electric trap.

We trap neutral ground-state rubidium atoms in a macroscopic trap based on purely electric fields. For this, three electrostatic field configurations are alternated in a periodic manner. The rubidium is precooled in a magneto-optical trap, transferred into a magnetic trap, and then translated into the electric trap. The electric trap consists of six rod-shaped electrodes in cubic arrangement, giving ample optical access. Up to 10;{5} atoms have been trapped with an initial temperature of around 20 microkelvin in the three-phase electric trap. The observations are in good agreement with detailed numerical simulations.

Continuous loading of an electrostatic trap for polar molecules.

A continuously operated electrostatic trap for polar molecules is demonstrated. The trap has a volume of approximately 0.6 cm3 and holds molecules with a positive Stark shift. With deuterated ammonia from a quadrupole velocity filter, a trap density of approximately 10(8) cm(-3) is achieved with an average lifetime of 130 ms and a motional temperature of approximately 300 mK. The trap offers good starting conditions for high-precision measurements, and can be used as a first stage in cooling schemes for molecules and as a "reaction vessel" in cold chemistry.

Two-dimensional trapping of dipolar molecules in time-varying electric fields.

Simultaneous two-dimensional trapping of neutral dipolar molecules in low- and high-field seeking states is analyzed. A trapping potential of the order of 20 mK can be produced for molecules such as ND3 with time-dependent electric fields. The analysis is in agreement with an experiment where slow molecules with longitudinal velocities of the order of 20 m/s are guided between four 50 cm long rods driven by an alternating electric potential at a frequency of a few kHz.

Humalog Mix50 before carbohydrate-rich meals in type 2 diabetes mellitus.

AIM: To compare pre-meal injection of Humalog Mix50 (Mix50) and Humalog Mix25 (Humalog Mix75/25 in the US; Mix25) with respect to 2 h postprandial (2 h pp) blood glucose (BG) control after a carbohydrate-rich breakfast in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: One hundred and sixteen patients were enrolled in a 16-week crossover trial and received two treatment regimens in a randomized crossover fashion: (i) Mix50 before breakfast and Mix25 before the evening meal (Mix50/Mix25) and (ii) Mix25 before both breakfast and the evening meal (Mix25 twice daily). Insulin doses were adjusted according to stated glycaemic targets. After 6 and 8 weeks of treatment, the patient's usual morning insulin dose was administered, followed immediately by a test breakfast representative of the patient's usual breakfast meal. Fasting and 2 h pp BG concentrations were measured at the time of the test meal. Haemoglobin A1c (A1C) was measured, and information regarding hypoglycaemia (symptoms) was collected at the end of each treatment period. RESULTS: Insulin doses were similar between treatments (morning = 31-33 U, evening = 26-28 U) at endpoint. Following the test breakfast, the 2 h pp BG was lower (10.9 +/- 0.3 mmol/l vs. 12.4 +/- 0.3 mmol/l, p = 0.0012) and the 2 h pp BG excursion was smaller (1.4 +/- 0.28 mmol/l vs. 3.5 +/- 0.28 mmol/l, p < 0.001) during treatment with Mix50/Mix25 than during treatment with Mix25 twice daily. There was no difference between the treatments with respect to fasting BG (Mix50/Mix25, 9.5 +/- 0.3 mmol/l vs. Mix25 twice daily, 8.9 +/- 0.3 mmol/l; p = NS), A1C (8.14% +/- 1.14% vs. 8.14% +/- 1.07%; p = NS) or the incidence of self-reported hypoglycaemia (34% vs. 23%; p = NS). CONCLUSIONS: Compared with treatment with Mix25 twice daily, treatment with Mix50 before breakfast and Mix25 before the evening meal resulted in better pp glycaemic control following a carbohydrate-rich meal, and similar fasting BG, A1C and incidence of hypoglycaemia in patients with type 2 diabetes.

Atom laser divergence.

We measure the angular divergence of a quasicontinuous, rf-outcoupled, free-falling atom laser as a function of the outcoupling frequency. The data are compared to a Gaussian-beam model of laser propagation that generalizes the standard formalism of photonic lasers. Our treatment includes diffraction, magnetic lensing, and interaction between the atom laser and the condensate. We find that the dominant source of divergence is the condensate-laser interaction.

Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin.

A series of nonsteroidal anti-inflammatory drugs (NSAIDs) [S(+)-naproxen, ibuprofen isomers, and indomethacin] were evaluated for their activation of peroxisome proliferator-activated receptor (PPAR) alpha and gamma isoforms in CV-1 cells co-transfected with rat PPAR alpha and gamma, and peroxisome proliferator response element (PPRE)-luciferase reporter gene plasmids, for stimulation of peroxisomal fatty acyl CoA beta-oxidase activity in H4IIEC3 cells, and for comparative inhibition of ovine prostaglandin endoperoxide H synthase (PGHS)-1 and PGHS-2 and arachidonic acid-induced human platelet activation. Each drug produced a concentration-dependent activation of the PPAR isoforms and fatty acid beta-oxidase activity, inhibition of human arachidonic acid-induced platelet aggregation and serotonin secretion, and inhibition of PGHS-1 and PGHS-2 activities. For PPARalpha activation in CV-1 and H4IIEC3 cells, and the stimulation of fatty acyl oxidase activity in H4IIEC3 cells, the rank order of stereoselectivity was S(+)- ibuprofen > R(-)-ibuprofen; S(+)-ibuprofen was more potent than indomethacin and naproxen on these parameters. On PPARgamma, the rank order was S(+)-naproxen > indomethacin > S(+)-ibuprofen > R(-)-ibuprofen. Each drug inhibited PGHS-1 activity and platelet aggregation with the same rank order of indomethacin > S(+)-ibuprofen > S(+)-naproxen > R(-)-ibuprofen. Notably, the S(+)-isomer of ibuprofen was 32-, 41-, and 96-fold more potent than the R(-)-isomer for the inhibition of PGHS-1 activity, human platelet aggregation, and serotonin secretion, respectively. On PGHS-2, the ibuprofen isomers showed no selectivity, and indomethacin, S(+)-ibuprofen, and S(+)-naproxen were 6-, 27-, and 5-fold more potent as inhibitors of PGHS-1 than PGHS-2 activity. These results demonstrate that the mechanisms of action of NSAIDs on these cell systems are different, and we propose that the pharmacological effects of NSAIDs may be related to both their profile of inhibition of PGHS enzymes and the activation of PPARalpha and/or PPARgamma isoforms.

Transcriptional control of adipogenesis.

The major transcriptional factors involved in the adipogenic process include proteins belonging to the CCAAT/enhancer binding protein family, peroxisome proliferator-activated receptor gamma, and adipocyte determination and differentiation dependent factor 1, also known as sterol regulatory element-binding protein 1. This process has been characterized with the aid of cell lines that represent various stages in the path of adipocyte commitment, ranging from pluripotent mesodermal fibroblasts to preadipocytes. Molecular analyses have led to a cascade model for adipogenesis based on timed expression of CCAAT/enhancer-binding proteins and peroxisome proliferator-activated receptor gamma. Gene targeting and transgenic-mouse technologies, which allow the manipulation of endogenous genes for these transcription factors, have also contributed to the understanding of adipogenesis. This review aims to integrate this information to gain an understanding of the transcriptional regulation of fat cell formation.

A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response.

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily originally shown to play a critical role in adipocyte differentiation and glucose homeostasis, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Colonic epithelial cells, which express high levels of PPAR-gamma protein, have the ability to produce inflammatory cytokines that may play a role in inflammatory bowel disease (IBD). We report here that PPAR-gamma ligands dramatically attenuate cytokine gene expression in colon cancer cell lines by inhibiting the activation of nuclear factor-kappaB via an IkappaB-alpha-dependent mechanism. Moreover, thiazolidinedione ligands for PPAR-gamma markedly reduce colonic inflammation in a mouse model of IBD. These results suggest that colonic PPAR-gamma may be a therapeutic target in humans suffering from IBD.

Discovery of a novel series of selective MMP inhibitors: identification of the gamma-sulfone-thiols.

We have discovered a new series of potent MMP Inhibitors that are selective for MMP-13 over MMP-1 incorporating a gamma-sulfone thiol.

Interdomain communication regulating ligand binding by PPAR-gamma.

Binding to receptors in the cell nucleus is crucial for the action of lipophilic hormones and ligands. PPAR-gamma (for peroxisome proliferator-activated receptor) is a nuclear hormone receptor that mediates adipocyte differentiation and modulates insulin sensitivity, cell proliferation and inflammatory processes. PPAR-gamma ligands have been implicated in the development of atherogenic foam cells and as potential cancer treatments. Transcriptional activity of PPAR-gamma is induced by binding diverse ligands, including natural fatty acid derivatives, antidiabetic thiazolidinediones, and non-steroidal anti-inflammatory drugs. Ligand binding by PPAR-gamma, as well as by the entire nuclear-receptor superfamily, is an independent property of the carboxy-terminal ligand-binding domain (LBD) of the receptor. Here we show that ligand binding by PPAR-gamma is regulated by intramolecular communication between its amino-terminal A/B domain and its carboxy-terminal LBD. Modification of the A/B domain, for example by physiological phosphorylation by MAP kinase, reduces ligand-binding affinity, thus negatively regulating the transcriptional and biological functions of PPAR-gamma. The ability of the A/B domain to regulate ligand binding has important implications for the evaluation and mechanism of action of potentially therapeutic ligands that bind PPAR-gamma and that are likely to extend to other members of the nuclear-receptor superfamily.