Apicidin, the histone deacetylase inhibitor, suppresses Th1 polarization of murine bone marrow-derived dendritic cells.

Apicidin is a fungal metabolite shown to exhibit anti-proliferative, anti-invasive, and anti-inflammatory properties by the inhibition of histone deacetylase (HDAC). However, the effects of apicidin on the maturation and immunostimulatory function of dendritic cells (DCs) remain unknown. In this study, we investigated whether apicidin modulates surface molecule expression, cytokine production, endocytosis capacity, and underlying signaling pathways in murine bone marrow-derived DCs. We observed that apicidin significantly attenuated surface molecule expression in LPS-stimulated DCs, suppressed production of interleukin (IL)-12 and proinflammatory cytokines (IL-6 and TNF-alpha) by DCs, and reduced IFN-gama production by T cells. The apicidin-treated DCs were found to be highly efficient in antigen capture via mannose receptor-mediated endocytosis. Apicidin also inhibited LPS-induced MAPK activation and NF-kB nuclear translocation in DCs. Moreover, the apicidin-treated DCs were incapable of inducing Th1 responses and normal cell-mediated immune responses. These novel findings not only provide new insights into the immunopharmacological role of apicidin in terms of its effects on DCs, but also broaden current perspectives of the immunopharmacological functions of apicidin, and have implications for the development of therapeutic adjuvants for the treatment of DC-related acute and chronic diseases.

Enzymatic activation of autotaxin by divalent cations without EF-hand loop region involvement.

Autotaxin (ATX) is a recently described member of the nucleotide pyrophosphatase/phosphodiesterase (NPP) family of proteins with potent tumor cell motility-stimulating activity. Like other NPPs, ATX is a glycoprotein with peptide sequences homologous to the catalytic site of bovine intestinal alkaline phosphodiesterase (PDE) and the loop region of an EF-hand motif. The PDE active site of ATX has been associated with the motility-stimulating activity of ATX. In this study, we examined the roles of the EF-hand loop region and of divalent cations on the enzymatic activities of ATX. Ca(2+) or Mg(2+) was each demonstrated to increase the PDE activity of ATX in a concentration-dependent manner, whereas incubation of ATX with chelating agents abolished this activity, indicating a requirement for divalent cations. Non-linear regression analysis of enzyme kinetic data indicated that addition of these divalent cations increases reaction velocity predominantly through an effect on V(max.) Three mutant proteins, Ala(740)-, Ala(742)-, and Ala(751)-ATX, in the EF-hand loop region of ATX had enzymatic activity comparable to that of the wild-type protein. A deletion mutation of the entire loop region resulted in slightly reduced PDE activity but normal motility-stimulating activity. However, the PDE activity of this same deletion mutant remained sensitive to augmentation by cations, strongly implying that cations exert their effect by interactions outside of the EF-hand loop region.

Self-starting 6.5-fs pulses from a Ti:sapphire laser.

We demonstrate self-starting 6.5-fs pulses from a Kerr-lens mode-locked Ti:sapphire laser with 200-mW average output power at a pulse repetition rate of ~86 M Hz. This is to our knowledge the shortest pulse ever generated directly from a laser. For dispersion compensation we used a prism pair in combination with double-chirped mirrors, which balances the higher-order dispersion of the prism pair and therefore flattens the average total group-delay dispersion in the laser cavity. For self-starting mode locking we used a broadband semiconductor saturable-absorber mirror.

Broadband saturable absorber for 10-fs pulse generation.

We demonstrate the fabrication of a broadband saturable absorber with a silver bottom mirror. The reflectivity bandwidth of the absorber shows the potential for generating sub-10-fs pulses. With a Ti:sapphire laser we obtained self-starting Kerr-lens mode-locked pulses as short as 10 fs at the cavity stability limit and selfstarting soliton mode-locked pulses of 16 fs over the full cavity stability regime.

Scaling of the antiresonant Fabry-Perot saturable absorber design toward a thin saturable absorber.

We demonstrate and discuss the scaling of the antiresonant Fabry-Perot saturable absorber toward a novel antiref lection-coated thin saturable absorber. With a Ti:sapphire laser we obtained self-starting Kerr-lens mode-locked pulses as short as 19 fs. With the higher modulation depth of the thin saturable absorber we obtained soliton mode-locked self-starting 34-fs pulses over the full cavity stability regime with a significantly shorter mode-locking buildup time. The pulse duration was limited only by the semiconductor Bragg mirror.

Characterization of short-pulse oscillators by means of a high-dynamic-range autocorrelation measurement.

A high-dynamic-range autocorrelation technique was used to characterize the temporal pulse shape of ultrashort laser pulses produced from four separate oscillators. These lasers included two Kerr-lens mode-locked Ti:sapphire oscillators as well as a Nd:glass and a Ti:sapphire oscillator, each passively mode locked by an antiresonant Fabry-Perot semiconductor saturable absorber. It was shown that the Nd:glass oscillator supported a pulse that was temporally clean over 8 orders of magnitude.

Experimental verification of soliton mode locking using only a slow saturable absorber.

We demonstrate experimentally that solid-state lasers with strong solitonlike pulse shaping can be mode locked by a slow saturable absorber only, i.e., the response time is much slower than the width of the soliton. A Ti:sapphire laser mode locked by a low-temperature-grown GaAs absorber with 10-ps recovery time generates pulses as short as 300 fs without the need for Kerr-lens mode locking and critical cavity alignment. An extrapolation of this result would predict that an asymptotically equal to 100-fs recovery time of a semiconductor absorber could support pulses into the 10-fs regime.