Structural rearrangement through lanthanide contraction in dinuclear complexes.

A new series of lanthanide complexes was synthesized, and the geometry and preliminary magnetic measurements of the complexes were explored. The specific ligand used (N'-(2-hydroxy-3-methoxybenzylidene)benzhydrazide) (H2hmb) was synthesized using a Schiff-base approach and was employed due to the presence of a coordination pocket that is able to accommodate magnetically selective lanthanide ions. The series can be divided into two groups that are categorized by a drastic structural rearrangement. The first group, Type I, contains six analogous complexes with the formula [M(III)2(Hhmb)3(NCS)3]·2MeOH·py (M = Y 1, Eu 2, Gd 3, Tb 4, Dy 5, Ho 6), while the second group, Type II, contains two dinuclear complexes with formula [M(III)2(Hhmb)2(NCS)4(MeOH)2] (M = Er 7, and Yb 8). Single-crystal X-ray analysis revealed that all M(III) ions in Type I exhibit monocapped distorted square antiprismatic geometries, while those of Type II exhibit distorted dodecahedron geometry. The direct current and alternating current magnetic measurements were carried out on all complexes, with 5, 7, and 8 exhibiting slow relaxation of the magnetization under an applied optimum dc field. Furthermore, complex 8 is the first example of a dinuclear Yb-based single-molecule magnet showing field-dependent multiple relaxation processes.

Hybrid nanomaterials: anchoring magnetic molecules on naked gold nanocrystals.

The pairing of molecular magnets and nanomaterials couples top-down and bottom-up approaches to nanotechnology; facilitating a unique methodology to the controlled study of interfacial magnetic properties. Attaching Single-Molecule Magnets (SMMs) to "naked" gold nanoparticles is a novel method of exploring various avenues of magnetic nanotechnology, such as drug delivery, information storage, catalysis, and assembly of magnetic-nanostructural motifs. Herein we report the successful capping of laser ablation synthesized "naked" gold nanoparticles with a dinuclear dysprosium complex, while introducing new information regarding the changes in molecular magnetic properties upon surface attachment. We anticipate that this methodology in producing these magneto-plasmonic nanostructures not only provides answers to fundamental questions but also has the potential to provide new avenues to applications including information storage, multimodal imaging, biomedicine, and optoelectronics.

Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective sphingosine-1-phosphate receptor subtype-1 agonists.

In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.

Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent sphingosine-1-phosphate receptor subtype-1 agonists.

In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.

Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels.

CRACM1 (also called Orai1) constitutes the pore subunit of store-operated calcium release-activated calcium channels. A point mutation in the gene encoding CRACM1 is associated with severe combined immunodeficiency disease in humans. Here we generated CRACM1-deficient mice in which beta-galactosidase activity 'reported' CRACM1 expression. CRACM1-deficient mice were smaller in size. Mast cells derived from CRACM1-deficient mice showed grossly defective degranulation and cytokine secretion, and the allergic reactions elicited in vivo were inhibited in CRACM1-deficient mice. We detected robust CRACM1 expression in skeletal muscles and some regions of the brain, heart and kidney but not in the lymphoid regions of thymus and spleen. In contrast, we found CRACM2 expression to be much higher in mouse T cells. In agreement with those findings, the store-operated calcium influx and development and proliferation of CRACM1-deficient T cells was unaffected. Thus, CRACM1 is crucial in mouse mast cell effector function, but mouse T cell calcium release-activated calcium channels are functional in the absence of CRACM1.

Secretory immunoglobulin A antibodies against the sigma1 outer capsid protein of reovirus type 1 Lang prevent infection of mouse Peyer's patches.

Reovirus type 1 Lang (T1L) adheres to M cells in the follicle-associated epithelium of mouse intestine and exploits the transport activity of M cells to enter and infect the Peyer's patch mucosa. Adult mice that have previously cleared a reovirus T1L infection have virus-specific immunoglobulin G (IgG) in serum and IgA in secretions and are protected against reinfection. Our aim in this study was to determine whether secretory IgA is sufficient for protection of Peyer's patches against oral reovirus challenge and, if so, against which reovirus antigen(s) the IgA may be directed. Monoclonal antibodies (MAbs) of the IgA isotype, directed against the sigma1 protein of reovirus T1L, the viral adhesin, were produced and tested along with other, existing IgA and IgG MAbs against reovirus T1L outer capsid proteins. Anti-sigma1 IgA and IgG MAbs neutralized reovirus T1L in L cell plaque reduction assays and inhibited T1L adherence to L cells and Caco-2(BBe) intestinal epithelial cells in vitro, but MAbs against other proteins did not. Passive oral administration of anti-sigma1 IgA and IgG MAbs prevented Peyer's patch infection in adult mice, but other MAbs did not. When anti-sigma1 IgA and IgG MAbs were produced in mice from hybridoma backpack tumors, however, the IgA prevented Peyer's patch infection, but the IgG did not. The results provide evidence that neutralizing IgA antibodies specific for the sigma1 protein are protective in vitro and in vivo and that the presence of these antibodies in intestinal secretions is sufficient for protection against entry of reovirus T1L into Peyer's patches.

The viral sigma1 protein and glycoconjugates containing alpha2-3-linked sialic acid are involved in type 1 reovirus adherence to M cell apical surfaces.

Type 1 reoviruses invade the intestinal mucosa of mice by adhering selectively to M cells in the follicle-associated epithelium and then exploiting M cell transport activity. The purpose of this study was to identify the apical cell membrane component and viral protein that mediate the M cell adherence of these viruses. Virions and infectious subviral particles of reovirus type 1 Lang (T1L) adhered to rabbit M cells in Peyer's patch mucosal explants and to tissue sections in an overlay assay. Viral adherence was abolished by pretreatment of sections with periodate and in the presence of excess sialic acid or lectins MAL-I and MAL-II (which recognize complex oligosaccharides containing sialic acid linked alpha2-3 to galactose). The binding of T1L particles to polarized human intestinal (Caco-2(BBe)) cell monolayers was correlated with the presence of MAL-I and MAL-II binding sites, blocked by excess MAL-I and -II, and abolished by neuraminidase treatment. Other type 1 reovirus isolates exhibited MAL-II-sensitive binding to rabbit M cells and polarized Caco-2(BBe) cells, but type 2 or type 3 isolates including type 3 Dearing (T3D) did not. In assays using T1L-T3D reassortants and recoated viral cores containing T1L, T3D, or no sigma1 protein, MAL-II-sensitive binding to rabbit M cells and polarized Caco-2(BBe) cells was consistently associated with the T1L sigma1. MAL-II-recognized oligosaccharide epitopes are not restricted to M cells in vivo, but MAL-II immobilized on virus-sized microparticles bound only to the follicle-associated epithelium and M cells. The results suggest that selective binding of type 1 reoviruses to M cells in vivo involves interaction of the type 1 sigma1 protein with glycoconjugates containing alpha2-3-linked sialic acid that are accessible to viral particles only on M cell apical surfaces.