The human CXC chemokine receptor 4 (CXCR4) is a receptor for the chemokine stromal cell-derived factor (SDF-1␣) and a co-receptor for the entry of specific strains of human immunodeficiency virus type I (HIV-1). CXCR4 is also recognized by an antagonistic chemokine, the viral macrophage inflammatory protein II (vMIP-II) encoded by human herpesvirus type VIII. SDF-1␣ or vMIP-II binding to CXCR4 can inhibit HIV-1 entry via this co-receptor. An approach combining protein structural modeling and site-directed mutagenesis was used to probe the structure-function relationship of CXCR4, and interactions with its ligands SDF-1␣ and vMIP-II and HIV-1 envelope protein gp120. Hypothetical threedimensional structures were proposed by molecular modeling studies of the CXCR4⅐SDF-1␣ complex, which rationalize extensive biological information on the role of CXCR4 in its interactions with HIV-1 envelope protein gp120. With site-directed mutagenesis, we have identified that the amino acid residues Asp (D20A) and Tyr (Y21A) in the N-terminal domain and the residue Glu (E268A) in extracellular loop 3 (ECL3) are involved in ligand binding, whereas the mutation Y190A in extracellular loop 2 (ECL2) impairs the signaling mediated by SDF-1␣. As an HIV-1 co-receptor, we found that the Nterminal domain, ECL2, and ECL3 of CXCR4 are involved in HIV-1 entry. These structural and mutational studies provide valuable information regarding the structural basis for CXCR4 activity in chemokine binding and HIV-1 viral entry, and could guide the design of novel targeted inhibitors.Chemokines are a family of 8 -10-kDa small proteins that act as chemoattractants of various types of leukocytes to sites of inflammation and to secondary lymphoid organs. Based on the positions of two conserved cysteine residues in their N termini, chemokines can be divided into four subfamilies: CC, CXC, CX3C, and C (1, 2). The stromal cell-derived factor-1 (SDF-1␣) 1 is one of the CXC chemokines, which plays critical roles in the migration, proliferation, and differentiation of leukocytes. SDF-1␣ is the only known natural ligand of CXCR4 receptor (3, 4). CXCR4 can also be recognized by an antagonistic ligand, the viral macrophage inflammatory protein-II (vMIP-II) encoded by the Kaposi's sarcoma-associated herpesvirus (5). vMIP-II acts as a selective chemoattractant for T helper 2 cells and monocytes and is an agonist for CCR8 (6). vMIP-II displays a broader spectrum of receptor activities than any mammalian chemokine, as it binds with high affinity to a number of both CC and CXC chemokine receptors including CXCR4 and CCR5 and inhibits cell entry of human immunodeficiency virus type I (HIV-1) mediated by these receptors (7,8).CXCR4 belongs to the family of seven transmembrane Gprotein-coupled receptors that transduce signals via heterotrimeric G-proteins (9). Recent studies with knockout mice of CXCR4 have demonstrated that this molecule plays an important role in immunomodulation, organogenesis, hematopoiesis, and derailed cerebellar neuron migration (10 -12). CXCR4 has...

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Recent experiments indicate that peripheral glucose administration enhances memory in rodents and humans. This study examined the effects of glucose on memory and nonmemory measures of neuropsychological functioning in elderly humans. Healthy older adults were given a series of neuropsychological tests after drinking glucose- or saccharin-flavored lemonade. A repeated measures design using counter-balanced beverages and tests was used. Glucose enhanced performance on declarative memory tests but not on short-term or nonmemory neuropsychological measures. Glucose tolerance predicted performance on declarative memory tasks but not on other measures.

The contemporary policy environment makes persistent demands on agency officials to use the best information available when making decisions about policies, programs, and practices. State and federal legislation calls on agencies to incorporate evidence-based practices (EBP) in their programs. Using data from a 2008 survey of state agency directors, we examine the extent to which state government agencies draw upon various sources of information to guide their decisions about programmatic operations. Our findings reveal the extent to which agencies rely on, or weight, sources of scientific studies and formal evaluations compared to other sources. Factor analysis identifies patterns of agency information use, providing a basis for further exploring agency differences in information consultation that underlie development of new policies and programs in the vein of EBP.

The viral macrophage inflammatory protein-II (vMIP-II) encoded by Kaposi's sarcoma-associated herpesvirus is unique among all known chemokines in that vMIP-II shows a broad-spectrum interaction with both CC and CXC chemokine receptors including CCR5 and CXCR4, two principal coreceptors for the cell entry of human immunodeficiency virus type 1 (HIV-1). To elucidate the mechanism of the promiscuous receptor interaction of vMIP-II, synthetic peptides derived from the N-terminus of vMIP-II were studied. In contrast to the full-length protein that recognizes both CXCR4 and CCR5, a peptide corresponding to residues 1−21 of vMIP-II (LGASWHRPDKCCLGYQKRPLP) was shown to strongly bind CXCR4, but not CCR5. The IC50 of this peptide in competing with CXCR4 binding of 125I-SDF-1α is 190 nM as compared to the IC50 of 14.8 nM of native vMIP-II in the same assay. The peptide selectively prevented CXCR4 signal transduction and coreceptor function in mediating the entry of T- and dual-tropic HIV-1 isolates, but not those of CCR5. Further analysis of truncated peptide analogues revealed the importance of the first five residues for the activity with CXCR4. These results suggest that the N-terminus of vMIP-II is essential for its function via CXCR4. In addition, they reveal a possible mechanism for the distinctive interactions of vMIP-II with different chemokine receptors, a notion that may be further exploited to dissect the structural basis of its promiscuous biological function. Finally, the potent CXCR4 peptide antagonist shown here could serve as a lead for the development of new therapeutic agents for HIV infection and other immune system diseases.