Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.

Scurfy (sf) is an X-linked recessive mouse mutant resulting in lethality in hemizygous males 16-25 days after birth, and is characterized by overproliferation of CD4+CD8- T lymphocytes, extensive multiorgan infiltration and elevation of numerous cytokines. Similar to animals that lack expression of either Ctla-4 or Tgf-beta, the pathology observed in sf mice seems to result from an inability to properly regulate CD4+CD8- T-cell activity. Here we identify the gene defective in sf mice by combining high-resolution genetic and physical mapping with large-scale sequence analysis. The protein encoded by this gene (designated Foxp3) is a new member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrates that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis.

Cellular and molecular characterization of the scurfy mouse mutant.

Mice hemizygous (Xsf/Y) for the X-linked mutation scurfy (sf) develop a severe and rapidly fatal lymphoproliferative disease mediated by CD4+CD8- T lymphocytes. We have undertaken phenotypic and functional studies to more accurately identify the immunologic pathway(s) affected by this important mutation. Flow cytometric analyses of lymphoid cell populations reveal that scurfy syndrome is characterized by changes in several phenotypic parameters, including an increase in Mac-1+ cells and a decrease in B220+ cells, changes that may result from the production of extremely high levels of the cytokine granulocyte-macrophage CSF by scurfy T cells. Scurfy T cells also exhibit strong up-regulation of cell surface Ags indicative of in vivo activation, including CD69, CD25, CD80, and CD86. Both scurfy and normal T cells are responsive to two distinct signals provided by the TCR and by ligation of CD28; scurfy cells, however, are hyperresponsive to TCR ligation and exhibit a decreased requirement for costimulation through CD28 relative to normal controls. This hypersensitivity may result, in part, from increased costimulation through B7-1 and B7-2, whose expression is up-regulated on scurfy T cells. Although the specific defect leading to this hyperactivation has not been identified, we also demonstrate that scurfy T cells are less sensitive than normal controls to inhibitors of tyrosine kinases such as genistein and herbimycin A, and the immunosuppressant cyclosporin A. One interpretation of our data would suggest that the scurfy mutation results in a defect, which interferes with the normal down-regulation of T cell activation.

Glycoluril.

The crystal structure of glycoluril [tetrahydroimidazo-[4,5-d]imidazole-2,5(1H,3H)-dione, C4H6N4O2] has been determined. The molecule has two equivalent planes containing urea moieties, and hence exhibits C2v symmetry. The dihedral angle is found to be 124.1 (4) degrees.

A woman's place.

Getting through dental school is only half the battle for a woman. There are a host of new frustrations when she enters the profession and finds herself battling misconceptions and questions concerning the seriousness of her career.

The changing face of dental students.

Today's dental students are more diverse than typical. What they have in common, however, is a desire for independence and stability in an increasingly more complex profession.

In search of a definition of AIDS.

The medical and ethical struggle for a proper response to the presence of AIDS may very well be resolved in the legislative and legal arenas.

Polarized electronic spectra of Z-DNA single crystals.

Polarized electronic absorption spectra of the (100) face of single crystals of the Z-form double helical duplex of d(m5CGUAm5CG) have been obtained from Kramers-Kronig analysis of reflection data. The c crystallographic axis is parallel to the helix axis and shows but weak absorption. The b axis is perpendicular to the helix axis and shows a structureless absorption band centered at 270 nm with an oscillator strength of 0.26. Calculations of the crystal spectra utilizing available transition moment data for the individual chromophores are carried through using the oriented gas model (no interbase interactions) and, again, employing all base-base interactions (point dipole) in the duplex. The calculated hypochromism of the 270 nm band is much less than the experimental value obtained from the crystal data. The crystal spectra appear to be representative of Z-form double helices of essentially infinite length and not of a collection of twelve base duplexes. No evidence for n pi* transitions polarized parallel to the helix axis is found.

Vacuum ultraviolet circular dichroism as an indicator of helical handedness in nucleic acids.

Calculated circular dichroism spectra are presented for double-stranded polynucleotides of regular sequences in A-RNA, A-DNA, B-DNA, and Z-DNA conformations. Quantum mechanical matrix method calculations were carried out in the near and vacuum ultraviolet regions. In the near UV, the calculated spectra agreed qualitatively with the measured spectra. However in the far and vacuum UV, the calculated CD compared nearly quantitatively with the experimental spectra. The calculations show that the sign of the CD in the vacuum UV, in contrast to that in the near UV, can be correlated with the handedness of the helix.