Faculty Bibliography

Human exposure to air pollutants, including ambient particulate matter, has been proposed as a mechanism for the rise in allergic disorders. Diesel exhaust particles, a major component of ambient particulate matter, induce sensitization to neoallergens, but the mechanisms by which sensitization occur remain unclear. We show that diesel exhaust particles upregulate thymic stromal lymphopoietin in human bronchial epithelial cells in an oxidant-dependent manner. Thymic stromal lymphopoietin induced by diesel exhaust particles was associated with maturation of myeloid dendritic cells, which was blocked by anti-thymic stromal lymphopoietin antibodies or silencing epithelial cell-derived thymic stromal lymphopoietin. Dendritic cells exposed to diesel exhaust particle-treated human bronchial epithelial cells induced Th2 polarization in a thymic stromal lymphopoietin-dependent manner. These findings provide new insight into the mechanisms by which diesel exhaust particles modify human lung mucosal immunity

Psoriatic arthritis is a complex, chronic inflammatory disease with both skin and joint involvement. Clinical presentation varies considerably among patients and during the course of the disease. Assessment of patients for psoriatic arthritis requires careful attention to patient history, a focused physical examination, and inspection for characteristic radiographic changes. Although this disease was once thought to be a rare and mild form of arthritis, recent studies have shown that patients with psoriatic arthritis may develop significant disability, with up to 20% of cases demonstrating a rapidly progressive, debilitating clinical course. Orthopedic manifestations of the disease can be severe and can cause significant physical disability. Although surgical intervention for psoriatic arthritis is relatively uncommon, having an understanding of the assessment, available treatment options, and surgical considerations allows for improved outcome in the management of this complex patient population

Constrained acetabular liners can fail leading to recurrent dislocation. Failure can occur at any of the five possible interfaces: bone-acetabular shell, acetabular shell-constrained liner insert, constrained liner insert-bipolar head, bipolar head- femoral head and femoral head-trunion. We report a patient who presented with dissociation of the cemented Osteonics acetabular constrained liner (Stryker-Howmedica-Osteonics, Rutherford, New Jersey). The failure interface was at the factory pre-assembled constrained liner insert-bipolar head without any locking ring failure; instead there was deformation of the constrained liner insert's polyethylene rim, which facilitated dissociation. To our knowledge, there are no previous reports of such a failure mode pertaining to this type of constrained liner. Constrained acetabular liners are indicated during primary or revision total hip arthroplasty for patients who are at high risk for dislocations or who have had recurrent dislocations. Failure rates (typically recurrent dislocation) range from 4% to 29% at mid-term follow-up. The first report on the Osteonics acetabular constrained liner was published in 1994. Failures have been reported previously to occur at surgically controllable interfaces, such as the acetabular shell from the bony surface and the constrained liner insert from the acetabular metal shell, and have been attributable to excessive constraint or improper technique. All dissociations pertaining to factory-preassembled component interfaces have been attributed to breakage of the locking ring. This article presents the first case of disengagement of the tripolar constrained liner without disruption of the locking ring

Proteomic analyses of the nucleolus have revealed almost 700 functionally diverse proteins implicated in ribosome biogenesis, nucleolar assembly, and regulation of vital cellular processes. However, this nucleolar inventory has not unveiled a specific consensus motif necessary for nucleolar binding. The ribosomal protein family characterized by their basic nature should exhibit distinct binding sequences that enable interactions with the rRNA precursor molecules facilitating subunit assembly. We succeeded in delineating 2 minimal nucleolar binding sequences of human ribosomal protein S6 by fusing S6 cDNA fragments to the 5' end of the LacZ gene and subsequently detecting the intracellular localization of the beta-galactosidase fusion proteins. Nobis1 (nucleolar binding sequence 1), comprising of 4 highly conserved amino acid clusters separated by glycine or proline, functions independently of the 3 authentic nuclear localization signals (NLSs). Nobis2 consists of 2 conserved peptide clusters and requires the authentic NLS2 in its native context. Similarly, we deduced from previous publications that the single Nobis of ribosomal protein S25 is also highly conserved. The functional protein domain organization of the ribosomal protein S6e family consists of 3 modules: NLS, Nobis, and the C-terminal serine cluster of the phosphorylation sites. This modular structure is evolutionary conserved in vertebrates, invertebrates, and fungi. Remarkably, nucleolar binding sequences of small and large ribosomal proteins reside in peptide clusters conserved over millions of years.

The KdpFABC complex (Kdp) functions as a K+ pump in Escherichia coli and is a member of the family of P-type ATPases. Unlike other family members, Kdp has a unique oligomeric composition and is notable for segregating K+ transport and ATP hydrolysis onto separate subunits (KdpA and KdpB, respectively). We have produced two-dimensional crystals of the KdpFABC complex within reconstituted lipid bilayers and determined its three-dimensional structure from negatively stained samples using a combination of electron tomography and real-space averaging. The resulting map is at a resolution of 2.4 nm and reveals a dimer of Kdp molecules as the asymmetric unit; however, only the cytoplasmic domains are visible due to the lack of stain penetration within the lipid bilayer. The sizes of these cytoplasmic domains are consistent with Kdp and, using a pseudo-atomic model, we have described the subunit interactions that stabilize the Kdp dimer within the larger crystallographic array. These results illustrate the utility of electron tomography in structure determination of ordered assemblies, especially when disorder is severe enough to hamper conventional crystallographic analysis

Fewer and fewer programs are training graduate students and postdoctoral fellows in the classical anatomical disciplines. Nonetheless, there remains a need at all levels of clinical and basic science education for skilled instructors of anatomy, histology, and embryology. Two sessions at the 2006 annual meeting of the American Association of Anatomists (AAA) explored whether a system of accreditation would benefit students, institutions, and training programs. Although the value of accreditation was controversial, three challenges for the various anatomical societies emerged from these discussions: (1) To identify the skills and knowledge that should be shared among all anatomists, and the more specific skills and knowledge needed for the diverse settings in which anatomists work. (2) To address the historical inattention of institutions to the training of educators. (3) To develop strategies to lobby institutions and national organizations to support the training and work of educators in the anatomical sciences. One approach to meeting these challenges would be to develop guidelines for training programs. These guidelines would help graduate students seek the training they need, provide institutions with a benchmark to assess or develop training programs, and provide the basis for focusing lobbying efforts targeted at institutions or existing accreditation bodies.

Prospective midbrain and cerebellum formation are coordinated by FGF ligands produced by the isthmic organizer. Previous studies have suggested that midbrain and cerebellum development require different levels of FGF signaling. However, little is known about the extent to which specific regions within these two parts of the brain differ in their requirement for FGF signaling during embryogenesis. Here, we have explored the effects of inhibiting FGF signaling within the embryonic mouse midbrain (mesencephalon) and cerebellum (rhombomere 1) by misexpressing sprouty2 (Spry2) from an early stage. We show that such Spry2 misexpression moderately reduces FGF signaling, and that this reduction causes cell death in the anterior mesencephalon, the region furthest from the source of FGF ligands. Interestingly, the remaining mesencephalon cells develop into anterior midbrain, indicating that a low level of FGF signaling is sufficient to promote only anterior midbrain development. Spry2 misexpression also affects development of the vermis, the part of the cerebellum that spans the midline. We found that, whereas misexpression of Spry2 alone caused loss of the anterior vermis, reducing FGF signaling further, by decreasing Fgf8 gene dose, resulted in loss of the entire vermis. Our data suggest that cell death is not responsible for vermis loss, but rather that it fails to develop because reducing FGF signaling perturbs the balance between vermis and roof plate development in rhombomere 1. We suggest a molecular explanation for this phenomenon by providing evidence that FGF signaling functions to inhibit the BMP signaling that promotes roof plate development