Fitting form to function: reorganization of faculty roles for a new dental curriculum and its governance.

The College of Dentistry at the University of Illinois at Chicago has reorganized its predoctoral curriculum to better integrate biomedical, clinical, and behavioral sciences using a systems-based framework. The resulting D.M.

Modulation of C1-Inhibitor and Plasma Kallikrein Activities by Type IV Collagen.

The contact system of coagulation can be activated when in contact with biomaterials. As collagen is being tested in novel biomaterials in this study, we have investigated how type IV collagen affects plasma kallikrein and C1-inhibitor. Firstly, we showed C1-inhibitor binds to type IV collagen with a Kd of 0.

Maximising the potential of part-time clinical teachers.

Background: A problem faced by health professions education throughout the world is a lack of full-time clinical teachers. This is particularly serious in dentistry and nursing, but is increasingly also true in medicine. To make up for this shortfall there is a growing reliance on part-time clinical teachers.

Estimating the additional cost of disability: beyond budget standards.

Disabled people have long advocated for sufficient resources to live a life with the same rights and responsibilities as non-disabled people. Identifying the unique resource needs of disabled people relative to the population as a whole and understanding the source of these needs is critical for determining adequate levels of income support and for prioritising service provision. Previous attempts to identify the resources and costs associated with disability have tended to rely on surveys of current resource use.

Explanation for the high heat stability of thyroxine binding globulin-Chicago.

Objective: Thyroxine binding globulin-Chicago (TBG-Chicago), a variant of TBG with enhanced heat stability, was isolated at the University of Chicago from a 22 year old subject of an African American lineage. High thermodynamic stability in serine proteinase inhibitors (serpin) is the hallmark of reactive center loop (RCL) inserted conformation and this aspect has not been explored in TBG-Chicago, a serpin molecule. It is hypothesised that the high heat stability of TBG-Chicago is due its loop inserted state.

Constructive Functional Diversity: a new paradigm beyond disability and impairment.

Aims Of The Paper: This article presents a more dynamic and constructive paradigm than the current dominant ones (for example medical or social models), to describe and change the impact of impairment and disability. The reflections contained are inspired by personal and professional frustration with the existing polarized ideology of human function, which fails to adequately describe the diversity of physiological and psychosocial function amongst people. It aims to provoke and inspire dialogue about our current paradigm of human function in relation to value and capacity.

Curriculum restructuring at a North American dental school: rationale for change.

The purpose of this article is to discuss how traditional dental school curricula are inconsistent with research in how learners learn. In the last ten years, there has been considerable discussion about the need for dental education reform, and innovative changes have occurred in the curricula of a number of U.S.

Expression of matrix metalloproteinase genes in the rat intramembranous bone during postnatal growth and upon mechanical stresses.

A cranial suture consists of neural-crest derived cells and matrices between mineralized skull bones. Little is known regarding the involvement of matrix metalloproteinases (MMPs) in the degradation of extracellular matrix of cranial sutures. In the postnatal rat model, the posterior frontal suture (PFS) undergoes complete ossification between P12-P22, whereas the sagittal suture (SS) remains patent.

Inhibition of plasma kallikrein by C1-inhibitor: role of endothelial cells and the amino-terminal domain of C1-inhibitor.

Activation of plasma prekallikein and generation of bradykinin are responsible for the angioedema attacks observed with C1-inhibitor deficiency. Heterozygous individuals with <50% levels of active C1-inhibitor are susceptible to angioedema attacks indicating a critical need for C1-inhibitor to be present at maximum levels to prevent unwanted prekallikrein activation. Studies with purified proteins do not adequately explain this observation.

Serpin-ligand interactions.

One of the more common features of serpins is the ability to bind various ligands. Ligand binding can occur so that the inhibitory properties of the serpin are regulated, so that the serpin can be localized, or to produce or modulate some other biological function of the serpin. Ligands known to affect serpin biologic activity include glycosaminoglycans such as heparin, heparan sulfate and dermatan sulfate, DNA, extracellular matrix proteins such as vitronectin and collagen, and small organic molecule hormones.

Characterization of different high molecular weight angiotensinogen forms.

Background: Angiotensinogen is the substrate for renin in the system that releases angiotensin II. This renin-angiotensin system is an important regulator of blood pressure (BP), and defects in the system are linked to the development of hypertension. Native angiotensinogen is a 62,000-dalton monomer, but various high molecular weight forms also exist, which have not been well characterized.

The reaction between plasmin and C1-inhibitor results in plasmin inhibition by the serpin mechanism.

C1-inhibitor is an important inhibitor of plasma kallikrein and C1, but also has inhibitory activity against numerous other plasma proteinases such as plasmin. The relevance of plasmin inhibition by the C1-inhibitor has been debated, with some evidence showing that plasmin causes significant proteolysis of C1-inhibitor. In the present study, we show that C1-inhibitor in its native state will inhibit plasmin without being significantly degraded, in a manner typical of all serpin reactions.

alpha(1)-Proteinase inhibitor mutants with specificity for plasma kallikrein and C1s but not C1.

Coagulation and complement proteinases are activated in sepsis, and one approach to therapy is to develop proteinase inhibitors that will specifically inhibit these proteinases without inhibiting activated protein C, a proteinase that is beneficial to survival. In this study, we made mutants of the serpin alpha(1)-PI, designed to mimic the specificity of C1-inhibitor. The P3-P2-P1 residues of alpha1-PI were changed from IPM to LGR and PFR, sequences preferred by C1s and kallikrein, respectively.

Release and degradation of angiotensin I and angiotensin II from angiotensinogen by neutrophil serine proteinases.

Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.

The inhibition of TNK-t-PA by C1-inhibitor.

TNK-t-PA is a recombinant mutant of tissue plasminogen activator that has a longer half-life and higher selectivity for fibrin than normal tissue plasminogen activator (t-PA). In addition, it is reported to be serpin resistant because of reduced inhibition by plasminogen activator inhibitor-1. In this study, we have investigated the inhibition of TNK-t-PA by the serpin C1-inhibitor.

Linkage between the hormone binding site and the reactive center loop of thyroxine binding globulin.

Thyroxine binding globulin (TBG) is the major carrier of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) in plasma. TBG is member of the serpin family of proteins although it has no proteinase inhibitory activity. In this study we show that TBG has properties typical of a metastable serpin and provide evidence that occupancy of the hormone binding site alters the conformation of the reactive center loop.

The native metastable fold of C1-inhibitor is stabilized by disulfide bonds.

C1-inhibitor is a member of the serpin family of proteinase inhibitors and is an important inhibitor of complement and contact system proteinases. The native protein has the characteristic serpin feature of being in a kinetically trapped metastable state rather than in the most stable state it could adopt. A consequence of this is that it readily forms loop-sheet dimers and polymers, by a mechanism believed to be the same as observed with other serpins.

C1 inhibitor cross-linking by tissue transglutaminase.

C1 inhibitor, a plasma proteinase inhibitor of the serpin superfamily involved in the regulation of complement classical pathway and intrinsic blood coagulation, has been shown to bind to several components of the extracellular matrix. These reactions may be responsible for C1 inhibitor localization in the perivascular space. In the study reported here, we have examined whether C1 inhibitor could function as a substrate for plasma (factor XIIIa) or tissue transglutaminase.

Influence of the P5 residue on alpha1-proteinase inhibitor mechanism.

The reactive center loop of native alpha1-proteinase inhibitor has been reported to be in a helical conformation and in a beta-strand conformation by two different studies. In the beta-strand loop structure the P5 glutamic acid plays a unique role by stabilizing the loop in the predicted optimal conformation for the interaction with target proteinases and insertion into beta-sheet A. We hypothesize here that disrupting the interactions that stabilize the beta-strand conformation of the loop would result in changes in the inhibitory properties of the serpin.

The P6-P2 region of serpins is critical for proteinase inhibition and complex stability.

Two of the prototypic serpins are alpha1-proteinase inhibitor and ovalbumin. alpha1-Proteinase inhibitor is a rapid inhibitor of a number of proteinases and undergoes the characteristic serpin conformational change on cleavage within the reactive center loop, whereas ovalbumin is noninhibitory and does not undergo the conformational change. To investigate if residues from P12 to P2 in the reactive center loop of ovalbumin are intrinsically incapable of being in an inhibitory serpin, we have made chimeric alpha1-proteinase inhibitor variants containing residues P12-P7, P6-P2, or P12-P2 of ovalbumin and determined their inhibitory properties with trypsin and human neutrophil elastase.

Reactivation of C1-inhibitor polymers by denaturation and gel-filtration chromatography.

C1-inhibitor is a proteinase inhibitor in the serpin family. It is an important inhibitor of complement C1, plasma kallikrein, and factor XIIa, and as such is involved in regulating inflammatory pathways. Studies on the plasma-derived protein are hampered by the relative ease with which the protein converts to an inactive state on storage, under mild denaturing conditions, or by incubating in some unfavorable buffers.

Apparent formation of sodium dodecyl sulfate-stable complexes between serpins and 3,4-dichloroisocoumarin-inactivated proteinases is due to regeneration of active proteinase from the inactivated enzyme.

Protein proteinase inhibitors of the serpin family were recently reported to form SDS-stable complexes with inactive serine proteinases modified at the catalytic serine with 3, 4-dichloroisocoumarin (DCI) that resembled the complexes formed with the active enzymes (Christensen, S., Valnickova, Z., Thogersen, I.

Regulation of C1-inhibitor function by binding to type IV collagen and heparin.

Serpins inhibit proteinases by a branched pathway, in which an intermediate serpin-proteinase complex can either form a stable covalent serpin-proteinase complex or produce reactive center cleaved serpin in a substrate reaction. It was tested whether these competing reactions could be regulated for the serpin C1-inhibitor by ligand binding. C1-inhibitor bound to type IV collagen, laminin, and entactin.