Faculty Bibliography

Studies on the relationship between female testosterone (T) measures and behavior, particularly in free-ranging primate populations, remain scant. In this study we used fecal steroid analysis to examine the effects of seasonal, reproductive, and social factors on female T in a group of free-ranging hybrid baboons (Papio sp.) in the Awash National Park of Ethiopia. We collected behavioral and hormonal data from 25 adult females across an 11-month period. Solid phase extraction and radioimmunoassay (RIA) techniques were used to quantify T in 776 fecal samples collected weekly from each female. The results indicate that 1) the females had elevated T during pregnancy and during the wet season relative to other periods, 2) female dominance rank was positively related to T measures, and 3) female T and aggression were positively related within subjects but not across subjects. Higher T concentrations during pregnancy are consistent with other published profiles of pregnancy in primates. In combination with data on foraging, wet season increases in T may indicate contest competition for females. The rank-T relationship may be mediated by supplants or aggression. Finally, we discuss the different interpretations of the hormone-behavior relationship based on within- and across-subject analyses.

OBJECTIVE: To investigate whether two different multiphasic implants could initiate and sustain repair of osteochondral defects in rabbits. The implants address the malleable properties of cartilage while also addressing the rigid characteristics of subchondral bone. DESIGN: The bone region of both devices consisted of D, D-L, L-polylactic acid invested with hyaluronan (HY). The cartilage region of the first device was a polyelectrolytic complex (PEC) hydrogel of HY and chitosan. In the second device the cartilage region consisted of type I collagen scaffold. Eighteen rabbits were implanted bilaterally with a device, or underwent defect creation with no implant. At 24 weeks, regenerated tissues were evaluated grossly, histologically and via immunostaining for type II collagen. RESULTS: PEC devices induced a significantly better repair than untreated shams. Collagen devices resulted in a quality of repair close to that of the PEC group, although its mean repair score (19.0+/-4.2) did not differ significantly from that of the PEC group (20.4+/-3.7) or the shams (16.5+/-6.3). The percentage of hyaline-appearing cartilage in the repair was highest with collagen implants, while the degree of bonding of repair to the host, structural integrity of the neocartilage, and reconstitution of the subchondral bone was greatest with PEC devices. Cartilage in both device-treated sites stained positive for type II collagen and GAG. CONCLUSIONS: Both implants are capable of maintaining hyaline-appearing tissue at 24 weeks. The physicochemical region between the cartilage and bone compartments makes these devices well suited for delivery of different growth factors or drugs in each compartment, or different doses of the same factor. It also renders these devices excellent vehicles for chondrocyte or stem cell transplantation

Implantation is the process by which the blastocyst comes into intimate physical and physiological contact with the uterine endometrium. This process is governed by an intimate cross-talk between the activated blastocyst and the receptive uterus. An increased understanding of mammalian implantation has been gained through the use of the mouse model. This review highlights the more recently defined signaling cascades involved in this dialogue, focusing specifically on cyclooxygenase-2-derived prostaglandins, endocannabinoids, Wnt proteins, homeotic transcription factors, and immunophilins. Unraveling the nature of these signals and discovering additional molecular cascades may lead to strategies to correct implantation failure and improve pregnancy rates in women.

Monitoring Editor: Jeffrey Brodsky The apical surface of mammalian urothelium is covered by 16-nm protein particles packed hexagonally to form 2D crystals of asymmetric unit membranes (AUM) that contribute to the remarkable permeability barrier function of the urinary bladder. We have shown previously that bovine AUMs contain four major integral membrane proteins, i.e., uroplakins Ia, Ib, II and IIIa, and that UPIa and Ib (both tetraspanins) form heterodimers with UPII and IIIa, respectively. Using a panel of antibodies recognizing different conformational states of uroplakins, we demonstrate that the UPIa-dependent, furin-mediated cleavage of the prosequence of UPII leads to global conformational changes in mature UPII, and that UPIb also induces conformational changes in its partner UPIIIa. We further demonstrate that tetraspanins CD9, CD81 and CD82 can stabilize their partner protein CD4. These results indicate that tetraspanin uroplakins, and some other tetraspanin proteins, can induce conformational changes leading to the ER-exit, stabilization and cell surface expression of their associated, single-transmembrane-domained partner proteins, and thus can function as 'maturation-facilitators.' We propose a model of AUM assembly in which conformational changes in integral membrane proteins induced by uroplakin interactions, differentiation-dependent glycosylation and the removal of the prosequence of UPII play roles in regulating the assembly of uroplakins to form AUM

Studies on various forms of synaptic plasticity have shown a link between messenger RNA translation, learning and memory. Like memory, synaptic plasticity includes an early phase that depends on modification of pre-existing proteins, and a late phase that requires transcription and synthesis of new proteins. Activation of postsynaptic targets seems to trigger the transcription of plasticity-related genes. The new mRNAs are either translated in the soma or transported to synapses before translation. GCN2, a key protein kinase, regulates the initiation of translation. Here we report a unique feature of hippocampal slices from GCN2(-/-) mice: in CA1, a single 100-Hz train induces a strong and sustained long-term potentiation (late LTP or L-LTP), which is dependent on transcription and translation. In contrast, stimulation that elicits L-LTP in wild-type slices, such as four 100-Hz trains or forskolin, fails to evoke L-LTP in GCN2(-/-) slices. This aberrant synaptic plasticity is mirrored in the behaviour of GCN2(-/-) mice in the Morris water maze: after weak training, their spatial memory is enhanced, but it is impaired after more intense training. Activated GCN2 stimulates mRNA translation of ATF4, an antagonist of cyclic-AMP-response-element-binding protein (CREB). Thus, in the hippocampus of GCN2(-/-) mice, the expression of ATF4 is reduced and CREB activity is increased. Our study provides genetic, physiological, behavioural and molecular evidence that GCN2 regulates synaptic plasticity, as well as learning and memory, through modulation of the ATF4/CREB pathway.

In this paper, we suggest a possible confluence of the theory of hybrid automata and the techniques of algorithmic algebra to create a computational basis for systems biology. We describe a method to compute bounded reachability by combining Taylor polynomials and cylindric algebraic decomposition algorithms. We discuss the power and limitations of the framework we propose and we suggest several possible extensions. We briefly show an application to the study of the Delta-Notch protein signaling system in biology