Endogenous tissue engineering: PTH therapy for skeletal repair

Based on its proven anabolic effects on bone in osteoporosis patients, recombinant parathyroid hormone (PTH_1-34) has been evaluated as a potential therapy for skeletal repair. In animals, the effect of PTH_1-34 has been investigated in various skeletal repair models such as fractures, allografting, spinal arthrodesis and distraction osteogenesis. These studies have demonstrated that intermittent PTH_1-34 treatment enhances and accelerates the skeletal repair process via a number of mechanisms, which include effects on mesenchymal stem cells, angiogenesis, chondrogenesis, bone formation and resorption. Furthermore, PTH_1-34 has been shown to enhance bone repair in challenged animal models of aging, inflammatory arthritis and glucocorticoid-induced bone loss. This pre-clinical success has led to off-label clinical use and a number of case reports documenting PTH_1-34 treatment of delayed-unions and non-unions have been published. Although a recently completed phase 2 clinical trial of PTH_1-34 treatment of patients with radius fracture has failed to achieve its primary outcome, largely because of effective healing in the placebo group, several secondary outcomes are statistically significant, highlighting important issues concerning the appropriate patient population for PTH_1-34 therapy in skeletal repair. Here, we review our current knowledge of the effects of PTH_1-34 therapy for bone healing, enumerate several critical unresolved issues (e.g., appropriate dosing regimen and indications) and discuss the long-term potential of this drug as an adjuvant for endogenous tissue engineering.     

The effect of mobbing vocalizations on risk perception in common mynas (Acridotheres tristis)

Journal of Ethology - Animals emit predator-elicited calls in response to potential predation threats. These vocalizations induce a variety of anti-predator behaviors in conspecific receivers...     

What life cycle graphs can tell about the evolution of life histories

We analyze long-term evolutionary dynamics in a large class of life history models. The model family is characterized by discrete-time population dynamics and a finite number of individual states such that the life cycle can be described in terms of a population projection matrix. We allow an arbitrary number of demographic parameters to be subject to density-dependent population regulation and two or more demographic parameters to be subject to evolutionary change. Our aim is to identify structural features of life cycles and modes of population regulation that correspond to specific evolutionary dynamics. Our derivations are based on a fitness proxy that is an algebraically simple function of loops within the life cycle. This allows us to phrase the results in terms of properties of such loops which are readily interpreted biologically. The following results could be obtained. First, we give sufficient conditions for the existence of optimisation principles in models with an arbitrary number of evolving traits. These models are then classified with respect to their appropriate optimisation principle. Second, under the assumption of just two evolving traits we identify structural features of the life cycle that determine whether equilibria of the monomorphic adaptive dynamics (evolutionarily singular points) correspond to fitness minima or maxima. Third, for one class of frequency-dependent models, where optimisation is not possible, we present sufficient conditions that allow classifying singular points in terms of the curvature of the trade-off curve. Throughout the article we illustrate the utility of our framework with a variety of examples.     

Retrograde Traffic Out of the Yeast Vacuole to the TGN Occurs via the Prevacuolar/Endosomal Compartment

A large number of trafficking steps occur between the last compartment of the Golgi apparatus (TGN) and the vacuole of the yeast Saccharomyces cerevisiae. To date, two intracellular routes from the TGN to the vacuole have been identified. Carboxypeptidase Y (CPY) travels through a prevacuolar/endosomal compartment (PVC), and subsequently on to the vacuole, while alkaline phosphatase (ALP) bypasses this compartment to reach the same organelle. Proteins resident to the TGN achieve their localization despite a continuous flux of traffic by continually being retrieved from the distal PVC by virtue of an aromatic amino acid–containing sorting motif. In this study we report that a hybrid protein based on ALP and containing this retrieval motif reaches the PVC not by following the CPY sorting pathway, but instead by signal-dependent retrograde transport from the vacuole, an organelle previously thought of as a terminal compartment. In addition, we show that a mutation in VAC7, a gene previously identified as being required for vacuolar inheritance, blocks this trafficking step. Finally we show that Vti1p, a v-SNARE required for the delivery of both CPY and ALP to the vacuole, uses retrograde transport out of the vacuole as part of its normal cellular itinerary.