Calreticulin (CRT), when localized to the endoplasmic reticulum (ER), has important functions in directing proper conformation of proteins and glycoproteins, as well as in homeostatic control of cytosolic and ER calcium levels. There is also steadily accumulating evidence for diverse roles for CRT localized outside the ER, including data suggesting important roles for CRT localized to the outer cell surface of a variety of cell types, in the cytosol, and in the extracellular matrix (ECM). Furthermore, the addition of exogenous CRT rescues numerous CRT-driven functions, such as adhesion, migration, phagocytosis, and immunoregulatory functions of CRT-null cells. Recent studies show that topically applied CRT has diverse and profound biological effects that enhance cutaneous wound healing in animal models. This evidence for extracellular bioactivities of CRT has provided new insights into this classically ER-resident protein, despite a lack of knowledge of how CRT exits from the ER to the cell surface or how it is released into the extracellular milieu. Nonetheless, it has become clear that CRT is a multicompartmental protein that regulates a wide array of cellular responses important in physiological and pathological processes, such as wound healing, the immune response, fibrosis, and cancer.-Gold, L. I., Eggleton, P., Sweetwyne, M. T., Van Duyn, L. B., Greives, M. R., Naylor, S.-M., Michalak, M., Murphy-Ullrich, J. E. Calreticulin: non-endoplamic reticulum functions in physiology and disease.

The pathophysiology of diabetic wound healing and the identification of new agents to improve clinical outcomes continue to be areas of intense research. There currently exist more than 10 different murine models of diabetes. The degree to which wound healing is impaired in these different mouse models has never been directly compared. We determined whether differences in wound impairment exist between diabetic models in order to elucidate which model would be the best to evaluate new treatment strategies. Three well-accepted mouse models of diabetes were used in this study: db/db, Akita, and streptozocin (STZ)-induced C57BL/6J. Using an excisional model of wound healing, we demonstrated that db/db mice exhibit severe impairments in wound healing compared with STZ and Akita mice. Excisional wounds in db/db mice show a statistically significant delay in wound closure, decreased granulation tissue formation, decreased wound bed vascularity, and markedly diminished proliferation compared with STZ, Akita, and control mice. There was no difference in the rate of epithelialization of the full-thickness wounds between the diabetic or control mice. Our results suggest that splinted db/db mice may be the most appropriate model for studying diabetic wound-healing interventions as they demonstrate the most significant impairment in wound healing. This study utilized a novel model of wound healing developed in our laboratory that stents wounds open using silicone splints to minimize the effects of wound contraction. As such, it was not possible to directly compare the results of this study with other studies that did not use this wound model.

Summary 1.Populations of white-footed mice Peromyscus leucopus and deer mice Peromyscus maniculatus increase dramatically in response to food availability from oak acorn masts. These populations subsequently decline following this resource pulse, but these crashes cannot be explained solely by resource depletion, as food resources are still available as population crashes begin. 2. We hypothesized that intestinal parasites contribute to these post-mast crashes; Peromyscus are infected by many intestinal parasites that are often transmitted by density-dependent contact and can cause harm to their hosts. To test our hypothesis, we conducted a factorial experiment in natural populations by supplementing food to mimic a mast and by removal of intestinal nematodes with the drug, ivermectin. 3. Both food supplementation and the removal of intestinal nematodes lessened the rate and magnitude of the seasonal population declines as compared with control populations. However, the combination of food supplementation and removal of intestinal nematodes prevented seasonal population crashes entirely. 4. We also showed a direct effect on the condition of individuals. Faecal corticosterone levels, an indicator of the stress response, were significantly reduced in populations receiving both food supplementation and removal of intestinal nematodes. This effect was observed in autumn, before the overwinter crash observed in control populations, which may indicate that stress caused by the combination of food limitation and parasite infection is a physiological signal that predicts low winter survival and reproduction. 5. This study is one of the few to demonstrate that the interaction between resource availability and infectious disease is important for shaping host population dynamics and emphasizes that multiple factors may drive oscillations in wild animal populations.

The KiSS-1 gene encodes the peptide hormone kisspeptin, which acts as a principal positive regulator of the reproductive axis by directly stimulating GnRH neuron activity. To gain insight into a potential role for kisspeptin in integrating and relaying reproductively relevant stimuli to the GnRH system, we investigated changes in kisspeptin peptide expression associated with photoperiodic changes in reproductive state as well as pituitary and gonadal responses to peripheral kisspeptin injections. Seasonally breeding rodents undergo pronounced fluctuations in reproductive state in response to changing day lengths. In common with other rodent species, a majority of male Siberian hamsters (Phodopus sungorus) exhibit reproductive decline after exposure to short-day lengths. A subset of individuals fails to respond to day length information, however, and maintains their reproductive function. We exploited these individual differences to examine whether kisspeptin may act at the interface between external stimuli and the reproductive system. After extended exposure to short days, animals with a quiescent reproductive axis displayed a marked reduction in kisspeptin cell labeling in the anteroventral periventricular nucleus but robust kisspeptin-immunoreactive staining in the arcuate nucleus. In contrast, animals with functional reproductive systems displayed high numbers of kisspeptin-immunoreactive neurons in the anteroventral periventricular nucleus but a paucity of expression in the arcuate nucleus. Kisspeptin injections significantly elevated LH over preinjection levels regardless of photoperiod or reproductive state. Collectively, these findings suggest an important role for kisspeptin in coordinating and relaying environmentally relevant information to the reproductive axis as well as a role for this peptide in regulating seasonal changes in reproductive function.

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Extracellular functions of the endoplasmic reticulum chaperone protein calreticulin (CRT) are emerging. Here we show novel roles for exogenous CRT in both cutaneous wound healing and diverse processes associated with repair. Compared with platelet-derived growth factor-BB-treated controls, topical application of CRT to porcine excisional wounds enhanced the rate of wound re-epithelialization. In both normal and steroid-impaired pigs, CRT increased granulation tissue formation. Immunohistochemical analyses of the wounds 5 and 10 days after injury revealed marked up-regulation of transforming growth factor-␤3 (a key regulator of wound healing), a threefold increase in macrophage influx, and an increase in the cellular proliferation of basal keratinocytes of the new epidermis and of cells of the neodermis. In vitro studies confirmed that CRT induced a greater than twofold increase in the cellular proliferation of primary human keratinocytes, fibroblasts, and microvascular endothelial cells (with 100 pg/ml, 100 ng/ ml, and 1.0 pg/ml, respectively). Moreover, using a scratch plate assay, CRT maximally induced the cellular migration of keratinocytes and fibroblasts (with 10 pg/ml and 1 ng/ml, respectively). In addition, CRT induced concentration-dependent migration of keratinocytes, fibroblasts macrophages, and monocytes in chamber assays. These in vitro bioactivities provide mechanistic support for the positive biological effects of CRT observed on both the epidermis and dermis of wounds in vivo, underscoring a significant role for

Anthropogenic disturbance is a relevant and widespread facilitator of environmental change and there is clear evidence that it impacts natural populations. While population-level responses to major anthropogenic changes have been well studied, individual physiological responses to mild disturbance can be equally critical to the long-term survival of a species, yet they remain largely unexamined. The current study investigated the impact of seemingly low-level anthropogenic disturbance (ecotourism) on stress responsiveness and specific fitness-related immune measures in different breeding stages of the marine iguana (Amblyrhynchus cristatus). Specifically, we found stress-induced elevations in plasma corticosterone among tourist-exposed populations relative to undisturbed populations. We also found changes in multiple immunological responses associated with stress-related effects of human disturbance, including bacterial killing ability, cutaneous wound healing, and hemolytic complement activity, and the responses varied according to reproductive state. By identifying health-related consequences of human disturbance, this study provides critical insight into the conservation of a well-known species that has a very distinct ecology. The study also broadens the foundation of knowledge needed to understand the global significance of various levels of human disturbance.

When male investment in mating varies with quality, reliable sexual signals may evolve. In many songbirds, testosterone mediates mating investment, suggesting that signals should be linked to testosterone production. However, because testosterone may change rapidly during behaviour such as territorial aggression and courtship, efforts to establish such a relationship have proved challenging. In a population of dark‐eyed juncos, we measured individual variation in the production of short‐term testosterone increases by injecting gonadotropin‐releasing hormone (GnRH). We found a positive correlation between the magnitude of these increases and the size of a plumage ornament (‘tail white’) previously shown to be important for female choice and male–male competition. We then measured naturally elevated testosterone levels produced during male–male competition and found that they covaried with those induced by GnRH. We suggest that the association between tail white and testosterone increases may allow conspecifics to assess potential mates and competitors reliably using tail white.