A linear-encoding model explains the variability of the target morphology in regeneration.

A fundamental assumption of today's molecular genetics paradigm is that complex morphology emerges from the combined activity of low-level processes involving proteins and nucleic acids. An inherent characteristic of such nonlinear encodings is the difficulty of creating the genetic and epigenetic information that will produce a given self-assembling complex morphology. This 'inverse problem' is vital not only for understanding the evolution, development and regeneration of bodyplans, but also for synthetic biology efforts that seek to engineer biological shapes. Importantly, the regenerative mechanisms in deer antlers, planarian worms and fiddler crabs can solve an inverse problem: their target morphology can be altered specifically and stably by injuries in particular locations. Here, we discuss the class of models that use pre-specified morphological goal states and propose the existence of a linear encoding of the target morphology, making the inverse problem easy for these organisms to solve. Indeed, many model organisms such as Drosophila, hydra and Xenopus also develop according to nonlinear encodings producing linear encodings of their final morphologies. We propose the development of testable models of regeneration regulation that combine emergence with a top-down specification of shape by linear encodings of target morphology, driving transformative applications in biomedicine and synthetic bioengineering.

Endocrine relationships between rank - related behavior and antler growth in deer.

In this review, we analyze endocrine aspects of the relationships between antlerogenesis and rank-related behavior. The explanation of these relationships has been based on the presumption that the antler growth is regulated by hormones modulated by agonistic behavior. Originally, we assumed that these relationships are primarily testosterone dependent. In the eighties, it was reported that the insulin-like growth factor 1 (IGF-1) is the antler-stimulating hormone. This hypothesis was supposed to replace an earlier theory that the antler-stimulating hormones are either androgens or their derivatives. Here, we present historical and recent views on these issues. In particular, we analyze the arguments in favor and against the role of testosterone and IGF-1 in antler growth and present a comparison of the results obtained across some deer species. In this context, we review and discuss experiments with castration of various deer species and analyze data from papers dealing with in vivo studies. We conclude that testosterone and not IGF-1 is the main antler stimulating and regulating hormone, and that concentrations of testosterone may be modified by social behavior.

Effect of different factors on proliferation of antler cells, cultured in vitro.

Antlers as a potential model for bone growth and development have become an object of rising interest. To elucidate processes explaining how antler growth is regulated, in vitro cultures have been established. However, until now, there has been no standard method to cultivate antler cells and in vitro results are often opposite to those reported in vivo. In addition, many factors which are often not taken into account under in vitro conditions may play an important role in the development of antler cells. In this study we investigated the effects of the antler growth stage, the male individuality, passaged versus primary cultures and the effect of foetal calf serum concentrations on proliferative potential of mixed antler cell cultures in vitro, derived from regenerating antlers of red deer males (Cervus elaphus). The proliferation potential of antler cells was measured by incorporation of (3)H thymidine. Our results demonstrate that there is no significant effect of the antler growth stage, whereas male individuality and all other examined factors significantly affected antler cell proliferation. Furthermore, our results suggest that primary cultures may better represent in vivo conditions and processes occurring in regenerating antlers. In conclusion, before all main factors affecting antler cell proliferation in vitro will be satisfactorily investigated, results of in vitro studies focused on hormonal regulation of antler growth should be taken with extreme caution.

Relationship between rank and plasma testosterone and cortisol in red deer males (Cervus elaphus).

The objective of this study was to assess the effect of a change in the social composition in a group of red deer males on the relationship between their rank and testosterone. A group of twelve adult red deer males (Cervus elaphus) was tested in two social settings. From April 15 to June 9 (Period 1) this group was kept separately in an enclosure. On June 10, nine 3-year-old males were added to that group of adult males. They were kept together until August 31. We performed 10 observations of the group when the agonistic interactions of the males were recorded and we took 9 blood samples per male in Period 1; 11 observations were made and 10 samples were taken in Period 2. Concentrations of testosterone and cortisol were later determined in plasma. Adding much younger and smaller sparring partners into the experimental group of adult males in Period 2 altered the agonistic behaviour of the adults even though this did not trigger any change in rank position of the experimental males except one. Adult males targeted preferentially their attacks on individuals much lower in the hierarchy. Experimental male deer with higher social rank had lower levels of testosterone in Period 1; in Period 2 it was just the opposite. In Period 1 the animals had higher cortisol levels than in Period 2. As controls we used four adult (5years old) males sharing the enclosure with four 3-year-old males. No changes in hormone concentrations were observed in the control group. Thus, changing the social environment of adult red deer males resulted in change of the relationship between rank and testosterone and cortisol concentrations.

Testosterone, but not IGF-1, LH, prolactin or cortisol, may serve as antler-stimulating hormone in red deer stags (Cervus elaphus).

The role of androgens and insulin-like growth factor 1 (IGF-1) in antler growth has been disputed. We predicted that the secretory of IGF-1 may be associated with an acceleration of body growth rather than with antler growth. Furthermore we anticipated a relationship between the increase of testosterone and the progress of antler growth. If IGF-1 is involved in the stimulation of antler growth, this should be more obvious in young than in mature stags. Eight two-year-old red deer stags (Cervus elaphus), and twelve adult red deer stags were blood sampled and the length of their velvet antlers was measured in one-week intervals during the period of antler growth. Concentrations of testosterone, cortisol, IGF-1, luteinizing hormone (LH), and prolactin were determined in plasma by enzyme immunoassay or radioimmunoassay. Antler growth per day was primarily dependent on changes in testosterone concentration per day in both groups of stags. As expected, only in two-year-old stags we detected a possible role of IGF-1 in the antler growth regulation, but that was not in agreement with previously published studies. Nevertheless, this effect was still utilized in interaction with testosterone. In addition to total antler length, only concentrations of testosterone and LH were significantly higher in adult males in comparison to two-year-old males. Our present results lead us to conclude that it is not IGF-1 but testosterone which is responsible for the intensity of antler growth in subadult and adult red deer stags.

Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research.

Ulcerative colitis (UC) is an inflammatory bowel disease that afflicts up to 1 million people in the US. Current treatments for UC are mostly nonspecific, not always effective, and often accompanied by serious side effects. Therefore, there is considerable interest in finding alternative and more tolerable treatments for this disease. Physiologic data suggest that melatonin is an important regulator of both inflammation and motility in the gastrointestinal tract, and data from in vitro studies, animal experiments, and limited studies in humans suggest that supplemental melatonin may have an ameliorative effect on colitis. In this review we summarize the evidence regarding melatonin as a possible therapeutic agent in UC and discuss possible biological mechanisms and directions for future research.

Testosterone and estradiol concentrations in serum, velvet skin, and growing antler bone of male white-tailed deer.

The growth and mineralization of antlers correlate with the seasonal variation of serum androgens. Whereas seasonal levels of testosterone (T) in plasma are well established, steroid concentrations have not yet been determined in the tissues of growing antlers. Therefore, RIA was used to determine T and 17beta estradiol (E2) in serum, and three areas (tip, middle, and base) of the antler bone and the antler skin, called velvet. Blood and antler tissues of white-tailed deer (Odocoileus virginianus) were collected from May to August. The difference between levels of T and E2 among the sites was calculated using the square root transformation followed by a mixed model analysis with individual deer and an interaction of individual and year (individual(*)year) as a random factor. Concentrations of T in serum (799+/-82 pg/ml) were higher than T values in the velvet (589+/-58 pg/ml, P<0.01) and in the antler bone (538+/-58 pg/ml, P<0.001). Estradiol concentrations differed among antler tissues and serum (P<0.001) and between years (P<0.01). Estradiol concentrations in serum (25+/-25 pg/ml) were consistently lower than those in antler bone (208+/-11 pg/ml, P<0.001) and velvet (150+/-12 pg/ml, P<0.001). The E2:T ratio in serum was 1:10-60. The same ratio for the antler bone was only 1:2-3 and for the velvet 1:3.5. It is concluded that higher T and lower E2 concentrations found in plasma, as compared to antler bone or antler velvet, may indicate a partial metabolism of systemic androgens into estrogens xin the tissues of growing antlers.

Gastrointestinal melatonin: localization, function, and clinical relevance.

The gastrointestinal tract of vertebrate species is a rich source of extrapineal melatonin. The concentration of melatonin in the gastrointestinal tissues surpasses blood levels by 10-100 times and there is at least 400x more melatonin in the gastrointestinal tract than in the pineal gland. The gastrointestinal tract contributes significantly to circulating concentrations of melatonin, especially during the daytime and melatonin may serve as an endocrine, paracrine, or autocrine hormone influencing the regeneration and function of epithelium, enhancing the immune system of the gut, and reducing the tone of gastrointestinal muscles. As binding sites for melatonin exhibit circadian variation in various species, it has been hypothesized that some melatonin found in the gastrointestinal tract might be of pineal origin. Unlike the photoperiodically regulated production of melatonin in the pineal, the release of gastrointestinal melatonin seems to be related to the periodicity of food intake. Phylogenetically, melatonin and its binding sites were detected in the gastrointestinal tract of lower vertebrates, birds, and mammals. Melatonin was found also in large quantities in the embryonic tissue of the mammalian and avian gastrointestinal tract. Food intake and, paradoxically, also longterm food deprivation resulted in an increase of tissue and plasma concentrations of melatonin. Melatonin release may have a direct effect on many gastrointestinal tissues but may also well influence the digestive tract indirectly, via the central nervous system and the sympathetic and parasympathetic nerves. Melatonin prevents ulcerations of gastrointestinal mucosa by an antioxidant action, reduction of secretion of hydrochloric acid, stimulation of the immune system, fostering epithelial regeneration, and increasing microcirculation. Because of its unique properties, melatonin could be considered for prevention or treatment of colorectal cancer, ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood colic.

Effect of antiandrogen cyproterone acetate on the development of the antler cycle in Southern pudu (Pudu puda).

The antler cycle of pudu is similar to other cervids, but unlike most boreal deer, male Southern pudu (Pudu puda) exhibits two seasonal peaks of LH and testosterone. In that respect, pudu is similar to roe deer. Whereas the antler cycle in some deer species, such as roe deer or white-tailed deer, is very sensitive to variation of testosterone, in other cervids, such as fallow deer or reindeer, a blockade of androgens with cyproterone acetate (CA) has little or no effect on the timing of the antler casting. In order to test the sensitivity of pudu antlers to variations of androgens, CA (administered 2x weekly at 50 mg/buck) was injected intramuscularly for 3 weeks in 5 adult male pudu, starting February 19 (late summer). Four other males of similar age served as controls. The experiment was performed at the University of Concepcion, Chile, latitude 36.6 degreeS. Blood samples were taken once a week between January 19 and April 3. In CA-treated bucks, the antlers were cast approximately 3 weeks after the initiation of CA treatment and a new antler growth began almost immediately. The antlers reached about 5 cm in length, before ceasing to grow at the end of April, when they became mineralized and were subsequently polished. CA had no effect on the already declining levels of LH. Plasma levels of testosterone in controls increased from February 15, whereas in CA-treated bucks remained depresses until March 21. It is concluded that similarly to white-tailed deer, the antler cycle of Southern pudu is very sensitive to manipulation of androgen levels.