Modeling the morphodynamic galectin patterning network of the developing avian limb skeleton.

We present a mathematical model for the morphogenesis and patterning of the mesenchymal condensations that serve as primordia of the avian limb skeleton. The model is based on the experimentally established dynamics of a multiscale regulatory network consisting of two glycan-binding proteins expressed early in limb development: CG (chicken galectin)-1A, CG-8 and their counterreceptors that determine the formation, size, number and spacing of the "protocondensations" that give rise to the condensations and subsequently the cartilaginous elements that serve as the templates of the bones. The model, a system of partial differential and integro-differential equations containing a flux term to represent local adhesion gradients, is simulated in a "full" and a "reduced" form to confirm that the system has pattern-forming capabilities and to explore the nature of the patterning instability. The full model recapitulates qualitatively and quantitatively the experimental results of network perturbation and leads to new predictions, which are verified by further experimentation. The reduced model is used to demonstrate that the patterning process is inherently morphodynamic, with cell motility being intrinsic to it. Furthermore, subtle relationships between cell movement and the positive and negative interactions between the morphogens produce regular patterns without the requirement for activators and inhibitors with widely separated diffusion coefficients. The described mechanism thus represents an extension of the category of activator-inhibitor processes capable of generating biological patterns with repetitive elements beyond the morphostatic mechanisms of the Turing/Gierer-Meinhardt type.

Review of evidence for dietary influences on atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting children and adolescents worldwide. The relationship of AD to diet has been a matter of curiosity for many years. Here we look at the evidence in the literature of the association between AD and diet, and the effectiveness of elimination diets and diet supplementation in the management of AD. Several studies have found an association between clinical food allergy and AD, and more recent investigations have also suggested that dietary elements may promote late AD exacerbations. Diet elimination trials in select patients who are clinically allergic to eggs have shown promise in reducing symptoms. Additionally, elimination of food additives in a subgroup of patients was found to be beneficial. Finally, diet supplementations with evening primrose oil and an omega-3 fatty acid (docosahexaenoic acid) may be appropriate in certain AD candidates.

A two-galectin network establishes mesenchymal condensation phenotype in limb development.

Previous work showed that Gal-1A and Gal-8, two proteins belonging to the galactoside-binding galectin family, are the earliest determinants of the patterning of the skeletal elements of embryonic chicken limbs, and further, that their experimentally determined interactions in the embryonic limb bud can be interpreted via a reaction-diffusion-adhesion (2GL: two galectin plus ligands) model. Here, we use an ordinary differential equation-based approach to analyze the intrinsic switching modality of the 2GL network and characterize the network behavior independent of the diffusive and adhesive arms of the patterning mechanism. We identify two states: where the concentrations of both the galectins are respectively, negligible, and very high. This bistable switch-like system arises via a saddle-node bifurcation from a monostable state. For the case of mass-action production terms, we provide an explicit Lyapunov function for the system, which shows that it has no periodic solutions. Our model therefore predicts that the galectin network may exist in low expression and high expression states separated in space or time, without any intermediate states. We test these predictions in experiments performed with high density cultures of chick limb mesenchymal cells and observe that cells inside precartilage protocondensations express Gal-1A at a much higher rate than those outside, for which it was negligible. The Gal-1A and -8-based patterning network is therefore sufficient to partition the mesenchymal cell population into two discrete cell states with different developmental (chondrogenic vs. non-chondrogenic) fates. When incorporated into an adhesion and diffusion-enabled framework this system can generate a spatially patterned limb skeleton.

Potential of in-plant intramuscular fat predictions to enable sheep breeders to incorporate consumer preferences in breeding programmes.

The inclusion of eating quality traits in sheep genetic improvement programmes is desirable. Intramuscular fat (IMF) plays a key role in ensuring consumer satisfaction when eating lamb, but genetic progress for IMF is constrained by a lack of routine data collection. This study investigated the potential for IMF predictor traits to substitute for measured IMF in genetic improvement programmes. Carcass and predicted IMF (near-infrared estimated IMF and marbling score) data were available on 10,113 New Zealand lambs, 1678 of which also had measured chemical IMF on a slice of M. longissimus lumborum on which the predictions of IMF had been made. Genetic antagonisms were observed between carcass lean traits and IMF. The genetic correlation between the predictors and measured IMF approached one, indicating that predictors of IMF can be used in genetic improvement programmes. Through using selection indexes, simultaneous increases in IMF and the existing terminal selection index are possible, provided all traits are measured. This study highlights the importance and potential of predicted IMF to achieve genetic improvement in traits of importance to consumers.

Dynamics of skeletal pattern formation in developing chick limb.

During development of the embryonic chick limb the skeletal pattern is laid out as cartilaginous primordia, which emerge in a proximodistal sequence over a period of 4 days. The differentiation of cartilage is preceded by changes in cellular contacts at specific locations in the precartilage mesenchyme. Under realistic assumptions, the biosynthesis and diffusion through the extracellular matrix of a cell surface protein, such as fibronectin, will lead to spatial patterns of this molecule that could be the basis of the emergent primordia. As cellular differentiation proceeds, the size of the mesenchymal diffusion chamber is reduced in descrete steps, leading to sequential reorganizations of the morphogen pattern. The successive patterns correspond to observed rows of skeletal elements, whose emergence, in theory and in practice, depends on the maintenance of a unique boundary condition at the limb bud apex.

Matrix-driven translocation of cells and nonliving particles.

Cells of metazoan organisms produce and react to complex macromolecular microenvironments known as extracellular matrices. Assembly in vitro of native, compositionally nonuniform collagen-fibronectin matrices caused translocation of certain types of cells or polystyrene-latex beads from regions lacking fibronectin into regions containing it. The translocation process was not due to diffusion, convection, or electrostatic distribution effects, but may depend on nonequilibrium phenomena at the interface of contiguous collagen matrices formed in the presence and absence of fibronectin or particles. Extracellular matrix formation alone was sufficient to drive translocation by a biophysical process that may play a role in cellular migration during embryogenesis, as well as in other types of tissue reorganization such as inflammation, wound healing, and tumor invasion.

A Field Guide to Finding Fossils on Mars.

The Martian surface is cold, dry, exposed to biologically harmful radiation and apparently barren today. Nevertheless, there is clear geological evidence for warmer, wetter intervals in the past that could have supported life at or near the surface. This evidence has motivated National Aeronautics and Space Administration and European Space Agency to prioritize the search for any remains or traces of organisms from early Mars in forthcoming missions. Informed by (1) stratigraphic, mineralogical and geochemical data collected by previous and current missions, (2) Earth's fossil record, and (3) experimental studies of organic decay and preservation, we here consider whether, how, and where fossils and isotopic biosignatures could have been preserved in the depositional environments and mineralizing media thought to have been present in habitable settings on early Mars. We conclude that Noachian-Hesperian Fe-bearing clay-rich fluvio-lacustrine siliciclastic deposits, especially where enriched in silica, currently represent the most promising and best understood astropaleontological targets. Siliceous sinters would also be an excellent target, but their presence on Mars awaits confirmation. More work is needed to improve our understanding of fossil preservation in the context of other environments specific to Mars, particularly within evaporative salts and pore/fracture-filling subsurface minerals.

Experimental fossilization of mat-forming cyanobacteria in coarse-grained siliciclastic sediments.

Microbial fossils and textures are commonly preserved in Ediacaran and early Cambrian coarse-grained siliciclastic sediments that were deposited in tidal and intertidal marine settings. In contrast, the fossilization of micro-organisms in similar marine environments of post-Cambrian age is less frequently reported. Thus, temporal discrepancies in microbial preservation may have resulted from the opening and closing of a unique taphonomic window during the terminal Proterozoic and early Phanerozoic, respectively. Here, we expand upon previous work to identify environmental factors which may have facilitated the preservation of cyanobacteria growing on siliciclastic sand, by experimentally determining the ability of microbial mats to trap small, suspended mineral grains, and precipitate minerals from ions in solution. We show that (i) fine grains coat the sheaths of filamentous cyanobacteria (e.g., Nodosilinea sp.) residing within the mat, after less than 1 week of cell growth under aerobic conditions, (ii) clay minerals do not coat sterile cellulose fibers and rarely coat unsheathed cyanobacterial cells (e.g., Nostoc sp.), (iii) stronger disturbances (where culture jars were agitated at 170 rpm; 3 mm orbital diameter) produce the smoothest and most extensive mineral veneers around cells, compared with those agitated at slower rotational speeds (150 and 0 rpm), and (iv) mineral veneers coating cyanobacterial cells are ~1 µm in width. These new findings suggest that sheathed filamentous cyanobacteria may be preferentially preserved under conditions of high fluid energy. We integrate these results into a mechanistic model that explains the preservation of microbial fossils and textures in Ediacaran sandstones and siltstones, and in fine-grained siliciclastic deposits that contain exceptionally preserved microbial mats.

Molecular biosignatures reveal common benthic microbial sources of organic matter in ooids and grapestones from Pigeon Cay, The Bahamas.

Ooids are sedimentary grains that are distributed widely in the geologic record. Their formation is still actively debated, which limits our understanding of the significance and meaning of these grains in Earth's history. Central questions include the role played by microbes in the formation of ooids and the sources of ubiquitous organic matter within ooid cortices. To address these issues, we investigated the microbial community composition and associated lipids in modern oolitic sands at Pigeon Cay on Cat Island, The Bahamas. Surface samples were taken along a transect from the shallow, turbulent surf zone to calmer, deeper water. Grains transitioned from shiny and abraded ooids in the surf zone, to biofilm-coated ooids at about 3 m water depth. Further offshore, grapestones (cemented aggregates of ooids) dominated. Benthic diatoms and Proteobacteria dominated biofilms. Taxa that may promote carbonate precipitation were abundant, particularly those associated with sulfur cycling. Compared to the lipids associated with surface biofilms, relict lipids bound within carbonate exhibited remarkably similar profiles in all grain types. The enhanced abundance of methyl-branched fatty acids and ß-hydroxy fatty acids, 1-O-monoalkyl glycerol ethers and hopanoids bound within ooid and grapestone carbonate confirms a clear association of benthic sedimentary bacteria with these grains. Lipids bound within ooid cortices also contain molecular indicators of microbial heterotrophic degradation of organic matter, possibly in locally reducing conditions. These included the loss of labile unsaturated fatty acids, enhanced long-chain fatty acids/short-chain fatty acids, enriched stable carbon isotopes ratios of fatty acids, and very high stanol/stenol ratios. To what extent some of these molecular signals are derived from later heterotrophic endolithic activity remains to be fully resolved. We speculate that some ooid carbonate forms in microbial biofilms and that early diagenetic degradation of biofilms may also play a role in early stage carbonate precipitation around ooids.

On multiscale approaches to three-dimensional modelling of morphogenesis.

In this paper we present the foundation of a unified, object-oriented, three-dimensional biomodelling environment, which allows us to integrate multiple submodels at scales from subcellular to those of tissues and organs. Our current implementation combines a modified discrete model from statistical mechanics, the Cellular Potts Model, with a continuum reaction-diffusion model and a state automaton with well-defined conditions for cell differentiation transitions to model genetic regulation. This environment allows us to rapidly and compactly create computational models of a class of complex-developmental phenomena. To illustrate model development, we simulate a simplified version of the formation of the skeletal pattern in a growing embryonic vertebrate limb.

Derivation of a new lamb survival trait for the New Zealand sheep industry.

Previous research identified that a review of the current industry New Zealand lamb survival trait was necessary as its recording accuracy was reliant on farmers notifying their Sheep Improvement Limited bureau of lamb deaths. This paper reports the decision rules and genetic parameters for a new lamb survival trait for the New Zealand sheep industry. These rules define the new lamb survival trait (NEWSUR) using lamb birth fate (BFATE) codes and the presence/absence of lamb weight measurements. Six univariate animal models were tested and used to estimate variance or covariance components and the resulting direct and maternal heritabilities for NEWSUR. The models differed in the way they adjust for the effect of day of birth, the exclusion or inclusion of a litter (dam/year of birth) random effect, and the application or not of a logit transformation of the phenotypes. For both the linear and logistic methods, models including the random effect of litter provided the best fit for NEWSUR according to log-likelihood values. Log-likelihoods for the linear and logistic models cannot be compared; therefore, a cross-validation method was used to assess whether the logit transformation was appropriate by analyzing the predictive ability of the models. The mean square errors were slightly lower for the linear compared with the logistic model, and therefore, the linear model was recommended for industry use. The heritability attributed to direct effects ranged from 2 to 5.5%. A direct heritability of 5.5% resulted from a linear model without litter effect and omitting the effect of day of birth on survival, whereas a direct heritability of 2% resulted from the logistic model fitting a random litter effect. The heritability attributed to maternal genetic effects ranged from 1.9 to 7.7%. A maternal genetic heritability of 7.7% resulted from the logistic model omitting the litter effect, whereas a maternal genetic heritability of 1.9% resulted from the linear model fitting a random litter effect. The addition of the litter random effect substantially decreased the maternal heritabilities in all cases and was recommended for industry use to avoid overestimation of the maternal genetic variance. Sheep Improvement Limited has implemented NEWSUR and the associated genetic evaluation model based on information described in this paper. Industry-wide implementation will enable sheep breeders to produce more accurate genetic evaluations to their commercial clients.

Genetic analysis and genomic selection of stayability and productive life in New Zealand ewes.

Genetic parameters for ewes were estimated for stayability (STAY) and productive life (Prodlife). Records from 658,871 animals from 241 seed stock or ram breeder flocks and one research flock were used to estimate parameters for ram breeder flock STAY and Prodlife. These flocks would have a culling policy based on criteria typical of a commercial enterprise, but including culls based on knowledge such as estimated breeding values. A subset of 35,688 of these animals from 4 ram breeder and one research flock was used to infer the animals that might be culled based on the perspective of a commercial flock as these flocks recorded reasons for culling. These data were used to estimate parameters for commercial flock STAY and Prodlife. Heritability for ram breeder flock STAY until age 3 to 6 yr ranged from 0.07 to 0.09. The heritability of commercial flock STAY was similar in yr 5 and 6, but lower at 0.05 (age 3) and 0.07 (age 4). Heritability of Prodlife for ram breeder flock and commercial flock was respectively 0.10 and 0.13. The genetic correlations between ram breeder flock STAY and commercial flock STAY ranged from 0.20 to 0.99. Both STAY and Prodlife were most correlated genetically with the trait number of lambs born, at about 0.4, and to a lesser degree, live weight up to the age of 12 mo for the traits analyzed with lower genetic correlations estimated for the commercial flocks. Live weight at 18 mo and fleece weight had little or no correlation with STAY and Prodlife. From the data set used to estimate genetic parameters from a ram breeder flock, 4,330 animals were genotyped with the Illumina OvineSNP50 BeadChip and the genotypes used to develop genomic predictions via genomic best linear unbiased prediction. The animals used in the training data set were multibreed, but were heavily Romney breed based. The genomic prediction accuracy for ram breeder flock STAY, according to breed, was dependent on sample size and ranged from 0.4 to 0.44 for Romney and 0.26 to 0.4 for Coopworth. Accuracies for Perendale and Composites, for which sample sizes were less, were more variable. This study has derived genetic parameters for STAY and Prodlife and investigated genomic predictions for these traits. As these traits are of low heritability, sex limited and expressed late in life genomic selection will be useful.

Levels of mineralocorticoids in whites and blacks.

Blacks appear, on average, to retain more Na than whites. A higher production rate of mineralocorticoids could explain the greater Na retention in blacks. Although production of aldosterone has been shown to be lower in blacks, the level of another mineralocorticoid may be increased. Plasma levels of deoxycorticosterone and cortisol were measured in young whites (n=23; age=16.4+/-3.1[SD] years) and young blacks (n=25; age=13.8+/-1.3 years). Blacks had lower plasma levels of renin activity and aldosterone and lower urinary aldosterone excretion rates; thus, they appeared to be representative of blacks that retain additional Na. Plasma deoxycorticosterone levels were lower in blacks than in whites both at baseline (247+/-161 versus 381+/-270 pmol/L, P=0.048) and after stimulation with adrenocorticotropic hormone (822+/-294 versus 1127+/-628 pmol/L at 30 minutes, P=0.047; 925+/-366 versus 1440+/-834 pmol/L at 60 minutes, P=0.013). Cortisol levels were also lower in blacks at baseline (P=0.014) but were not significantly different from levels in whites after stimulation with adrenocorticotropic hormone. In a larger cohort of 407 whites (age=12.0+/-2.9 years) and 247 blacks (age=12.9+/-3.1 years), 18-hydroxycortisol excretion rates were also lower in blacks (P=0. 021). In conclusion, increased Na retention in blacks does not appear to be secondary to increased production of either aldosterone, deoxycorticosterone, cortisol, or 18-hydroxycortisol. A primary renal mechanism may mediate the increase in Na reabsorption in blacks.

Abnormal ocular motor control in Huntington's disease.

We studied eye movements in 50 patients with Huntington's disease. Fixation was impaired in 73% of patients; such individuals had difficulty in suppressing saccades toward novel visual stimuli. Impaired initiation of saccades was manifest by increased reaction time (89%) and inability to make a saccade without head movement (89%) or blink (35%). Saccades and quick phases of nystagmus were slowed in 62%. Smooth pursuit was abnormal in 60%, and vergence in 33%. The vestibulo-ocular reflex and the ability to hold eccentric gaze were preserved even late in the disease.

Unusual sinonasal small-cell neoplasms following radiotherapy for bilateral retinoblastomas.

Two patients developed sinonasal small-cell neoplasms that arose 22 years and 37 years, respectively, following radiotherapy for bilateral retinoblastomas. The tumors were composed of small cells with scant cytoplasm and had a few scattered Homer-Wright rosettes. Immunohistochemically, one tumor was positive for keratin (CAM 5.2 and AE1/AE3), epithelial membrane antigen, and neuron-specific enolase. The other neoplasm was immunoreactive for keratin (CAM 5.2 only) and neuron-specific enolase; it also had focal immunopositivity for S-100 protein, desmin, and muscle-specific actin. Both were negative for CEA, vimentin, melanocyte-specific antigen (HMB45), chromogranin A, synaptophysin, Leu-7, 200 kd neurofilament, and retinal S-antigen. Despite aggressive multimodal therapy, the patients died of metastatic tumor 7 months and 10 months following their initial diagnosis, respectively. Although osteosarcoma is the most frequent second cancer following bilateral retinoblastomas, some patients develop clinically aggressive sinonasal small-cell tumors that are difficult to place into conventional classifications. Both of our cases showed evidence of multidirectional differentiation; one tumor labeled with epithelial and neural markers, and the other expressed epithelial, neural, and myogenous antigens.

Generation, integration, autonomy: three steps in the evolution of homology.

The homology concept harbours implicit assumptions about the evolution of morphological organization. Homologues are natural units in the construction of organismal body plans. Their origin and maintenance should represent a key element of a comprehensive theory of morphological evolution. Therefore, it is necessary to understand the causation of homology and to investigate the mechanisms underlying its origination. The study of this issue cannot be limited to the molecular level, because there appears to exist no strict correspondence between genetic and morphological evolution. It is argued that the establishment of homology follows three distinct (if overlapping) steps: (a) the generation of morphological building elements; (b) the integration of new elements into a body plan; and (c) the autonomization of integrated construction units as lineage-specific homologues of phenotypic evolution. In contrast with traditional views, it is proposed that the mechanistic basis for steps (a) and (b) is largely epigenetic, i.e. a consequence of the inherent propensities of developmental system under changing conditions. Step (c) transcends the proximate mechanisms underlying the establishment of homologues and makes them independent attractors of morphological organization at the phenotypic level.

Optic tract syndrome. Neuro-ophthalmologic considerations.

A review of the case histories of ten patients with optic tract lesions, an uncommon clinical entity, showed the primary characteristic to be a homonymous visual field defect that may be complete or incomplete. When the defect is incomplete, there is relative incongruity. When it is complete, there is an associated contralateral relative afferent pupillary defect. Visual acuity and color vision are preserved, unless there is bilateral involvement or anterior extension to involve the optic nerve or chiasm. When of sufficient duration, the contralateral fundus demonstrates band or "bow tie" atrophy of the disc and nerve fiber layer.

Branch artery occlusion. An unusual complication of external carotid embolization.

A case of retinal branch artery occlusion was caused by migration of emboli, presumably via collateral circulation, during therapeutic embolization of the maxillary artery. Migration of particles to the ophthalmic circulation is unusual with embolization of the branches of the external carotid artery. Meticulous technique, careful angiographic monitoring, and proper selection of embolic material may reduce, but not eliminate, migration of emboli to undesirable locations. Therapeutic embolization of vascular tumors and malformations in the external carotid territory is a recent radiologic innovation that is becoming increasingly popular. Therefore, we may expect to see more ocular complications from aberrant emboli as the use of this technique becomes more widespread.

Ciliary body adenoma in a 10-year-old girl who had a rhabdomyosarcoma.

A retrolenticular fibrovascular membrane occurred in the setting of a ciliary body mass in a 10-year-old black girl who had been successfully treated for a rhabdomyosarcoma of the lung. The results of a transscleral biopsy of the mass demonstrated it to be a pigmented adenoma of the ciliary body. A lensectomy and membranectomy were performed to aid in the follow-up and rehabilitation of the eye. At 9 months after surgery, the patient had 20/25 vision with no evidence of tumor growth. This case demonstrates an unusual cause of cyclitic membrane formation and suggests that transscleral biopsy may be a useful adjunct in the management of selected ciliary body masses.

Optic neuropathy in systemic lupus erythematosus.

We report data from seven cases of optic neuropathy in systemic lupus erythematosus. The visual outcome varied, but improvement occasionally occurred following treatment with corticosteroids. The clinical picture was variable and could present as acute retrobulbar optic neuritis, ischemic optic neuropathy, or slowly progressive visual loss. Visual evoked response testing revealed increased latency in two patients and loss of amplitude in two others; a fifth patient had both findings in the involved eye. Despite the variable presentation, the probable pathogenesis in all cases is vaso-occlusive disease in small vessels of the optic nerves.