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The validity of the Bagnold constitutive relation in gravity-driven granular flow down an inclined plane is studied by discrete element (DEM) simulations. In the limit of infinitely hard particles, the Bagnold relation is known to hold exactly. We determine deviations from this relation as a function of all parameters governing interparticle interactions. These include elastic compliance, inelastic dissipation, friction coefficient, and interparticle cohesion. We find significant deviations from Bagnold rheology in some regions of this parameter space and propose a generalized Bagnold relation to account for this effect. Moreover, we note a significant correlation between the breakdown of Bagnold rheology in the bulk and the appearance of a long-time tail in the two-particle contact time distributions.

Background: The anterior-posterior axis of the vertebrate embryo undergoes a dramatic elongation during early development. Convergence and extension of the mesoderm, occurring during gastrulation, initiates the narrowing and lengthening of the embryo. However the lengthening of the axis continues during post-gastrula stages in the tailbud region, and is thought to involve convergent extension movements as well as other cell behaviors specific to posterior regions., Results: We demonstrate here, using a semi-dominant N-cadherin allele, that members of the classical cadherin subfamily of cell-cell adhesion molecules are required for tailbud elongation in the zebrafish. In vivo imaging of cell behaviors suggests that the extension of posterior axial mesodermal cells is impaired in embryos that carry the semi-dominant N-cadherin allele. This defect most likely results from a general loss of cell-cell adhesion in the tailbud region. Consistent with these observations, N-cadherin is expressed throughout the tailbud during post-gastrulation stages. In addition, we show that N-cadherin interacts synergistically with vang-like 2, a member of the non-canonical Wnt signaling/planar cell polarity pathway, to mediate tail morphogenesis., Conclusion: We provide the first evidence here that N-cadherin and other members of the classical cadherin subfamily function in parallel with the planar cell polarity pathway to shape the posterior axis during post-gastrulation stages. These findings further highlight the central role that adhesion molecules play in the cellular rearrangements that drive morphogenesis in vertebrates and identify classical cadherins as major contributors to tail development.

We study the rheology and distribution of interparticle contact lifetimes for gravity-driven, dense granular flows of noncohesive particles down an inclined plane using large-scale, three dimensional, granular dynamics simulations. Rather than observing a large number of long-lived contacts as might be expected for dense flows, brief binary collisions predominate. In the hard-particle limit, the rheology conforms to Bagnold scaling, where the shear stress is quadratic in the strain rate. As the particles are made softer, however, we find significant deviations from Bagnold rheology; the material flows more like a viscous fluid. We attribute this change in the collective rheology of the material to subtle changes in the contact lifetime distribution involving the increasing lifetime and number of the long-lived contacts in the softer particle systems.

Through the direct analysis of cell behaviors, we address the mechanisms underlying anterior neural tube morphogenesis in the zebrafish and the role of the cell adhesion molecule N-cadherin (N-cad) in this process. We demonstrate that although the mode of neurulation differs at the morphological level between amphibians and teleosts, the underlying cellular mechanisms are conserved. Contrary to previous reports, the zebrafish neural plate is a multi-layered structure, composed of deep and superficial cells that converge medially while undergoing radial intercalation, to form a single cell-layered neural tube. Time-lapse recording of individual cell behaviors reveals that cells are polarized along the mediolateral axis and exhibit protrusive activity. In N-cad mutants, both convergence and intercalation are blocked. Moreover, although N-cad-depleted cells are not defective in their ability to form protrusions, they are unable to maintain them stably. Taken together, these studies uncover key cellular mechanisms underlying neural tube morphogenesis in teleosts, and reveal a role for cadherins in promoting the polarized cell behaviors that underlie cellular rearrangements and shape the vertebrate embryo.

Cohesive granular media flowing down an inclined plane are studied by discrete element simulations. Previous work on cohesionless granular media demonstrated that within the steady flow regime where gravitational energy is balanced by dissipation arising from intergrain forces, the velocity profile in the flow direction scales with depth in a manner consistent with the predictions of Bagnold. Here we demonstrate that this Bagnold scaling does not hold for the analogous steady flows in cohesive granular media. We develop a generalization of the Bagnold constitutive relation to account for our observation and speculate as to the underlying physical mechanisms responsible for the different constitutive laws for cohesive and noncohesive granular media.

The neural selector gene cut, a homeobox transcription factor, is required for the specification of the correct identity of external (bristle-type) sensory organs in Drosophila. Targets of cut function, however, have not been described. Here, we study bereft (bft) mutants, which exhibit loss or malformation of a majority of the interommatidial bristles of the eye and cause defects in other external sensory organs. These mutants were generated by excising a P element located at chromosomal location 33AB, the enhancer trap line E8-2-46, indicating that a gene near the insertion site is responsible for this phenotype. Similar to the transcripts of the gene nearest to the insertion, reporter gene expression of E8-2-46 coincides with Cut in the support cells of external sensory organs, which secrete the bristle shaft and socket. Although bft transcripts do not obviously code for a protein product, its expression is abolished in bft deletion mutants, and the integrity of the bft locus is required for (interommatidial) bristle morphogenesis. This suggests that disruption of the bft gene is the cause of the observed bristle phenotype. We also sought to determine what factors regulate the expression of bft and the enhancer trap line. The correct specification of individual external sensory organ cells involves not only cut, but also the lineage genes numb and tramtrack. We demonstrate that mutations of these three genes affect the expression levels at the bft locus. Furthermore, cut overexpression is sufficient to induce ectopic bft expression in the PNS and in nonneuronal epidermis. On the basis of these results, we propose that bft acts downstream of cut and tramtrack to implement correct bristle morphogenesis.

Computational fluid dynamics (CFD) predictions of the flow patterns and heat transfer in simplified ribbed-wall turbine blade cooling passages were performed for representative stationary and rotating conditions. Analyses have been performed with different mesh densities and using different turbulence models to assess the sensitivity of predictions to these variables. Computed local heat transfer results are compared to measurements available in the literature to assess their accuracy. The results generally agree well with experiment, although the peak values of the heat transfer coefficients were under-predicted in the first leg of the channel. Some sensitivity to mesh density was seen, while the choice of near-wall turbulence model appeared to have little effect.

The molecular mechanisms that drive the development of embryonic tissues are being uncovered rapidly. One such fascinating example is the development of the forebrain, the most anterior part of the nervous system. In this review, we will discuss the mechanisms that induce the formation of the forebrain in multiple vertebrate systems, placing emphasis on a recent article published by Grinblat et al. ((1)) Using zebrafish as a model system, these authors combine elegant embryological manipulations with the use of early markers of the presumptive forebrain, to show that initial induction and patterning of this tissue occurs near the onset of gastrulation. In addition, their results confirm observations made in other systems that planar signals, those traveling in the plane of the ectoderm, are involved in forebrain induction and patterning., (Copyright 1999 John Wiley & Sons, Inc.)

The peripheral nervous system (PNS) of Drosophila provides a very well-characterized model system for studying the genes involved in basic processes of neurogenesis. Because of its simplicity and stereotyped pattern, each cell of the PNS can be individually identified and the phenotypic consequences of mutations can be studied in detail. Thus, some of the genetic mechanisms leading to the formation of type I sensory organs, the external, bristle-type sensory organs (es), and the internal, stretch-receptive chordotonal organs (ch) have been elucidated. Each sensory organ seems to be generated by a stereotyped pattern of cell division of individual ectodermal precursor cells. Recent advances in cell lineage analysis of the PNS have provided a detailed picture of almost all the lineages in the PNS, including those giving rise to the type II sensory neurons, also known as multiple dendritic (md) neurons. This knowledge will be instrumental in the precise characterization of the phenotypes associated with mutations in known and new genes and their interactions which determine cell fate decisions during neurogenesis. Here, we describe and compare three recently developed methods by which cell lineages have been assessed: single cell transplantation, bromodeoxyuridine (BrdU) incorporation studies, and the flp/FRT recombinase system from yeast. In the light of a more complete knowledge of the PNS lineages, we will discuss the effects of known mutations that alter neuronal cell fates.

The neurokinin-1 (NK-1, substance P) receptor belongs to the class of seven transmembrane domain (7-TM) receptors that interact with cellular effector systems via guanine nucleotide binding regulatory proteins (G-proteins). In this study, coupling mechanisms of functional NK-1 receptors endogenously expressed in a human astrocytoma cell line (U373MG) were analyzed. Stimulation with substance P (SP) resulted in 1) a rapid increase in inositol 1,4,5-trisphosphate (IP3) synthesis; 2) a rise in cytosolic free calcium concentration ([Ca2+]i); 3) induction of immediate early gene transcription as monitored by c-fos and c-jun expression; and 4) a significant increase in de novo DNA synthesis. Thus, the functional responses induced by stimulation of NK-1 receptors on U373MG strongly correlate with those observed after treatment of primary astrocytes with SP and make U373MG cells a useful in vitro model system for the analysis of NK-1 receptor function on astrocytes in vivo.

Hypothermia is used to prolong the safe period of ischemic arrest by reducing the heart's oxygen demands. Due to this effect, hypothermia has been the fundamental component of most methods of myocardial protection during cardiac surgery. However, hypothermia has a number of unwanted side effects, such as detrimental effects on enzyme function, energy generation, and cell membranes. Since electromechanical arrest accounts for 90% of myocardial oxygen consumption, arresting the heart with chemical cardioplegia will reduce O2 consumption dramatically. Therefore, if the resting (arrested) heart is continuously perfused with oxygenated blood cardioplegia, one can easily provide the remaining 10% of O2 that it requires. Under these conditions, the need for hypothermia becomes questionable. In this paper, we describe the perfusionist's experience using the antegrade and retrograde technique of continuous warm blood cardioplegia.

Right heart failure associated with postmortem evidence of pulmonary hypertension (cor pulmonale) was observed in nearly 1% of the young beagles of a large research colony. During the past 18 years, 176 dogs with cor pulmonale were observed. Most cases occurred between September and April of each year. Nearly equal numbers of males and females were involved, and some siblings were affected. Ninety-six percent of known affected dogs died, and 85% of the deaths occurred by 5 weeks of age. Clinically, most dogs were stunted and exhibited ascites, subcutaneous edema, hypothermia, dyspnea, cyanosis, and systolic murmur. Radiography revealed cardiomegaly, and electrocardiography revealed right axis deviation and an enlarged right atrium. Postmortem evidence of cor pulmonale included subcutaneous edema, ascites, hydrothorax, mediastinal and mesenteric edema, splenomegaly, centrolobular hepatic congestion and necrosis, right ventricular hypertrophy, interstitial pneumonia, and medial hypertrophy of pulmonary arteries and arterioles. The specific cause of the disease was not determined.

For a study of the life-time effects of irradiation during development, 1,680 beagles were given single, whole-body exposures to 60Co gamma-radiation at one of three prenatal (preimplantation, embryonic, and fetal) or at one of three postnatal (neonatal, juvenile, and young adult) ages. Mean doses were 0, 0.16, or 0.83 Gy. For comparison with data on childhood cancer after prenatal irradiation, examination was made of tumors occurring in young dogs in this life-span experiment. Up to 4 years of age, 18 dogs had neoplasms diagnosed, 2 of these being in controls. Four dogs that were irradiated in the perinatal (late fetal or neonatal) period died of cancers prior to 2 years of age. This risk was of significant increase compared to the risks for other experimental groups and for the canine population in general. Overall, 71% (5 of 7) of all cancers and 56% (10 of 18) of all benign and malignant neoplasms seen in the first 4 years of life occurred in 29% (480 of 1,680) of the dogs irradiated in the perinatal period. These data suggest an increased risk for neoplasia after perinatal irradiation in dogs.

A 2-dimensional motion and force study of the ankle joint during gait has been carried out on normal subjects and patients with ankle joint disease, before and 1 year following total ankle replacemetn. The methods employed involved the use of high-speed motion picture film, force plate and foot-switch data. The Achilles and anterior tibial tendon forces, the compressive and tangential (shear) forces across the ankle during stance phase of gait were determined, based on a quasi-static analysis. During stance phase of gait normal subjects used a mean of 24.4 degree of sagittal plane ankle motion. Patients with ankle joint disease showed reduced motion which returned to near normal values 1 year following total ankle replacement. Compressive force across the ankle joint rose to about 5 times body weight during the latter part of stance phase. Backward, or aft, shear forces or nearly full body weight were demonstrated during all but the last 20% of stance phase. Patients with ankle joint disease apparently altered their gait to markedly reduce these forces. Following total ankle replacement, shear forces returned toward more normal values, but compressive forces were not significantly changed.

Total hip arthroplasty was done in thirty-three patients who had had previous surgical attempts at arthrodesis of the hip. The arthrodesis had failed in nineteen patients, and the other fourteen patients had fused hips with symptoms in the knee and lower back. Thirty-one of the patients had satisfactory functional ability after total hip arthroplasty after one to three and one-half years' follow-up. The two patients in whom the procedure failed had complicating infections.

Review of 484 records for colony Beagles revealed an association between hypothyroidism and diabetes mellitus. The average time between first notation of hypothyroidism and later development of diabetes mellitus was 2.8 years. An association was also made with hypothyroidism, renal amyloidosis, and thrombosis. Hypothyroidism was significantly related to thrombosis, thrombosis was significantly related to renal amyloidosis, but hypothyroidism and renal amyloidosis were not significantly related. Of 62 hypothyroid dogs, 11 were diabetic and 7 others had thrombosis. Six hypothyroid dogs had renal amyloidosis, 4 of which had thrombosis. One dog had renal amyloidosis and thrombosis in the absence of hypothyroidism. There does not appear to be an association with any of the lesions and previous low-dose, whole-body gamma, or sham irradiation.