Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function.

Journal ArticleAlveolar rhabdomyosarcoma is an aggressive childhood muscle cancer for which outcomes are poor when the disease is advanced. Although well-developed mouse models exist for embryonal and pleomorphic rhabdomyosarcomas, neither a spontaneous nor a transgenic mouse model of alveolar rhabdomyosarcoma has yet been reported. We report the first mouse model of alveolar rhabdomyosarcoma using a conditional Pax3:Fkhr knock-in allele whose activation in late embryogenesis and postnatally is targeted to terminally differentiating Myf6-expressing skeletal muscle. In these mice, alveolar rhabdomyosarcomas occur but at low frequency, and Fkhr haploinsufficiency does not appear to accelerate tumorigenesis. However, Pax3:Fkhr homozygosity with accompanying Ink4a/ARF or Trp53 pathway disruption, by means of conditional Trp53 or Ink4a/ARF loss of function, substantially increases the frequencies of tumor formation. These results of successful tumor generation postnatally from a target pool of differentiating myofibers are in sharp contrast to the birth defects and lack of tumors for mice with prenatal and postnatal satellite cell triggering of Pax3:Fkhr. Furthermore, these murine alveolar rhabdomyosarcomas have an immunohistochemical profile similar to human alveolar rhabdomyosarcoma, suggesting that this conditional mouse model will be relevant to study of the disease and will be useful for preclinical therapeutic testing

Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration.

Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair. Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair

Data-Driven Homologue Matching for Chromosome Identification

Karyotyping involves the visualization and classification of chromosomes into standard classes. In normal human metaphase spreads, chromosomes occur in homologous pairs for the autosomal classes 1-22, and X chromosome for females. Many existing approaches for performing automated human chromosome image analysis presuppose cell normalcy, containing 46 chromosomes within a metaphase spread with two chromosomes per class. This is an acceptable assumption for routine automated chromosome image analysis. However, many genetic abnormalities are directly linked to structural or numerical aberrations of chromosomes within the metaphase spread. Thus, two chromosomes per class cannot be assumed for anomaly analysis. This paper presents the development of image analysis techniques which are extendible to detecting numerical aberrations evolving from structural abnormalities. Specifically, an approach to identifying normal chromosomes from selected class(es) within a metaphase spread is presented. Chromosome assignment to a specific class is initially based on neural networks, followed by banding pattern and centromeric index criteria checking, and concluding with homologue matching. Experimental results are presented comparing neural networks as the sole classifier to the authors\u27 homologue matcher for identifying class 17 within normal and abnormal metaphase spreads

Abnormal Cell Detection using the Choquet Integral

Automated Giemsa-banded chromosome image research has been largely restricted to classification schemes associated with isolated chromosomes within metaphase spreads. In normal human metaphase spreads, there are 46 chromosomes occurring in homologous pairs for the autosomal classes 1-22 and the X chromosome for females. Many genetic abnormalities are directly linked to structural and/or numerical aberrations of chromosomes within metaphase spreads. Cells with the Philadelphia chromosome contain an abnormal chromosome for class 9 and for class 22, leaving a single normal chromosome for each class. A data-driven homologue matching technique is applied to recognizing normal chromosomes from classes 9 and 22. Homologue matching integrates neural networks, dynamic programming and the Choquet integral for chromosome recognition. The inability to locate matching homologous pairs for classes 9 and 22 provides an indication that the cell is abnormal, potentially containing the Philadelphia chromosome. Applying this technique to 50 normal and to 48 abnormal cells containing the Philadelphia chromosome yields 100.0% correct abnormal cell detection with a 24.0% false positive rate

Abundance and Sizes of Bay Scallops in Heterogeneous Habitats Along the Gulf Coast of Florida

Southern bay scallops (Argopecten irradians concentricus) form the basis of a recreational fishery along Florida\u27s Gulf Coast. Recent declines in scallop abundances have led to significant harvest restrictions. As a way to gain insight into influences on scallop abundances and size, surveys of bay scallops and coastal habitats were conducted in two relatively undisturbed, shallow estuaries along the north-central Gulf Coast of Florida. Scallop abundances did not vary significantly between years or between locations kilometers apart. Shell heights did vary significantly between years at locations kilometers apart; however, these differences were not consistently related to differences in chlorophyll concentrations in the water column or distributions of benthic habitat classes. At the 100-m scale within locations, scallops were not proportionally distributed across the major habitat classes (i.e., Syringodium filiforme, Thalassia testudinum, mixed seagrass assemblage, other seagrasses, and areas of no/low seagrass cover). In general, proportionately more scallops were observed in association with S. filiforme, T. testudinum, and mixed seagrass habitats. Bay scallops collected from S. filiforme and areas of no/low grass cover were consistently 1-3 mm larger than those collected from T. testudinum and mixed seagrass assemblages. These results suggest the importance of S. filiforme and T. testudinum as habitats for bay scallops. The results also point to the need for further investigation into possible functional differences among seagrass species that may influence the ecology of bay scallops at a small spatial scale and the need for closer examination of scallop movement that may allow for active habitat selection. The work presented here, plus further efforts to elucidate the drivers of small-scale differences in scallop abundances and sizes, will benefit managers who seek to enhance scallop fisheries or protect and restore coastal habitats

Determinants of serum polychlorinated biphenyls and organochlorine pesticides measured in women from the child health and development study cohort, 1963-1967.

We examined predictors of organochlorine concentrations in serum specimens from women who were pregnant in the 1960s and participated in the Child Health and Development Study in the San Francisco Bay Area of California. That study enrolled pregnant women at the Kaiser-Permanente Medical Facilities, conducted interviews, and drew blood specimens; these specimens were centrifuged and the resulting serum specimens were frozen and placed in long-term storage. For the current investigation, organochlorines were measured by dual-column GC-electron capture detection in specimens collected in 1963-1967 from 399 pregnant women during the second and third trimesters. Using multiple linear regression models adjusted for serum lipids, we evaluated factors predicting concentrations of 11 polychlorinated biphenyl (PCB) congeners, their sum, and several pesticides and metabolites. Variables evaluated were age, race, place of birth, date of blood draw, body mass index, occupation, past residence on a farm, parity, and duration of pregnancy at blood draw. Concentrations of highly chlorinated PCBs and the sum of the PCBs increased with age. Concentrations of certain PCB congeners, as well as the sum, were significantly higher among nonwhites and increased with calendar date of blood draw. (italic)p,p(/italic) -DDT and (italic)p,p(/italic) -DDE concentrations were about 50% higher for nonwhites compared with whites and for those born in California or the southeastern United States versus elsewhere in the United States. Higher body mass index was associated with lower concentrations of several PCBs and (italic)p,p(/italic) -DDE but with higher heptachlor epoxide and DDT levels. The increase in use of PCBs during the 1960s is apparently detectable as increasing concentrations in maternal sera between 1963 and 1967. Marked racial and regional differences in serum pesticide levels were likely caused by geographic variation in previous agricultural and vector-control uses. The relationship to body mass index appears to be complex

Transcriptomics modeling of the late-gestation fetal pituitary response to transient hypoxia

Background The late-gestation fetal sheep responds to hypoxia with physiological, neuroendocrine, and cellular responses that aid in fetal survival. The response of the fetus to hypoxia represents a coordinated effort to maximize oxygen transfer from the mother and minimize wasteful oxygen consumption by the fetus. While there have been many studies aimed at investigating the coordinated physiological and endocrine responses to hypoxia, and while immunohistochemical or in situ hybridization studies have revealed pathways supporting the endocrine function of the pituitary, there is little known about the coordinated cellular response of the pituitary to the hypoxia. Results Thirty min hypoxia (from 17.0±1.7 to 8.0±0.8 mm Hg, followed by 30 min normoxia) upregulated 595 and downregulated 790 genes in fetal pituitary (123-132 days' gestation; term = 147 days). Network inference of up- and down- regulated genes revealed a high degree of functional relatedness amongst the gene sets. Gene ontology analysis revealed upregulation of cellular metabolic processes (e.g., RNA synthesis, response to estrogens) and downregulation Conclusions The multiple analytical approaches used in this study suggests that the acute response to 30 min of transient hypoxia in the late-gestation fetus results in reduced cellular metabolism and a pattern of gene expression that is consistent with cellular oxygen and ATP starvation. In this early time point, we see a vigorous gene response. But, like the hypothalamus, the transcriptomic response is not consistent with mediation by HIF-1. If HIF-1 is a significant controller of gene expression in the fetal pituitary after hypoxia, it must be at a later time.Fil: Wood, Charles E.. University of Florida; Estados UnidosFil: Chang, Eileen I.. University of Florida; Estados UnidosFil: Richards, Elaine M.. University of Florida; Estados UnidosFil: Rabaglino, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Keller Wood, Maureen. University of Florida; Estados Unido

The future of human nature: a symposium on the promises and challenges of the revolutions in genomics and computer science, April 10, 11, and 12, 2003

This repository item contains a single issue of the Pardee Conference Series, a publication series that began publishing in 2006 by the Boston University Frederick S. Pardee Center for the Study of the Longer-Range Future. This was the Center's Symposium on the Promises and Challenges of the Revolutions in Genomics and Computer Science took place during April 10, 11, and 12, 2003. Co-organized by Charles DeLisi and Kenneth Lewes; sponsored by Boston University, the Frederick S. Pardee Center for the Study of the Longer-Range Future.This conference focused on scientific and technological advances in genetics, computer science, and their convergence during the next 35 to 250 years. In particular, it focused on directed evolution, the futures it allows, the shape of society in those futures, and the robustness of human nature against technological change at the level of individuals, groups, and societies. It is taken as a premise that biotechnology and computer science will mature and will reinforce one another. During the period of interest, human cloning, germ-line genetic engineering, and an array of reproductive technologies will become feasible and safe. Early in this period, we can reasonably expect the processing power of a laptop computer to exceed the collective processing power of every human brain on the planet; later in the period human/machine interfaces will begin to emerge. Whether such technologies will take hold is not known. But if they do, human evolution is likely to proceed at a greatly accelerated rate; human nature as we know it may change markedly, if it does not disappear altogether, and new intelligent species may well be created

The future of human nature: a symposium on the promises and challenges of the revolutions in genomics and computer science, April 10, 11, and 12, 2003

This repository item contains a single issue of the Pardee Conference Series, a publication series that began publishing in 2006 by the Boston University Frederick S. Pardee Center for the Study of the Longer-Range Future. This was the Center's Symposium on the Promises and Challenges of the Revolutions in Genomics and Computer Science took place during April 10, 11, and 12, 2003. Co-organized by Charles DeLisi and Kenneth Lewes; sponsored by Boston University, the Frederick S. Pardee Center for the Study of the Longer-Range Future.This conference focused on scientific and technological advances in genetics, computer science, and their convergence during the next 35 to 250 years. In particular, it focused on directed evolution, the futures it allows, the shape of society in those futures, and the robustness of human nature against technological change at the level of individuals, groups, and societies. It is taken as a premise that biotechnology and computer science will mature and will reinforce one another. During the period of interest, human cloning, germ-line genetic engineering, and an array of reproductive technologies will become feasible and safe. Early in this period, we can reasonably expect the processing power of a laptop computer to exceed the collective processing power of every human brain on the planet; later in the period human/machine interfaces will begin to emerge. Whether such technologies will take hold is not known. But if they do, human evolution is likely to proceed at a greatly accelerated rate; human nature as we know it may change markedly, if it does not disappear altogether, and new intelligent species may well be created

Radiostereometric Evaluation of Tendon Elongation After Distal Biceps Repair.

BACKGROUND: Operative repair of distal biceps tendon ruptures has shown successful outcomes. However, little is known about the amount of tendon or repair site lengthening after repair. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate distal biceps tendon repair via intratendinous radiostereometric analysis to analyze tendon lengthening at different time intervals of healing. The hypothesis was that there is significant lengthening after repair. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Eleven patients with distal biceps ruptures requiring operative repair were recruited. During repair, two 2-mm tantalum beads with laser-etched holes were sutured to the distal biceps tendon. Beads were evaluated via computed tomography scans immediately postoperatively and at 16 weeks. Radiographs were obtained at time 0 and then at 4, 8, and 16 weeks postoperatively. Measurements were made using the button-to-bead and bead-to-bead distances to assess repair site elongation as well as tendon elongation over time. After final follow-up, patients filled out the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and underwent ultrasound to confirm the integrity of the tendon. RESULTS: Ten patients had complete ruptures, with 1 having a partial rupture that underwent completion of the tear and subsequent repair. All patients showed statistically significant lengthening after surgery. The mean amount of tendon lengthening after surgery was 22.8 mm (range, 11.2-30.9 mm; P \u3c .05), and the repair site lengthened a mean 17.0 mm (range, 9.6-30.6 mm; P \u3c .05) from surgery to final follow-up. The greatest change in lengthening was noted between time 0 and week 4 (mean, 11.3 mm; P \u3c .05), with the least amount of lengthening between weeks 8 and 16 (mean, 2.6 mm; P \u3c .05). The mean DASH score was 11.2. Final ultrasound evaluations found all tendons to be in continuity. CONCLUSION: All patients undergoing distal biceps tendon repair have significant elongation after surgery, with the greatest amount of lengthening seen in the early postoperative period