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Sample records for mammalian development implications

  1. Mammalian development in space

    NASA Technical Reports Server (NTRS)

    Ronca, April E.

    2003-01-01

    Life on Earth, and thus the reproductive and ontogenetic processes of all extant species and their ancestors, evolved under the constant influence of the Earth's l g gravitational field. These considerations raise important questions about the ability of mammals to reproduce and develop in space. In this chapter, I review the current state of our knowledge of spaceflight effects on developing mammals. Recent studies are revealing the first insights into how the space environment affects critical phases of mammalian reproduction and development, viz., those events surrounding fertilization, embryogenesis, pregnancy, birth, postnatal maturation and parental care. This review emphasizes fetal and early postnatal life, the developmental epochs for which the greatest amounts of mammalian spaceflight data have been amassed. The maternal-offspring system, the coordinated aggregate of mother and young comprising mammalian development, is of primary importance during these early, formative developmental phases. The existing research supports the view that biologically meaningful interactions between mothers and offspring are changed in the weightlessness of space. These changes may, in turn, cloud interpretations of spaceflight effects on developing offspring. Whereas studies of mid-pregnant rats in space have been extraordinarily successful, studies of young rat litters launched at 9 days of postnatal age or earlier, have been encumbered with problems related to the design of in-flight caging and compromised maternal-offspring interactions. Possibilities for mammalian birth in space, an event that has not yet transpired, are considered. In the aggregate, the results indicate a strong need for new studies of mammalian reproduction and development in space. Habitat development and systematic ground-based testing are important prerequisites to future research with young postnatal rodents in space. Together, the findings support the view that the environment within which young

  2. An evolutionary link for developing mammalian lungs.

    PubMed

    Maloney, J E; Darian-Smith, C; Russell, B; Varghese, M; Cooper, J; Limpus, C J

    1989-09-01

    Lungs of the human infant and those of other mammals are filled with fluid immediately prior to birth. Studies of the ionic composition of this fluid indicate that active ionic transport processes occur in the epithelial cells of the potential airspaces. The purpose of this study was to see if these active ion pumps were present in developing species other than mammals thus providing a possible evolutionary link to mammals. A series of samples of lung liquid, amniotic fluid, and plasma were taken from embryonic marine turtles gathered from clutches incubating in the beach at Mon Repos, Queensland, Australia during the summer of 1986-87. The concentrations of sodium, potassium and chloride ions and protein measured in these liquids indicated that active pumping processes similar to that seen in the mammalian lung were present in the developing lungs of these marine reptiles and further, circumstantial evidence was gathered to suggest that this liquid was partially reabsorbed prior to hatching. The results support the notion that processes responsible for the normal development of the human lung and lungs of other mammals are also present in the hollow lungs of marine turtles. Thus there is an evolutionary counterpart controlling lung development in more ancient species. It may be possible to generalize this observation to the development of hollow lungs of other species.

  3. Ontogenetic development of the mammalian circadian system.

    PubMed

    Weinert, Dietmar

    2005-01-01

    This review summarizes the current knowledge about the ontogenetic development of the circadian system in mammals. The developmental changes of overt rhythms are discussed, although the main focus of the review is the underlying neuronal and molecular mechanisms. In addition, the review describes ontogenetic development, not only as a process of morpho-functional maturation. The need of repeated adaptations and readaptations due to changing developmental stage and environmental conditions is also considered. The review analyzes mainly rodent data, obtained from the literature and from the author's own studies. Results from other species, including humans, are presented to demonstrate common features and species-dependent differences. The review first describes the development of the suprachiasmatic nuclei as the central pacemaker system and shows that intrinsic circadian rhythms are already generated in the mammalian fetus. As in adult organisms, the period length is different from 24 h and needs continuous correction by environmental periodicities, or zeitgebers. The investigation of the ontogenetic development of the mechanisms of entrainment reveals that, at prenatal and early postnatal stages, non-photic cues deriving from the mother are effective. Light-dark entrainment develops later. At a certain age, both photic and non-photic zeitgebers may act in parallel, even though the respective time information is 12 h out of phase. That leads to a temporary internal desynchronization. Because rhythmic information needs to be transferred to effector organs, the corresponding neural and humoral signalling pathways are also briefly described. Finally, to be able to transform a rhythmic signal into an overt rhythm, the corresponding effector organs must be functionally mature. As many of these organs are able to generate their own intrinsic rhythms, another aspect of the review is dedicated to the development of peripheral oscillators and mechanisms of their entrainment

  4. Programmed cell senescence during mammalian embryonic development.

    PubMed

    Muñoz-Espín, Daniel; Cañamero, Marta; Maraver, Antonio; Gómez-López, Gonzalo; Contreras, Julio; Murillo-Cuesta, Silvia; Rodríguez-Baeza, Alfonso; Varela-Nieto, Isabel; Ruberte, Jesús; Collado, Manuel; Serrano, Manuel

    2013-11-21

    Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence.

  5. Functions of miRNAs during Mammalian Heart Development

    PubMed Central

    Yan, Shun; Jiao, Kai

    2016-01-01

    MicroRNAs (miRNAs) play essential roles during mammalian heart development and have emerged as attractive therapeutic targets for cardiovascular diseases. The mammalian embryonic heart is mainly derived from four major cell types during development. These include cardiomyocytes, endocardial cells, epicardial cells, and neural crest cells. Recent data have identified various miRNAs as critical regulators of the proper differentiation, proliferation, and survival of these cell types. In this review, we briefly introduce the contemporary understanding of mammalian cardiac development. We also focus on recent developments in the field of cardiac miRNAs and their functions during the development of different cell types. PMID:27213371

  6. Nucleotide metabolic mismatches in mammalian hearts: implications for transplantation

    PubMed Central

    Yacoub, MH; Smolenski, RT

    2013-01-01

    Introduction Human donor organ shortages have led surgeons and scientists to explore the use of animals as alternative organ sources. Acute thrombovascular rejection (AVR) is the main hurdle in xenotransplantation. Disparities in nucleotide metabolism in the vessels of different species may contribute significantly to the microvascular component of AVR. Methods We evaluated the extent of nucleotide metabolism mismatch in selected organs and endothelial cells of different mammals with particular focus on the changes in activity of ecto-5’-nucleotidase (E5’N) elicited by exposure of porcine hearts or endothelial cells to human blood (ex vivo) or human plasma (in vitro). Results E5’N activity in the rat heart was significantly higher than in other species. We noted a significant difference (p<0.001) in E5’N activity between human and pig endothelial cell lines. Initial pig aortic endothelial E5’N activity decreased in vitro after a three-hour exposure to human and porcine plasma while remaining constant in controls. Ex vivo perfusion with fresh human blood for four hours resulted in a significant decrease of E5’N activity in both wild type and transgenic pig hearts overexpressing human decay accelerating factor (p<0.001). Conclusions This study provides evidence that mismatches in basal mammalian metabolic pathways and humoral immunity interact in a xenogeneic environment. Understanding the role of nucleotide metabolism and signalling in xenotransplantation may identify new targets for genetic modifications and may lead to the development of new therapies extending graft survival. PMID:23317713

  7. Some process control/design considerations in the development of a microgravity mammalian cell bioreactor

    NASA Technical Reports Server (NTRS)

    Goochee, Charles F.

    1987-01-01

    The purpose is to review some of the physical/metabolic factors which must be considered in the development of an operating strategy for a mammalian cell bioreactor. Emphasis is placed on the dissolved oxygen and carbon dioxide requirements of growing mammalian epithelial cells. Literature reviews concerning oxygen and carbon dioxide requirements are discussed. A preliminary, dynamic model which encompasses the current features of the NASA bioreactor is presented. The implications of the literature survey and modeling effort on the design and operation of the NASA bioreactor are discussed.

  8. IMMUNOLOGICAL IMPLICATIONS IN MAMMALIAN SEMI-ALLOGENEIC PREGNANCY.

    PubMed

    Krupanidhi, Srirama

    2015-01-01

    The mammalian conceptus is a semi-allograft. The maternal tolerance towards semi-allograft is primed by a battery of cytokines and resident decidual cells. Invasion of embryonic trophoblast, decidual vascular remodeling and unresponsive incipient 'Triple-negative' (CD3-, CD4- and CD8-) T-cells of foetus promote normal pregnancy. On the other hand, the maternal cytokine profile shift towards Th1 response is shown to enhance the risk during pregnancy. The periodical examination of maternal serum levels of Th1 and Th2 response mediated cytokines constitutes prognostic biomarkers to initiate therapeutic regimens. PMID:27328524

  9. Axonal oscillations in developing mammalian nerve axons

    NASA Astrophysics Data System (ADS)

    Zeng, Shangyou; Jung, Peter

    2005-01-01

    We study neuronal spike propagation in a developing myelinated axon in various stages of its development through detailed computational modeling. Recently, a form of bursting (axonal bursting), has been reported in axons in developing nerves in the absence of potassium channels. We present a computational study using a detailed model for a myelinated nerve in development to explore under what circumstances such an effect can be expected. It is shown that axonal oscillation may be caused by backfiring between the nodes of Ranvier or through backfiring from internodal sodium channels or by reducing the thickness of the myelin wrapping the axon between the nodes of Ranvier.

  10. Where hearing starts: The development of the mammalian cochlea

    PubMed Central

    Basch, Martin L.; Brown, Rogers M.; Jen, Hsin-I; Groves, Andrew K.

    2016-01-01

    The mammalian cochlea is a remarkable sensory organ, capable of perceiving sound over a range of 1012 in pressure and discriminating both infrasonic and ultrasonic frequencies in different species. The sensory hair cells of the mammalian cochlea are exquisitely sensitive, responding to atomic-level deflections at speeds on the order of tens of microseconds. The number and placement of hair cells are precisely determined during inner ear development, and a large number of developmental processes sculpt the shape, size and morphology of these cells along the length of the cochlear duct to make them optimally responsive to different sound frequencies. In this review, we briefly discuss the evolutionary origins of the mammalian cochlea, and then describe the successive developmental processes that lead to its induction, cell cycle exit, cellular patterning and the establishment of topologically distinct frequency responses along its length. PMID:26052920

  11. The Role of Autophagy in Mammalian Development

    PubMed Central

    Cecconi, Francesco; Levine, Beth

    2009-01-01

    Autophagy is important for the degradation of bulk cytoplasm, long-lived proteins, and entire organelles. In lower eukaryotes, autophagy functions as a cell death mechanism or as a stress response during development. However, autophagy’s significance in vertebrate development, and the role (if any) of vertebrate-specific factors in its regulation, remains unexplained. Through careful analysis of the current autophagy gene mutant mouse models, we propose that in mammals, autophagy may be involved in specific cytosolic rearrangements needed for proliferation, death, and differentiation during embryogenesis and postnatal development. Thus, autophagy is a process of cytosolic “renovation,” crucial in cell fate decisions. PMID:18804433

  12. Mammalian oocyte development: checkpoints for competence.

    PubMed

    Fair, Trudee

    2010-01-01

    During the lifespan of the female, biochemical changes occur in the ovarian environment. These changes are brought about by numerous endogenous and exogenous factors, including husbandry practices, production demands and disease, and can have a profound effect on ovarian oocyte quality and subsequent embryo development. Despite many investigations, there is no consensus regarding the time or period of follicular oocyte development that is particularly sensitive to insult. Here, the key molecular and morphological events that occur during oocyte and follicle growth are reviewed, with a specific focus on identifying critical checkpoints in oocyte development. The secondary follicle stage appears to be a key phase in follicular oocyte development because major events such as activation of the oocyte transcriptome, sequestration of the zona pellucida, establishment of bidirectional communication between the granulosa cells and the oocyte and cortical granule synthesis occur during this period of development. Several months later, the periovulatory period is also characterised by the occurrence of critical events, including appropriate degradation or polyadenylation of mRNA transcripts, resumption of meiosis, spindle formation, chromosome alignment and segregation, and so should also be considered as a potential checkpoint of oocyte development.

  13. Lung development of monotremes: evidence for the mammalian morphotype.

    PubMed

    Ferner, Kirsten; Zeller, Ulrich; Renfree, Marilyn B

    2009-02-01

    The reproductive strategies and the extent of development of neonates differ markedly between the three extant mammalian groups: the Monotremata, Marsupialia, and Eutheria. Monotremes and marsupials produce highly altricial offspring whereas the neonates of eutherian mammals range from altricial to precocial. The ability of the newborn mammal to leave the environment in which it developed depends highly on the degree of maturation of the cardio-respiratory system at the time of birth. The lung structure is thus a reflection of the metabolic capacity of neonates. The lung development in monotremes (Ornithorhynchus anatinus, Tachyglossus aculeatus), in one marsupial (Monodelphis domestica), and one altricial eutherian (Suncus murinus) species was examined. The results and additional data from the literature were integrated into a morphotype reconstruction of the lung structure of the mammalian neonate. The lung parenchyma of monotremes and marsupials was at the early terminal air sac stage at birth, with large terminal air sacs. The lung developed slowly. In contrast, altricial eutherian neonates had more advanced lungs at the late terminal air sac stage and postnatally, lung maturation proceeded rapidly. The mammalian lung is highly conserved in many respects between monotreme, marsupial, and eutherian species and the structural differences in the neonatal lungs can be explained mainly by different developmental rates. The lung structure of newborn marsupials and monotremes thus resembles the ancestral condition of the mammalian lung at birth, whereas the eutherian newborns have a more mature lung structure.

  14. Genetic regulation of mammalian gonad development.

    PubMed

    Eggers, Stefanie; Ohnesorg, Thomas; Sinclair, Andrew

    2014-11-01

    Sex-specific gonadal development starts with formation of the bipotential gonad, which then differentiates into either a mature testis or an ovary. This process is dependent on activation of either the testis-specific or the ovary-specific pathway while the opposite pathway is continuously repressed. A network of transcription factors tightly regulates initiation and maintenance of these distinct pathways; disruption of these networks can lead to disorders of sex development in humans and male-to-female or female-to-male sex reversal in mice. Sry is the Y-linked master switch that is both required and sufficient to drive the testis-determining pathway. Another key component of the testis pathway is Sox9, which acts immediately downstream of Sry. In contrast to the testis pathway, no single sex-determining factor has been identified in the ovary pathway; however, multiple genes, such as Foxl2, Rspo1, Ctnnb1, and Wnt4, seem to work synergistically and in parallel to ensure proper ovary development. Our understanding of the regulatory networks that underpin testis and ovary development has grown substantially over the past two decades.

  15. The evolution and development of mammalian flight.

    PubMed

    Cooper, Lisa Noelle; Cretekos, Chris J; Sears, Karen E

    2012-01-01

    Mammals have evolved a stunning diversity of limb morphologies (e.g., wings, flippers, hands, and paws) that allowed access to a wide range of habitats. Over 50 million years ago, bats (Order Chiroptera) evolved a wing (composed of a thin membrane encasing long digits) and thereby achieved powered flight. Unfortunately, the fossil record currently lacks any transitional fossils between a rodent-like ancestor and a winged bat. To reconstruct how this important evolutionary transition occurred, researchers have begun to employ an evolutionary developmental approach. This approach has revealed some of the embryological and molecular changes that have contributed to the evolution of the bat wing. For example, bat and mouse forelimb morphologies are similar during earliest limb development. Despite this, some key signaling centers for limb development are already divergent in bat and mouse at these early stages. Bat and mouse limb development continues to diverge, such that at later stages many differences are apparent. For example, at these later stages bats redeploy expression of toolkit genes (i.e., Fgf, Shh, Bmp, Grem) in a novel expression domain to inhibit apoptosis of the interdigital tissues. When results are taken together, a broad picture of the developmental changes that drove the transition from a hand to a wing over 50 million years ago is beginning to take shape. Moreover, studies seem to suggest that small changes in gene regulation during organogenesis can generate large evolutionary changes in phenotype.

  16. A systematic molecular genetic approach to study mammalian germline development

    PubMed Central

    Abe, Kuniya; Ko, Minoru S. H.; MacGregor, Grant R.

    2011-01-01

    It is difficult to study gene expression in mammalian embryonic germ cells as PGCs constitute only a minor proportion of the mouse embryo. We have overcome this problem by using a novel combination of established molecular and transgenic approaches. A line of mice has been generated in which the cells of the germ lineage express the β-galactosidase reporter gene during embryogenesis. Using this line, germ cells have been purified to near homogeneity from embryos at discrete stages during germline development by use of a stain for β-gal activity and a fluorescence activated cell sorter. Subsequently, cDNA libraries have been constructed from each germ cell population using a modified lone-linker PCR strategy. These combined cDNA libraries represent genes expressed in PGCs during mammalian germline development. To facilitate a molecular genetic approach to studying mammalian germline development, these cDNA libraries will be pooled to form an arrayed, addressed reference embryonic germ cell cDNA library. In parallel with large-scale cDNA sequencing efforts, genes that are differentially expressed in germ cells will be identified by screening the reference library with probes generated by subtractive hybridization. Complementary DNAs identified using this approach will be analyzed by sequencing, database comparison, genomic mapping and in situ hybridization to ascertain the potential functional importance of each gene to germline development. In addition to providing a wealth of novel information regarding patterns of gene expression during mammalian germline development, these results will form the basis for future experiments to determine the function of these genes in this process. PMID:9853837

  17. Studies toward birth and early mammalian development in space.

    PubMed

    Ronca, April E

    2003-01-01

    Sustaining life beyond Earth on either space stations or other planets will require a clear understanding of how the space environment affects key phases of mammalian reproduction and development. Pregnancy, parturition (birth) and the early development of offspring are complex processes essential for successful reproduction and the proliferation of mammalian species. While no mammal has yet undergone birth within the space environment, studies spanning the gravity continuum from 0- to 2-g are revealing startling insights into how reproduction and development may proceed under gravitational conditions deviating from those typically experienced on Earth. In this report, I review studies of pregnant Norway rats and their offspring flown in microgravity onboard the NASA Space Shuttle throughout the period corresponding to mid- to late gestation, and analogous studies of pregnant rats exposed to hypergravity (hg) onboard the NASA Ames Research Center 24-ft centrifuge. Studies of postnatal rats flown in space or exposed to centrifugation are reviewed. Although many important questions remain unanswered, the available data suggest that numerous aspects of pregnancy, birth and early mammalian development can proceed under altered gravity conditions.

  18. Dynamic regulation of DNA methylation during mammalian development.

    PubMed

    Guibert, Sylvain; Forné, Thierry; Weber, Michael

    2009-10-01

    DNA methylation occurs on cytosines, is catalyzed by DNA methyltransferases (DNMTs), and is present at high levels in all vertebrates. DNA methylation plays essential roles in maintaining genome integrity, but its implication in orchestrating gene-expression patterns remained a matter of debate for a long time. Recent efforts to map DNA methylation at the genome level helped to get a better picture of the distribution of this mark and revealed that DNA methylation is more dynamic between cell types than previously anticipated. In particular, these datasets showed that DNA methylation is targeted to important developmental genes and might act as a barrier to prevent accidental cellular reprogramming. In this review, we will discuss the distribution and function of DNA methylation in mammalian genomes, with particular emphasis on the waves of global DNA methylation reprogramming occurring in early embryos and primordial germ cells. PMID:22122638

  19. Post-transcriptional control of the mammalian circadian clock: implications for health and disease.

    PubMed

    Preußner, Marco; Heyd, Florian

    2016-06-01

    Many aspects of human physiology and behavior display rhythmicity with a period of approximately 24 h. Rhythmic changes are controlled by an endogenous time keeper, the circadian clock, and include sleep-wake cycles, physical and mental performance capability, blood pressure, and body temperature. Consequently, many diseases, such as metabolic, sleep, autoimmune and mental disorders and cancer, are connected to the circadian rhythm. The development of therapies that take circadian biology into account is thus a promising strategy to improve treatments of diverse disorders, ranging from allergic syndromes to cancer. Circadian alteration of body functions and behavior are, at the molecular level, controlled and mediated by widespread changes in gene expression that happen in anticipation of predictably changing requirements during the day. At the core of the molecular clockwork is a well-studied transcription-translation negative feedback loop. However, evidence is emerging that additional post-transcriptional, RNA-based mechanisms are required to maintain proper clock function. Here, we will discuss recent work implicating regulated mRNA stability, translation and alternative splicing in the control of the mammalian circadian clock, and its role in health and disease.

  20. Post-transcriptional control of the mammalian circadian clock: implications for health and disease.

    PubMed

    Preußner, Marco; Heyd, Florian

    2016-06-01

    Many aspects of human physiology and behavior display rhythmicity with a period of approximately 24 h. Rhythmic changes are controlled by an endogenous time keeper, the circadian clock, and include sleep-wake cycles, physical and mental performance capability, blood pressure, and body temperature. Consequently, many diseases, such as metabolic, sleep, autoimmune and mental disorders and cancer, are connected to the circadian rhythm. The development of therapies that take circadian biology into account is thus a promising strategy to improve treatments of diverse disorders, ranging from allergic syndromes to cancer. Circadian alteration of body functions and behavior are, at the molecular level, controlled and mediated by widespread changes in gene expression that happen in anticipation of predictably changing requirements during the day. At the core of the molecular clockwork is a well-studied transcription-translation negative feedback loop. However, evidence is emerging that additional post-transcriptional, RNA-based mechanisms are required to maintain proper clock function. Here, we will discuss recent work implicating regulated mRNA stability, translation and alternative splicing in the control of the mammalian circadian clock, and its role in health and disease. PMID:27108448

  1. The development of the mammalian outer and middle ear.

    PubMed

    Anthwal, Neal; Thompson, Hannah

    2016-02-01

    The mammalian ear is a complex structure divided into three main parts: the outer; middle; and inner ear. These parts are formed from all three germ layers and neural crest cells, which have to integrate successfully in order to form a fully functioning organ of hearing. Any defect in development of the outer and middle ear leads to conductive hearing loss, while defects in the inner ear can lead to sensorineural hearing loss. This review focuses on the development of the parts of the ear involved with sound transduction into the inner ear, and the parts largely ignored in the world of hearing research: the outer and middle ear. The published data on the embryonic origin, signalling, genetic control, development and timing of the mammalian middle and outer ear are reviewed here along with new data showing the Eustachian tube cartilage is of dual embryonic origin. The embryonic origin of some of these structures has only recently been uncovered (Science, 339, 2013, 1453; Development, 140, 2013, 4386), while the molecular mechanisms controlling the growth, structure and integration of many outer and middle ear components are hardly known. The genetic analysis of outer and middle ear development is rather limited, with a small number of genes often affecting either more than one part of the ear or having only very small effects on development. This review therefore highlights the necessity for further research into the development of outer and middle ear structures, which will be important for the understanding and treatment of conductive hearing loss.

  2. Fibroblast growth factor signaling in mammalian tooth development.

    PubMed

    Li, Chun-Ying; Prochazka, Jan; Goodwin, Alice F; Klein, Ophir D

    2014-01-01

    In this review, we discuss the central role of fibroblast growth factor (FGF) signaling in mammalian tooth development. The FGF family consists of 22 members, most of which bind to four different receptor tyrosine kinases, which in turn signal through a cascade of intracellular proteins. This signaling regulates a number of cellular processes, including proliferation, differentiation, cell adhesion and cell mobility. FGF signaling first becomes important in the presumptive dental epithelium at the initiation stage of tooth development, and subsequently, it controls the invagination of the dental epithelium into the underlying mesenchyme. Later, FGFs are critical in tooth shape formation and differentiation of ameloblasts and odontoblasts, as well as in the development and homeostasis of the stem cell niche that fuels the continuously growing mouse incisor. In addition, FGF signaling is critical in human teeth, as mutations in genes encoding FGF ligands or receptors result in several congenital syndromes characterized by alterations in tooth number, morphology or enamel structure. The parallel roles of FGF signaling in mouse and human tooth development demonstrate the conserved importance of FGF signaling in mammalian odontogenesis.

  3. Engineering considerations for process development in mammalian cell cultivation.

    PubMed

    Zhang, Hu; Wang, Weixiang; Quan, Chunshan; Fan, Shengdi

    2010-01-01

    Mammalian cell cultivation plays a great role in producing protein therapeutics in the last decades. Many engineering parameters are considered for optimization during process development in mammalian cell cultivation, only shear and mixing are especially highlighted in this paper. It is believed that shear stress due to agitation has been over-estimated to damage cells, but shear may result in nonlethal physiological responses. There is no cell damage in the regions where bubbles form, break up and coalescence, but shear stress becomes significant in the wake of rising bubbles and causes great damage to cells in bubble burst regions. Mixing is not sufficient to provide homogeneous dissolved oxygen tension, pH, CO2 and nutrients in large-scale bioreactors, which can bring severe problems for cell growth, product formation and process control. Scale-down reactors have been developed to address mixing and shear problems for parallel operations. Engineering characterization in conventional and recently developed scale-down bioreactors has been briefly introduced. Process challenges for cultivation of industrial cell lines in high cell densities as well as cultivation of stem cells and other human cells for regenerative medicine, tissue engineering and gene therapy are prospected. Important techniques, such as micromanipulation and nanomanipulation (optical tweezers) for single cell analysis, computational fluid dynamics (CFD) for shear and mixing characterization, and miniaturized bioreactors, are being developed to address those challenges. PMID:19929819

  4. Regulation of the Embryonic Cell Cycle During Mammalian Preimplantation Development.

    PubMed

    Palmer, N; Kaldis, P

    2016-01-01

    The preimplantation development stage of mammalian embryogenesis consists of a series of highly conserved, regulated, and predictable cell divisions. This process is essential to allow the rapid expansion and differentiation of a single-cell zygote into a multicellular blastocyst containing cells of multiple developmental lineages. This period of development, also known as the germinal stage, encompasses several important developmental transitions, which are accompanied by dramatic changes in cell cycle profiles and dynamics. These changes are driven primarily by differences in the establishment and enforcement of cell cycle checkpoints, which must be bypassed to facilitate the completion of essential cell cycle events. Much of the current knowledge in this area has been amassed through the study of knockout models in mice. These mouse models are powerful experimental tools, which have allowed us to dissect the relative dependence of the early embryonic cell cycles on various aspects of the cell cycle machinery and highlight the extent of functional redundancy between members of the same gene family. This chapter will explore the ways in which the cell cycle machinery, their accessory proteins, and their stimuli operate during mammalian preimplantation using mouse models as a reference and how this allows for the usually well-defined stages of the cell cycle to be shaped and transformed during this unique and critical stage of development. PMID:27475848

  5. Studies Toward Birth and Early Mammalian Development in Space

    NASA Technical Reports Server (NTRS)

    Ronca, April E.; Dalton, Bonnie (Technical Monitor)

    2002-01-01

    Successful reproduction is the hallmark of a species' ability to adapt to its environment and must be realized to sustain life beyond Earth. Before taking this immense step, we need to understand the effects of altered gravity on critical phases of mammalian reproduction, viz., those events surrounding pregnancy, birth and the early development of offspring. No mammal has yet undergone birth in space. however studies spanning the gravity continuum from 0 to 2-g are revealing insights into how birth and early postnatal development will proceed in space. In this presentation, I will report the results of behavioral studies of rat mothers and offspring exposed from mid- to late pregnancy to either hypogravity (0-g) or hypergravity (1.5 or 2-g).

  6. Drosophila homolog of the mammalian jun oncogene is expressed during embryonic development and activates transcription in mammalian cells.

    PubMed Central

    Zhang, K; Chaillet, J R; Perkins, L A; Halazonetis, T D; Perrimon, N

    1990-01-01

    By means of low-stringency cross-species hybridization to Southern DNA blots, human c-jun sequences were used to identify a unique Drosophila melanogaster locus (Djun). The predicted DJun protein is highly homologous to members of the mammalian Jun family in both the DNA binding and leucine zipper regions. Djun was mapped by in situ hybridization to position 46E of the second chromosome. It encodes a 1.7-kilobase transcript constitutively expressed at all developmental stages. Functionally, Djun in cooperation with mouse c-fos can trans-activate activator protein 1 DNA binding site when introduced into mammalian cells. Taken together, these data suggest that Djun, much like its mammalian homolog, may activate transcription of genes involved in regulation of cell growth, differentiation, and development. Furthermore, the identification of Djun allows one to exploit the genetics of Drosophila to identify genes in signal transduction pathways involving Djun and thus c-jun. Images PMID:1696724

  7. Mammalian development does not recapitulate suspected key transformations in the evolutionary detachment of the mammalian middle ear.

    PubMed

    Ramírez-Chaves, Héctor E; Wroe, Stephen W; Selwood, Lynne; Hinds, Lyn A; Leigh, Chris; Koyabu, Daisuke; Kardjilov, Nikolay; Weisbecker, Vera

    2016-01-13

    The ectotympanic, malleus and incus of the developing mammalian middle ear (ME) are initially attached to the dentary via Meckel's cartilage, betraying their origins from the primary jaw joint of land vertebrates. This recapitulation has prompted mostly unquantified suggestions that several suspected--but similarly unquantified--key evolutionary transformations leading to the mammalian ME are recapitulated in development, through negative allometry and posterior/medial displacement of ME bones relative to the jaw joint. Here we show, using µCT reconstructions, that neither allometric nor topological change is quantifiable in the pre-detachment ME development of six marsupials and two monotremes. Also, differential ME positioning in the two monotreme species is not recapitulated. This challenges the developmental prerequisites of widely cited evolutionary scenarios of definitive mammalian middle ear (DMME) evolution, highlighting the requirement for further fossil evidence to test these hypotheses. Possible association between rear molar eruption, full ME ossification and ME detachment in marsupials suggests functional divergence between dentary and ME as a trigger for developmental, and possibly also evolutionary, ME detachment. The stable positioning of the dentary and ME supports suggestions that a 'partial mammalian middle ear' as found in many mammaliaforms--probably with a cartilaginous Meckel's cartilage--represents the only developmentally plausible evolutionary DMME precursor.

  8. Mammalian development does not recapitulate suspected key transformations in the evolutionary detachment of the mammalian middle ear.

    PubMed

    Ramírez-Chaves, Héctor E; Wroe, Stephen W; Selwood, Lynne; Hinds, Lyn A; Leigh, Chris; Koyabu, Daisuke; Kardjilov, Nikolay; Weisbecker, Vera

    2016-01-13

    The ectotympanic, malleus and incus of the developing mammalian middle ear (ME) are initially attached to the dentary via Meckel's cartilage, betraying their origins from the primary jaw joint of land vertebrates. This recapitulation has prompted mostly unquantified suggestions that several suspected--but similarly unquantified--key evolutionary transformations leading to the mammalian ME are recapitulated in development, through negative allometry and posterior/medial displacement of ME bones relative to the jaw joint. Here we show, using µCT reconstructions, that neither allometric nor topological change is quantifiable in the pre-detachment ME development of six marsupials and two monotremes. Also, differential ME positioning in the two monotreme species is not recapitulated. This challenges the developmental prerequisites of widely cited evolutionary scenarios of definitive mammalian middle ear (DMME) evolution, highlighting the requirement for further fossil evidence to test these hypotheses. Possible association between rear molar eruption, full ME ossification and ME detachment in marsupials suggests functional divergence between dentary and ME as a trigger for developmental, and possibly also evolutionary, ME detachment. The stable positioning of the dentary and ME supports suggestions that a 'partial mammalian middle ear' as found in many mammaliaforms--probably with a cartilaginous Meckel's cartilage--represents the only developmentally plausible evolutionary DMME precursor. PMID:26763693

  9. Understanding Mammalian Germ Line Development with In Vitro Models.

    PubMed

    Martínez-Arroyo, Ana M; Míguez-Forján, Jose M; Remohí, Jose; Pellicer, Antonio; Medrano, Jose V

    2015-09-15

    Germ line development is crucial in organisms with sexual reproduction to complete their life cycle. In mammals, knowledge about germ line development is based mainly on the mouse model, in which genetic and epigenetic events are well described. However, little is known about how germ line development is orchestrated in humans, especially in the earliest stages. New findings derived from human in vitro models to obtain germ cells can shed light on these questions. This comprehensive review summarizes the current knowledge about mammalian germ line development, emphasizing the state of the art obtained from in vitro models for germ cell-like cell derivation. Current knowledge of the pluripotency cycle and germ cell specification has allowed different in vitro strategies to obtain germ cells with proven functionality in mouse models. Several reports during the last 10 years show that in vitro germ cell derivation with proven functionality to generate a healthy offspring is possible in mice. However, differences in the embryo development and pluripotency potential between human and mouse make it difficult to extrapolate these results. Further efforts on both human and mouse in vitro models to obtain germ cells from pluripotent stem cells may help to elucidate how human physiological events take place; therefore, therapeutic strategies can also be considered.

  10. Expression patterns of FGF receptors in the developing mammalian cochlea

    PubMed Central

    Hayashi, Toshinori; Ray, Catherine A.; Younkins, Christa; Bermingham-McDonogh, Olivia

    2010-01-01

    Many studies have shown the importance of the fibroblast growth factor (FGF) family of factors in the development of the mammalian cochlea. There are four fibroblast growth factor receptors (FGFR1-4) and all four are expressed in the cochlea during development. While there are examples in the literature of expression patterns of some of the receptors at specific stages of cochlear development there has been no systematic study. We have assembled a full analysis of the patterns of receptor expression during cochlear development for all four Fgfrs using in situ hybridization. We have analyzed the expression patterns from E13.5 through post-natal ages. We find that Fgfr1, 2 and 3 are expressed in the epithelium of the cochlear duct and Fgfr4 is limited in its expression to the mesenchyme surrounding the duct. We compare the receptor expression pattern to markers of the sensory domain (p27kip1) and the early hair cells (math1). PMID:20131355

  11. Histone H3.3 maintains genome integrity during mammalian development

    PubMed Central

    Jang, Chuan-Wei; Shibata, Yoichiro; Starmer, Joshua; Yee, Della; Magnuson, Terry

    2015-01-01

    Histone H3.3 is a highly conserved histone H3 replacement variant in metazoans and has been implicated in many important biological processes, including cell differentiation and reprogramming. Germline and somatic mutations in H3.3 genomic incorporation pathway components or in H3.3 encoding genes have been associated with human congenital diseases and cancers, respectively. However, the role of H3.3 in mammalian development remains unclear. To address this question, we generated H3.3-null mouse models through classical genetic approaches. We found that H3.3 plays an essential role in mouse development. Complete depletion of H3.3 leads to developmental retardation and early embryonic lethality. At the cellular level, H3.3 loss triggers cell cycle suppression and cell death. Surprisingly, H3.3 depletion does not dramatically disrupt gene regulation in the developing embryo. Instead, H3.3 depletion causes dysfunction of heterochromatin structures at telomeres, centromeres, and pericentromeric regions of chromosomes, leading to mitotic defects. The resulting karyotypical abnormalities and DNA damage lead to p53 pathway activation. In summary, our results reveal that an important function of H3.3 is to support chromosomal heterochromatic structures, thus maintaining genome integrity during mammalian development. PMID:26159997

  12. Histone H3.3 maintains genome integrity during mammalian development.

    PubMed

    Jang, Chuan-Wei; Shibata, Yoichiro; Starmer, Joshua; Yee, Della; Magnuson, Terry

    2015-07-01

    Histone H3.3 is a highly conserved histone H3 replacement variant in metazoans and has been implicated in many important biological processes, including cell differentiation and reprogramming. Germline and somatic mutations in H3.3 genomic incorporation pathway components or in H3.3 encoding genes have been associated with human congenital diseases and cancers, respectively. However, the role of H3.3 in mammalian development remains unclear. To address this question, we generated H3.3-null mouse models through classical genetic approaches. We found that H3.3 plays an essential role in mouse development. Complete depletion of H3.3 leads to developmental retardation and early embryonic lethality. At the cellular level, H3.3 loss triggers cell cycle suppression and cell death. Surprisingly, H3.3 depletion does not dramatically disrupt gene regulation in the developing embryo. Instead, H3.3 depletion causes dysfunction of heterochromatin structures at telomeres, centromeres, and pericentromeric regions of chromosomes, leading to mitotic defects. The resulting karyotypical abnormalities and DNA damage lead to p53 pathway activation. In summary, our results reveal that an important function of H3.3 is to support chromosomal heterochromatic structures, thus maintaining genome integrity during mammalian development.

  13. Monotreme ossification sequences and the riddle of mammalian skeletal development.

    PubMed

    Weisbecker, Vera

    2011-05-01

    The developmental differences between marsupials, placentals, and monotremes are thought to be reflected in differing patterns of postcranial development and diversity. However, developmental polarities remain obscured by the rarity of monotreme data. Here, I present the first postcranial ossification sequences of the monotreme echidna and platypus, and compare these with published data from other mammals and amniotes. Strikingly, monotreme stylopodia (humerus, femur) ossify after the more distal zeugopodia (radius/ulna, tibia/fibula), resembling only the European mole among all amniotes assessed. European moles also share extreme humeral adaptations to rotation digging and/or swimming with monotremes, suggesting a causal relationship between adaptation and ossification heterochrony. Late femoral ossification with respect to tibia/fibula in monotremes and moles points toward developmental integration of the serially homologous fore- and hindlimb bones. Monotreme cervical ribs and coracoids ossify later than in most amniotes but are similarly timed as homologous ossifications in therians, where they are lost as independent bones. This loss may have been facilitated by a developmental delay of coracoids and cervical ribs at the base of mammals. The monotreme sequence, although highly derived, resembles placentals more than marsupials. Thus, marsupial postcranial development, and potentially related diversity constraints, may not represent the ancestral mammalian condition. PMID:21521190

  14. Autosomal location of genes from the conserved mammalian X in the platypus (Ornithorhynchus anatinus): implications for mammalian sex chromosome evolution.

    PubMed

    Waters, Paul D; Delbridge, Margaret L; Deakin, Janine E; El-Mogharbel, Nisrine; Kirby, Patrick J; Carvalho-Silva, Denise R; Graves, Jennifer A Marshall

    2005-01-01

    Mammalian sex chromosomes evolved from an ancient autosomal pair. Mapping of human X- and Y-borne genes in distantly related mammals and non-mammalian vertebrates has proved valuable to help deduce the evolution of this unique part of the genome. The platypus, a monotreme mammal distantly related to eutherians and marsupials, has an extraordinary sex chromosome system comprising five X and five Y chromosomes that form a translocation chain at male meiosis. The largest X chromosome (X1), which lies at one end of the chain, has considerable homology to the human X. Using comparative mapping and the emerging chicken database, we demonstrate that part of the therian X chromosome, previously thought to be conserved across all mammals, was lost from the platypus X1 to an autosome. This region included genes flanking the XIST locus, and also genes with Y-linked homologues that are important to male reproduction in therians. Since these genes lie on the X in marsupials and eutherians, and also on the homologous region of chicken chromosome 4, this represents a loss from the monotreme X rather than an additional evolutionary stratum of the human X. PMID:15973504

  15. Phytochemical Antioxidants Modulate Mammalian Cellular Epigenome: Implications in Health and Disease

    PubMed Central

    Malireddy, Smitha; Kotha, Sainath R.; Secor, Jordan D.; Gurney, Travis O.; Abbott, Jamie L.; Maulik, Gautam; Maddipati, Krishna R.

    2012-01-01

    In living systems, the mechanisms of inheritance involving gene expression are operated by (i) the traditional model of genetics where the deoxyribonucleic acid (DNA) transcription and messenger ribonucleic acid stability are influenced by the DNA sequences and any aberrations in the primary DNA sequences and (ii) the epigenetic (above genetics) model in which the gene expression is regulated by mechanisms other than the changes in DNA sequences. The widely studied epigenetic alterations include DNA methylation, covalent modification of chromatin structure, state of histone acetylation, and involvement of microribonucleic acids. Significance: Currently, the role of cellular epigenome in health and disease is rapidly emerging. Several factors are known to modulate the epigenome-regulated gene expression that is crucial in several pathophysiological states and diseases in animals and humans. Phytochemicals have occupied prominent roles in human diet and nutrition as protective antioxidants in prevention/protection against several disorders and diseases in humans. Recent Advances: However, it is beginning to surface that the phytochemical phenolic antioxidants such as polyphenols, flavonoids, and nonflavonoid phenols function as potent modulators of the mammalian epigenome-regulated gene expression through regulation of DNA methylation, histone acetylation, and histone deacetylation in experimental models. Critical Issues and Future Directions: The antioxidant or pro-oxidant actions and their involvement in the epigenome regulation by the phytochemical phenolic antioxidants should be at least established in the cellular models under normal and pathophysiological states. The current review discusses the mechanisms of modulation of the mammalian cellular epigenome by the phytochemical phenolic antioxidants with implications in human diseases. Antioxid. Redox Signal. 17, 327–339. PMID:22404530

  16. Transcription initiation factor IID-interactive histone chaperone CIA-II implicated in mammalian spermatogenesis.

    PubMed

    Umehara, Takashi; Horikoshi, Masami

    2003-09-12

    Histones are thought to have specific roles in mammalian spermatogenesis, because several subtypes of histones emerge that are post-translationally modified during spermatogenesis. Though regular assembly of nucleosome is guaranteed by histone chaperones, their involvement in spermatogenesis is yet to be characterized. Here we identified a histone chaperone-related factor, which we designated as CCG1-interacting factor A-II (CIA-II), through interaction with bromodomains of TAFII250/CCG1, which is the largest subunit of human transcription initiation factor IID (TFIID). We found that human CIA-II (hCIA-II) localizes in HeLa nuclei and is highly expressed in testis and other proliferating cell-containing tissues. Expression of mouse CIA-II (mCIA-II) does not occur in the germ cell-lacking testes of adult WBB6F1-W/Wv mutant mice, indicating its expression in testis to be specific to germ cells. Fractionation of testicular germ cells revealed that mCIA-II transcripts accumulate in pachytene spermatocytes but not in spermatids. In addition, the mCIA-II transcripts in testis were present as early as 4 days after birth and decreased at 56 days after birth. These findings indicate that mCIA-II expression in testis is restricted to premeiotic to meiotic stages during spermatogenesis. Also, we found that hCIA-II interacts with histone H3 in vivo and with histones H3/H4 in vitro and that it facilitates supercoiling of circular DNA when it is incubated with core histones and topoisomerase I in vitro. These data suggest that CIA-II is a histone chaperone and is implicated in the regulation of mammalian spermatogenesis.

  17. Development-Inspired Reprogramming of the Mammalian Central Nervous System

    PubMed Central

    Amamoto, Ryoji; Arlotta, Paola

    2014-01-01

    In 2012, John Gurdon and Shinya Yamanaka shared the Nobel Prize for the exciting demonstration that the identity of differentiated cells is not irreversibly determined but can be changed back to a pluripotent state under appropriate instructive signals. The principle that differentiated cells can revert to an embryonic state and even be converted directly from one cell-type into another not only turns fundamental principles of development on their head but also has profound implications for regenerative medicine. Replacement of diseased tissue with newly reprogrammed cells and modeling of human disease are concrete opportunities. Here, we focus on the central nervous system to consider whether and how reprogramming of cell identity may impact regeneration and modeling of a system historically considered immutable and hardwired. PMID:24482482

  18. Stereological and allometric studies on mammalian cerebral cortex with implications for medical brain imaging.

    PubMed Central

    Mayhew, T M; Mwamengele, G L; Dantzer, V

    1996-01-01

    Design-based stereological methods (the Cavalieri principle and vertical sectioning) have been used to estimate the volumes, surface areas and thicknesses of the cerebral cortex. Cortices of individual hemispheres were analysed in a selection of 31 adult domestic mammals (horses, oxen, pigs, goats, dogs, cats and rabbits). There were 13 females and 18 males. After correcting for fixation shrinkage effects, results were tested for species, laterality and sex differences using linear regression and analysis of variance. Mean body weights of domestic mammals varied from 4 kg to 460 kg and brain volumes from 11 cm3 to 603 cm3. Hemisphere dimensions varied between species but, except for volume (which exhibited a species x sex interaction effect), no other differences were detected. It is concluded that these mammalian brains are, in terms of their gross anatomy, symmetric and not sexually dimorphic. Apparent cortical thickness (measured directly on slices) proved to be a satisfactory estimate of true thickness (estimated by dividing cortical volume by the mean of outer and inner cortical surfaces). This has implications for medical slice images on which mean cortical thickness can be estimated only from apparent local thicknesses. PMID:8771409

  19. Vitronectin is not essential for normal mammalian development and fertility.

    PubMed Central

    Zheng, X; Saunders, T L; Camper, S A; Samuelson, L C; Ginsburg, D

    1995-01-01

    Vitronectin (VN) is an abundant glycoprotein present in plasma and the extracellular matrix of most tissues. Though the precise function of VN in vivo is unknown, it has been implicated as a participant in diverse biological processes, including cell attachment and spreading, complement activation, and regulation of hemostasis. The major site of synthesis appears to be the liver, though VN is also found in the brain at an early stage of mouse organogenesis, suggesting that it may play an important role in mouse development. Genetic deficiency of VN has not been reported in humans or in other higher organisms. To examine the biologic function of VN within the context of the intact animal, we have established a murine model for VN deficiency through targeted disruption of the murine VN gene. Southern blot analysis of DNA obtained from homozygous null mice demonstrates deletion of all VN coding sequences, and immunological analysis confirms the complete absence of VN protein expression in plasma. However, heterozygous mice carrying one normal and one null VN allele and homozygous null mice completely deficient in VN demonstrate normal development, fertility, and survival. Sera obtained from VN-deficient mice are completely deficient in "serum spreading factor" and plasminogen activator inhibitor 1 binding activities. These observations demonstrate that VN is not essential for cell adhesion and migration during normal mouse development and suggest that its role in these processes may partially overlap with other adhesive matrix components. Images Fig. 1 Fig. 2 Fig. 3 PMID:8618914

  20. The origin of the mammalian kidney: implications for recreating the kidney in vitro.

    PubMed

    Takasato, Minoru; Little, Melissa H

    2015-06-01

    The mammalian kidney, the metanephros, is a mesodermal organ classically regarded as arising from the intermediate mesoderm (IM). Indeed, both the ureteric bud (UB), which gives rise to the ureter and the collecting ducts, and the metanephric mesenchyme (MM), which forms the rest of the kidney, derive from the IM. Based on an understanding of the signalling molecules crucial for IM patterning and kidney morphogenesis, several studies have now generated UB or MM, or both, in vitro via the directed differentiation of human pluripotent stem cells. Although these results support the IM origin of the UB and the MM, they challenge the simplistic view of a common progenitor for these two populations, prompting a reanalysis of early patterning events within the IM. Here, we review our understanding of the origin of the UB and the MM in mouse, and discuss how this impacts on kidney regeneration strategies and furthers our understanding of human development.

  1. The origin of the mammalian kidney: implications for recreating the kidney in vitro.

    PubMed

    Takasato, Minoru; Little, Melissa H

    2015-06-01

    The mammalian kidney, the metanephros, is a mesodermal organ classically regarded as arising from the intermediate mesoderm (IM). Indeed, both the ureteric bud (UB), which gives rise to the ureter and the collecting ducts, and the metanephric mesenchyme (MM), which forms the rest of the kidney, derive from the IM. Based on an understanding of the signalling molecules crucial for IM patterning and kidney morphogenesis, several studies have now generated UB or MM, or both, in vitro via the directed differentiation of human pluripotent stem cells. Although these results support the IM origin of the UB and the MM, they challenge the simplistic view of a common progenitor for these two populations, prompting a reanalysis of early patterning events within the IM. Here, we review our understanding of the origin of the UB and the MM in mouse, and discuss how this impacts on kidney regeneration strategies and furthers our understanding of human development. PMID:26015537

  2. Effects of simulated weightlessness on mammalian development. Part 1: Development of clinostat for mammalian tissue culture and use in studies on meiotic maturation of mouse oocytes

    NASA Technical Reports Server (NTRS)

    Wolegemuth, D. J.; Grills, G. S.

    1984-01-01

    The effects of weightlessness on three aspects of mammalian reproduction: oocyte development, fertilization, and early embryogenesis was studied. Zero-gravity conditions within the laboratory by construction of a clinostat designed to support in vitro tissue culture were simulated and the effects of simulated weightlessness on meiotic maturation in mammalian oocytes using mouse as the model system were studied. The timing and frequency of germinal vesicule breakdown and polar body extrusion, and the structural and numerical properties of meiotic chromosomes at Metaphase and Metaphase of meiosis are assessed.

  3. Regulation of lifespan by chemosensory and thermosensory systems: findings in invertebrates and their implications in mammalian aging.

    PubMed

    Jeong, Dae-Eun; Artan, Murat; Seo, Keunhee; Lee, Seung-Jae

    2012-01-01

    Many environmental factors that dynamically change in nature influence various aspects of animal physiology. Animals are equipped with sensory neuronal systems that help them properly sense and respond to environmental factors. Several studies have shown that chemosensory and thermosensory neurons affect the lifespan of invertebrate model animals, including Caenorhabditis elegans and Drosophila melanogaster. Although the mechanisms by which these sensory systems modulate lifespan are incompletely understood, hormonal signaling pathways have been implicated in sensory system-mediated lifespan regulation. In this review, we describe findings regarding how sensory nervous system components elicit physiological changes to regulate lifespan in invertebrate models, and discuss their implications in mammalian aging. PMID:23087711

  4. Kremen1 regulates mechanosensory hair cell development in the mammalian cochlea and the zebrafish lateral line

    PubMed Central

    Mulvaney, Joanna F.; Thompkins, Cathrine; Noda, Teppei; Nishimura, Koji; Sun, Willy W.; Lin, Shuh-Yow; Coffin, Allison; Dabdoub, Alain

    2016-01-01

    Here we present spatio-temporal localization of Kremen1, a transmembrane receptor, in the mammalian cochlea, and investigate its role in the formation of sensory organs in mammal and fish model organisms. We show that Kremen1 is expressed in prosensory cells during cochlear development and in supporting cells of the adult mouse cochlea. Based on this expression pattern, we investigated whether Kremen1 functions to modulate cell fate decisions in the prosensory domain of the developing cochlea. We used gain and loss-of-function experiments to show that Kremen1 is sufficient to bias cells towards supporting cell fate, and is implicated in suppression of hair cell formation. In addition to our findings in the mouse cochlea, we examined the effects of over expression and loss of Kremen1 in the zebrafish lateral line. In agreement with our mouse data, we show that over expression of Kremen1 has a negative effect on the number of mechanosensory cells that form in the zebrafish neuromasts, and that fish lacking Kremen1 protein develop more hair cells per neuromast compared to wild type fish. Collectively, these data support an inhibitory role for Kremen1 in hair cell fate specification. PMID:27550540

  5. Kremen1 regulates mechanosensory hair cell development in the mammalian cochlea and the zebrafish lateral line.

    PubMed

    Mulvaney, Joanna F; Thompkins, Cathrine; Noda, Teppei; Nishimura, Koji; Sun, Willy W; Lin, Shuh-Yow; Coffin, Allison; Dabdoub, Alain

    2016-01-01

    Here we present spatio-temporal localization of Kremen1, a transmembrane receptor, in the mammalian cochlea, and investigate its role in the formation of sensory organs in mammal and fish model organisms. We show that Kremen1 is expressed in prosensory cells during cochlear development and in supporting cells of the adult mouse cochlea. Based on this expression pattern, we investigated whether Kremen1 functions to modulate cell fate decisions in the prosensory domain of the developing cochlea. We used gain and loss-of-function experiments to show that Kremen1 is sufficient to bias cells towards supporting cell fate, and is implicated in suppression of hair cell formation. In addition to our findings in the mouse cochlea, we examined the effects of over expression and loss of Kremen1 in the zebrafish lateral line. In agreement with our mouse data, we show that over expression of Kremen1 has a negative effect on the number of mechanosensory cells that form in the zebrafish neuromasts, and that fish lacking Kremen1 protein develop more hair cells per neuromast compared to wild type fish. Collectively, these data support an inhibitory role for Kremen1 in hair cell fate specification. PMID:27550540

  6. Intracellular protein degradation in mammalian cells: recent developments.

    PubMed

    Knecht, Erwin; Aguado, Carmen; Cárcel, Jaime; Esteban, Inmaculada; Esteve, Juan Miguel; Ghislat, Ghita; Moruno, José Félix; Vidal, José Manuel; Sáez, Rosana

    2009-08-01

    In higher organisms, dietary proteins are broken down into amino acids within the digestive tract but outside the cells, which incorporate the resulting amino acids into their metabolism. However, under certain conditions, an organism loses more nitrogen than is assimilated in the diet. This additional loss was found in the past century to come from intracellular proteins and started an intensive research that produced an enormous expansion of the field and a dispersed literature. Therefore, our purpose is to provide an updated summary of the current knowledge on the proteolytic machinery involved in intracellular protein degradation and its physiological and pathological relevance, especially addressed to newcomers in the field who may find further details in more specialized reviews. However, even providing a general overview, this is an extremely wide field and, therefore, we mainly focus on mammalian cells, while other cells will be mentioned only for comparison purposes.

  7. Mammalian-derived respiratory allergens - implications for diagnosis and therapy of individuals allergic to furry animals.

    PubMed

    Nilsson, Ola B; van Hage, Marianne; Grönlund, Hans

    2014-03-01

    Furry animals cause respiratory allergies in a significant proportion of the population. A majority of all mammalian allergens are spread as airborne particles, and several have been detected in environments where furry animals are not normally kept. The repertoire of allergens from each source belongs to a restricted number of allergen families. Classification of allergen families is particularly important for the characterization of allergenicity and cross-reactivity of allergens. In fact, major mammalian allergens are taken from only three protein families, i.e. the secretoglobin, lipocalin and kallikrein families. In particular, the lipocalin superfamily harbours major allergens in all important mammalian allergen sources, and cross-reactivity between lipocalin allergens may explain cross-species sensitization between mammals. The identification of single allergen components is of importance to improve diagnosis and therapy of allergic patients using component-resolved diagnostics and allergen-specific immunotherapy (ASIT) respectively. Major disadvantages with crude allergen extracts for these applications emphasize the benefits of careful characterization of individual allergens. Furthermore, detailed knowledge of the characteristics of an allergen is crucial to formulate attenuated allergy vaccines, e.g. hypoallergens. The diverse repertoires of individual allergens from different mammalian species influence the diagnostic potential and clinical efficacy of ASIT to furry animals. As such, detailed knowledge of individual allergens is essential for adequate clinical evaluation. This review compiles current knowledge of the allergen families of mammalian species, and discusses how this information may be used for improved diagnosis and therapy of individuals allergic to mammals. PMID:24041755

  8. Mammalian-derived respiratory allergens - implications for diagnosis and therapy of individuals allergic to furry animals.

    PubMed

    Nilsson, Ola B; van Hage, Marianne; Grönlund, Hans

    2014-03-01

    Furry animals cause respiratory allergies in a significant proportion of the population. A majority of all mammalian allergens are spread as airborne particles, and several have been detected in environments where furry animals are not normally kept. The repertoire of allergens from each source belongs to a restricted number of allergen families. Classification of allergen families is particularly important for the characterization of allergenicity and cross-reactivity of allergens. In fact, major mammalian allergens are taken from only three protein families, i.e. the secretoglobin, lipocalin and kallikrein families. In particular, the lipocalin superfamily harbours major allergens in all important mammalian allergen sources, and cross-reactivity between lipocalin allergens may explain cross-species sensitization between mammals. The identification of single allergen components is of importance to improve diagnosis and therapy of allergic patients using component-resolved diagnostics and allergen-specific immunotherapy (ASIT) respectively. Major disadvantages with crude allergen extracts for these applications emphasize the benefits of careful characterization of individual allergens. Furthermore, detailed knowledge of the characteristics of an allergen is crucial to formulate attenuated allergy vaccines, e.g. hypoallergens. The diverse repertoires of individual allergens from different mammalian species influence the diagnostic potential and clinical efficacy of ASIT to furry animals. As such, detailed knowledge of individual allergens is essential for adequate clinical evaluation. This review compiles current knowledge of the allergen families of mammalian species, and discusses how this information may be used for improved diagnosis and therapy of individuals allergic to mammals.

  9. Effects of vulture declines on facultative scavengers and potential implications for mammalian disease transmission.

    PubMed

    Ogada, D L; Torchin, M E; Kinnaird, M F; Ezenwa, V O

    2012-06-01

    Vultures (Accipitridae and Cathartidae) are the only known obligate scavengers. They feed on rotting carcasses and are the most threatened avian functional group in the world. Possible effects of vulture declines include longer persistence of carcasses and increasing abundance of and contact between facultative scavengers at these carcasses. These changes could increase rates of transmission of infectious diseases, with carcasses serving as hubs of infection. To evaluate these possibilities, we conducted a series of observations and experimental tests of the effects of vulture extirpation on decomposition rates of livestock carcasses and mammalian scavengers in Kenya. We examined whether the absence of vultures changed carcass decomposition time, number of mammalian scavengers visiting carcasses, time spent by mammals at carcasses, and potential for disease transmission at carcasses (measured by changes in intraspecific contact rates). In the absence of vultures, mean carcass decomposition rates nearly tripled. Furthermore, the mean number of mammals at carcasses increased 3-fold (from 1.5 to 4.4 individuals/carcass), and the average time spent by mammals at carcasses increased almost 3-fold (from 55 min to 143 min). There was a nearly 3-fold increase in the mean number of contacts between mammalian scavengers at carcasses without vultures. These results highlight the role of vultures in carcass decomposition and level of contact among mammalian scavengers. In combination, our findings lead us to hypothesize that changes in vulture abundance may affect patterns of disease transmission among mammalian carnivores.

  10. Implications of recent geological investigations of the Mozambique Channel for the mammalian colonization of Madagascar.

    PubMed Central

    McCall, R A

    1997-01-01

    Madagascar separated from continental Africa during the break-up of Gondwanaland early in the Cretaceous. The presence of several terrestrial mammalian groups on Madagascar is paradoxical as (i) these groups postdate the departure of Madagascar from Africa: and ii) terrestrial mammals are poor dispersers across wide water barriers. Recent geological studies focusing on the Davie Fracture Zone of the Mozambique Channel offer a resolution to this situation, by suggesting the presence of a land-bridge from the mid-Eocene to the early Miocene, an interval that matches the ages of Madagascar's mammalian groups. PMID:9178538

  11. Development of Orientation Preference in the Mammalian Visual Cortex

    PubMed Central

    Chapman, Barbara; Gödecke, Imke; Bonhoeffer, Tobias

    2008-01-01

    Recent experiments have studied the development of orientation selectivity in normal animals, visually deprived animals, and animals where patterns of neuronal activity have been altered. Results of these experiments indicate that orientation tuning appears very early in development, and that normal patterns of activity are necessary for its normal development. Visual experience is not needed for early development of orientation, but is crucial for maintaining orientation selectivity. Neuronal activity and vision thus seem to play similar roles in the development of orientation selectivity as they do in the development of eyespecific segregation in the visual system. PMID:10504188

  12. Use of short hairpin RNA expression vectors to study mammalian neural development.

    PubMed

    Yu, Jenn-Yah; Wang, Tsu-Wei; Vojtek, Anne B; Parent, Jack M; Turner, David L

    2005-01-01

    The use of RNA interference (RNAi) in mammalian cells has become a powerful tool for the analysis of gene function. Here we discuss the use of DNA vectors to produce short hairpin RNAs (shRNAs) and inhibit gene expression in mammalian neural progenitors and neurons. Protocols are presented for introducing shRNA vectors into mouse P19 cells differentiated as neurons in vitro and for electroporation of shRNA vectors into primary neural progenitors from the embryonic mouse dorsal telencephalon (prospective cerebral cortex). Transfected primary cortical progenitors can be differentiated in vitro either in dissociated culture or organotypic slice culture. The use of shRNA vectors for RNAi provides a versatile approach to understand gene function during mammalian neural development.

  13. Embryonic development of circadian clocks in the mammalian suprachiasmatic nuclei

    PubMed Central

    Landgraf, Dominic; Koch, Christiane E.; Oster, Henrik

    2014-01-01

    In most species, self-sustained molecular clocks regulate 24-h rhythms of behavior and physiology. In mammals, a circadian pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN) receives photic signals from the retina and synchronizes subordinate clocks in non-SCN tissues. The emergence of circadian rhythmicity during development has been extensively studied for many years. In mice, neuronal development in the presumptive SCN region of the embryonic hypothalamus occurs on days 12–15 of gestation. Intra-SCN circuits differentiate during the following days and retinal projections reach the SCN, and thus mediate photic entrainment, only after birth. In contrast the genetic components of the clock gene machinery are expressed much earlier and during midgestation SCN explants and isolated neurons are capable of generating molecular oscillations in culture. In vivo metabolic rhythms in the SCN, however, are observed not earlier than the 19th day of rat gestation, and rhythmic expression of clock genes is hardly detectable until after birth. Together these data indicate that cellular coupling and, thus, tissue-wide synchronization of single-cell rhythms, may only develop very late during embryogenesis. In this mini-review we describe the developmental origin of the SCN structure and summarize our current knowledge about the functional initiation and entrainment of the circadian pacemaker during embryonic development. PMID:25520627

  14. An Obligatory Role of Mind Bomb-1 in Notch Signaling of Mammalian Development

    PubMed Central

    Im, Sun-Kyoung; Kim, Yoon-Young; Kim, Cheol-Hee; Suh, Pann-Ghill; Jan, Yuh Nung; Kong, Young-Yun

    2007-01-01

    Background The Notch signaling pathway is an evolutionarily conserved intercellular signaling module essential for cell fate specification that requires endocytosis of Notch ligands. Structurally distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), cooperatively regulate the endocytosis of Notch ligands in Drosophila. However, the respective roles of the mammalian E3 ubiquitin ligases, Neur1, Neur2, Mib1, and Mib2, in mammalian development are poorly understood. Methodology/Principal Findings Through extensive use of mammalian genetics, here we show that Neur1 and Neur2 double mutants and Mib2−/− mice were viable and grossly normal. In contrast, conditional inactivation of Mib1 in various tissues revealed the representative Notch phenotypes: defects of arterial specification as deltalike4 mutants, abnormal cerebellum and skin development as jagged1 conditional mutants, and syndactylism as jagged2 mutants. Conclusions/Significance Our data provide the first evidence that Mib1 is essential for Jagged as well as Deltalike ligand-mediated Notch signaling in mammalian development, while Neur1, Neur2, and Mib2 are dispensable. PMID:18043734

  15. Functions of DNA methylation and hydroxymethylation in mammalian development.

    PubMed

    Guibert, Sylvain; Weber, Michael

    2013-01-01

    DNA methylation occurs at cytosines, predominantly in the CpG dinucleotide context and is a key epigenetic regulator of embryogenesis and stem-cell differentiation in mammals. The genomic patterns of 5-methylcytosine are extensively reprogrammed during early embryonic development as well as in the germ-cell lineage. Thanks to improvements in high-throughput mapping technologies, it is now possible to characterize the dynamics of this epigenetic mark at the genome scale. DNA methylation plays multiple roles during development and serves to establish long-term gene silencing. In 2009, it was revealed that 5-hydroxymethylcytosine (5hmC) is another prominent cytosine modification catalyzed by the enzymes of the TET family and abundant in certain cell types. 5hmC has been thought to serve as an intermediate in the reaction of DNA demethylation or act as a signal for chromatin factors. Here, we review the current knowledge on the roles of these DNA epigenetic marks in development, epigenetic reprogramming, and pluripotency. PMID:23587238

  16. The influence of growth factors on the development of preimplantation mammalian embryos.

    PubMed

    Díaz-Cueto, L; Gerton, G L

    2001-01-01

    The development of the preimplantation mammalian embryo from a fertilized egg to a blastocyst capable of implanting in the uterus is a complex process. Cell division must be carefully programmed. The embryonic genome must be activated at the appropriate stage of development, and the pattern of gene expression must be carefully coordinated for the initiation of the correct program of differentiation. Cell fates must be chosen to establish specific cell types such as the inner cell mass and the trophectoderm, which give rise to the embryo proper and the placenta, respectively. This review summarizes recent findings concerning the influence of growth factors on the development of preimplantation mammalian embryos. Maternal factors secreted into the lumen of the female reproductive tract as well as substances synthesized by the developing embryo itself help to regulate this process. Studies of embryos in culture and investigations using homologous recombination to create embryos and animals null for specific genes have enabled the identification of several growth factors that appear essential for preimplantation mammalian embryo development. Some of the factors are required maternal factors; others are embryo-derived autocrine and paracrine factors. Studies using molecular biology are beginning to identify differences in the patterns of genes expressed by naturally derived embryos and those developing in culture. The knowledge gained from studies on growth factors, media, embryonic development, and gene expression should help improve culture conditions for embryos and will provide for safer outcomes from assisted reproductive procedures in human and animal clinics. PMID:11750739

  17. A new symmetrodont mammal from China and its implications for mammalian evolution.

    PubMed

    Hu, Y; Wang, Y; Luo, Z; Li, C

    1997-11-13

    A new symmetrodont mammal has been discovered in the Mesozoic era (Late Jurassic or Early Cretaceous period) of Liaoning Province, China. Archaic therian mammals, including symmetrodonts, are extinct relatives of the living marsupial and placental therians. However, these archaic therians have been mostly documented by fragmentary fossils. This newfossil taxon, represented by a nearly complete postcranial skeleton and a partial skull with dentition, is the best-preserved symmetrodont mammal yet discovered. It provides a new insight into the relationships of the major lineages of mammals and the evolution of the mammalian skeleton. Our analysis suggests that this new taxon represents a part of the early therian radiation before the divergence of living marsupials and placentals; that therians and multituberculates are more closely related to each other than either group is to other mammalian lineages; that archaic therians lacked the more parasagittal posture of the forelimb of most living therian mammals; and that archaic therians, such as symmetrodonts, retained the primitive feature of a finger-like promontorium (possibly with a straight cochlea) of the non-therian mammals. The fully coiled cochlea evolved later in more derived therian mammals, and is therefore convergent to the partially coiled cochlea of monotremes. PMID:9367151

  18. A new symmetrodont mammal from China and its implications for mammalian evolution.

    PubMed

    Hu, Y; Wang, Y; Luo, Z; Li, C

    1997-11-13

    A new symmetrodont mammal has been discovered in the Mesozoic era (Late Jurassic or Early Cretaceous period) of Liaoning Province, China. Archaic therian mammals, including symmetrodonts, are extinct relatives of the living marsupial and placental therians. However, these archaic therians have been mostly documented by fragmentary fossils. This newfossil taxon, represented by a nearly complete postcranial skeleton and a partial skull with dentition, is the best-preserved symmetrodont mammal yet discovered. It provides a new insight into the relationships of the major lineages of mammals and the evolution of the mammalian skeleton. Our analysis suggests that this new taxon represents a part of the early therian radiation before the divergence of living marsupials and placentals; that therians and multituberculates are more closely related to each other than either group is to other mammalian lineages; that archaic therians lacked the more parasagittal posture of the forelimb of most living therian mammals; and that archaic therians, such as symmetrodonts, retained the primitive feature of a finger-like promontorium (possibly with a straight cochlea) of the non-therian mammals. The fully coiled cochlea evolved later in more derived therian mammals, and is therefore convergent to the partially coiled cochlea of monotremes.

  19. Implications for the mammalian sialidases in the physiopathology of skeletal muscle

    PubMed Central

    2012-01-01

    The family of mammalian sialidases is composed of four distinct versatile enzymes that remove negatively charged terminal sialic acid residues from gangliosides and glycoproteins in different subcellular areas and organelles, including lysosomes, cytosol, plasma membrane and mitochondria. In this review we summarize the growing body of data describing the important role of sialidases in skeletal muscle, a complex apparatus involved in numerous key functions and whose functional integrity can be affected by various conditions, such as aging, chronic diseases, cancer and neuromuscular disorders. In addition to supporting the proper catabolism of glycoconjugates, sialidases can affect different signaling pathways by desialylation of many receptors and modulation of ganglioside content in cell membranes, thus actively participating in myoblast proliferation, differentiation and hypertrophy, insulin responsiveness and skeletal muscle architecture. PMID:23114189

  20. Identification of molecular compartments and genetic circuitry in the developing mammalian kidney

    PubMed Central

    Yu, Jing; Valerius, M. Todd; Duah, Mary; Staser, Karl; Hansard, Jennifer K.; Guo, Jin-jin; McMahon, Jill; Vaughan, Joe; Faria, Diane; Georgas, Kylie; Rumballe, Bree; Ren, Qun; Krautzberger, A. Michaela; Junker, Jan P.; Thiagarajan, Rathi D.; Machanick, Philip; Gray, Paul A.; van Oudenaarden, Alexander; Rowitch, David H.; Stiles, Charles D.; Ma, Qiufu; Grimmond, Sean M.; Bailey, Timothy L.; Little, Melissa H.; McMahon, Andrew P.

    2012-01-01

    Lengthy developmental programs generate cell diversity within an organotypic framework, enabling the later physiological actions of each organ system. Cell identity, cell diversity and cell function are determined by cell type-specific transcriptional programs; consequently, transcriptional regulatory factors are useful markers of emerging cellular complexity, and their expression patterns provide insights into the regulatory mechanisms at play. We performed a comprehensive genome-scale in situ expression screen of 921 transcriptional regulators in the developing mammalian urogenital system. Focusing on the kidney, analysis of regional-specific expression patterns identified novel markers and cell types associated with development and patterning of the urinary system. Furthermore, promoter analysis of synexpressed genes predicts transcriptional control mechanisms that regulate cell differentiation. The annotated informational resource (www.gudmap.org) will facilitate functional analysis of the mammalian kidney and provides useful information for the generation of novel genetic tools to manipulate emerging cell populations. PMID:22510988

  1. Complex interactions among mammalian carnivores in Australia, and their implications for wildlife management.

    PubMed

    Glen, Alistair S; Dickman, Chris R

    2005-08-01

    Mammalian carnivore populations are often intensively managed, either because the carnivore in question is endangered, or because it is viewed as a pest and is subjected to control measures, or both. Most management programmes treat carnivore species in isolation. However, there is a large and emerging body of evidence to demonstrate that populations of different carnivores interact with each other in a variety of complex ways. Thus, the removal or introduction of predators to or from a system can often affect other species in ways that are difficult to predict. Wildlife managers must consider such interactions when planning predator control programmes. Integrated predator control will require a greater understanding of the complex relationships between species. In many parts of the world, sympatric species of carnivores have coexisted over an evolutionary time scale so that niche differentiation has occurred, and competition is difficult to observe. Australia has experienced numerous introductions during the past 200 years, including those of the red fox (Vulpes vulpes) and the feral cat (Felis catus). These species now exist in sympatry with native mammalian predators, providing ecologists with the opportunity to study their interactions without the confounding effects of coevolution. Despite an increasing body of observational evidence for complex interactions among native and introduced predators in Australia, few studies have attempted to clarify these relationships experimentally, and the interactions remain largely unacknowledged. A greater understanding of these interactions would provide ecologists and wildlife managers world-wide with the ability to construct robust predictive models of carnivore communities, and to identify their broader effects on ecosystem functioning. We suggest that future research should focus on controlled and replicated predator removal or addition experiments. The dingo (Canis lupus dingo), as a likely keystone species, should be

  2. Behavioral biology of mammalian reproduction and development for a space station

    NASA Technical Reports Server (NTRS)

    Alberts, J. R.

    1983-01-01

    Space Station research includes two kinds of adaption to space: somatic (the adjustments made by an organism, within its lifetime, in response to local conditions), and transgenerational adaption (continuous exposure across sequential life cycles of genetic descendents). Transgenerational effects are akin to evolutionary process. Areas of a life Sciences Program in a space station address the questions of the behavioral biology of mammalian reproduction and development, using the Norway rat as the focus of experimentation.

  3. Metabolic plasticity during mammalian development is directionally dependent on early nutritional status.

    PubMed

    Gluckman, Peter D; Lillycrop, Karen A; Vickers, Mark H; Pleasants, Anthony B; Phillips, Emma S; Beedle, Alan S; Burdge, Graham C; Hanson, Mark A

    2007-07-31

    Developmental plasticity in response to environmental cues can take the form of polyphenism, as for the discrete morphs of some insects, or of an apparently continuous spectrum of phenotype, as for most mammalian traits. The metabolic phenotype of adult rats, including the propensity to obesity, hyperinsulinemia, and hyperphagia, shows plasticity in response to prenatal nutrition and to neonatal administration of the adipokine leptin. Here, we report that the effects of neonatal leptin on hepatic gene expression and epigenetic status in adulthood are directionally dependent on the animal's nutritional status in utero. These results demonstrate that, during mammalian development, the direction of the response to one cue can be determined by previous exposure to another, suggesting the potential for a discontinuous distribution of environmentally induced phenotypes, analogous to the phenomenon of polyphenism.

  4. A new subdivision of mammalian neostriatum with functional implications to learning and memory.

    PubMed

    Shu, S Y; Bao, X; Li, S; Niu, D; Xu, Z; Li, Y

    1999-10-15

    A new subdivision with distinctive morphological and functional attributes has been identified at the caudomedial margin of the neostriatum and surrounding the rostrolateral border of the globus pallidus in the brains of the rat, cat, monkey, and human. The subdivision is termed marginal division (MrD) based on its location. It is readily distinguishable from the rest of striatum by consisting of spindle-shaped neurons, special connections, and intensely expressed immunoreactivities of many neuropeptides and some monoamines in the fibers, terminals, and neuronal somata. Three-dimensional reconstruction from Nissl-stained sections of the rat brain revealed that the MrD is a flat, pan-shaped zone between the neostriatum and globus pallidus. Functional neuronal connections were delineated by chemical-induced c-Fos expression between the MrD and hippocampus, amygdala, as well as the basal nucleus of Meynert. In rats with chemical lesions of bilateral MrD, learning and memory functions were severely impaired as demonstrated by double blind Y-maze test. Our results thus suggested that the MrD is a distinct part and a universal structure in the neostriatum of the mammalian brain and might play an important role in the mechanism of learning and memory.

  5. Conserved microRNA editing in mammalian evolution, development and disease

    PubMed Central

    2014-01-01

    Background Mammalian microRNAs (miRNAs) are sometimes subject to adenosine-to-inosine RNA editing, which can lead to dramatic changes in miRNA target specificity or expression levels. However, although a few miRNAs are known to be edited at identical positions in human and mouse, the evolution of miRNA editing has not been investigated in detail. In this study, we identify conserved miRNA editing events in a range of mammalian and non-mammalian species. Results We demonstrate deep conservation of several site-specific miRNA editing events, including two that date back to the common ancestor of mammals and bony fishes some 450 million years ago. We also find evidence of a recent expansion of an edited miRNA family in placental mammals and show that editing of these miRNAs is associated with changes in target mRNA expression during primate development and aging. While global patterns of miRNA editing tend to be conserved across species, we observe substantial variation in editing frequencies depending on tissue, age and disease state: editing is more frequent in neural tissues compared to heart, kidney and testis; in older compared to younger individuals; and in samples from healthy tissues compared to tumors, which together suggests that miRNA editing might be associated with a reduced rate of cell proliferation. Conclusions Our results show that site-specific miRNA editing is an evolutionarily conserved mechanism, which increases the functional diversity of mammalian miRNA transcriptomes. Furthermore, we find that although miRNA editing is rare compared to editing of long RNAs, miRNAs are greatly overrepresented among conserved editing targets. PMID:24964909

  6. Implication of mammalian ribosomal protein S3 in the processing of DNA damage.

    PubMed

    Kim, J; Chubatsu, L S; Admon, A; Stahl, J; Fellous, R; Linn, S

    1995-06-01

    A human apurinic/apyrimidinic endonuclease activity, called AP endonuclease I, is missing from or altered specifically in cells cultured from Xeroderma pigmentosum group-D individuals (XP-D cells) (Kuhnlein, U., Lee, B., Penhoet, E. E., and Linn, S. (1978) Nucleic Acids Res. 5,951-960). We have now observed that another nuclease activity, UV endonuclease III, is similarly not detected in XP-D cells and is inseparable from the AP endonuclease I activity. This activity preferentially cleaves the phosphodiester backbone of heavily ultraviolet-irradiated DNA at unknown lesions as well as at one of the phosphodiester bonds within a cyclobutane pyrimidine dimer. The nuclease activities have been purified from mouse cells to yield a peptide of M(r) = 32,000, whose sequence indicates identity with ribosomal protein S3. The nuclease activities all cross-react with immunopurified antibody directed against authentic rat ribosomal protein S3, and, upon expression in Escherichia coli of a cloned rat cDNA for ribosomal protein S3, each of the activities was recovered and was indistinguishable from those of the mammalian UV endonuclease III. Moreover, the protein expressed in E. coli and its activities cross-react with the rat protein antibody. Ribosomal protein S3 contains a potential nuclear localization signal, and the protein isolated as a nuclease also has a glycosylation pattern consistent with a nuclear localization as determined by lectin binding. The unexpected role of a ribosomal protein in DNA damage processing and the unexplained inability to detect the nuclease activities in extracts from XP-D cells are discussed. PMID:7775413

  7. Scavenging by mammalian carnivores on prairie dog colonies: implications for the spread of plague.

    PubMed

    Boone, Amanda; Kraft, John P; Stapp, Paul

    2009-04-01

    Plague causes mass mortality of prairie dogs (Cynomys ludovicianus) in shortgrass steppe. Although the pathogen, the bacterium Yersinia pestis, is spread within colonies by flea bites or contact between infected hosts, it is unclear how Y. pestis is transported over long distances between isolated colonies. One possibility is that wideranging, plague-resistant mammalian carnivores pick up fleas when scavenging prairie dog carcasses. Using guinea pigs as surrogates for prairie dogs, we compared how quickly scavengers discovered carcasses on active prairie dog colonies, on colonies recently extirpated by plague, and in grasslands without prairie dogs. In June-July 2007, we monitored the fates of 20 guinea pig carcasses for 4 consecutive days on each site type. Ten carcasses were placed in wire exclosures that restricted access only to arthropods and small rodents; the other 10 were exposed to all scavengers. Scavengers were identified by tracks, evidence of consumption, and/or remote cameras. Carnivores discovered carcasses more quickly on active and plague colonies (mean +/- 95% confidence interval [CI]: 1.6 +/- 0.7, 1.4 +/- 1.4 days, respectively) than on grasslands (3.1 +/- 0.7 days). By the end of the trials, all (100%) exposed carcasses were removed from active colonies, whereas 60% were removed from plague colonies and 30% were removed from grasslands. Rates of carcass discovery and removal on active colonies were significantly greater than in grasslands, which mirrored differences in carnivore activity recorded during earlier scat surveys. A small fraction (30%-40%) of carcasses in exclosures were eaten by rodents, but only on active and plague colonies, suggesting that small rodents, presumably grasshopper mice (Onychomys leucogaster), may also consume carcasses and pick up fleas if carcasses are not removed by carnivores first. These results, combined with observations that fleas remain alive on prairie dogs at least 1 day following their death, suggest that

  8. Mammalian evolution: timing and implications from using the LogDeterminant transform for proteins of differing amino acid composition.

    PubMed

    Penny, D; Hasegawa, M; Waddell, P J; Hendy, M D

    1999-03-01

    We explore the tree of mammalian mtDNA sequences, using particularly the LogDet transform on amino acid sequences, the distance Hadamard transform, and the Closest Tree selection criterion. The amino acid composition of different species show significant differences, even within mammals. After compensating for these differences, nearest-neighbor bootstrap results suggest that the tree is locally stable, though a few groups show slightly greater rearrangements when a large proportion of the constant sites are removed. Many parts of the trees we obtain agree with those on published protein ML trees. Interesting results include a preference for rodent monophyly. The detection of a few alternative signals to those on the optimal tree were obtained using the distance Hadamard transform (with results expressed as a Lento plot). One rearrangement suggested was the interchange of the position of primates and rodents on the optimal tree. The basic stability of the tree, combined with two calibration points (whale/cow and horse/rhinoceros), together with a distant secondary calibration from the mammal/bird divergence, allows inferences of the times of divergence of putative clades. Allowing for sampling variances due to finite sequence length, most major divergences amongst lineages leading to modern orders, appear to occur well before the Cretaceous/Tertiary (K/T) boundary. Implications arising from these early divergences are discussed, particularly the possibility of competition between the small dinosaurs and the new mammal clades. PMID:12078647

  9. A gene network model accounting for development and evolution of mammalian teeth.

    PubMed

    Salazar-Ciudad, Isaac; Jernvall, Jukka

    2002-06-11

    Generation of morphological diversity remains a challenge for evolutionary biologists because it is unclear how an ultimately finite number of genes involved in initial pattern formation integrates with morphogenesis. Ideally, models used to search for the simplest developmental principles on how genes produce form should account for both developmental process and evolutionary change. Here we present a model reproducing the morphology of mammalian teeth by integrating experimental data on gene interactions and growth into a morphodynamic mechanism in which developing morphology has a causal role in patterning. The model predicts the course of tooth-shape development in different mammalian species and also reproduces key transitions in evolution. Furthermore, we reproduce the known expression patterns of several genes involved in tooth development and their dynamics over developmental time. Large morphological effects frequently can be achieved by small changes, according to this model, and similar morphologies can be produced by different changes. This finding may be consistent with why predicting the morphological outcomes of molecular experiments is challenging. Nevertheless, models incorporating morphology and gene activity show promise for linking genotypes to phenotypes.

  10. The evolution of basal progenitors in the developing non-mammalian brain

    PubMed Central

    Nomura, Tadashi; Ohtaka-Maruyama, Chiaki; Yamashita, Wataru; Wakamatsu, Yoshio; Murakami, Yasunori; Calegari, Federico; Suzuki, Kunihiro; Gotoh, Hitoshi; Ono, Katsuhiko

    2016-01-01

    The amplification of distinct neural stem/progenitor cell subtypes during embryogenesis is essential for the intricate brain structures present in various vertebrate species. For example, in both mammals and birds, proliferative neuronal progenitors transiently appear on the basal side of the ventricular zone of the telencephalon (basal progenitors), where they contribute to the enlargement of the neocortex and its homologous structures. In placental mammals, this proliferative cell population can be subdivided into several groups that include Tbr2+ intermediate progenitors and basal radial glial cells (bRGs). Here, we report that basal progenitors in the developing avian pallium show unique morphological and molecular characteristics that resemble the characteristics of bRGs, a progenitor population that is abundant in gyrencephalic mammalian neocortex. Manipulation of LGN (Leu-Gly-Asn repeat-enriched protein) and Cdk4/cyclin D1, both essential regulators of neural progenitor dynamics, revealed that basal progenitors and Tbr2+ cells are distinct cell lineages in the developing avian telencephalon. Furthermore, we identified a small population of subapical mitotic cells in the developing brains of a wide variety of amniotes and amphibians. Our results suggest that unique progenitor subtypes are amplified in mammalian and avian lineages by modifying common mechanisms of neural stem/progenitor regulation during amniote brain evolution. PMID:26732839

  11. Advances in Mammalian Cell Line Development Technologies for Recombinant Protein Production

    PubMed Central

    Lai, Tingfeng; Yang, Yuansheng; Ng, Say Kong

    2013-01-01

    From 2006 to 2011, an average of 15 novel recombinant protein therapeutics have been approved by US Food and Drug Administration (FDA) annually. In addition, the expiration of blockbuster biologics has also spurred the emergence of biosimilars. The increasing numbers of innovator biologic products and biosimilars have thus fuelled the demand of production cell lines with high productivity. Currently, mammalian cell line development technologies used by most biopharmaceutical companies are based on either the methotrexate (MTX) amplification technology or the glutamine synthetase (GS) system. With both systems, the cell clones obtained are highly heterogeneous, as a result of random genome integration by the gene of interest and the gene amplification process. Consequently, large numbers of cell clones have to be screened to identify rare stable high producer cell clones. As such, the cell line development process typically requires 6 to 12 months and is a time, capital and labour intensive process. This article reviews established advances in protein expression and clone screening which are the core technologies in mammalian cell line development. Advancements in these component technologies are vital to improve the speed and efficiency of generating robust and highly productive cell line for large scale production of protein therapeutics. PMID:24276168

  12. The evolution of basal progenitors in the developing non-mammalian brain.

    PubMed

    Nomura, Tadashi; Ohtaka-Maruyama, Chiaki; Yamashita, Wataru; Wakamatsu, Yoshio; Murakami, Yasunori; Calegari, Federico; Suzuki, Kunihiro; Gotoh, Hitoshi; Ono, Katsuhiko

    2016-01-01

    The amplification of distinct neural stem/progenitor cell subtypes during embryogenesis is essential for the intricate brain structures present in various vertebrate species. For example, in both mammals and birds, proliferative neuronal progenitors transiently appear on the basal side of the ventricular zone of the telencephalon (basal progenitors), where they contribute to the enlargement of the neocortex and its homologous structures. In placental mammals, this proliferative cell population can be subdivided into several groups that include Tbr2(+) intermediate progenitors and basal radial glial cells (bRGs). Here, we report that basal progenitors in the developing avian pallium show unique morphological and molecular characteristics that resemble the characteristics of bRGs, a progenitor population that is abundant in gyrencephalic mammalian neocortex. Manipulation of LGN (Leu-Gly-Asn repeat-enriched protein) and Cdk4/cyclin D1, both essential regulators of neural progenitor dynamics, revealed that basal progenitors and Tbr2(+) cells are distinct cell lineages in the developing avian telencephalon. Furthermore, we identified a small population of subapical mitotic cells in the developing brains of a wide variety of amniotes and amphibians. Our results suggest that unique progenitor subtypes are amplified in mammalian and avian lineages by modifying common mechanisms of neural stem/progenitor regulation during amniote brain evolution. PMID:26732839

  13. The role of tumor necrosis factor receptor superfamily members in mammalian brain development, function and homeostasis

    PubMed Central

    Twohig, Jason P.; Cuff, Simone M.; Yong, Audrey A.; Wang, Eddie C.Y.

    2012-01-01

    Tumor necrosis factor receptor superfamily (TNFRSF) members were initially identified as immunological mediators, and are still commonly perceived as immunological molecules. However, our understanding of the diversity of TNFRSF members’ roles in mammalian physiology has grown significantly since the first discovery of TNFRp55 (TNFRSF1) in 1975. In particular, the last decade has provided evidence for important roles in brain development, function and the emergent field of neuronal homeostasis. Recent evidence suggests that TNFRSF members are expressed in an overlapping regulated pattern during neuronal development, participating in the regulation of neuronal expansion, growth, differentiation and regional pattern development. This review examines evidence for non-immunological roles of TNFRSF members in brain development, function and maintenance under normal physiological conditions. In addition, several aspects of brain function during inflammation will also be described, when illuminating and relevant to the non-immunological role of TNFRSF members. Finally, key questions in the field will be outlined. PMID:21861782

  14. Functional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development

    PubMed Central

    Nishimura, Sayoko; Bilgüvar, Kaya; Ishigame, Keiko; Sestan, Nenad; Günel, Murat; Louvi, Angeliki

    2015-01-01

    Cholecystokinin (CCK), a peptide hormone and one of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system. Here, we demonstrate that the CCK receptors have a dynamic and largely reciprocal expression in embryonic and postnatal brain. Using compound homozygous mutant mice lacking the activity of both CCK receptors, we uncover their additive, functionally synergistic effects in brain development and demonstrate that CCK receptor loss leads to abnormalities of cortical development, including defects in the formation of the midline and corpus callosum, and cortical interneuron migration. Using comparative transcriptome analysis of embryonic neocortex, we define the molecular mechanisms underlying these defects. Thus we demonstrate a developmental, hitherto unappreciated, role of the two CCK receptors in mammalian neocortical development. PMID:25875176

  15. The mouse fidgetin gene defines a new role for AAA family proteins in mammalian development.

    PubMed

    Cox, G A; Mahaffey, C L; Nystuen, A; Letts, V A; Frankel, W N

    2000-10-01

    The mouse mutation fidget arose spontaneously in a heterogeneous albino stock. This mutant mouse is characterized by a side-to-side head-shaking and circling behaviour, due to reduced or absent semicircular canals. Fidget mice also have small eyes, associated with cell-cycle delay and insufficient growth of the retinal neural epithelium, and lower penetrance skeletal abnormalities, including pelvic girdle dysgenesis, skull bone fusions and polydactyly. By positional cloning, we found the gene mutated in fidget mice, fidgetin (Fign), which encodes a new member of the 'meiotic' or subfamily-7 (SF7; ref. 7) group of ATPases associated with diverse cellular activities (AAA proteins). We also discovered two closely related mammalian genes. AAA proteins are molecular chaperones that facilitate a variety of functions, including membrane fusion, proteolysis, peroxisome biogenesis, endosome sorting and meiotic spindle formation, but functions for the SF7 AAA proteins are largely unknown. Fidgetin is the first mutant AAA protein found in a mammalian developmental mutant, thus defining a new role for these proteins in embryonic development.

  16. Rapid and Pervasive Changes in Genome-Wide Enhancer Usage During Mammalian Development

    PubMed Central

    Nord, Alex S.; Blow, Matthew J.; Attanasio, Catia; Akiyama, Jennifer A.; Holt, Amy; Hosseini, Roya; Phouanenavong, Sengthavy; Plajzer-Frick, Ingrid; Shoukry, Malak; Afzal, Veena; Rubenstein, John L. R.; Rubin, Edward M.; Pennacchio, Len A.; Visel, Axel

    2014-01-01

    Summary Enhancers are distal regulatory elements that can activate tissue-specific gene expression and are abundant throughout mammalian genomes. While substantial progress has been made towards genome-wide annotation of mammalian enhancers, their temporal activity patterns and global contributions in the context of developmental in vivo processes remain poorly explored. Here we used epigenomic profiling for H3K27ac, a mark of active enhancers, coupled to transgenic mouse assays to examine the genome-wide utilization of enhancers in three different mouse tissues across seven developmental stages. The majority of the ~90,000 enhancers identified exhibited tightly temporally restricted predicted activity windows and were associated with stage-specific biological functions and regulatory pathways in individual tissues. Comparative genomic analysis revealed that evolutionary conservation of enhancers decreases following mid-gestation across all tissues examined. The dynamic enhancer activities uncovered in this study illuminate rapid and pervasive temporal in vivo changes in enhancer usage underlying processes central to development and disease. PMID:24360275

  17. ttime: an R package for translating the timing of brain development across mammalian species.

    PubMed

    Nagarajan, Radhakrishnan; Darlington, Richard B; Finlay, Barbara L; Clancy, Barbara

    2010-10-01

    Understanding relationships between the sequence and timing of brain developmental events across a given set of mammalian species can provide information about both neural development and evolution. Yet neurodevelopmental event timing data available from the published literature are incomplete, particularly for humans. Experimental documentation of unknown event timings requires considerable effort that can be expensive, time consuming, and for humans, often impossible. Application of suitable statistical models for translating neurodevelopmental event timings across mammalian species is essential. The present study implements an established statistical model and related functions as an open-source R package (ttime, translating time). The model incorporated into ttime allows predictions of unknown neurodevelopmental timings and explorations of phylogenetic relationships. The open-source package will enable transparency and reproducibility while minimizing redundancy. Sustainability and widespread dissemination will be guaranteed by the active CRAN (Comprehensive R Archive Network) community. The package updates the web-service (Clancy et al. 2007b) www.translatingtime.net by permitting predictions based on curated event timing databases which may include species not yet incorporated in the current model. The R package can be integrated into complex workflows that use the event predictions in their analyses. The package ttime is publicly available and can be downloaded from http://cran.r-project.org/web/packages/ttime/index.html .

  18. Mechanisms of the genotoxicity of crocidolite asbestos in mammalian cells: implication from mutation patterns induced by reactive oxygen species.

    PubMed Central

    Xu, An; Zhou, Hongning; Yu, Dennis Zengliang; Hei, Tom K

    2002-01-01

    Asbestos is an important environmental carcinogen in the United States and remains the primary occupational concern in many developing countries; however, the underlying mechanisms of its genotoxicity are not known. We showed previously that asbestos is a potent gene and chromosomal mutagen in mammalian cells and that it induces mostly multilocus deletions. Furthermore, reactive oxygen species (ROS) are associated with the mutagenic process. To evaluate the contribution of ROS to the mutagenicity of asbestos, we examined their generation, particularly hydrogen peroxide, and compared the types of mutants induced by crocidolite fibers with those generated by H(2)O(2 )in human-hamster hybrid (A(L)) cells. Using confocal scanning microscopy together with the radical probe 5,6 -chloromethy-2,7 -dichlorodihydrofluorescein diacetate (CM-H(2)DCFDA), we found that asbestos induces a dose-dependent increase in the level of ROS among fiber-treated A(L) cells, which is suppressed by concurrent treatment with dimethyl sulfoxide. Using N-acetyl-3,7-dihydroxyphenoxazine (Amplex Red reagent) together with horseradish peroxidase, we further demonstrated that there was a dose-dependent induction of H(2)O(2) in crocidolite-treated A(L) cells. The amount of H(2)O(2 )induced by asbestos reached a plateau at a dose of 6 microg/cm(2). Concurrent treatment with catalase (1,000 U/mL) inhibited this induction by 7- to 8-fold. Mutation spectrum analysis showed that the types of CD59(-) mutants induced by crocidolite fibers were similar to those induced by equitoxic doses of H(2)O(2). These results provide direct evidence that the mutagenicity of asbestos is mediated by ROS in mammalian cells. PMID:12361925

  19. Variation in mammalian proximal femoral development: comparative analysis of two distinct ossification patterns

    PubMed Central

    Serrat, Maria A; Reno, Philip L; McCollum, Melanie A; Meindl, Richard S; Lovejoy, C Owen

    2007-01-01

    The developmental anatomy of the proximal femur is complex. In some mammals, including humans, the femoral head and greater trochanter emerge as separate ossification centres within a common chondroepiphysis and remain separate throughout ontogeny. In other species, these secondary centres coalesce within the chondroepiphysis to form a single osseous epiphysis much like the proximal humerus. These differences in femoral ontogeny have not been previously addressed, yet are critical to an understanding of femoral mineralization and architecture across a wide range of mammals and may have key implications for understanding and treating hip abnormalities in humans. We evaluated femora from 70 mammalian species and categorized each according to the presence of a ‘separate’ or ‘coalesced’ proximal epiphysis based on visual assessment. We found that ossification type varies widely among mammals: taxa in the ‘coalesced’ group include marsupials, artiodactyls, perissodactyls, bats, carnivores and several primates, while the ‘separate’ group includes hominoids, many rodents, tree shrews and several marine species. There was no clear relationship to body size, phylogeny or locomotion, but qualitative and quantitative differences between the groups suggest that ossification type may be primarily an artefact of femoral shape and neck length. As some osseous abnormalities of the human hip appear to mimic the normal morphology of species with coalesced epiphyses, these results may provide insight into the aetiology and treatment of human hip disorders such as femoroacetabular impingement and early-onset osteoarthritis. PMID:17331175

  20. BMP-FGF Signaling Axis Mediates Wnt-Induced Epidermal Stratification in Developing Mammalian Skin

    PubMed Central

    Zhu, Xiao-Jing; Liu, YuDong; Dai, Zhong-Min; Zhang, Xiaoyun; Yang, XueQin; Li, Yan; Qiu, Mengsheng; Fu, Jiang; Hsu, Wei; Chen, YiPing; Zhang, Zunyi

    2014-01-01

    Epidermal stratification of the mammalian skin requires proliferative basal progenitors to generate intermediate cells that separate from the basal layer and are replaced by post-mitotic cells. Although Wnt signaling has been implicated in this developmental process, the mechanism underlying Wnt-mediated regulation of basal progenitors remains elusive. Here we show that Wnt secreted from proliferative basal cells is not required for their differentiation. However, epidermal production of Wnts is essential for the formation of the spinous layer through modulation of a BMP-FGF signaling cascade in the dermis. The spinous layer defects caused by disruption of Wnt secretion can be restored by transgenically expressed Bmp4. Non-cell autonomous BMP4 promotes activation of FGF7 and FGF10 signaling, leading to an increase in proliferative basal cell population. Our findings identify an essential BMP-FGF signaling axis in the dermis that responds to the epidermal Wnts and feedbacks to regulate basal progenitors during epidermal stratification. PMID:25329657

  1. Amino acid metabolism in intestinal bacteria and its potential implications for mammalian reproduction.

    PubMed

    Dai, Zhaolai; Wu, Zhenlong; Hang, Suqin; Zhu, Weiyun; Wu, Guoyao

    2015-05-01

    Reproduction is vital for producing offspring and preserving genetic resources. However, incidences of many reproductive disorders (e.g. miscarriage, intrauterine growth restriction, premature delivery and lower sperm quality) have either increased dramatically or remained at high rates over the last decades. Mounting evidence shows a strong correlation between enteral protein nutrition and reproduction. Besides serving as major nutrients in the diet, amino acids (AA) are signaling molecules in the regulation of diverse physiological processes, ranging from spermatogenesis to oocyte fertilization and to embryo implantation. Notably, the numbers of bacteria in the intestine exceed the numbers of host cells by 10 times. Microbes in the small-intestinal lumen actively metabolize large amounts of dietary AA and, therefore, affect the entry of AA into the portal circulation for whole-body utilization. Changes in the composition and abundance of AA-metabolizing bacteria in the gut during pregnancy, as well as their translocation to the uterus, may alter uterine function and epigenetic modifications of maternal physiology and metabolism, which are crucial for pregnancy recognition and fetal development. Thus, the presence of the maternal gut microbiota and AA metabolites in the intrauterine environments (e.g. endometrium and placenta) and breast milk is likely a unique signature for the programming of the whole-body microbiome and metabolism in both the fetus and infant. Dietary intervention with functional AA, probiotics and prebiotics to alter the abundance and activity of intestinal bacteria may ameliorate or prevent the development of metabolic syndrome, while improving reproductive performance in both males and females as well as their offspring.

  2. Placental, Matrilineal, and Epigenetic Mechanisms Promoting Environmentally Adaptive Development of the Mammalian Brain

    PubMed Central

    Broad, Kevin D.; Rocha-Ferreira, Eridan; Hristova, Mariya

    2016-01-01

    The evolution of intrauterine development, vivipary, and placentation in eutherian mammals has introduced new possibilities and constraints in the regulation of neural plasticity and development which promote neural function that is adaptive to the environment that a developing brain is likely to encounter in the future. A range of evolutionary adaptations associated with placentation transfers disproportionate control of this process to the matriline, a period unique in mammalian development in that there are three matrilineal genomes interacting in the same organism at the same time (maternal, foetal, and postmeiotic oocytes). The interactions between the maternal and developing foetal hypothalamus and placenta can provide a template by which a mother can transmit potentially adaptive information concerning potential future environmental conditions to the developing brain. In conjunction with genomic imprinting, it also provides a template to integrate epigenetic information from both maternal and paternal lineages. Placentation also hands ultimate control of genomic imprinting and intergenerational epigenetic information transfer to the matriline as epigenetic markers undergo erasure and reprogramming in the developing oocyte. These developments, in conjunction with an expanded neocortex, provide a unique evolutionary template by which matrilineal transfer of maternal care, resources, and culture can be used to promote brain development and infant survival. PMID:27069693

  3. From Meiosis to Mitosis: The Astonishing Flexibility of Cell Division Mechanisms in Early Mammalian Development.

    PubMed

    Bury, L; Coelho, P A; Glover, D M

    2016-01-01

    The execution of female meiosis and the establishment of the zygote is arguably the most critical stage of mammalian development. The egg can be arrested in the prophase of meiosis I for decades, and when it is activated, the spindle is assembled de novo. This spindle must function with the highest of fidelity and yet its assembly is unusually achieved in the absence of conventional centrosomes and with minimal influence of chromatin. Moreover, its dramatic asymmetric positioning is achieved through remarkable properties of the actin cytoskeleton to ensure elimination of the polar bodies. The second meiotic arrest marks a uniquely prolonged metaphase eventually interrupted by egg activation at fertilization to complete meiosis and mark a period of preparation of the male and female pronuclear genomes not only for their entry into the mitotic cleavage divisions but also for the imminent prospect of their zygotic expression. PMID:27475851

  4. Forced and natural convective drying of trehalose/water thin films: implication in the desiccation preservation of Mammalian cells.

    PubMed

    Chen, Bingyan; Fowler, Alex; Bhowmick, Sankha

    2006-06-01

    Trehalose is believed to offer desiccation protection to mammalian cells by forming stable glassy matrices. The goal of the current study was to explore the desiccation kinetics of thin films of trehalose-water solution under forced and natural convective conditions and to investigate the thermophysical state of mammalian cells at the bottom of the thin film. We developed a finite difference model based on the mass and energy conservation equations coupled to the water transport model from the cells. The boundary conditions were obtained from correlations or experimental measurements and the Gordon-Taylor equation was used to predict the glass transition temperature at every location. Results indicated that there are three distinct regimes for drying for both forced and natural convection, characterized by the slope of the moisture content plot as a function of time. Our results also indicate that the surface of the solution reached the glassy state in less than 10 min for the Reynolds (forced) numbers explored and approximately 30 min for some Rayleigh (natural convective) numbers; however, significant water was trapped at this instant. Larger drying force hastened quicker glass formation but trapped more water. The numerical model was capable of predicting the drying kinetics for the dilute region accurately, but deviated while predicting the other regimes. Based on these experimental validations of the model, the osmotic response of different cells located at the bottom of the solution with orders of magnitude difference in their membrane permeability (Lp) was predicted. The results suggested that extracellular glass formed around cells at the bottom of a trehalose-water solution by the propagation of glass into the solution; however it takes more than an order of magnitude time (approximately 7 min to >100 min for forced convective drying) to remove sufficient water to form glass around cells from the time when the first surface glass is formed. This is

  5. Keeping things quiet: Roles of NuRD and Sin3 co-repressor complexes during mammalian development

    PubMed Central

    McDonel, Patrick; Costello, Ita; Hendrich, Brian

    2010-01-01

    Gene inactivation studies of mammalian histone and DNA-modifying proteins have demonstrated a role for many such proteins in embryonic development. Post-implantation embryonic lethality implies a role for epigenetic factors in differentiation and in development of specific lineages or tissues. However a handful of chromatin-modifying enzymes have been found to be required in pre- or peri-implantation embryos. This is significant as implantation is the time when inner cell mass cells of the blastocyst exit pluripotency and begin to commit to form the various lineages that will eventually form the adult animal. These observations indicate a critical role for chromatin-modifying proteins in the earliest lineage decisions of mammalian development, and/or in the formation of the first embryonic cell types. Recent work has shown that the two major class I histone deacetylase-containing co-repressor complexes, the NuRD and Sin3 complexes, are both required at peri-implantation stages of mouse development, demonstrating the importance of histone deacetylation in cell fate decisions. Over the past 10 years both genetic and biochemical studies have revealed surprisingly divergent roles for these two co-repressors in mammalian cells. In this review we will summarise the evidence that the two major class I histone deacetylase complexes in mammalian cells, the NuRD and Sin3 complexes, play important roles in distinct aspects of embryonic development. PMID:18775506

  6. Regulation of mammalian epithelial differentiation and intestine development by class I histone deacetylases.

    PubMed

    Tou, Liqiang; Liu, Qiang; Shivdasani, Ramesh A

    2004-04-01

    The biochemical mechanisms underlying epigenetic control of gene expression are increasingly well known. In contrast, the contributions of individual modifications toward activation of lineage-specific genes during vertebrate development are poorly understood. Class II histone deacetylases (HDACs), which show restricted tissue distribution, regulate muscle-specific gene expression, in part through interactions with myogenic transcription factors. We have combined gene expression profiling with manipulation of fetal mouse intestinal tissue to define roles for other regulatory factors. We found that in the developing mouse intestine class I HDACs are confined to the prospective epithelium and that their levels decline coincidently with activation of differentiation genes, suggesting a functional relationship between these events. Overexpression of wild-type but not of mutant HDACs 1 and 2 in fetal intestine explants reverses expression of certain maturation markers. HDAC inhibitors, including the selective class I antagonist valproic acid, activate the same genes prematurely and accelerate cytodifferentiation. Chromatin immunoprecipitation of freshly isolated organs reveals early HDAC2 occupancy at differentiation gene promoters and corresponding histone hypoacetylation that reverses as HDAC levels fall. Thus, modulation of endogenous class I HDAC levels represents a previously unappreciated mechanism to enable onset of tissue-restricted gene expression in a developing mammalian organ.

  7. Building up the nucleus: nuclear organization in the establishment of totipotency and pluripotency during mammalian development

    PubMed Central

    Borsos, Máté; Torres-Padilla, Maria-Elena

    2016-01-01

    In mammals, epigenetic reprogramming, the acquisition and loss of totipotency, and the first cell fate decision all occur within a 3-d window after fertilization from the one-cell zygote to the formation of the blastocyst. These processes are poorly understood in molecular detail, yet this is an essential prerequisite to uncover principles of stem cells, chromatin biology, and thus regenerative medicine. A unique feature of preimplantation development is the drastic genome-wide changes occurring to nuclear architecture. From studying somatic and in vitro cultured embryonic stem cells (ESCs) it is becoming increasingly established that the three-dimensional (3D) positions of genomic loci relative to each other and to specific compartments of the nucleus can act on the regulation of gene expression, potentially driving cell fate. However, the functionality, mechanisms, and molecular characteristics of the changes in nuclear organization during preimplantation development are only now beginning to be unraveled. Here, we discuss the peculiarities of nuclear compartments and chromatin organization during mammalian preimplantation development in the context of the transition from totipotency to pluripotency. PMID:26980186

  8. Development of a Safeguard System Using an Episomal Mammalian Artificial Chromosome for Gene and Cell Therapy

    PubMed Central

    Uno, Narumi; Uno, Katsuhiro; Komoto, Shinya; Suzuki, Teruhiko; Hiratsuka, Masaharu; Osaki, Mitsuhiko; Kazuki, Yasuhiro; Oshimura, Mitsuo

    2015-01-01

    The development of a safeguard system to remove tumorigenic cells would allow safer clinical applications of stem cells for the treatment of patients with an intractable disease including genetic disorders. Such safeguard systems should not disrupt the host genome and should have long-term stability. Here, we attempted to develop a tumor-suppressing mammalian artificial chromosome containing a safeguard system that uses the immune rejection system against allogeneic tissue from the host. For proof-of-concept of the safeguard system, B16F10 mouse melanoma cells expressing the introduced H2-K(d) major histocompatibility complex (MHC class I)-allogenic haplotype were transplanted into recipient C57BL/6J mice expressing MHC H2-K(b). Subcutaneous implantation of B16F10 cells into C57BL/6J mice resulted in high tumorigenicity. The volume of tumors derived from B16F10 cells expressing allogenic MHC H2-K(d) was decreased significantly (P < 0.01). Suppression of MHC H2-K(d)-expressing tumors in C57BL/6J mice was enhanced by immunization with MHC H2-K(d)-expressing splenocytes (P < 0.01). These results suggest that the safeguard system is capable of suppressing tumor formation by the transplanted cells. PMID:26670279

  9. Impact of maternal malnutrition during the periconceptional period on mammalian preimplantation embryo development.

    PubMed

    Velazquez, M A

    2015-04-01

    During episodes of undernutrition and overnutrition the mammalian preimplantation embryo undergoes molecular and metabolic adaptations to cope with nutrient deficits or excesses. Maternal adaptations also take place to keep a nutritional microenvironment favorable for oocyte development and embryo formation. This maternal-embryo communication takes place via several nutritional mediators. Although adaptive responses to malnutrition by both the mother and the embryo may ensure blastocyst formation, the resultant quality of the embryo can be compromised, leading to early pregnancy failure. Still, studies have shown that, although early embryonic mortality can be induced during malnutrition, the preimplantation embryo possesses an enormous plasticity that allows it to implant and achieve a full-term pregnancy under nutritional stress, even in extreme cases of malnutrition. This developmental strategy, however, may come with a price, as shown by the adverse developmental programming induced by even subtle nutritional challenges exerted exclusively during folliculogenesis and the preimplantation period, resulting in offspring with a higher risk of developing deleterious phenotypes in adulthood. Overall, current evidence indicates that malnutrition during the periconceptional period can induce cellular and molecular alterations in preimplantation embryos with repercussions for fertility and postnatal health. PMID:25498236

  10. Impact of maternal malnutrition during the periconceptional period on mammalian preimplantation embryo development.

    PubMed

    Velazquez, M A

    2015-04-01

    During episodes of undernutrition and overnutrition the mammalian preimplantation embryo undergoes molecular and metabolic adaptations to cope with nutrient deficits or excesses. Maternal adaptations also take place to keep a nutritional microenvironment favorable for oocyte development and embryo formation. This maternal-embryo communication takes place via several nutritional mediators. Although adaptive responses to malnutrition by both the mother and the embryo may ensure blastocyst formation, the resultant quality of the embryo can be compromised, leading to early pregnancy failure. Still, studies have shown that, although early embryonic mortality can be induced during malnutrition, the preimplantation embryo possesses an enormous plasticity that allows it to implant and achieve a full-term pregnancy under nutritional stress, even in extreme cases of malnutrition. This developmental strategy, however, may come with a price, as shown by the adverse developmental programming induced by even subtle nutritional challenges exerted exclusively during folliculogenesis and the preimplantation period, resulting in offspring with a higher risk of developing deleterious phenotypes in adulthood. Overall, current evidence indicates that malnutrition during the periconceptional period can induce cellular and molecular alterations in preimplantation embryos with repercussions for fertility and postnatal health.

  11. Towards the Development of a Potent and Selective Organoruthenium Mammalian Sterile 20 Kinase Inhibitor

    PubMed Central

    Anand, Ruchi; Maksimoska, Jasna; Pagano, Nicholas; Wong, Eric Y.; Gimotty, Phyllis A.; Diamond, Scott L.; Meggers, Eric

    2009-01-01

    Mammalian sterile 20 (MST1) kinase, a member of the sterile 20 (Ste-20) family of proteins, is a proapoptotic cytosolic kinase that plays an important role in the cellular response to oxidative stress. In this study, we report on the development of a potent and selective MST1 kinase inhibitor based on a ruthenium half-sandwich scaffold. We show that the enantiopure organoruthenium inhibitor, 9E1, has an IC50 value of 45 nM for MST1 and a greater than 25-fold inhibitor selectivity over the related Ste-20 kinases, p21 activated kinase 1 (PAK1), and p21 activated kinase 4 (PAK4) and an almost 10-fold selectivity over the related Thousand and one amino acids kinase 2 (TAO2). Compound 9E1 also displays a promising selectivity profile against unrelated protein kinases, however, the proto-oncogene serine/threonine protein kinase PIM1 (PIM-1) and glycogen synthase kinase 3 (GSK-3β) are inhibited with IC50 values in the low nanomolar range. We also show that 9E1 can inhibit MST1 function in cells. A cocrystal structure of a related compound with PIM-1 and a homology model with MST1 reveals the binding mode of this scaffold to MST1 and provides a starting point for the development of improved MST1 kinase inhibitors for possible therapeutic application. PMID:19226137

  12. Mammalian Brain Development is Accompanied by a Dramatic Increase in Bipolar DNA Methylation

    PubMed Central

    Sun, Ming-an; Sun, Zhixiong; Wu, Xiaowei; Rajaram, Veena; Keimig, David; Lim, Jessica; Zhu, Hongxiao; Xie, Hehuang

    2016-01-01

    DNA methylation is an epigenetic mechanism critical for tissue development and cell specification. Mammalian brains consist of many different types of cells with assumedly distinct DNA methylation profiles, and thus some genomic loci may demonstrate bipolar DNA methylation pattern, i.e. hypermethylated in one cell subset but hypomethylated in others. Currently, how extensive methylation patterns vary among brain cells is unknown and bipolar methylated genomic loci remain largely unexplored. In this study, we implemented a procedure to infer cell-subset specific methylated (CSM) loci from the methylomes of human and mouse frontal cortices at different developmental stages. With the genome-scale hairpin bisulfite sequencing approach, we demonstrated that the majority of CSM loci predicted likely resulted from the methylation differences among brain cells rather than from asymmetric DNA methylation between DNA double strands. Correlated with enhancer-associated histone modifications, putative CSM loci increased dramatically during early stages of brain development and were enriched for GWAS variants associated with neurological disorder-related diseases/traits. Altogether, this study provides a procedure to identify genomic regions showing methylation differences in a mixed cell population and our results suggest that a set of cis-regulatory elements are primed in early postnatal life whose functions may be compromised in human neurological disorders. PMID:27585862

  13. Mammalian Brain Development is Accompanied by a Dramatic Increase in Bipolar DNA Methylation.

    PubMed

    Sun, Ming-An; Sun, Zhixiong; Wu, Xiaowei; Rajaram, Veena; Keimig, David; Lim, Jessica; Zhu, Hongxiao; Xie, Hehuang

    2016-01-01

    DNA methylation is an epigenetic mechanism critical for tissue development and cell specification. Mammalian brains consist of many different types of cells with assumedly distinct DNA methylation profiles, and thus some genomic loci may demonstrate bipolar DNA methylation pattern, i.e. hypermethylated in one cell subset but hypomethylated in others. Currently, how extensive methylation patterns vary among brain cells is unknown and bipolar methylated genomic loci remain largely unexplored. In this study, we implemented a procedure to infer cell-subset specific methylated (CSM) loci from the methylomes of human and mouse frontal cortices at different developmental stages. With the genome-scale hairpin bisulfite sequencing approach, we demonstrated that the majority of CSM loci predicted likely resulted from the methylation differences among brain cells rather than from asymmetric DNA methylation between DNA double strands. Correlated with enhancer-associated histone modifications, putative CSM loci increased dramatically during early stages of brain development and were enriched for GWAS variants associated with neurological disorder-related diseases/traits. Altogether, this study provides a procedure to identify genomic regions showing methylation differences in a mixed cell population and our results suggest that a set of cis-regulatory elements are primed in early postnatal life whose functions may be compromised in human neurological disorders. PMID:27585862

  14. How does Reelin control neuronal migration and layer formation in the developing mammalian neocortex?

    PubMed

    Sekine, Katsutoshi; Kubo, Ken-ichiro; Nakajima, Kazunori

    2014-09-01

    The mammalian neocortex has a laminar structure that develops in a birth-date-dependent "inside-out" pattern. Its layered structure is established by neuronal migration accompanied by sequential changes in migratory mode regulated by several signaling cascades. Although Reelin was discovered about two decades ago and is one of the best known molecules that is indispensable to the establishment of the "inside-out" neuron layers, the cellular and molecular functions of Reelin in layer formation are still largely unknown. In this review article, we summarize our recent understanding of Reelin's functions during neuronal migration. Reelin acts in at least two different steps of neuronal migration: the final step of neuronal migration (somal/terminal translocation) just beneath the marginal zone (MZ) and the regulation of cell polarity step when the neurons change their migratory mode from multipolar migration to locomotion. During the translocation mode, Reelin activates integrin α5β1 through an intracellular pathway that triggers the translocation and activates N-cadherin in concert with the nectin-afadin system. Reelin is also involved in the termination of neuronal migration by degrading Dab1 via the SOCS7-Cullin5-Rbx2 system, and Reelin has been found to induce the birth-date-dependent neuronal aggregation in vivo. Based on these findings, we hypothesize that the molecular function of Reelin during neuronal migration is to control cell-adhesiveness during development by regulating the expression/activation of cell adhesion molecules.

  15. Nutrition and brain development: social policy implications.

    PubMed

    Tanner, Emily M; Finn-Stevenson, Matia

    2002-04-01

    Undernutrition among young children is widespread in the United States and has a detrimental impact on brain development. This article explores the risks associated with undernutrition and the potential for recovery when diet and the environment improve. Three policy implications are discussed: (a) increasing access to federal food programs, (b) promoting breastfeeding, and (c) working toward reducing child poverty. PMID:15792058

  16. Cultural Implications of Human Resource Development.

    ERIC Educational Resources Information Center

    Hiranpruk, Chaiskran

    A discussion of the cultural effects of economic and, by extension, human resource development in Southeast Asia looks at short- and long-term implications. It is suggested that in the short term, increased competition will affect distribution of wealth, which can promote materialism and corruption. The introduction of labor-saving technology may…

  17. Expanding the test set: Chemicals with potential to disrupt mammalian brain development.

    PubMed

    Mundy, William R; Padilla, Stephanie; Breier, Joseph M; Crofton, Kevin M; Gilbert, Mary E; Herr, David W; Jensen, Karl F; Radio, Nicholas M; Raffaele, Kathleen C; Schumacher, Kelly; Shafer, Timothy J; Cowden, John

    2015-01-01

    High-throughput test methods including molecular, cellular, and alternative species-based assays that examine critical events of normal brain development are being developed for detection of developmental neurotoxicants. As new assays are developed, a "training set" of chemicals is used to evaluate the relevance of individual assays for specific endpoints. Different training sets are necessary for each assay that would comprise a developmental neurotoxicity test battery. In contrast, evaluation of the predictive ability of a comprehensive test battery requires a set of chemicals that have been shown to alter brain development after in vivo exposure ("test set"). Because only a small number of substances have been well documented to alter human neurodevelopment, we have proposed an expanded test set that includes chemicals demonstrated to adversely affect neurodevelopment in animals. To compile a list of potential developmental neurotoxicants, a literature review of compounds that have been examined for effects on the developing nervous system was conducted. The search was limited to mammalian studies published in the peer-reviewed literature and regulatory studies submitted to the U.S. EPA. The definition of developmental neurotoxicity encompassed changes in behavior, brain morphology, and neurochemistry after gestational or lactational exposure. Reports that indicated developmental neurotoxicity was observed only at doses that resulted in significant maternal toxicity or were lethal to the fetus or offspring were not considered. As a basic indication of reproducibility, we only included a chemical if data on its developmental neurotoxicity were available from more than one laboratory (defined as studies originating from laboratories with a different senior investigator). Evidence from human studies was included when available. Approximately 100 developmental neurotoxicity test set chemicals were identified, with 22% having evidence in humans. PMID:26476195

  18. Essential role of the zinc finger transcription factor Casz1 for mammalian cardiac morphogenesis and development.

    PubMed

    Liu, Zhihui; Li, Wenling; Ma, Xuefei; Ding, Nancy; Spallotta, Francesco; Southon, Eileen; Tessarollo, Lino; Gaetano, Carlo; Mukouyama, Yoh-Suke; Thiele, Carol J

    2014-10-24

    Chromosome 1p36 deletion syndrome is one of the most common terminal deletions observed in humans and is related to congenital heart disease (CHD). However, the 1p36 genes that contribute to heart disease have not been clearly delineated. Human CASZ1 gene localizes to 1p36 and encodes a zinc finger transcription factor. Casz1 is required for Xenopus heart ventral midline progenitor cell differentiation. Whether Casz1 plays a role during mammalian heart development is unknown. Our aim is to determine 1p36 gene CASZ1 function at regulating heart development in mammals. We generated a Casz1 knock-out mouse using Casz1-trapped embryonic stem cells. Casz1 deletion in mice resulted in abnormal heart development including hypoplasia of myocardium, ventricular septal defect, and disorganized morphology. Hypoplasia of myocardium was caused by decreased cardiomyocyte proliferation. Comparative genome-wide RNA transcriptome analysis of Casz1 depleted embryonic hearts identifies abnormal expression of genes that are critical for muscular system development and function, such as muscle contraction genes TNNI2, TNNT1, and CKM; contractile fiber gene ACTA1; and cardiac arrhythmia associated ion channel coding genes ABCC9 and CACNA1D. The transcriptional regulation of some of these genes by Casz1 was also found in cellular models. Our results showed that loss of Casz1 during mouse development led to heart defect including cardiac noncompaction and ventricular septal defect, which phenocopies 1p36 deletion syndrome related CHD. This suggests that CASZ1 is a novel 1p36 CHD gene and that the abnormal expression of cardiac morphogenesis and contraction genes induced by loss of Casz1 contributes to the heart defect.

  19. Expanding the test set: Chemicals with potential to disrupt mammalian brain development.

    PubMed

    Mundy, William R; Padilla, Stephanie; Breier, Joseph M; Crofton, Kevin M; Gilbert, Mary E; Herr, David W; Jensen, Karl F; Radio, Nicholas M; Raffaele, Kathleen C; Schumacher, Kelly; Shafer, Timothy J; Cowden, John

    2015-01-01

    High-throughput test methods including molecular, cellular, and alternative species-based assays that examine critical events of normal brain development are being developed for detection of developmental neurotoxicants. As new assays are developed, a "training set" of chemicals is used to evaluate the relevance of individual assays for specific endpoints. Different training sets are necessary for each assay that would comprise a developmental neurotoxicity test battery. In contrast, evaluation of the predictive ability of a comprehensive test battery requires a set of chemicals that have been shown to alter brain development after in vivo exposure ("test set"). Because only a small number of substances have been well documented to alter human neurodevelopment, we have proposed an expanded test set that includes chemicals demonstrated to adversely affect neurodevelopment in animals. To compile a list of potential developmental neurotoxicants, a literature review of compounds that have been examined for effects on the developing nervous system was conducted. The search was limited to mammalian studies published in the peer-reviewed literature and regulatory studies submitted to the U.S. EPA. The definition of developmental neurotoxicity encompassed changes in behavior, brain morphology, and neurochemistry after gestational or lactational exposure. Reports that indicated developmental neurotoxicity was observed only at doses that resulted in significant maternal toxicity or were lethal to the fetus or offspring were not considered. As a basic indication of reproducibility, we only included a chemical if data on its developmental neurotoxicity were available from more than one laboratory (defined as studies originating from laboratories with a different senior investigator). Evidence from human studies was included when available. Approximately 100 developmental neurotoxicity test set chemicals were identified, with 22% having evidence in humans.

  20. Thoughts on the development, structure and evolution of the mammalian and avian telencephalic pallium.

    PubMed Central

    Puelles, L

    2001-01-01

    Various lines of evidence suggest that the development and evolution of the mammalian isocortex cannot be easily explained without an understanding of correlative changes in surrounding areas of the telencephalic pallium and subpallium. These are close neighbours in a common morphogenetic field and are postulated as sources of some cortical neuron types (and even of whole cortical areas). There is equal need to explain relevant developmental evolutionary changes in the dorsal thalamus, the major source of afferent inputs to the telencephalon (to both the pallium and subpallium). The mammalian isocortex evolved within an initially small dorsal part of the pallium of vertebrates, surrounded by other pallial parts, including some with a non-cortical, nuclear structure. Nuclear pallial elements are markedly voluminous in reptiles and birds, where they build the dorsal ventricular ridge, or hypopallium, which has been recently divided molecularly and structurally into a lateral pallium and a ventral pallium. Afferent pallial connections are often simplified as consisting of thalamic fibres that project either to focal cell aggregates in the ventral pallium (predominant in reptiles and birds) or to corticoid areas in the dorsal pallium (predominant in mammals). Karten's hypothesis, put forward in 1969, on the formation of some isocortical areas postulates an embryonic translocation into the nascent isocortex of the ventropallial thalamorecipient foci and respective downstream ventropallial target populations, as specific layer IV, layers II- III, or layers V-VI neuron populations. This view is considered critically in the light of various recent data, contrasting with the alternative possibility of a parallel, separate evolution of the different pallial parts. The new scenario reveals as well a separately evolving tiered structure of the dorsal thalamus, some of whose parts receive input from midbrain sensory centres (collothalamic nuclei), whereas other parts receive

  1. Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea.

    PubMed

    Stojanova, Zlatka P; Kwan, Tao; Segil, Neil

    2015-10-15

    In the developing cochlea, sensory hair cell differentiation depends on the regulated expression of the bHLH transcription factor Atoh1. In mammals, if hair cells die they do not regenerate, leading to permanent deafness. By contrast, in non-mammalian vertebrates robust regeneration occurs through upregulation of Atoh1 in the surviving supporting cells that surround hair cells, leading to functional recovery. Investigation of crucial transcriptional events in the developing organ of Corti, including those involving Atoh1, has been hampered by limited accessibility to purified populations of the small number of cells present in the inner ear. We used µChIP and qPCR assays of FACS-purified cells to track changes in the epigenetic status of the Atoh1 locus during sensory epithelia development in the mouse. Dynamic changes in the histone modifications H3K4me3/H3K27me3, H3K9ac and H3K9me3 reveal a progression from poised, to active, to repressive marks, correlating with the onset of Atoh1 expression and its subsequent silencing during the perinatal (P1 to P6) period. Inhibition of acetylation blocked the increase in Atoh1 mRNA in nascent hair cells, as well as ongoing hair cell differentiation during embryonic organ of Corti development ex vivo. These results reveal an epigenetic mechanism of Atoh1 regulation underlying hair cell differentiation and subsequent maturation. Interestingly, the H3K4me3/H3K27me3 bivalent chromatin structure observed in progenitors persists at the Atoh1 locus in perinatal supporting cells, suggesting an explanation for the latent capacity of these cells to transdifferentiate into hair cells, and highlighting their potential as therapeutic targets in hair cell regeneration.

  2. Analysis of gene-environment interactions in postnatal development of the mammalian intestine.

    PubMed

    Rakoff-Nahoum, Seth; Kong, Yong; Kleinstein, Steven H; Subramanian, Sathish; Ahern, Philip P; Gordon, Jeffrey I; Medzhitov, Ruslan

    2015-02-17

    Unlike mammalian embryogenesis, which takes place in the relatively predictable and stable environment of the uterus, postnatal development can be affected by a multitude of highly variable environmental factors, including diet, exposure to noxious substances, and microorganisms. Microbial colonization of the intestine is thought to play a particularly important role in postnatal development of the gastrointestinal, metabolic, and immune systems. Major changes in environmental exposure occur right after birth, upon weaning, and during pubertal maturation into adulthood. These transitions include dramatic changes in intestinal contents and require appropriate adaptations to meet changes in functional demands. Here, we attempt to both characterize and provide mechanistic insights into postnatal intestinal ontogeny. We investigated changes in global intestinal gene expression through postnatal developmental transitions. We report profound alterations in small and large intestinal transcriptional programs that accompany both weaning and puberty in WT mice. Using myeloid differentiation factor 88 (MyD88)/TIR-domain-containing adapter-inducing interferon-β (TRIF) double knockout littermates, we define the role of toll-like receptors (TLRs) and interleukin (IL)-1 receptor family member signaling in postnatal gene expression programs and select ontogeny-specific phenotypes, such as vascular and smooth muscle development and neonatal epithelial and mast cell homeostasis. Metaanalysis of the effect of the microbiota on intestinal gene expression allowed for mechanistic classification of developmentally regulated genes by TLR/IL-1R (TIR) signaling and/or indigenous microbes. We find that practically every aspect of intestinal physiology is affected by postnatal transitions. Developmental timing, microbial colonization, and TIR signaling seem to play distinct and specific roles in regulation of gene-expression programs throughout postnatal development.

  3. Analysis of gene–environment interactions in postnatal development of the mammalian intestine

    PubMed Central

    Rakoff-Nahoum, Seth; Kong, Yong; Kleinstein, Steven H.; Subramanian, Sathish; Ahern, Philip P.; Gordon, Jeffrey I.; Medzhitov, Ruslan

    2015-01-01

    Unlike mammalian embryogenesis, which takes place in the relatively predictable and stable environment of the uterus, postnatal development can be affected by a multitude of highly variable environmental factors, including diet, exposure to noxious substances, and microorganisms. Microbial colonization of the intestine is thought to play a particularly important role in postnatal development of the gastrointestinal, metabolic, and immune systems. Major changes in environmental exposure occur right after birth, upon weaning, and during pubertal maturation into adulthood. These transitions include dramatic changes in intestinal contents and require appropriate adaptations to meet changes in functional demands. Here, we attempt to both characterize and provide mechanistic insights into postnatal intestinal ontogeny. We investigated changes in global intestinal gene expression through postnatal developmental transitions. We report profound alterations in small and large intestinal transcriptional programs that accompany both weaning and puberty in WT mice. Using myeloid differentiation factor 88 (MyD88)/TIR-domain-containing adapter-inducing interferon-β (TRIF) double knockout littermates, we define the role of toll-like receptors (TLRs) and interleukin (IL)-1 receptor family member signaling in postnatal gene expression programs and select ontogeny-specific phenotypes, such as vascular and smooth muscle development and neonatal epithelial and mast cell homeostasis. Metaanalysis of the effect of the microbiota on intestinal gene expression allowed for mechanistic classification of developmentally regulated genes by TLR/IL-1R (TIR) signaling and/or indigenous microbes. We find that practically every aspect of intestinal physiology is affected by postnatal transitions. Developmental timing, microbial colonization, and TIR signaling seem to play distinct and specific roles in regulation of gene-expression programs throughout postnatal development. PMID:25691701

  4. Product quality considerations for mammalian cell culture process development and manufacturing.

    PubMed

    Gramer, Michael J

    2014-01-01

    The manufacturing of a biologic drug from mammalian cells results in not a single substance, but an array of product isoforms, also known as variants. These isoforms arise due to intracellular or extracellular events as a result of biological or chemical modification. The most common examples related to biomanufacturing include amino acid modifications (glycosylation, isomerization, oxidation, adduct formation, pyroglutamate formation, phosphorylation, sulfation, amidation), amino acid sequence variants (genetic mutations, amino acid misincorporation, N- and C-terminal heterogeneity, clipping), and higher-order structure modifications (misfolding, aggregation, disulfide pairing). Process-related impurities (HCP, DNA, media components, viral particles) are also important quality attributes related to product safety. The observed ranges associated with each quality attribute define the product quality profile. A biologic drug must have a correct and consistent quality profile throughout clinical development and scale-up to commercial production to ensure product safety and efficacy. In general, the upstream process (cell culture) defines the quality of product-related substances, whereas the downstream process (purification) defines the residual level of process- and product-related impurities. The purpose of this chapter is to review the impact of the cell culture process on product quality. Emphasis is placed on studies with industrial significance and where the direct mechanism of product quality impact was determined. Where possible, recommendations for maintaining consistent or improved quality are provided.

  5. Axotomy of single fluorescent nerve fibers in developing mammalian spinal cord by photoconversion of diaminobenzidine.

    PubMed

    De-Miguel, Francisco F; Muller, Kenneth J; Adams, William B; Nicholls, John G

    2002-05-30

    A technique has been developed for cutting single nerve fibers in mammalian spinal cord. In the presence of diaminobenzidine (DAB), a laser microbeam was applied to carbocyanine (Dil) stained sensory fibers in cultured spinal cords of the newly born opossum Monodelphis domestica. Digital images of fluorescent fibers were acquired with an intensified video CCD-camera coupled to an image processor. Laser illumination of two spots on a fiber in the presence of 3 mg/ml DAB cut it, so that following DAB wash out, Dil fluorescence did not return after the intermediate segment was bleached. In contrast, when a similar procedure was carried out without DAB, fluorescence of the bleached segment was recovered within minutes in darkness, by dye diffusion from adjacent regions of the uncut fiber. After exposure to DAB, through-conduction of compound action potentials continued in undamaged fibers. The DAB reaction product remained as a dark precipitate, helping to localize the lesion sites. By illuminating a continuous series of spots it was possible to cut whole nerve roots. Fluorescent fibers extended across the cut segment 24 h later. With minor modifications, the procedure described here allows a precise lesioning of single fibers within an intact nervous system.

  6. DEVELOPMENT OF A REFINED DATABASE OF MAMMALIAN RELATIVE POTENCY ESTIMATES FOR DIOXIN-LIKE COMPOUNDS

    EPA Science Inventory

    The toxic equivalency factor (TEF) approach has been widely accepted as the most feasible method available at present for evaluating potential health risks associated with exposure to mixtures of dioxin-like compounds (DLCs). The current mammalian TEFs for the DLCs were establis...

  7. Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice

    SciTech Connect

    Zhang, Pengpeng; Shan, Tizhong; Liang, Xinrong; Deng, Changyan; Kuang, Shihuan

    2014-09-12

    Highlights: • mTOR is a critical regulator of many biological processes yet its function in heart is not well understood. • MCK-Cre/Mtor{sup flox/flox} mice were established to delete Mtor in cardiomyocytes. • The mTOR-mKO mice developed normally but die prematurely within 5 weeks after birth due to heart disease. • The mTOR-mKO mice had dilated myocardium and increased cell death. • mTOR-mKO hearts had reduced expression of metabolic genes and activation of mTOR target proteins. - Abstract: Mammalian target of rapamycin (mTOR) is a critical regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive knockout of Mtor leads to embryonic lethality, the in vivo function of mTOR in perinatal development and postnatal growth of heart is not well defined. In this study, we established a muscle-specific mTOR conditional knockout mouse model (mTOR-mKO) by crossing MCK-Cre and Mtor{sup flox/flox} mice. Although the mTOR-mKO mice survived embryonic and perinatal development, they exhibited severe postnatal growth retardation, cardiac muscle pathology and premature death. At the cellular level, the cardiac muscle of mTOR-mKO mice had fewer cardiomyocytes due to apoptosis and necrosis, leading to dilated cardiomyopathy. At the molecular level, the cardiac muscle of mTOR-mKO mice expressed lower levels of fatty acid oxidation and glycolysis related genes compared to the WT littermates. In addition, the mTOR-mKO cardiac muscle had reduced Myh6 but elevated Myh7 expression, indicating cardiac muscle degeneration. Furthermore, deletion of Mtor dramatically decreased the phosphorylation of S6 and AKT, two key targets downstream of mTORC1 and mTORC2 mediating the normal function of mTOR. These results demonstrate that mTOR is essential for cardiomyocyte survival and cardiac muscle function.

  8. The parental non-equivalence of imprinting control regions during mammalian development and evolution.

    PubMed

    Schulz, Reiner; Proudhon, Charlotte; Bestor, Timothy H; Woodfine, Kathryn; Lin, Chyuan-Sheng; Lin, Shau-Ping; Prissette, Marine; Oakey, Rebecca J; Bourc'his, Déborah

    2010-11-01

    In mammals, imprinted gene expression results from the sex-specific methylation of imprinted control regions (ICRs) in the parental germlines. Imprinting is linked to therian reproduction, that is, the placenta and imprinting emerged at roughly the same time and potentially co-evolved. We assessed the transcriptome-wide and ontology effect of maternally versus paternally methylated ICRs at the developmental stage of setting of the chorioallantoic placenta in the mouse (8.5dpc), using two models of imprinting deficiency including completely imprint-free embryos. Paternal and maternal imprints have a similar quantitative impact on the embryonic transcriptome. However, transcriptional effects of maternal ICRs are qualitatively focused on the fetal-maternal interface, while paternal ICRs weakly affect non-convergent biological processes, with little consequence for viability at 8.5dpc. Moreover, genes regulated by maternal ICRs indirectly influence genes regulated by paternal ICRs, while the reverse is not observed. The functional dominance of maternal imprints over early embryonic development is potentially linked to selection pressures favoring methylation-dependent control of maternal over paternal ICRs. We previously hypothesized that the different methylation histories of ICRs in the maternal versus the paternal germlines may have put paternal ICRs under higher mutational pressure to lose CpGs by deamination. Using comparative genomics of 17 extant mammalian species, we show here that, while ICRs in general have been constrained to maintain more CpGs than non-imprinted sequences, the rate of CpG loss at paternal ICRs has indeed been higher than at maternal ICRs during evolution. In fact, maternal ICRs, which have the characteristics of CpG-rich promoters, have gained CpGs compared to non-imprinted CpG-rich promoters. Thus, the numerical and, during early embryonic development, functional dominance of maternal ICRs can be explained as the consequence of two

  9. Effects of Simulated Weightlessness on Mammalian Development. Part 2: Meiotic Maturation of Mouse Oocytes During Clinostat Rotation

    NASA Technical Reports Server (NTRS)

    Wolgemuth, D. J.; Grills, G. S.

    1985-01-01

    In order to understand the role of gravity in basic cellular processes that are important during development, the effects of a simulated microgravity environment on mammalian gametes and early embryos cultured in vitro are examined. A microgravity environment is simulated by use of a clinostat, which essentially reorients cells relative to the gravity vector. Initial studies have focused on assessing the effects of clinostat rotation on the meiotic progression of mouse oocytes. Modifications centered on providing the unique in vitro culture of the clinostat requirements of mammalian oocytes and embryos: 37 C temperature, constant humidity, and a 5% CO2 in air environment. The oocytes are observed under the dissecting microscope for polar body formation and gross morphological appearance. They are then processed for cytogenetic analysis.

  10. Mammalian sleep

    NASA Astrophysics Data System (ADS)

    Staunton, Hugh

    2005-05-01

    This review examines the biological background to the development of ideas on rapid eye movement sleep (REM sleep), so-called paradoxical sleep (PS), and its relation to dreaming. Aspects of the phenomenon which are discussed include physiological changes and their anatomical location, the effects of total and selective sleep deprivation in the human and animal, and REM sleep behavior disorder, the latter with its clinical manifestations in the human. Although dreaming also occurs in other sleep phases (non-REM or NREM sleep), in the human, there is a contingent relation between REM sleep and dreaming. Thus, REM is taken as a marker for dreaming and as REM is distributed ubiquitously throughout the mammalian class, it is suggested that other mammals also dream. It is suggested that the overall function of REM sleep/dreaming is more important than the content of the individual dream; its function is to place the dreamer protagonist/observer on the topographical world. This has importance for the developing infant who needs to develop a sense of self and separateness from the world which it requires to navigate and from which it is separated for long periods in sleep. Dreaming may also serve to maintain a sense of ‘I’ness or “self” in the adult, in whom a fragility of this faculty is revealed in neurological disorders.

  11. Phonological development in young bilinguals: clinical implications.

    PubMed

    Core, Cynthia; Scarpelli, Chiara

    2015-05-01

    This article reviews recent research on bilingual phonological development and describes the nature of bilingual phonology, focusing on characteristics of cross-linguistic influence on bilingual phonological abilities. There is evidence of positive and negative transfer (acceleration and deceleration) on children's phonological abilities. Several methodological issues limit the ability to generalize findings from previous research to larger groups of bilingual children (e.g., small sample size, lack of consideration of age of acquisition of each language, and language abilities of the participants). Sources of heterogeneity in language development are presented and discussed. Phonological abilities are related to language abilities in bilingual first language learners of English and Spanish. Empirical evidence from research in our laboratory supports this claim. We discuss implications of research findings and limitations for future research and clinical practice. We provide specific recommendations for bilingual research and for clinical assessment of young bilingual children.

  12. Genes and Conditions Controlling Mammalian Pre- and Post-implantation Embryo Development

    PubMed Central

    Anifandis, G.; Messini, C.I.; Dafopoulos, K.; Messinis, I.E.

    2015-01-01

    Embryo quality during the in vitro developmental period is of great clinical importance. Experimental genetic studies during this period have demonstrated the association between specific gene expression profiles and the production of healthy blastocysts. Although the quality of the oocyte may play a major role in embryo development, it has been well established that the post – fertilization period also has an important and crucial role in the determination of blastocyst quality. A variety of genes (such as OCT, SOX2, NANOG) and their related signaling pathways as well as transcription molecules (such as TGF-β, BMP) have been implicated in the pre- and post-implantation period. Furthermore, DNA methylation has been lately characterized as an epigenetic mark since it is one of the most important processes involved in the maintenance of genome stability. Physiological embryo development appears to depend upon the correct DNA methylation pattern. Due to the fact that soon after fertilization the zygote undergoes several morphogenetic and developmental events including activation of embryonic genome through the transition of the maternal genome, a diverse gene expression pattern may lead to clinically important conditions, such as apoptosis or the production of a chromosomically abnormal embryo. The present review focused on genes and their role during pre-implantation embryo development, giving emphasis on the various parameters that may alter gene expression or DNA methylation patterns. The pre-implantation embryos derived from in vitro culture systems (in vitro fertilization) and the possible effects on gene expression after the prolonged culture conditions are also discussed. PMID:25937812

  13. Recent advances in developing molecular tools for targeted genome engineering of mammalian cells.

    PubMed

    Lim, Kwang-il

    2015-01-01

    Various biological molecules naturally existing in diversified species including fungi, bacteria, and bacteriophage have functionalities for DNA binding and processing. The biological molecules have been recently actively engineered for use in customized genome editing of mammalian cells as the molecule-encoding DNA sequence information and the underlying mechanisms how the molecules work are unveiled. Excitingly, multiple novel methods based on the newly constructed artificial molecular tools have enabled modifications of specific endogenous genetic elements in the genome context at efficiencies that are much higher than that of the conventional homologous recombination based methods. This minireview introduces the most recently spotlighted molecular genome engineering tools with their key features and ongoing modifications for better performance. Such ongoing efforts have mainly focused on the removal of the inherent DNA sequence recognition rigidity from the original molecular platforms, the addition of newly tailored targeting functions into the engineered molecules, and the enhancement of their targeting specificity. Effective targeted genome engineering of mammalian cells will enable not only sophisticated genetic studies in the context of the genome, but also widely-applicable universal therapeutics based on the pinpointing and correction of the disease-causing genetic elements within the genome in the near future.

  14. Carbon dioxide starvation, the development of C4 ecosystems, and mammalian evolution.

    PubMed Central

    Cerling, T E; Ehleringer, J R; Harris, J M

    1998-01-01

    The decline of atmospheric CO2 over the last 65 million years (Ma) resulted in the 'CO2-starvation' of terrestrial ecosystems and led to the widespread distribution of C4 plants, which are less sensitive to CO2 levels than are C3 plants. Global expansion of C4 biomass is recorded in the diets of mammals from Asia, Africa, North America, and South America during the interval from about 8 to 5 Ma. This was accompanied by the most significant Cenozoic faunal turnover on each of these continents, indicating that ecological changes at this time were an important factor in mammalian extinction. Further expansion of tropical C4 biomass in Africa also occurred during the last glacial interval confirming the link between atmospheric CO2 levels and C4 biomass response. Changes in fauna and flora at the end of the Miocene, and between the last glacial and interglacial, have previously been attributed to changes in aridity; however, an alternative explanation for a global expansion of C4 biomass is CO2 starvation of C3 plants when atmospheric CO2 levels dropped below a threshold significant to C3 plants. Aridity may also have been a factor in the expansion of C4 ecosystems but one that was secondary to, and perhaps because of, gradually decreasing CO2 concentrations in the atmosphere. Mammalian evolution in the late Neogene, then, may be related to the CO2 starvation of C3 ecosystems. PMID:9507562

  15. Recent advances in developing molecular tools for targeted genome engineering of mammalian cells.

    PubMed

    Lim, Kwang-il

    2015-01-01

    Various biological molecules naturally existing in diversified species including fungi, bacteria, and bacteriophage have functionalities for DNA binding and processing. The biological molecules have been recently actively engineered for use in customized genome editing of mammalian cells as the molecule-encoding DNA sequence information and the underlying mechanisms how the molecules work are unveiled. Excitingly, multiple novel methods based on the newly constructed artificial molecular tools have enabled modifications of specific endogenous genetic elements in the genome context at efficiencies that are much higher than that of the conventional homologous recombination based methods. This minireview introduces the most recently spotlighted molecular genome engineering tools with their key features and ongoing modifications for better performance. Such ongoing efforts have mainly focused on the removal of the inherent DNA sequence recognition rigidity from the original molecular platforms, the addition of newly tailored targeting functions into the engineered molecules, and the enhancement of their targeting specificity. Effective targeted genome engineering of mammalian cells will enable not only sophisticated genetic studies in the context of the genome, but also widely-applicable universal therapeutics based on the pinpointing and correction of the disease-causing genetic elements within the genome in the near future. PMID:25104401

  16. Carbon dioxide starvation, the development of C4 ecosystems, and mammalian evolution.

    PubMed

    Cerling, T E; Ehleringer, J R; Harris, J M

    1998-01-29

    The decline of atmospheric CO2 over the last 65 million years (Ma) resulted in the 'CO2-starvation' of terrestrial ecosystems and led to the widespread distribution of C4 plants, which are less sensitive to CO2 levels than are C3 plants. Global expansion of C4 biomass is recorded in the diets of mammals from Asia, Africa, North America, and South America during the interval from about 8 to 5 Ma. This was accompanied by the most significant Cenozoic faunal turnover on each of these continents, indicating that ecological changes at this time were an important factor in mammalian extinction. Further expansion of tropical C4 biomass in Africa also occurred during the last glacial interval confirming the link between atmospheric CO2 levels and C4 biomass response. Changes in fauna and flora at the end of the Miocene, and between the last glacial and interglacial, have previously been attributed to changes in aridity; however, an alternative explanation for a global expansion of C4 biomass is CO2 starvation of C3 plants when atmospheric CO2 levels dropped below a threshold significant to C3 plants. Aridity may also have been a factor in the expansion of C4 ecosystems but one that was secondary to, and perhaps because of, gradually decreasing CO2 concentrations in the atmosphere. Mammalian evolution in the late Neogene, then, may be related to the CO2 starvation of C3 ecosystems. PMID:9507562

  17. Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development

    PubMed Central

    2011-01-01

    Background We present the genome sequence of the tammar wallaby, Macropus eugenii, which is a member of the kangaroo family and the first representative of the iconic hopping mammals that symbolize Australia to be sequenced. The tammar has many unusual biological characteristics, including the longest period of embryonic diapause of any mammal, extremely synchronized seasonal breeding and prolonged and sophisticated lactation within a well-defined pouch. Like other marsupials, it gives birth to highly altricial young, and has a small number of very large chromosomes, making it a valuable model for genomics, reproduction and development. Results The genome has been sequenced to 2 × coverage using Sanger sequencing, enhanced with additional next generation sequencing and the integration of extensive physical and linkage maps to build the genome assembly. We also sequenced the tammar transcriptome across many tissues and developmental time points. Our analyses of these data shed light on mammalian reproduction, development and genome evolution: there is innovation in reproductive and lactational genes, rapid evolution of germ cell genes, and incomplete, locus-specific X inactivation. We also observe novel retrotransposons and a highly rearranged major histocompatibility complex, with many class I genes located outside the complex. Novel microRNAs in the tammar HOX clusters uncover new potential mammalian HOX regulatory elements. Conclusions Analyses of these resources enhance our understanding of marsupial gene evolution, identify marsupial-specific conserved non-coding elements and critical genes across a range of biological systems, including reproduction, development and immunity, and provide new insight into marsupial and mammalian biology and genome evolution. PMID:21854559

  18. Molecular Analysis of Aedes aegypti Classical Protein Tyrosine Phosphatases Uncovers an Ortholog of Mammalian PTP-1B Implicated in the Control of Egg Production in Mosquitoes

    PubMed Central

    Moretti, Debora Monteiro; Ahuja, Lalima Gagan; Nunes, Rodrigo Dutra; Cudischevitch, Cecília Oliveira; Daumas-Filho, Carlos Renato Oliveira; Medeiros-Castro, Priscilla; Ventura-Martins, Guilherme; Jablonka, Willy; Gazos-Lopes, Felipe; Senna, Raquel; Sorgine, Marcos Henrique Ferreira; Hartfelder, Klaus; Capurro, Margareth; Atella, Georgia Correa; Mesquita, Rafael Dias; Silva-Neto, Mário Alberto Cardoso

    2014-01-01

    Background Protein Tyrosine Phosphatases (PTPs) are enzymes that catalyze phosphotyrosine dephosphorylation and modulate cell differentiation, growth and metabolism. In mammals, PTPs play a key role in the modulation of canonical pathways involved in metabolism and immunity. PTP1B is the prototype member of classical PTPs and a major target for treating human diseases, such as cancer, obesity and diabetes. These signaling enzymes are, hence, targets of a wide array of inhibitors. Anautogenous mosquitoes rely on blood meals to lay eggs and are vectors of the most prevalent human diseases. Identifying the mosquito ortholog of PTP1B and determining its involvement in egg production is, therefore, important in the search for a novel and crucial target for vector control. Methodology/Principal Findings We conducted an analysis to identify the ortholog of mammalian PTP1B in the Aedes aegypti genome. We identified eight genes coding for classical PTPs. In silico structural and functional analyses of proteins coded by such genes revealed that four of these code for catalytically active enzymes. Among the four genes coding for active PTPs, AAEL001919 exhibits the greatest degree of homology with the mammalian PTP1B. Next, we evaluated the role of this enzyme in egg formation. Blood feeding largely affects AAEL001919 expression, especially in the fat body and ovaries. These tissues are critically involved in the synthesis and storage of vitellogenin, the major yolk protein. Including the classical PTP inhibitor sodium orthovanadate or the PTP substrate DiFMUP in the blood meal decreased vitellogenin synthesis and egg production. Similarly, silencing AAEL001919 using RNA interference (RNAi) assays resulted in 30% suppression of egg production. Conclusions/Significance The data reported herein implicate, for the first time, a gene that codes for a classical PTP in mosquito egg formation. These findings raise the possibility that this class of enzymes may be used as novel

  19. Transcript Expression Analysis of Putative Trypanosoma brucei GPI-Anchored Surface Proteins during Development in the Tsetse and Mammalian Hosts

    PubMed Central

    Savage, Amy F.; Cerqueira, Gustavo C.; Regmi, Sandesh; Wu, Yineng; El Sayed, Najib M.; Aksoy, Serap

    2012-01-01

    Human African Trypanosomiasis is a devastating disease caused by the parasite Trypanosoma brucei. Trypanosomes live extracellularly in both the tsetse fly and the mammal. Trypanosome surface proteins can directly interact with the host environment, allowing parasites to effectively establish and maintain infections. Glycosylphosphatidylinositol (GPI) anchoring is a common posttranslational modification associated with eukaryotic surface proteins. In T. brucei, three GPI-anchored major surface proteins have been identified: variant surface glycoproteins (VSGs), procyclic acidic repetitive protein (PARP or procyclins), and brucei alanine rich proteins (BARP). The objective of this study was to select genes encoding predicted GPI-anchored proteins with unknown function(s) from the T. brucei genome and characterize the expression profile of a subset during cyclical development in the tsetse and mammalian hosts. An initial in silico screen of putative T. brucei proteins by Big PI algorithm identified 163 predicted GPI-anchored proteins, 106 of which had no known functions. Application of a second GPI-anchor prediction algorithm (FragAnchor), signal peptide and trans-membrane domain prediction software resulted in the identification of 25 putative hypothetical proteins. Eighty-one gene products with hypothetical functions were analyzed for stage-regulated expression using semi-quantitative RT-PCR. The expression of most of these genes were found to be upregulated in trypanosomes infecting tsetse salivary gland and proventriculus tissues, and 38% were specifically expressed only by parasites infecting salivary gland tissues. Transcripts for all of the genes specifically expressed in salivary glands were also detected in mammalian infective metacyclic trypomastigotes, suggesting a possible role for these putative proteins in invasion and/or establishment processes in the mammalian host. These results represent the first large-scale report of the differential expression of

  20. Developing a de novo targeted knock-in method based on in utero electroporation into the mammalian brain.

    PubMed

    Tsunekawa, Yuji; Terhune, Raymond Kunikane; Fujita, Ikumi; Shitamukai, Atsunori; Suetsugu, Taeko; Matsuzaki, Fumio

    2016-09-01

    Genome-editing technology has revolutionized the field of biology. Here, we report a novel de novo gene-targeting method mediated by in utero electroporation into the developing mammalian brain. Electroporation of donor DNA with the CRISPR/Cas9 system vectors successfully leads to knock-in of the donor sequence, such as EGFP, to the target site via the homology-directed repair mechanism. We developed a targeting vector system optimized to prevent anomalous leaky expression of the donor gene from the plasmid, which otherwise often occurs depending on the donor sequence. The knock-in efficiency of the electroporated progenitors reached up to 40% in the early stage and 20% in the late stage of the developing mouse brain. Furthermore, we inserted different fluorescent markers into the target gene in each homologous chromosome, successfully distinguishing homozygous knock-in cells by color. We also applied this de novo gene targeting to the ferret model for the study of complex mammalian brains. Our results demonstrate that this technique is widely applicable for monitoring gene expression, visualizing protein localization, lineage analysis and gene knockout, all at the single-cell level, in developmental tissues. PMID:27578183

  1. Developing a de novo targeted knock-in method based on in utero electroporation into the mammalian brain

    PubMed Central

    Tsunekawa, Yuji; Terhune, Raymond Kunikane; Fujita, Ikumi; Shitamukai, Atsunori; Suetsugu, Taeko

    2016-01-01

    Genome-editing technology has revolutionized the field of biology. Here, we report a novel de novo gene-targeting method mediated by in utero electroporation into the developing mammalian brain. Electroporation of donor DNA with the CRISPR/Cas9 system vectors successfully leads to knock-in of the donor sequence, such as EGFP, to the target site via the homology-directed repair mechanism. We developed a targeting vector system optimized to prevent anomalous leaky expression of the donor gene from the plasmid, which otherwise often occurs depending on the donor sequence. The knock-in efficiency of the electroporated progenitors reached up to 40% in the early stage and 20% in the late stage of the developing mouse brain. Furthermore, we inserted different fluorescent markers into the target gene in each homologous chromosome, successfully distinguishing homozygous knock-in cells by color. We also applied this de novo gene targeting to the ferret model for the study of complex mammalian brains. Our results demonstrate that this technique is widely applicable for monitoring gene expression, visualizing protein localization, lineage analysis and gene knockout, all at the single-cell level, in developmental tissues. PMID:27578183

  2. Enzymatic Removal of Ribonucleotides from DNA Is Essential for Mammalian Genome Integrity and Development

    PubMed Central

    Reijns, Martin A.M.; Rabe, Björn; Rigby, Rachel E.; Mill, Pleasantine; Astell, Katy R.; Lettice, Laura A.; Boyle, Shelagh; Leitch, Andrea; Keighren, Margaret; Kilanowski, Fiona; Devenney, Paul S.; Sexton, David; Grimes, Graeme; Holt, Ian J.; Hill, Robert E.; Taylor, Martin S.; Lawson, Kirstie A.; Dorin, Julia R.; Jackson, Andrew P.

    2012-01-01

    Summary The presence of ribonucleotides in genomic DNA is undesirable given their increased susceptibility to hydrolysis. Ribonuclease (RNase) H enzymes that recognize and process such embedded ribonucleotides are present in all domains of life. However, in unicellular organisms such as budding yeast, they are not required for viability or even efficient cellular proliferation, while in humans, RNase H2 hypomorphic mutations cause the neuroinflammatory disorder Aicardi-Goutières syndrome. Here, we report that RNase H2 is an essential enzyme in mice, required for embryonic growth from gastrulation onward. RNase H2 null embryos accumulate large numbers of single (or di-) ribonucleotides embedded in their genomic DNA (>1,000,000 per cell), resulting in genome instability and a p53-dependent DNA-damage response. Our findings establish RNase H2 as a key mammalian genome surveillance enzyme required for ribonucleotide removal and demonstrate that ribonucleotides are the most commonly occurring endogenous nucleotide base lesion in replicating cells. PMID:22579044

  3. Early mammalian development under conditions of reorientation relative to the gravity vector

    NASA Technical Reports Server (NTRS)

    Wolgemuth, D. J.; Grills, G. S.

    1985-01-01

    A clinostat was used to assess the effects of reorientation relative to the gravity vector on mammalian germ cells cultured in vitro. Previous studies using this system revealed an inhibition of meiotic maturation of mouse oocytes. In the present study, the effects of clinostat rotation on in vitro fertilization were examined. The frequency of fertilization of experimental cultures did not vary from that of the clinostat vertical control cultures at either of the rotation rates examined. Importantly, no abnormalities of fertilization, such as parthenogenetic activation, fragmentation, or polyspermy were seen. It is concluded that the initial events of fertilization were unaffected by this treatment, although the developmental potential of these embryos remains to be assessed.

  4. Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function.

    PubMed

    Garza-Lombó, Carla; Gonsebatt, María E

    2016-01-01

    The kinase mammalian target of rapamycin (mTOR) integrates signals triggered by energy, stress, oxygen levels, and growth factors. It regulates ribosome biogenesis, mRNA translation, nutrient metabolism, and autophagy. mTOR participates in various functions of the brain, such as synaptic plasticity, adult neurogenesis, memory, and learning. mTOR is present during early neural development and participates in axon and dendrite development, neuron differentiation, and gliogenesis, among other processes. Furthermore, mTOR has been shown to modulate lifespan in multiple organisms. This protein is an important energy sensor that is present throughout our lifetime its role must be precisely described in order to develop therapeutic strategies and prevent diseases of the central nervous system. The aim of this review is to present our current understanding of the functions of mTOR in neural development, the adult brain and aging. PMID:27378854

  5. Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function

    PubMed Central

    Garza-Lombó, Carla; Gonsebatt, María E.

    2016-01-01

    The kinase mammalian target of rapamycin (mTOR) integrates signals triggered by energy, stress, oxygen levels, and growth factors. It regulates ribosome biogenesis, mRNA translation, nutrient metabolism, and autophagy. mTOR participates in various functions of the brain, such as synaptic plasticity, adult neurogenesis, memory, and learning. mTOR is present during early neural development and participates in axon and dendrite development, neuron differentiation, and gliogenesis, among other processes. Furthermore, mTOR has been shown to modulate lifespan in multiple organisms. This protein is an important energy sensor that is present throughout our lifetime its role must be precisely described in order to develop therapeutic strategies and prevent diseases of the central nervous system. The aim of this review is to present our current understanding of the functions of mTOR in neural development, the adult brain and aging. PMID:27378854

  6. Mammalian PNLDC1 is a novel poly(A) specific exonuclease with discrete expression during early development

    PubMed Central

    Anastasakis, Dimitrios; Skeparnias, Ilias; Shaukat, Athanasios-Nasir; Grafanaki, Katerina; Kanellou, Alexandra; Taraviras, Stavros; Papachristou, Dionysios J.; Papakyriakou, Athanasios; Stathopoulos, Constantinos

    2016-01-01

    PNLDC1 is a homologue of poly(A) specific ribonuclease (PARN), a known deadenylase with additional role in processing of non-coding RNAs. Both enzymes were reported recently to participate in piRNA biogenesis in silkworm and C. elegans, respectively. To get insights on the role of mammalian PNLDC1, we characterized the human and mouse enzymes. PNLDC1 shows limited conservation compared to PARN and represents an evolutionary related but distinct group of enzymes. It is expressed specifically in mouse embryonic stem cells, human and mouse testes and during early mouse embryo development, while it fades during differentiation. Its expression in differentiated cells, is suppressed through methylation of its promoter by the de novo methyltransferase DNMT3B. Both enzymes are localized mainly in the ER and exhibit in vitro specificity restricted solely to 3′ RNA or DNA polyadenylates. Knockdown of Pnldc1 in mESCs and subsequent NGS analysis showed that although the expression of the remaining deadenylases remains unaffected, it affects genes involved mainly in reprogramming, cell cycle and translational regulation. Mammalian PNLDC1 is a novel deadenylase expressed specifically in cell types which share regulatory mechanisms required for multipotency maintenance. Moreover, it could be involved both in posttranscriptional regulation through deadenylation and genome surveillance during early development. PMID:27515512

  7. Differential localization of SNARE complex proteins SNAP-25, syntaxin, and VAMP during development of the mammalian retina.

    PubMed

    Greenlee, M H; Roosevelt, C B; Sakaguchi, D S

    2001-02-12

    SNARE complex proteins have critical functions during regulated vesicular release of neurotransmitter. In addition, they play critical roles during neurite outgrowth and synaptogenesis. Although it is clear that the function of any one SNARE complex protein during release of neurotransmitter is dependent on its association with other members of the complex, it is less certain whether their function during development and differentiation is dependent on interaction with one another. Previously, we have observed transient high levels of SNARE complex protein SNAP-25 in developing cholinergic amacrine cells (West Greenlee et al. [1998] J Comp Neurol 394:374-385). In addition, we detected, high levels of SNAP-25 in developing and mature photoreceptors. To better understand the functional significance of these high levels of SNAP-25 expression, we used immunocytochemistry to examine the developmental expression of the three members of the SNARE complex, SNAP-25, Syntaxin, and vesicle associated membrane protein (VAMP/also Synaptobrevin). Our results demonstrate that the high levels of SNAP-25 in cholinergic amacrine cells and photoreceptors are not accompanied by the same relatively high levels of other SNARE complex proteins. These results suggest that high levels of SNAP-25 in specific cell types may function independently of association with Syntaxin and VAMP. In this analysis, we characterized the changing patterns of immunoreactivity for the three SNARE complex proteins during the development and differentiation of the mammalian retina. We have compared the pattern of expression of the core SNARE complex proteins in the Brazilian opossum, Monodelphis domestica, and in the rat and found common patterns of expression between these diverse mammalian species. We observed temporal differences in the onset of immunoreactivity between these three proteins, and differences in their localization within synaptic layers in the developing and mature mammalian retina. This

  8. The gyrification of mammalian cerebral cortex: quantitative evidence of anisomorphic surface expansion during phylogenetic and ontogenetic development.

    PubMed Central

    Mayhew, T M; Mwamengele, G L; Dantzer, V; Williams, S

    1996-01-01

    Describing the shapes of 3D objects has proved to be as problematical in biology as in other areas. In an attempt to tackle this problem, established stereological methods (the Cavalieri principle and vertical sectioning) have been used to estimate a 3D shape-dependent quantity which can detect anisomorphic changes and is related to the degree of cortical convolution or gyrification. This isomophy factor is employed to assess phylogenetic and ontogenetic changes in the mammalian cerebral cortex. Gross anatomical differences between cerebral hemispheres of adult domestic mammals (horses, oxen, pigs, goats, dogs, cats and rabbits) were tested by paying attention to species, laterality and sex differences. Human fetal brains were also studied. Mean body weights of domestic mammals varied from 4 kg to 460 kg and brain weights from 10 g to 636 g. Fetuses weighed 39-610 g (crown-rump lengths 85-185 mm) and brain volumes were 4-56 cm3. Isomorphy factors were derived from estimates of hemisphere volumes and cortical surface areas. Hemisphere shape varied between species but no lateral or sex differences were detected. It is concluded that these mammalian brains are, in terms of their gross anatomy, symmetric and not sexually dimorphic. Fetal brains became more convoluted during uterine development. The isomorphy factor offers a convenient measure of gyrification which demonstrates that brains become more convoluted as they enlarge. PMID:8655415

  9. The inverted neurogenetic gradient of the mammalian isocortex: development and evolution.

    PubMed

    Aboitiz, F; Morales, D; Montiel, J

    2001-12-01

    In this paper we review recent evidence on the molecular control of cell migration in the isocortex, and present an hypothesis for the evolutionary origin of the inside-out neurogenetic gradient of this structure. We suggest that there are at least two key factors involved in the acquisition of the inside-out gradient: (i) the expression of the protein reelin, which arrests the migration of cortical plate cells by detaching them from the radial glial fiber. This permits younger neurons to use the same fiber to migrate past the previous neurons; and (ii) the second factor is an intracellular signaling pathway dependent on a cyclin-dependent protein kinase (Cdk5). Cdk5 may work by inhibiting N-cadherin mediated cell aggregation as young cells cross the cortical plate, permitting them to move to the more superficial layers. Interestingly, the mutation in Cdk5 affects the migration of only those cells belonging to superficial layers, which are considered to be an evolutionary acquisition of the mammalian isocortex.

  10. Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin.

    PubMed

    Saito, Kota; Araki, Yasuhiro; Kontani, Kenji; Nishina, Hiroshi; Katada, Toshiaki

    2005-03-01

    The Ras-homologous GTPase Rheb that is conserved from yeast to human appears to be involved not only in cell growth but also in nutrient uptake. Recent biochemical analysis revealed that tuberous sclerosis complex (TSC), a GTPase-activating protein (GAP), deactivates Rheb and that phosphatidylinositol 3'-kinase (PI3k)-Akt/PKB kinase pathway activates Rheb through inhibition of the GAP-mediated deactivation. Although mammalian target of rapamycin (mTOR) kinase is implicated in the downstream target of Rheb, the direct effector(s) and exact functions of Rheb have not been fully elucidated. Here we identified that Rheb expression in cultured cells induces the formation of large cytoplasmic vacuoles, which are characterized as late endocytic (late endosome- and lysosome-like) components. The vacuole formation required the GTP form of Rheb, but not the activation of the downstream mTOR kinase. These results suggest that Rheb regulates endocytic trafficking pathway independent of the previously identified mTOR pathway. The physiological roles of the two Rheb-dependent signaling pathways are discussed in terms of nutrient uptake and cell growth or cell cycle progression. PMID:15809346

  11. Cortactin is implicated in murine zygotic development

    PubMed Central

    Yu, Dan; Zhang, Helin; Blanpied, Thomas A.; Smith, Elizabeth; Zhan, Xi

    2009-01-01

    Cortactin is a cortex-enriched protein implicated in Arp2/3 complex-mediated actin polymerization. However, the physiological role of cortactin remains unknown. We have generated a mouse strain in which the allele of murine cortactin was disrupted by a gene trapping vector. The resulting heterozygous mice developed normally and were fertile, but embryonic fibroblasts derived from heterozygous animals displayed partial impairment in PDGF-induced membrane ruffling. No homozygous offspring or early embryos even at the two-cell stage were detected. Analysis of oocytes revealed a gradual decrease in the detection of homozygous zygotes after fertilization. In normal oocytes arrested at meiotic metaphase II (MII), cortactin immunoreactivity was detected in an apical layer that overlies the maternal chromosome and overlaps with a polarized cortex enriched with actin. The formation of the polarized cortactin layer was diminished upon treatment with latrunculin B, an actin polymerization inhibitor. After resumption of meiosis II, the majority of cortactin protein was accumulated into the second polar body. Microinjection of MII-arrested eggs with either cortactin antibody or RNA encoding a cortactin mutant deficient in Arp2/3 complex binding disrupted the integrity of the actin cap and inhibited emission of the second polar body triggered by parthenogenesis. Our data suggest that cortactin plays an important role in the mechanics of asymmetric division in oocytes. PMID:20004659

  12. Environmental, ecological, and paleoanthropological implications of the late Pleistocene mammalian fauna from Equus Cave, northern Cape Province, South Africa

    NASA Astrophysics Data System (ADS)

    Klein, Richard G.; Cruz-Uribe, Kathryn; Beaumont, Peter B.

    1991-07-01

    The late Pleistocene deposits of Equus Cave, northern Cape Province, South Africa, have provided more than 30,000 taxonomically identifiable mammal bones from 48 species. Context, associations, and features of the bone assemblage implicate brown hyenas as the main accumulators. The fauna is significant mainly because (1) it supplements previous evidence that regional climate was cooler and possibly also somewhat moister during part(s) of the late Pleistocene, but deviated less from the historic norm than in areas farther south; (2) it shows that Bond's springbok, which became extinct in the early Holocene, differed from the surviving common springbok not only in important morphological respects but also in reproductive pattern; and (3) it sustains earlier suggestions that an abundance of carnivores, a paucity of small hard bones, and increase in the cranial/postcranial ratio with species size, and exclusively attritional mortality profiles are features that tend to differentiate assemblages accumulated by brown hyenas from those accumulated by people. In addition, pending firmer dating, the fragmentary human fossils from Equus Cave may support an exclusively African origin for anatomically modern humans.

  13. Mammalian Pheromones

    PubMed Central

    Liberles, Stephen D.

    2015-01-01

    Mammalian pheromones control a myriad of innate social behaviors and acutely regulate hormone levels. Responses to pheromones are highly robust, reproducible, and stereotyped and likely involve developmentally predetermined neural circuits. Here, I review several facets of pheromone transduction in mammals, including (a) chemosensory receptors and signaling components of the main olfactory epithelium and vomeronasal organ involved in pheromone detection; (b) pheromone-activated neural circuits subject to sex-specific and state-dependent modulation; and (c) the striking chemical diversity of mammalian pheromones, which range from small, volatile molecules and sulfated steroids to large families of proteins. Finally, I review (d ) molecular mechanisms underlying various behavioral and endocrine responses, including modulation of puberty and estrous; control of reproduction, aggression, suckling, and parental behaviors; individual recognition; and distinguishing of own species from predators, competitors, and prey. Deconstruction of pheromone transduction mechanisms provides a critical foundation for understanding how odor response pathways generate instinctive behaviors. PMID:23988175

  14. Transnational Education: Current Developments and Policy Implications

    ERIC Educational Resources Information Center

    Gu, Jianxin

    2009-01-01

    Ever since the transnational education trend took off since the 1980s, transnational education has come to bearing political, economic and cultural implications. Different approaches have been formulated to achieve specific policy objectives by both importing and exporting countries. Such approaches demonstrate a four dimensional composition,…

  15. Women at Midlife: Implications for Theories of Women's Adult Development.

    ERIC Educational Resources Information Center

    Lippert, Laurel

    1997-01-01

    Discusses research on midlife transitions in women and its implications for theories of women's adult development. Presents findings on menopause, the postparental period, and the roles of women at midlife. Offers several theoretical approaches in light of research findings and makes recommendations for future research. Suggests implications for…

  16. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development.

    PubMed

    Khodiyar, Varsha K; Howe, Doug; Talmud, Philippa J; Breckenridge, Ross; Lovering, Ruth C

    2013-01-01

    For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer's vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer's vesicle determine asymmetry in the developing heart, the direction of 'heart jogging' and the direction of 'heart looping'.  'Heart jogging' is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward 'jog'. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development.    We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging.  We found that the human, mouse and zebrafish 'heart jogging orthologs' are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging.    This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach.

  17. Development of transgenic animals for optogenetic manipulation of mammalian nervous system function: Progress and prospects for behavioral neuroscience

    PubMed Central

    Ting, Jonathan T.; Feng, Guoping

    2014-01-01

    Here we review the rapidly growing toolbox of transgenic mice and rats that exhibit functional expression of engineered opsins for neuronal activation and silencing with light. Collectively, these transgenic animals are enabling neuroscientists to access and manipulate the many diverse cell types in the mammalian nervous system in order to probe synaptic and circuitry connectivity, function, and dysfunction. The availability of transgenic lines affords important advantages such as stable and heritable transgene expression patterns across experimental cohorts. As such, the use of transgenic lines precludes the need for other costly and labor-intensive procedures to achieve functional transgene expression in each individual experimental animal. This represents an important consideration when large cohorts of experimental animals are desirable as in many common behavioral assays. We describe the diverse strategies that have been implemented for developing transgenic mouse and rat lines and highlight recent advances that have led to dramatic improvements in achieving functional transgene expression of engineered opsins. Furthermore, we discuss considerations and caveats associated with implementing recently developed transgenic lines for optogenetics-based experimentation. Lastly, we propose strategies that can be implemented to develop and refine the next generation of genetically modified animals for behaviorally-focused optogenetics-based applications. PMID:23473879

  18. The Niche Factor Syndecan-1 Regulates the Maintenance and Proliferation of Neural Progenitor Cells during Mammalian Cortical Development

    PubMed Central

    Wang, Qingjie; Yang, Landi; Alexander, Caroline; Temple, Sally

    2012-01-01

    Neural progenitor cells (NPCs) divide and differentiate in a precisely regulated manner over time to achieve the remarkable expansion and assembly of the layered mammalian cerebral cortex. Both intrinsic signaling pathways and environmental factors control the behavior of NPCs during cortical development. Heparan sulphate proteoglycans (HSPG) are critical environmental regulators that help modulate and integrate environmental cues and downstream intracellular signals. Syndecan-1 (Sdc1), a major transmembrane HSPG, is highly enriched in the early neural germinal zone, but its function in modulating NPC behavior and cortical development has not been explored. In this study we investigate the expression pattern and function of Sdc1 in the developing mouse cerebral cortex. We found that Sdc1 is highly expressed by cortical NPCs. Knockdown of Sdc1 in vivo by in utero electroporation reduces NPC proliferation and causes their premature differentiation, corroborated in isolated cells in vitro. We found that Sdc1 knockdown leads to reduced levels of β-catenin, indicating reduced canonical Wnt signaling. Consistent with this, GSK3β inhibition helps rescue the Sdc1 knockdown phenotype, partially restoring NPC number and proliferation. Moreover, exogenous Wnt protein promotes cortical NPC proliferation, but this is prevented by Sdc1 knockdown. Thus, Sdc1 in the germinal niche is a key HSPG regulating the maintenance and proliferation of NPCs during cortical neurogenesis, in part by modulating the ability of NPCs to respond to Wnt ligands. PMID:22936997

  19. Development of a UHPLC-MS/MS method for the determination of plasma histamine in various mammalian species.

    PubMed

    Liu, Jia; Wang, Lei; Hu, Wenjuan; Chen, Xiaoyan; Zhong, Dafang

    2014-11-15

    Histamine is an important mediator of anaphylactic reactions. Although several methods have been developed to measure histamine levels, each has its limitations. In this study, we developed and validated a convenient bioanalytical method for the qualitative and quantitative determination of histamine in plasma samples from humans, beagle dogs, Sprague-Dawley rats, and imprinting control region mice. A simple plasma protein precipitation method using acetonitrile was selected, and hydrophilic interaction liquid chromatography coupled with mass spectrometry was used for sample separation and detection. Histamine was subjected to gradient elution with acetonitrile, ammonium acetate buffer, and formic acid. A mass spectrometer equipped with an electrospray ionization source was operated in the positive-ion multiple reaction monitoring mode for the detection of histamine and the internal standard. The [M+H](+) transitions were m/z 112→95 for histamine and m/z 116→99 for d4-histamine, which was used as the internal standard. The lower limit of quantification was 0.2μg/L and the calibration range was 0.2-500μg/L. The overall recovery ranged from 93.6% to 102.8%. The intra- and inter-run precision and accuracy were <15% for plasma samples from all four species. The method was validated by measuring the plasma histamine concentrations in five healthy human volunteers. In conclusion, we have developed and validated a novel bioanalytical method for the quantification of histamine levels in plasma samples from various mammalian species.

  20. Activins and inhibins in mammalian testis development: new models, new insights.

    PubMed

    Barakat, B; Itman, C; Mendis, S H; Loveland, K L

    2012-08-15

    The discovery of activin and inhibins as modulators of the hypothalamic-pituitary-gonadal axis has set the foundation for understanding their central importance to many facets of development and disease. This review contains an overview of the processes and cell types that are central to testis development and spermatogenesis and then provides an update focussed on information gathered over the past five years to address new concepts about how these proteins function to control testis development in fetal and juvenile life. Current knowledge about the interactive nature of the transforming growth factor-β (TGFβ) superfamily signalling network is applied to recent findings about activins and inhibins in the testis. Information about the regulated synthesis of signalling components and signalling regulators in the testis is integrated with new concepts that demonstrate their functional significance. The importance of activin bioactivity levels or dosage in controlling balanced growth of spermatogonial cells and their niche at different stages of testis development is highlighted.

  1. Timing of mammalian peripheral trigeminal system development relative to body size: A comparison of metatherians with rodents and monotremes.

    PubMed

    Ashwell, Ken W S

    2015-01-01

    Specializations of the trigeminal sensory system are present in all three infraclasses of mammals (metatheria, eutheria, prototheria or monotremata). The trigeminal sensory system has been suggested as a critically important modality for sampling the path to the pouch and detecting the nipple or milk patch, but the degree to which that system may be required to function at birth varies significantly. Archived sections of the snout and brainstem of embryonic and postnatal mammals were used to test the relationship between structural maturity of the two ends of the trigeminal nerve pathway and the body size of mammalian young in metatherians, rodents and monotremes. A system for staging different levels of structural maturity of the vibrissae and trigeminal sensory was applied to embryos, pouch young and hatchlings and correlated with body length. Dasyurids are born at the most immature state with respect to vibrissal and trigeminal sensory nucleus development of any available metatherian, but these components of the trigeminal system are also developmentally advanced relative to body size when dasyurids are compared to other metatherians. Vibrissal and trigeminal sensory nucleus development is at a similar stage of development at birth and for a given body size in non-dasyurid metatherians; and trigeminal sensory nucleus development in monotremes is at a similar stage at birth to metatherians. Rodents reach a far more advanced stage of vibrissal and trigeminal sensory nucleus development at birth than do metatherians, and in the case of the mouse have a more developmentally advanced trigeminal system than all available metatherians at any given body length. Precocious development of the trigeminal sensory pathway relative to body size is evident in dasyurids, as might be expected given the small birth size of those metatherians. Nevertheless, the trigeminal sensory system in metatherians in general is not precocious relative to body size when these species are

  2. Timing of mammalian peripheral trigeminal system development relative to body size: A comparison of metatherians with rodents and monotremes.

    PubMed

    Ashwell, Ken W S

    2015-01-01

    Specializations of the trigeminal sensory system are present in all three infraclasses of mammals (metatheria, eutheria, prototheria or monotremata). The trigeminal sensory system has been suggested as a critically important modality for sampling the path to the pouch and detecting the nipple or milk patch, but the degree to which that system may be required to function at birth varies significantly. Archived sections of the snout and brainstem of embryonic and postnatal mammals were used to test the relationship between structural maturity of the two ends of the trigeminal nerve pathway and the body size of mammalian young in metatherians, rodents and monotremes. A system for staging different levels of structural maturity of the vibrissae and trigeminal sensory was applied to embryos, pouch young and hatchlings and correlated with body length. Dasyurids are born at the most immature state with respect to vibrissal and trigeminal sensory nucleus development of any available metatherian, but these components of the trigeminal system are also developmentally advanced relative to body size when dasyurids are compared to other metatherians. Vibrissal and trigeminal sensory nucleus development is at a similar stage of development at birth and for a given body size in non-dasyurid metatherians; and trigeminal sensory nucleus development in monotremes is at a similar stage at birth to metatherians. Rodents reach a far more advanced stage of vibrissal and trigeminal sensory nucleus development at birth than do metatherians, and in the case of the mouse have a more developmentally advanced trigeminal system than all available metatherians at any given body length. Precocious development of the trigeminal sensory pathway relative to body size is evident in dasyurids, as might be expected given the small birth size of those metatherians. Nevertheless, the trigeminal sensory system in metatherians in general is not precocious relative to body size when these species are

  3. PROTEOMICS OF MINUTE AMOUNTS OF TISSUE SAMPLE IN AQUATIC SPECIES: APPLICATION TO DEVELOPMENT OF NON-MAMMALIAN SCREENING ASSAYS FOR ENDOCRINE DISRUPTERS

    EPA Science Inventory

    When combined with other biochemical/toxicology assays, this type of information will contribute to the classification of chemicals based upon their effects at different levels of biological organization, and to the development of a cost-effective, non-mammalian screening assay f...

  4. The biology of mammalian parenting and its effect on offspring social development

    PubMed Central

    Rilling, James K.; Young, Larry J.

    2015-01-01

    Parents know the transformative nature of having and caring for a child. Among many mammals, giving birth leads from an aversion to infant stimuli to irresistible attraction. Here, we review the biological mechanisms governing this shift in parental motivation in mammals. Estrogen and progesterone prepare the uterus for embryo implantation and placental development. Prolactin stimulates milk production, whereas oxytocin initiates labor and triggers milk ejection during nursing. These same molecules, interacting with dopamine, also activate specific neural pathways to motivate parents to nurture, bond with, and protect their offspring. Parenting in turn shapes the neural development of the infant social brain. Recent work suggests that many of the principles governing parental behavior and its effect on infant development are conserved from rodent to humans. PMID:25124431

  5. Gravity in mammalian organ development: differentiation of cultured lung and pancreas rudiments during spaceflight

    NASA Technical Reports Server (NTRS)

    Spooner, B. S.; Hardman, P.; Paulsen, A.

    1994-01-01

    Organ culture of embryonic mouse lung and pancreas rudiments has been used to investigate development and differentiation, and to assess the effects of microgravity on culture differentiation, during orbital spaceflight of the shuttle Endeavour (mission STS-54). Lung rudiments continue to grow and branch during spaceflight, an initial result that should allow future detailed study of lung morphogenesis in microgravity. Cultured embryonic pancreas undergoes characteristic exocrine acinar tissue and endocrine islet tissue differentiation during spaceflight, and in ground controls. The rudiments developing in the microgravity environment of spaceflight appear to grow larger than their ground counterparts, and they may have differentiated more rapidly than controls, as judged by exocrine zymogen granule presence.

  6. Importance of the pluripotency factor LIN28 in the mammalian nucleolus during early embryonic development

    PubMed Central

    Vogt, Edgar J.; Meglicki, Maciej; Hartung, Kristina Ilka; Borsuk, Ewa; Behr, Rüdiger

    2012-01-01

    The maternal nucleolus is required for proper activation of the embryonic genome (EGA) and early embryonic development. Nucleologenesis is characterized by the transformation of a nucleolar precursor body (NPB) to a mature nucleolus during preimplantation development. However, the function of NPBs and the involved molecular factors are unknown. We uncover a novel role for the pluripotency factor LIN28, the biological significance of which was previously demonstrated in the reprogramming of human somatic cells to induced pluripotent stem (iPS) cells. Here, we show that LIN28 accumulates at the NPB and the mature nucleolus in mouse preimplantation embryos and embryonic stem cells (ESCs), where it colocalizes with the nucleolar marker B23 (nucleophosmin 1). LIN28 has nucleolar localization in non-human primate (NHP) preimplantation embryos, but is cytoplasmic in NHP ESCs. Lin28 transcripts show a striking decline before mouse EGA, whereas LIN28 protein localizes to NPBs at the time of EGA. Following knockdown with a Lin28 morpholino, the majority of embryos arrest between the 2- and 4-cell stages and never develop to morula or blastocyst. Lin28 morpholino-injected embryos arrested at the 2-cell stage were not enriched with nucleophosmin at presumptive NPB sites, indicating that functional NPBs were not assembled. Based on these results, we propose that LIN28 is an essential factor of nucleologenesis during early embryonic development. PMID:23172912

  7. Importance of the pluripotency factor LIN28 in the mammalian nucleolus during early embryonic development.

    PubMed

    Vogt, Edgar J; Meglicki, Maciej; Hartung, Kristina Ilka; Borsuk, Ewa; Behr, Rüdiger

    2012-12-01

    The maternal nucleolus is required for proper activation of the embryonic genome (EGA) and early embryonic development. Nucleologenesis is characterized by the transformation of a nucleolar precursor body (NPB) to a mature nucleolus during preimplantation development. However, the function of NPBs and the involved molecular factors are unknown. We uncover a novel role for the pluripotency factor LIN28, the biological significance of which was previously demonstrated in the reprogramming of human somatic cells to induced pluripotent stem (iPS) cells. Here, we show that LIN28 accumulates at the NPB and the mature nucleolus in mouse preimplantation embryos and embryonic stem cells (ESCs), where it colocalizes with the nucleolar marker B23 (nucleophosmin 1). LIN28 has nucleolar localization in non-human primate (NHP) preimplantation embryos, but is cytoplasmic in NHP ESCs. Lin28 transcripts show a striking decline before mouse EGA, whereas LIN28 protein localizes to NPBs at the time of EGA. Following knockdown with a Lin28 morpholino, the majority of embryos arrest between the 2- and 4-cell stages and never develop to morula or blastocyst. Lin28 morpholino-injected embryos arrested at the 2-cell stage were not enriched with nucleophosmin at presumptive NPB sites, indicating that functional NPBs were not assembled. Based on these results, we propose that LIN28 is an essential factor of nucleologenesis during early embryonic development.

  8. A Mammalian Cell Based FACS-Panning Platform for the Selection of HIV-1 Envelopes for Vaccine Development

    PubMed Central

    Bruun, Tim-Henrik; Mühlbauer, Katharina; Benen, Thomas; Kliche, Alexander; Wagner, Ralf

    2014-01-01

    An increasing number of broadly neutralizing monoclonal antibodies (bnMAb) against the HIV-1 envelope (Env) protein has been discovered recently. Despite this progress, vaccination efforts with the aim to re-elicit bnMAbs that provide protective immunity have failed so far. Herein, we describe the development of a mammalian cell based FACS-panning method in which bnMAbs are used as tools to select surface-exposed envelope variants according to their binding affinity. For that purpose, an HIV-1 derived lentiviral vector was developed to infect HEK293T cells at low multiplicity of infection (MOI) in order to link Env phenotype and genotype. For proof of principle, a gp145 Env model-library was established in which the complete V3 domain was substituted by five strain specific V3 loop sequences with known binding affinities to nMAb 447-52D, respectively. Env genes were recovered from selected cells by PCR, subcloned into a lentiviral vector (i) to determine and quantify the enrichment nMAb binders and (ii) to generate a new batch of transduction competent particles. After 2 selection cycles the Env variant with highest affinity was enriched 20-fold and represented 80% of the remaining Env population. Exploiting the recently described bnMAbs, this procedure might prove useful in selecting Env proteins from large Env libraries with the potential to elicit bnMAbs when used as vaccine candidates. PMID:25279768

  9. Dynamic transcriptional symmetry-breaking in pre-implantation mammalian embryo development revealed by single-cell RNA-seq.

    PubMed

    Shi, Junchao; Chen, Qi; Li, Xin; Zheng, Xiudeng; Zhang, Ying; Qiao, Jie; Tang, Fuchou; Tao, Yi; Zhou, Qi; Duan, Enkui

    2015-10-15

    During mammalian pre-implantation embryo development, when the first asymmetry emerges and how it develops to direct distinct cell fates remain longstanding questions. Here, by analyzing single-blastomere transcriptome data from mouse and human pre-implantation embryos, we revealed that the initial blastomere-to-blastomere biases emerge as early as the first embryonic cleavage division, following a binomial distribution pattern. The subsequent zygotic transcriptional activation further elevated overall blastomere-to-blastomere biases during the two- to 16-cell embryo stages. The trends of transcriptional asymmetry fell into two distinct patterns: for some genes, the extent of asymmetry was minimized between blastomeres (monostable pattern), whereas other genes, including those known to be lineage specifiers, showed ever-increasing asymmetry between blastomeres (bistable pattern), supposedly controlled by negative or positive feedbacks. Moreover, our analysis supports a scenario in which opposing lineage specifiers within an early blastomere constantly compete with each other based on their relative ratio, forming an inclined 'lineage strength' that pushes the blastomere onto a predisposed, yet flexible, lineage track before morphological distinction.

  10. Cell Arrest and Cell Death in Mammalian Preimplantation Development: Lessons from the Bovine Model

    PubMed Central

    Leidenfrost, Sandra; Boelhauve, Marc; Reichenbach, Myriam; Güngör, Tuna; Reichenbach, Horst-Dieter; Sinowatz, Fred; Wolf, Eckhard; Habermann, Felix A.

    2011-01-01

    Background The causes, modes, biological role and prospective significance of cell death in preimplantation development in humans and other mammals are still poorly understood. Early bovine embryos represent a very attractive experimental model for the investigation of this fundamental and important issue. Methods and Findings To obtain reference data on the temporal and spatial occurrence of cell death in early bovine embryogenesis, three-dimensionally preserved embryos of different ages and stages of development up to hatched blastocysts were examined in toto by confocal laser scanning microscopy. In parallel, transcript abundance profiles for selected apoptosis-related genes were analyzed by real-time reverse transcriptase-polymerase chain reaction. Our study documents that in vitro as well as in vivo, the first four cleavage cycles are prone to a high failure rate including different types of permanent cell cycle arrest and subsequent non-apoptotic blastomere death. In vitro produced and in vivo derived blastocysts showed a significant incidence of cell death in the inner cell mass (ICM), but only in part with morphological features of apoptosis. Importantly, transcripts for CASP3, CASP9, CASP8 and FAS/FASLG were not detectable or found at very low abundances. Conclusions In vitro and in vivo, errors and failures of the first and the next three cleavage divisions frequently cause immediate embryo death or lead to aberrant subsequent development, and are the main source of developmental heterogeneity. A substantial occurrence of cell death in the ICM even in fast developing blastocysts strongly suggests a regular developmentally controlled elimination of cells, while the nature and mechanisms of ICM cell death are unclear. Morphological findings as well as transcript levels measured for important apoptosis-related genes are in conflict with the view that classical caspase-mediated apoptosis is the major cause of cell death in early bovine development. PMID

  11. Construction and development of a mammalian cell-based full-length antibody display library for targeting hepatocellular carcinoma.

    PubMed

    Li, Feng; Liu, Yan-Hong; Li, Yan-Wen; Li, Yue-Hui; Xie, Ping-Li; Ju, Qiang; Chen, Lin; Li, Guan-Cheng

    2012-12-01

    We present a detailed method for constructing a mammalian cell-based full-length antibody display library for targeting hepatocellular carcinoma. Two novel mammalian library vectors pcDNA3-CHm and pcDNA3-CLm were constructed that contained restriction enzyme sites NheI, ClaI and antibody constant domain. Mammalian expression vector pcDNA3-CHm contains IgG heavy-chain (HC) constant region and glycosylphosphatidylinositol anchor (GPI) that could be anchored full-length antibodies on the surface of mammalian cells. GOLPH2 prokaryotic expression vector was carried out in Escherichia coli and purified by immobilized metal affinity chromatography. Variable domain of heavy-chain and variable domain of light-chain genes were respectively inserted into the vector pcDNA3-CHm and pcDNA3-CLm by ligation, and antibody libraries are displayed as whole IgG molecules on the cell surface by co-transfecting this HC-GPI with a light chain. By screening the cell library using magnetic beads and cell ELISA, the cell clone that displayed GOLPH2-specific antibodies on cell surfaces was identified. The mammalian cell-based antibody display library is a great potential application for displaying full-length functional antibodies of targeting hepatocellular carcinoma on the surface of mammalian cells. Anti-GOLPH2 display antibody was successfully isolated from the library.

  12. Development and evolution of the vestibular sensory apparatus of the mammalian ear

    PubMed Central

    Beisel, Kirk W.; Wang-Lundberg, Yesha; Maklad, Adel; Fritzsch, Bernd

    2014-01-01

    Herein, we will review molecular aspects of vestibular ear development and present them in the context of evolutionary changes and hair cell regeneration. Several genes guide the development of anterior and posterior canals. Although some of these genes are also important for horizontal canal development, this canal strongly depends on a single gene, Otx1. Otx1 also governs the segregation of saccule and utricle. Several genes are essential for otoconia and cupula formation, but protein interactions necessary to form and maintain otoconia or a cupula are not yet understood. Nerve fiber guidance to specific vestibular endorgans is predominantly mediated by diffusible neurotrophic factors that work even in the absence of differentiated hair cells. Neurotrophins, in particular Bdnf, are the most crucial attractive factor released by hair cells. If Bdnf is misexpressed, fibers can be redirected away from hair cells. Hair cell differentiation is mediated by Atoh1. However, Atoh1 may not initiate hair cell precursor formation. Resolving the role of Atoh1 in postmitotic hair cell precursors is crucial for future attempts in hair cell regeneration. Additional analyses are needed before gene therapy can help regenerate hair cells, restore otoconia, and reconnect sensory epithelia to the brain. PMID:16614470

  13. microRNA-dependent Temporal Gene Expression in the Ureteric Bud Epithelium during Mammalian Kidney Development

    PubMed Central

    Nagalakshmi, Vidya K.; Lindner, Volkhard; Wessels, Andy; Yu, Jing

    2014-01-01

    Background Our previous study on mouse mutants with the ureteric bud (UB) epithelium-specific Dicer deletion (Dicer UB mutants) demonstrated the significance of UB epithelium-derived miRNAs in UB development. Results Our whole-genome transcriptional profiling showed that the Dicer mutant UB epithelium abnormally retained transcriptional features of the early UB epithelium and failed to express many genes associated with collecting duct differentiation. Further, we identified a temporal expression pattern of early UB genes during UB epithelium development in which gene expression was detected at early developmental stages and became undetectable by E14.5. In contrast, expression of early UB genes persisted at later stages in the Dicer mutant UB epithelium and increased at early stages. Our bioinformatics analysis of the abnormally persistently expressed early genes in the Dicer mutant UB epithelium showed significant enrichment of the let-7 family miRNA targets. We further identified a temporal expression pattern of let-7 miRNAs in the UB epithelium that is anti-parallel to that of some early UB genes during kidney development. Conclusions We propose a model in which the let-7 family miRNAs silence the expression of a subset of early genes in the UB epithelium at later developmental stages in order to promote collecting duct differentiation. PMID:25369991

  14. Notes on the role of dynamic DNA methylation in mammalian development.

    PubMed

    Bestor, Timothy H; Edwards, John R; Boulard, Mathieu

    2015-06-01

    It has been nearly 40 y since it was suggested that genomic methylation patterns could be transmitted via maintenance methylation during S phase and might play a role in the dynamic regulation of gene expression during development [Holliday R, Pugh JE (1975) Science 187(4173):226-232; Riggs AD (1975) Cytogenet Cell Genet 14(1):9-25]. This revolutionary proposal was justified by "... our almost complete ignorance of the mechanism for the unfolding of the genetic program during development" that prevailed at the time. Many correlations between transcriptional activation and demethylation have since been reported, but causation has not been demonstrated and to date there is no reasonable proof of the existence of a complex biochemical system that activates and represses genes via reversible DNA methylation. Such a system would supplement or replace the conserved web of transcription factors that regulate cellular differentiation in organisms that have unmethylated genomes (such as Caenorhaditis elegans and the Dipteran insects) and those that methylate their genomes. DNA methylation does have essential roles in irreversible promoter silencing, as in the monoallelic expression of imprinted genes, in the silencing of transposons, and in X chromosome inactivation in female mammals. Rather than reinforcing or replacing regulatory pathways that are conserved between organisms that have either methylated or unmethylated genomes, DNA methylation endows genomes with the ability to subject specific sequences to irreversible transcriptional silencing even in the presence of all of the factors required for their expression, an ability that is generally unavailable to organisms that have unmethylated genomes.

  15. Expression and function of FGF10 in mammalian inner ear development

    NASA Technical Reports Server (NTRS)

    Pauley, Sarah; Wright, Tracy J.; Pirvola, Ulla; Ornitz, David; Beisel, Kirk; Fritzsch, Bernd

    2003-01-01

    We have investigated the expression of FGF10 during ear development and the effect of an FGF10 null mutation on ear development. Our in situ hybridization data reveal expression of FGF10 in all three canal crista sensory epithelia and the cochlea anlage as well as all sensory neurons at embryonic day 11.5 (E11.5). Older embryos (E18.5) displayed strong graded expression in all sensory epithelia. FGF10 null mutants show complete agenesis of the posterior canal crista and the posterior canal. The posterior canal sensory neurons form initially and project rather normally by E11.5, but they disappear within 2 days. FGF10 null mutants have no posterior canal system at E18.5. In addition, these mutants have deformations of the anterior and horizontal cristae, reduced formation of the anterior and horizontal canals, as well as altered position of the remaining sensory epithelia with respect to the utricle. Hair cells form but some have defects in their cilia formation. No defects were detected in the organ of Corti at the cellular level. Together these data suggest that FGF10 plays a major role in ear morphogenesis. Most of these data are consistent with earlier findings on a null mutation in FGFR2b, one of FGF10's main receptors. Copyright 2003 Wiley-Liss, Inc.

  16. Skeletal development in sloths and the evolution of mammalian vertebral patterning.

    PubMed

    Hautier, Lionel; Weisbecker, Vera; Sánchez-Villagra, Marcelo R; Goswami, Anjali; Asher, Robert J

    2010-11-01

    Mammals show a very low level of variation in vertebral count, particularly in the neck. Phenotypes exhibited at various stages during the development of the axial skeleton may play a key role in testing mechanisms recently proposed to explain this conservatism. Here, we provide osteogenetic data that identify developmental criteria with which to recognize cervical vs. noncervical vertebrae in mammals. Except for sloths, all mammals show the late ossification of the caudal-most centra in the neck after other centra and neural arches. In sloths with 8-10 ribless neck vertebrae, the caudal-most neck centra ossify early, matching the pattern observed in cranial thoracic vertebrae of other mammals. Accordingly, we interpret the ribless neck vertebrae of three-toed sloths caudal to V7 as thoracic based on our developmental criterion. Applied to the unusual vertebral phenotype of long-necked sloths, these data support the interpretation that elements of the axial skeleton with origins from distinct mesodermal tissues have repatterned over the course of evolution.

  17. Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series.

    PubMed

    Bowman, Caitlyn E; Zhao, Liang; Hartung, Thomas; Wolfgang, Michael J

    2016-08-01

    Glucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. Mpc1 deletion was homozygous lethal in midgestation, but Mpc1 hypomorphs and tissue-specific deletion of Mpc1 presented as early perinatal lethality. The allelic series demonstrated that graded suppression of MPC resulted in dose-dependent metabolic and transcriptional changes. Steady-state metabolomics analysis of brain and liver from Mpc1 hypomorphic embryos identified compensatory changes in amino acid and lipid metabolism. Flux assays in Mpc1-deficient embryonic fibroblasts also reflected these changes, including a dramatic increase in mitochondrial alanine utilization. The mitochondrial alanine transaminase GPT2 was found to be necessary and sufficient for increased alanine flux upon MPC inhibition. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be mitigated in part by alternative anaplerotic substrates in utero. PMID:27215380

  18. Golgb1 regulates protein glycosylation and is crucial for mammalian palate development.

    PubMed

    Lan, Yu; Zhang, Nian; Liu, Han; Xu, Jingyue; Jiang, Rulang

    2016-07-01

    Cleft palate is a common major birth defect for which currently known causes account for less than 30% of pathology in humans. In this study, we carried out mutagenesis screening in mice to identify new regulators of palatogenesis. Through genetic linkage mapping and whole-exome sequencing, we identified a loss-of-function mutation in the Golgb1 gene that co-segregated with cleft palate in a new mutant mouse line. Golgb1 is a ubiquitously expressed large coiled-coil protein, also known as giantin, that is localized at the Golgi membrane. Using CRISPR/Cas9-mediated genome editing, we generated and analyzed developmental defects in mice carrying additional Golgb1 loss-of-function mutations, which supported a crucial requirement for Golgb1 in palate development. Through maxillary explant culture assays, we demonstrate that the Golgb1 mutant embryos have intrinsic defects in palatal shelf elevation. Just prior to the developmental stage of palatal shelf elevation in wild-type littermates, Golgb1 mutant embryos exhibit increased cell density, reduced hyaluronan accumulation and impaired protein glycosylation in the palatal mesenchyme. Together, these results demonstrate that, although it is a ubiquitously expressed Golgi-associated protein, Golgb1 has specific functions in protein glycosylation and tissue morphogenesis. PMID:27226319

  19. Skeletal development in sloths and the evolution of mammalian vertebral patterning.

    PubMed

    Hautier, Lionel; Weisbecker, Vera; Sánchez-Villagra, Marcelo R; Goswami, Anjali; Asher, Robert J

    2010-11-01

    Mammals show a very low level of variation in vertebral count, particularly in the neck. Phenotypes exhibited at various stages during the development of the axial skeleton may play a key role in testing mechanisms recently proposed to explain this conservatism. Here, we provide osteogenetic data that identify developmental criteria with which to recognize cervical vs. noncervical vertebrae in mammals. Except for sloths, all mammals show the late ossification of the caudal-most centra in the neck after other centra and neural arches. In sloths with 8-10 ribless neck vertebrae, the caudal-most neck centra ossify early, matching the pattern observed in cranial thoracic vertebrae of other mammals. Accordingly, we interpret the ribless neck vertebrae of three-toed sloths caudal to V7 as thoracic based on our developmental criterion. Applied to the unusual vertebral phenotype of long-necked sloths, these data support the interpretation that elements of the axial skeleton with origins from distinct mesodermal tissues have repatterned over the course of evolution. PMID:20956304

  20. Golgb1 regulates protein glycosylation and is crucial for mammalian palate development.

    PubMed

    Lan, Yu; Zhang, Nian; Liu, Han; Xu, Jingyue; Jiang, Rulang

    2016-07-01

    Cleft palate is a common major birth defect for which currently known causes account for less than 30% of pathology in humans. In this study, we carried out mutagenesis screening in mice to identify new regulators of palatogenesis. Through genetic linkage mapping and whole-exome sequencing, we identified a loss-of-function mutation in the Golgb1 gene that co-segregated with cleft palate in a new mutant mouse line. Golgb1 is a ubiquitously expressed large coiled-coil protein, also known as giantin, that is localized at the Golgi membrane. Using CRISPR/Cas9-mediated genome editing, we generated and analyzed developmental defects in mice carrying additional Golgb1 loss-of-function mutations, which supported a crucial requirement for Golgb1 in palate development. Through maxillary explant culture assays, we demonstrate that the Golgb1 mutant embryos have intrinsic defects in palatal shelf elevation. Just prior to the developmental stage of palatal shelf elevation in wild-type littermates, Golgb1 mutant embryos exhibit increased cell density, reduced hyaluronan accumulation and impaired protein glycosylation in the palatal mesenchyme. Together, these results demonstrate that, although it is a ubiquitously expressed Golgi-associated protein, Golgb1 has specific functions in protein glycosylation and tissue morphogenesis.

  1. Development, reliability, and validation of an infant mammalian penetration-aspiration scale.

    PubMed

    Holman, Shaina Devi; Campbell-Malone, Regina; Ding, Peng; Gierbolini-Norat, Estela M; Griffioen, Anne M; Inokuchi, Haruhi; Lukasik, Stacey L; German, Rebecca Z

    2013-06-01

    A penetration-aspiration scale exists for assessing airway protection in adult videofluoroscopy and fiberoptic endoscopic swallowing studies; however, no such scale exists for animal models. The aim of this study was threefold: (1) develop a penetration-aspiration scale (PAS) for infant mammals, (2) test the scale's intra- and interrater reliabilities, and (3) validate the use of the scale for distinguishing between abnormal and normal animals. After discussion and reviewing many videos, the result was a 7-point infant mammal PAS. Reliability was tested by having five judges score 90 swallows recorded with videofluoroscopy across two time points. In these videos, the frame rate was either 30 or 60 frames per second and the animals were either normal, had a unilateral superior laryngeal nerve (SLN) lesion, or had hard palate local anesthesia. The scale was validated by having one judge score videos of both normal and SLN lesioned pigs and testing the difference using a t test. Raters had a high intrarater reliability [average κ = 0.82, intraclass correlation coefficient (ICC) = 0.92] and high interrater reliability (average κ = 0.68, ICC = 0.66). There was a significant difference in reliability for videos captured at 30 and 60 frames per second for scores of 3 and 7 (P < 0.001). The scale was also validated for distinguishing between normal and abnormal pigs (P < 0.001). Given the increasing number of animal studies using videofluoroscopy to study dysphagia, this scale provides a valid and reliable measure of airway protection during swallowing in infant pigs that will give these animal models increased translational significance.

  2. Development, reliability and validation of an infant mammalian penetration-aspiration scale

    PubMed Central

    Holman, Shaina Devi; Campbell-Malone, Regina; Ding, Peng; Gierbolini-Norat, Estela M.; Griffioen, Anne M.; Inokuchi, Haruhi; Lukasik, Stacey L.; German, Rebecca Z.

    2012-01-01

    A penetration-aspiration scale exists for assessing airway protection in adult videofluoroscopy and fiberoptic endoscopic swallowing studies, however no such scale exists for animal models. The aim of this study was threefold to 1) develop a Penetration-Aspiration Scale (PAS) for infant mammals, 2) test the scale’s intra- and inter-rater reliability, and 3) to validate the use of the scale for distinguishing between abnormal and normal animals. After discussion and reviewing many videos, the result was a 7-Point Infant Mammal PAS. Reliability was tested by having 5 judges score 90 swallows recorded with videofluoroscopy across two time points. In these videos, the frame rate was either 30 or 60 frames per second and the animals were either normal, had a unilateral superior laryngeal nerve (SLN) lesion, or had hard palate local anesthesia. The scale was validated by having one judge score videos of both normal and SLN lesioned pigs and testing the difference using a t-test. Raters had a high intra-rater (average kappa of 0.82, intraclass correlation coefficient (ICC)= 0.92) and high inter-rater reliability (average kappa of 0.68, ICC= 0.66). There was a significant difference in reliability for videos captured at 30 and 60 frames per second for scores of 3 and 7 (p<0.001). The scale was also validated for distinguishing between normal and abnormal pigs (p<0.001). Given the increasing number of animal studies using videofluoroscopy to study dysphagia, this scale provides a valid and reliable measure of airway protection during swallowing in infant pigs that will give these animal models increased translational significance. PMID:23129423

  3. Notes on the role of dynamic DNA methylation in mammalian development

    PubMed Central

    Bestor, Timothy H.; Edwards, John R.; Boulard, Mathieu

    2015-01-01

    It has been nearly 40 y since it was suggested that genomic methylation patterns could be transmitted via maintenance methylation during S phase and might play a role in the dynamic regulation of gene expression during development [Holliday R, Pugh JE (1975) Science 187(4173):226–232; Riggs AD (1975) Cytogenet Cell Genet 14(1):9–25]. This revolutionary proposal was justified by “... our almost complete ignorance of the mechanism for the unfolding of the genetic program during development” that prevailed at the time. Many correlations between transcriptional activation and demethylation have since been reported, but causation has not been demonstrated and to date there is no reasonable proof of the existence of a complex biochemical system that activates and represses genes via reversible DNA methylation. Such a system would supplement or replace the conserved web of transcription factors that regulate cellular differentiation in organisms that have unmethylated genomes (such as Caenorhaditis elegans and the Dipteran insects) and those that methylate their genomes. DNA methylation does have essential roles in irreversible promoter silencing, as in the monoallelic expression of imprinted genes, in the silencing of transposons, and in X chromosome inactivation in female mammals. Rather than reinforcing or replacing regulatory pathways that are conserved between organisms that have either methylated or unmethylated genomes, DNA methylation endows genomes with the ability to subject specific sequences to irreversible transcriptional silencing even in the presence of all of the factors required for their expression, an ability that is generally unavailable to organisms that have unmethylated genomes. PMID:25368180

  4. Effect of postnatal development on calcium currents and slow charge movement in mammalian skeletal muscle

    PubMed Central

    Beam, KG; Knudson, CM

    1988-01-01

    Single- (whole-cell patch) and two-electrode voltage-clamp techniques were used to measure transient (Ifast) and sustained (Islow) calcium currents, linear capacitance, and slow, voltage-dependent charge movements in freshly dissociated fibers of the flexor digitorum brevis (FDB) muscle of rats of various postnatal ages. Peak Ifast was largest in FDB fibers of neonatal (1-5 d) rats, having a magnitude in 10 mM external Ca of 1.4 +/- 0.9 pA/pF (mean +/- SD; current normalized by linear fiber capacitance). Peak Ifast was smaller in FDB fibers of older animals, and by approximately 3 wk postnatal, it was so small as to be unmeasurable. By contrast, the magnitudes of Islow and charge movement increased substantially during postnatal development. Peak Islow was 3.6 +/- 2.5 pA/pF in FDB fibers of 1-5-d rats and increased to 16.4 +/- 6.5 pA/pF in 45-50-d-old rats; for these same two age groups, Qmax, the total mobile charge measurable as charge movement, was 6.0 +/- 1.7 and 23.8 +/- 4.0 nC/microF, respectively. As both Islow and charge movement are thought to arise in the transverse-tubular system, linear capacitance normalized by the area of fiber surface was determined as an indirect measure of the membrane area of the t-system relative to that of the fiber surface. This parameter increased from 1.5 +/- 0.2 microF/cm2 in 2-d fibers to 2.9 +/- 0.4 microF/cm2 in 44-d fibers. The increases in peak Islow, Qmax, and normalized linear capacitance all had similar time courses. Although the function of Islow is unknown, the substantial postnatal increase in its magnitude suggests that it plays an important role in the physiology of skeletal muscle. PMID:2458430

  5. Web Database Development: Implications for Academic Publishing.

    ERIC Educational Resources Information Center

    Fernekes, Bob

    This paper discusses the preliminary planning, design, and development of a pilot project to create an Internet accessible database and search tool for locating and distributing company data and scholarly work. Team members established four project objectives: (1) to develop a Web accessible database and decision tool that creates Web pages on the…

  6. Career Plateauing: Implications for Career Development Specialists.

    ERIC Educational Resources Information Center

    Weiner, Andrew; And Others

    1992-01-01

    Reaction to career plateaus depends on the employee's resources as well as the organization's response. Counseling, training and development, job enrichment, and other activities can minimize the stressful effects of involuntary plateauing. (SK)

  7. Cross-Cultural Studies of Child Development: Implications for Clinicians.

    ERIC Educational Resources Information Center

    Fenichel, Emily, Ed.

    1994-01-01

    This theme issue contains six articles on the development of infants and toddlers: (1) "Cross-Cultural Studies of Child Development: Implications for Clinicians" (J. Kevin Nugent); (2) "Therapeutic Work with African-American Families: Using Knowledge of the Culture" (Cheryl Polk); (3) "Psychotherapy in Specific Cultural Contexts: Resources for the…

  8. Culture and Early Language Development: Implications for Assessment and Intervention

    ERIC Educational Resources Information Center

    Parada, Patricia M.

    2013-01-01

    The purpose of this qualitative study--"Culture and Early Language Development: Implications for Assessment and Intervention"--was to explore and describe the perceptions and beliefs of Salvadoran mothers of low socioeconomic status regarding the language development of their young children in order to identify cultural variations in…

  9. Cis-Suppression to Arrest Protein Aggregation in Mammalian Cells

    PubMed Central

    Gregoire, Simpson; Zhang, Shaojie; Costanzo, Joseph; Wilson, Kelly; Fernandez, Erik J.; Kwon, Inchan

    2015-01-01

    Protein misfolding and aggregation are implicated in numerous human diseases and significantly lower production yield of proteins expressed in mammalian cells. Despite the importance of understanding and suppressing protein aggregation in mammalian cells, a protein design and selection strategy to modulate protein misfolding/aggregation in mammalian cells has not yet been reported. In this work, we address the particular challenge presented by mutation-induced protein aggregation in mammalian cells. We hypothesize that an additional mutation(s) can be introduced in an aggregation-prone protein variant, spatially near the original mutation, to suppress misfolding and aggregation (cis-suppression). As a model protein, we chose human copper, zinc superoxide dismutase mutant (SOD1A4V) containing an alanine to valine mutation at residue 4, associated with the familial form of amyotrophic lateral sclerosis. We used the program RosettaDesign to identify Phe20 in SOD1A4V as a key residue responsible for SOD1A4V conformational destabilization. This information was used to rationally develop a pool of candidate mutations at the Phe20 site. After two rounds of mammalian-cell based screening of the variants, three novel SOD1A4V variants with a significantly reduced aggregation propensity inside cells were selected. The enhanced stability and reduced aggregation propensity of the three novel SOD1A4V variants were verified using cell fractionation and in vitro stability assays. PMID:24114411

  10. Growth and Development: Implications for Teaching.

    ERIC Educational Resources Information Center

    Haywood, Kathleen M.; Loughrey, Thomas J.

    1981-01-01

    A significant relationship exists between a person's body concept and his general self-concept. Physical educators need to be more concerned with the development of the body concept in children. Understanding how the growth process affects performance ability can help the teacher plan activities based on individual readiness factors. (JN)

  11. Community Leadership Development: Implications for Extension.

    ERIC Educational Resources Information Center

    Northeast Regional Center for Rural Development, University Park, PA.

    Designed for extension personnel who are involved in community leadership (CL) programs, this publication summarizes recent national efforts that could be useful in developing and conducting CL programs, and current leadership theory and literature. Part 1 reports the results of the national survey, initiated in April 1985, of extension staff…

  12. Development and Families: Implications for Home Economics.

    ERIC Educational Resources Information Center

    Murray, Eloise

    1985-01-01

    This article integrates literature from such diverse sources as population, agriculture, women in development, macro-economics, and health studies to document the changes that have occurred in families in the last 20-25 years. Program issues for the home economics profession are considered in light of these changes. (CT)

  13. The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome.

    PubMed

    Harlow, Philippa H; Perry, Simon J; Widdison, Stephanie; Daniels, Shannon; Bondo, Eddie; Lamberth, Clemens; Currie, Richard A; Flemming, Anthony J

    2016-01-01

    To determine whether a C. elegans bioassay could predict mammalian developmental activity, we selected diverse compounds known and known not to elicit such activity and measured their effect on C. elegans egg viability. 89% of compounds that reduced C. elegans egg viability also had mammalian developmental activity. Conversely only 25% of compounds found not to reduce egg viability in C. elegans were also inactive in mammals. We conclude that the C. elegans egg viability assay is an accurate positive predictor, but an inaccurate negative predictor, of mammalian developmental activity. We then evaluated C. elegans as a tool to identify mechanisms affecting toxicological outcomes among related compounds. The difference in developmental activity of structurally related fungicides in C. elegans correlated with their rate of metabolism. Knockdown of the cytochrome P450s cyp-35A3 and cyp-35A4 increased the toxicity to C. elegans of the least developmentally active compounds to the level of the most developmentally active. This indicated that these P450s were involved in the greater rate of metabolism of the less toxic of these compounds. We conclude that C. elegans based approaches can predict mammalian developmental activity and can yield plausible hypotheses for factors affecting the biological potency of compounds in mammals.

  14. The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome

    PubMed Central

    Harlow, Philippa H.; Perry, Simon J.; Widdison, Stephanie; Daniels, Shannon; Bondo, Eddie; Lamberth, Clemens; Currie, Richard A.; Flemming, Anthony J.

    2016-01-01

    To determine whether a C. elegans bioassay could predict mammalian developmental activity, we selected diverse compounds known and known not to elicit such activity and measured their effect on C. elegans egg viability. 89% of compounds that reduced C. elegans egg viability also had mammalian developmental activity. Conversely only 25% of compounds found not to reduce egg viability in C. elegans were also inactive in mammals. We conclude that the C. elegans egg viability assay is an accurate positive predictor, but an inaccurate negative predictor, of mammalian developmental activity. We then evaluated C. elegans as a tool to identify mechanisms affecting toxicological outcomes among related compounds. The difference in developmental activity of structurally related fungicides in C. elegans correlated with their rate of metabolism. Knockdown of the cytochrome P450s cyp-35A3 and cyp-35A4 increased the toxicity to C. elegans of the least developmentally active compounds to the level of the most developmentally active. This indicated that these P450s were involved in the greater rate of metabolism of the less toxic of these compounds. We conclude that C. elegans based approaches can predict mammalian developmental activity and can yield plausible hypotheses for factors affecting the biological potency of compounds in mammals. PMID:26987796

  15. Private health insurance: implications for developing countries.

    PubMed Central

    Sekhri, Neelam; Savedoff, William

    2005-01-01

    Private health insurance is playing an increasing role in both high- and low-income countries, yet is poorly understood by researchers and policy-makers. This paper shows that the distinction between private and public health insurance is often exaggerated since well regulated private insurance markets share many features with public insurance systems. It notes that private health insurance preceded many modern social insurance systems in western Europe, allowing these countries to develop the mechanisms, institutions and capacities that subsequently made it possible to provide universal access to health care. We also review international experiences with private insurance, demonstrating that its role is not restricted to any particular region or level of national income. The seven countries that finance more than 20% of their health care via private health insurance are Brazil, Chile, Namibia, South Africa, the United States, Uruguay and Zimbabwe. In each case, private health insurance provides primary financial protection for workers and their families while public health-care funds are targeted to programmes covering poor and vulnerable populations. We make recommendations for policy in developing countries, arguing that private health insurance cannot be ignored. Instead, it can be harnessed to serve the public interest if governments implement effective regulations and focus public funds on programmes for those who are poor and vulnerable. It can also be used as a transitional form of health insurance to develop experience with insurance institutions while the public sector increases its own capacity to manage and finance health-care coverage. PMID:15744405

  16. Implications of pharmacogenomics for drug development.

    PubMed

    Kirk, Randal J; Hung, Jeffrey L; Horner, Scott R; Perez, Jeffrey T

    2008-12-01

    The use of pharmacogenomics (PGx) today is almost ubiquitous in drug development and is advancing into the practice of medicine as an increasing number of drugs come to market with indications that are related to the presence or absence of a specific genetic biomarker. The authors review the history of PGx and its tools in research, in clinical trials and in clinical medicine. The economic, regulatory, and technological driving forces for adoption of PGx are then considered. Current impediments to a more robust proliferation of the benefits of these technologies are discussed-pharmaceutical companies, clinical education, required statistical methods, and intellectual property landscape.

  17. Perfluorocarbons: recent developments and implications for neurosurgery.

    PubMed

    Sakas, D E; Whittaker, K W; Crowell, R M; Zervas, N T

    1996-08-01

    Over the last 30 years, perfluorocarbons (PFCs) have been extensively investigated as oxygen carriers. Early studies indicated that these compounds could be used as blood substitutes or protective agents against ischemia. Adverse characteristics such as instability, short intravascular half-life, and uncertainties concerning possible toxicity precluded wide clinical application. However, advances in PFC technology have led to the development of improved second-generation oxygen carriers that incorporate well-tolerated emulsifiers (egg-yolk phospholipids). The authors review recent developments in this field and consider the potential role of PFCs in future neurosurgical practice. Diagnostic applications could include their use to assess cerebral blood flow, local oxygen tension, and brain metabolism or to achieve enhanced imaging and precise staging of inflammatory, neoplastic, or vascular disease processes by means of computerized tomography, ultrasonography, and magnetic resonance studies. Therapeutic applications could include cerebral protection, an adjunctive role in radiotherapy of malignant brain tumors, protection against air embolism, the preservation of organs for transplantation, and ventilatory support in head-injured patients with compromised lung function. In addition, PFCs have been used successfully as a tool in ophthalmic microsurgery and potentially they could fulfill a similar role in microneurosurgery. PMID:8755753

  18. Live-cell quantification and comparison of mammalian oocyte cytosolic lipid content between species, during development, and in relation to body composition using nonlinear vibrational microscopy.

    PubMed

    Jasensky, Joshua; Boughton, Andrew P; Khmaladze, Alexander; Ding, Jun; Zhang, Chi; Swain, Jason E; Smith, George W; Chen, Zhan; Smith, Gary D

    2016-08-01

    Cytosolic lipids participate in the growth, development, and overall health of mammalian oocytes including many roles in cellular homeostasis. Significant emphasis has been placed on the study of lipids as a dynamic organelle, which in turn requires the development of tools and techniques to quantitate and compare how lipid content relates to cellular structure, function, and normalcy. Objectives of this study were to determine if nonlinear vibrational microscopy (e.g., coherent anti-Stokes Raman scattering or CARS microscopy) could be used for live-cell imaging to quantify and compare lipid content in mammalian oocytes during development and in relation to body composition; and compare its efficacy to methods involving cellular fixation and staining protocols. Results of this study demonstrate that CARS is able to identify lipids in live mammalian oocytes, and there exists quantifiable and consistent differences in percent lipid composition across ooctyes of different species, developmental stages, and in relation to body composition. Such a method of live-cell lipid quantification has (i) experimental power in basic cell biology, (ii) practical utility for identifying developmental predictive biomarkers while advancing biology-based oocyte/embryo selection, and (iii) ability to yield rationally supporting technology for decision-making in rodents, domestic species, and human assisted reproduction and/or fertility preservation.

  19. Aquaporin 0 plays a pivotal role in refractive index gradient development in mammalian eye lens to prevent spherical aberration.

    PubMed

    Kumari, S Sindhu; Varadaraj, Kulandaiappan

    2014-10-01

    Aquaporin 0 (AQP0) is a transmembrane channel that constitutes ∼45% of the total membrane protein of the fiber cells in mammalian lens. It is critical for lens transparency and homeostasis as mutations and knockout cause autosomal dominant lens cataract. AQP0 functions as a water channel and as a cell-to-cell adhesion (CTCA) molecule in the lens. Our recent in vitro studies showed that the CTCA function of AQP0 could be crucial to establish lens refractive index gradient (RING). However, there is a lack of in vivo data to corroborate the role of AQP0 as a fiber CTCA molecule which is critical for creating lens RING. The present investigation is undertaken to gather in vivo evidence for the involvement of AQP0 in developing lens RING. Lenses of wild type (WT) mouse, AQP0 knockout (heterozygous, AQP0(+/-)) and AQP0 knockout lens transgenically expressing AQP1 (heterozygous AQP0(+/)(-)/AQP1(+/)(-)) mouse models were used for the study. Data on AQP0 protein profile of intact and N- and/or C-terminal cleaved AQP0 in the lens by MALDI-TOF mass spectrometry and SDS-PAGE revealed that outer cortex fiber cells have only intact AQP0 of ∼28kDa, inner cortical and outer nuclear fiber cells have both intact and cleaved forms, and inner nuclear fiber cells have only cleaved forms (∼26-24kDa). Knocking out of 50% of AQP0 protein caused light scattering, spherical aberration (SA) and cataract. Restoring the lost fiber cell membrane water permeability (Pf) by transgene AQP1 did not reinstate complete lens transparency and the mouse lenses showed light scattering and SA. Transmission and scanning electron micrographs of lenses of both mouse models showed increased extracellular space between fiber cells. Water content determination study showed increase in water in the lenses of these mouse models. In summary, lens transparency, CTCA and compact packing of fiber cells were affected due to the loss of 50% AQP0 leading to larger extracellular space, more water content and SA

  20. Aquaporin 0 plays a pivotal role in refractive index gradient development in mammalian eye lens to prevent spherical aberration

    SciTech Connect

    Kumari, S. Sindhu; Varadaraj, Kulandaiappan

    2014-10-03

    Highlights: • Intact AQP0 functions as fiber cell-to-fiber cell adhesion protein. • AQP0 facilitates reduction in extracellular space and lens water content. • AQP0 adhesion function aids in lens refractive index gradient (RING) formation. • AQP0 prevents lens spherical aberration by establishing RING. • AQP0 is critical for lens transparency and homeostasis. - Abstract: Aquaporin 0 (AQP0) is a transmembrane channel that constitutes ∼45% of the total membrane protein of the fiber cells in mammalian lens. It is critical for lens transparency and homeostasis as mutations and knockout cause autosomal dominant lens cataract. AQP0 functions as a water channel and as a cell-to-cell adhesion (CTCA) molecule in the lens. Our recent in vitro studies showed that the CTCA function of AQP0 could be crucial to establish lens refractive index gradient (RING). However, there is a lack of in vivo data to corroborate the role of AQP0 as a fiber CTCA molecule which is critical for creating lens RING. The present investigation is undertaken to gather in vivo evidence for the involvement of AQP0 in developing lens RING. Lenses of wild type (WT) mouse, AQP0 knockout (heterozygous, AQP0{sup +/−}) and AQP0 knockout lens transgenically expressing AQP1 (heterozygous AQP0{sup +/−}/AQP1{sup +/−}) mouse models were used for the study. Data on AQP0 protein profile of intact and N- and/or C-terminal cleaved AQP0 in the lens by MALDI-TOF mass spectrometry and SDS–PAGE revealed that outer cortex fiber cells have only intact AQP0 of ∼28 kDa, inner cortical and outer nuclear fiber cells have both intact and cleaved forms, and inner nuclear fiber cells have only cleaved forms (∼26–24 kDa). Knocking out of 50% of AQP0 protein caused light scattering, spherical aberration (SA) and cataract. Restoring the lost fiber cell membrane water permeability (P{sub f}) by transgene AQP1 did not reinstate complete lens transparency and the mouse lenses showed light scattering and SA

  1. Some Instructional Implications from a Mathematical Model of Cognitive Development.

    ERIC Educational Resources Information Center

    Mierkiewicz, Diane B.

    Cognitive development and various educational implications are discussed in terms of Donald Saari's model of the interaction of a learner and the enviroment and the constraints imposed by the inefficiency of the learner's cognitive system. Saari proposed a hierarchical system of cognitive structures such that the relationships between structures…

  2. Effective Organizational Vision: Implications for Human Resource Development

    ERIC Educational Resources Information Center

    Foster, Rex D.; Akdere, Mesut

    2007-01-01

    Purpose: The purpose of this paper is to examine the existing literature related to organizational vision and discusses its potential implications for human resource development (HRD). Furthermore, the paper aims to provide a forum for debate on the utility and effectiveness of organizational vision and how it is related to HRD and strategic…

  3. Diagnosing Organization-Environment "Fit": Implications for Organization Development

    ERIC Educational Resources Information Center

    Gabarro, John J.

    1974-01-01

    This article has attempted to: (1) describe several dimensions of organization-environment fit; (2) describe some concepts which can be used in diagnosing the degree to which a school system's organization matches the demands and needs of its environment; (3) present some implications of such a diagnosis for OD [organizational development]…

  4. Research on Bereavement: Implications for Social Policy Development.

    ERIC Educational Resources Information Center

    Kiely, Margaret C.

    This paper describes the results of an evaluation of the Palliative Care Service, one of the first hospices in North America (Montreal), and the implications of that research for social policy development. The objectives of the research were to evaluate the reliability of predictive assessments of bereavement risk and the effectiveness of…

  5. Some Implications of Career Theory for Adult Development and Aging.

    ERIC Educational Resources Information Center

    Holland, John L.

    Structural-interactive vocational theory shows that both aspirational and work histories have continuity over the life span and provide useful explanations of stability and change. This paper suggests some implications of structural-interactive theory for the study of adult development. Common principles of structural-interactive theories are…

  6. Cognitive Science: Implications for Curriculum Research and Development.

    ERIC Educational Resources Information Center

    Posner, George J.

    A model of human information processing is summarized and discussed in terms of the implications of the model and its associated technologies for curriculum research and development. Description of the model focuses on its input and output systems and its memory systems, i.e., long-term memory (LTM). Semantic networks are described as a…

  7. Coverage with evidence development: ethical issues and policy implications.

    PubMed

    Miller, Franklin G; Pearson, Steven D

    2008-07-01

    Coverage with evidence development (CED) is an evolving method of providing provisional access to novel medical interventions while generating the evidence needed to determine whether unconditional coverage is warranted. In this article we review the policy rationale for CED and present a normative analysis that addresses ethical concerns and policy implications.

  8. A genome-wide screen identifies a single Β-defensin gene cluster in the chicken: implications for the origin and evolution of mammalian defensins

    SciTech Connect

    Xiao, Yanjing; Hughes, Austin L.; Ando, Junko; Matsuda, Yoichi; Cheng, Jan-Fang; Skinner-Noble, Donald; Zhang, Guolong

    2004-08-13

    Defensins comprise a large family of cationic antimicrobial peptides that are characterized by the presence of a conserved cysteine-rich defensin motif. Based on the spacing pattern of cysteines, these defensins are broadly divided into five groups, namely plant, invertebrate, {alpha}-, {beta}-, and {theta}-defensins, with the last three groups being mostly found in mammalian species. However, the evolutionary relationships among these five groups of defensins remain controversial.

  9. Use of a cytogenetic whole-genome comparison to resolve phylogenetic relationships among three species: implications for mammalian systematics and conservation biology.

    PubMed

    Yu, Hon-Tsen; Ma, Gwo-Chin; Lee, Dong-Jay; Chin, Shih-Chien; Chen, Ting-Li; Tsao, Hsien-Shao; Lin, Wen-Hsiang; Wu, Sheng-Hai; Lin, Chyi-Chyang; Chen, Ming

    2012-05-01

    The objective was to apply a novel modification of a genome-wide, comparative cytogenetic technique (comparative genomic hybridization, comparative genomic hybridization (CGH)), to study species belonging to the myrmecophagous (ant/termite eating) mammalian orders/superorders (Pholidota, Tubulidentata, Carnivora, and Xenarthra), as a model for other applications in mammalian systematics and conservation biology. In this study, CGH was applied to high-quality metaphase spreads of pangolin (Pholidota), using probes of sloth and canine (Xenarthra and Carnivora, respectively) genomic DNA labeled with different fluorophores, thereby facilitating analysis of the visible color spectrum on pangolin karyotypes. Our results posited that pholidotes are closer to carnivores than to xenarthrans, which confirmed the current consensus that myrmecophagy in these mammalian lineages was more likely because of homoplasy (convergent evolution) than being an ancestral character. Since the modified CGH technique used is genome-wide, has chromosome-level resolution, and does not need full genome sequencing, it has considerable potential in systematics and other fields. PMID:22192390

  10. Use of a cytogenetic whole-genome comparison to resolve phylogenetic relationships among three species: implications for mammalian systematics and conservation biology.

    PubMed

    Yu, Hon-Tsen; Ma, Gwo-Chin; Lee, Dong-Jay; Chin, Shih-Chien; Chen, Ting-Li; Tsao, Hsien-Shao; Lin, Wen-Hsiang; Wu, Sheng-Hai; Lin, Chyi-Chyang; Chen, Ming

    2012-05-01

    The objective was to apply a novel modification of a genome-wide, comparative cytogenetic technique (comparative genomic hybridization, comparative genomic hybridization (CGH)), to study species belonging to the myrmecophagous (ant/termite eating) mammalian orders/superorders (Pholidota, Tubulidentata, Carnivora, and Xenarthra), as a model for other applications in mammalian systematics and conservation biology. In this study, CGH was applied to high-quality metaphase spreads of pangolin (Pholidota), using probes of sloth and canine (Xenarthra and Carnivora, respectively) genomic DNA labeled with different fluorophores, thereby facilitating analysis of the visible color spectrum on pangolin karyotypes. Our results posited that pholidotes are closer to carnivores than to xenarthrans, which confirmed the current consensus that myrmecophagy in these mammalian lineages was more likely because of homoplasy (convergent evolution) than being an ancestral character. Since the modified CGH technique used is genome-wide, has chromosome-level resolution, and does not need full genome sequencing, it has considerable potential in systematics and other fields.

  11. U.S. commercial space policies - Implications for developing countries

    NASA Technical Reports Server (NTRS)

    Gillam, Isaac T., IV; Stone, Barbara A.

    1987-01-01

    Recent U.S. policy developments on the commercial use of space are summarized and their international implications are considered. Attention is given to successful applications of technology developed in space, including an implantable cancer medication system, an implantable defibrillator, an ultrasonic residual stress monitor, and aquaculture treatment techniques. NASA projects involving bioengineering and rehabilitation applications are summarized, and plans to investigate high-temperature superconductors in space are addressed. Recent agreements entred into by NASA for space commercial studies are reviewed.

  12. DNA modifications in the mammalian brain

    PubMed Central

    Shin, Jaehoon; Ming, Guo-li; Song, Hongjun

    2014-01-01

    DNA methylation is a crucial epigenetic mark in mammalian development, genomic imprinting, X-inactivation, chromosomal stability and suppressing parasitic DNA elements. DNA methylation in neurons has also been suggested to play important roles for mammalian neuronal functions, and learning and memory. In this review, we first summarize recent discoveries and fundamental principles of DNA modifications in the general epigenetics field. We then describe the profiles of different DNA modifications in the mammalian brain genome. Finally, we discuss roles of DNA modifications in mammalian brain development and function. PMID:25135973

  13. New Developments in Mast Cell Biology: Clinical Implications.

    PubMed

    Arthur, Greer; Bradding, Peter

    2016-09-01

    Mast cells (MCs) are present in connective tissue and at mucosal surfaces in all classes of vertebrates. In health, they contribute to tissue homeostasis, host defense, and tissue repair via multiple receptors regulating the release of a vast stockpile of proinflammatory mediators, proteases, and cytokines. However, these potentially protective cells are a double-edged sword. When there is a repeated or long-term stimulus, MC activation leads to tissue damage and dysfunction. Accordingly, MCs are implicated in the pathophysiologic aspects of numerous diseases covering all organs. Understanding the biology of MCs, their heterogeneity, mechanisms of activation, and signaling cascades may lead to the development of novel therapies for many diseases for which current treatments are lacking or are of poor efficacy. This review will focus on updates and developments in MC biology and their clinical implications, with a particular focus on their role in respiratory diseases.

  14. Regulation of mammalian cell differentiation by long non-coding RNAs.

    PubMed

    Hu, Wenqian; Alvarez-Dominguez, Juan R; Lodish, Harvey F

    2012-11-01

    Differentiation of specialized cell types from stem and progenitor cells is tightly regulated at several levels, both during development and during somatic tissue homeostasis. Many long non-coding RNAs have been recognized as an additional layer of regulation in the specification of cellular identities; these non-coding species can modulate gene-expression programmes in various biological contexts through diverse mechanisms at the transcriptional, translational or messenger RNA stability levels. Here, we summarize findings that implicate long non-coding RNAs in the control of mammalian cell differentiation. We focus on several representative differentiation systems and discuss how specific long non-coding RNAs contribute to the regulation of mammalian development.

  15. Women Education and Economic Development in Kenya: Implications for Curriculum Development and Implementation Processes

    ERIC Educational Resources Information Center

    Syomwene, Anne; Kindiki, Jonah Nyaga

    2015-01-01

    This paper is a discussion of the relationship between women education and sustainable economic development in Kenya and its implications for curriculum development and implementation processes. The argument advanced in this paper is that the solution to the development problems in Kenya and other developing nations lies on women education.…

  16. Recovered Alcoholics and Career Development: Implications for Human Resource Development

    ERIC Educational Resources Information Center

    Gedro, Julie; Mercer, Frances; Iodice, Jody D.

    2012-01-01

    This article presents three issues regarding alcoholism, recovery, and career development. First, alcoholism is a disease that creates health and wellness problems for those it afflicts. It also impacts individual and workplace productivity. Second, alcoholism has a persistent stigmatization. As a result, those alcoholics who are in recovery face…

  17. Rhenium and technetium tricarbonyl, {M(CO)3} (+) (M = Tc, Re), binding to mammalian metallothioneins: new insights into chemical and radiopharmaceutical implications.

    PubMed

    Lecina, Joan; Palacios, Òscar; Atrian, Sílvia; Capdevila, Mercè; Suades, Joan

    2015-04-01

    This paper deals with the binding of the four mammalian metallothioneins (MTs) to the organometallic metal fragment {fac-M(CO)3}(+) (M = (99)Tc, Re), which is highly promising for the preparation of second-generation radiopharmaceuticals. The study of the transmetallation reaction between zinc and rhenium in Zn7-MT1 by means of UV-vis and CD spectroscopy demonstrated the incorporation of the {fac-Re(CO)3}(+) fragment to the MTs. This reaction should be performed at 70 °C to accelerate the reaction rate, a result that is consistent with the reported reactivity of the rhenium fragment. ESI-TOF MS demonstrated the formation of mixed-metal species as Zn6,{Re(CO)3}-MT, Zn6,{Re(CO)3}2-MT, and Zn5,{Re(CO)3}3-MT, as well as the different reactivity of the four MT isoforms. Hence, Zn-MT3 showed the highest reactivity, in agreement with its high Cu-thionein character, whereas Zn-MT2 exhibited the lowest reactivity, in line with its high Zn-thionein character. The reactivity of the Zn-loaded forms of MT1 and MT4 is intermediate between those of MT3 and MT2. The study of the binding of the {fac-(99)Tc(CO)3}(+) fragment to MTs showed a significant and very interesting different reactivity in relation to rhenium. The transmetallation reaction is much more effective with technetium than with rhenium and significant amounts of mixed Zn x ,{(99)Tc(CO)3} y -MT species were formed with the four MT isoforms whereas only MT3 rendered similar amounts of rhenium derivatives. The results obtained in this study support the possible use of technetium for labelling mammalian metallothioneins and also for possible radiopharmaceutical applications.

  18. Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea.

    PubMed

    Vendrell, Victor; López-Hernández, Iris; Durán Alonso, María Beatriz; Feijoo-Redondo, Ana; Abello, Gina; Gálvez, Héctor; Giráldez, Fernando; Lamonerie, Thomas; Schimmang, Thomas

    2015-08-15

    Transcriptional regulatory networks are essential during the formation and differentiation of organs. The transcription factor N-myc is required for proper morphogenesis of the cochlea and to control correct patterning of the organ of Corti. We show here that the Otx2 gene, a mammalian ortholog of the Drosophila orthodenticle homeobox gene, is a crucial target of N-myc during inner ear development. Otx2 expression is lost in N-myc mouse mutants, and N-myc misexpression in the chick inner ear leads to ectopic expression of Otx2. Furthermore, Otx2 enhancer activity is increased by N-myc misexpression, indicating that N-myc may directly regulate Otx2. Inactivation of Otx2 in the mouse inner ear leads to ectopic expression of prosensory markers in non-sensory regions of the cochlear duct. Upon further differentiation, these domains give rise to an ectopic organ of Corti, together with the re-specification of non-sensory areas into sensory epithelia, and the loss of Reissner's membrane. Therefore, the Otx2-positive domain of the cochlear duct shows a striking competence to develop into a mirror-image copy of the organ of Corti. Taken together, these data show that Otx2 acts downstream of N-myc and is essential for patterning and spatial restriction of the sensory domain of the mammalian cochlea. PMID:26160903

  19. Development and Aging of the Kisspeptin–GPR54 System in the Mammalian Brain: What are the Impacts on Female Reproductive Function?

    PubMed Central

    Franceschini, Isabelle; Desroziers, Elodie

    2012-01-01

    The prominent role of the G protein coupled receptor GPR54 and its peptide ligand kisspeptin in the progression of puberty has been extensively documented in many mammalian species including humans. Kisspeptins are very potent gonadotropin-releasing hormone secretagogues produced by two main populations of neurons located in two ventral forebrain regions, the preoptic area and the arcuate nucleus. Within the last 2 years a substantial amount of data has accumulated concerning the development of these neuronal populations and their timely regulation by central and peripheral factors during fetal, neonatal, and peripubertal stages of development. This review focuses on the development of the kisspeptin–GPR54 system in the brain of female mice, rats, sheep, monkeys, and humans. We will also discuss the notion that this system represents a major target through which signals from the environment early in life can reprogram reproductive function. PMID:23543285

  20. Implications of plant glycans in the development of innovative vaccines.

    PubMed

    Rosales-Mendoza, Sergio; Salazar-González, Jorge A; Decker, Eva L; Reski, Ralf

    2016-07-01

    Plant glycans play a central role in vaccinology: they can serve as adjuvants and/or delivery vehicles or backbones for the synthesis of conjugated vaccines. In addition, genetic engineering is leading to the development of platforms for the production of novel polysaccharides in plant cells, an approach with relevant implications for the design of new types of vaccines. This review contains an updated outlook on this topic and provides key perspectives including a discussion on how the molecular pharming field can be linked to the production of innovative glycan-based and conjugate vaccines.

  1. Implications of plant glycans in the development of innovative vaccines.

    PubMed

    Rosales-Mendoza, Sergio; Salazar-González, Jorge A; Decker, Eva L; Reski, Ralf

    2016-07-01

    Plant glycans play a central role in vaccinology: they can serve as adjuvants and/or delivery vehicles or backbones for the synthesis of conjugated vaccines. In addition, genetic engineering is leading to the development of platforms for the production of novel polysaccharides in plant cells, an approach with relevant implications for the design of new types of vaccines. This review contains an updated outlook on this topic and provides key perspectives including a discussion on how the molecular pharming field can be linked to the production of innovative glycan-based and conjugate vaccines. PMID:26890067

  2. Yapsin 1 immunoreactivity in alpha cells of human pancreatic Islets: Implications for the processing of human proglucagon by mammalian aspartic proteases

    PubMed Central

    Cawley, Niamh X.; Portela-Gomes, Guida; Lou, Hong; Loh, Y. Peng

    2013-01-01

    Yapsin 1 is an aspartic protease from Saccharomyces cerevisiae and belongs to a class of aspartic proteases that demonstrate specificity for basic amino acids. It is capable of processing prohormone substrates at specific basic residue cleavage sites, similar to that of the prohormone convertases, to generate bioactive peptide hormones. An antibody raised against yapsin 1 was previously shown to immuno-stain endocrine cells of rat pituitary and brain as well as lysates from bovine pituitary secretory granules demonstrating the existence of yapsin 1-like aspartic proteases in mammalian endocrine tissues, potentially involved in peptide hormone production. Here we show the specific staining of yapsin 1 immunoreactivity in the alpha cells of human pancreatic islets. No staining was observed in the beta or delta cells indicating a specificity of the staining for glucagon producing and not insulin or somatostatin producing cells. Purified yapsin 1 was also shown to process proglucagon into authentic glucagon in vitro demonstrating that the prototypical enzyme of this sub-class of enzymes can correctly process proglucagon to glucagon. These findings suggest the existence of a yapsin 1-like enzyme exclusively in the alpha cells of the islets of Langerhans in humans and may play a role in the production of glucagon in that tissue. PMID:21632904

  3. Evolving targets for DEMO: Implications for materials development

    NASA Astrophysics Data System (ADS)

    Cook, Ian; Maisonnier, David; Ward, David

    2009-04-01

    Current reference fusion development scenarios assume the sequential achievement of key milestones. Firstly, the qualification of the plasma physics basis in ITER, together with the qualification of materials for in-vessel components in IFMIF. Secondly, the qualification of components and processes in DEMO. However, the circumstances, within which fusion development planning is undertaken, are changing, and it is becoming reasonable to plan on the assumption that within 20 years ITER and IFMIF will have been successful and the world will be eager for clean, secure energy supplies. This motivates supplementing the reference scenario with the consideration of reduced targets for the economic performance of a first generation of fusion power plants that could be deployed as early as possible, and so reduced targets for the technical performance of early DEMOs. The implications of the reference scenario and variants for fusion materials development are considerable, and these are discussed in this paper.

  4. Implications of temperature variation for malaria parasite development across Africa

    PubMed Central

    Blanford, J. I.; Blanford, S.; Crane, R. G.; Mann, M. E.; Paaijmans, K. P.; Schreiber, K. V.; Thomas, M. B.

    2013-01-01

    Temperature is an important determinant of malaria transmission. Recent work has shown that mosquito and parasite biology are influenced not only by average temperature, but also by the extent of the daily temperature variation. Here we examine how parasite development within the mosquito (Extrinsic Incubation Period) is expected to vary over time and space depending on the diurnal temperature range and baseline mean temperature in Kenya and across Africa. Our results show that under cool conditions, the typical approach of using mean monthly temperatures alone to characterize the transmission environment will underestimate parasite development. In contrast, under warmer conditions, the use of mean temperatures will overestimate development. Qualitatively similar patterns hold using both outdoor and indoor temperatures. These findings have important implications for defining malaria risk. Furthermore, understanding the influence of daily temperature dynamics could provide new insights into ectotherm ecology both now and in response to future climate change. PMID:23419595

  5. Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development.

    PubMed

    Dorr, Kerry M; Amin, Nirav M; Kuchenbrod, Lauren M; Labiner, Hanna; Charpentier, Marta S; Pevny, Larysa H; Wessels, Andy; Conlon, Frank L

    2015-06-01

    Organ growth occurs through the integration of external growth signals during the G1 phase of the cell cycle to initiate DNA replication. Although numerous growth factor signals have been shown to be required for the proliferation of cardiomyocytes, genetic studies have only identified a very limited number of transcription factors that act to regulate the entry of cardiomyocytes into S phase. Here, we report that the cardiac para-zinc-finger protein CASZ1 is expressed in murine cardiomyocytes. Genetic fate mapping with an inducible Casz1 allele demonstrates that CASZ1-expressing cells give rise to cardiomyocytes in the first and second heart fields. We show through the generation of a cardiac conditional null mutation that Casz1 is essential for the proliferation of cardiomyocytes in both heart fields and that loss of Casz1 leads to a decrease in cardiomyocyte cell number. We further report that the loss of Casz1 leads to a prolonged or arrested S phase, a decrease in DNA synthesis, an increase in phospho-RB and a concomitant decrease in the cardiac mitotic index. Taken together, these studies establish a role for CASZ1 in mammalian cardiomyocyte cell cycle progression in both the first and second heart fields.

  6. The mammalian blastocyst.

    PubMed

    Frankenberg, Stephen R; de Barros, Flavia R O; Rossant, Janet; Renfree, Marilyn B

    2016-01-01

    The blastocyst is a mammalian invention that carries the embryo from cleavage to gastrulation. For such a simple structure, it exhibits remarkable diversity in its mode of formation, morphology, longevity, and intimacy with the uterine endometrium. This review explores this diversity in the light of the evolution of viviparity, comparing the three main groups of mammals: monotremes, marsupials, and eutherians. The principal drivers in blastocyst evolution were loss of yolk coupled with evolution of the placenta. An important outcome of blastocyst development is differentiation of two extraembryonic lineages (trophoblast and hypoblast) that contribute to the placenta. While in many species trophoblast segregation is often coupled with blastocyst formation, in marsupials and at least some Afrotherians, these events do not coincide. Thus, many questions regarding the conservation of molecular mechanisms controlling these events are of great interest but currently unresolved. For further resources related to this article, please visit the WIREs website. PMID:26799266

  7. Perceptual skill in soccer: implications for talent identification and development.

    PubMed

    Williams, A M

    2000-09-01

    In this review, key components of perceptual skill in soccer are identified and implications for talent identification and development highlighted. Skilled soccer players can recall and recognize patterns of play more effectively than their less skilled counterparts. This ability to encode, retrieve and recognize sport-specific information is due to complex and discriminating long-term memory structures and is crucial to anticipation in soccer. Similarly, experts use their knowledge of situational probabilities (i.e. expectations) to anticipate future events. They have a better than average idea of what is likely to happen given a particular set of circumstances. Also, proficiency-related differences in visual search strategy are observed. Skilled players use their superior knowledge to control the eye movement patterns necessary for seeking and picking up important sources of information. The nature of the task plays an important role in constraining the type of search used. Skilled soccer players use different search strategies when viewing the whole field (i.e. 11 vs 11 situations) compared with micro-states of the game (i.e. 1 vs 1, 3 vs 3 situations). Visual search behaviour also differs between defensive and offensive plays. These observations have implications for the development of perceptual training programmes and the identification of potential elite soccer players.

  8. cAMP-dependent activation of mammalian target of rapamycin (mTOR) in thyroid cells. Implication in mitogenesis and activation of CDK4.

    PubMed

    Blancquaert, Sara; Wang, Lifu; Paternot, Sabine; Coulonval, Katia; Dumont, Jacques E; Harris, Thurl E; Roger, Pierre P

    2010-07-01

    How cAMP-dependent protein kinases [protein kinase A (PKA)] transduce the mitogenic stimulus elicited by TSH in thyroid cells to late activation of cyclin D3-cyclin-dependent kinase 4 (CDK4) remains enigmatic. Here we show in PC Cl3 rat thyroid cells that TSH/cAMP, like insulin, activates the mammalian target of rapamycin (mTOR)-raptor complex (mTORC1) leading to phosphorylation of S6K1 and 4E-BP1. mTORC1-dependent S6K1 phosphorylation in response to both insulin and cAMP required amino acids, whereas inhibition of AMP-activated protein kinase and glycogen synthase kinase 3 enhanced insulin but not cAMP effects. Unlike insulin, TSH/cAMP did not activate protein kinase B or induce tuberous sclerosis complex 2 phosphorylation at T1462 and Y1571. However, like insulin, TSH/cAMP produced a stable increase in mTORC1 kinase activity that was associated with augmented 4E-BP1 binding to raptor. This could be caused in part by T246 phosphorylation of PRAS40, which was found as an in vitro substrate of PKA. Both in PC Cl3 cells and primary dog thyrocytes, rapamycin inhibited DNA synthesis and retinoblastoma protein phosphorylation induced by TSH and insulin. Although rapamycin reduced cyclin D3 accumulation, the abundance of cyclin D3-CDK4 complexes was not affected. However, rapamycin inhibited the activity of these complexes by decreasing the TSH and insulin-mediated stimulation of activating T172 phosphorylation of CDK4. We propose that mTORC1 activation by TSH, at least in part through PKA-dependent phosphorylation of PRAS40, crucially contributes to mediate cAMP-dependent mitogenesis by regulating CDK4 T172-phosphorylation. PMID:20484410

  9. Ontogeny of joint mechanics in squirrel monkeys (Saimiri boliviensis): functional implications for mammalian limb growth and locomotor development.

    PubMed

    Young, Jesse W

    2009-05-01

    Juvenile animals must often compete against adults for common resources, keep pace during group travel and evade common predators, despite reduced body size and an immature musculoskeletal system. Previous morphometric studies of a diverse array of mammals, including jack rabbits, cats and capuchin monkeys, have identified growth-related changes in anatomy, such as negative allometry of limb muscle mechanical advantage, which should theoretically permit young mammals to overcome such ontogenetic limits on performance. However, it is important to evaluate the potential impact of such ;compensatory' growth trajectories within the context of developmental changes in locomotor behavior. I used standard kinematic and kinetic techniques to investigate the ontogenetic scaling of joint postures, substrate reaction forces, joint load arm lengths and external joint moments in an ontogenetic sample of squirrel monkeys (Saimiri boliviensis). Results indicated that young squirrel monkeys were frequently able to limit forelimb and hind limb joint loading via a combination of changes in limb posture and limb force distribution, potentially compensating for limited muscularity at younger ages. These results complement previous morphometric studies and suggest that immature mammals may utilize a combination of behavioral and anatomical mechanisms to mitigate ontogenetic limits on locomotor performance. However, ontogenetic changes in joint posture, not limb length per se, explained most of the variation in load arm lengths and joint loading in growing squirrel monkeys, indicating the importance of incorporating both anatomical and performance measures when studying the ontogeny of limb joint mechanics.

  10. A sociological implication of environment in social development.

    PubMed

    Jeong, D Y

    1997-12-01

    This study, which identifies the sociological implication of the environment in social development, was based on the notion that environmental research should recognize that the environment consists of 3 main, interdependent components: the natural environment, the man-made environment, and the social environment. The study first examines these components of environment and their internal mechanisms and, after noting that sociology has failed to explore the interdependence among these components, offers a new notion of ecosystem that modifies and expands the framework offered by Duncan's POET model (increased population creates pressure for technological change, increases urbanization, and creates more pollution). Next, the paper examines the emerging natural and social environmental problems caused by industrialization. The concluding section reviews the development of concepts about the relationship between the environment and social development based on the assumption of limited natural resources. Because it is now understood that it is more appropriate to consider the limit of ecological capacity, it is important to learn to measure social development by the successful achievement of an adaptation or by harmonization with the environment, rather than by material growth. This requires a conceptualization of man as being part of, rather than independent of, nature. New indicators must be developed to measure the degree of social development achieved.

  11. A sociological implication of environment in social development.

    PubMed

    Jeong, D Y

    1997-12-01

    This study, which identifies the sociological implication of the environment in social development, was based on the notion that environmental research should recognize that the environment consists of 3 main, interdependent components: the natural environment, the man-made environment, and the social environment. The study first examines these components of environment and their internal mechanisms and, after noting that sociology has failed to explore the interdependence among these components, offers a new notion of ecosystem that modifies and expands the framework offered by Duncan's POET model (increased population creates pressure for technological change, increases urbanization, and creates more pollution). Next, the paper examines the emerging natural and social environmental problems caused by industrialization. The concluding section reviews the development of concepts about the relationship between the environment and social development based on the assumption of limited natural resources. Because it is now understood that it is more appropriate to consider the limit of ecological capacity, it is important to learn to measure social development by the successful achievement of an adaptation or by harmonization with the environment, rather than by material growth. This requires a conceptualization of man as being part of, rather than independent of, nature. New indicators must be developed to measure the degree of social development achieved. PMID:12293790

  12. Amino acids and mammary gland development: nutritional implications for milk production and neonatal growth.

    PubMed

    Rezaei, Reza; Wu, Zhenlong; Hou, Yongqing; Bazer, Fuller W; Wu, Guoyao

    2016-01-01

    Milk is synthesized by mammary epithelial cells of lactating mammals. The synthetic capacity of the mammary gland depends largely on the number and efficiency of functional mammary epithelial cells. Structural development of the mammary gland occurs during fetal growth, prepubertal and post-pubertal periods, pregnancy, and lactation under the control of various hormones (particularly estrogen, growth hormone, insulin-like growth factor-I, progesterone, placental lactogen, and prolactin) in a species- and stage-dependent manner. Milk is essential for the growth, development, and health of neonates. Amino acids (AA), present in both free and peptide-bound forms, are the most abundant organic nutrients in the milk of farm animals. Uptake of AA from the arterial blood of the lactating dam is the ultimate source of proteins (primarily β-casein and α-lactalbumin) and bioactive nitrogenous metabolites in milk. Results of recent studies indicate extensive catabolism of branched-chain AA (leucine, isoleucine and valine) and arginine to synthesize glutamate, glutamine, alanine, aspartate, asparagine, proline, and polyamines. The formation of polypeptides from AA is regulated not only by hormones (e.g., prolactin, insulin and glucocorticoids) and the rate of blood flow across the lactating mammary gland, but also by concentrations of AA, lipids, glucose, vitamins and minerals in the maternal plasma, as well as the activation of the mechanistic (mammalian) target rapamycin signaling by certain AA (e.g., arginine, branched-chain AA, and glutamine). Knowledge of AA utilization (including metabolism) by mammary epithelial cells will enhance our fundamental understanding of lactation biology and has important implications for improving the efficiency of livestock production worldwide. PMID:27042295

  13. Photodynamic Inactivation of Mammalian Viruses and Bacteriophages

    PubMed Central

    Costa, Liliana; Faustino, Maria Amparo F.; Neves, Maria Graça P. M. S.; Cunha, Ângela; Almeida, Adelaide

    2012-01-01

    Photodynamic inactivation (PDI) has been used to inactivate microorganisms through the use of photosensitizers. The inactivation of mammalian viruses and bacteriophages by photosensitization has been applied with success since the first decades of the last century. Due to the fact that mammalian viruses are known to pose a threat to public health and that bacteriophages are frequently used as models of mammalian viruses, it is important to know and understand the mechanisms and photodynamic procedures involved in their photoinactivation. The aim of this review is to (i) summarize the main approaches developed until now for the photodynamic inactivation of bacteriophages and mammalian viruses and, (ii) discuss and compare the present state of the art of mammalian viruses PDI with phage photoinactivation, with special focus on the most relevant mechanisms, molecular targets and factors affecting the viral inactivation process. PMID:22852040

  14. Photodynamic inactivation of mammalian viruses and bacteriophages.

    PubMed

    Costa, Liliana; Faustino, Maria Amparo F; Neves, Maria Graça P M S; Cunha, Angela; Almeida, Adelaide

    2012-07-01

    Photodynamic inactivation (PDI) has been used to inactivate microorganisms through the use of photosensitizers. The inactivation of mammalian viruses and bacteriophages by photosensitization has been applied with success since the first decades of the last century. Due to the fact that mammalian viruses are known to pose a threat to public health and that bacteriophages are frequently used as models of mammalian viruses, it is important to know and understand the mechanisms and photodynamic procedures involved in their photoinactivation. The aim of this review is to (i) summarize the main approaches developed until now for the photodynamic inactivation of bacteriophages and mammalian viruses and, (ii) discuss and compare the present state of the art of mammalian viruses PDI with phage photoinactivation, with special focus on the most relevant mechanisms, molecular targets and factors affecting the viral inactivation process.

  15. Recent advances in mammalian protein production

    PubMed Central

    Bandaranayake, Ashok D.; Almo, Steven C.

    2014-01-01

    Mammalian protein production platforms have had a profound impact in many areas of basic and applied research, and an increasing number of blockbuster drugs are recombinant mammalian proteins. With global sales of these drugs exceeding US$120 billion per year, both industry and academic research groups continue to develop cost effective methods for producing mammalian proteins to support preclinical and clinical evaluations of potential therapeutics. While a wide range of platforms have been successfully exploited for laboratory use, the bulk of recent biologics have been produced in mammalian cell lines due to the requirement for post translational modification and the biosynthetic complexity of the target proteins. In this review we highlight the range of mammalian expression platforms available for recombinant protein production, as well as advances in technologies for the rapid and efficient selection of highly productive clones. PMID:24316512

  16. Community-building principles: implications for professional development.

    PubMed

    Austin, Sandra

    2005-01-01

    This article reviews a Think Tank meeting among child welfare practitioners at the 2003 Building Communities for 21st-Century Child Welfare Symposium. The Child Welfare League of America's focus on community building is recognition of the vital importance of promoting and fostering collaboration with community members to enhance the well-being of children, families, and communities. The Think Tank participants responded to four questions concerning the knowledge, policies, and strategies that are needed for the development of strategies for community building and child welfare. This article highlights several of the findings of the preconference, which addressed the challenges and opportunities inherent in community-building practices and discusses the key principles that emerged from the Think Tank. The article emphasizes implications for professional education and cites selected examples of innovative community-building initiatives with families.

  17. [Effects of phosphatidylinositol-3 kinase/protein kinase b/bone morphogenetic protein-15 pathway on the follicular development in the mammalian ovary].

    PubMed

    Wu, Yan-qing; Chen, Li-yun; Zhang, Zheng-hong; wang, Zheng-chao

    2013-04-01

    In mammals, ovarian follicle is made of an oocyte with its surrounding granulosa cells and theca cells. Follicular growth and development is a highly coordinated programmable process, which guarantees the normal oocyte maturation and makes it having the fertilizing capacity. The paracrine and autocrine between oocytes and granulosa cells are essential for the follicular development to provide a suitable microenvironment. Phosphatidylinositol-3 kinase /protein kinase B is one of these important regulatory signaling pathways during this developmental process, and bone morphogenetic protein-15 an oocyte-specific secreted signal molecule, which regulates the follicular development by paracrine in the mammalian ovary. The present article overviewed the role of phosphatidylinositol-3 kinase / protein kinase B signaling during the follicular development based on our previous investigation about protein kinase B /forkhead transcription factor forkhead family of transcription factors -3a, and then focused on the regulatory effects of bone morphogenetic protein-15, as a downstream signal molecule of phosphatidylinositol-3 kinase / forkhead family of transcription factors -3a pathway, on ovarian follicular development, which helped to further understand the molecular mechanism regulating the follicular development and to treat ovarian diseases like infertility.

  18. Slip of the tongue: Implications for evolution and language development.

    PubMed

    Forrester, Gillian S; Rodriguez, Alina

    2015-08-01

    A prevailing theory regarding the evolution of language implicates a gestural stage prior to the emergence of speech. In support of a transition of human language from a gestural to a vocal system, articulation of the hands and the tongue are underpinned by overlapping left hemisphere dominant neural regions. Behavioral studies demonstrate that human adults perform sympathetic mouth actions in imitative synchrony with manual actions. Additionally, right-handedness for precision manual actions in children has been correlated with the typical development of language, while a lack of hand bias has been associated with psychopathology. It therefore stands to reason that sympathetic mouth actions during fine precision motor action of the hands may be lateralized. We employed a fine-grained behavioral coding paradigm to provide the first investigation of tongue protrusions in typically developing 4-year old children. Tongue protrusions were investigated across a range of cognitive tasks that required varying degrees of manual action: precision motor action, gross motor action and no motor actions. The rate of tongue protrusions was influenced by the motor requirements of the task and tongue protrusions were significantly right-biased for only precision manual motor action (p<.001). From an evolutionary perspective, tongue protrusions can drive new investigations regarding how an early human communication system transitioned from hand to mouth. From a developmental perspective, the present study may serve to reveal patterns of tongue protrusions during the motor development of typically developing children.

  19. Development and disadvantage: implications for the early years and beyond.

    PubMed

    Locke, Ann; Ginsborg, Jane; Peers, Ian

    2002-01-01

    Links have long been made between literacy and economic development, and recent governments in the UK have put great emphasis on the teaching of literacy to raise educational standards. There is substantial evidence to show that spoken and written language share some processes in common and that the development of literacy is supported by the development of spoken language. Anecdotal evidence from early years practitioners suggests that many children coming into early years education, particularly those from disadvantaged socioeconomic backgrounds, may not have the spoken language skills needed to develop reading and writing. This preliminary study aimed to investigate the extent to which the spoken language skills of children reared in poverty are depressed in comparison with the general population, and in comparison with their general cognitive abilities. Two tests were administered to children in their first term at nursery school to measure their spoken language skills and cognitive abilities: CELF-PUK and BAS II. More than half of the children were found to be language-delayed, although girls' receptive language abilities were significantly better than those of boys. Participants' language skills were also significantly depressed in comparison with their cognitive abilities. Government initiatives to raise awareness of spoken language in the early years are discussed, and implications for the future role of speech and language therapists working in the pre-school sector are considered. PMID:11852457

  20. Responses to Cell Loss Become Restricted as the Supporting Cells in Mammalian Vestibular Organs Grow Thick Junctional Actin Bands That Develop High Stability

    PubMed Central

    Burns, Joseph C.

    2014-01-01

    Sensory hair cell (HC) loss is a major cause of permanent hearing and balance impairments for humans and other mammals. Yet, fish, amphibians, reptiles, and birds readily replace HCs and recover from such sensory deficits. It is unknown what prevents replacement in mammals, but cell replacement capacity declines contemporaneously with massive postnatal thickening of F-actin bands at the junctions between vestibular supporting cells (SCs). In non-mammals, SCs can give rise to regenerated HCs, and the bands remain thin even in adults. Here we investigated the stability of the F-actin bands between SCs in ears from chickens and mice and Madin-Darby canine kidney cells. Pharmacological experiments and fluorescence recovery after photobleaching (FRAP) of SC junctions in utricles from mice that express a γ-actin–GFP fusion protein showed that the thickening F-actin bands develop increased resistance to depolymerization and exceptional stability that parallels a sharp decline in the cell replacement capacity of the maturing mammalian ear. The FRAP recovery rate and the mobile fraction of γ-actin–GFP both decreased as the bands thickened with age and became highly stabilized. In utricles from neonatal mice, time-lapse recordings in the vicinity of dying HCs showed that numerous SCs change shape and organize multicellular actin purse strings that reseal the epithelium. In contrast, adult SCs appeared resistant to deformation, with resealing responses limited to just a few neighboring SCs that did not form purse strings. The exceptional stability of the uniquely thick F-actin bands at the junctions of mature SCs may play an important role in restricting dynamic repair responses in mammalian vestibular epithelia. PMID:24478379

  1. Long-term live-cell imaging of mammalian preimplantation development and derivation process of pluripotent stem cells from the embryos.

    PubMed

    Yamagata, Kazuo; Ueda, Jun

    2013-05-01

    Mammalian fertilization is a process in which two highly specialized haploid gametes unite and endow totipotency to the resulting diploid zygote. This is followed by cell proliferation and the onset of differentiation during the brief period leading up to implantation. In these processes, a number of cellular components and structures are regulated spatially and temporally, as seen in repeated cell division, cell cycle progression, and epigenetic reprogramming. In mammals, the numbers of oocytes and embryos that can be collected are very limited. Therefore, analyses of molecular mechanisms are hampered because of difficulties in conducting biochemical analyses on such limited material. Furthermore, immunostaining methods require cell fixation and are insufficient for understanding ontogeny, because the processes observed in fertilization and early embryonic development progress in time-dependent manners and each phenomenon is connected with others by cause-and-effect relationships. Consequently, it is important to develop an experimental system that enables molecular imaging without affecting embryonic development. To achieve the above advantages, especially retrospective and prospective analyses, we have established a live-cell imaging system that enables observations under minimally invasive conditions. Using this approach, we have succeeded in visualizing and predicting the developmental potential of embryos after various perturbations. We also succeeded in imaging embryonic stem (ES) cell derivation in natural conditions. In this review, we describe a brief history of embryonic imaging and detailed protocols. We also discuss promising aspects of imaging in the fields of developmental and stem cell biology.

  2. Cell-to-cell diffusion of glucose in the mammalian heart is disrupted by high glucose. Implications for the diabetic heart.

    PubMed

    De Mello, Walmor C

    2015-06-10

    between cardiac myocytes. These observations support the view that the intracrine renin angiotensin system is a modulator of chemical communication in the heart. The implications of these findings for the diabetic heart were discussed.

  3. Patterning of the mammalian cochlea

    PubMed Central

    Cantos, Raquel; Cole, Laura K.; Acampora, Dario; Simeone, Antonio; Wu, Doris K.

    2000-01-01

    The mammalian cochlea is sophisticated in its function and highly organized in its structure. Although the anatomy of this sense organ has been well documented, the molecular mechanisms underlying its development have remained elusive. Information generated from mutant and knockout mice in recent years has increased our understanding of cochlear development and physiology. This article discusses factors important for the development of the inner ear and summarizes cochlear phenotypes of mutant and knockout mice, particularly Otx and Otx2. We also present data on gross development of the mouse cochlea. PMID:11050199

  4. Bifurcation in epigenetics: Implications in development, proliferation, and diseases

    NASA Astrophysics Data System (ADS)

    Jost, Daniel

    2014-01-01

    Cells often exhibit different and stable phenotypes from the same DNA sequence. Robustness and plasticity of such cellular states are controlled by diverse transcriptional and epigenetic mechanisms, among them the modification of biochemical marks on chromatin. Here, we develop a stochastic model that describes the dynamics of epigenetic marks along a given DNA region. Through mathematical analysis, we show the emergence of bistable and persistent epigenetic states from the cooperative recruitment of modifying enzymes. We also find that the dynamical system exhibits a critical point and displays, in the presence of asymmetries in recruitment, a bifurcation diagram with hysteresis. These results have deep implications for our understanding of epigenetic regulation. In particular, our study allows one to reconcile within the same formalism the robust maintenance of epigenetic identity observed in differentiated cells, the epigenetic plasticity of pluripotent cells during differentiation, and the effects of epigenetic misregulation in diseases. Moreover, it suggests a possible mechanism for developmental transitions where the system is shifted close to the critical point to benefit from high susceptibility to developmental cues.

  5. Simplified Bioreactor For Growing Mammalian Cells

    NASA Technical Reports Server (NTRS)

    Spaulding, Glenn F.

    1995-01-01

    Improved bioreactor for growing mammalian cell cultures developed. Designed to support growth of dense volumes of mammalian cells by providing ample, well-distributed flows of nutrient solution with minimal turbulence. Cells relatively delicate and, unlike bacteria, cannot withstand shear forces present in turbulent flows. Bioreactor vessel readily made in larger sizes to accommodate greater cell production quantities. Molding equipment presently used makes cylinders up to 30 centimeters long. Alternative sintered plastic techniques used to vary pore size and quantity, as necessary.

  6. Rhabdomyosarcoma: current challenges and their implications for developing therapies.

    PubMed

    Hettmer, Simone; Li, Zhizhong; Billin, Andrew N; Barr, Frederic G; Cornelison, D D W; Ehrlich, Alan R; Guttridge, Denis C; Hayes-Jordan, Andrea; Helman, Lee J; Houghton, Peter J; Khan, Javed; Langenau, David M; Linardic, Corinne M; Pal, Ranadip; Partridge, Terence A; Pavlath, Grace K; Rota, Rossella; Schäfer, Beat W; Shipley, Janet; Stillman, Bruce; Wexler, Leonard H; Wagers, Amy J; Keller, Charles

    2014-11-03

    Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNA-binding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in <30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusion-positive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate

  7. Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

    PubMed Central

    Hettmer, Simone; Li, Zhizhong; Billin, Andrew N.; Barr, Frederic G.; Cornelison, D.D.W.; Ehrlich, Alan R.; Guttridge, Denis C.; Hayes-Jordan, Andrea; Helman, Lee J.; Houghton, Peter J.; Khan, Javed; Langenau, David M.; Linardic, Corinne M.; Pal, Ranadip; Partridge, Terence A.; Pavlath, Grace K.; Rota, Rossella; Schäfer, Beat W.; Shipley, Janet; Stillman, Bruce; Wexler, Leonard H.; Wagers, Amy J.; Keller, Charles

    2014-01-01

    Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called “fusion-positive” tumors) carries exclusive chromosomal translocations that join the DNA-binding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in <30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusion-positive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate

  8. The International Implications of the Development of Microelectronics.

    ERIC Educational Resources Information Center

    Sieghart, Paul

    1981-01-01

    Synthesizes issues covered at a conference on microelectronics: production, productivity, and employment; social implications; market mechanisms v government intervention; the role of national governments; data protection laws; and cultural pollution. (SW)

  9. Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs.

    PubMed

    Markey, Caroline M; Coombs, Macall A; Sonnenschein, Carlos; Soto, Ana M

    2003-01-01

    Recent findings in the field of environmental endocrine disruption have revealed that developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. The aim of the present study was to determine the effects of in utero exposure to low doses of the estrogenic chemical bisphenol A (BPA) on the development of the female reproductive tissues and mammary glands in CD-1 mice. Humans are exposed to BPA, which leaches from dental materials and plastic food and beverage containers. Here we report that prenatal exposure to BPA induces alterations in tissue organization within the ovaries and mammary glands and disrupts estrous cyclicity in adulthood. Because estrogen receptors are expressed developmentally in these estrogen-target organs, we propose that BPA may directly affect the expression of genes involved in their morphogenesis. In addition, alterations in the sexual differentiation of the brain, and thus the hypothalamic-pituitary-gonadal axis, may further contribute to the observed phenotype. The emerging field of endocrine disruptors promises to provide new insights into the mechanisms underlying the development of hormone-target organs and demonstrates that the environment plays important roles in the making of phenotypes.

  10. The Wellcome Prize Lecture. A map of auditory space in the mammalian brain: neural computation and development.

    PubMed

    King, A J

    1993-09-01

    The experiments described in this review have demonstrated that the SC contains a two-dimensional map of auditory space, which is synthesized within the brain using a combination of monaural and binaural localization cues. There is also an adaptive fusion of auditory and visual space in this midbrain nucleus, providing for a common access to the motor pathways that control orientation behaviour. This necessitates a highly plastic relationship between the visual and auditory systems, both during postnatal development and in adult life. Because of the independent mobility of difference sense organs, gating mechanisms are incorporated into the auditory representation to provide up-to-date information about the spatial orientation of the eyes and ears. The SC therefore provides a valuable model system for studying a number of important issues in brain function, including the neural coding of sound location, the co-ordination of spatial information between different sensory systems, and the integration of sensory signals with motor outputs. PMID:8240794

  11. Development of a new screening assay to identify proteratogenic substances using zebrafish danio rerio embryo combined with an exogenous mammalian metabolic activation system (mDarT).

    PubMed

    Busquet, François; Nagel, Roland; von Landenberg, Friedrich; Mueller, Stefan O; Huebler, Nicole; Broschard, Thomas H

    2008-07-01

    The assessment of teratogenic effects of chemicals is generally performed using in vivo teratogenicity assays, for example, in rats or rabbits. We have developed an in vitro teratogenicity assay using the zebrafish Danio rerio embryo combined with an exogenous mammalian metabolic activation system (MAS), able to biotransform proteratogenic compounds. Cyclophosphamide (CPA) and ethanol were used as proteratogens to test the efficiency of this assay. Briefly, the zebrafish embryos were cocultured at 2 hpf (hours postfertilization) with the test material at varying concentrations, induced male rat liver microsomes and nicotinamide adenine dinucleotide phosphate (reduced) for 60 min at 32 degrees C under moderate agitation in Tris-buffer. The negative control (test material alone) and the MAS control (MAS alone) were incubated in parallel. For each test group, 20 eggs were used for statistical robustness. Afterward fish embryos were transferred individually into 24-well plates filled with fish medium for 48 h at 26 degrees C with a 12-h light cycle. Teratogenicity was scored after 24 and 48 hpf using morphological endpoints. No teratogenic effects were observed in fish embryos exposed to the proteratogens alone, that is, without metabolic activation. In contrast, CPA and ethanol induced abnormalities in fish embryos when coincubated with microsomes. The severity of malformations increased with increasing concentrations of the proteratogens. We conclude that the application of microsomes will improve and refine the D. rerio teratogenicity assay as a predictive and valuable alternative method to screen teratogenic substances.

  12. An SRY-related sequence on the marsupial X chromosome: implications for the evolution of the mammalian testis-determining gene.

    PubMed Central

    Foster, J W; Graves, J A

    1994-01-01

    The SRY gene on the human, mouse, and marsupial Y chromosomes is the testis-determining gene that initiates male development in mammals. The SRY protein has a DNA-binding domain (high mobility group or HMG box) similar to those found in the high-mobility-group proteins. SRY is specific for the Y chromosome, but many autosomal genes have been identified that possess a similar HMG box region; those with the most closely SRY-related box regions form a gene family now referred to as SOX genes. We have identified a sequence on the marsupial X chromosome that shares homology with SRY. Sequence comparisons show near-identity with the mouse and human SOX3 gene (formerly called a3), the SOX gene which is the most closely related to SRY. We suggest here that the highly conserved X chromosome-linked SOX3 represents the ancestral SOX gene from which the sex-determining gene SRY was derived. In this model SOX3/SRY divergence and the acquisition of a testis-determining role by SRY might have preceded (and initiated) sex chromosome differentiation or, alternatively, might have been a consequence of X chromosome-Y chromosome differentiation initiated at the locus of an original sex-determining gene(s), later superseded by SRY. Images PMID:8127908

  13. Implications of a Bayesian radiocarbon calibration of colonization ages for mammalian megafauna in glaciated New York State after the Last Glacial Maximum

    NASA Astrophysics Data System (ADS)

    Feranec, Robert S.; Kozlowski, Andrew L.

    2016-03-01

    To understand what factors control species colonization and extirpation within specific paleoecosystems, we analyzed radiocarbon dates of megafaunal mammal species from New York State after the Last Glacial Maximum. We hypothesized that the timing of colonization and extirpation were both driven by access to preferred habitat types. Bayesian calibration of a database of 39 radiocarbon dates shows that caribou (Rangifer tarandus) were the first colonizers, then mammoth (Mammuthus sp.), and finally American mastodon (Mammut americanum). The timing of colonization cannot reject the hypothesis that colonizing megafauna tracked preferred habitats, as caribou and mammoth arrived when tundra was present, while mastodon arrived after boreal forest was prominent in the state. The timing of caribou colonization implies that ecosystems were developed in the state prior to 16,000 cal yr BP. The contemporaneous arrival of American mastodon with Sporormiella spore decline suggests the dung fungus spore is not an adequate indicator of American mastodon population size. The pattern in the timing of extirpation is opposite to that of colonization. The lack of environmental changes suspected to be ecologically detrimental to American mastodon and mammoth coupled with the arrival of humans shortly before extirpation suggests an anthropogenic cause in the loss of the analyzed species.

  14. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development.

    PubMed

    Kobayashi, Akio; Valerius, M Todd; Mugford, Joshua W; Carroll, Thomas J; Self, Michelle; Oliver, Guillermo; McMahon, Andrew P

    2008-08-01

    Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population.

  15. Mammalian airborne allergens.

    PubMed

    Aalberse, Rob C

    2014-01-01

    Historically, horse dandruff was a favorite allergen source material. Today, however, allergic symptoms due to airborne mammalian allergens are mostly a result of indoor exposure, be it at home, at work or even at school. The relevance of mammalian allergens in relation to the allergenic activity of house dust extract is briefly discussed in the historical context of two other proposed sources of house dust allergenic activity: mites and Maillard-type lysine-sugar conjugates. Mammalian proteins involved in allergic reactions to airborne dust are largely found in only 2 protein families: lipocalins and secretoglobins (Fel d 1-like proteins), with a relatively minor contribution of serum albumins, cystatins and latherins. Both the lipocalin and the secretoglobin family are very complex. In some instances this results in a blurred separation between important and less important allergenic family members. The past 50 years have provided us with much detailed information on the genomic organization and protein structure of many of these allergens. However, the complex family relations, combined with the wide range of post-translational enzymatic and non-enzymatic modifications, make a proper qualitative and quantitative description of the important mammalian indoor airborne allergens still a significant proteomic challenge. PMID:24925404

  16. The Inhibition of Pretend Play and Its Implications for Development.

    ERIC Educational Resources Information Center

    Gordon, Debra E.

    1993-01-01

    Describes four kinds of pretend play inhibition observed in children from three to nine years of age. Proposes hypotheses regarding potential causes and developmental sequelae of pretend play difficulties, in both cognitive and socioaffective realms. Discusses the implications of children's pretend play inhibition for examining relationships…

  17. Behavioral Momentum: Implications and Development from Reinforcement Theories.

    ERIC Educational Resources Information Center

    Plaud, Joseph J.; Gaither, George A.

    1996-01-01

    Analyzes historical and contemporary theories of reinforcement and clinical application of reinforcement principles to behavior and modification therapy. Presents a behavioral momentum model that studies the allocation of behavior under changed environmental constraints and discusses the implications of this model on behavior modification and…

  18. Eastern Kentuckians View Their Quality of Life: Implications for Development.

    ERIC Educational Resources Information Center

    Coughenour, C. Milton; Coleman, A. Lee

    Data from 1961, 1971, and 1973 surveys of households and community "knowledgeables" focused on the subjective assesssments of the quality of life (QOL) of residents of Harlan, Perry, Whitley, and Wolfe counties in Eastern Kentucky, and assessed policy implications. Overall, residents assessed their counties favorably. They rated wages and income,…

  19. Cooperative Education in the New Millennium: Implications for Faculty Development.

    ERIC Educational Resources Information Center

    Crow, Cal

    1997-01-01

    Colleges and universities are being challenged to examine their mission, structure, and delivery of services for two reasons with far-reaching implications for cooperative education. The first is the move from an industrial to a postindustrial economy. The second deals with incorrect assumptions about learning based on outmoded information and…

  20. Local Citation Analysis of Graduate Biology Theses: Collection Development Implications

    ERIC Educational Resources Information Center

    Miller, Laura Newton

    2011-01-01

    This paper will focus on the citation analysis of graduate masters theses from Carleton University's Biology Department with implications for library collection management decisions. Twenty-five masters theses were studied to determine citation types and percentages, ranking of journals by frequency of citation and by number of authors citing, and…

  1. Implications of Post-Natal Cortical Development for Creativity Research.

    ERIC Educational Resources Information Center

    Gordon, Marjory; Dacey, John

    Man's long period of cerebral growth has important implications for education. The brain goes through major developmental changes after birth, and researchers have suggested that this growth process presents an opportunity for fostering the plasticity of genetically determined connections. Animal studies show that postnatal growth of the brain is…

  2. Epigenetics in preimplantation mammalian development.

    PubMed

    Canovas, Sebastian; Ross, Pablo Juan

    2016-07-01

    Fertilization is a very dynamic period of comprehensive chromatin remodeling, from which two specialized cells result in a totipotent zygote. The formation of a totipotent cell requires extensive epigenetic remodeling that, although independent of modifications in the DNA sequence, still entails a profound cell-fate change, supported by transcriptional profile modifications. As a result of finely tuned interactions between numerous mechanisms, the goal of fertilization is to form a full healthy new individual. To avoid the persistence of alterations in epigenetic marks, the epigenetic information contained in each gamete is reset during early embryogenesis. Covalent modification of DNA by methylation, as well as posttranslational modifications of histone proteins and noncoding RNAs, appears to be the main epigenetic mechanisms that control gene expression. These allow different cells in an organism to express different transcription profiles, despite each cell containing the same DNA sequence. In the context of replacement of spermatic protamine with histones from the oocyte, active cell division, and specification of different lineages, active and passive mechanisms of epigenetic remodeling have been revealed as critical for editing the epigenetic profile of the early embryo. Importantly, redundant factors and mechanisms are likely in place, and only a few have been reported as critical for fertilization or embryo survival by the use of knockout models. The aim of this review is to highlight the main mechanisms of epigenetic remodeling that ensue after fertilization in mammals.

  3. Evolutionary paths to mammalian cochleae.

    PubMed

    Manley, Geoffrey A

    2012-12-01

    Evolution of the cochlea and high-frequency hearing (>20 kHz; ultrasonic to humans) in mammals has been a subject of research for many years. Recent advances in paleontological techniques, especially the use of micro-CT scans, now provide important new insights that are here reviewed. True mammals arose more than 200 million years (Ma) ago. Of these, three lineages survived into recent geological times. These animals uniquely developed three middle ear ossicles, but these ossicles were not initially freely suspended as in modern mammals. The earliest mammalian cochleae were only about 2 mm long and contained a lagena macula. In the multituberculate and monotreme mammalian lineages, the cochlea remained relatively short and did not coil, even in modern representatives. In the lineage leading to modern therians (placental and marsupial mammals), cochlear coiling did develop, but only after a period of at least 60 Ma. Even Late Jurassic mammals show only a 270 ° cochlear coil and a cochlear canal length of merely 3 mm. Comparisons of modern organisms, mammalian ancestors, and the state of the middle ear strongly suggest that high-frequency hearing (>20 kHz) was not realized until the early Cretaceous (~125 Ma). At that time, therian mammals arose and possessed a fully coiled cochlea. The evolution of modern features of the middle ear and cochlea in the many later lineages of therians was, however, a mosaic and different features arose at different times. In parallel with cochlear structural evolution, prestins in therian mammals evolved into effective components of a new motor system. Ultrasonic hearing developed quite late-the earliest bat cochleae (~60 Ma) did not show features characteristic of those of modern bats that are sensitive to high ultrasonic frequencies.

  4. Evolutionary paths to mammalian cochleae.

    PubMed

    Manley, Geoffrey A

    2012-12-01

    Evolution of the cochlea and high-frequency hearing (>20 kHz; ultrasonic to humans) in mammals has been a subject of research for many years. Recent advances in paleontological techniques, especially the use of micro-CT scans, now provide important new insights that are here reviewed. True mammals arose more than 200 million years (Ma) ago. Of these, three lineages survived into recent geological times. These animals uniquely developed three middle ear ossicles, but these ossicles were not initially freely suspended as in modern mammals. The earliest mammalian cochleae were only about 2 mm long and contained a lagena macula. In the multituberculate and monotreme mammalian lineages, the cochlea remained relatively short and did not coil, even in modern representatives. In the lineage leading to modern therians (placental and marsupial mammals), cochlear coiling did develop, but only after a period of at least 60 Ma. Even Late Jurassic mammals show only a 270 ° cochlear coil and a cochlear canal length of merely 3 mm. Comparisons of modern organisms, mammalian ancestors, and the state of the middle ear strongly suggest that high-frequency hearing (>20 kHz) was not realized until the early Cretaceous (~125 Ma). At that time, therian mammals arose and possessed a fully coiled cochlea. The evolution of modern features of the middle ear and cochlea in the many later lineages of therians was, however, a mosaic and different features arose at different times. In parallel with cochlear structural evolution, prestins in therian mammals evolved into effective components of a new motor system. Ultrasonic hearing developed quite late-the earliest bat cochleae (~60 Ma) did not show features characteristic of those of modern bats that are sensitive to high ultrasonic frequencies. PMID:22983571

  5. Cryopreservation of Mammalian Oocytes by Using Sugars: Intra- and extracellular raffinose with small amounts of dimethylsulfoxide yields high cryosurvival, fertilization, and development rates

    PubMed Central

    Eroglu, Ali

    2009-01-01

    Accumulation of intra- and extracellular sugars such as trehalose, glucose, and raffinose is central to survival strategies of a variety of organisms coping with extreme conditions including freezing and almost complete drying. The objective of the present study was to investigate the potential application of intra- and extracellular raffinose in combination with low concentrations of dimethylsulfoxide (Me2SO) to mammalian oocyte cryopreservation. To this end, the fertilization and embryonic development of cryopreserved metaphase II (M II) mouse oocytes were studied in comparison to unfrozen controls. For cryopreservation, M II oocytes were microinjected with 0.1 M raffinose, and then cooled to -196°C in the presence of either 0.3 M raffinose and 0.5 M Me2SO (cryopreservation group 1) or 0.3 M raffinose and 1.0 M Me2SO (cryopreservation group 2). The control groups included untreated oocytes (untreated control) and oocytes microinjected with raffinose, but not frozen (injection control). The post-thaw survival rates were 83.9% and 80.6% for the cryopreservation group 1 and 2, respectively. The fertilization and blastocyst rates in the cryopreservation group 1 (90.0% and 77.8%, respectively) and 2 (94.6% and 72.5%, respectively) were also high and similar to the ones of the injection controls (97.8% and 78.5%, respectively) and untreated controls (98.8% and 83.6%, respectively). These results are consistent with the findings of our earlier studies and support the use of sugars as intra- and extracellular cryoprotectants. Furthermore, the results of the present study indicate that the presence of intra- and extracellular sugars alleviates high concentrations of conventional penetrating cryoprotectants, and thus minimizes their toxicity. PMID:19596315

  6. Biotinylation of the Fcγ receptor ectodomains by mammalian cell co-transfection: application to the development of a surface plasmon resonance-based assay.

    PubMed

    Dorion-Thibaudeau, July; St-Laurent, Gilles; Raymond, Céline; De Crescenzo, Gregory; Durocher, Yves

    2016-02-01

    We here report the production of four biotinylated Fcγ receptor (FcγR) ectodomains and their subsequent stable capture on streptavidin-biosensor surfaces. For receptor biotinylation, we first describe an in-cell protocol based on the co-transfection of two plasmids corresponding to one of the FcγR ectodomains and the BirA enzyme in mammalian cells. This strategy is compared with a standard sequential in vitro enzymatic biotinylation with respect to biotinylation level and yield. Biotinylated FcγR ectodomains that have been prepared with both strategies are then compared by analytical ultracentrifugation and surface plasmon resonance (SPR) analyses. Overall, we demonstrate that in-cell biotinylation is an interesting alternative to standard biotinylation protocol, as it requires less purification steps while yielding higher titers. Finally, biotin-tagged FcγRs produced with the in-cell approach are successfully applied to the development of SPR-based assays to evaluate the impact of the glycosylation pattern of monoclonal antibodies on their interaction with CD16a and CD64. In that endeavor, we unambiguously observe that highly galactosylated trastuzumab (TZM-gal), non-glycosylated trastuzumab (TZM-NG), and reference trastuzumab are characterized by different kinetic profiles upon binding to CD16a and CD64 that had been captured at the biosensor surface via their biotin tag. More precisely, while TZM-NG binding to CD16a was not detected, TZM-gal formed a more stable complex with CD16a than our reference TZM. In contrast, both glycosylated TZM bound to captured CD64 in a stable and similar fashion, whereas the interaction of their non-glycosylated form with CD64 was characterized by a higher dissociation rate. PMID:26762306

  7. Cryopreservation of mammalian oocytes by using sugars: Intra- and extracellular raffinose with small amounts of dimethylsulfoxide yields high cryosurvival, fertilization, and development rates.

    PubMed

    Eroglu, Ali

    2010-07-01

    Accumulation of intra- and extracellular sugars such as trehalose, glucose, and raffinose is central to survival strategies of a variety of organisms coping with extreme conditions including freezing and almost complete drying. The objective of the present study was to investigate the potential application of intra- and extracellular raffinose in combination with low concentrations of dimethylsulfoxide (Me(2)SO) to mammalian oocyte cryopreservation. To this end, the fertilization and embryonic development of cryopreserved metaphase II (M II) mouse oocytes were studied in comparison to unfrozen controls. For cryopreservation, M II oocytes were microinjected with 0.1M raffinose, and then cooled to -196 degrees C in the presence of either 0.3M raffinose and 0.5M Me(2)SO (cryopreservation group 1) or 0.3M raffinose and 1.0M Me(2)SO (cryopreservation group 2). The control groups included untreated oocytes (untreated control) and oocytes microinjected with raffinose, but not frozen (injection control). The post-thaw survival rates were 83.9% and 80.6% for the cryopreservation group 1 and 2, respectively. The fertilization and blastocyst rates in the cryopreservation group 1 (90.0% and 77.8%, respectively) and 2 (94.6% and 72.5%, respectively) were also high and similar to the ones of the injection controls (97.8% and 78.5%, respectively) and untreated controls (98.8% and 83.6%, respectively). These results are consistent with the findings of our earlier studies and support the use of sugars as intra- and extracellular cryoprotectants. Furthermore, the results of the present study indicate that the presence of intra- and extracellular sugars alleviates high concentrations of conventional penetrating cryoprotectants, and thus minimizes their toxicity.

  8. Genomics in mammalian cell culture bioprocessing

    PubMed Central

    Wuest, Diane M.; Harcum, Sarah W.; Lee, Kelvin H.

    2013-01-01

    Explicitly identifying the genome of a host organism including sequencing, mapping, and annotating its genetic code has become a priority in the field of biotechnology with aims at improving the efficiency and understanding of cell culture bioprocessing. Recombinant protein therapeutics, primarily produced in mammalian cells, constitute a $108 billion global market. The most common mammalian cell line used in biologic production processes is the Chinese hamster ovary (CHO) cell line, and although great improvements have been made in titer production over the past 25 years, the underlying molecular and physiological factors are not well understood. Confident understanding of CHO bioprocessing elements (e.g. cell line selection, protein production, and reproducibility of process performance and product specifications) would significantly improve with a well understood genome. This review describes mammalian cell culture use in bioprocessing, the importance of obtaining CHO cell line genetic sequences, and the current status of sequencing efforts. Furthermore, transcriptomic techniques and gene expression tools are presented, and case studies exploring genomic techniques and applications aimed to improve mammalian bioprocess performance are reviewed. Finally, future implications of genomic advances are surmised. PMID:22079893

  9. AP1- and NF-kappaB-binding sites conserved among mammalian WNT10B orthologs elucidate the TNFalpha-WNT10B signaling loop implicated in carcinogenesis and adipogenesis.

    PubMed

    Katoh, Masuko; Katoh, Masaru

    2007-04-01

    WNT signals are context-dependently transduced to canonical and non-canonical signaling cascades. We cloned and characterized wild-type human WNT10B, while another group cloned aberrant human WNT10B with Gly60Asp amino-acid substitution. Proto-oncogene WNT10B is expressed in gastric cancer, pancreatic cancer, breast cancer, esophageal cancer, and cervical cancer. Because WNT10B blocks adipocyte differentiation, coding SNP of WNT10B gene is associated with familial obesity. In 2001, we reported WNT10B upregulation by TNFalpha. Here, comparative integromics analyses on WNT10B orthologs were performed to elucidate the transcriptional mechanism of WNT10B. Chimpanzee WNT10B and cow Wnt10b genes were identified within NW_001223159.1 and AC150975.2 genome sequences, respectively, by using bioinformatics (Techint) and human intelligence (Humint). Chimpanzee WNT10B and cow Wnt10b showed 98.7% and 95.1% total-amino-acid identity with human WNT10B, respectively. N-terminal signal peptide, 24 Cys residues, two Asn-linked glycosylation sites, and Gly60 of human WNT10B were conserved among mammalian WNT10B orthologs. Transcription start site of human WNT10B gene was 106-bp upstream of NM_003394.2 RefSeq 5'-end. Number of GC di-nucleotide repeats just down-stream of WNT10B transcription start site varied among primates and human population. Comparative genomics analyses revealed that double AP1-binding sites in the 5'-flanking promoter region and NF-kappaB-binding site in intron 3 were conserved among human, chimpanzee, cow, mouse, and rat WNT10B orthologs. Because TNFalpha signaling through TNFR1 and TRADD/RIP/TRAF2 complex activates JUN kinase (JNK) and IkappaB kinase (IKK) signaling cascades, conserved AP1- and NF-kappaB-binding sites explain the mechanism of TNFalpha-induced WNT10B upregulation. TNFalpha-WNT10B signaling loop is the negative feedback mechanism of adipogenesis to prevent obesity and metabolic syndrome. On the other hand, TNFalpha-WNT10B signaling loop is

  10. Ecological Network Analysis for Economic Systems: Growth and Development and Implications for Sustainable Development

    PubMed Central

    Huang, Jiali; Ulanowicz, Robert E.

    2014-01-01

    The quantification of growth and development is an important issue in economics, because these phenomena are closely related to sustainability. We address growth and development from a network perspective in which economic systems are represented as flow networks and analyzed using ecological network analysis (ENA). The Beijing economic system is used as a case study and 11 input–output (I-O) tables for 1985–2010 are converted into currency networks. ENA is used to calculate system-level indices to quantify the growth and development of Beijing. The contributions of each direct flow toward growth and development in 2010 are calculated and their implications for sustainable development are discussed. The results show that during 1985–2010, growth was the main attribute of the Beijing economic system. Although the system grew exponentially, its development fluctuated within only a small range. The results suggest that system ascendency should be increased in order to favor more sustainable development. Ascendency can be augmented in two ways: (1) strengthen those pathways with positive contributions to increasing ascendency and (2) weaken those with negative effects. PMID:24979465

  11. Ecological network analysis for economic systems: growth and development and implications for sustainable development.

    PubMed

    Huang, Jiali; Ulanowicz, Robert E

    2014-01-01

    The quantification of growth and development is an important issue in economics, because these phenomena are closely related to sustainability. We address growth and development from a network perspective in which economic systems are represented as flow networks and analyzed using ecological network analysis (ENA). The Beijing economic system is used as a case study and 11 input-output (I-O) tables for 1985-2010 are converted into currency networks. ENA is used to calculate system-level indices to quantify the growth and development of Beijing. The contributions of each direct flow toward growth and development in 2010 are calculated and their implications for sustainable development are discussed. The results show that during 1985-2010, growth was the main attribute of the Beijing economic system. Although the system grew exponentially, its development fluctuated within only a small range. The results suggest that system ascendency should be increased in order to favor more sustainable development. Ascendency can be augmented in two ways: (1) strengthen those pathways with positive contributions to increasing ascendency and (2) weaken those with negative effects.

  12. Mammalian touch catches up

    PubMed Central

    Walsh, Carolyn M.; Bautista, Diana M.; Lumpkin, Ellen A.

    2015-01-01

    An assortment of touch receptors innervate the skin and encode different tactile features of the environment. Compared with invertebrate touch and other sensory systems, our understanding of the molecular and cellular underpinnings of mammalian touch lags behind. Two recent breakthroughs have accelerated progress. First, an arsenal of cell-type-specific molecular markers allowed the functional and anatomical properties of sensory neurons to be matched, thereby unraveling a cellular code for touch. Such markers have also revealed key roles of non-neuronal cell types, such as Merkel cells and keratinocytes, in touch reception. Second, the discovery of Piezo genes as a new family of mechanically activated channels has fueled the discovery of molecular mechanisms that mediate and mechanotransduction in mammalian touch receptors. PMID:26100741

  13. Rheotaxis guides mammalian sperm

    PubMed Central

    Miki, Kiyoshi; Clapham, David E

    2013-01-01

    Background In sea urchins, spermatozoan motility is altered by chemotactic peptides, giving rise to the assumption that mammalian eggs also emit chemotactic agents that guide spermatozoa through the female reproductive tract to the mature oocyte. Mammalian spermatozoa indeed undergo complex adaptations within the female (the process of capacitation) that are initiated by agents ranging from pH to progesterone, but these factors are not necessarily taxic. Currently, chemotaxis, thermotaxis, and rheotaxis have not been definitively established in mammals. Results Here, we show that positive rheotaxis, the ability of organisms to orient and swim against the flow of surrounding fluid, is a major taxic factor for mouse and human sperm. This flow is generated within 4 hours of sexual stimulation and coitus in female mice; prolactin-triggered oviductal fluid secretion clears the oviduct of debris, lowers viscosity, and generates the stream that guides sperm migration in the oviduct. Rheotaxic movement is demonstrated in capacitated and uncapacitated spermatozoa in low and high viscosity medium. Finally, we show that a unique sperm motion we quantify using the sperm head's rolling rate reflects sperm rotation that generates essential force for positioning the sperm in the stream. Rotation requires CatSper channels, presumably by enabling Ca2+ influx. Conclusions We propose that rheotaxis is a major determinant of sperm guidance over long distances in the mammalian female reproductive tract. Coitus induces fluid flow to guide sperm in the oviduct. Sperm rheotaxis requires rotational motion during CatSper channel-dependent hyperactivated motility. PMID:23453951

  14. Workplace Democracy: A Review of Literature and Implications for Human Resource Development

    ERIC Educational Resources Information Center

    Hatcher, Tim

    2007-01-01

    A review of workplace democracy revealed that both practice and research need updating. The results are discussed in terms of history, theory, research and practice. Implications for human resource development research and practice are also included. (Contains 2 tables.)

  15. Mammalian lipoxygenases and their biological relevance

    PubMed Central

    Kuhn, Hartmut; Banthiya, Swathi; van Leyen, Klaus

    2015-01-01

    Lipoxygenases (LOXs) form a heterogeneous class of lipid peroxidizing enzymes, which have been implicated in cell proliferation and differentiation but also in the pathogenesis of various diseases with major public health relevance. As other fatty acid dioxygenases LOX oxidize polyunsaturated fatty acids to their corresponding hydroperoxy derivatives, which are further transformed to bioactive lipid mediators (eicosanoids and related substances). On the other hand, lipoxygenases are key players in regulation of the cellular redox homeostasis, which is an important element in gene expression regulation. Although the first mammalian lipoxygenases were discovered 40 years ago and although the enzymes have been well characterized with respect to their structural and functional properties the biological roles of the different lipoxygenase isoforms are not completely understood. This review is aimed at summarizing the current knowledge on the physiological roles of different mammalian LOX-isoforms and their patho-physiological function in inflammatory, metabolic, hyperproliferative, neurodegenerative and infectious disorders. PMID:25316652

  16. Developments in cognitive socialization: implications for deaf education.

    PubMed

    Muma, J R; Teller, H

    2001-03-01

    Over the past 2 to 3 decades, the cognitive socialization literature has advanced about 40 major issues that could have a major impact on the principles and procedures of deaf education. The article presents a conceptual model of the cognitive social bases of language that is derived from the philosophical view of constructionism and theoretical perspectives of speech act theory and relevance theory. With the cognitive socialization perspective and this conceptual model, 4 of the 40 issues are discussed: (a) the centrality of intent replacing reinforcement as a more viable account of language acquisition, (b) modality and core issues of language, (c) lack of construct validity in assessment, and (d) heterogeneity. Implications for the advancement of deaf education are discussed throughout.

  17. Characteristics of the Successful Researcher and Implications for Faculty Development.

    ERIC Educational Resources Information Center

    Bland, Carole J.; Schmitz, Constance C.

    1986-01-01

    To understand better the role of faculty development in training family medicine researchers, the characteristics of productive researchers, their training, and their work environment were examined. Areas reviewed were faculty development and evaluation, career development, professional socialization, organizational development, and faculty…

  18. MicroRNA-mediated regulation in the mammalian circadian rhythm.

    PubMed

    Liu, Kaihui; Wang, Ruiqi

    2012-07-01

    Mammalian circadian rhythms have been extensively studied for many years and many computational models have been presented. Most of the circadian rhythms are based on interlocked positive and negative feedback loops involving coding regions of some 'clock' genes. Recent works have implicated that microRNAs (miRNAs) may play crucial roles in modulating the circadian clock. Here we develop a computational model involving four genes, Per, Cry, Bmal1, and Clock, and two miRNAs, miRNA-219 and miRNA-132, to show their post-transcriptional roles in the modulation of the circadian rhythm. The model is based on experimental observations, by which the miRNAs are incorporated into a classic model including only coding genes. In agreement with experimental observations, the model predicts that miRNA-mediated regulation plays critical roles in modulating the circadian clock. In addition, parameter sensitivity analysis indicates that the period of circadian rhythm with miRNA-mediated regulation is more insensitive to perturbations, showing that the miRNA-mediated regulation can enhance the robustness of the circadian rhythms. This study may help us understand the microRNA-mediated regulation in the mammalian circadian rhythm more clearly.

  19. Mammalian glycosylation in immunity

    PubMed Central

    Marth, Jamey D.; Grewal, Prabhjit K.

    2009-01-01

    Glycosylation produces a diverse and abundant repertoire of glycans, which are collectively known as the glycome. Glycans are one of the four fundamental macromolecular components of all cells, and are highly regulated in the immune system. Their diversity reflects their multiple biological functions that encompass ligands for proteinaceous of receptors known as lectins. Since the discovery that selectins and their glycan ligands are important for the regulation of leukocyte trafficking, it has been shown that additional features of the vertebrate immune system are also controlled by endogenous cellular glycosylation. This Review focuses on the emerging immunological roles of the mammalian glycome. PMID:18846099

  20. Mammalian diversity: gametes, embryos and reproduction.

    PubMed

    Behringer, Richard R; Eakin, Guy S; Renfree, Marilyn B

    2006-01-01

    The class Mammalia is composed of approximately 4800 extant species. These mammalian species are divided into three subclasses that include the monotremes, marsupials and eutherians. Monotremes are remarkable because these mammals are born from eggs laid outside of the mother's body. Marsupial mammals have relatively short gestation periods and give birth to highly altricial young that continue a significant amount of 'fetal' development after birth, supported by a highly sophisticated lactation. Less than 10% of mammalian species are monotremes or marsupials, so the great majority of mammals are grouped into the subclass Eutheria, including mouse and human. Mammals exhibit great variety in morphology, physiology and reproduction. In the present article, we highlight some of this remarkable diversity relative to the mouse, one of the most widely used mammalian model organisms, and human. This diversity creates challenges and opportunities for gamete and embryo collection, culture and transfer technologies.

  1. Cognitive competence as a positive youth development construct: conceptual bases and implications for curriculum development.

    PubMed

    Sun, Rachel C F; Hui, Eadaoin K P

    2006-01-01

    This paper outlines the conceptual bases of "cognitive competence" as a positive youth development construct and the implications for curriculum development. Cognitive competence refers to the cognitive processes that comprise (i) creative thinking, which includes various creative thinking styles, such as legislative, global, and local thinking styles; and (ii) critical thinking, which includes reasoning, making inferences, self-reflection, and coordination of multiple views. Based on the adolescent development progression on cognitive competence, and with reference to Hong Kong Chinese context, six units are designed to promote creative and critical thinking for Secondary 1-3 students in the Project P.A.T.H.S., supported by the Hong Kong Jockey Club Charities Trust. In the Secondary 1 curriculum, the goals of the units are to enable students to recognize different but inter-related thinking styles and to apply these thinking skills to deal with daily life issues. The goal in the Secondary 2 curriculum is to enhance students' creative thinking skills to solve problems, whereas the goal in the Secondary 3 curriculum is to enhance students' critical thinking skills to accept beliefs and make decisions.

  2. Odor Coding by a Mammalian Receptor Repertoire

    PubMed Central

    Saito, Harumi; Chi, Qiuyi; Zhuang, Hanyi; Matsunami, Hiro; Mainland, Joel D.

    2009-01-01

    Deciphering olfactory encoding requires a thorough description of the ligands that activate each odorant receptor (OR). In mammalian systems, however, ligands are known for fewer than 50 of over 1400 human and mouse ORs, greatly limiting our understanding of olfactory coding. We performed high-throughput screening of 93 odorants against 464 ORs expressed in heterologous cells and identified agonists for 52 mouse and 10 human ORs. We used the resulting interaction profiles to develop a predictive model relating physicochemical odorant properties, OR sequences, and their interactions. Our results provide a basis for translating odorants into receptor neuron responses and unraveling mammalian odor coding. PMID:19261596

  3. Implications of Climate Change for Children in Developing Countries

    ERIC Educational Resources Information Center

    Hanna, Rema; Oliva, Paulina

    2016-01-01

    Climate change may be particularly dangerous for children in developing countries. Even today, many developing countries experience a disproportionate share of extreme weather, and they are predicted to suffer disproportionately from the effects of climate change in the future. Moreover, developing countries often have limited social safety nets,…

  4. Implications of Land Policy and Rural Development in Botswana.

    ERIC Educational Resources Information Center

    Milazi, Dominic

    1988-01-01

    Examines land tenure alteration in relation to rural development programs in Botswana. Development efforts have had a class differentiated effect, aiding the relatively well-off cattle owners, but ignoring the small crop producers. A rural development strategy that benefits all rural groups must contain measures specifically tailored to each. (DHP)

  5. Cultured normal mammalian tissue and process

    NASA Technical Reports Server (NTRS)

    Goodwin, Thomas J. (Inventor); Prewett, Tacey L. (Inventor); Wolf, David A. (Inventor); Spaulding, Glenn F. (Inventor)

    1993-01-01

    Normal mammalian tissue and the culturing process has been developed for the three groups of organ, structural and blood tissue. The cells are grown in vitro under microgravity culture conditions and form three dimensional cell aggregates with normal cell function. The microgravity culture conditions may be microgravity or simulated microgravity created in a horizontal rotating wall culture vessel.

  6. Mitochondria and mammalian reproduction.

    PubMed

    Ramalho-Santos, João; Amaral, Sandra

    2013-10-15

    Mitochondria are cellular organelles with crucial roles in ATP synthesis, metabolic integration, reactive oxygen species (ROS) synthesis and management, the regulation of apoptosis (namely via the intrinsic pathway), among many others. Additionally, mitochondria in different organs or cell types may have distinct properties that can decisively influence functional analysis. In terms of the importance of mitochondria in mammalian reproduction, and although there are species-specific differences, these aspects involve both energetic considerations for gametogenesis and fertilization, control of apoptosis to ensure the proper production of viable gametes, and ROS signaling, as well as other emerging aspects. Crucially, mitochondria are the starting point for steroid hormone biosynthesis, given that the conversion of cholesterol to pregnenolone (a common precursor for all steroid hormones) takes place via the activity of the cytochrome P450 side-chain cleavage enzyme (P450scc) on the inner mitochondrial membrane. Furthermore, mitochondrial activity in reproduction has to be considered in accordance with the very distinct strategies for gamete production in the male and female. These include distinct gonad morpho-physiologies, different types of steroids that are more prevalent (testosterone, estrogens, progesterone), and, importantly, the very particular timings of gametogenesis. While spermatogenesis is complete and continuous since puberty, producing a seemingly inexhaustible pool of gametes in a fixed environment; oogenesis involves the episodic production of very few gametes in an environment that changes cyclically. These aspects have always to be taken into account when considering the roles of any common element in mammalian reproduction.

  7. The virome in mammalian physiology and disease

    PubMed Central

    Virgin, Herbert W.

    2014-01-01

    The virome contains the most abundant and fastest-mutating genetic elements on Earth. The mammalian virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. Virome interactions with the host cannot be encompassed by a monotheistic view of viruses as pathogens. Instead, the genetic and transcriptional identity of mammals is defined in part by our co-evolved virome, a concept with profound implications for understanding health and disease. PMID:24679532

  8. Nursing and health care reform: implications for curriculum development.

    PubMed

    Bowen, M; Lyons, K J; Young, B E

    2000-01-01

    The health care system is undergoing profound changes. Cost containment efforts and restructuring have resulted in cutbacks in registered nurse (RN) positions. These changes are often related to the increased market penetration by managed care companies. To determine how RN graduates perceive these changes and their impact on the delivery of patient care, Healthcare Environment Surveys were mailed to graduates of the classes of 1986 and 1991. Using the Survey's 5-point Likert Scale, we measured the graduates' satisfaction with their salary, quality of supervision they received, opportunities for advancement, recognition for their job, working conditions, the overall job and the changes in their careers over the previous five year period. Our study suggests that the changes in the health care system are having an impact on how health care is being delivered and the way nurses view their jobs. Respondents reported that insurance companies are exerting increased control over patient care and perceive that the quality of patient care is declining. Increased workloads and an increase in the amount of paperwork were reported. Participants perceived that there were fewer jobs available and that job security was decreasing. The percentage of nurses who see job satisfaction as remaining the same or increasing are a majority. However, the relatively high percent of nurses who see job satisfaction as declining should provide a note of warning. The major implications of this study are that the professional nursing curriculum must be modified to include content on communication, organization, legislative/policy skills, and leadership. The nation's health care system is undergoing profound changes. There are numerous forces at work that are effecting the delivery of care and, consequently, the work of health professionals. These forces include significant efforts at cost containment, restructuring and downsizing of hospitals, and the movement of health care delivery out of acute

  9. Men's Identity Development: Issues and Implications for Residence Life

    ERIC Educational Resources Information Center

    Scott, David A.; Livingston, Wade G.; Havice, Pamela A.; Cawthon, Tony W.

    2012-01-01

    Young men struggle with privilege and oppression in college and university residence halls just as they do in other educational and social contexts. While discussions and research about adolescent and adult identity development continue, little attention has focused on how a male student's identity development can impact residence life cultures on…

  10. Development of a Structured Undergraduate Research Experience: Framework and Implications

    ERIC Educational Resources Information Center

    Brown, Anne M.; Lewis, Stephanie N.; Bevan, David R.

    2016-01-01

    Participating in undergraduate research can be a pivotal experience for students in life science disciplines. Development of critical thinking skills, in addition to conveying scientific ideas in oral and written formats, is essential to ensuring that students develop a greater understanding of basic scientific knowledge and the research process.…

  11. RE Student Teachers' Professional Development: Results, Reflections and Implications

    ERIC Educational Resources Information Center

    Ubani, Martin

    2016-01-01

    This article discusses some issues related to the professional development of Religious Education (RE) student teachers in initial teacher education based on empirical results on the development of the pedagogical thinking of Finnish RE student teachers during their teacher education. The article begins by describing the concept of professionalism…

  12. Implications of Right Brain Research on Curriculum Development.

    ERIC Educational Resources Information Center

    MacKinnon, Colin

    The idea that the brain may be more complex and varied in the ways that it responds to and interprets information than is generally recognized suggests that both the left and right hemispheres are in need of total development. In discussing the development of curriculum that will bring into harmony the functions of both brain hemispheres, it is…

  13. Psychosexual Development in Infants and Young Children: Implications for Caregivers.

    ERIC Educational Resources Information Center

    Honig, Alice Sterling

    Psychosexual development in young children is a topic that early childhood educators often ignore in the belief that children are not sexual beings. This paper discusses psychosexual development in young children, noting that preschoolers are often puzzled by sexual anatomical differences, that children need names for sexual body parts, and that…

  14. Teachers as Learners: Implications of Adult Education for Professional Development

    ERIC Educational Resources Information Center

    Beavers, Amy

    2009-01-01

    Effective communication with teachers is a critical element of any successful professional development. Teachers are the foundational component of any educational system. It is vital that adequate attention is focused on appropriate and effective training of these teachers. Ideally, professional development offers a means of collaborative support…

  15. Organizational Development and Its Implications for Adult Basic Education Programs

    ERIC Educational Resources Information Center

    Hohn, Marcia Drew

    2001-01-01

    In this chapter, Marcia Drew Hohn provides an overview of organizational development theory for adult educators interested in applying the lessons of such theory to the strengthening of ABE programs and systems. She begins the chapter with a brief history of the development of organizational theory, noting the progression from a mechanistic…

  16. Implications for a Green Curriculum Application toward Sustainable Development

    ERIC Educational Resources Information Center

    Sahin, Elvan; Ertepinar, Hamide; Teksoz, Gaye

    2009-01-01

    The aim of present study was two-fold: (1) to determine university students' familiarity and understandings of "sustainable development", (2) to examine their attitudes toward sustainable development, environmental values, and their behaviors toward sustainable life styles. The data collected by on-line administration of a questionnaire to 958…

  17. Implications of Bilingual Development for Specific Language Impairments in Turkey

    ERIC Educational Resources Information Center

    Topbas, Seyhun

    2011-01-01

    The potential impact of bilingualism on children's language development has emerged as a crucial concern for Turkey, but so far it has not been addressed from the point of view of language disorders. This short review examines the potential impact of bilingual language development for language impairments in Turkey, with special emphasis on the…

  18. [Placental developmental defects in cloned mammalian animals].

    PubMed

    Ao, Zheng; Liu, Dewu; Cai, Gengyuan; Wu, Zhenfang; Li, Zicong

    2016-05-01

    The cloning technique, also called somatic cell nuclear transfer (SCNT), has been successfully established and gradually applied to various mammalian species. However, the developmental rate of SCNT mammalian embryos is very low, usually at 1% to 5%, which limits the application of SCNT. Placental developmental defects are considered as the main cause of SCNT embryo development inhibition. Almost all of SCNT-derived mammalian placentas exhibit various abnormalities, such as placental hyperplasia, vascular defects and umbilical cord malformation. Mechanistically, these abnormalities result from failure of establishment of correct epigenetic modification in the trophectoderm genome, which leads to erroneous expression of important genes for placenta development-related, particularly imprinted genes. Consequently, aberrant imprinted gene expression gives rise to placental morphologic abnormalities and functional defects, therefore decreases developmental competence of cloned embryos. Currently, although numerous methods that can improve the developmental ability of SCNT-derived embryos have been reported, most of them are unable to substantially enhance the success rate of SCNT due to failure to eliminate the placental development defects. In this review, we summarize placental abnormalities and imprinted gene expression in mammalian cloning, and propose directions for the future research aiming to improve the cloning efficiency. PMID:27232488

  19. Some technical implications of Klein's concept of 'premature ego development'.

    PubMed

    Mitrani, Judith L

    2007-08-01

    In this paper, the author revisits the problem of 'premature ego development' first introduced by Melanie Klein in 1930. She also highlights several developments in post-Kleinian thinking since the publication of that paper, which can be seen as offshoots of or complements to Klein's work. The author proposes a link between this category of precocious development and the absence of the experience of what Bion termed the 'containing object.' She puts forward several technical considerations relevant to analytic work with patients who suffer as a result of early developmental failures and presents various clinical vignettes in order to demonstrate the ways in which these considerations take shape in the analytic setting.

  20. Schizophrenia risk genes: Implications for future drug development and discovery.

    PubMed

    O'Connell, Garret; Lawrie, Stephen M; McIntosh, Andrew M; Hall, Jeremy

    2011-06-15

    Present-day development of improved treatments for schizophrenia is hindered by uncertain models of disease, inter-individual response variability in clinical trials and a paucity of sensitive measures of treatment effects. Findings from genetic research emphasize the potential for schizophrenia risk genes to help develop focused treatments, discover new drug targets and provide markers of clinical subtypes. Advances in genetic technologies also provide novel modes of drug discovery in schizophrenia such as transcriptomics, epigenetics and transgenic animal models. In this review, we discuss proven and proposed ways risk genes can be used to enhance the development and discovery of treatments for schizophrenia and highlight key studies in these approaches. PMID:21093417

  1. Producing Newborn Synchronous Mammalian Cells

    NASA Technical Reports Server (NTRS)

    Gonda, Steve R.; Helmstetter, Charles E.; Thornton, Maureen

    2008-01-01

    A method and bioreactor for the continuous production of synchronous (same age) population of mammalian cells have been invented. The invention involves the attachment and growth of cells on an adhesive-coated porous membrane immersed in a perfused liquid culture medium in a microgravity analog bioreactor. When cells attach to the surface divide, newborn cells are released into the flowing culture medium. The released cells, consisting of a uniform population of synchronous cells are then collected from the effluent culture medium. This invention could be of interest to researchers investigating the effects of the geneotoxic effects of the space environment (microgravity, radiation, chemicals, gases) and to pharmaceutical and biotechnology companies involved in research on aging and cancer, and in new drug development and testing.

  2. The Psychology of Writing Development--And Its Implications for Assessment

    ERIC Educational Resources Information Center

    Camp, Heather

    2012-01-01

    This article reviews key developmental theories that have been adopted by writing development researchers over the last fifty years. It describes how researchers have translated these theories into definitions of writing development capable of influencing curricular design and interpretations of student writing and explores the implications for…

  3. Racial Identity Development and Academic Achievement of Academically Gifted African American Students: Implications for School Counselors

    ERIC Educational Resources Information Center

    Spencer, Natalie F.; Dowden, Angel Riddick

    2014-01-01

    Gifted African American students are underrepresented and underserved in gifted education. The current article provides an overview of proper identification, racial identity development implications, psycho-social concerns and the importance of family involvement in the development of gifted African American students. A case study is presented to…

  4. Development of the Adolescent Brain: Implications for Executive Function and Social Cognition

    ERIC Educational Resources Information Center

    Blakemore, Sarah-Jayne; Choudhury, Suparna

    2006-01-01

    Adolescence is a time of considerable development at the level of behaviour, cognition and the brain. This article reviews histological and brain imaging studies that have demonstrated specific changes in neural architecture during puberty and adolescence, outlining trajectories of grey and white matter development. The implications of brain…

  5. The Legacy of Lawrence Kohlberg: Implications for Counseling and Human Development.

    ERIC Educational Resources Information Center

    Hayes, Richard L.

    1994-01-01

    Notes that, despite great contributions by Lawrence Kohlberg to understanding of moral development, counselors are only beginning to appreciate fully implications of his developmental psychology for practice of counseling and human development. Draws on collective body of Kohlberg's work to show how seven assumptions have direct relevance for…

  6. Implications of Piagetian Theory for Early Childhood Industrial Arts: Cognitive Development. ACESIA Monograph 6.

    ERIC Educational Resources Information Center

    Dahl, Richard J.

    The two purposes of this paper are to provide the uninitiated reader with a skeletal overview of Piaget's cognitive development theory and to identify general educational implications, especially for the development of early childhood industrial arts (ECIA) programs. The "Piaget Primer" for ECIA educators overviews such topics as (1) the four…

  7. Suspension culture of mammalian cells.

    PubMed

    Birch, J R; Arathoon, R

    1990-01-01

    Mammalian cell suspension culture systems are being used increasingly in the biotechnology industry. This is due to their many advantages including simplicity and homogeneity of culture. Suspension systems are very adaptable (e.g., for microcarrier, microencapsulation, or other methods of culture). Their engineering is thoroughly understood and standardized at large scale, and automation and cleaning procedures are well established. Suspension systems offer the possibility of quick implementation of production protocols due to their ability to be scaled easily once the basic culture parameters are understood. The only main disadvantage of the suspension culture systems to date is their inapplicability for the production of human vaccines from either primary cell lines or from normal human diploid cell lines (Hayflick et al., 1987 and references therein). One of the great advantages of suspension culture is the opportunity it provides to study interactions of metabolic and production phenomena in chemostat or turbidostat steady-state systems. Furthermore, in suspension culture systems from which cell number and cell mass measurements are easy to obtain, rigorous and quantitative estimations of the effects of growth conditions or perturbations of metabolic homeostasis can be made. Such studies can speed up the development of optimal processes. With our increasing understanding of factors influencing expression in mammalian cells (Cohen and Levinson, 1988; Santoro et al., 1988) and the direct application of new methods in suspension culture (Rhodes and Birch, 1988), its usefulness and importance is likely to increase in the future. In this chapter, we have described some of the potential uses of the various suspension culture systems and have covered most of the established technology and literature. Due to the rapid developments and needs in the biotechnology industry and the versatility of suspension culture systems, it is probable that many more variations on this

  8. Development of a structured undergraduate research experience: Framework and implications.

    PubMed

    Brown, Anne M; Lewis, Stephanie N; Bevan, David R

    2016-09-10

    Participating in undergraduate research can be a pivotal experience for students in life science disciplines. Development of critical thinking skills, in addition to conveying scientific ideas in oral and written formats, is essential to ensuring that students develop a greater understanding of basic scientific knowledge and the research process. Modernizing the current life sciences research environment to accommodate the growing demand by students for experiential learning is needed. By developing and implementing a structured, theory-based approach to undergraduate research in the life sciences, specifically biochemistry, it has been successfully shown that more students can be provided with a high-quality, high-impact research experience. The structure of this approach allowed students to develop novel, independent projects in a computational molecular modeling lab. Students engaged in an experience in which career goals, problem-solving skills, time management skills, and independence in a research lab were developed. After experiencing this approach to undergraduate research, students reported feeling challenged to think critically and prepared for future career paths. The approach allowed for a progressive learning environment where more undergraduate students could participate in publishable research. Future areas for development include implementation in a bench-top lab and extension to disciplines beyond biochemistry. In this study, it has been shown that utilizing the structured approach to undergraduate research could allow for more students to experience undergraduate research and develop into more confident, independent life scientists well prepared for graduate schools and professional research environments. © 2016 by The International Union of Biochemistry and Molecular Biology, 44(5):463-474, 2016.

  9. Development of a structured undergraduate research experience: Framework and implications.

    PubMed

    Brown, Anne M; Lewis, Stephanie N; Bevan, David R

    2016-09-10

    Participating in undergraduate research can be a pivotal experience for students in life science disciplines. Development of critical thinking skills, in addition to conveying scientific ideas in oral and written formats, is essential to ensuring that students develop a greater understanding of basic scientific knowledge and the research process. Modernizing the current life sciences research environment to accommodate the growing demand by students for experiential learning is needed. By developing and implementing a structured, theory-based approach to undergraduate research in the life sciences, specifically biochemistry, it has been successfully shown that more students can be provided with a high-quality, high-impact research experience. The structure of this approach allowed students to develop novel, independent projects in a computational molecular modeling lab. Students engaged in an experience in which career goals, problem-solving skills, time management skills, and independence in a research lab were developed. After experiencing this approach to undergraduate research, students reported feeling challenged to think critically and prepared for future career paths. The approach allowed for a progressive learning environment where more undergraduate students could participate in publishable research. Future areas for development include implementation in a bench-top lab and extension to disciplines beyond biochemistry. In this study, it has been shown that utilizing the structured approach to undergraduate research could allow for more students to experience undergraduate research and develop into more confident, independent life scientists well prepared for graduate schools and professional research environments. © 2016 by The International Union of Biochemistry and Molecular Biology, 44(5):463-474, 2016. PMID:27124101

  10. Evaluation of population health short courses: implications for developing and evaluating population health professional development initiatives.

    PubMed

    Naccarella, Lucio; Greenstock, Louise; Butterworth, Iain

    2016-01-01

    Population health as an approach to planning is key to improving the health and well-being of whole populations and to reduce inequities within and between population groups. The Victorian Department of Health North and West Metropolitan Region, in collaboration with The University of Melbourne (School of Population Health), have delivered four annual population health short courses. The short courses were designed to equip participants with knowledge and skills to implement population health approaches upon their return to their workplaces. For three consecutive years, online surveys (n=41) and semi-structured interviews (n=35), underpinned by participatory and realist evaluation approaches, were conducted to obtain the perceptions and experiences of the population health short course participants. Evaluation findings indicate that participants' understanding of population health concepts increased; however, there were mixed outcomes in assisting participants' implementation of population health approaches upon their return to their workplaces. A core list of perceived requirements, enablers and barriers emerged at an individual, organisational and system level as influencing the capability of participants to implement population health approaches. Evaluation recommendations and actions taken to revise short course iterations are presented, providing evidence that the evaluation approaches were appropriate and increased the use of evaluation learnings. Implications of evaluation findings for professional development practice (i.e. shift from a 'Course' as a one-off event to a Population Health 'Program' of inter-dependent components) and evaluation (i.e. participatory realist evaluation approaches) are presented.

  11. Development of PACS Digital Pump and implications for other industries

    NASA Astrophysics Data System (ADS)

    Banister, M.; Vohnout, S.; Kenman, D.

    2007-04-01

    This paper discusses the development and system integration of the Pulse Activated Cell System (PACS) Digital Pump technology using 2 types of electro-activated polymer (EAP) actuators. This is a platform specifically developed for the integration of sensor feedback loops to create an autonomous fluidic monitoring, reaction and delivery system. Initial, proof of concept, performance testing results are discussed as well as development for a medical drug delivery device and higher volume infusion therapy device. Uses and applications of the technology in other industries is considered as the PAC System provides a new ability to pump single or multiple fluid flows in a single pump that is programmable with the ability to vary direction, pressure and flow rates. The result is digital control of fluidic delivery, testing and mixing in application scaleable product packages. This technology will lead to new low cost yet sophisticated fluidic processing products and devices for many industries.

  12. Some technical implications of Klein's concept of 'premature ego development'.

    PubMed

    Mitrani, Judith L

    2007-08-01

    In this paper, the author revisits the problem of 'premature ego development' first introduced by Melanie Klein in 1930. She also highlights several developments in post-Kleinian thinking since the publication of that paper, which can be seen as offshoots of or complements to Klein's work. The author proposes a link between this category of precocious development and the absence of the experience of what Bion termed the 'containing object.' She puts forward several technical considerations relevant to analytic work with patients who suffer as a result of early developmental failures and presents various clinical vignettes in order to demonstrate the ways in which these considerations take shape in the analytic setting. PMID:17681895

  13. Development of Managers' Emotional Competencies: Mind-Body Training Implication

    ERIC Educational Resources Information Center

    Gruicic, Dusan; Benton, Stephen

    2015-01-01

    Purpose: This paper aims to research about the effect of mind-body training on the development of emotional competencies of managers. Design/methodology/approach: Quasi-experimental design, i.e. before and after (test-retest). Findings: Results showed that the experimental group, after training, achieved around 15 per cent higher scores compared…

  14. Soil development on stable landforms and implications for landscape studies

    USGS Publications Warehouse

    Harden, J.W.

    1990-01-01

    Soil development parameters include a wide variety of morphological, chemical, and mineralogical parameters, but some of the best indicators of time and surface stability are derived from field morphology. Over long time-spans, the most common time function for soil development is exponential or logarithmic, in which rates decrease with increasing age. Over shorter time-spans in semi-arid and moister climates, Holocene and Pleistocene soil development functions appear as linear segments, with Holocene rates about 10 to 50 times those of Pleistocene rates. In contrast to significant temporal variation in rates, geographical variation in rates within (a) the southern Great Basin and (b) the east Central Valley of California is on the order of 2 or 3 times. When comparing soil development indices of the semi-arid Great Basin to those of moister central California, Holocene rates are similar, but Pleistocene rates are more than 10 times slower in the Great Basin. In a range of climatic settings, the reasons for declining rates over time are several and are complexly related to erosional history, fluxes in water and dust related to climatic changes, rates of primary mineral dissolution, and intrinsic soil processes. ?? 1990.

  15. Public Understanding of Sustainable Development: Some Implications for Education

    ERIC Educational Resources Information Center

    Scott, William

    2015-01-01

    A number of recent surveys of public opinion claim that there is now widespread acceptance of the need for sustainable development, and that the general public, through its social and consumer activity is already successfully engaged. However, in all this, the focus has primarily been on individual and family behaviours such as recycling and…

  16. The Educational Implications of Introducing a NQF for Developing Countries

    ERIC Educational Resources Information Center

    Young, Michael

    2011-01-01

    The one-year research project on the implementation of NQFs in developing countries was launched by the ILO 2009 in collaboration with the ETF. This article reviews some of the educational issues that arose from the project. The findings of the case studies raise issues that are important for how future research and policy on NQFs is taken…

  17. Burnout among Career Development Professionals: Preliminary Findings and Implications.

    ERIC Educational Resources Information Center

    Forney, Deanna S.; And Others

    1982-01-01

    Presents the results of the initial stage of research conducted to explore the relationship between burnout and career development professionals through interviews (N=24). Formulates definition of burnout and identifies burnout symptoms and causes. Results pointed out the individualized nature of burnout, both in terms of symptoms/causes and…

  18. Teachers' Professional Development Experiences: Implications for Teaching Practice

    ERIC Educational Resources Information Center

    Vail, Teresa M.

    2011-01-01

    The purpose of this study was to inquire into the ways in which participation in physical science professional development impacts science teachers' professional learning and ultimately their practice over time. This study strove to provide a greater understanding of teachers' processes as they engage in professional learning and make changes in…

  19. Social Interactions of Mothers and Young Children: Implications for Development.

    ERIC Educational Resources Information Center

    Farran, Dale C.; And Others

    This study attempted to identify maternal variables within social class which were predictive of child status over time. Data on patterns of mother/child interactions were collected for the experimental and control groups of poverty mother/child dyads at the Frank Porter Graham Child Development Center and a group of general population high…

  20. Development of the Visual System and Implications for Early Intervention.

    ERIC Educational Resources Information Center

    Glass, Penny

    2002-01-01

    This article summarizes the early development of the visual system within the context of the other sensory systems and preterm birth and relates this information to early intervention. Retinopathy of prematurely, ocular defects, cortical visual impairment and potential impact of the neonatal intensive care unit environment are discussed. (Contains…

  1. Fatherhood in Kenyan Ethnic Communities: Implication for Child Development

    ERIC Educational Resources Information Center

    Lasser, Jon; Fite, Kathleen; Wadende, Akinyi P.

    2011-01-01

    This article reviews the traditional and evolving constructions of fatherhood in Kenyan society, with an emphasis on fatherhood's impact on child development outcomes. Western influence and increased access to technology have changed the role of the Kenyan father, and in turn affected his role in the family. Special attention is given to…

  2. Professional development implications of Ebola virus disease education: part II.

    PubMed

    Smith, Elaine L; Kerner, Robert L; Schindler, Jaclyn S; DeVoe, Barbara

    2015-02-01

    This article is the second in a two-part series that explores how one large, integrated health care system swiftly responded to the emerging threat of Ebola virus disease. In this second article, the educational and training activities that were developed are described.

  3. Plasticity in the Developing Brain: Implications for Rehabilitation

    ERIC Educational Resources Information Center

    Johnston, Michael V.

    2009-01-01

    Neuronal plasticity allows the central nervous system to learn skills and remember information, to reorganize neuronal networks in response to environmental stimulation, and to recover from brain and spinal cord injuries. Neuronal plasticity is enhanced in the developing brain and it is usually adaptive and beneficial but can also be maladaptive…

  4. Relational Aggression in School Settings: Definition, Development, Strategies, and Implications

    ERIC Educational Resources Information Center

    Dailey, Alicia L.; Frey, Andy J.; Walker, Hill M.

    2015-01-01

    Relational aggression (RA) is a nonphysical form of aggression whereby the perpetrator's goal is to inflict or threaten damage to relationships, including harm to the target child's social standing or reputation. This form of aggression may result in long-term psychological harm to victims. This article defines RA, summarizes its development, and…

  5. Organisational Learning in International Joint Ventures: Implications for Management Development.

    ERIC Educational Resources Information Center

    Berrell, Mike; Gloet, Marianne; Wright, Phil

    2002-01-01

    Malaysian and Australian managers enrolled in a training program exhibited differences attributed to national culture in their approaches to learning, influences on management behavior, and ways of knowing. National culture had greater influence on management development and organizational learning than did organizational or systems cultures.…

  6. Creating World-Class Universities: Implications for Developing Countries

    ERIC Educational Resources Information Center

    Lee, Jeongwoo

    2013-01-01

    Many countries are now creating world-class universities (WCUs) as essential parts of their higher education reform agendas, and as national goals. It is legitimate to ask whether every country that aspires to build a WCU can do so--especially developing countries. To answer this question, this paper provides a three-step framework. The first step…

  7. Robert's Rules for Optimal Learning: Model Development, Field Testing, Implications!

    ERIC Educational Resources Information Center

    McGinty, Robert L.

    The value of accelerated learning techniques developed by the national organization for Suggestive Accelerated Learning Techniques (SALT) was tested in a study using Administrative Policy students taking the capstone course in the Eastern Washington University School of Business. Educators have linked the brain and how it functions to various…

  8. Professional Development for Elementary Science Teachers: Implications for Practice.

    ERIC Educational Resources Information Center

    Hernandez, Patricia; Arrington, Jeff; Whitworth, Jerry

    This project's goal was to design a professional development model to improve the skills of elementary teachers in providing quality science instruction. Surveys have concluded that lack of training, time, and instructional materials are obstacles for elementary science teachers. Eight elementary schools in a mid-sized west central Texas school…

  9. Implications of New and Changing Occupations for Instructional Development.

    ERIC Educational Resources Information Center

    Russell, Jill Frymier

    A study was conducted to determine what occupations nationally are new and changing and if they need curriculum development at the vocational education level. The process used to conduct this study involved four steps: identifying new and changing occupations, collecting information about the occupations, locating available instructional…

  10. Adult Children of Alcoholics: Implications for Career Development.

    ERIC Educational Resources Information Center

    Mathews, Bernadette; Halbrook, Michael

    1990-01-01

    Two characteristics of adult children of alcoholics are external orientation and disruption of ego boundaries, which inhibit the development of a sense of self. The dependent attitudes and behaviors associated with these traits affect work habits, career selection, and work relationships. (SK)

  11. Systems Applications in Higher Education: Implications for Research and Development.

    ERIC Educational Resources Information Center

    Molnar, Andrew R.

    Both the trend toward the scientific information explosion and the trend toward equal opportunity of education are altering what we teach and how we teach. While the movement in research and development in education has been toward using systems applications to deal with these changes, there are some problems with this approach. The domain of…

  12. Intellectual Development and Elementary Science: Some Implications from Piagetian Research

    ERIC Educational Resources Information Center

    Howe, Ann; Johnson, Janice

    1975-01-01

    Suggestions are given relating to having plants and animals in the classroom to stimulate development of the understanding of the concept of being alive, a concept not really understood by children under age nine. The research reviewed promotes firsthand experiences to help form concepts of living and nonliving, of identity and causality. (EB)

  13. Some implications of in situ uranium mining technology development

    SciTech Connect

    Cowan, C.E.; Parkhurst, M.A.; Cole, R.J.; Keller, D.; Mellinger, P.J.; Wallace, R.W.

    1980-09-01

    A technology assessment was initiated in March 1979 of the in-situ uranium mining technology. This report explores the impediments to development and deployment of this technology and evaluates the environmental impacts of a generic in-situ facility. The report is divided into the following sections: introduction, technology description, physical environment, institutional and socioeconomic environment, impact assessment, impediments, and conclusions. (DLC)

  14. The environmental implications of intensified land use in developing countries

    PubMed Central

    Tinker, P. B.

    1997-01-01

    The major agricultural intensifications in the developed world over the last half century have produced a range of important environmental problems. These include pollution, damage to wildlife and landscape and other issues, both on- and off-site. These are largely being controlled by scientific investigation and Government regulation. As developing countries increase agricultural production over the next 30 years, this may also cause even more serious environmental damage.
    The paper distinguishes between production-related on-site damage, and off-site and more extensive effects. Both may involve soil and water effects, such as soil erosion, salinization, siltation, eutrophication and loss of water quality. The use of more agrochemicals can damage water quality, health, wildlife and biodiversity. Loss of habitat from the extension of farming is particularly damaging to biodiversity. A developing off-site problem is the production of greenhouse gases by farming systems, including the conversion of forests to farmland. In the future the introduction of genetically engineered species of plants, animals or microbes will need secure control.
    Work, probably on a catchment basis, is necessary to understand and control these problems. The three main requirements are much better environmental information from the developing world; the selection of environmental indicators to be monitored; and the support of local farmers in protecting the environment. There are encouraging indications of farmer concern and action over obvious on-site damage, but this may not extend to extensive off-site issues. The main danger is that developing food scarcity would cause the environmental issues to be ignored in a race for production.

  15. Implications of climate change mitigation for sustainable development

    NASA Astrophysics Data System (ADS)

    Jakob, Michael; Steckel, Jan Christoph

    2016-10-01

    Evaluating the trade-offs between the risks related to climate change, climate change mitigation as well as co-benefits requires an integrated scenarios approach to sustainable development. We outline a conceptual multi-objective framework to assess climate policies that takes into account climate impacts, mitigation costs, water and food availability, technological risks of nuclear energy and carbon capture and sequestration as well as co-benefits of reducing local air pollution and increasing energy security. This framework is then employed as an example to different climate change mitigation scenarios generated with integrated assessment models. Even though some scenarios encompass considerable challenges for sustainability, no scenario performs better or worse than others in all dimensions, pointing to trade-offs between different dimensions of sustainable development. For this reason, we argue that these trade-offs need to be evaluated in a process of public deliberation that includes all relevant social actors.

  16. Preschool child development: implications for investigation of child abuse allegations.

    PubMed

    Sivan, A B

    1991-01-01

    Allegations of mistreatment by adults made by children of preschool age are often dismissed as fictitious with the suggestion that children of this age are prone to fantasy and unable to discriminate fact from fiction. This paper is intended to familiarize those with a general concern about child abuse with the research and theories in child development. Specifically, it reviews those aspects of normal child development which have direct relevance to the question of the veracity of reports made by children ages 2 to 5 years. Examination of the research on children's thought and language, memory and learning, fears, fantasy, and play, as well as the research on the influence of television on children of this age, led to the conclusion that preschoolers base their play on the reality of their experience.

  17. Implication of epigenetics in pancreas development and disease.

    PubMed

    Quilichini, Evans; Haumaitre, Cécile

    2015-12-01

    Pancreas development is controlled by a complex interaction of signaling pathways and transcription factor networks that determine pancreatic specification and differentiation of exocrine and endocrine cells. Epigenetics adds a new layer of gene regulation. DNA methylation, histone modifications and non-coding RNAs recently appeared as important epigenetic factors regulating pancreas development. In this review, we report recent findings obtained by analyses in model organisms as well as genome-wide approaches that demonstrate the role of these epigenetic regulators in the control of exocrine and endocrine cell differentiation, identity, function, proliferation and regeneration. We also highlight how altered epigenetic processes contribute to pancreatic disorders: diabetes and pancreatic cancer. Uncovering these epigenetic events can help to better understand these diseases, provide novel therapeutical targets for their treatment, and improve cell-based therapies for diabetes. PMID:26696517

  18. The implications of health sector reform for human resources development.

    PubMed Central

    Alwan, Ala'; Hornby, Peter

    2002-01-01

    The authors argue that "health for all" is not achievable in most countries without health sector reform that incorporates a process of coordinated health and human resources development. They examine the situation in countries in the Eastern Mediterranean Region of the World Health Organization. Though advances have been made, further progress is inhibited by the limited adaptation of traditional health service structures and processes in many of these countries. National reform strategies are needed. These require the active participation of health professional associations and academic training institutions as well as health service managers. The paper indicates some of the initiatives required and suggests that the starting point for many countries should be a rigorous appraisal of the current state of human resources development in health. PMID:11884974

  19. Policy implications in developing a land use management information systems

    NASA Technical Reports Server (NTRS)

    Landini, A. J.

    1975-01-01

    The current land use map for the city of Los Angeles was developed by the guesstimation process and provides single stage information for each level in the critical geographical hierarchy for land use planning management. Processing and incorporation of LANDSAT data in the land use information system requires special funding; however, computergraphic maps are able to provide a viable information system for city planning and management.

  20. Implications of learning theory for developing programs to decrease overeating.

    PubMed

    Boutelle, Kerri N; Bouton, Mark E

    2015-10-01

    Childhood obesity is associated with medical and psychological comorbidities, and interventions targeting overeating could be pragmatic and have a significant impact on weight. Calorically dense foods are easily available, variable, and tasty which allows for effective opportunities to learn to associate behaviors and cues in the environment with food through fundamental conditioning processes, resulting in measurable psychological and physiological food cue reactivity in vulnerable children. Basic research suggests that initial learning is difficult to erase, and that it is vulnerable to a number of phenomena that will allow the original learning to re-emerge after it is suppressed or replaced. These processes may help explain why it may be difficult to change food cue reactivity and overeating over the long term. Extinction theory may be used to develop effective cue-exposure treatments to decrease food cue reactivity through inhibitory learning, although these processes are complex and require an integral understanding of the theory and individual differences. Additionally, learning theory can be used to develop other interventions that may prove to be useful. Through an integration of learning theory, basic and translational research, it may be possible to develop interventions that can decrease the urges to overeat, and improve the weight status of children. PMID:25998235

  1. Leadership theory: implications for developing dental surgeons in primary care?

    PubMed

    Willcocks, S

    2011-02-12

    The development of leadership in healthcare has been seen as important in recent years, particularly at the clinical level. There have been various specific initiatives focusing on the development of leadership for doctors, nurses and other health care professions: for example, a leadership competency framework for doctors, the LEO programme and the RCN clinical leadership programme for nurses. The NHS has set up a Leadership Council to coordinate further developments. However, there has not been the same focus in dentistry, although the recent review of NHS dental services (Steele review) has proposed a need for leadership initiatives in NHS dentistry as a medium-term action. Central to this will be a need to focus on the leadership role for dental surgeons. Leadership is all the more important in dentistry, given the change of government and the policy of retrenchment, major public sector reform, the emergence of new organisations such as new commissioning consortia, possible changes to the dental contract, new ways of working, and changes to the profession such as the requirements for the revalidation of dental surgeons. The question is: which leadership theory or approach is best for dental surgeons working in primary care? This paper builds on earlier work exploring this question in relation to doctors generally, and GPs, in particular, and planned work on nurses. It will seek to address this question in relation to dental surgeons working in primary care.

  2. Implications of learning theory for developing programs to decrease overeating.

    PubMed

    Boutelle, Kerri N; Bouton, Mark E

    2015-10-01

    Childhood obesity is associated with medical and psychological comorbidities, and interventions targeting overeating could be pragmatic and have a significant impact on weight. Calorically dense foods are easily available, variable, and tasty which allows for effective opportunities to learn to associate behaviors and cues in the environment with food through fundamental conditioning processes, resulting in measurable psychological and physiological food cue reactivity in vulnerable children. Basic research suggests that initial learning is difficult to erase, and that it is vulnerable to a number of phenomena that will allow the original learning to re-emerge after it is suppressed or replaced. These processes may help explain why it may be difficult to change food cue reactivity and overeating over the long term. Extinction theory may be used to develop effective cue-exposure treatments to decrease food cue reactivity through inhibitory learning, although these processes are complex and require an integral understanding of the theory and individual differences. Additionally, learning theory can be used to develop other interventions that may prove to be useful. Through an integration of learning theory, basic and translational research, it may be possible to develop interventions that can decrease the urges to overeat, and improve the weight status of children.

  3. Implications of learning theory for developing programs to decrease overeating

    PubMed Central

    Boutelle, Kerri N.; Bouton, Mark E.

    2015-01-01

    Childhood obesity is associated with medical and psychological comorbidities, and interventions targeting overeating could be pragmatic and have a significant impact on weight. Calorically dense foods are easily available, variable, and tasty which allows for effective opportunities to learn to associate behaviors and cues in the environment with food through fundamental conditioning processes, resulting in measurable psychological and physiological food cue reactivity in vulnerable children. Basic research suggests that initial learning is difficult to erase, and that it is vulnerable to a number of phenomena that will allow the original learning to re-emerge after it is suppressed or replaced. These processes may help explain why it may be difficult to change food cue reactivity and overeating over the long term. Extinction theory may be used to develop effective cue-exposure treatments to decrease food cue reactivity through inhibitory learning, although these processes are complex and require an integral understanding of the theory and individual differences. Additionally, learning theory can be used to develop other interventions that may prove to be useful. Through an integration of learning theory, basic and translational research, it may be possible to develop interventions that can decrease the urges to overeat, and improve the weight status of children. PMID:25998235

  4. Mammalian septin function in hemostasis and beyond.

    PubMed

    Martinez, Constantino; Ware, Jerry

    2004-12-01

    Interest in the biology of mammalian septin proteins has undergone a birth in recent years. Originally identified as critical for yeast budding throughout the 1970s, the septin family is now recognized to extend from yeast to humans and is associated with a variety of events ranging from cytokinesis to vesicle trafficking. An emerging theme for septins is their presence at sites where active membrane or cytoplasmic partitioning is occurring. Here, we briefly review the mammalian septin protein family and focus on a prototypic human and mouse septin, termed SEPT5, that is expressed in the brain, heart, and megakaryocytes. Work from neurobiology laboratories has linked SEPT5 to the exocytic complex of neurons, with implications that SEPT5 regulates neurotransmitter release. Striking similarities exist between neurotransmitter release and the platelet-release reaction, which is a critical step in platelet response to vascular injury. Work from our laboratory has characterized the platelet phenotype from mice containing a targeted deletion of SEPT5. Most strikingly, platelets from SEPT5(null) animals aggregate and release granular contents in response to subthreshold levels of agonists. Thus, the characterization of a SEPT5-deficient mouse has linked SEPT5 to the platelet exocytic process and, as such, illustrates it as an important protein for regulating platelet function. Recent data suggest that platelets contain a wide repertoire of different septin proteins and assemble to form macromolecular septin complexes. The mouse platelet provides an experimental framework to define septin function in hemostasis, with implications for neurobiology and beyond.

  5. Metabolic costs and evolutionary implications of human brain development.

    PubMed

    Kuzawa, Christopher W; Chugani, Harry T; Grossman, Lawrence I; Lipovich, Leonard; Muzik, Otto; Hof, Patrick R; Wildman, Derek E; Sherwood, Chet C; Leonard, William R; Lange, Nicholas

    2014-09-01

    The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate. PMID:25157149

  6. Metabolic costs and evolutionary implications of human brain development

    PubMed Central

    Kuzawa, Christopher W.; Chugani, Harry T.; Grossman, Lawrence I.; Lipovich, Leonard; Muzik, Otto; Hof, Patrick R.; Wildman, Derek E.; Sherwood, Chet C.; Leonard, William R.; Lange, Nicholas

    2014-01-01

    The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain’s glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain–body metabolic trade-offs using the ratios of brain glucose uptake to the body’s resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate. PMID:25157149

  7. Metabolic costs and evolutionary implications of human brain development.

    PubMed

    Kuzawa, Christopher W; Chugani, Harry T; Grossman, Lawrence I; Lipovich, Leonard; Muzik, Otto; Hof, Patrick R; Wildman, Derek E; Sherwood, Chet C; Leonard, William R; Lange, Nicholas

    2014-09-01

    The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.

  8. Subglacial extensional fracture development and implications for Alpine Valley evolution

    NASA Astrophysics Data System (ADS)

    Leith, Kerry; Moore, Jeffrey R.; Amann, Florian; Loew, Simon

    2014-01-01

    stresses induced through exhumation and tectonic processes play a key role in the topographic evolution of alpine valleys. Using a finite difference model combining the effects of tectonics, erosion, and long-term bedrock strength, we assess the development of near-surface in situ stresses and predict bedrock behavior in response to glacial erosion in an Alpine Valley (the Matter Valley, southern Switzerland). Initial stresses are derived from the regional tectonic history, which is characterized by ongoing transtensional or extensional strain throughout exhumation of the brittle crust. We find that bedrock stresses beneath glacial ice in an initial V-shaped topography are sufficient to induce localized extensional fracturing in a zone extending laterally 600 m from the valley axis. The limit of this zone is reflected in the landscape today by a valley "shoulder," separating linear upper mountain slopes from the deep U-shaped inner valley. We propose that this extensional fracture development enhanced glacial quarrying between the valley shoulder and axis and identify a positive feedback where enhanced quarrying promoted valley incision, which in turn increased in situ stress concentrations near the valley floor, assisting erosion and further driving rapid U-shaped valley development. During interglacial periods, these stresses were relieved through brittle strain or topographic modification, and without significant erosion to reach more highly stressed bedrock, subsequent glaciation caused a reduction in differential stress and suppressed extensional fracturing. A combination of stress relief during interglacial periods, and increased ice accumulation rates in highly incised valleys, will reduce the likelihood of repeat enhanced erosion events.

  9. Nigerian population growth and its implications for economic development.

    PubMed

    Okpala, A O

    1990-12-01

    The population of Nigeria is growing at a rate of 3.75%/year indicating a doubling of the population every 22 years. Demographers estimated the population to be 91,178,000 in 1985. Even though population density is high (288 people/square mile), it is not equally distributed. It is highest in the south and southwest urban areas such as Lagos (1045 people/square mile) and lowest in the northeast (75 people/square mile). Moreover rural-urban migration is growing. A major reason for rural-urban migration is the dual nature of the economy in Nigeria. In urban areas, economic development brings about higher standards of living, but, in rural areas, a subsistence economy predominates. This coupled with rapid population growth results in small or no growth in per capita income. Only if the government were to integrate redistribution policies into complete economic development plans should it consider redistributing the population. It should stress rural development (e.g., incentives for firms to set up in rural areas). Further it should move some government offices to rural areas. The government also needs to adopt population policies encouraging the lowering of fertility levels. If it were to provide education through the secondary and prevocational education level free of charge, educated women will lower their fertility. Sex education should be included in the curriculum. Further the government must play an active role in family planning programs, especially educating rural women about family planning. It should also use the mass media to promote small family size, but it should not dictate family size. It also needs to recognize that population growth puts much pressure on the environment. For example, population growth causes soil erosion, nutrient exhaustion, rapid deforestation, and other problems which render the land unusable for agriculture.

  10. Increased Screen Time: Implications for Early Childhood Development and Behavior.

    PubMed

    Radesky, Jenny S; Christakis, Dimitri A

    2016-10-01

    The authors review trends in adoption of new digital technologies (eg, mobile and interactive media) by families with young children (ages 0-8 years), continued use of television and video games, and the evidence for learning from digital versus hands-on play. The authors also discuss continued concerns about health and developmental/behavioral risks of excessive media use for child cognitive, language, literacy, and social-emotional development. This evidence is then applied to clinical care in terms of the screening questions providers can use, tools available to providers and parents, and changes in anticipatory guidance.

  11. Increased Screen Time: Implications for Early Childhood Development and Behavior.

    PubMed

    Radesky, Jenny S; Christakis, Dimitri A

    2016-10-01

    The authors review trends in adoption of new digital technologies (eg, mobile and interactive media) by families with young children (ages 0-8 years), continued use of television and video games, and the evidence for learning from digital versus hands-on play. The authors also discuss continued concerns about health and developmental/behavioral risks of excessive media use for child cognitive, language, literacy, and social-emotional development. This evidence is then applied to clinical care in terms of the screening questions providers can use, tools available to providers and parents, and changes in anticipatory guidance. PMID:27565361

  12. Clinical implications of thyroid hormones effects on nervous system development.

    PubMed

    Carreón-Rodríguez, Alfonso; Pérez-Martínez, Leonor

    2012-03-01

    Thyroid hormones have an important role throughout prenatal and postnatal nervous system development. They are involved in several processes such as neurogenesis, gliogenesis, myelination, synaptogenesis, etc., as shown in many cases of deficiency like congenital hypothyroidism or hypothyroxinemia. Those pathologies if untreated could lead to severe damages in cognitive, motor, neudoendocrine functions among other effects. Some could be reversed after adequate supplementation of thyroid hormones at birth, however there are other cellular processes highly sensitive to low levels of thyroid hormones and lasting a limited period of time during which if thyroid hormone action is lacking or deficient, the functional and structural damages would produce permanent defects. PMID:22523832

  13. Lava thicknesses: Implications for rheological and crustal development

    NASA Technical Reports Server (NTRS)

    Kilburn, C. R. J.; Lopes, R. M. C.

    1988-01-01

    The morphology of a lava flow is strongly influenced by its rheological structure. The rheological structure is, in turn, dependent on numerous factors including: (1) bulk composition, (2) crystallingity, (3) vesicularity, and (4) crustal development. Identifying which of the latter factors are most significant, and hence most readily investigated by remote-sensing techniques, is necessary to clarify short-term objectives and expectations from the study of Martian lava flows. Insights into the rheological controls on flow morphology are provided by variations in thickness of undrained lava streams on Etna and Vesuvius, Southern Italy. Both pahoehoe and aa lavas were studied.

  14. Cholinesterases in neural development: new findings and toxicologic implications.

    PubMed Central

    Brimijoin, S; Koenigsberger, C

    1999-01-01

    Developing animals are more sensitive than adults to acute cholinergic toxicity from anticholinesterases, including organophosphorus pesticides, when administered in a laboratory setting. It is also possible that these agents adversely affect the process of neural development itself, leading to permanent deficits in the architecture of the central and peripheral nervous systems. Recent observations indicate that organophosphorus exposure can affect DNA synthesis and cell survival in neonatal rat brain. New evidence that acetylcholinesterase may have a direct role in neuronal differentiation provides additional grounds for interest in the developmental toxicity of anticholinesterases. For example, correlative anatomic studies show that transient bursts of acetylcholinesterase expression often coincide with periods of axonal outgrowth in maturing avian, rodent, and primate brain. Some selective cholinesterase inhibitors effectively suppress neurite outgrowth in model systems like differentiating neuroblastoma cells and explanted sensory ganglia. When enzyme expression is altered by genetic engineering, acetylcholinesterase levels on the outer surface of transfected neurons correlate with ability to extend neurites. Certain of these "morphogenic" effects may depend on protein-protein interactions rather than catalytic acetylcholinesterase activity. Nonetheless, it remains possible that some pesticides interfere with important developmental functions of the cholinesterase enzyme family. Images Figure 1 Figure 3 PMID:10229707

  15. Animal biotechnology: applications and economic implications in developing countries.

    PubMed

    Madan, M L

    2005-04-01

    In most developing countries, biotechnological applications relating to livestock need to be suitable for animal owners who are resource-poor small-scale operators who own little or no land and few animals. Livestock is becoming increasingly important to economic growth in developing countries and the application of biotechnology is largely dictated by commercial considerations and socio-economic goals. Using technology to support livestock production is an integral part of viable agriculture in multi-enterprise systems. Livestock are part of a fragile ecosystem and a rich source of animal biodiversity, as local species and breeds possess genes and traits of excellence. Molecular markers are increasingly being used to identify and select the particular genes that lead to these desirable traits and it is now possible to select superior germ plasm and disseminate it using artificial insemination, embryo transfer and other assisted reproductive technologies. These technologies have been used in the genetic improvement of livestock, particularly in cattle and buffaloes, and the economic returns are significant. However, morbidity and mortality among animals produced using assisted reproductive technologies lead to high economic losses, so the principal application of animal biotechnology at present is in the production of cheap and dependable diagnostic kits and vaccines. Several obstacles limit the application of biotechnology at present: there is a lack of infrastructure and insufficient manpower, so funding is needed if resource-poor farmers are to benefit from biotechnology. PMID:16110883

  16. EVOLUTION OF MYCOBACTERIUM TUBERCULOSIS AND IMPLICATIONS FOR VACCINE DEVELOPMENT.

    PubMed

    Gagneux, Sebastien

    2016-04-01

    Tuberculosis (TB) is a growing public health threat, particularly in the face of the global epidemics of multidrug resistance. Given the limited efficacy of the current TB vaccine and the recent clinical failure of the most advanced new TB vaccine candidate, novel concepts for vaccine design should be explored. Most T cell antigens in the human-adapted Mycobacterium tuberculosis complex (MTBC) are evolutionarily conserved and under strong purifying selection, indicating that host immune responses targeting these antigens might not be protective. By contrast, a few highly variable T cell epitopes have recently been discovered, which could serve as alternative vaccine antigens. Moreover, there is increasing evidence that the human-adapted MTBC has been co-evolving with the human host for a long time. Hence, studying the interaction between bacterial and human genetic diversity might help identify additional targets that could be exploited for TB vaccine development.

  17. REDD: a reckoning of environment and development implications.

    PubMed

    Ghazoul, Jaboury; Butler, Rhett A; Mateo-Vega, Javier; Koh, Lian Pin

    2010-07-01

    Reducing Emissions from Deforestation (REDD) aims to curb carbon emissions from deforestation by financially compensating forest owners. However, compensation based on the opportunity costs of REDD might underestimate true costs by failing to account for downstream economic values of current land uses, including employment and wealth generated by processing and service industries. A comprehensive analysis of REDD impacts should also include sociopolitical impacts. REDD might exclude people from forest land, causing demographic shifts, and the declining tax revenues from commodity production and associated industries might be a disincentive to government investment in forested regions to the detriment of forest communities and regional development. We argue for the need to recognize and appropriately compensate the full range of economic, social and political net costs of REDD.

  18. Auxin metabolism rates and implications for plant development

    PubMed Central

    Kramer, Eric M.; Ackelsberg, Ethan M.

    2015-01-01

    Studies of auxin metabolism rarely express their results as a metabolic rate, although the data obtained would often permit such a calculation to be made. We analyze data from 31 previously published papers to quantify the rates of auxin biosynthesis, conjugation, conjugate hydrolysis, and catabolism in seed plants. Most metabolic pathways have rates in the range 10 nM/h–1 μM/h, with the exception of auxin conjugation, which has rates as high as ~100 μM/h. The high rates of conjugation suggest that auxin metabolic sinks may be very small, perhaps as small as a single cell. By contrast, the relatively low rate of auxin biosynthesis requires plants to conserve and recycle auxin during long-distance transport. The consequences for plant development are discussed. PMID:25852709

  19. [Implications of publication bias on guideline development and appraisal].

    PubMed

    Kopp, Ina B

    2011-01-01

    The issue of selective publishing of research results is gaining more and more scientific, public and political awareness. For guideline authors, in particular, it leads to uncertainty about the interpretability of the methodological quality and clinical relevance of the available evidence and the risk of bias where their conclusions and thus guideline recommendations are concerned. The actual impact of publication bias on guideline contents appears to be low if a systematic and methodically sound approach is followed in the process of guideline development. However, the quality of the evidence on this topic is poor. Different strategies to deal with publication bias have been proposed for authors of systematic reviews but they are of limited use for guideline authors. The goal must therefore be to implement appropriate measures in order to avoid the problem ex ante. The first step would be the systematic registration of study results in publicly accessible registers.

  20. Cell competition and its implications for development and cancer

    PubMed Central

    Tamori, Yoichiro; Deng, Wu-Min

    2013-01-01

    Cell competition is a struggle for existence between cells in heterogeneous tissues of multicellular organisms. Loser cells, which die during cell competition, are normally viable when grown only with other loser cells, but when mixed with winner cells, they are at a growth disadvantage and undergo apoptosis. Intriguingly, several recent studies have revealed that cells bearing mutant tumor-suppressor genes, which show overgrowth and tumorigenesis in a homotypic situation, are frequently eliminated, through cell competition, from tissues in which they are surrounded by wild-type cells. Here, we focus on the regulation of cellular competitiveness and the mechanism of cell competition as inferred from two different categories of mutant cells: (1) slower-growing cells and (2) structurally defective cells. We also discuss the possible role of cell competition as an intrinsic homeostasis system through which normal cells sense and remove aberrant cells, such as precancerous cells, to maintain the integrity and normal development of tissues and organs. PMID:22035869

  1. Implications of enterotoxigenic Escherichia coli genomics for vaccine development.

    PubMed

    Sjöling, Åsa; von Mentzer, Astrid; Svennerholm, Ann-Mari

    2015-04-01

    Enterotoxigenic Escherichia coli (ETEC) is a major cause of morbidity and mortality caused by diarrhea in children less than 5 years of age in low- and middle-income countries. Despite a wealth of research elucidating the mechanisms of disease, the immunological responses and vaccine development, ETEC is still relatively uncharacterized when it comes to regulation of virulence and detailed immune mechanisms. The recent emergence of next-generation sequencing now offers the possibility to screen genomes of ETEC strains isolated globally to identify novel vaccine targets in addition to those already established. In this review, we discuss how recent findings on ETEC genomics using novel sequencing techniques will aid in finding novel protective antigens that can be used in vaccine approaches. PMID:25540974

  2. REDD: a reckoning of environment and development implications.

    PubMed

    Ghazoul, Jaboury; Butler, Rhett A; Mateo-Vega, Javier; Koh, Lian Pin

    2010-07-01

    Reducing Emissions from Deforestation (REDD) aims to curb carbon emissions from deforestation by financially compensating forest owners. However, compensation based on the opportunity costs of REDD might underestimate true costs by failing to account for downstream economic values of current land uses, including employment and wealth generated by processing and service industries. A comprehensive analysis of REDD impacts should also include sociopolitical impacts. REDD might exclude people from forest land, causing demographic shifts, and the declining tax revenues from commodity production and associated industries might be a disincentive to government investment in forested regions to the detriment of forest communities and regional development. We argue for the need to recognize and appropriately compensate the full range of economic, social and political net costs of REDD. PMID:20417579

  3. The Concept of Nondeterminism: Its Development and Implications for Teaching

    NASA Astrophysics Data System (ADS)

    Armoni, Michal; Ben-Ari, Mordechai

    2009-08-01

    Nondeterminism is a fundamental concept in computer science that appears in various contexts such as automata theory, algorithms and concurrent computation. We present a taxonomy of the different ways that nondeterminism can be defined and used; the categories of the taxonomy are domain, nature, implementation, consistency, execution and semantics. An historical survey shows how the concept was developed from its inception by Rabin & Scott, Floyd and Dijkstra, as well as the interplay between nondeterminism and concurrency. Computer science textbooks and pedagogical software are surveyed to determine how they present the concept; the results show that the treatment of nondeterminism is generally fragmentary and unsystematic. We conclude that the teaching of nondeterminism must be integrated through the computer science curriculum so that students learn to see nondeterminism both in terms of abstract mathematical entities and in terms of machines whose execution is unpredictable.

  4. Some implications of in situ uranium mining technology development

    SciTech Connect

    Cowan, C.E.; Parkhurst, M.A.; Cole, R.J.; Keller, D.; Mellinger, P.J.; Wallace, R.W.

    1980-09-01

    The assessment indicates that there do not appear to be any significant demonstrated negative environmental impacts. Moreover, the impacts of in situ mining compare favorably with those impacts expected from conventional mining techniques. Exposure to radioactive elements is less, atmospheric emissions of radioactive and nonradioactive materials are generally less and socioeconomic impacts are decreased. In fact, because of the generally small and unskilled labor forces associated with in-situ mining, development has provided much needed economic stimulus to economically depressed areas of Texas. There are still, however, several areas of unknowns and several areas of inadequate information that will need to be addressed before a complete quantification evaluation of impacts can be made. These areas include levels of radon emissions and groundwater restoration methods and impacts. Several issues mostly relating to the interaction of industry with state and Federal regulators need to be addressed.

  5. Implications of enterotoxigenic Escherichia coli genomics for vaccine development.

    PubMed

    Sjöling, Åsa; von Mentzer, Astrid; Svennerholm, Ann-Mari

    2015-04-01

    Enterotoxigenic Escherichia coli (ETEC) is a major cause of morbidity and mortality caused by diarrhea in children less than 5 years of age in low- and middle-income countries. Despite a wealth of research elucidating the mechanisms of disease, the immunological responses and vaccine development, ETEC is still relatively uncharacterized when it comes to regulation of virulence and detailed immune mechanisms. The recent emergence of next-generation sequencing now offers the possibility to screen genomes of ETEC strains isolated globally to identify novel vaccine targets in addition to those already established. In this review, we discuss how recent findings on ETEC genomics using novel sequencing techniques will aid in finding novel protective antigens that can be used in vaccine approaches.

  6. Evidence for soft bounds in Ubuntu package sizes and mammalian body masses.

    PubMed

    Gherardi, Marco; Mandrà, Salvatore; Bassetti, Bruno; Cosentino Lagomarsino, Marco

    2013-12-24

    The development of a complex system depends on the self-coordinated action of a large number of agents, often determining unexpected global behavior. The case of software evolution has great practical importance: knowledge of what is to be considered atypical can guide developers in recognizing and reacting to abnormal behavior. Although the initial framework of a theory of software exists, the current theoretical achievements do not fully capture existing quantitative data or predict future trends. Here we show that two elementary laws describe the evolution of package sizes in a Linux-based operating system: first, relative changes in size follow a random walk with non-Gaussian jumps; second, each size change is bounded by a limit that is dependent on the starting size, an intriguing behavior that we call "soft bound." Our approach is based on data analysis and on a simple theoretical model, which is able to reproduce empirical details without relying on any adjustable parameter and generates definite predictions. The same analysis allows us to formulate and support the hypothesis that a similar mechanism is shaping the distribution of mammalian body sizes, via size-dependent constraints during cladogenesis. Whereas generally accepted approaches struggle to reproduce the large-mass shoulder displayed by the distribution of extant mammalian species, this is a natural consequence of the softly bounded nature of the process. Additionally, the hypothesis that this model is valid has the relevant implication that, contrary to a common assumption, mammalian masses are still evolving, albeit very slowly.

  7. Development and implication of a human-volcano system model

    NASA Astrophysics Data System (ADS)

    Bachri, Syamsul; Stötter, Johann; Monreal, Matthias; Sartohadi, Junun

    2014-05-01

    In an attempt to understand the complexity of human-environment systems, models help to define, quantify, describe, or simulate complex interactions. With regards to the human-volcano system, we develop a conceptual model in order to assist analysis of its two basic elements, the physical and the social environment. A field survey of the human environment interaction of two of the most active volcanic areas in Indonesia (Mt. Merapi and Mt. Bromo) and a corresponding literature review from other case studies was carried out. A differentiated understanding of human interaction with hazard potential elements within the human-volcano system is the main focus of the model development. We classified volcanic processes and effects as three pairs of dichotomies: positive or negative impacts, on society or environment in an indirect or direct way. Each volcanically induced process or effect characterized accordingly leads to eight distinct process/effect classes. They are positive direct effects on society (PDS); positive direct effects on natural resources (PDN); positive indirect effects on society (PIS); positive indirect effects on natural resources (PIN); negative direct effects on society (NDS); negative direct effects on natural resources (NDN); negative indirect effects on society (NIS) and lastly negative indirect effects on natural resources (NIN). Such differentiated view of volcanic process/effects bears several advantages. First, whereas volcanic processes have hitherto been viewed as hazards only, it becomes possible now to describe a particular process/effect in a particular context as negative or positive. Secondly, such a categorization makes it possible to account for processes of the human-volcano system that do not have a direct physical expression but are of socio-cultural relevance. Thirdly, the greater degree of differentiation that is made possible when evaluating volcanic processes has significant repercussions on the way volcanic risk must be

  8. Transboundary air pollution in Asia: Model development and policy implications

    NASA Astrophysics Data System (ADS)

    Holloway, Tracey

    2001-12-01

    This work investigates transboundary air pollution in Asia through atmospheric modeling and public policy analysis. As an example of models actively shaping environmental policy, the Convention on Long-Range Transboundary Air Pollution in Europe (LRTAP) is selected as a case study. The LRTAP Convention is the only mulit- lateral air pollution agreement to date, and results from the RAINS integrated assessment model were heavily used to calculate nationally differentiated emission ceilings. Atmospheric chemistry and transport are included in RAINS through the use of transfer coefficients (or ``source-receptor relationships'') relating pollutant transfer among European nations. Following past work with ATMOS to simulate sulfur species in Asia, here ATMOS is developed to include odd-nitrogen. Fitting with the linear structure of ATMOS and the emphasis on computational efficiency, a simplified chemical scheme developed for use in the NOAA Geophysical Fluid Dynamics Laboratory Global Chemical Transport Model (GFDL GCTM) is adopted. The method solves for the interconversions between NOx, HNO3, and PAN based on five reaction rates stored in look-up tables. ATMOS is used to calculate source-receptor relationships for Asia. Significant exchange of NOy occurs among China, North and South Korea, and Japan. On an annual average basis, China contributes 18% to Japan's total nitrate deposition, 46% to North Korea, and 26% to South Korea. Nitrate deposition is an important component of acidification (along with sulfate deposition), contributing 30-50% to the acid burden over most of Japan, and more than 50% to acid deposition in southeast Asia, where biomass burning emits high levels of NOx. In evaluating the policy-relevance of results from the ATMOS model, four factors are taken into account: the uncertainty and limitations of ATMOS, the environmental concerns facing Asia, the current status of the scientific community in relation to regional air pollution in the region, and

  9. Cholinergic functioning in stimulant addiction: implications for medications development.

    PubMed

    Sofuoglu, Mehmet; Mooney, Marc

    2009-11-01

    Acetylcholine, the first neurotransmitter discovered, participates in many CNS functions, including sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal, memory, motivation and reward. These diverse cholinergic effects are mediated by nicotinic- and muscarinic-type cholinergic receptors (nAChR and mAChR, respectively). The goal of this review is to synthesize a growing literature that supports the potential role of acetylcholine as a treatment target for stimulant addiction. Acetylcholine interacts with the dopaminergic reward system in the ventral tegmental area, nucleus accumbens and prefrontal cortex. In the ventral tegmental area, both nAChR and mAChR stimulate the dopaminergic system. In the nucleus accumbens, cholinergic interneurons integrate cortical and subcortical information related to reward. In the prefrontal cortex, the cholinergic system contributes to the cognitive aspects of addiction. Preclinical studies support a facilitative role of nicotinic receptor agonists in the development of stimulant addiction. In contrast, nonselective muscarinic receptor agonists seem to have an inhibitory role. In human studies, acetylcholinesterase inhibitors, which increase synaptic acetylcholine levels, have shown promise for the treatment of stimulant addiction. Further studies testing the efficacy of cholinergic medications for stimulant addiction are warranted. PMID:19845415

  10. Animal models for influenza viruses: implications for universal vaccine development.

    PubMed

    Margine, Irina; Krammer, Florian

    2014-10-21

    Influenza virus infections are a significant cause of morbidity and mortality in the human population. Depending on the virulence of the influenza virus strain, as well as the immunological status of the infected individual, the severity of the respiratory disease may range from sub-clinical or mild symptoms to severe pneumonia that can sometimes lead to death. Vaccines remain the primary public health measure in reducing the influenza burden. Though the first influenza vaccine preparation was licensed more than 60 years ago, current research efforts seek to develop novel vaccination strategies with improved immunogenicity, effectiveness, and breadth of protection. Animal models of influenza have been essential in facilitating studies aimed at understanding viral factors that affect pathogenesis and contribute to disease or transmission. Among others, mice, ferrets, pigs, and nonhuman primates have been used to study influenza virus infection in vivo, as well as to do pre-clinical testing of novel vaccine approaches. Here we discuss and compare the unique advantages and limitations of each model.

  11. Implications of scavenger receptors in the safe development of nanotherapeutics

    PubMed Central

    Shannahan, Jonathan H.; Bai, Wei; Brown, Jared M.

    2015-01-01

    Nanomaterials (NMs) are being utilized in a variety of biomedical applications including drug delivery, diagnostics, and therapeutic targeting. These applications are made possible due to the unique physicochemical properties that are exhibited at the nanoscale. To ensure safe development of NMs for clinical use, it is necessary to understand their interactions with cells and specifically cell surface receptors, which will facilitate either their toxicity and/or clinical function. Recently our research and others have investigated the role of scavenger receptors in mediating NM-cell interactions and responses. Scavenger receptors are expressed by a variety of cell types that are first to encounter NMs during clinical use such as macrophages and endothelial cells. Scavenger receptors are recognized to facilitate uptake of a wide variety of ligands ranging from foreign substances to endogenous lipids/proteins. While interaction of NMs with scavenger receptors may allow therapeutic targeting in some instances, it also presents a challenge for the stealth delivery of NMs and avoidance of the scavenging capability of this class of receptors. Due to their role in facilitating immune responses, scavenger receptor-mediated inflammation is also of concern following NM delivery. The research highlighted in this brief review intends to summarize our current understanding regarding the consequences of NM-scavenger receptor interactions. PMID:26005702

  12. Developing Biological ISRU: Implications for Life Support and Space Exploration

    NASA Technical Reports Server (NTRS)

    Brown, I. I.; Allen, C. C.; Garrison, D. H.; Sarkisova, S. A.; Galindo, C.; Mckay, David S.

    2010-01-01

    Main findings: 1) supplementing very dilute media for cultivation of CB with analogs of lunar or Martian regolith effectively supported the proliferation of CB; 2) O2 evolution by siderophilic cyanobacteria cultivated in diluted media but supplemented with iron-rich rocks was higher than O2 evolution by same strain in undiluted medium; 3) preliminary data suggest that organic acids produced by CB are involved in iron-rich mineral dissolution; 4) the CB studied can accumulate iron on and in their cells; 4) sequencing of the cyanobacterium JSC-1 genome revealed that this strain possesses molecular features which make it applicable for the cultivation in special photoreactors on Moon and Mars. Conclusion: As a result of pilot studies, we propose, to develop a concept for semi-closed integrated system that uses CB to extract useful elements to revitalize air and produce valuable biomolecules. Such a system could be the foundation of a self-sustaining extraterrestrial outpost (Hendrickx, De Wever et al., 2005; Handford, 2006). A potential advantage of a cyanobacterial photoreactor placed between LSS and ISRU loops is the possibility of supplying these systems with extracted elements and compounds from the regolith. In addition, waste regolith may be transformed into additional products such as methane, biomass, and organic and inorganic soil enrichment for the cultivation of higher plants.

  13. Commodification of human tissue: implications for feminist and development ethics.

    PubMed

    Dickenson, Donna

    2002-05-01

    One effect of late capitalism--the commodification of practically everything--is to knock down the Chinese walls between the natural and productive realms, to use a Marxist framework. Women's labour in egg extraction and 'surrogate' motherhood might then be seen as what it is, labour which produces something of value. But this does not necessarily mean that women will benefit from the commodification of practically everything, in either North or South. In the newly developing biotechnologies involving stem cells, the reverse is more likely, particular given the the shortage in the North of the egg donors who will be increasingly necessary to therapeutic cloning. Although most of the ethical debate has focused on the status of the embryo, this is to define ethics with no reference to global or gender justice. There has been little or no debate about possible exploitation of women, particularly of ovum donors from the South. Countries of the South without national ethics committees or guidelines may be particularly vulnerable: although there is increasing awareness of the susceptibility of poorer countries to abuses in research ethics, very little has been written about how they might be affected by the enormously profitable new technologies exploiting human tissue. Even in the UK, although the new Medical Research Council guidelines make a good deal of the 'gift relationship', what they are actually about is commodification. If donors believe they are demonstrating altruism, but biotechnology firms and researchers use the discourse of commodity and profit, we have not 'incomplete commodification' but complete commodification with a plausibly human face. PMID:12872770

  14. Teenage pregnancy in developed countries: determinants and policy implications.

    PubMed

    Jones, E F; Forrest, J D; Goldman, N; Henshaw, S K; Lincoln, R; Rosoff, J I; Westoff, C F; Wulf, D

    1985-01-01

    Because of the high adolescent fertility rates in the US, the Alan Guttmacher Institute (AGI) conducted a 1985 study of adolescent pregnancy and childbearing in 37 developed countries. This was an effort to unveil those factors responsible for determining teenage reproductive behavior. This article presents the data from that study. Birthrates were collected and separated into 2 age groups: for those under 18 and those women 18 to 19 years of age. A 42 variable questionnaire was sent to the public affairs officer of the American embassy and family planning organization in each foreign country to provide additional socioeconomic, behavioral, and educational data. Childbearing was found to be positively correlated with agricultural work, denoting a socioeconomic influence. Adolescent birthrates showed a positive correlation with levels of maternity leaves and benefits offered in the country. The lowest birthrates were found in those countries with the most liberal attitudes toward sex as demonstrated through media representation of female nudity, extent of nudity on public beaches, sales of sexually explicit literature, and media advertising of condoms. A negative correlation was seen for equitable distribution of income and the under 18 birthrate. The older teenage birthrate was found to be lower for countries with higher minimum ages for marriage. They also suggested a responsiveness to government efforts to increase fertility. Some general patterns emerged to explain the high teenage birthrate for the US: it is less open about sexual matters than countries with lower adolescent birthrates and the income in the US is distributed to families of low economic status. A more subtle factor is that although contraception is available, it is not that accessible to young men and women because of the cost. Case studies were presented to provide a more detailed understanding of the reasons for the high adolescent birthrates. Examined are desire for pregnancy, exposure to

  15. Mammalian Wax Biosynthesis

    PubMed Central

    Cheng, Jeffrey B.; Russell, David W.

    2009-01-01

    Wax monoesters are synthesized by the esterification of fatty alcohols and fatty acids. A mammalian enzyme that catalyzes this reaction has not been isolated. We used expression cloning to identify cDNAs encoding a wax synthase in the mouse preputial gland. The wax synthase gene is located on the X chromosome and encodes a member of the acyltransferase family of enzymes that synthesize neutral lipids. Expression of wax synthase in cultured cells led to the formation of wax monoesters from straight chain saturated, unsaturated, and polyunsaturated fatty alcohols and acids. Polyisoprenols also were incorporated into wax monoesters by the enzyme. The wax synthase had little or no ability to synthesize cholesteryl esters, diacylglycerols, or triacylglycerols, whereas other acyltransferases, including the acyl-CoA:monoacylglycerol acyltransferase 1 and 2 enzymes and the acyl-CoA:diacylglycerol acyltransferase 1 and 2 enzymes, exhibited modest wax monoester synthesis activities. Confocal light microscopy indicated that the wax synthase was localized in membranes of the endoplasmic reticulum. Wax synthase mRNA was abundant in tissues rich in sebaceous glands such as the preputial gland and eyelid and was present at lower levels in other tissues. Coexpression of cDNAs specifying fatty acyl-CoA reductase 1 and wax synthase led to the synthesis of wax monoesters. The data suggest that wax monoester synthesis in mammals involves a two step biosynthetic pathway catalyzed by fatty acyl-CoA reductase and wax synthase enzymes. PMID:15220349

  16. Mammalian Wax Biosynthesis

    PubMed Central

    Cheng, Jeffrey B.; Russell, David W.

    2009-01-01

    The conversion of fatty acids to fatty alcohols is required for the synthesis of wax monoesters and ether lipids. The mammalian enzymes that synthesize fatty alcohols have not been identified. Here, an in silico approach was used to discern two putative reductase enzymes designated FAR1 and FAR2. Expression studies in intact cells showed that FAR1 and FAR2 cDNAs encoded isozymes that reduced fatty acids to fatty alcohols. Fatty acyl-CoA esters were the substrate of FAR1, and the enzyme required NADPH as a cofactor. FAR1 preferred saturated and unsaturated fatty acids of 16 or 18 carbons as substrates, whereas FAR2 preferred saturated fatty acids of 16 or 18 carbons. Confocal light microscopy indicated that FAR1 and FAR2 were localized in the peroxisome. The FAR1 mRNA was detected in many mouse tissues with the highest level found in the preputial gland, a modified sebaceous gland. The FAR2 mRNA was more restricted in distribution and most abundant in the eyelid, which contains wax-laden meibomian glands. Both FAR mRNAs were present in the brain, a tissue rich in ether lipids. The data suggest that fatty alcohol synthesis in mammals is accomplished by two fatty acyl-CoA reductase isozymes that are expressed at high levels in tissues known to synthesize wax monoesters and ether lipids. PMID:15220348

  17. Mammalian Gut Immunity

    PubMed Central

    Chassaing, Benoit; Kumar, Manish; Baker, Mark T.; Singh, Vishal; Vijay-Kumar, Matam

    2016-01-01

    The mammalian intestinal tract is the largest immune organ in the body and comprises cells from non-hemopoietic (epithelia, Paneth cells, goblet cells) and hemopoietic (macrophages, dendritic cells, T-cells) origin, and is also a dwelling for trillions of microbes collectively known as the microbiota. The homeostasis of this large microbial biomass is prerequisite to maintain host health by maximizing beneficial symbiotic relationships and minimizing the risks of living in such close proximity. Both microbiota and host immune system communicate with each other to mutually maintain homeostasis in what could be called a “love–hate relationship.” Further, the host innate and adaptive immune arms of the immune system cooperate and compensate each other to maintain the equilibrium of a highly complex gut ecosystem in a stable and stringent fashion. Any imbalance due to innate or adaptive immune deficiency or aberrant immune response may lead to dysbiosis and low-grade to robust gut inflammation, finally resulting in metabolic diseases. PMID:25163502

  18. Historical Development of Guidance and Counseling and Implications for the Future

    ERIC Educational Resources Information Center

    Aubrey, Roger F.

    1977-01-01

    The author traces the development of guidance and counseling from the nineteenth century to the present with implications for the future. The impact of the progressive movement, vocational guidance, industrialization, psychometrics, and Carl Rogers are highlighted. The 1950's are singled out as the decade having the greatest effect on counselors.…

  19. Improving Instruction in Middle Level Schools: Implications of Neurological Data for Curriculum Development.

    ERIC Educational Resources Information Center

    Toepfer, Conrad F., Jr.

    Implications of biophysicist Herman Epstein's research on brain growth periodization, which develop a neurobiological consideration of learning issues for middle school curricula, have created controversy among educators and stimulus for further research. This presentation (1) summarizes the writer's interpretations of these data and implications…

  20. Function as a Determinant of Speech Production--Implications for Language Development in Schools.

    ERIC Educational Resources Information Center

    Skull, John

    The function of speech and its implications for studying, understanding, and promoting language development are explored in this paper. Function is considered to be the purpose of the speaker when speaking, variously termed context of situation, situation, context, circumstance, or mode. It is noted that very few studies of speech and speech…

  1. Research Overview: Implications for Staff Development. Higher Education in TAFE. Monograph Series 01/2009

    ERIC Educational Resources Information Center

    Moodie, Gavin; Wheelahan, Leesa; Billett, Stephen; Kelly, Ann

    2009-01-01

    A project funded through the National Vocational Education and Training Research and Evaluation program investigated higher education programs--mostly bachelor's and associate degrees--offered by technical and further education (TAFE) institutes. This overview highlights some of the implications for staff development identified through this…

  2. Theory Development and Convergence of Human Resource Fields: Implications for Human Performance Technology

    ERIC Educational Resources Information Center

    Cho, Yonjoo; Yoon, Seung Won

    2010-01-01

    This study examines major theory developments in human resource (HR) fields and discusses implications for human performance technology (HPT). Differentiated HR fields are converging to improve organizational performance through knowledge-based innovations. Ruona and Gibson (2004) made a similar observation and analyzed the historical evolution…

  3. Implications of the International Classification of Functioning, Disability and Health (ICF) for Test Development and Use

    ERIC Educational Resources Information Center

    Carlson, Janet F.; Benson, Nicholas; Oakland, Thomas

    2010-01-01

    Implications of the International Classification of Functioning, Disability and Health (ICF) on the development and use of tests in school settings are enumerated. We predict increased demand for behavioural assessments that consider a person's activities, participation and person-environment interactions, including measures that: (a) address…

  4. Water Supply Deficiency and Implications for Rural Development in the Niger-Delta Region of Nigeria

    ERIC Educational Resources Information Center

    Nkwocha, E. E.

    2009-01-01

    There is a growing concern about the marginalization of the Niger Delta region of Nigeria in terms of infrastructural and social services provision. This study examined the water supply deficiency and its general implications for rural development within the region. Data and other study characteristics were extracted from 501 subjects drawn from…

  5. Some Implications of Body Build Stereotypes for the Development of Body Concept and Interpersonal Relations.

    ERIC Educational Resources Information Center

    Lerner, Richard M.

    In this paper the author tries to indicate, through a review of his research, that the scope of the study of body build stereotypes has been broadened to address the larger issues involved in assessing some of the implications of body build stereotypes for the development of body concept and interpersonal relations. Among the topics discussed are:…

  6. What Performance Technologists Should Know about Public Education: Implications for Professional Development and Training.

    ERIC Educational Resources Information Center

    Hirumi, Atsusi

    1995-01-01

    Discussion of performance technologists' contributions to improving public education highlights 10 essential components of an educational system, including family and community, business and industry, government agencies, and higher education. Implications of the systemic perspective for the professional development and training of performance…

  7. Developing Young Children's Curiosity: A Review of Research with Implications for Teachers.

    ERIC Educational Resources Information Center

    Bradbard, Marilyn R.; Endsley, Richard C.

    This review of the literature on the development of young children's curiosity is directed specifically toward teachers and other practitioners and emphasizes what socialization agents can do to influence children's curiosity. Gaps in current knowledge about children's curiosity and implications of research findings are discussed. Theoretical…

  8. Gender Barriers in the Legal Profession: Implications for Career Development of Female Law Students.

    ERIC Educational Resources Information Center

    Krakauer, Lianne; Chen, Charles P.

    2003-01-01

    Examines some of the key issues pertinent to the life career development of female students in law schools. Explore gender-related psychosocial aspects, such as the differences between the career patterns of men and women. Several specific career counseling implications and strategies, aimed at addressing the unique needs of women studying in a…

  9. Implications for Students Role Character Development When the Teacher Becomes an Actor in the Production.

    ERIC Educational Resources Information Center

    Buckner, Debi

    A case study explored the implications for secondary school acting students in developing character in a role when the theater teacher assumes the role of actor in a student production. Two of Albuquerque, New Mexico's 11 public high schools co-produced "Romeo and Juliet." Pre- and posttests of student perceptions of acting and character…

  10. The Effects of Early Religious Training: Implications for Counseling and Development.

    ERIC Educational Resources Information Center

    Hanna, Fred J.; And Others

    1994-01-01

    Many children feel a considerable amount of anxiety in connection with their deity and internalize an authoritative being who is both good and evil, kind and abusive. Modeling of this being can continue into adulthood thus continuing to affect cognition and behavior. Implications for counseling and development are discussed. (LKS)

  11. Monitoring and Evaluation of an Early Childhood Development Programme: Implications for Leadership and Management

    ERIC Educational Resources Information Center

    Hodgson, Sarah; Papatheodorou, Theodora; James, Mary

    2014-01-01

    The article aims to discuss preliminary findings from a participatory monitoring and evaluation (M&E) framework, used in a community-based early childhood development (ECD) programme in KwaZulu-Natal South Africa, and their implications for leadership and management. The purposes of the M&E were for LETCEE, the implementing organization,…

  12. Immune Response in Microgravity: Genetic Basis and Countermeasure Development Implications

    NASA Technical Reports Server (NTRS)

    Risin, Diana; Ward, Nancy E.; Risin, Semyon A.; Pellis, Neal R.

    2006-01-01

    expression were identified in the apoptosis related group (Granzyme B, APO2 ligand and Beta3endonexin). All of them were downregulated. Gene expression changes in MG might appear pivotal in identifying potential molecular targets for countermeasure development. (Supported by NRA OLMSA02 and NSCORT NAG54072 grants).

  13. Stem Cells in Mammalian Gonads.

    PubMed

    Wu, Ji; Ding, Xinbao; Wang, Jian

    2016-01-01

    Stem cells have great value in clinical application because of their ability to self-renew and their potential to differentiate into many different cell types. Mammalian gonads, including testes for males and ovaries for females, are composed of germline and somatic cells. In male mammals, spermatogonial stem cells maintain spermatogenesis which occurs continuously in adult testis. Likewise, a growing body of evidence demonstrated that female germline stem cells could be found in mammalian ovaries. Meanwhile, prior studies have shown that somatic stem cells exist in both testes and ovaries. In this chapter, we focus on mammalian gonad stem cells and discuss their characteristics as well as differentiation potentials.

  14. Stressor and glucocorticoid-dependent induction of the immediate early gene kruppel-like factor 9: implications for neural development and plasticity.

    PubMed

    Bonett, Ronald M; Hu, Fang; Bagamasbad, Pia; Denver, Robert J

    2009-04-01

    Krüppel-like factor 9 (KLF9) is a thyroid hormone-induced, immediate early gene implicated in neural development in vertebrates. We analyzed stressor and glucocorticoid (GC)-dependent regulation of KLF9 expression in the brain of the frog Xenopus laevis, and investigated a possible role for KLF9 in neuronal differentiation. Exposure to shaking/confinement stressor increased plasma corticosterone (CORT) concentration, and KLF9 immunoreactivity in several brain regions, which included the medial amygdala and bed nucleus of the stria terminalis, anterior preoptic area (homologous to the mammalian paraventricular nucleus), and optic tectum (homologous to the mammalian superior colliculus). The stressor-induced KLF9 mRNA expression in the brain was blocked by pretreatment with the GC receptor antagonist RU486, or mimicked by injection of CORT. Treatment with CORT also caused a rapid and dose-dependent increase in KLF9 mRNA in X. laevis XTC-2 cells that was resistant to inhibition of protein synthesis. The action of CORT on KLF9 expression in XTC-2 cells was blocked by RU486, but not by the mineralocorticoid receptor antagonist spironolactone. To test for functional consequences of up-regulation of KLF9, we introduced a KLF9 expression plasmid into living tadpole brain by electroporation-mediated gene transfer. Forced expression of KLF9 in tadpole brain caused an increase in Golgi-stained cells, reflective of neuronal differentiation/maturation. Our results support that KLF9 is a direct, GC receptor target gene that is induced by stress, and functions as an intermediary in the actions of GCs on brain gene expression and neuronal structure.

  15. Mapping post-translational modifications of mammalian testicular specific histone variant TH2B in tetraploid and haploid germ cells and their implications on the dynamics of nucleosome structure.

    PubMed

    Pentakota, Satya Krishna; Sandhya, Sankaran; P Sikarwar, Arun; Chandra, Nagasuma; Satyanarayana Rao, Manchanahalli R

    2014-12-01

    Histones regulate a variety of chromatin templated events by their post-translational modifications (PTMs). Although there are extensive reports on the PTMs of canonical histones, the information on the histone variants remains very scanty. Here, we report the identification of different PTMs, such as acetylation, methylation, and phosphorylation of a major mammalian histone variant TH2B. Our mass spectrometric analysis has led to the identification of both conserved and unique modifications across tetraploid spermatocytes and haploid spermatids. We have also computationally derived the 3-dimensional model of a TH2B containing nucleosome in order to study the spatial orientation of the PTMs identified and their effect on nucleosome stability and DNA binding potential. From our nucleosome model, it is evident that substitution of specific amino acid residues in TH2B results in both differential histone-DNA and histone-histone contacts. Furthermore, we have also observed that acetylation on the N-terminal tail of TH2B weakens the interactions with the DNA. These results provide direct evidence that, similar to somatic H2B, the testis specific histone TH2B also undergoes multiple PTMs, suggesting the possibility of chromatin regulation by such covalent modifications in mammalian male germ cells.

  16. Positive Selection Linked with Generation of Novel Mammalian Dentition Patterns.

    PubMed

    Machado, João Paulo; Philip, Siby; Maldonado, Emanuel; O'Brien, Stephen J; Johnson, Warren E; Antunes, Agostinho

    2016-01-01

    A diverse group of genes are involved in the tooth development of mammals. Several studies, focused mainly on mice and rats, have provided a detailed depiction of the processes coordinating tooth formation and shape. Here we surveyed 236 tooth-associated genes in 39 mammalian genomes and tested for signatures of selection to assess patterns of molecular adaptation in genes regulating mammalian dentition. Of the 236 genes, 31 (∼13.1%) showed strong signatures of positive selection that may be responsible for the phenotypic diversity observed in mammalian dentition. Mammalian-specific tooth-associated genes had accelerated mutation rates compared with older genes found across all vertebrates. More recently evolved genes had fewer interactions (either genetic or physical), were associated with fewer Gene Ontology terms and had faster evolutionary rates compared with older genes. The introns of these positively selected genes also exhibited accelerated evolutionary rates, which may reflect additional adaptive pressure in the intronic regions that are associated with regulatory processes that influence tooth-gene networks. The positively selected genes were mainly involved in processes like mineralization and structural organization of tooth specific tissues such as enamel and dentin. Of the 236 analyzed genes, 12 mammalian-specific genes (younger genes) provided insights on diversification of mammalian teeth as they have higher evolutionary rates and exhibit different expression profiles compared with older genes. Our results suggest that the evolution and development of mammalian dentition occurred in part through positive selection acting on genes that previously had other functions. PMID:27613398

  17. Positive Selection Linked with Generation of Novel Mammalian Dentition Patterns.

    PubMed

    Machado, João Paulo; Philip, Siby; Maldonado, Emanuel; O'Brien, Stephen J; Johnson, Warren E; Antunes, Agostinho

    2016-09-11

    A diverse group of genes are involved in the tooth development of mammals. Several studies, focused mainly on mice and rats, have provided a detailed depiction of the processes coordinating tooth formation and shape. Here we surveyed 236 tooth-associated genes in 39 mammalian genomes and tested for signatures of selection to assess patterns of molecular adaptation in genes regulating mammalian dentition. Of the 236 genes, 31 (∼13.1%) showed strong signatures of positive selection that may be responsible for the phenotypic diversity observed in mammalian dentition. Mammalian-specific tooth-associated genes had accelerated mutation rates compared with older genes found across all vertebrates. More recently evolved genes had fewer interactions (either genetic or physical), were associated with fewer Gene Ontology terms and had faster evolutionary rates compared with older genes. The introns of these positively selected genes also exhibited accelerated evolutionary rates, which may reflect additional adaptive pressure in the intronic regions that are associated with regulatory processes that influence tooth-gene networks. The positively selected genes were mainly involved in processes like mineralization and structural organization of tooth specific tissues such as enamel and dentin. Of the 236 analyzed genes, 12 mammalian-specific genes (younger genes) provided insights on diversification of mammalian teeth as they have higher evolutionary rates and exhibit different expression profiles compared with older genes. Our results suggest that the evolution and development of mammalian dentition occurred in part through positive selection acting on genes that previously had other functions.

  18. Neurosciences of infant mental health development: recent findings and implications for counseling psychology.

    PubMed

    Sampaio, Adriana; Lifter, Karin

    2014-10-01

    This article is about the neural correlates of infant mental health and their correspondences to social emotional development. These correspondences are organized in terms of the definition of infant mental provided by Zero to Three (2001), centered on infants' capacities regarding the experience and expression of emotions, interpersonal relationships, and learning. We conclude with implications of these correspondences for counseling psychology-namely, working with children's caregivers to maximize children's healthy social and emotional development.

  19. Neurosciences of infant mental health development: recent findings and implications for counseling psychology.

    PubMed

    Sampaio, Adriana; Lifter, Karin

    2014-10-01

    This article is about the neural correlates of infant mental health and their correspondences to social emotional development. These correspondences are organized in terms of the definition of infant mental provided by Zero to Three (2001), centered on infants' capacities regarding the experience and expression of emotions, interpersonal relationships, and learning. We conclude with implications of these correspondences for counseling psychology-namely, working with children's caregivers to maximize children's healthy social and emotional development. PMID:25285709

  20. Mammalian DNA Repair. Final Report

    SciTech Connect

    2003-01-24

    The Gordon Research Conference (GRC) on Mammalian DNA Repair was held at Harbortown Resort, Ventura Beach, CA. Emphasis was placed on current unpublished research and discussion of the future target areas in this field.

  1. Polysome analysis of mammalian cells.

    PubMed

    He, Shan L; Green, Rachel

    2013-01-01

    To assess the global translational level of mammalian cells (see similar protocols for bacteria and yeast on Analysis of polysomes from bacteria, Polysome Profile Analysis - Yeast and Polysome analysis for determining mRNA and ribosome association in Saccharomyces cerevisiae).

  2. Maturation of the mammalian secretome

    PubMed Central

    Simpson, Jeremy C; Mateos, Alvaro; Pepperkok, Rainer

    2007-01-01

    A recent use of quantitative proteomics to determine the constituents of the endoplasmic reticulum and Golgi complex is discussed in the light of other available methodologies for cataloging the proteins associated with the mammalian secretory pathway. PMID:17472737

  3. Mammalian cell cultivation in space

    NASA Astrophysics Data System (ADS)

    Gmünder, Felix K.; Suter, Robert N.; Kiess, M.; Urfer, R.; Nordau, C.-G.; Cogoli, A.

    Equipment used in space for the cultivation of mammalian cells does not meet the usual standard of earth bound bioreactors. Thus, the development of a space worthy bioreactor is mandatory for two reasons: First, to investigate the effect on single cells of the space environment in general and microgravity conditions in particular, and second, to provide researchers on long term missions and the Space Station with cell material. However, expertise for this venture is not at hand. A small and simple device for animal cell culture experiments aboard Spacelab (Dynamic Cell Culture System; DCCS) was developed. It provides 2 cell culture chambers, one is operated as a batch system, the other one as a perfusion system. The cell chambers have a volume of 200 μl. Medium exchange is achieved with an automatic osmotic pump. The system is neither mechanically stirred nor equipped with sensors. Oxygen for cell growth is provided by a gas chamber that is adjacent to the cell chambers. The oxygen gradient produced by the growing cells serves to maintain the oxygen influx by diffusion. Hamster kidney cells growing on microcarriers were used to test the biological performance of the DCCS. On ground tests suggest that this system is feasible.

  4. Molecular sled sequences are common in mammalian proteins

    PubMed Central

    Xiong, Kan; Blainey, Paul C.

    2016-01-01

    Recent work revealed a new class of molecular machines called molecular sleds, which are small basic molecules that bind and slide along DNA with the ability to carry cargo along DNA. Here, we performed biochemical and single-molecule flow stretching assays to investigate the basis of sliding activity in molecular sleds. In particular, we identified the functional core of pVIc, the first molecular sled characterized; peptide functional groups that control sliding activity; and propose a model for the sliding activity of molecular sleds. We also observed widespread DNA binding and sliding activity among basic polypeptide sequences that implicate mammalian nuclear localization sequences and many cell penetrating peptides as molecular sleds. These basic protein motifs exhibit weak but physiologically relevant sequence-nonspecific DNA affinity. Our findings indicate that many mammalian proteins contain molecular sled sequences and suggest the possibility that substantial undiscovered sliding activity exists among nuclear mammalian proteins. PMID:26857546

  5. Molecular sled sequences are common in mammalian proteins.

    PubMed

    Xiong, Kan; Blainey, Paul C

    2016-03-18

    Recent work revealed a new class of molecular machines called molecular sleds, which are small basic molecules that bind and slide along DNA with the ability to carry cargo along DNA. Here, we performed biochemical and single-molecule flow stretching assays to investigate the basis of sliding activity in molecular sleds. In particular, we identified the functional core of pVIc, the first molecular sled characterized; peptide functional groups that control sliding activity; and propose a model for the sliding activity of molecular sleds. We also observed widespread DNA binding and sliding activity among basic polypeptide sequences that implicate mammalian nuclear localization sequences and many cell penetrating peptides as molecular sleds. These basic protein motifs exhibit weak but physiologically relevant sequence-nonspecific DNA affinity. Our findings indicate that many mammalian proteins contain molecular sled sequences and suggest the possibility that substantial undiscovered sliding activity exists among nuclear mammalian proteins. PMID:26857546

  6. Cell-surface remodelling during mammalian erythropoiesis.

    PubMed

    Wraith, D C; Chesterton, C J

    1982-10-15

    Current evidence suggests that the major cell-surface modification occurring during mammalian erythropoiesis could be generated by two separate mechanisms: either selective loss of membrane proteins during enucleation or endocytosis at the subsequent reticulocyte and erythrocyte stages. The former idea was tested by collecting developing rabbit erythroid cells before and after the enucleation step and comparing their cell-surface protein composition via radiolabelling and electrophoresis. Few changes were observed. Our data thus lend support to the endocytosis mechanism.

  7. Implications of Montreal Protocol: With particular reference to India and other developing countries

    NASA Astrophysics Data System (ADS)

    Chatterjee, K.

    The various international measures like the Vienna Convention and Montreal Protocol to protect the ozone layer have been discussed. The predicted depletion of the ozone layer will cause increased ultraviolet radiation-B(UV-B) reaching the Earth's surface which is known to have various adverse impacts on the environment. A study on the state of ozone and UV-B radiation climate over India based on 25 years of network ozone and derived UV-B data which was carried out in Development Alternatives (DA) have been discussed and various likely environmental implications of ozone depletion brought out. The economic implications including the economic costs to India for the implementation of the Montreal Protocol have been addressed. In the conclusion, some of the critical issues of the developing countries and suggested alternative response strategies including R&D activities required for the implementation of the Protocol by the developing countries have been discussed.

  8. Gestational nanomaterial exposures: microvascular implications during pregnancy, fetal development and adulthood.

    PubMed

    Stapleton, P A

    2016-04-15

    Air pollution particulate matter and engineered nanomaterials are encompassed in the broad definition of xenobiotic particles. While the effects of perinatal air pollution exposure have been investigated, elucidation of outcomes associated with nanomaterial exposure, the focus of this review, is still in its infancy. As the potential uses of nanomaterials, and therefore exposures, increase exponentially so does the need for thorough evaluation. Up to this point, the majority of research in the field of cardiovascular nanotoxicology has focused on the coronary and vascular reactions to pulmonary exposures in young adult, healthy, male models; however, as intentional and unintentional contacts persist, the non-pulmonary risks to under-represented populations become a critical concern. Development of the maternal-fetal circulation during successful mammalian gestation is one of the most unusual complex, dynamic, and acutely demanding physiological systems. Fetal development in a hostile gestational environment can lead to systemic alterations, which may encourage adult disease. Therefore, the purpose of this review is to highlight the few knowns associated with gestational engineered nanomaterial exposure segmented by physiological periods of development or systemic targets: preconception and maternal, gestational, fetal and progeny (Abstract figure). Overall, the limited studies currently available provide compelling evidence of maternal, fetal and offspring dysfunctions after engineered nanomaterial exposure. Understanding the mechanisms associated with these multigenerational effects may allow pregnant women to safely reap the benefits of nanotechnology-enabled products and assist in the implementation of exposure controls to protect the mother and fetus allowing for development of safety by design for engineered nanomaterials.

  9. Structure of mammalian metallothionein.

    PubMed Central

    Kägi, J H; Vasák, M; Lerch, K; Gilg, D E; Hunziker, P; Bernhard, W R; Good, M

    1984-01-01

    All mammalian metallothioneins characterized contain a single polypeptide chain of 61 amino acid residues, among them 20 cysteines providing the ligands for seven metal-binding sites. Native metallothioneins are usually heterogeneous in metal composition, with Zn, Cd, and Cu occurring in varying proportions. However, forms containing only a single metal species, i.e., Zn, Cd, Ni, Co, Hg, Pb, Bi, have now been prepared by in vitro reconstitution from the metal-free apoprotein. By spectroscopic analysis of such derivatives it was established that all cysteine residues participate in metal binding, that each metal ion is bound to four thiolate ligands, and that the symmetry of each complex is close to that of a tetrahedron. To satisfy the requirements of the overall Me7(Cys-)20 stoichiometry, the complexes must be combined to form metal-thiolate cluster structures. Experimental proof for the occurrence of such clusters comes from the demonstration of metal-metal interactions by spectroscopic and magnetic means. Thus, in Co(II)7-metallothionein, the Co(II)-specific ESR signals are effectively suppressed by antiferromagnetic coupling of juxtaposed paramagnetic metal ions. By monitoring changes in ESR signal size occurring on stepwise incorporation of Co(II) into the protein, it is possible to follow the building up of the clusters. This process is biphasic. Up to binding of four equivalents of Co(II), the ESR amplitude increases in proportion to the metal content, indicating generation of magnetically noninteracting high-spin complexes. However, upon addition of the remaining three equivalents of Co(II), these features are progressively suppressed, signaling the formation of clusters. The same mode of cluster formation has also been documented for Cd and Hg. The actual spatial organization of the clusters and the polypeptide chain remains to be established. An attractive possibility is the arrangement of the tetrahedral metal-thiolates in adamantane-like structures

  10. DNA replication and transcription in mammalian mitochondria.

    PubMed

    Falkenberg, Maria; Larsson, Nils-Göran; Gustafsson, Claes M

    2007-01-01

    The mitochondrion was originally a free-living prokaryotic organism, which explains the presence of a compact mammalian mitochondrial DNA (mtDNA) in contemporary mammalian cells. The genome encodes for key subunits of the electron transport chain and RNA components needed for mitochondrial translation. Nuclear genes encode the enzyme systems responsible for mtDNA replication and transcription. Several of the key components of these systems are related to proteins replicating and transcribing DNA in bacteriophages. This observation has led to the proposition that some genes required for DNA replication and transcription were acquired together from a phage early in the evolution of the eukaryotic cell, already at the time of the mitochondrial endosymbiosis. Recent years have seen a rapid development in our molecular understanding of these machineries, but many aspects still remain unknown.

  11. Freezing mammalian cells for production of biopharmaceuticals.

    PubMed

    Seth, Gargi

    2012-03-01

    Cryopreservation techniques utilize very low temperatures to preserve the structure and function of living cells. Various strategies have been developed for freezing mammalian cells of biological and medical significance. This paper highlights the importance and application of cryopreservation for recombinant mammalian cells used in the biopharmaceutical industry to produce high-value protein therapeutics. It is a primer that aims to give insight into the basic principles of cell freezing for the benefit of biopharmaceutical researchers with limited or no prior experience in cryobiology. For the more familiar researchers, key cell banking parameters such as the cell density and hold conditions have been reviewed to possibly help optimize their specific cell freezing protocols. It is important to understand the mechanisms underlying the freezing of complex and sensitive cellular entities as we implement best practices around the techniques and strategies used for cryopreservation. PMID:22226818

  12. Development of the Synarcual in the Elephant Sharks (Holocephali; Chondrichthyes): Implications for Vertebral Formation and Fusion.

    PubMed

    Johanson, Zerina; Boisvert, Catherine; Maksimenko, Anton; Currie, Peter; Trinajstic, Kate

    2015-01-01

    The synarcual is a structure incorporating multiple elements of two or more anterior vertebrae of the axial skeleton, forming immediately posterior to the cranium. It has been convergently acquired in the fossil group 'Placodermi', in Chondrichthyes (Holocephali, Batoidea), within the teleost group Syngnathiformes, and to varying degrees in a range of mammalian taxa. In addition, cervical vertebral fusion presents as an abnormal pathology in a variety of human disorders. Vertebrae develop from axially arranged somites, so that fusion could result from a failure of somite segmentation early in development, or from later heterotopic development of intervertebral bone or cartilage. Examination of early developmental stages indicates that in the Batoidea and the 'Placodermi', individual vertebrae developed normally and only later become incorporated into the synarcual, implying regular somite segmentation and vertebral development. Here we show that in the holocephalan Callorhinchus milii, uniform and regular vertebral segmentation also occurs, with anterior individual vertebra developing separately with subsequent fusion into a synarcual. Vertebral elements forming directly behind the synarcual continue to be incorporated into the synarcual through growth. This appears to be a common pattern through the Vertebrata. Research into human disorders, presenting as cervical fusion at birth, focuses on gene misexpression studies in humans and other mammals such as the mouse. However, in chondrichthyans, vertebral fusion represents the normal morphology, moreover, taxa such Leucoraja (Batoidea) and Callorhinchus (Holocephali) are increasingly used as laboratory animals, and the Callorhinchus genome has been sequenced and is available for study. Our observations on synarcual development in three major groups of early jawed vertebrates indicate that fusion involves heterotopic cartilage and perichondral bone/mineralised cartilage developing outside the regular skeleton. We

  13. Development of the Synarcual in the Elephant Sharks (Holocephali; Chondrichthyes): Implications for Vertebral Formation and Fusion

    PubMed Central

    Johanson, Zerina; Boisvert, Catherine; Maksimenko, Anton; Currie, Peter; Trinajstic, Kate

    2015-01-01

    The synarcual is a structure incorporating multiple elements of two or more anterior vertebrae of the axial skeleton, forming immediately posterior to the cranium. It has been convergently acquired in the fossil group ‘Placodermi’, in Chondrichthyes (Holocephali, Batoidea), within the teleost group Syngnathiformes, and to varying degrees in a range of mammalian taxa. In addition, cervical vertebral fusion presents as an abnormal pathology in a variety of human disorders. Vertebrae develop from axially arranged somites, so that fusion could result from a failure of somite segmentation early in development, or from later heterotopic development of intervertebral bone or cartilage. Examination of early developmental stages indicates that in the Batoidea and the ‘Placodermi’, individual vertebrae developed normally and only later become incorporated into the synarcual, implying regular somite segmentation and vertebral development. Here we show that in the holocephalan Callorhinchus milii, uniform and regular vertebral segmentation also occurs, with anterior individual vertebra developing separately with subsequent fusion into a synarcual. Vertebral elements forming directly behind the synarcual continue to be incorporated into the synarcual through growth. This appears to be a common pattern through the Vertebrata. Research into human disorders, presenting as cervical fusion at birth, focuses on gene misexpression studies in humans and other mammals such as the mouse. However, in chondrichthyans, vertebral fusion represents the normal morphology, moreover, taxa such Leucoraja (Batoidea) and Callorhinchus (Holocephali) are increasingly used as laboratory animals, and the Callorhinchus genome has been sequenced and is available for study. Our observations on synarcual development in three major groups of early jawed vertebrates indicate that fusion involves heterotopic cartilage and perichondral bone/mineralised cartilage developing outside the regular skeleton

  14. Payload test philosophy. [implications of STS development at Goddard Space Flight Center

    NASA Technical Reports Server (NTRS)

    Arman, A.

    1979-01-01

    The implications of STS development for payload testing at the Goddard Space Flight Center are reviewed. The biggest impact of STS may be that instead of testing the entire payload, most of the testing may have to be limited to the subsystem or subassembly level. Particular consideration is given to the Goddard protoflight concept in which the test is geared to the design qualification levels, the test durations being those that are expected during the actual launch sequence.

  15. Analysis of chromosome segregation during mammalian meiosis using combined immunofluorescence and fluorescence in situ hubridization

    SciTech Connect

    Hunt, P.A.; Embury, P.B.; Mroz, K.M.

    1994-09-01

    Meiotic non-disjunction is thought to occur in 10-20% of all human oocytes, making this the most common genetic abnormality in our species. Aberrant recombination has been implicated in the genesis of these errors; however, direct studies of the meiotic process have been hampered by the lack of material and appropriate technology. We have developed a technique for the evaluation of meiosis in intact mammalian oocytes that combines immunofluorescence and fluorescence in situ hybridization (FISH). This allows for simultaneous, 3-dimensional visualization of the meiotic spindle, the alignment of the chromosomes on the spindle, and the placement of specific chromosomes. We have used this technology to follow meiotic progression in oocytes from XO female mice to evaluate the behavior of an unsynapsed chromosome during mammalian meiosis. Perturbations in chromosome behavior are evident early in meiosis: during the formation of the first meiotic spindle, the univalent X chromosome is properly positioned. With the onset of anaphase, the single X chromosome most commonly segregates as an intact chromosome, although equational segregation of the X chromatids is seen in a significant minority (approximately 20%) of oocytes. These observations demonstrate that failure of pairing/recombination can result in segregation of sister chromatids at meiosis I. This has obvious implications for human non-disjunction, much of which is thought to be due to recombination deficiencies; accordingly, we are now extending our studies to include analyses of human oocytes.

  16. Differential toxicity of three PCB congeners in developing sea urchin embryos and implication of TEQ approach

    SciTech Connect

    Schweitzer, L.; Suffet, I.; Hose, J.; Bay, S.

    1995-12-31

    The relationship between body burden and toxicity of three individual PCB congeners in developing sea urchin embryos was investigated to evaluate the validity of current predictive models of PCB toxicity in an invertebrate system. The uptake and accumulation of radiolabeled PCB congeners from sea water was measured in the sea urchin embryo tissues and the relative toxicity determined. According to the toxic equivalents (TEQ) approach of assessing risk to mammals, congener 77, a nonortho-substituted congener, is predicted to be more toxic than the diortho-substituted congeners 47 and 153. Using a 72 hour embryo development assay, congener 47 was found to be at least four times as toxic as congener 77, with EC50s of 15.7 and > 72.5 mmol/kg, respectively. Congener 153, a hexachlorobiphenyl, was virtually nontoxic even at the highest dose used. Cytologic and cytogenetic anomalies were studied to find a possibly more sensitive endpoint and to suggest a mechanism of toxicity. The cytogenetic analysis revealed that the PCBs inhibited mitosis. At the highest doses, complete mitotic arrest was observed. Congener 77 was found to be at least two times more toxic than congener 153 but not as toxic as congener 47 using mitotic activity as the endpoint. Thus, the two endpoints of toxicity did not change the order in which the congeners are toxic, but established different EC50s. The relative toxicities of these congeners in this study contradict the structure-activity prediction of the mammalian-based TEQ approach.

  17. Implications of newborn amygdala connectivity for fear and cognitive development at 6-months-of-age.

    PubMed

    Graham, Alice M; Buss, Claudia; Rasmussen, Jerod M; Rudolph, Marc D; Demeter, Damion V; Gilmore, John H; Styner, Martin; Entringer, Sonja; Wadhwa, Pathik D; Fair, Damien A

    2016-04-01

    The first year of life is an important period for emergence of fear in humans. While animal models have revealed developmental changes in amygdala circuitry accompanying emerging fear, human neural systems involved in early fear development remain poorly understood. To increase understanding of the neural foundations of human fear, it is important to consider parallel cognitive development, which may modulate associations between typical development of early fear and subsequent risk for fear-related psychopathology. We, therefore, examined amygdala functional connectivity with rs-fcMRI in 48 neonates (M=3.65 weeks, SD=1.72), and measured fear and cognitive development at 6-months-of-age. Stronger, positive neonatal amygdala connectivity to several regions, including bilateral anterior insula and ventral striatum, was prospectively associated with higher fear at 6-months. Stronger amygdala connectivity to ventral anterior cingulate/anterior medial prefrontal cortex predicted a specific phenotype of higher fear combined with more advanced cognitive development. Overall, findings demonstrate unique profiles of neonatal amygdala functional connectivity related to emerging fear and cognitive development, which may have implications for normative and pathological fear in later years. Consideration of infant fear in the context of cognitive development will likely contribute to a more nuanced understanding of fear, its neural bases, and its implications for future mental health.

  18. Factors Influencing the Central Nervous System Distribution of a Novel Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GSK2126458: Implications for Overcoming Resistance with Combination Therapy for Melanoma Brain Metastases.

    PubMed

    Vaidhyanathan, Shruthi; Wilken-Resman, Brynna; Ma, Daniel J; Parrish, Karen E; Mittapalli, Rajendar K; Carlson, Brett L; Sarkaria, Jann N; Elmquist, William F

    2016-02-01

    Small molecule inhibitors targeting the mitogen-activated protein kinase pathway (Braf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) have had success in extending survival for patients with metastatic melanoma. Unfortunately, resistance may occur via cross-activation of alternate signaling pathways. One approach to overcome resistance is to simultaneously target the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. Recent reports have shown that GSK2126458 [2,4-difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl) benzenesulfonamide], a dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor, can overcome acquired resistance to Braf and mitogen-activated protein kinase kinase inhibitors in vitro. These resistance mechanisms may be especially important in melanoma brain metastases because of limited drug delivery across the blood-brain barrier. The purpose of this study was to investigate factors that influence the brain distribution of GSK2126458 and to examine the efficacy of GSK2126458 in a novel patient-derived melanoma xenograft (PDX) model. Both in vitro and in vivo studies indicate that GSK2126458 is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), two dominant active efflux transporters in the blood-brain barrier. The steady-state brain distribution of GSK2126458 was 8-fold higher in the P-gp/Bcrp knockout mice compared with the wild type. We also observed that when simultaneously infused to steady state, GSK212658, dabrafenib, and trametinib, a rational combination to overcome mitogen-activated protein kinase inhibitor resistance, all had limited brain distribution. Coadministration of elacridar, a P-gp/Bcrp inhibitor, increased the brain distribution of GSK2126458 by approximately 7-fold in wild-type mice. In the PDX model, GSK2126458 showed efficacy in flank tumors but was ineffective in intracranial melanoma. These results show that

  19. Electroporation into Cultured Mammalian Embryos

    NASA Astrophysics Data System (ADS)

    Nomura, Tadashi; Takahashi, Masanori; Osumi, Noriko

    Over the last century, mammalian embryos have been used extensively as a common animal model to investigate fundamental questions in the field of developmental biology. More recently, the establishment of transgenic and gene-targeting systems in laboratory mice has enabled researchers to unveil the genetic mechanisms under lying complex developmental processes (Mak, 2007). However, our understanding of cell—cell interactions and their molecular basis in the early stages of mammalian embryogenesis is still very fragmentary. One of the major problems is the difficulty of precise manipulation and limited accessibility to mammalian embryos via uterus wall. Unfortunately, existing tissue and organotypic culture systems per se do not fully recapitulate three-dimensional, dynamic processes of organogenesis observed in vivo. Although transgenic animal technology and virus-mediated gene delivery are useful to manipulate gene expression, these techniques take much time and financial costs, which limit their use.

  20. Energetic and nutritional constraints on infant brain development: implications for brain expansion during human evolution.

    PubMed

    Cunnane, Stephen C; Crawford, Michael A

    2014-12-01

    The human brain confronts two major challenges during its development: (i) meeting a very high energy requirement, and (ii) reliably accessing an adequate dietary source of specific brain selective nutrients needed for its structure and function. Implicitly, these energetic and nutritional constraints to normal brain development today would also have been constraints on human brain evolution. The energetic constraint was solved in large measure by the evolution in hominins of a unique and significant layer of body fat on the fetus starting during the third trimester of gestation. By providing fatty acids for ketone production that are needed as brain fuel, this fat layer supports the brain's high energy needs well into childhood. This fat layer also contains an important reserve of the brain selective omega-3 fatty acid, docosahexaenoic acid (DHA), not available in other primates. Foremost amongst the brain selective minerals are iodine and iron, with zinc, copper and selenium also being important. A shore-based diet, i.e., fish, molluscs, crustaceans, frogs, bird's eggs and aquatic plants, provides the richest known dietary sources of brain selective nutrients. Regular access to these foods by the early hominin lineage that evolved into humans would therefore have helped free the nutritional constraint on primate brain development and function. Inadequate dietary supply of brain selective nutrients still has a deleterious impact on human brain development on a global scale today, demonstrating the brain's ongoing vulnerability. The core of the shore-based paradigm of human brain evolution proposes that sustained access by certain groups of early Homo to freshwater and marine food resources would have helped surmount both the nutritional as well as the energetic constraints on mammalian brain development.

  1. Mutations in MAP3K1 Cause 46,XY Disorders of Sex Development and Implicate a Common Signal Transduction Pathway in Human Testis Determination

    PubMed Central

    Pearlman, Alexander; Loke, Johnny; Le Caignec, Cedric; White, Stefan; Chin, Lisa; Friedman, Andrew; Warr, Nicholas; Willan, John; Brauer, David; Farmer, Charles; Brooks, Eric; Oddoux, Carole; Riley, Bridget; Shajahan, Shahin; Camerino, Giovanna; Homfray, Tessa; Crosby, Andrew H.; Couper, Jenny; David, Albert; Greenfield, Andy; Sinclair, Andrew; Ostrer, Harry

    2010-01-01

    Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)—18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination. PMID:21129722

  2. Genes in mammalian reproduction

    SciTech Connect

    Gwatkin, R.B.L.

    1996-11-01

    This is an informative book which deals mainly with genomic imprinting, the role of steroid hormones in development, the expression of a variety of genes during development and the link to hereditary diseases. It is an up-to-date review in a field that is quickly changing and provides valuable basic information and current research trends.

  3. Spatial Analysis on Future Housing Markets: Economic Development and Housing Implications

    PubMed Central

    Liu, Xin; Wang, Lizhe

    2014-01-01

    A coupled projection method combining formal modelling and other statistical techniques was developed to delineate the relationship between economic and social drivers for net new housing allocations. Using the example of employment growth in Tyne and Wear, UK, until 2016, the empirical analysis yields housing projections at the macro- and microspatial levels (e.g., region to subregion to elected ward levels). The results have important implications for the strategic planning of locations for housing and employment, demonstrating both intuitively and quantitatively how local economic developments affect housing demand. PMID:24892097

  4. Spatial analysis on future housing markets: economic development and housing implications.

    PubMed

    Liu, Xin; Wang, Lizhe

    2014-01-01

    A coupled projection method combining formal modelling and other statistical techniques was developed to delineate the relationship between economic and social drivers for net new housing allocations. Using the example of employment growth in Tyne and Wear, UK, until 2016, the empirical analysis yields housing projections at the macro- and microspatial levels (e.g., region to subregion to elected ward levels). The results have important implications for the strategic planning of locations for housing and employment, demonstrating both intuitively and quantitatively how local economic developments affect housing demand.

  5. Optogenetics for gene expression in mammalian cells.

    PubMed

    Müller, Konrad; Naumann, Sebastian; Weber, Wilfried; Zurbriggen, Matias D

    2015-02-01

    Molecular switches that are controlled by chemicals have evolved as central research instruments in mammalian cell biology. However, these tools are limited in terms of their spatiotemporal resolution due to freely diffusing inducers. These limitations have recently been addressed by the development of optogenetic, genetically encoded, and light-responsive tools that can be controlled with the unprecedented spatiotemporal precision of light. In this article, we first provide a brief overview of currently available optogenetic tools that have been designed to control diverse cellular processes. Then, we focus on recent developments in light-controlled gene expression technologies and provide the reader with a guideline for choosing the most suitable gene expression system.

  6. Gestational nanomaterial exposures: microvascular implications during pregnancy, fetal development and adulthood.

    PubMed

    Stapleton, P A

    2016-04-15

    Air pollution particulate matter and engineered nanomaterials are encompassed in the broad definition of xenobiotic particles. While the effects of perinatal air pollution exposure have been investigated, elucidation of outcomes associated with nanomaterial exposure, the focus of this review, is still in its infancy. As the potential uses of nanomaterials, and therefore exposures, increase exponentially so does the need for thorough evaluation. Up to this point, the majority of research in the field of cardiovascular nanotoxicology has focused on the coronary and vascular reactions to pulmonary exposures in young adult, healthy, male models; however, as intentional and unintentional contacts persist, the non-pulmonary risks to under-represented populations become a critical concern. Development of the maternal-fetal circulation during successful mammalian gestation is one of the most unusual complex, dynamic, and acutely demanding physiological systems. Fetal development in a hostile gestational environment can lead to systemic alterations, which may encourage adult disease. Therefore, the purpose of this review is to highlight the few knowns associated with gestational engineered nanomaterial exposure segmented by physiological periods of development or systemic targets: preconception and maternal, gestational, fetal and progeny (Abstract figure). Overall, the limited studies currently available provide compelling evidence of maternal, fetal and offspring dysfunctions after engineered nanomaterial exposure. Understanding the mechanisms associated with these multigenerational effects may allow pregnant women to safely reap the benefits of nanotechnology-enabled products and assist in the implementation of exposure controls to protect the mother and fetus allowing for development of safety by design for engineered nanomaterials. PMID:26332609

  7. Changes in vitelline and utero-placental hemodynamics: implications for cardiovascular development

    PubMed Central

    Linask, Kersti K.; Han, Mingda; Bravo-Valenzuela, Nathalie J. M.

    2014-01-01

    Analyses of cardiovascular development have shown an important interplay between heart function, blood flow, and morphogenesis of heart structure during the formation of a four-chambered heart. It is known that changes in vitelline and placental blood flow seemingly contribute substantially to early cardiac hemodynamics. This suggests that in order to understand mammalian cardiac structure-hemodynamic functional relationships, blood flow from the extra-embryonic circulation needs to be taken into account and its possible impact on cardiogenesis defined. Previously published Doppler ultrasound analyses and data of utero-placental blood flow from human studies and those using the mouse model are compared to changes observed with environmental exposures that lead to cardiovascular anomalies. Use of current concepts and models related to mechanotransduction of blood flow and fluid forces may help in the future to better define the characteristics of normal and abnormal utero-placental blood flow and the changes in the biophysical parameters that may contribute to congenital heart defects. Evidence from multiple studies is discussed to provide a framework for future modeling of the impact of experimental changes in blood flow on the mouse heart during normal and abnormal cardiogenesis. PMID:25426076

  8. Technological implications of SNAP reactor power system development on future space nuclear power systems

    SciTech Connect

    Anderson, R.V.

    1982-11-16

    Nuclear reactor systems are one method of satisfying space mission power needs. The development of such systems must proceed on a path consistent with mission needs and schedules. This path, or technology roadmap, starts from the power system technology data base available today. Much of this data base was established during the 1960s and early 1970s, when government and industry developed space nuclear reactor systems for steady-state power and propulsion. One of the largest development programs was the Systems for Nuclear Auxiliary Power (SNAP) Program. By the early 1970s, a technology base had evolved from this program at the system, subsystem, and component levels. There are many implications of this technology base on future reactor power systems. A review of this base highlights the need for performing a power system technology and mission overview study. Such a study is currently being performed by Rockwell's Energy Systems Group for the Department of Energy and will assess power system capabilities versus mission needs, considering development, schedule, and cost implications. The end product of the study will be a technology roadmap to guide reactor power system development.

  9. Chemosignals, Hormones and Mammalian Reproduction

    PubMed Central

    Petrulis, Aras

    2013-01-01

    Many mammalian species use chemosignals to coordinate reproduction by altering the physiology and behavior of both sexes. Chemosignals prime reproductive physiology so that individuals become sexually mature and active at times when mating is most probable and suppress it when it is not. Once in reproductive condition, odors produced and deposited by both males and females are used to find and select individuals for mating. The production, dissemination and appropriate responses to these cues are modulated heavily by organizational and activational effects of gonadal sex steroids and thereby intrinsically link chemical communication to the broader reproductive context. Many compounds have been identified as “pheromones” but very few have met the expectations of that term: a unitary, species-typical substance that is both necessary and sufficient for an experience-independent behavioral or physiological response. In contrast, most responses to chemosignals are dependent or heavily modulated by experience, either in adulthood or during development. Mechanistically, chemosignals are perceived by both main and accessory (vomeronasal) olfactory systems with the importance of each system tied strongly to the nature of the stimulus rather than to the response. In the central nervous system, the vast majority of responses to chemosignals are mediated by cortical and medial amygdala connections with hypothalamic and other forebrain structures. Despite the importance of chemosignals in mammals, many details of chemical communication differ even among closely related species and defy clear categorization. Although generating much research and public interest, strong evidence for the existence of a robust chemical communication among humans is lacking. PMID:23545474

  10. Political Implications of the Southern African Development Community Agenda on Educational Development in the Region.

    ERIC Educational Resources Information Center

    Nziramasanga, Caiphas T.

    This paper briefly describes the historical development of the Southern African Development Coordination Conference (SADCC) from its roots in 1980 and examines the work of the Southern African Development Community (SADC) today. The objectives of the SADCC are listed from the 1980 declaration and the achievement of those objectives are assessed.…

  11. Mammalian-specific genomic functions: Newly acquired traits generated by genomic imprinting and LTR retrotransposon-derived genes in mammals

    PubMed Central

    KANEKO-ISHINO, Tomoko; ISHINO, Fumitoshi

    2015-01-01

    Mammals, including human beings, have evolved a unique viviparous reproductive system and a highly developed central nervous system. How did these unique characteristics emerge in mammalian evolution, and what kinds of changes did occur in the mammalian genomes as evolution proceeded? A key conceptual term in approaching these issues is “mammalian-specific genomic functions”, a concept covering both mammalian-specific epigenetics and genetics. Genomic imprinting and LTR retrotransposon-derived genes are reviewed as the representative, mammalian-specific genomic functions that are essential not only for the current mammalian developmental system, but also mammalian evolution itself. First, the essential roles of genomic imprinting in mammalian development, especially related to viviparous reproduction via placental function, as well as the emergence of genomic imprinting in mammalian evolution, are discussed. Second, we introduce the novel concept of “mammalian-specific traits generated by mammalian-specific genes from LTR retrotransposons”, based on the finding that LTR retrotransposons served as a critical driving force in the mammalian evolution via generating mammalian-specific genes. PMID:26666304

  12. Correlations between Human Development and CO2 emissions: projections and implications

    NASA Astrophysics Data System (ADS)

    Rybski, D.; Costa, L.; Kropp, J.

    2011-12-01

    Although developing countries are called to participate on the efforts of reducing CO2 emissions in order to avoid dangerous climate change, the implications of CO2 reduction targets in human development standards of developing countries remain a matter of debate. We find positive and time dependent correlation between the Human Development Index (HDI) and per capita CO2 emissions from fossil fuel combustion. Based on this empirical relation, extrapolated HDI, and three population scenarios extracted from the Millennium Ecosystem Assessment report, we estimate future cumulative CO2 emissions. If current demographic and development trends are maintained, we estimate that by 2050 around 85% of the world's population will live in countries with high HDI (above 0.8) as defined in the United Nations Human Development Report 2009. In particular, we estimate that at least 300Gt of cumulative CO2 emissions between 2000 and 2050 are necessary for the development of developing countries in the year 2000. This value represents 30% of a previously calculated CO2 budget yielding a 75% probability of limiting global warming to 2°C. Since human development has been proved to be time and country dependent, we plead for future climate negotiations to consider a differentiated CO2 emissions reduction scheme for developing countries based on the achievement of concrete development goals.

  13. Retrotransposon-Derived Promoter of Mammalian Aebp2

    PubMed Central

    Kim, Hana; Bakshi, Arundhati; Kim, Joomyeong

    2015-01-01

    Variable DNA methylation in promoter regions has been implicated in altering transcriptional regulation. The current study analyzed the evolutionary origin and DNA methylation pattern of one of the promoters of Aebp2. According to the results, the first promoter of Aebp2 has been derived from retrotransposons independently in the primate and rodent lineages. DNA methylation analyses revealed that this promoter is unmethylated in sperm, methylated in mature oocytes, and partially methylated at embryonic day 10.5 (78.3%) and 14.5 (58.3%). This promoter also shows variable levels of DNA methylation among adult organs, ranging from the highest in spleen (~80%) to the lowest in tail (~50%). The results from the F1 hybrid of interspecific crossing further indicated that both alleles are equally methylated without any allele bias, also supported by its biallelic expression. Therefore, the partial methylation observed among somatic tissues is an outcome of the genome-wide resetting of DNA methylation during the implantation stage, but not of the inherited allelic methylation pattern preset during gametogenesis. Taken together, mammalian Aebp2 has adopted retrotransposons as its promoter, which displays partial DNA methylation pattern of allelic- or non-allelic origin during the different stages of development. PMID:25915901

  14. X Chromosome Abnormalities and Cognitive Development: Implications for Understanding Normal Human Development.

    ERIC Educational Resources Information Center

    Walzer, Stanley

    1985-01-01

    Argues that knowledge from studies of individuals with sex chromosome abnormalities can further understanding of aspects of normal human development. Studies of XO girls, XXY boys, XXX girls, and males with a fragile X chromosome are summarized to demonstrate how results contribute to knowledge about normal cognitive development and about…

  15. Communication for Development: A Personal Experience with Implications for Development Policy

    ERIC Educational Resources Information Center

    Agunga, Robert

    2012-01-01

    Purpose: Communication for Development (C4D) is a new academic discipline and profession for addressing human dimension concerns in development, such as local participation, integration and capacity building, which are the main issues limiting aid effectiveness. However, my experience in Malawi, one of the poorest countries in Africa and where a…

  16. Coaching in the Context of Social-Emotional Development: Implications for Targeted Early Childhood Professional Development

    ERIC Educational Resources Information Center

    Harkins, Diane M.

    2013-01-01

    This study was designed to inform professional development in early childhood education (ECE) by examining the use of coaching to improve teacher performance in the classroom. Professional development programs that include coaching, a relationship-based method of enhancing application of newly acquired knowledge and skills, have received…

  17. Implications of MMPI/MMPI--a findings for understanding adolescent development and psychopathology.

    PubMed

    Archer, Robert P

    2005-12-01

    The MMPI (Hathaway & McKinley, 1943) and the MMPI-Adolescent (MMPI-A; Butcher et al., 1992) have been used in the evaluation of adolescents for over 60 years, resulting in over 200 studies involving tens of thousands of adolescents. This literature not only informs us concerning characteristics of this test instrument but also holds important implications for our understanding of adolescent development and psychopathology. In this article, based on an invited master lecture at the 2005 Annual Meeting of the Society for Personality Assessment, I present several points illustrating the relevance of MMPI and MMPI--A research in enriching our understanding of adolescence.

  18. Implications of MMPI/MMPI--a findings for understanding adolescent development and psychopathology.

    PubMed

    Archer, Robert P

    2005-12-01

    The MMPI (Hathaway & McKinley, 1943) and the MMPI-Adolescent (MMPI-A; Butcher et al., 1992) have been used in the evaluation of adolescents for over 60 years, resulting in over 200 studies involving tens of thousands of adolescents. This literature not only informs us concerning characteristics of this test instrument but also holds important implications for our understanding of adolescent development and psychopathology. In this article, based on an invited master lecture at the 2005 Annual Meeting of the Society for Personality Assessment, I present several points illustrating the relevance of MMPI and MMPI--A research in enriching our understanding of adolescence. PMID:16318565

  19. Technology survey of nursing programs: implications for electronic end-of-life teaching tool development.

    PubMed

    Wells, Marjorie J; Wilkie, Diana J; Brown, Marie-Annette; Corless, Inge B; Farber, Stuart J; Judge, M Kay M; Shannon, Sarah E

    2003-01-01

    From an online survey of current technological capabilities of US undergraduate nursing programs, we found almost universal use of Microsoft Windows-based computers and Microsoft Office Suite software. Netscape and Microsoft Internet Explorer were the most popular browsers for Internet access. The survey also assessed faculty preferences for end-of-life care teaching materials and found that nurse educators preferred simple easy-to-use tools provided on CD-ROM or the Internet, with instructions provided via CD-ROM, the Internet, and demonstration workshops. Our findings have numerous implications for the development of electronic teaching materials for nursing.

  20. Joint Alpharma-Beef Species Symposium: implications of beef heifer development systems and lifetime productivity.

    PubMed

    Endecott, R L; Funston, R N; Mulliniks, J T; Roberts, A J

    2013-03-01

    Research emphasis has been placed on heifer development strategies in recent years, comparing traditional, more intensive systems to more extensive systems using less feed and relying on compensatory gain to reach a target BW. Recent research has indicated that developing heifers to a lighter target BW at breeding (i.e., 50 to 57% of mature BW compared with 60 to 65% BW) reduced development costs and did not impair reproductive performance. Research published through the late 1980s demonstrated greater negative effects of limited postweaning growth on age at puberty and pregnancy rates whereas more recent studies demonstrate less of a negative impact of delayed puberty on pregnancy rate. A limitation of most research concerning influences of nutrition on heifer development and cow reproductive performance is little or limited consideration of long-term implications. Longevity has relatively low heritability; therefore, heifer development and other management strategies have a greater potential to impact cow retention. Establishing the impact of heifer development protocols on longevity is complex, requiring consideration of nutritional factors after the start of breeding and through subsequent calvings. Lower-input heifer development, where all heifers are managed together after the postweaning period, did not impair rebreeding, but continued subsequent restriction in the form of marginal winter supplementation resulted in decreased retention in the breeding herd. Therefore, the compensatory BW gain period for restricted-growth heifers may be important to longevity and lifetime productivity. Adequate growth and development to ensure minimal calving difficulty can be of critical importance for longevity; however, providing additional supplemental feed during postweaning development to accomplish this may be less efficient than later in development. Restricting gain during postweaning development by limiting DMI or developing heifers on dormant winter forage resulted

  1. Mammalian developmental genetics in the twentieth century.

    PubMed

    Artzt, Karen

    2012-12-01

    This Perspectives is a review of the breathtaking history of mammalian genetics in the past century and, in particular, of the ways in which genetic thinking has illuminated aspects of mouse development. To illustrate the power of that thinking, selected hypothesis-driven experiments and technical advances are discussed. Also included in this account are the beginnings of mouse genetics at the Bussey Institute, Columbia University, and The Jackson Laboratory and a retrospective discussion of one of the classic problems in developmental genetics, the T/t complex and its genetic enigmas.

  2. Mammalian Developmental Genetics in the Twentieth Century

    PubMed Central

    Artzt, Karen

    2012-01-01

    This Perspectives is a review of the breathtaking history of mammalian genetics in the past century and, in particular, of the ways in which genetic thinking has illuminated aspects of mouse development. To illustrate the power of that thinking, selected hypothesis-driven experiments and technical advances are discussed. Also included in this account are the beginnings of mouse genetics at the Bussey Institute, Columbia University, and The Jackson Laboratory and a retrospective discussion of one of the classic problems in developmental genetics, the T/t complex and its genetic enigmas. PMID:23212897

  3. Ubiquitin is conjugated by membrane ubiquitin ligase to three sites, including the N terminus, in transmembrane region of mammalian 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for sterol-regulated enzyme degradation.

    PubMed

    Doolman, Ram; Leichner, Gil S; Avner, Rachel; Roitelman, Joseph

    2004-09-10

    The stability of the endoplasmic reticulum (ER) glycoprotein 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), the key enzyme in cholesterol biosynthesis, is negatively regulated by sterols. HMGR is anchored in the ER via its N-terminal region, which spans the membrane eight times and contains a sterol-sensing domain. We have previously established that degradation of mammalian HMGR is mediated by the ubiquitin-proteasome system (Ravid, T., Doolman, R., Avner, R., Harats, D., and Roitelman, J. (2000) J. Biol. Chem. 275, 35840-35847). Here we expressed in HEK-293 cells an HA-tagged-truncated version of HMGR that encompasses all eight transmembrane spans (350 N-terminal residues). Similar to endogenous HMGR, degradation of this HMG(350)-3HA protein was accelerated by sterols, validating it as a model to study HMGR turnover. The degradation of HMG(240)-3HA, which lacks the last two transmembrane spans yet retains an intact sterol-sensing domain, was no longer accelerated by sterols. Using HMG(350)-3HA, we demonstrate that transmembrane region of HMGR is ubiquitinated in a sterol-regulated fashion. Through site-directed Lys --> Arg mutagenesis, we pinpoint Lys(248) and Lys(89) as the internal lysines for ubiquitin attachment, with Lys(248) serving as the major acceptor site for polyubiquitination. Moreover, the data indicate that the N terminus is also ubiquitinated. The degradation rates of the Lys --> Arg mutants correlates with their level of ubiquitination. Notably, lysine-less HMG(350)-3HA is degraded faster than wild-type protein, suggesting that lysines other than Lys(89) and Lys(248) attenuate ubiquitination at the latter residues. The ATP-dependent ubiquitination of HMGR in isolated microsomes requires E1 as the sole cytosolic protein, indicating that ER-bound E2 and E3 enzymes catalyze this modification. Polyubiquitination of HMGR is correlated with its extraction from the ER membrane, a process likely to be assisted by cytosolic p97/VCP/Cdc48p-Ufd1-Npl

  4. Potential Mammalian Filovirus Reservoirs

    PubMed Central

    Carroll, Darin S.; Mills, James N.; Johnson, Karl M.

    2004-01-01

    Ebola and Marburg viruses are maintained in unknown reservoir species; spillover into human populations results in occasional human cases or epidemics. We attempted to narrow the list of possibilities regarding the identity of those reservoir species. We made a series of explicit assumptions about the reservoir: it is a mammal; it supports persistent, largely asymptomatic filovirus infections; its range subsumes that of its associated filovirus; it has coevolved with the virus; it is of small body size; and it is not a species that is commensal with humans. Under these assumptions, we developed priority lists of mammal clades that coincide distributionally with filovirus outbreak distributions and compared these lists with those mammal taxa that have been tested for filovirus infection in previous epidemiologic studies. Studying the remainder of these taxa may be a fruitful avenue for pursuing the identity of natural reservoirs of filoviruses. PMID:15663841

  5. Exploring the implications of social change for human development: perspectives, issues and future directions.

    PubMed

    Chen, Xinyin

    2015-02-01

    Researchers have investigated the implications of social change for human development from different perspectives. The studies published in this special section were conducted within Greenfield's theoretical framework (2009). The findings concerning links between specific sociodemographic features (e.g., commercial activities, schooling) and individual cognition and social behaviour are particularly interesting because they tap the underlying forces that drive human development. To further understand the issues in these studies and in the field, a pluralist-constructive perspective is discussed, which emphasises the integration of diverse values and practices in both Western and non-Western societies and its effects on the development of sophisticated competencies in individual adaptation to the changing global community. In addition, several issues are highlighted and some suggestions are provided for future explorations in this field.

  6. Key issues in the management of patients with systemic lupus erythematosus: latest developments and clinical implications

    PubMed Central

    Jordan, Natasha; D’Cruz, David

    2015-01-01

    Systemic lupus erythematous (SLE) is a chronic multisystem disease with significant associated morbidity and mortality. A deeper understanding of the pathogenesis of SLE has led to the development of biologic agents, primarily targeting B cells and others inhibiting costimulatory molecules, type I interferons and cytokines such as interleukin-6. Several of these agents have been studied in clinical trials; some have shown promise while others have yielded disappointing results. Economic and regulatory issues continue to hamper the availability of such therapies for SLE patients. With increasing recognition that recurrent flares of disease activity lead to long-term damage accrual, one of the most important recent developments in patient management has been the concept of treat-to-target in SLE while minimizing patient exposure to excessive corticosteroid and other immunosuppressive therapy. This article reviews these key issues in SLE management, outlining recent developments and clinical implications for patients. PMID:26622325

  7. Interplay between progesterone and prolactin in mammary development and implications for breast cancer.

    PubMed

    Lee, Heather J; Ormandy, Christopher J

    2012-06-24

    Progesterone and prolactin remodel mammary morphology during pregnancy by acting on the mammary epithelial cell hierarchy. The roles of each hormone in mammary development have been well studied, but evidence of signalling cross-talk between progesterone and prolactin is still emerging. Factors such as receptor activator of NFkB ligand (RANKL) may integrate signals from both hormones to orchestrate their joint actions on the epithelial cell hierarchy. Common targets of progesterone and prolactin signalling are also likely to integrate their pro-proliferative actions in breast cancer. Therefore, a thorough understanding of the interplay between progesterone and prolactin in mammary development may reveal therapeutic targets for breast cancer. This review summarises our understanding of Pg and PRL action in mammary gland development before focusing on molecular mechanisms of signalling cross-talk and the implications for breast cancer.

  8. LncRNAs and Esophageal Squamous Cell Carcinoma - Implications for Pathogenesis and Drug Development

    PubMed Central

    Shen, Wen-Jun; Zhang, Fan; Zhao, Xing; Xu, Jianzhen

    2016-01-01

    LncRNAs are a group of ncRNA species longer than 200 nt, which have fundamental regulatory roles in diverse cellular processes and diseases progression. Esophageal cancer is a serious malignancy with respect to prognosis and mortality rate. It is among the five leading cancer types for the cancer deaths in males of middle age in the United States. In China, esophageal cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death. The molecular mechanisms of esophageal cancer development are not fully understood, but emerging studies point out that lncRNAs may actively associate with the pathogenesis. In this review, we first provided an introduction of lncRNAs classifications. Then we focused on the recent findings on lncRNA expression and function in esophageal cancer development. Implications for pathogenesis and potential drug developments will also be discussed. PMID:27390601

  9. Exploring the implications of social change for human development: perspectives, issues and future directions.

    PubMed

    Chen, Xinyin

    2015-02-01

    Researchers have investigated the implications of social change for human development from different perspectives. The studies published in this special section were conducted within Greenfield's theoretical framework (2009). The findings concerning links between specific sociodemographic features (e.g., commercial activities, schooling) and individual cognition and social behaviour are particularly interesting because they tap the underlying forces that drive human development. To further understand the issues in these studies and in the field, a pluralist-constructive perspective is discussed, which emphasises the integration of diverse values and practices in both Western and non-Western societies and its effects on the development of sophisticated competencies in individual adaptation to the changing global community. In addition, several issues are highlighted and some suggestions are provided for future explorations in this field. PMID:25501915

  10. Reflections of evolution and culture in children's cognition. Implications for mathematical development and instruction.

    PubMed

    Geary, D C

    1995-01-01

    An evolution-based framework for understanding biological and cultural influences on children's cognitive and academic development is presented. The utility of this framework is illustrated within the mathematical domain and serves as a foundation for examining current approaches to educational reform in the United States. Within this framework, there are two general classes of cognitive ability, biologically primary and biologically secondary. Biologically primary cognitive abilities appear to have evolved largely by means of natural or sexual selection. Biologically secondary cognitive abilities reflect the co-optation of primary abilities for purposes other than the original evolution-based function and appear to develop only in specific cultural contexts. A distinction between these classes of ability has important implications for understanding children's cognitive development and achievement. PMID:7872578

  11. The cell biology of neural stem and progenitor cells and its significance for their proliferation versus differentiation during mammalian brain development.

    PubMed

    Farkas, Lilla M; Huttner, Wieland B

    2008-12-01

    The switch of neural stem and progenitor cells from proliferation to differentiation during development is a crucial determinant of brain size. This switch is intimately linked to the architecture of the two principal classes of neural stem and progenitor cells, the apical (neuroepithelial, radial glial) and basal (intermediate) progenitors, which in turn is crucial for their symmetric versus asymmetric divisions. Focusing on the developing rodent neocortex, we discuss here recent advances in understanding the cell biology of apical and basal progenitors, place key regulatory molecules into subcellular context, and highlight their roles in the control of proliferation versus differentiation. PMID:18930817

  12. Recognition for Positive Behavior as a Critical Youth Development Construct: Conceptual Bases and Implications on Youth Service Development

    PubMed Central

    Law, Ben M. F.; Siu, Andrew M. H.; Shek, Daniel T. L.

    2012-01-01

    Recognition for positive behavior is an appropriate response of the social environment to elicit desirable external behavior among the youth. Such positive responses, rendered from various social systems, include tangible and intangible reinforcements. The following theories are used to explain the importance of recognizing positive behavior: operational conditioning, observational learning, self-determination, and humanistic perspective. In the current work, culturally and socially desirable behaviors are discussed in detail with reference to Chinese adolescents. Positive behavior recognition is especially important to adolescent development because it promotes identity formation as well as cultivates moral reasoning and social perspective thinking from various social systems. The significance of recognizing positive behavior is illustrated through the support, tutorage, invitation, and subsidy provided by Hong Kong's social systems in recognition of adolescent volunteerism. The practical implications of positive behavior recognition on youth development programs are also discussed in this work. PMID:22666155

  13. Modelling mammalian cellular quiescence

    PubMed Central

    Yao, Guang

    2014-01-01

    Cellular quiescence is a reversible non-proliferating state. The reactivation of ‘sleep-like’ quiescent cells (e.g. fibroblasts, lymphocytes and stem cells) into proliferation is crucial for tissue repair and regeneration and a key to the growth, development and health of higher multicellular organisms, such as mammals. Quiescence has been a primarily phenotypic description (i.e. non-permanent cell cycle arrest) and poorly studied. However, contrary to the earlier thinking that quiescence is simply a passive and dormant state lacking proliferating activities, recent studies have revealed that cellular quiescence is actively maintained in the cell and that it corresponds to a collection of heterogeneous states. Recent modelling and experimental work have suggested that an Rb-E2F bistable switch plays a pivotal role in controlling the quiescence–proliferation balance and the heterogeneous quiescent states. Other quiescence regulatory activities may crosstalk with and impinge upon the Rb-E2F bistable switch, forming a gene network that controls the cells’ quiescent states and their dynamic transitions to proliferation in response to noisy environmental signals. Elucidating the dynamic control mechanisms underlying quiescence may lead to novel therapeutic strategies that re-establish normal quiescent states, in a variety of hyper- and hypo-proliferative diseases, including cancer and ageing. PMID:24904737

  14. Amino acids in the cultivation of mammalian cells.

    PubMed

    Salazar, Andrew; Keusgen, Michael; von Hagen, Jörg

    2016-05-01

    Amino acids are crucial for the cultivation of mammalian cells. This importance of amino acids was realized soon after the development of the first cell lines, and a solution of a mixture of amino acids has been supplied to cultured cells ever since. The importance of amino acids is further pronounced in chemically defined mammalian cell culture media, making the consideration of their biological and chemical properties necessary. Amino acids concentrations have been traditionally adjusted to their cellular consumption rates. However, since changes in the metabolic equilibrium of amino acids can be caused by changes in extracellular concentrations, metabolomics in conjunction with flux balance analysis is being used in the development of culture media. The study of amino acid transporters is also gaining importance since they control the intracellular concentrations of these molecules and are influenced by conditions in cell culture media. A better understanding of the solubility, stability, dissolution kinetics, and interactions of these molecules is needed for an exploitation of these properties in the development of dry powdered chemically defined media for mammalian cells. Due to the complexity of these mixtures however, this has proven to be challenging. Studying amino acids in mammalian cell culture media will help provide a better understanding of how mammalian cells in culture interact with their environment. It would also provide insight into the chemical behavior of these molecules in solutions of complex mixtures, which is important in the understanding of the contribution of individual amino acids to protein structure. PMID:26832172

  15. Amino acids in the cultivation of mammalian cells.

    PubMed

    Salazar, Andrew; Keusgen, Michael; von Hagen, Jörg

    2016-05-01

    Amino acids are crucial for the cultivation of mammalian cells. This importance of amino acids was realized soon after the development of the first cell lines, and a solution of a mixture of amino acids has been supplied to cultured cells ever since. The importance of amino acids is further pronounced in chemically defined mammalian cell culture media, making the consideration of their biological and chemical properties necessary. Amino acids concentrations have been traditionally adjusted to their cellular consumption rates. However, since changes in the metabolic equilibrium of amino acids can be caused by changes in extracellular concentrations, metabolomics in conjunction with flux balance analysis is being used in the development of culture media. The study of amino acid transporters is also gaining importance since they control the intracellular concentrations of these molecules and are influenced by conditions in cell culture media. A better understanding of the solubility, stability, dissolution kinetics, and interactions of these molecules is needed for an exploitation of these properties in the development of dry powdered chemically defined media for mammalian cells. Due to the complexity of these mixtures however, this has proven to be challenging. Studying amino acids in mammalian cell culture media will help provide a better understanding of how mammalian cells in culture interact with their environment. It would also provide insight into the chemical behavior of these molecules in solutions of complex mixtures, which is important in the understanding of the contribution of individual amino acids to protein structure.

  16. The mammalian ovary from genesis to revelation.

    PubMed

    Edson, Mark A; Nagaraja, Ankur K; Matzuk, Martin M

    2009-10-01

    Two major functions of the mammalian ovary are the production of germ cells (oocytes), which allow continuation of the species, and the generation of bioactive molecules, primarily steroids (mainly estrogens and progestins) and peptide growth factors, which are critical for ovarian function, regulation of the hypothalamic-pituitary-ovarian axis, and development of secondary sex characteristics. The female germline is created during embryogenesis when the precursors of primordial germ cells differentiate from somatic lineages of the embryo and take a unique route to reach the urogenital ridge. This undifferentiated gonad will differentiate along a female pathway, and the newly formed oocytes will proliferate and subsequently enter meiosis. At this point, the oocyte has two alternative fates: die, a common destiny of millions of oocytes, or be fertilized, a fate of at most approximately 100 oocytes, depending on the species. At every step from germline development and ovary formation to oogenesis and ovarian development and differentiation, there are coordinated interactions of hundreds of proteins and small RNAs. These studies have helped reproductive biologists to understand not only the normal functioning of the ovary but also the pathophysiology and genetics of diseases such as infertility and ovarian cancer. Over the last two decades, parallel progress has been made in the assisted reproductive technology clinic including better hormonal preparations, prenatal genetic testing, and optimal oocyte and embryo analysis and cryopreservation. Clearly, we have learned much about the mammalian ovary and manipulating its most important cargo, the oocyte, since the birth of Louise Brown over 30 yr ago.

  17. The Mammalian Ovary from Genesis to Revelation

    PubMed Central

    Edson, Mark A.; Nagaraja, Ankur K.; Matzuk, Martin M.

    2009-01-01

    Two major functions of the mammalian ovary are the production of germ cells (oocytes), which allow continuation of the species, and the generation of bioactive molecules, primarily steroids (mainly estrogens and progestins) and peptide growth factors, which are critical for ovarian function, regulation of the hypothalamic-pituitary-ovarian axis, and development of secondary sex characteristics. The female germline is created during embryogenesis when the precursors of primordial germ cells differentiate from somatic lineages of the embryo and take a unique route to reach the urogenital ridge. This undifferentiated gonad will differentiate along a female pathway, and the newly formed oocytes will proliferate and subsequently enter meiosis. At this point, the oocyte has two alternative fates: die, a common destiny of millions of oocytes, or be fertilized, a fate of at most approximately 100 oocytes, depending on the species. At every step from germline development and ovary formation to oogenesis and ovarian development and differentiation, there are coordinated interactions of hundreds of proteins and small RNAs. These studies have helped reproductive biologists to understand not only the normal functioning of the ovary but also the pathophysiology and genetics of diseases such as infertility and ovarian cancer. Over the last two decades, parallel progress has been made in the assisted reproductive technology clinic including better hormonal preparations, prenatal genetic testing, and optimal oocyte and embryo analysis and cryopreservation. Clearly, we have learned much about the mammalian ovary and manipulating its most important cargo, the oocyte, since the birth of Louise Brown over 30 yr ago. PMID:19776209

  18. The implications of future building scenarios for long-term building energy research and development

    SciTech Connect

    Flynn, W.T.

    1986-12-01

    This report presents a discussion of alternative future scenarios of the building environment to the year 2010 and assesses the implications these scenarios present for long-term building energy R and D. The scenarios and energy R and D implications derived from them are intended to serve as the basis from which a strategic plan can be developed for the management of R and D programs conducted by the Office of Buildings and Community Systems, US Department of Energy. The scenarios and analysis presented here have relevance not only for government R and D programs; on the contrary, it is hoped that the results of this effort will be of interest and useful to researchers in both private and public sector organizations that deal with building energy R and D. Making R and D decisions today based on an analysis that attempts to delineate the nexus of events 25 years in the future are clearly decisions made in the face of uncertainty. Yet, the effective management of R and D programs requires a future-directed understanding of markets, technological developments, and environmental factors, as well as their interactions. The analysis presented in this report is designed to serve that need. Although the probability of any particular scenario actually occurring is uncertain, the scenarios to be presented are sufficiently robust to set bounds within which to examine the interaction of forces that will shape the future building environment.

  19. Mechanisms of mammalian iron homeostasis.

    PubMed

    Pantopoulos, Kostas; Porwal, Suheel Kumar; Tartakoff, Alan; Devireddy, L

    2012-07-24

    Iron is vital for almost all organisms because of its ability to donate and accept electrons with relative ease. It serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism, as well as for several other essential processes. Mammalian cells utilize multiple mechanisms to acquire iron. Disruption of iron homeostasis is associated with various human diseases: iron deficiency resulting from defects in the acquisition or distribution of the metal causes anemia, whereas iron surfeit resulting from excessive iron absorption or defective utilization causes abnormal tissue iron deposition, leading to oxidative damage. Mammals utilize distinct mechanisms to regulate iron homeostasis at the systemic and cellular levels. These involve the hormone hepcidin and iron regulatory proteins, which collectively ensure iron balance. This review outlines recent advances in iron regulatory pathways as well as in mechanisms underlying intracellular iron trafficking, an important but less studied area of mammalian iron homeostasis.

  20. Mapping Gray Matter Development: Implications for Typical Development and Vulnerability to Psychopathology

    ERIC Educational Resources Information Center

    Gogtay, Nitin; Thompson, Paul M.

    2010-01-01

    Recent studies with brain magnetic resonance imaging (MRI) have scanned large numbers of children and adolescents repeatedly over time, as their brains develop, tracking volumetric changes in gray and white matter in remarkable detail. Focusing on gray matter changes specifically, here we explain how earlier studies using lobar volumes of specific…

  1. Expression patterns of cotton chloroplast genes during development: implications for development of plastid transformation vectors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In order to express genes of interest in plastids, transformation vectors must be developed that include appropriate promoters to drive expression at effective levels in both green and non-green tissues. Typically, chloroplasts are transformed with vectors that contain ribosomal RNA promoters for h...

  2. Understanding the Varying Investments in Researcher and Teacher Development and Enhancement: Implications for Academic Developers

    ERIC Educational Resources Information Center

    Petrova, Petia; Hadjianastasis, Marios

    2015-01-01

    The increasing disparity between the research and teaching aspects of academic careers has been an area of concern in different national contexts over a number of decades. Anyone working with educational enhancement will have encountered the binary choice between research development and educational enhancement that academics are forced to make,…

  3. Selective processes in development: implications for the costs and benefits of phenotypic plasticity.

    PubMed

    Snell-Rood, Emilie C

    2012-07-01

    Adaptive phenotypic plasticity, the ability of a genotype to develop a phenotype appropriate to the local environment, allows organisms to cope with environmental variation and has implications for predicting how organisms will respond to rapid, human-induced environmental change. This review focuses on the importance of developmental selection, broadly defined as a developmental process that involves the sampling of a range of phenotypes and feedback from the environment reinforcing high-performing phenotypes. I hypothesize that understanding the degree to which developmental selection underlies plasticity is key to predicting the costs, benefits, and consequences of plasticity. First, I review examples that illustrate that elements of developmental selection are common across the development of many different traits, from physiology and immunity to circulation and behavior. Second, I argue that developmental selection, relative to a fixed strategy or determinate (switch) mechanisms of plasticity, increases the probability that an individual will develop a phenotype best matched to the local environment. However, the exploration and environmental feedback associated with developmental selection is costly in terms of time, energy, and predation risk, resulting in major changes in life history such as increased duration of development and greater investment in individual offspring. Third, I discuss implications of developmental selection as a mechanism of plasticity, from predicting adaptive responses to novel environments to understanding conditions under which genetic assimilation may fuel diversification. Finally, I outline exciting areas of future research, in particular exploring costs of selective processes in the development of traits outside of behavior and modeling developmental selection and evolution in novel environments.

  4. DAX1/NR0B1 was expressed during mammalian gonadal development and gametogenesis before it was recruited to the eutherian X chromosome.

    PubMed

    Stickels, Robert; Clark, Kevin; Heider, Thomas N; Mattiske, Deidre M; Renfree, Marilyn B; Pask, Andrew J

    2015-01-01

    The nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene is an orphan nuclear receptor that is X-linked in eutherian mammals and plays a critical role in the establishment and function of the hypothalamic-pituitary-adrenal-gonadal axis. Duplication or overexpression of NR0B1 in eutherian males causes male to female sex reversal, and mutation and deletions of NR0B1 cause testicular defects. Thus, gene dosage is critical for the function of NR0B1 in normal gonadogenesis. However, NR0B1 is autosomal in all noneutherian vertebrates, including marsupials and monotreme mammals, and two active copies of the gene are compatible with both male and female gonadal development. In the current study, we examined the evolution and expression of autosomal NR0B1 during gonadal development in a marsupial (the tammar wallaby) as compared to the role of its X-linked orthologues in a eutherian (the mouse). We show that NR0B1 underwent rapid evolutionary change when it relocated from its autosomal position in the nonmammalian vertebrates, monotremes, and marsupials to an X-linked location in eutherian mammals. Despite the acquisition of a novel genomic location and a unique N-terminal domain, NR0B1 protein distribution was remarkably similar between mice and marsupials both throughout gonadal development and during gamete formation. A conserved accumulation of NR0B1 protein was observed in developing oocytes, where its function appears to be critical in the early embryo, prior to zygotic genome activation. Together these findings suggest that NR0B1 had a conserved role in gonadogenesis that existed long before it moved to the X chromosome and despite undergoing significant evolutionary change.

  5. DAX1/NR0B1 was expressed during mammalian gonadal development and gametogenesis before it was recruited to the eutherian X chromosome.

    PubMed

    Stickels, Robert; Clark, Kevin; Heider, Thomas N; Mattiske, Deidre M; Renfree, Marilyn B; Pask, Andrew J

    2015-01-01

    The nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene is an orphan nuclear receptor that is X-linked in eutherian mammals and plays a critical role in the establishment and function of the hypothalamic-pituitary-adrenal-gonadal axis. Duplication or overexpression of NR0B1 in eutherian males causes male to female sex reversal, and mutation and deletions of NR0B1 cause testicular defects. Thus, gene dosage is critical for the function of NR0B1 in normal gonadogenesis. However, NR0B1 is autosomal in all noneutherian vertebrates, including marsupials and monotreme mammals, and two active copies of the gene are compatible with both male and female gonadal development. In the current study, we examined the evolution and expression of autosomal NR0B1 during gonadal development in a marsupial (the tammar wallaby) as compared to the role of its X-linked orthologues in a eutherian (the mouse). We show that NR0B1 underwent rapid evolutionary change when it relocated from its autosomal position in the nonmammalian vertebrates, monotremes, and marsupials to an X-linked location in eutherian mammals. Despite the acquisition of a novel genomic location and a unique N-terminal domain, NR0B1 protein distribution was remarkably similar between mice and marsupials both throughout gonadal development and during gamete formation. A conserved accumulation of NR0B1 protein was observed in developing oocytes, where its function appears to be critical in the early embryo, prior to zygotic genome activation. Together these findings suggest that NR0B1 had a conserved role in gonadogenesis that existed long before it moved to the X chromosome and despite undergoing significant evolutionary change. PMID:25395677

  6. Evolution and development of dual ingestion systems in mammals: notes on a new thesis and its clinical implications.

    PubMed

    Alberts, Jeffrey R; Pickler, Rita H

    2012-01-01

    Traditionally, the development of oral feeding is viewed as a continuous, unitary process in which reflex-dominated sucking behavior gives rise to a more varied and volitional feeding behavior. In contrast, we consider the thesis that the infant develops two separable ingestive systems, one for suckling and one for feeding. First, we apply an evolutionary perspective, recognizing that suckling-feeding is a universal, mammalian developmental sequence. We find that in mammalian evolution, feeding systems in offspring were established prior to the evolution of lactation, and therefore suckling is a separable feature that was added to feeding. We next review an experimental literature that characterizes suckling and feeding as separable in terms of their topography, sensory controls, physiological controls, neural substrates, and experience-based development. Together, these considerations constitute a view of "dual ingestive systems." The thesis, then, is that suckling is not a simple precursor of feeding but is a complete behavior that emerges, forms, and then undergoes a dissolution that overlaps with the emergence of independent feeding. This thesis guides us to focus differently on the challenges of properly managing and facilitating oral ingestion in infants, especially those born preterm, prior to the developmental onset of suckling.

  7. Evolution and Development of Dual Ingestion Systems in Mammals: Notes on a New Thesis and Its Clinical Implications

    PubMed Central

    Alberts, Jeffrey R.; Pickler, Rita H.

    2012-01-01

    Traditionally, the development of oral feeding is viewed as a continuous, unitary process in which reflex-dominated sucking behavior gives rise to a more varied and volitional feeding behavior. In contrast, we consider the thesis that the infant develops two separable ingestive systems, one for suckling and one for feeding. First, we apply an evolutionary perspective, recognizing that suckling-feeding is a universal, mammalian developmental sequence. We find that in mammalian evolution, feeding systems in offspring were established prior to the evolution of lactation, and therefore suckling is a separable feature that was added to feeding. We next review an experimental literature that characterizes suckling and feeding as separable in terms of their topography, sensory controls, physiological controls, neural substrates, and experience-based development. Together, these considerations constitute a view of “dual ingestive systems.” The thesis, then, is that suckling is not a simple precursor of feeding but is a complete behavior that emerges, forms, and then undergoes a dissolution that overlaps with the emergence of independent feeding. This thesis guides us to focus differently on the challenges of properly managing and facilitating oral ingestion in infants, especially those born preterm, prior to the developmental onset of suckling. PMID:23028391

  8. Olfactory sensitivity in mammalian species.

    PubMed

    Wackermannová, M; Pinc, L; Jebavý, L

    2016-07-18

    Olfaction enables most mammalian species to detect and discriminate vast numbers of chemical structures called odorants and pheromones. The perception of such chemical compounds is mediated via two major olfactory systems, the main olfactory system and the vomeronasal system, as well as minor systems, such as the septal organ and the Grueneberg ganglion. Distinct differences exist not only among species but also among individuals in terms of their olfactory sensitivity; however, little is known about the mechanisms that determine these differences. In research on the olfactory sensitivity of mammals, scientists thus depend in most cases on behavioral testing. In this article, we reviewed scientific studies performed on various mammalian species using different methodologies and target chemical substances. Human and non-human primates as well as rodents and dogs are the most frequently studied species. Olfactory threshold studies on other species do not exist with the exception of domestic pigs. Olfactory testing performed on seals, elephants, and bats focused more on discriminative abilities than on sensitivity. An overview of olfactory sensitivity studies as well as olfactory detection ability in most studied mammalian species is presented here, focusing on comparable olfactory detection thresholds. The basics of olfactory perception and olfactory sensitivity factors are also described. PMID:27070753

  9. An Overview of Models of Speaking Performance and Its Implications for the Development of Procedural Framework for Diagnostic Speaking Tests

    ERIC Educational Resources Information Center

    Zhao, Zhongbao

    2013-01-01

    This paper aims at developing a procedural framework for the development and validation of diagnostic speaking tests. The researcher reviews the current available models of speaking performance, analyzes the distinctive features and then points out the implications for the development of a procedural framework for diagnostic speaking tests. On…

  10. Development of the carapacial ridge: implications for the evolution of genetic networks in turtle shell development.

    PubMed

    Moustakas, Jacqueline E

    2008-01-01

    Paleontologists and neontologists have long looked to development to understand the homologies of the dermal bones that form the "armor" of turtles, crocodiles, armadillos, and other vertebrates. This study shows molecular evidence supporting a dermomyotomal identity for the mesenchyme of the turtle carapacial ridge. The mesenchyme of the carapace primordium expresses Pax3, Twist1, Dermo1, En1, Sim1, and Gremlin at early stages and before overt ossification expresses Pax1. A hypothesis is proposed that this mesenchyme forms dermal bone in the turtle carapace. A comparison of regulatory gene expression in the primordia of the turtle carapace, the vertebrate limb, and the vertebral column implies the exaptation of key genetic networks in the development of the turtle shell. This work establishes a new role for this mesodermal compartment and highlights the importance of changes in genetic regulation in the evolution of morphology. PMID:18184355

  11. Endocrinology of the mammalian fetal testis.

    PubMed

    O'Shaughnessy, Peter J; Fowler, Paul A

    2011-01-01

    The testes are essential endocrine regulators of fetal masculinization and male development and are, themselves, subject to hormonal regulation during gestation. This review focuses, primarily, on this latter control of testicular function. Data available suggest that, in most mammalian species, the testis goes through a period of independent function before the fetal hypothalamic-pituitary-gonadal axis develops at around 50% of gestation. This pituitary-independent phase coincides with the most critical period of fetal masculinization. Thereafter, the fetal testes appear to become pituitary hormone-dependent, concurrent with declining Leydig cell function, but increasing Sertoli cell numbers. The two orders of mammals most commonly used for these types of studies (rodents and primates) appear to represent special cases within this general hypothesis. In terms of testicular function, rodents are born 'early' before the pituitary-dependent phase of fetal development, while the primate testis is dependent upon placental gonadotropin released during the pituitary-independent phase of development.

  12. Implications of climate change for economic development in northern Canada: energy, resource, and transportation sectors.

    PubMed

    Prowse, Terry D; Furgal, Chris; Chouinard, Rebecca; Melling, Humfrey; Milburn, David; Smith, Sharon L

    2009-07-01

    Northern Canada is projected to experience major changes to its climate, which will have major implications for northern economic development. Some of these, such as mining and oil and gas development, have experienced rapid expansion in recent years and are likely to expand further, partly as the result of indirect effects of changing climate. This article reviews how a changing climate will affect several economic sectors including the hydroelectric, oil and gas, and mining industries as well as infrastructure and transportation, both marine and freshwater. Of particular importance to all sectors are projected changes in the cryosphere, which will create both problems and opportunities. Potential adaptation strategies that could be used to minimize the negative impacts created by a climate change are also reviewed.

  13. Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4.

    PubMed

    Nagarajan, Prabakaran; Ge, Zhongqi; Sirbu, Bianca; Doughty, Cheryl; Agudelo Garcia, Paula A; Schlederer, Michaela; Annunziato, Anthony T; Cortez, David; Kenner, Lukas; Parthun, Mark R

    2013-06-01

    Histone acetyltransferase 1 is an evolutionarily conserved type B histone acetyltransferase that is thought to be responsible for the diacetylation of newly synthesized histone H4 on lysines 5 and 12 during chromatin assembly. To understand the function of this enzyme in a complex organism, we have constructed a conditional mouse knockout model of Hat1. Murine Hat1 is essential for viability, as homozygous deletion of Hat1 results in neonatal lethality. The lungs of embryos and pups genetically deficient in Hat1 were much less mature upon histological evaluation. The neonatal lethality is due to severe defects in lung development that result in less aeration and respiratory distress. Many of the Hat1(-/-) neonates also display significant craniofacial defects with abnormalities in the bones of the skull and jaw. Hat1(-/-) mouse embryonic fibroblasts (MEFs) are defective in cell proliferation and are sensitive to DNA damaging agents. In addition, the Hat1(-/-) MEFs display a marked increase in genome instability. Analysis of histone dynamics at sites of replication-coupled chromatin assembly demonstrates that Hat1 is not only responsible for the acetylation of newly synthesized histone H4 but is also required to maintain the acetylation of histone H3 on lysines 9, 18, and 27 during replication-coupled chromatin assembly.

  14. Elsevier Trophoblast Research Award lecture: The multifaceted role of Nodal signaling during mammalian reproduction.

    PubMed

    Park, C B; Dufort, D

    2011-03-01

    Nodal, a secreted signaling protein in the transforming growth factor-beta (TGF-β) superfamily, has established roles in vertebrate development. However, components of the Nodal signaling pathway are also expressed at the maternal-fetal interface and have been implicated in many processes of mammalian reproduction. Emerging evidence indicates that Nodal and its extracellular inhibitor Lefty are expressed in the uterus and complex interactions between the two proteins mediate menstruation, decidualization and embryo implantation. Furthermore, several studies have shown that Nodal from both fetal and maternal sources may regulate trophoblast cell fate and facilitate placentation as both embryonic and uterine-specific Nodal knockout mouse strains exhibit disrupted placenta morphology. Here we review the established and prospective roles of Nodal signaling in facilitating successful pregnancy, including recent evidence supporting a potential link to parturition and preterm birth.

  15. Optimizing transient recombinant protein expression in mammalian cells.

    PubMed

    Hopkins, Ralph F; Wall, Vanessa E; Esposito, Dominic

    2012-01-01

    Transient gene expression (TGE) in mammalian cells has become a routine process for expressing recombinant proteins in cell lines such as human embryonic kidney 293 and Chinese hamster ovary cells. The rapidly increasing need for recombinant proteins requires further improvements in TGE technology. While a great deal of focus has been directed toward optimizing the secretion of antibodies and other naturally secreted targets, much less work has been done on ways to improve cytoplasmic expression in mammalian cells. The benefits to protein production in mammalian cells, particularly for eukaryotic proteins, should be very significant - glycosylation and other posttranslational modifications will likely be native or near-native, solubility and protein folding would likely improve overexpression in heterologous hosts, and expression of proteins in their proper intracellular compartments is much more likely to occur. Improvements in this area have been slow, however, due to limited development of the cell culture processes needed for low-cost, higher-throughput expression in mammalian cells, and the relatively low diversity of DNA vectors for protein production in these systems. Here, we describe how the use of recombinational cloning, coupled with improvements in transfection protocols which increase speed and lower cost, can be combined to make mammalian cells much more amenable for routine recombinant protein expression. PMID:21987258

  16. An Adaptive Threshold in Mammalian Neocortical Evolution

    PubMed Central

    Kalinka, Alex T.; Tomancak, Pavel; Huttner, Wieland B.

    2014-01-01

    Expansion of the neocortex is a hallmark of human evolution. However, determining which adaptive mechanisms facilitated its expansion remains an open question. Here we show, using the gyrencephaly index (GI) and other physiological and life-history data for 102 mammalian species, that gyrencephaly is an ancestral mammalian trait. We find that variation in GI does not evolve linearly across species, but that mammals constitute two principal groups above and below a GI threshold value of 1.5, approximately equal to 109 neurons, which may be characterized by distinct constellations of physiological and life-history traits. By integrating data on neurogenic period, neuroepithelial founder pool size, cell-cycle length, progenitor-type abundances, and cortical neuron number into discrete mathematical models, we identify symmetric proliferative divisions of basal progenitors in the subventricular zone of the developing neocortex as evolutionarily necessary for generating a 14-fold increase in daily prenatal neuron production, traversal of the GI threshold, and thus establishment of two principal groups. We conclude that, despite considerable neuroanatomical differences, changes in the length of the neurogenic period alone, rather than any novel neurogenic progenitor lineage, are sufficient to explain differences in neuron number and neocortical size between species within the same principal group. PMID:25405475

  17. Calcium Signaling in Mammalian Eggs at Fertilization.

    PubMed

    Shirakawa, Hideki; Kikuchi, Takashi; Ito, Masahiko

    2016-01-01

    The innovation and development of live-cell fluorescence imaging methods have revealed the dynamic aspects of intracellular Ca2+ in a wide variety of cells. The fertilized egg, the very first cell to be a new individual, has long been under extensive investigations utilizing Ca2+ imaging since its early days, and spatiotemporal Ca2+ dynamics and underlying mechanisms of Ca2+ mobilization, as well as physiological roles of Ca2+ at fertilization, have become more or less evident in various animal species. In this article, we illustrate characteristic patterns of Ca2+ dynamics in mammalian gametes and molecular basis for Ca2+ release from intracellular stores leading to the elevation in cytoplasmic Ca2+ concentration, and describe the identity and properties of sperm-borne egg-activating factor in relation to the induction of Ca2+ waves and Ca2+ oscillations, referring to its potential use in artificial egg activation as infertility treatment. In addition, a possible Ca2+ influx-driven mechanism for slow and long-lasting Ca2+ oscillations characteristic of mammalian eggs is proposed, based on the recent experimental findings and mathematical modeling. Cumulative knowledge about the roles of Ca2+ in the egg activation leading to early embryogenesis is summarized, to emphasize the diversity of functions that Ca2+ can perform in a single type of cell.

  18. The cellular code for mammalian thermosensation.

    PubMed

    Pogorzala, Leah A; Mishra, Santosh K; Hoon, Mark A

    2013-03-27

    Mammalian somatosenory neurons respond to thermal stimuli and allow animals to reliably discriminate hot from cold and to select their preferred environments. Previously, we generated mice that are completely insensitive to temperatures from noxious cold to painful heat (-5 to 55°C) by ablating several different classes of nociceptor early in development. In the present study, we have adopted a selective ablation strategy in adult mice to study this phenotype and have demonstrated that separate populations of molecularly defined neurons respond to hot and cold. TRPV1-expressing neurons are responsible for all behavioral responses to temperatures between 40 and 50°C, whereas TRPM8 neurons are required for cold aversion. We also show that more extreme cold and heat activate additional populations of nociceptors, including cells expressing Mrgprd. Therefore, although eliminating Mrgprd neurons alone does not affect behavioral responses to temperature, when combined with ablation of TRPV1 or TRPM8 cells, it significantly decreases responses to extreme heat and cold, respectively. Ablation of TRPM8 neurons distorts responses to preferred temperatures, suggesting that the pleasant thermal sensation of warmth may in fact just reflect reduced aversive input from TRPM8 and TRPV1 neurons. As predicted by this hypothesis, mice lacking both classes of thermosensor exhibited neither aversive nor attractive responses to temperatures between 10 and 50°C. Our results provide a simple cellular basis for mammalian thermosensation whereby two molecularly defined classes of sensory neurons detect and encode both attractive and aversive cues. PMID:23536068

  19. Neurodevelopmental LincRNA Microsyteny Conservation and Mammalian Brain Size Evolution

    PubMed Central

    Lewitus, Eric; Huttner, Wieland B.

    2015-01-01

    The mammalian neocortex has undergone repeated selection for increases and decreases in size and complexity, often over relatively short evolutionary time. But because probing developmental mechanisms across many species is experimentally unfeasible, it is unknown whether convergent morphologies in distantly related species are regulated by conserved developmental programs. In this work, we have taken advantage of the abundance of available mammalian genomes to find evidence of selection on genomic regions putatively regulating neurogenesis in large- versus small-brained species. Using published fetal human RNA-seq data, we show that the gene-neighborhood (i.e., microsynteny) of long intergenic non-coding RNAs (lincRNAs) implicated in cortical development is differentially conserved in large-brained species, lending support to the hypothesis that lincRNAs regulating neurogenesis are selectively lost in small-brained species. We provide evidence that this is not a phenomenon attributable to lincRNA expressed in all tissue types and is therefore likely to represent an adaptive function in the evolution of neurogenesis. A strong correlation between transcription factor-adjacency and lincRNA sequence conservation reinforces this conclusion. PMID:26134977

  20. Rapid parallel measurements of macroautophagy and mitophagy in mammalian cells using a single fluorescent biosensor

    PubMed Central

    Sargsyan, A.; Cai, J.; Fandino, L. B.; Labasky, M. E.; Forostyan, T.; Colosimo, L. K.; Thompson, S. J.; Graham, T. E.

    2015-01-01

    Mitochondrial dysfunction is implicated in many human diseases and occurs in normal aging. Mitochondrial health is maintained through organelle biogenesis and repair or turnover of existing mitochondria. Mitochondrial turnover is principally mediated by mitophagy, the trafficking of damaged mitochondria to lysosomes via macroautophagy (autophagy). Mitophagy requires autophagy, but is itself a selective process that relies on specific autophagy-targeting mechanisms, and thus can be dissociated from autophagy under certain circumstances. Therefore, it is important to assess autophagy and mitophagy together and separately. We sought to develop a robust, high-throughput, quantitative method for monitoring both processes in parallel. Here we report a flow cytometry-based assay capable of rapid parallel measurements of mitophagy and autophagy in mammalian cells using a single fluorescent protein biosensor. We demonstrate the ability of the assay to quantify Parkin-dependent selective mitophagy in CCCP-treated HeLa cells. In addition, we show the utility of the assay for measuring mitophagy in other cell lines, as well as for Parkin-independent mitophagy stimulated by deferiprone. The assay makes rapid measurements (10,000 cells per 6 seconds) and can be combined with other fluorescent indicators to monitor distinct cell populations, enabling design of high-throughput screening experiments to identify novel regulators of mitophagy in mammalian cells. PMID:26215030

  1. Uranium resources and their implications for fission breeder and fusion hybrid development

    SciTech Connect

    Max, C.E.

    1984-05-15

    Present estimates of uranium resources and reserves in the US and the non-Communist world are reviewed. The resulting implications are considered for two proposed breeder technologies: the liquid metal fast breeder reactor (LMFBR) and the fusion hybrid reactor. Using both simple arguments and detailed scenarios from the published literature, conditions are explored under which the LMFBR and fusion hybrid could respectively have the most impact, considering both fuel-supply and economic factors. The conclusions emphasize strong potential advantages of the fusion hybrid, due to its inherently large breeding rate. A discussion is presented of proposed US development strategies for the fusion hybrid, which at present is far behind the LMFBR in its practical application and maturity.

  2. The immune system in the normal endometrium and implications for endometrial cancer development.

    PubMed

    Vanderstraeten, A; Tuyaerts, S; Amant, F

    2015-06-01

    Although described for the first time some decades ago, the contribution of the immune system to the establishment of tumors has not been extensively pursued for a long time. Over the last decade, however, more and more evidence has been accumulating concerning the role the immune system plays in tumor development and progression and its possible role in patient prognosis. In addition, interest is growing in preclinical and clinical research concerning the use of the immune system in the treatment of cancer. Immunotherapy for gynecological cancers in general, and for endometrial cancer in particular, is still in its infancy. Only a small number of studies, with varying success rates, have been published. Here, we provide a concise overview of the literature available on the role of the immune system in the normal endometrium and in endometrial cancer, in addition to the possible implications for future immunotherapeutic studies.

  3. Experience as Knowledge in a New Product Development Team: Implications for Knowledge Management

    NASA Technical Reports Server (NTRS)

    Cooper, Lynne P.

    2009-01-01

    This study was conducted to better understand how New Product Development (NPD) team members apply their experiences to meet the task needs of their project. Although "experience" is highly valued in team members, little research has looked specifically at experiences as a type of knowledge, and how this knowledge is used in work settings. This research evaluated nearly 200 instances where team members referenced past experiences during team meetings. During these experience exchanges, team members structured the sharing of their experiences to include three common elements: the source of the experience, the nature of the experience, and the degree of relevance to the current work of the team. The experiences fell into four categories: people (relationships), process, product, and politics. This paper describes how team members structured, applied, and integrated their individual experiences and presents the resulting implications for knowledge management systems that wish to exploit experience knowledge.

  4. Political and legal implications of developing and operating a satellite power system

    NASA Technical Reports Server (NTRS)

    Hazelrigg, G. A., Jr.

    1977-01-01

    A number of political and legal implications of developing and operating a satellite power system (SPS) are identified and studied in this report. These include the vulnerability of SPS to actions of adversaries, communications impacts, the legality of an SPS in orbit including on-orbit military protection, alleviation of political concerns about deployment and operation of SPS, programmatic planning for SPS and the interaction of SPS with federal regulatory agencies and major departments. In comparing SPS to terrestrial power stations, it is seen that the political problems are neither clearly larger nor clearly smaller--they are clearly different and they are international in nature. If SPS is to become a reality these problems must be dealt with. Five major issues are identified. These must be resolved in order to obtain international acceptance of SPS. However, this study has found no insurmountable obstacles that would clearly prohibit the deployment, operation and protection of an SPS fleet.

  5. LIS1 and DCX: Implications for Brain Development and Human Disease in Relation to Microtubules

    PubMed Central

    2013-01-01

    Proper lamination of the cerebral cortex requires the orchestrated motility of neurons from their place of birth to their final destination. Improper neuronal migration may result in a wide range of diseases, including brain malformations, such as lissencephaly, mental retardation, schizophrenia, and autism. Ours and other studies have implicated that microtubules and microtubule-associated proteins play an important role in the regulation of neuronal polarization and neuronal migration. Here, we will review normal processes of brain development and neuronal migration, describe neuronal migration diseases, and will focus on the microtubule-associated functions of LIS1 and DCX, which participate in the regulation of neuronal migration and are involved in the human developmental brain disease, lissencephaly. PMID:24278775

  6. Current Developments in Public Relations and a Review of their Implications on Public Relations Curriculum in Canada.

    ERIC Educational Resources Information Center

    Wills, Sandra Judith Abiola

    Intended to review the recent professional developments in public relations as they are documented in the literature and to explore the implications of these developments for public relations education in Canada at the university level, this thesis is in six chapters, as follows: (1) Introduction; (2) Defining Public Relations; (3) Current Public…

  7. Sustainable development, demography and sexual and reproductive health: inseparable linkages and their policy implications.

    PubMed

    Herrmann, Michael

    2014-05-01

    The greatest challenge today is to meet the needs of current and future generations, of a large and growing world population, without imposing catastrophic pressures on the natural environment. Meeting this challenge depends on decisive policy changes in three areas: more inclusive economic growth, greener economic growth, and population policies. This article focuses on efforts to address and harness demographic changes for sustainable development, which are largely outside the purview of the current debate. Efforts to this end must be based on the recognition that demographic changes are the cumulative result of individual choices and opportunities, and that demographic changes are best addressed through policies that enlarge these choices and opportunities, with a focus on ensuring unrestricted and universal access to sexual and reproductive health information and services, empowering women to fully participate in social, economic and political life, and investing in the education of the younger generation beyond the primary level. The article provides a strong argument for why the Programme of Action that was agreed at the International Conference on Population and Development (ICPD) 20 years ago continues to hold important implications and lessons for the formulation of the post-2015 development agenda, which is expected to supersede the Millennium Development Goals (MDGs). PMID:24908454

  8. Coping with a diagnosis of breast cancer-literature review and implications for developing countries.

    PubMed

    Al-Azri, Mohammed; Al-Awisi, Huda; Al-Moundhri, Mansour

    2009-01-01

    Breast cancer is the most common cancer affecting women worldwide. Women are at an increased risk of developing both physical and psychological morbidity after diagnosis; however, many use different strategies to cope with the disease. The aim of this article is to review the available literature on the impact of breast cancer diagnoses and the strategies used by women to cope with this disease. The implications of these emerging findings are extrapolated within the context of health services provided in developing countries. Electronic databases were used to search the relevant literature. The findings showed that women who were diagnosed with breast cancer are at risk of developing several psychological morbidities such as depression, anxiety, fatigue, negative thoughts, suicidal thoughts, fear of dying, sense of aloneness, sexual and body images problems, as well as an overall decrease in the quality of life. Several strategies are used by women with breast cancer to cope with the disease, including positive cognitive restructuring, wishful thinking, emotional expression, disease acceptance, increased religious practice, family and social support, and yoga and exercise. Breast cancer diagnoses have been associated with several devastating psychological consequences; however, many women have used different coping strategies to adjust their lives accordingly. Healthcare professionals in developing countries, who work with women with breast cancer, should be aware of the different coping mechanisms that women use when diagnosed with cancer. Integrating a coping strategy into the treatment regimen would constitute an important milestone in the palliative care of patients with breast cancer. PMID:19686231

  9. Oxidative Stress: Implications for the Development of Diabetic Retinopathy and Antioxidant Therapeutic Perspectives

    PubMed Central

    Tang, Luosheng; Chen, Baihua

    2014-01-01

    In recent decades, localized tissue oxidative stress has been implicated as a key component in the development of diabetic retinopathy (DR). Increasing evidence shows that oxidative stress caused by diabetes-induced metabolic abnormalities is the most common mechanism associated with the pathogenesis of DR for both type 1 and type 2 diabetes. Increase in intracellular reactive oxygen species (ROS) concentrations results in the activation of several mechanisms involved in the pathogenesis of DR. In particular, damage or dysfunction caused by oxidative stress still persists even after glycemia has been normalized. Despite considerable evidence showing the beneficial effects of antioxidants in preventing the development of retinopathy, results from large-scale clinical trials on classic antioxidants are somewhat ambiguous. Scavenging reactive radicals may not be the most ideal antioxidant strategy in DR. Advances in understanding the function of ROS in the development of DR can lead to the development of new therapeutic strategies based on the mechanisms of ROS generation and scavenging. Increasing amounts of data have demonstrated the promising prospect of antioxidant therapy and its beneficial effects in vision protection. Therefore, new strategies that utilize antioxidants as additive therapy should be implemented in the treatment of DR. PMID:25180070

  10. White matter development in adolescence: the influence of puberty and implications for affective disorders.

    PubMed

    Ladouceur, Cecile D; Peper, Jiska S; Crone, Eveline A; Dahl, Ronald E

    2012-01-01

    There have been rapid advances in understanding a broad range of changes in brain structure and function during adolescence, and a growing interest in identifying which of these neurodevelopmental changes are directly linked with pubertal maturation—at least in part because of their potential to provide insights into the numerous emotional and behavioral health problems that emerge during this developmental period. This review focuses on what is known about the influence of puberty on white matter development in adolescence.We focus on white matter because of its role in providing the structural architectural organization of the brain and as a structural correlate of communication within complex neural systems. We begin with a review of studies that report sex differences or sex by age interactions in white matter development as these findings can provide, although indirectly,information relevant to puberty-related changes. Studies are also critically reviewed based on methodological procedures used to assess pubertal maturation and relations with white matter changes. Findings are discussed in light of their implications for the development of neural systems underlying the regulation of emotion and behavior and how alterations in the development of these systems may mediate risk for affective disorders in vulnerable adolescents.

  11. White Matter Development in Adolescence: The Influence of Puberty and Implications for Affective Disorders

    PubMed Central

    Ladouceur, Cecile D.; Peper, Jiska S.; Crone, Eveline A.; Dahl, Ronald E.

    2011-01-01

    There have been rapid advances in understanding a broad range of changes in brain structure and function during adolescence, and a growing interest in identifying which of these neurodevelopmental changes are directly linked with pubertal maturation—at least in part because of their potential to provide insights into the numerous emotional and behavioral health problems that emerge during this developmental period. This review focuses on what is known about the influence of puberty on white matter development in adolescence. We focus on white matter because of its role in providing the structural architectural organization of the brain and as a structural correlate of communication within complex neural systems. We begin with a review of studies that report sex differences or sex by age interactions in white matter development as these findings can provide, although indirectly, information relevant to puberty-related changes. Studies are also critically reviewed based on methodological procedures used to assess pubertal maturation and relations with white matter changes. Findings are discussed in light of their implications for the development of neural systems underlying the regulation of emotion and behavior and how alterations in the development of these systems may mediate risk for affective disorders in vulnerable adolescents. PMID:22247751

  12. Oxidative stress: implications for the development of diabetic retinopathy and antioxidant therapeutic perspectives.

    PubMed

    Wu, Ying; Tang, Luosheng; Chen, Baihua

    2014-01-01

    In recent decades, localized tissue oxidative stress has been implicated as a key component in the development of diabetic retinopathy (DR). Increasing evidence shows that oxidative stress caused by diabetes-induced metabolic abnormalities is the most common mechanism associated with the pathogenesis of DR for both type 1 and type 2 diabetes. Increase in intracellular reactive oxygen species (ROS) concentrations results in the activation of several mechanisms involved in the pathogenesis of DR. In particular, damage or dysfunction caused by oxidative stress still persists even after glycemia has been normalized. Despite considerable evidence showing the beneficial effects of antioxidants in preventing the development of retinopathy, results from large-scale clinical trials on classic antioxidants are somewhat ambiguous. Scavenging reactive radicals may not be the most ideal antioxidant strategy in DR. Advances in understanding the function of ROS in the development of DR can lead to the development of new therapeutic strategies based on the mechanisms of ROS generation and scavenging. Increasing amounts of data have demonstrated the promising prospect of antioxidant therapy and its beneficial effects in vision protection. Therefore, new strategies that utilize antioxidants as additive therapy should be implemented in the treatment of DR. PMID:25180070

  13. Sustainable development, demography and sexual and reproductive health: inseparable linkages and their policy implications.

    PubMed

    Herrmann, Michael

    2014-05-01

    The greatest challenge today is to meet the needs of current and future generations, of a large and growing world population, without imposing catastrophic pressures on the natural environment. Meeting this challenge depends on decisive policy changes in three areas: more inclusive economic growth, greener economic growth, and population policies. This article focuses on efforts to address and harness demographic changes for sustainable development, which are largely outside the purview of the current debate. Efforts to this end must be based on the recognition that demographic changes are the cumulative result of individual choices and opportunities, and that demographic changes are best addressed through policies that enlarge these choices and opportunities, with a focus on ensuring unrestricted and universal access to sexual and reproductive health information and services, empowering women to fully participate in social, economic and political life, and investing in the education of the younger generation beyond the primary level. The article provides a strong argument for why the Programme of Action that was agreed at the International Conference on Population and Development (ICPD) 20 years ago continues to hold important implications and lessons for the formulation of the post-2015 development agenda, which is expected to supersede the Millennium Development Goals (MDGs).

  14. Putrescine catabolism in mammalian brain

    PubMed Central

    Seiler, N.; Al-Therib, M. J.

    1974-01-01

    In contrast with putrescine (1,4-diaminobutane), which is a substrate of diamine oxidase, monoacetylputrescine is oxidatively deaminated both in vitro and in vivo by monoamine oxidase. The product of this reaction is N-acetyl-γ-aminobutyrate. The existence of a degradative pathway in mammalian brain for putrescine is shown, which comprises acetylation of putrescine, oxidative deamination of monoacetylputrescine to N-acetyl-γ-aminobutyrate, transformation of N-acetyl-γ-aminobutyrate to γ-aminobutyrate and degradation of γ-aminobutyrate to CO2 via the tricarboxylic acid cycle. PMID:4156831

  15. Systems approaches for synthetic biology: a pathway toward mammalian design

    PubMed Central

    Rekhi, Rahul; Qutub, Amina A.

    2013-01-01

    We review methods of understanding cellular interactions through computation in order to guide the synthetic design of mammalian cells for translational applications, such as regenerative medicine and cancer therapies. In doing so, we argue that the challenges of engineering mammalian cells provide a prime opportunity to leverage advances in computational systems biology. We support this claim systematically, by addressing each of the principal challenges to existing synthetic bioengineering approaches—stochasticity, complexity, and scale—with specific methods and paradigms in systems biology. Moreover, we characterize a key set of diverse computational techniques, including agent-based modeling, Bayesian network analysis, graph theory, and Gillespie simulations, with specific utility toward synthetic biology. Lastly, we examine the mammalian applications of synthetic biology for medicine and health, and how computational systems biology can aid in the continued development of these applications. PMID:24130532

  16. [Application of capillary electrophoresis in analysis of intact mammalian cells].

    PubMed

    Zhang, Lu; Qu, Feng; Lou, Beilei

    2012-02-01

    Cell is the basic structural and functional unit of human body. The research of cells' structure, function and behavior is very important. Capillary electrophoresis (CE) is a powerful tool for the separation and analysis, the application of which in cell analysis has progressed significantly. In this paper, the developments of CE applied in the intact mammalian cell analysis are reviewed, which consist of cell population and single cell analysis. The erythrocyte, boar sperm, HeLa cells, SH-SY5Y cells, Caco-2 cells, K562 cells and rat cerebellar granule cells are involved in this review. The methods and conditions for the intact mammalian cell analysis are summarized. In addition, the problems caused by the breakage, aggregation, sedimentation, adsorption and electrophoretic heterogeneity of the cell in the intact mammalian cell analysis by CE are discussed, and the corresponding solutions are introduced. Also, the future research trends are presented. Forty nine papers in all are reviewed.

  17. Role of ortho-retronasal olfaction in mammalian cortical evolution.

    PubMed

    Rowe, Timothy B; Shepherd, Gordon M

    2016-02-15

    Fossils of mammals and their extinct relatives among cynodonts give evidence of correlated transformations affecting olfaction as well as mastication, head movement, and ventilation, and suggest evolutionary coupling of these seemingly separate anatomical regions into a larger integrated system of ortho-retronasal olfaction. Evidence from paleontology and physiology suggests that ortho-retronasal olfaction played a critical role at three stages of mammalian cortical evolution: early mammalian brain development was driven in part by ortho-retronasal olfaction; the bauplan for neocortex had higher-level association functions derived from olfactory cortex; and human cortical evolution was enhanced by ortho-retronasal smell.

  18. Mitochondrial dynamics in mammalian health and disease.

    PubMed

    Liesa, Marc; Palacín, Manuel; Zorzano, Antonio

    2009-07-01

    The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes (MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.

  19. The National Health Service Knowledge and Skills Framework and its implications for continuing professional development in nursing.

    PubMed

    Gould, Dinah; Berridge, Emma-Jane; Kelly, Daniel

    2007-01-01

    The National Health Service Knowledge and Skills Framework has been introduced as part of the Agenda for Change Reforms in the United Kingdom to link pay and career progression to competency. The purpose of this paper is to consider the implications for nurses, their managers and the impact on university departments delivering continuing professional development for nurses. The new system has the potential to increase the human resources management aspect of the clinical nurse managers' role and could have legal implications, for example if practitioners perceive that their needs for continuing professional development have been overlooked to the detriment of their pay and career aspirations. The new system also has implications for providers of continuing professional development in the universities and is likely to demand closer liaison between education providers and trust staff who commission education and training. The Knowledge and Skills Framework is of interest to nurses and nurse educators internationally because the system, if effective, could be introduced elsewhere.

  20. Regulation of Rap GTPases in mammalian neurons.

    PubMed

    Shah, Bhavin; Püschel, Andreas W

    2016-10-01

    Small GTPases are central regulators of many cellular processes. The highly conserved Rap GTPases perform essential functions in the mammalian nervous system during development and in mature neurons. During neocortical development, Rap1 is required to regulate cadherin- and integrin-mediated adhesion. In the adult nervous system Rap1 and Rap2 regulate the maturation and plasticity of dendritic spine and synapses. Although genetic studies have revealed important roles of Rap GTPases in neurons, their regulation by guanine nucleotide exchange factors (GEFs) that activate them and GTPase activating proteins (GAPs) that inactivate them by stimulating their intrinsic GTPase activity is just beginning to be explored in vivo. Here we review how GEFs and GAPs regulate Rap GTPases in the nervous system with a focus on their in vivo function.

  1. Regulation of Rap GTPases in mammalian neurons.

    PubMed

    Shah, Bhavin; Püschel, Andreas W

    2016-10-01

    Small GTPases are central regulators of many cellular processes. The highly conserved Rap GTPases perform essential functions in the mammalian nervous system during development and in mature neurons. During neocortical development, Rap1 is required to regulate cadherin- and integrin-mediated adhesion. In the adult nervous system Rap1 and Rap2 regulate the maturation and plasticity of dendritic spine and synapses. Although genetic studies have revealed important roles of Rap GTPases in neurons, their regulation by guanine nucleotide exchange factors (GEFs) that activate them and GTPase activating proteins (GAPs) that inactivate them by stimulating their intrinsic GTPase activity is just beginning to be explored in vivo. Here we review how GEFs and GAPs regulate Rap GTPases in the nervous system with a focus on their in vivo function. PMID:27186679

  2. Mammalian cloning: possibilities and threats.

    PubMed

    Mitalipov, S M; Wolf, D P

    2000-10-01

    The cloning of mammals originated with the production of limited numbers of genetically identical offspring by blastomere separation or embryo splitting. In the past few years, remarkable progress has been reported in cloning by nuclear transfer (NT) with donor nuclei recovered from embryonic, fetal or adult cells. Factors that contribute to the successful reprogramming of the transferred nucleus and the normal term development of the newly reconstructed embryo include the cell cycle stage of both the donor nucleus and recipient cytoplast, the timing of fusion and cytoplast activation, and the source of donor nuclei. The possibility of producing live offspring by somatic cell NT carries potential applications in animal husbandry, biotechnology, transgenic and pharmaceutical production, biomedical research, and the preservation of endangered species. However, the low efficiencies of cloning by NT coupled with high embryonic, fetal and neonatal losses may restrict immediate commercial applications in agriculture. These limitations notwithstanding, the greatest benefits and practical implications of this new technology could be in transplantation medicine and therapeutic cloning.

  3. A history of mammalian embryological research.

    PubMed

    Alexandre, H

    2001-01-01

    Although Reinier DE GRAAF (1641-1673) can be considered the founder of modern reproductive biology, scientific knowledge of mammalian development did not progress significantly until the XlXth century. Determining contributions to this progress were the discovery of the ovum by Karl von BAER (1792-1876), his meticulous observations of the stages of embryogenesis, and, half a century later, the remarkable descriptions made by Edouard VAN BENEDEN (1845-1910) of egg development in rabbits and bats. Yet mammalian embryology remained a purely descriptive discipline until the second half of the XXth century, when a handful of exceptional scientists (notably including John D. BIGGERS, Ralph BRINSTER, Anne McLAREN, and W. WHITTEN) managed to obtain reproducibly the development of mouse eggs in a chemically defined medium and to transfer the eggs to the uterine horns of pseudopregnant females. Around the same time (1959), M.C. CHANG was the first to obtain a mammal (a rabbit) by in vitro fertilisation, thus opening the way to assisted procreation. This was achieved in our species in 1978, by Robert EDWARDS and Patrick STEPTOE. With these feats, mammalian embryology could at last become causal, as A. BRACHET already in 1912 had hoped it would. New concepts soon emerged from the delicate manipulations performed on mouse eggs by scientists such as A. TARKOWSKI, B. MINTZ, J. MULNARD, and R. GARDNER, concepts such as the oustside-inside hypothesis proposed to explain the determination of the ICM and trophectoderm or the clonal theory of cell determination during development. These new ideas were soon to become the focus of intense study. Other investigators, interested in the synthesis and roles of macromolecules, contributed in the late 1960's most of our knowledge on global trends in gene expression during the first stages of development. As for the many unfruitful attempts to obtain artificial parthenogenetic development in mice, these would lead to the discovery of parental

  4. Fate and Metabolism of PBDEs in Mammalian Systems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polybrominated diphenyl ethers (PBDEs) belong to an emerging class of persistent organic pollutants (POPs). Although the toxicology of PBDEs is not well developed, they are persistent and bioaccumulative, and therefore, of growing environmental concern. The metabolism of PBDEs in mammalian systems h...

  5. Modeling stress and drug craving in the laboratory: implications for addiction treatment development

    PubMed Central

    Sinha, Rajita

    2009-01-01

    Addition is a chronic relapsing illness affected by multiple social, individual and biological factors that significantly impact course and recovery of the illness. Stress interacts with these factors and increases addiction vulnerability and relapse risk, thereby playing a significant role in the course of the illness. This paper reviews our efforts in developing and validating laboratory models of stress and drug cue-related provocation to assess stress responses and stress-related adaptation in addicted individuals compared with healthy controls. Empirical findings from human laboratory and brain imaging studies are presented to show the specific stress-related dysregulation that accompanies the drug-craving state in addicted individuals. In order to adequately validate our laboratory model, we have also carefully examined relapse susceptibility in the addicted individuals and these data are reviewed. The overarching goal of these efforts is to develop a valid laboratory model to identify the stress-related pathophysiology in addiction with specific regard to persistent craving and compulsive seeking. Finally, the significant implications of these findings for the development of novel treatment interventions that target stress processes and drug craving to improve addiction relapse outcomes are discussed. PMID:18945295

  6. Demoralization in health professional practice: development, amelioration, and implications for continuing education.

    PubMed

    Gabel, Stewart

    2013-01-01

    Demoralization is a feeling state of dejection, hopelessness, and a sense of personal "incompetence" that may be tied to a loss of or threat to one's own goals or values. It has an existential dimension when beliefs and values about oneself are disconfirmed. Numerous sources describe high rates of dissatisfaction and burnout in physicians and other health professionals. This article reviews historical and empirical findings that describe the professional and personal value orientations of physicians and other health professionals. It reviews empirical and theoretical findings to consider the implications of conflict between these values and negatively perceived ethical and values orientations of health care organizations and commercial health care entities. Conflicts between personal and professional values of health professionals and larger health care related organizations and commercial entities with which they are associated may contribute to the development of demoralization and burnout. Physicians and other health professionals frequently experience values related conflicts with larger social, organizational or bureaucratic systems. These conflicts place health professionals at risk for demoralization and burnout. "Remoralization," or renewal of morale, depends on the reestablishment of the potential for fulfillment of one's values in the work environment. This depends on organizational, group, and personal efforts. Continuing education and continuing professional development programs should have a programmatic focus on the importance of a values orientation in health care and support program development aimed at recognizing, addressing, and reducing demoralization and its potential for negative health care consequences for health professionals and patients. PMID:23775912

  7. Clamping down on mammalian meiosis

    PubMed Central

    Lyndaker, Amy M; Vasileva, Ana; Wolgemuth, Debra J; Weiss, Robert S; Lieberman, Howard B

    2013-01-01

    The RAD9A-RAD1-HUS1 (9-1-1) complex is a PCNA-like heterotrimeric clamp that binds damaged DNA to promote cell cycle checkpoint signaling and DNA repair. While various 9-1-1 functions in mammalian somatic cells have been established, mounting evidence from lower eukaryotes predicts critical roles in meiotic germ cells as well. This was investigated in 2 recent studies in which the 9-1-1 complex was disrupted specifically in the mouse male germline through conditional deletion of Rad9a or Hus1. Loss of these clamp subunits led to severely impaired fertility and meiotic defects, including faulty DNA double-strand break repair. While 9-1-1 is critical for ATR kinase activation in somatic cells, these studies did not reveal major defects in ATR checkpoint pathway signaling in meiotic cells. Intriguingly, this new work identified separable roles for 9-1-1 subunits, namely RAD9A- and HUS1-independent roles for RAD1. Based on these studies and the high-level expression of the paralogous proteins RAD9B and HUS1B in testis, we propose a model in which multiple alternative 9-1-1 clamps function during mammalian meiosis to ensure genome maintenance in the germline. PMID:24013428

  8. Loss of Panx1 Impairs Mammary Gland Development at Lactation: Implications for Breast Tumorigenesis

    PubMed Central

    Stewart, Michael K. G.; Plante, Isabelle; Penuela, Silvia; Laird, Dale W.

    2016-01-01

    Pannexin1 (Panx1) subunits oligomerize to form large-pore channels between the intracellular and extracellular milieu that have been shown to regulate proliferation, differentiation and cell death mechanisms. These key cellular responses are ultimately necessary for normal tissue development and function but the role of Panx1 in development, differentiation and function in many tissues remains unexplored, including that of the breast. Panx1 was identified to be expressed in the mammary gland through western blot and immunofluorescent analysis and is dynamically upregulated during pregnancy and lactation. In order to evaluate the role of Panx1 in the context of mammary gland development and function, Panx1-/- mice were evaluated in comparison to wild-type mice in the mammary glands of virgin, lactating and involuting mice. Our results revealed that Panx1 ablation did not affect virgin or involuting mammary glands following histological and whole mount analysis. Panx1 was necessary for timely alveolar development during early lactation based on a decreased number of alveolar lumen following histological analysis and reduced proliferation following Ki67 immunofluorescent labelling. Importantly, the loss of Panx1 in lactating mammary glands did not overtly affect epithelial or secretory differentiation of the mammary gland suggesting that Panx1 is not critical in normal mammary gland function. In addition, PANX1 mRNA expression was correlated with negative clinical outcomes in patients with breast cancer using in silico arrays. Together, our results suggest that Panx1 is necessary for timely alveolar development following the transition from pregnancy to lactation, which may have implications extending to patients with breast cancer. PMID:27099931

  9. Loss of Panx1 Impairs Mammary Gland Development at Lactation: Implications for Breast Tumorigenesis.

    PubMed

    Stewart, Michael K G; Plante, Isabelle; Penuela, Silvia; Laird, Dale W

    2016-01-01

    Pannexin1 (Panx1) subunits oligomerize to form large-pore channels between the intracellular and extracellular milieu that have been shown to regulate proliferation, differentiation and cell death mechanisms. These key cellular responses are ultimately necessary for normal tissue development and function but the role of Panx1 in development, differentiation and function in many tissues remains unexplored, including that of the breast. Panx1 was identified to be expressed in the mammary gland through western blot and immunofluorescent analysis and is dynamically upregulated during pregnancy and lactation. In order to evaluate the role of Panx1 in the context of mammary gland development and function, Panx1-/- mice were evaluated in comparison to wild-type mice in the mammary glands of virgin, lactating and involuting mice. Our results revealed that Panx1 ablation did not affect virgin or involuting mammary glands following histological and whole mount analysis. Panx1 was necessary for timely alveolar development during early lactation based on a decreased number of alveolar lumen following histological analysis and reduced proliferation following Ki67 immunofluorescent labelling. Importantly, the loss of Panx1 in lactating mammary glands did not overtly affect epithelial or secretory differentiation of the mammary gland suggesting that Panx1 is not critical in normal mammary gland function. In addition, PANX1 mRNA expression was correlated with negative clinical outcomes in patients with breast cancer using in silico arrays. Together, our results suggest that Panx1 is necessary for timely alveolar development following the transition from pregnancy to lactation, which may have implications extending to patients with breast cancer. PMID:27099931

  10. Hypothesis on the Dual Origin of the Mammalian Subplate

    PubMed Central

    Montiel, Juan F.; Wang, Wei Zhi; Oeschger, Franziska M.; Hoerder-Suabedissen, Anna; Tung, Wan Ling; García-Moreno, Fernando; Holm, Ida Elizabeth; Villalón, Aldo; Molnár, Zoltán

    2011-01-01

    The development of the mammalian neocortex relies heavily on subplate. The proportion of this cell population varies considerably in different mammalian species. Subplate is almost undetectable in marsupials, forms a thin, but distinct layer in mouse and rat, a larger layer in carnivores and big-brained mammals as pig, and a highly developed embryonic structure in human and non-human primates. The evolutionary origin of subplate neurons is the subject of current debate. Some hypothesize that subplate represents the ancestral cortex of sauropsids, while others consider it to be an increasingly complex phylogenetic novelty of the mammalian neocortex. Here we review recent work on expression of several genes that were originally identified in rodent as highly and differentially expressed in subplate. We relate these observations to cellular morphology, birthdating, and hodology in the dorsal cortex/dorsal pallium of several amniote species. Based on this reviewed evidence we argue for a third hypothesis according to which subplate contains both ancestral and newly derived cell populations. We propose that the mammalian subplate originally derived from a phylogenetically ancient structure in the dorsal pallium of stem amniotes, but subsequently expanded with additional cell populations in the synapsid lineage to support an increasingly complex cortical plate development. Further understanding of the detailed molecular taxonomy, somatodendritic morphology, and connectivity of subplate in a comparative context should contribute to the identification of the ancestral and newly evolved populations of subplate neurons. PMID:21519390

  11. Meis1 coordinates a network of genes implicated in eye development and microphthalmia.

    PubMed

    Marcos, Séverine; González-Lázaro, Monica; Beccari, Leonardo; Carramolino, Laura; Martin-Bermejo, Maria Jesus; Amarie, Oana; Mateos-San Martín, Daniel; Torroja, Carlos; Bogdanović, Ozren; Doohan, Roisin; Puk, Oliver; Hrabě de Angelis, Martin; Graw, Jochen; Gomez-Skarmeta, Jose Luis; Casares, Fernando; Torres, Miguel; Bovolenta, Paola

    2015-09-01

    Microphthalmos is a rare congenital anomaly characterized by reduced eye size and visual deficits of variable degree. Sporadic and hereditary microphthalmos have been associated with heterozygous mutations in genes fundamental for eye development. Yet, many cases are idiopathic or await the identification of molecular causes. Here we show that haploinsufficiency of Meis1, which encodes a transcription factor with evolutionarily conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment in adult mice. By combining analysis of Meis1 loss-of-function and conditional Meis1 functional rescue with ChIP-seq and RNA-seq approaches we show that, in contrast to its preferential association with Hox-Pbx BSs in the trunk, Meis1 binds to Hox/Pbx-independent sites during optic cup development. In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway. In addition, Meis1 is required for eye patterning by controlling a set of eye territory-specific transcription factors, so that in Meis1(-/-) embryos boundaries among the different eye territories are shifted or blurred. We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations.

  12. Nature of Technology: Implications for design, development, and enactment of technological tools in school science classrooms

    NASA Astrophysics Data System (ADS)

    Waight, Noemi; Abd-El-Khalick, Fouad

    2012-12-01

    This position paper provides a theory-based explanation informed by philosophy of technology (PoT) of the recurrent documented patterns often associated with attempts to enact technology-supported, inquiry-based approaches in precollege science classrooms. Understandings derived from the history of technological development in other domains (e.g. medicine, transportation, and warfare) reveal numerous parallels that help to explain these recurrent patterns. Historical analyses of major technologies reveal a conglomerate of factors that interact to produce benefits, as well as intended and unintended consequences. On a macro-scale, PoT facilitates understandings of how technologies interact and are impacted by individuals, society, institutions, economy, politics, and culture. At the micro-level, and most relevant to science education, PoT engages the inherent nature of technology along a number of key dimensions: role of culture and values, notions of technological progression, technology as part of systems, technological diffusion, technology as a fix, and the notions of expertise. Overall, the present analysis has implications for the design, development, implementation, and adoption of technological tools for use in precollege science education, and highlights the role of technology as both artifact and process.

  13. Perspectives on the rhythm–grammar link and its implications for typical and atypical language development

    PubMed Central

    Gordon, Reyna L.; Jacobs, Magdalene S.; Schuele, C. Melanie; McAuley, J. Devin

    2014-01-01

    This paper reviews the mounting evidence for shared cognitive mechanisms and neural resources for rhythm and grammar. Evidence for a role of rhythm skills in language development and language comprehension is reviewed here in three lines of research: (a) behavioral and brain data from adults and children, showing that prosody and other aspects of timing of sentences influence online morpho-syntactic processing; (b) co-morbidity of impaired rhythm with grammatical deficits in children with language impairment; and (c) our recent work showing a strong positive association between rhythm perception skills and expressive grammatical skills in young school-age children with typical development. Our preliminary follow-up study presented here revealed that musical rhythm perception predicted variance in six-year-old children’s production of complex syntax, as well as online reorganization of grammatical information (transformation); these data provide an additional perspective on the hierarchical relations potentially shared by rhythm and grammar. A theoretical framework for shared cognitive resources for the role of rhythm in perceiving and learning grammatical structure is elaborated on in light of potential implications for using rhythm-emphasized musical training to improve language skills in children. PMID:25773612

  14. Emerging diseases and implications for Millennium Development Goals in Africa by 2015 - an overview.

    PubMed

    Aluwong, Tagang; Bello, Mohammed

    2010-01-01

    Emerging zoonotic diseases have assumed increasing fundamental importance in both public and animal health, as the last few years have seen a steady increase of new cases, each emerging from an unsuspected geographic area and causing serious problems, often leading to mortalities among animals and humans. The reasons for disease emergence or re-emergence are multiple and include certain major factors, such as expansion of the human population, climate change and globalisation of trade. Further contributing issues, such as the increased movement of animal species, microbial evolution, ecological disruption, changes in human behaviour, all imply that emerging diseases will not only continue to occur, but the rate of their emergence will also increase. These will constitute constraints for the attainment of the Millennium Development Goals by African Governments by 2015. There is no doubt that the current trend calls for more and stronger partnerships between national and international organisations, veterinary and medical communities, environmentalists, academics and policy-makers of various governments on the continent within the context of the global 'One Health' movement. This article attempts to analyse the impact of emerging diseases and the implications for the achievement of the Millennium Development Goals in Africa by the year 2015. PMID:20560123

  15. Neurobiology of Empathy and Callousness: Implications for the Development of Antisocial Behavior

    PubMed Central

    Shirtcliff, Elizabeth A.; Vitacco, Michael J.; Graf, Alexander R.; Gostisha, Andrew J.; Merz, Jenna L.; Zahn-Waxler, Carolyn

    2009-01-01

    Information on the neurobiology of empathy and callousness provides clinicians an opportunity to develop sophisticated understanding of mechanisms underpinning antisocial behavior and its counterpart, moral decision making. This paper provides an integrated in-depth review of hormones (e.g., peripheral steroid hormones like cortisol) and brain structures (e.g., insula, anterior cingulate cortex, and amygdala) implicated in empathy, callousness and psychopathic-like behavior. The overarching goal of this paper is to relate these hormones and brain structures to moral decision-making. This review will begin in the brain, but will then integrate information about biological functioning in the body, specifically stress-reactivity. Our aim is to integrate understanding of neural processes with hormones like cortisol, both of which have demonstrated relationships to empathy, psychopathy, and antisocial behavior. The review proposes neurobiological impairments in individuals who display little empathy are not necessarily due to a reduced ability to understand the emotions of others. Instead, evidence suggests individuals who show little arousal to the distress of others likewise show decreased physiological arousal to their own distress; one manifestation of reduced stress reactivity may be a dysfunction in empathy which supports psychopathic-like constructs (e.g., callousness). This integration will assist in the development of objective methodologies that can inform and monitor treatment interventions focused on decreasing antisocial behavior. PMID:19319834

  16. Perspectives on the rhythm-grammar link and its implications for typical and atypical language development.

    PubMed

    Gordon, Reyna L; Jacobs, Magdalene S; Schuele, C Melanie; McAuley, J Devin

    2015-03-01

    This paper reviews the mounting evidence for shared cognitive mechanisms and neural resources for rhythm and grammar. Evidence for a role of rhythm skills in language development and language comprehension is reviewed here in three lines of research: (1) behavioral and brain data from adults and children, showing that prosody and other aspects of timing of sentences influence online morpho-syntactic processing; (2) comorbidity of impaired rhythm with grammatical deficits in children with language impairment; and (3) our recent work showing a strong positive association between rhythm perception skills and expressive grammatical skills in young school-age children with typical development. Our preliminary follow-up study presented here revealed that musical rhythm perception predicted variance in 6-year-old children's production of complex syntax, as well as online reorganization of grammatical information (transformation); these data provide an additional perspective on the hierarchical relations potentially shared by rhythm and grammar. A theoretical framework for shared cognitive resources for the role of rhythm in perceiving and learning grammatical structure is elaborated on in light of potential implications for using rhythm-emphasized musical training to improve language skills in children.

  17. Emerging diseases and implications for Millennium Development Goals in Africa by 2015 - an overview.

    PubMed

    Aluwong, Tagang; Bello, Mohammed

    2010-01-01

    Emerging zoonotic diseases have assumed increasing fundamental importance in both public and animal health, as the last few years have seen a steady increase of new cases, each emerging from an unsuspected geographic area and causing serious problems, often leading to mortalities among animals and humans. The reasons for disease emergence or re-emergence are multiple and include certain major factors, such as expansion of the human population, climate change and globalisation of trade. Further contributing issues, such as the increased movement of animal species, microbial evolution, ecological disruption, changes in human behaviour, all imply that emerging diseases will not only continue to occur, but the rate of their emergence will also increase. These will constitute constraints for the attainment of the Millennium Development Goals by African Governments by 2015. There is no doubt that the current trend calls for more and stronger partnerships between national and international organisations, veterinary and medical communities, environmentalists, academics and policy-makers of various governments on the continent within the context of the global 'One Health' movement. This article attempts to analyse the impact of emerging diseases and the implications for the achievement of the Millennium Development Goals in Africa by the year 2015.

  18. Movement Pattern Variability in Stone Knapping: Implications for the Development of Percussive Traditions

    PubMed Central

    Rein, Robert; Nonaka, Tetsushi; Bril, Blandine

    2014-01-01

    The earliest direct evidence for tool-use by our ancestors are 2.6 million year old stone tools from Africa. These earliest artifacts show that, already, early hominins had developed the required advanced movement skills and cognitive capacities to manufacture stone tools. Currently, it is not well understood, however, which specific movement skills are required for successful stone knapping and accordingly it is unknown how these skills emerged during early hominin evolution. In particular, it is not clear which striking movements are indicative of skilled performance, how striking movement patterns vary with task and environmental constraints, and how movement patterns are passed on within social groups. The present study addresses these questions by investigating striking movement patterns and striking variability in 18 modern stone knappers (nine experienced and nine novices). The results suggest that no single movement pattern characterizes successful stone knapping. Participants showed large inter-individual movement variability of the elementary knapping action irrespective of knapping experience and knapping performance. Changes in task- and environmental constraints led knappers to adapt their elementary striking actions using a combination of individual and common strategies. Investigation of striking pattern similarities within social groups showed only partial overlap of striking patterns across related individuals. The results therefore suggest that striking movement patterns in modern stone knappers are largely specific to the individual and movement variability is not indicative of knapping performance. The implications of these results for the development of percussive traditions are discussed. PMID:25426630

  19. Crystal structure of mammalian acid sphingomyelinase

    PubMed Central

    Gorelik, Alexei; Illes, Katalin; Heinz, Leonhard X.; Superti-Furga, Giulio; Nagar, Bhushan

    2016-01-01

    Acid sphingomyelinase (ASMase, ASM, SMPD1) converts sphingomyelin into ceramide, modulating membrane properties and signal transduction. Inactivating mutations in ASMase cause Niemann–Pick disease, and its inhibition is also beneficial in models of depression and cancer. To gain a better understanding of this critical therapeutic target, we determined crystal structures of mammalian ASMase in various conformations. The catalytic domain adopts a calcineurin-like fold with two zinc ions and a hydrophobic track leading to the active site. Strikingly, the membrane interacting saposin domain assumes either a closed globular conformation independent from the catalytic domain, or an open conformation, which establishes an interface with the catalytic domain essential for activity. Structural mapping of Niemann–Pick mutations reveals that most of them likely destabilize the protein's fold. This study sheds light on the molecular mechanism of ASMase function, and provides a platform for the rational development of ASMase inhibitors and therapeutic use of recombinant ASMase. PMID:27435900

  20. Crystal structure of mammalian acid sphingomyelinase.

    PubMed

    Gorelik, Alexei; Illes, Katalin; Heinz, Leonhard X; Superti-Furga, Giulio; Nagar, Bhushan

    2016-01-01

    Acid sphingomyelinase (ASMase, ASM, SMPD1) converts sphingomyelin into ceramide, modulating membrane properties and signal transduction. Inactivating mutations in ASMase cause Niemann-Pick disease, and its inhibition is also beneficial in models of depression and cancer. To gain a better understanding of this critical therapeutic target, we determined crystal structures of mammalian ASMase in various conformations. The catalytic domain adopts a calcineurin-like fold with two zinc ions and a hydrophobic track leading to the active site. Strikingly, the membrane interacting saposin domain assumes either a closed globular conformation independent from the catalytic domain, or an open conformation, which establishes an interface with the catalytic domain essential for activity. Structural mapping of Niemann-Pick mutations reveals that most of them likely destabilize the protein's fold. This study sheds light on the molecular mechanism of ASMase function, and provides a platform for the rational development of ASMase inhibitors and therapeutic use of recombinant ASMase. PMID:27435900