174 research outputs found
Phase Structure of Dynamical Triangulation Models in Three Dimensions
The dynamical triangulation model of three-dimensional quantum gravity is
shown to have a line of transitions in an expanded phase diagram which includes
a coupling mu to the order of the vertices. Monte Carlo renormalization group
and finite size scaling techniques are used to locate and characterize this
line. Our results indicate that for mu < mu1 ~ -1.0 the model is always in a
crumpled phase independent of the value of the curvature coupling. For mu < 0
the results are in agreement with an approximate mean field treatment. We find
evidence that this line corresponds to first order transitions extending to
positive mu. However, the behavior appears to change for mu > mu2 ~ 2-4. The
simplest scenario that is consistent with the data is the existence of a
critical end point
The Extended Loop Group: An Infinite Dimensional Manifold Associated with the Loop Space
A set of coordinates in the non parametric loop-space is introduced. We show
that these coordinates transform under infinite dimensional linear
representations of the diffeomorphism group. An extension of the group of loops
in terms of these objects is proposed. The enlarged group behaves locally as an
infinite dimensional Lie group. Ordinary loops form a subgroup of this group.
The algebraic properties of this new mathematical structure are analized in
detail. Applications of the formalism to field theory, quantum gravity and knot
theory are considered.Comment: The resubmited paper contains the title and abstract, that were
omitted in the previous version. 42 pages, report IFFI/93.0
Classical Loop Actions of Gauge Theories
Since the first attempts to quantize Gauge Theories and Gravity in the loop
representation, the problem of the determination of the corresponding classical
actions has been raised. Here we propose a general procedure to determine these
actions and we explicitly apply it in the case of electromagnetism. Going to
the lattice we show that the electromagnetic action in terms of loops is
equivalent to the Wilson action, allowing to do Montecarlo calculations in a
gauge invariant way. In the continuum these actions need to be regularized and
they are the natural candidates to describe the theory in a ``confining
phase''.Comment: LaTeX 14 page
Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling
PURPOSE:
Head and neck squamous cell carcinoma (HNSCC) remains a devastating disease, and Fanconi anemia (FA) gene mutations and transcriptional repression are common. Invasive tumor behavior is associated with poor outcome, but relevant pathways triggering invasion are poorly understood. There is a significant need to improve our understanding of genetic pathways and molecular mechanisms driving advanced tumor phenotypes, to develop tailored therapies. Here we sought to investigate the phenotypic and molecular consequences of FA pathway loss in HNSCC cells.
EXPERIMENTAL DESIGN:
Using sporadic HNSCC cell lines with and without FA gene knockdown, we sought to characterize the phenotypic and molecular consequences of FA deficiency. FA pathway inactivation was confirmed by the detection of classic hallmarks of FA following exposure to DNA cross-linkers. Cells were subjected to RNA sequencing with qRT-PCR validation, followed by cellular adhesion and invasion assays in the presence and absence of DNA-dependent protein kinase (DNA-PK) and Rac1 inhibitors.
RESULTS:
We demonstrate that FA loss in HNSCC cells leads to cytoskeletal reorganization and invasive tumor cell behavior in the absence of proliferative gains. We further demonstrate that cellular invasion following FA loss is mediated, at least in part, through NHEJ-associated DNA-PK and downstream Rac1 GTPase activity.
CONCLUSIONS:
These findings demonstrate that FA loss stimulates HNSCC cell motility and invasion, and implicate a targetable DNA-PK/Rac1 signaling axis in advanced tumor phenotypes
Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders
Mutations in the ARID1B subunit of the BAF chromatin remodeling complex are associated with the neurodevelopmental Coffin-Siris syndrome. Here the authors reveal that there is a transition from ARID1A-containing complexes to ARID1B during cranial neural crest cell differentiation that is impaired in Coffin-Siris patient-derived cells, which is important for exit from pluripotency.Subunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we leveraged ARID1B(+/-) Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF). ARID1B-BAF regulates exit from pluripotency and lineage commitment by attenuating thousands of enhancers and genes of the NANOG and SOX2 networks. In iPSCs, these enhancers are maintained active by ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A- to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at the pluripotency enhancers throughout all stages of CNCC formation. This leads to persistent NANOG/SOX2 activity which impairs CNCC formation. Despite showing the typical neural crest signature (TFAP2A/SOX9-positive), ARID1B-haploinsufficient CNCCs are also aberrantly NANOG-positive. These findings suggest a connection between ARID1B mutations, neuroectoderm specification and a pathogenic mechanism for Coffin-Siris syndrome.Therapeutic cell differentiatio
Behaviour and Climate Change: Consumer Perceptions of Responsibility
This paper explores the under-researched notion of consumer responsibility, a potentially significant influence on consumer behaviour that marketers and policymakers may be able to harness as they attempt to respond to environmental challenges such as climate change. The paper uses data derived from a commercially motivated survey (n = 1513) to explore domestic consumption behaviours most closely associated with the issue of disruptive climate change. A measure of 'General Environmental Responsiveness' (GER) is used to test: (1) the effects of consumers both taking responsibility for their actions and placing responsibility on others for the consequences of their consumption behaviour; and (2) whether sociodemographic variables can aid the targeting of consumers by the level and type of responsibility and pro-environmental behavioural intentions expressed. The study's findings demonstrate clear, if not strong, relationships between consumer conceptions of responsibilities for causing and tackling climate change and environment-related consumer behaviour. The study's implications both challenge accepted wisdom about environment-related consumer behaviour and suggest avenues for future research
β1L=10L for Africaβ: Corporate social responsibility and the transformation of bottled water into a βconsumer activistβ commodity
In recent years, it has become an increasingly common marketing practice to connect the sale of consumer products to corporate social responsibility (CSR) initiatives, such as aid and development projects in so-called βdevelopingβ countries. One example is Volvicβs pioneering β1L=10L for Africaβ campaign (2005β2010), which linked the sale of each liter of bottled water in βdevelopedβ countries with the promise by Danone, Volvicβs owner, to provide 10 liters of drinking water in Africa. In this article, we engage with this βcause-related marketingβ campaign, using critical discourse analysis (CDA) to uncover its mechanisms and ideological functioning. We show how Volvic was able to transform an ordinary commodity, bottled water, into a consumer activist brand through which consumers could take part in solving global social problems, such as the access to safe drinking water in βdevelopingβ countries. Our analysis of this exemplary case shows the ways that CSR often operates to deflect ethical critiques, consolidate brand loyalty and corporate profits, and defuse political struggles around consumption. By doing so, we suggest that CSR forms part of a complex strategy deployed to legitimize particular brands and commodities. In this way CSR can be seen as playing an important role in the ideological makeup of contemporary consumer capitalism. </jats:p
Identification of Early Requirements for Preplacodal Ectoderm and Sensory Organ Development
Preplacodal ectoderm arises near the end of gastrulation as a narrow band of cells surrounding the anterior neural plate. This domain later resolves into discrete cranial placodes that, together with neural crest, produce paired sensory structures of the head. Unlike the better-characterized neural crest, little is known about early regulation of preplacodal development. Classical models of ectodermal patterning posit that preplacodal identity is specified by readout of a discrete level of Bmp signaling along a DV gradient. More recent studies indicate that Bmp-antagonists are critical for promoting preplacodal development. However, it is unclear whether Bmp-antagonists establish the proper level of Bmp signaling within a morphogen gradient or, alternatively, block Bmp altogether. To begin addressing these issues, we treated zebrafish embryos with a pharmacological inhibitor of Bmp, sometimes combined with heat shock-induction of Chordin and dominant-negative Bmp receptor, to fully block Bmp signaling at various developmental stages. We find that preplacodal development occurs in two phases with opposing Bmp requirements. Initially, Bmp is required before gastrulation to co-induce four transcription factors, Tfap2a, Tfap2c, Foxi1, and Gata3, which establish preplacodal competence throughout the nonneural ectoderm. Subsequently, Bmp must be fully blocked in late gastrulation by dorsally expressed Bmp-antagonists, together with dorsally expressed Fgf and Pdgf, to specify preplacodal identity within competent cells abutting the neural plate. Localized ventral misexpression of Fgf8 and Chordin can activate ectopic preplacodal development anywhere within the zone of competence, whereas dorsal misexpression of one or more competence factors can activate ectopic preplacodal development in the neural plate. Conversely, morpholino-knockdown of competence factors specifically ablates preplacodal development. Our work supports a relatively simple two-step model that traces regulation of preplacodal development to late blastula stage, resolves two distinct phases of Bmp dependence, and identifies the main factors required for preplacodal competence and specification
Estrogen/Estrogen Receptor Alpha Signaling in Mouse Posterofrontal Cranial Suture Fusion
BACKGROUND: While premature suture fusion, or craniosynostosis, is a relatively common condition, the cause is often unknown. Estrogens are associated with growth plate fusion of endochondral bones. In the following study, we explore the previously unknown significance of estrogen/estrogen receptor signaling in cranial suture biology. METHODOLOGY/PRINCIPAL FINDINGS: Firstly, estrogen receptor (ER) expression was examined in physiologically fusing (posterofrontal) and patent (sagittal) mouse cranial sutures by quantitative RT-PCR. Next, the cranial suture phenotype of ER alpha and ER beta knockout (alphaERKO, betaERKO) mice was studied. Subsequently, mouse suture-derived mesenchymal cells (SMCs) were isolated; the effects of 17-beta estradiol or the estrogen antagonist Fulvestrant on gene expression, osteogenic and chondrogenic differentiation were examined in vitro. Finally, in vivo experiments were performed in which Fulvestrant was administered subcutaneously to the mouse calvaria. Results showed that increased ERalpha but not ERbeta transcript abundance temporally coincided with posterofrontal suture fusion. The alphaERKO but not betaERKO mouse exhibited delayed posterofrontal suture fusion. In vitro, addition of 17-beta estradiol enhanced both osteogenic and chondrogenic differentiation in suture-derived mesenchymal cells, effects reversible by Fulvestrant. Finally, in vivo application of Fulvestrant significantly diminished calvarial osteogenesis, inhibiting suture fusion. CONCLUSIONS/SIGNIFICANCE: Estrogen signaling through ERalpha but not ERbeta is associated with and necessary for normal mouse posterofrontal suture fusion. In vitro studies suggest that estrogens may play a role in osteoblast and/or chondrocyte differentiation within the cranial suture complex
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