466 research outputs found
Cell Death in the Embryonic Developing Limb
In amniote vertebrates, the development of form and structure of the limb bud is accompanied by precise patterns of massive mesodermal cell death with morphological features of apoptosis. These areas of cell death appear to eliminate undifferentiated cells which are required only for a limited time period of limb development. Predictable skeletal and morphological anomalies of the limb occur when the pattern of cell death is modified in mutant species or under experimental conditions. Most evidence points to the occurrence of local triggering mechanisms to account for the establishment of the areas of cell death and the subsequent activation of cell death genes. Modifications of the extracellular matrix and diminution in the contribution of growth factors by neighbouring tissues appear as the most likely potential candidates for triggering the cell death program. Information on the genetical basis of cell death in the developing limb is very scarce. Among the increasing number of cell death genes identified in other cell death systems, such as p-53 and the ced-3/ICE and ced-9/bcl-2 gene families, only bcl-2 has been studied in detail during limb development and yet, the information obtained is contradictory. Bcl-2 is not expressed in the areas of cell death of the developing limb, but normal limbs develop in mice with disruption of the bcl-2 gene. Obviously, the clarification of the role of the cell death genes constitute a major task in future studies of cell death in the developing limb
Tgfβ2 and 3 are coexpressed with their extracellular regulator Ltbp1 in the early limb bud and modulate mesodermal outgrowth and BMP signaling in chicken embryos
<p>Abstract</p> <p>Background</p> <p>Transforming growth factor β proteins (Tgfβs) are secreted cytokines with well-defined functions in the differentiation of the musculoskeletal system of the developing limb. Here we have studied in chicken embryos, whether these cytokines are implicated in the development of the embryonic limb bud at stages preceding tissue differentiation.</p> <p>Results</p> <p>Immunohistochemical detection of phosphorylated Smad2 and Smad3 indicates that signaling by this pathway is active in the undifferentiated mesoderm and AER. Gene expression analysis shows that transcripts of <it>tgfβ2 </it>and <it>tgfβ3 </it>but not <it>tgfβ1 </it>are abundant in the growing undifferentiated limb mesoderm. Transcripts of <it>tgfβ2 </it>are also found in the AER, which is the signaling center responsible for limb outgrowth. Furthermore, we show that Latent Tgfβ Binding protein 1 (LTBP1), which is a key extracellular modulator of Tgfβ ligand bioavailability, is coexpressed with <it>Tgfβs </it>in the early limb bud. Administration of exogenous Tgfβs to limb buds growing in explant cultures provides evidence of these cytokines playing a role in the regulation of mesodermal limb proliferation. In addition, analysis of gene regulation in these experiments revealed that Tgfβ signaling has no effect on the expression of master genes of musculoskeletal tissue differentiation but negatively regulates the expression of the BMP-antagonist Gremlin.</p> <p>Conclusion</p> <p>We propose the occurrence of an interplay between Tgfβ and BMP signaling functionally associated with the regulation of early limb outgrowth by modulating limb mesenchymal cell proliferation.</p
Activin/TGFβ and BMP crosstalk determines digit chondrogenesis
AbstractThe progress zone (PZ) is a specialized area at the distal margin of the developing limb where mesodermal cells are kept in proliferation and undifferentiated, allowing limb outgrowth. At stages of digit morphogenesis the PZ cells can undergo two possible fates, either aggregate initiating chondrogenic differentiation to configure the digit blastemas, or to die by apoptosis if they are incorporated in the interdigital mesenchyme. While both processes are controlled by bone morphogenetic proteins (BMPs) the molecular basis for such contrasting differential behavior of the autopodial mesoderm remains unknown. Here we show that a well-defined crescent domain of high BMP activity located at the tip of the forming digits, which we termed the digit crescent (DC), directs incorporation and differentiation of the PZ mesenchymal cells into the digit aggregates. The presence of this domain does not correlate with an exclusive expression domain of BMP receptors and its abrogation by surgical approaches or by local application of BMP antagonists is followed by digit truncation and cell death. We further show that establishment of the DC is directed by Activin/TGFβ signaling, which inhibits Smad 6 and Bambi, two specific BMP antagonists expressed in the interdigits and progress zone mesoderm. The interaction between Activin/TGFβ and BMP pathways at the level of DC promotes the expression of the chondrogenic factor SOX9 accompanied by a local decrease in cell proliferation. Characteristically, the DC domain is asymmetric, it being extended towards the posterior interdigit. The presence of the DC is transitorily dependent of the adjacent posterior interdigit and its maintenance requires also the integrity of the AER
Activin/TGFβ and BMP crosstalk determines digit chondrogenesis
AbstractThe progress zone (PZ) is a specialized area at the distal margin of the developing limb where mesodermal cells are kept in proliferation and undifferentiated, allowing limb outgrowth. At stages of digit morphogenesis the PZ cells can undergo two possible fates, either aggregate initiating chondrogenic differentiation to configure the digit blastemas, or to die by apoptosis if they are incorporated in the interdigital mesenchyme. While both processes are controlled by bone morphogenetic proteins (BMPs) the molecular basis for such contrasting differential behavior of the autopodial mesoderm remains unknown. Here we show that a well-defined crescent domain of high BMP activity located at the tip of the forming digits, which we termed the digit crescent (DC), directs incorporation and differentiation of the PZ mesenchymal cells into the digit aggregates. The presence of this domain does not correlate with an exclusive expression domain of BMP receptors and its abrogation by surgical approaches or by local application of BMP antagonists is followed by digit truncation and cell death. We further show that establishment of the DC is directed by Activin/TGFβ signaling, which inhibits Smad 6 and Bambi, two specific BMP antagonists expressed in the interdigits and progress zone mesoderm. The interaction between Activin/TGFβ and BMP pathways at the level of DC promotes the expression of the chondrogenic factor SOX9 accompanied by a local decrease in cell proliferation. Characteristically, the DC domain is asymmetric, it being extended towards the posterior interdigit. The presence of the DC is transitorily dependent of the adjacent posterior interdigit and its maintenance requires also the integrity of the AER
On the principal bifurcation branch of a third order nonlinear long-wave equation
We study the principal bifurcation curve of a third order equation which
describes the nonlinear evolution of several systems with a long--wavelength
instability. We show that the main bifurcation branch can be derived from a
variational principle. This allows to obtain a close estimate of the complete
branch. In particular, when the bifurcation is subcritical, the large amplitude
stable branch can be found in a simple manner.Comment: 11 pages, 3 figure
Testimony at court: a randomised controlled trial investigating the art and science of persuading witnesses and victims to attend trial
The presence of civilian witnesses and victims in court is central to the effective operation of the criminal justice system. However, there is evidence of significant non-attendance which can result in ineffective and cracked trials. To address this, West Midlands Police Witness Care Unit and the Behavioural Insights Team designed an intervention using behavioural insight principles consisting of (1) a new conversation guide for Witness Care Officers (WCOs); (2) a redesigned ‘Warning Letter’ confirming details of the proceedings; and (3) a new reminder call and SMS. The impact of the new approach was evaluated through a randomised controlled trial in which 36 WCOs were randomly assigned to either “business as usual” (control) or treatment. The evaluation used an intention-to-treat design with implementation guided and encouraged at several points. Subgroup analysis was undertaken to explore whether differential effects were seen for domestic violence cases or between those that were victims and witnesses. Results indicated that the treatment approach was directionally positive in all cases, but that the increase in attendance was not statistically significant. This is in line with findings of other similar research in this area
Early Detection of Prostate Cancer: The Role of Scent
Prostate cancer (PCa) represents the cause of the second highest number of cancer-related
deaths worldwide, and its clinical presentation can range from slow-growing to rapidly spreading
metastatic disease. As the characteristics of most cases of PCa remains incompletely understood, it
is crucial to identify new biomarkers that can aid in early detection. Despite the prostate-specific
antigen serum (PSA) levels, prostate biopsy, and imaging representing the actual gold-standard
for diagnosing PCa, analyzing volatile organic compounds (VOCs) has emerged as a promising
new frontier. We and other authors have reported that highly trained dogs can recognize specific
VOCs associated with PCa with high accuracy. However, using dogs in clinical practice has several
limitations. To exploit the potential of VOCs, an electronic nose (eNose) that mimics the dog olfactory
system and can potentially be used in clinical practice was designed. To explore the eNose as an
alternative to dogs in diagnosing PCa, we conducted a systematic literature review and meta-analysis
of available studies. PRISMA guidelines were used for the identification, screening, eligibility,
and selection process. We included six studies that employed trained dogs and found that the
pooled diagnostic sensitivity was 0.87 (95% CI 0.86–0.89; I2, 98.6%), the diagnostic specificity was
0.83 (95% CI 0.80–0.85; I2, 98.1%), and the area under the summary receiver operating characteristic
curve (sROC) was 0.64 (standard error, 0.25). We also analyzed five studies that used an eNose to
diagnose PCa and found that the pooled diagnostic sensitivity was 0.84 (95% CI, 0.80–0.88; I2, 57.1%),
the diagnostic specificity was 0.88 (95% CI, 0.84–0.91; I2, 66%), and the area under the sROC was
0.93 (standard error, 0.03). These pooled results suggest that while highly trained dogs have the
potentiality to diagnose PCa, the ability is primarily related to olfactory physiology and training
methodology. The adoption of advanced analytical techniques, such as eNose, poses a significant
challenge in the field of clinical practice due to their growing effectiveness. Nevertheless, the presence
of limitations and the requirement for meticulous study design continue to present challenges when
employing eNoses for the diagnosis of PCa
First-principles study of As interstitials in GaAs: Convergence, relaxation, and formation energy
Convergence of density-functional supercell calculations for defect formation
energies, charge transition levels, localized defect state properties, and
defect atomic structure and relaxation is investigated using the arsenic split
interstitial in GaAs as an example. Supercells containing up to 217 atoms and a
variety of {\bf k}-space sampling schemes are considered. It is shown that a
good description of the localized defect state dispersion and charge state
transition levels requires at least a 217-atom supercell, although the defect
structure and atomic relaxations can be well converged in a 65-atom cell.
Formation energies are calculated for the As split interstitial, Ga vacancy,
and As antisite defects in GaAs, taking into account the dependence upon
chemical potential and Fermi energy. It is found that equilibrium
concentrations of As interstitials will be much lower than equilibrium
concentrations of As antisites in As-rich, -type or semi-insulating GaAs.Comment: 10 pages, 5 figure
Eutectic Colony Formation: A Stability Analysis
Experiments have widely shown that a steady-state lamellar eutectic
solidification front is destabilized on a scale much larger than the lamellar
spacing by the rejection of a dilute ternary impurity and forms two-phase cells
commonly referred to as `eutectic colonies'. We extend the stability analysis
of Datye and Langer for a binary eutectic to include the effect of a ternary
impurity. We find that the expressions for the critical onset velocity and
morphological instability wavelength are analogous to those for the classic
Mullins-Sekerka instability of a monophase planar interface, albeit with an
effective surface tension that depends on the geometry of the lamellar
interface and, non-trivially, on interlamellar diffusion. A qualitatively new
aspect of this instability is the occurence of oscillatory modes due to the
interplay between the destabilizing effect of the ternary impurity and the
dynamical feedback of the local change in lamellar spacing on the front motion.
In a transient regime, these modes lead to the formation of large scale
oscillatory microstructures for which there is recent experimental evidence in
a transparent organic system. Moreover, it is shown that the eutectic front
dynamics on a scale larger than the lamellar spacing can be formulated as an
effective monophase interface free boundary problem with a modified
Gibbs-Thomson condition that is coupled to a slow evolution equation for the
lamellar spacing. This formulation provides additional physical insights into
the nature of the instability and a simple means to calculate an approximate
stability spectrum. Finally, we investigate the influence of the ternary
impurity on a short wavelength oscillatory instability that is already present
at off-eutectic compositions in binary eutectics.Comment: 26 pages RevTex, 14 figures (28 EPS files); some minor changes;
references adde
Bistability of Slow and Fast Traveling Waves in Fluid Mixtures
The appearence of a new type of fast nonlinear traveling wave states in
binary fluid convection with increasing Soret effect is elucidated and the
parameter range of their bistability with the common slower ones is evaluated
numerically. The bifurcation behavior and the significantly different
spatiotemporal properties of the different wave states - e.g. frequency, flow
structure, and concentration distribution - are determined and related to each
other and to a convenient measure of their nonlinearity. This allows to derive
a limit for the applicability of small amplitude expansions. Additionally an
universal scaling behavior of frequencies and mixing properties is found.
PACS: 47.20.-k, 47.10.+g, 47.20.KyComment: 4 pages including 5 Postscript figure
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