120 research outputs found
Robust growth termination through local mechanical feedback in the Drosophila wing disc
How does a cell in an organ know the overall size of the organ? It is thought
that the Drosophila wing disc grows to the right size because its cells respond
to both signalling proteins (morphogens) and mechanical stress. We show that
size regulation can be achieved if cells respond exclusively to stress with an
anisotropic growth response. To test this, we develop a continuum model which
assumes the spatial uniformity of cell proliferation in the wing disc and
predicts compression in the disc center, tension in its periphery, and a
sigmoidal evolution of the disc size, all of which have been observed in
experiments. We further show that the addition of a basal growth term is
necessary for the wing disc to always reach the same size. Contrary to the
current paradigm, our results suggest that local mechanical feedback is the
primary mechanism in regulating the final disc size
The role of topology and mechanics in uniaxially growing cell networks
In biological systems, the growth of cells, tissues, and organs is influenced
by mechanical cues. Locally, cell growth leads to a mechanically heterogeneous
environment as cells pull and push their neighbors in a cell network. Despite
this local heterogeneity, at the tissue level, the cell network is remarkably
robust, as it is not easily perturbed by changes in the mechanical environment
or the network connectivity. Through a network model, we relate global tissue
structure (i.e. the cell network topology) and local growth mechanisms (growth
laws) to the overall tissue response. Within this framework, we investigate the
two main mechanical growth laws that have been proposed: stress-driven or
strain-driven growth. We show that in order to create a robust and stable
tissue environment, networks with predominantly series connections are
naturally driven by stress-driven growth, whereas networks with predominantly
parallel connections are associated with strain-driven growth
Quantifying the impact of tissue metabolism on solute transport in feto-placental microvascular networks
The primary exchange units in the human placenta are terminal villi, in which fetal capillary networks are surrounded by a thin layer of villous tissue, separating fetal from maternal blood. To understand how the complex spatial structure of villi influences their function, we use an image-based theoretical model to study the effect of tissue metabolism on the transport of solutes from maternal blood into the fetal circulation. For solute that is taken up under first-order kinetics, we show that the transition between flow-limited and diffusion-limited transport depends on two new dimensionless parameters defined in terms of key geometric quantities, with strong solute uptake promoting flow-limited transport conditions. We present a simple algebraic
approximation for solute uptake rate as a function of flow conditions, metabolic rate and villous geometry. For oxygen, accounting for nonlinear kinetics using physiological parameter values, our model predicts that villous metabolism does not significantly impact oxygen transfer to fetal blood, although the partitioning of fluxes between the villous tissue and the capillary network depends strongly on the flow regim
siRNA Targeted to p53 Attenuates Ischemic and Cisplatin-Induced Acute Kidney Injury
Proximal tubule cells (PTCs), which are the primary site of kidney injury associated with ischemia or nephrotoxicity, are the site of oligonucleotide reabsorption within the kidney. We exploited this property to test the efficacy of siRNA targeted to p53, a pivotal protein in the apoptotic pathway, to prevent kidney injury. Naked synthetic siRNA to p53 injected intravenously 4 h after ischemic injury maximally protected both PTCs and kidney function. PTCs were the primary site for siRNA uptake within the kidney and body. Following glomerular filtration, endocytic uptake of Cy3-siRNA by PTCs was rapid and extensive, and significantly reduced ischemia-induced p53 upregulation. The duration of the siRNA effect in PTCs was 24 to 48 h, determined by levels of p53 mRNA and protein expression. Both Cy3 fluorescence and in situ hybridization of siRNA corroborated a short t½ for siRNA. The extent of renoprotection, decrease in cellular p53 and attenuation of p53-mediated apoptosis by siRNA were dose- and time-dependent. Analysis of renal histology and apoptosis revealed improved injury scores in both cortical and corticomedullary regions. siRNA to p53 was also effective in a model of cisplatin-induced kidney injury. Taken together, these data indicate that rapid delivery of siRNA to proximal tubule cells follows intravenous administration. Targeting siRNA to p53 leads to a dose-dependent attenuation of apoptotic signaling, suggesting potential therapeutic benefit for ischemic and nephrotoxic kidney injury
Swift: primary data analysis for the Illumina Solexa sequencing platform
Motivation: Primary data analysis methods are of critical importance in second generation DNA sequencing. Improved methods have the potential to increase yield and reduce the error rates. Openly documented analysis tools enable the user to understand the primary data, this is important for the optimization and validity of their scientific work
Primary accumulation in the Soviet transition
The Soviet background to the idea of primary socialist accumulation is presented. The mobilisation of labour power and of products into public sector investment from outside are shown to have been the two original forms of the concept. In Soviet primary accumulation the mobilisation of labour power was apparently more decisive than the mobilisation of products. The primary accumulation process had both intended and unintended results. Intended results included bringing most of the economy into the public sector, and industrialisation of the economy as a whole. Unintended results included substantial economic losses, and the proliferation of coercive institutions damaging to attainment of the ultimate goal - the building of a communist society
The Effect of Pre-Injury Anti-Platelet Therapy on the Development of Complications in Isolated Blunt Chest Wall Trauma: A Retrospective Study
INTRODUCTION: The difficulties in the management of the blunt chest wall trauma patient in the Emergency Department due to the development of late complications are well recognised in the literature. Pre-injury anti-platelet therapy has been previously investigated as a risk factor for poor outcomes following traumatic head injury, but not in the blunt chest wall trauma patient cohort. The aim of this study was to investigate pre-injury anti-platelet therapy as a risk factor for the development of complications in the recovery phase following blunt chest wall trauma. METHODS: A retrospective study was completed in which the medical notes were analysed of all blunt chest wall trauma patients presenting to a large trauma centre in Wales in 2012 and 2013. Using univariate and multivariable logistic regression analysis, pre-injury platelet therapy was investigated as a risk factor for the development of complications following blunt chest wall trauma. Previously identified risk factors were included in the analysis to address the influence of confounding. RESULTS: A total of 1303 isolated blunt chest wall trauma patients presented to the ED in Morriston Hospital in 2012 and 2013 with complications recorded in 144 patients (11%). On multi-variable analysis, pre-injury anti-platelet therapy was found to be a significant risk factor for the development of complications following isolated blunt chest wall trauma (odds ratio: 16.9; 95% confidence intervals: 8.2-35.2). As in previous studies patient age, number of rib fractures, chronic lung disease and pre-injury anti-coagulant use were also found to be significant risk factors. CONCLUSIONS: Pre-injury anti-platelet therapy is being increasingly used as a first line treatment for a number of conditions and there is a concurrent increase in trauma in the elderly population. Pre-injury anti-platelet therapy should be considered as a risk factor for the development of complications by clinicians managing blunt chest wall trauma
Acute Response of Peripheral Blood Cell to Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetic Patient
Autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) was the first therapeutic approach that can improve β cell function in type 1 diabetic (T1D) patients. This study was designed to investigate the potential mechanisms involved.We applied AHST to nine T1D patients diagnosed within six months and analyzed the acute responses in peripheral blood for lymphocyte subpopulation as well as for genomic expression profiling at the six-month follow-up.We found six patients obtained insulin free (IF group) and three remained insulin dependent (ID group); C-peptide production was significantly higher in IF group compared to ID group. The acute responses in lymphocytes at six-month follow-up include declined CD3(+)CD4(+), CD3(+)CD8(+) T cell population and recovered B cell, NK cell population in both groups but with no significant differences between the two groups; most immune-related genes and pathways were up-regulated in peripheral blood mononuclear cell (PBMC) of both groups while none of transcription factors for immune regulatory component were significantly changed; the IF group demonstrated more AHST-modified genetic events than the ID group and distinct pattern of top pathways, co-expression network as well as 'hub' genes (eg, TCF7 and GZMA) were associated with each group.AHST could improve the islet function in newly diagnosed T1D patients and elimination of the islet specific autoreactive T cells might be one of the mechanisms involved; T1D patients responded differently to AHST possibly due to the distinct transcriptional events occurring in PBMC.ClinicalTrials.gov NCT00807651
The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns
T-bet acts as a functional repressor in association with Bcl-6 to antagonize SOCS1, SOCS3, TCF-1, and late-stage IFN-γ to regulate Th1 development
Gravitational Lorentz Violations and Adjustment of the Cosmological Constant in Asymmetrically Warped Spacetimes
We investigate spacetimes in which the speed of light along flat 4D sections
varies over the extra dimensions due to different warp factors for the space
and the time coordinates (``asymmetrically warped'' spacetimes). The main
property of such spaces is that while the induced metric is flat, implying
Lorentz invariant particle physics on a brane, bulk gravitational effects will
cause apparent violations of Lorentz invariance and of causality from the brane
observer's point of view. An important experimentally verifiable consequence of
this is that gravitational waves may travel with a speed different from the
speed of light on the brane, and possibly even faster. We find the most general
spacetimes of this sort, which are given by AdS-Schwarzschild or
AdS-Reissner-Nordstrom black holes, assuming the simplest possible sources in
the bulk. Due to the gravitational Lorentz violations these models do not have
an ordinary Lorentz invariant effective description, and thus provide a
possible way around Weinberg's no-go theorem for the adjustment of the
cosmological constant. Indeed we show that the cosmological constant may relax
in such theories by the adjustment of the mass and the charge of the black
hole. The black hole singularity in these solutions can be protected by a
horizon, but the existence of a horizon requires some exotic energy densities
on the brane. We investigate the cosmological expansion of these models and
speculate that it may provide an explanation for the accelerating Universe,
provided that the timescale for the adjustment is shorter than the Hubble time.
In this case the accelerating Universe would be a manifestation of
gravitational Lorentz violations in extra dimensions.Comment: 28 pages, LaTeX, 4 figures included. v2: references added, added
comment on experimental observations, and clarified comment on Lorentz
violations in non-commutative theories. v3: typos fixed, eqs. 2.30 and 2.31
correcte
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