222 research outputs found
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Continuous-Flow Synthesis and Derivatization of Aziridines through Palladium-Catalyzed C(sp 3 )âH Activation
A continuousâflow synthesis of aziridines by palladiumâcatalyzed C(sp3)âH activation is described. The new flow reaction could be combined with an aziridineâringâopening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the CâH activation flow process and illustrates an approach towards firstâprinciples design based on novel catalytic reactions.We are grateful to the Department of Chemical Engineering and Biotechnology (J.Z.) and the EPSRC (A.P.S.) for studentships, and to the ERC and EPSRC (EP/100548X/1) for fellowships (M.J.G.). Mass spectroscopy data were acquired at the EPSRC UK National Mass Spectroscopy Facility at Swansea Universit
MultiMetEval: comparative and multi-objective analysis of genome-scale metabolic models
Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEvâal/downloads
Quantized reduction as a tensor product
Symplectic reduction is reinterpreted as the composition of arrows in the
category of integrable Poisson manifolds, whose arrows are isomorphism classes
of dual pairs, with symplectic groupoids as units. Morita equivalence of
Poisson manifolds amounts to isomorphism of objects in this category.
This description paves the way for the quantization of the classical
reduction procedure, which is based on the formal analogy between dual pairs of
Poisson manifolds and Hilbert bimodules over C*-algebras, as well as with
correspondences between von Neumann algebras. Further analogies are drawn with
categories of groupoids (of algebraic, measured, Lie, and symplectic type). In
all cases, the arrows are isomorphism classes of appropriate bimodules, and
their composition may be seen as a tensor product. Hence in suitable categories
reduction is simply composition of arrows, and Morita equivalence is
isomorphism of objects.Comment: 44 pages, categorical interpretation adde
Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes
Background: PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response.
Methods: PPARα, ÎČ and Îł mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARα protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARα was analyzed by gel shift assay.
Results: In lymphocytes, the expression of PPARα mRNA, but not of PPARÎČ, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARα was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARα and PPARÎČ mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARÎł mRNA levels were below the detection limit.
Conclusion: Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARα may therefore contribute to the inflammatory processes that are observed in CF
Dynamics of a Quantum Phase Transition and Relaxation to a Steady State
We review recent theoretical work on two closely related issues: excitation
of an isolated quantum condensed matter system driven adiabatically across a
continuous quantum phase transition or a gapless phase, and apparent relaxation
of an excited system after a sudden quench of a parameter in its Hamiltonian.
Accordingly the review is divided into two parts. The first part revolves
around a quantum version of the Kibble-Zurek mechanism including also phenomena
that go beyond this simple paradigm. What they have in common is that
excitation of a gapless many-body system scales with a power of the driving
rate. The second part attempts a systematic presentation of recent results and
conjectures on apparent relaxation of a pure state of an isolated quantum
many-body system after its excitation by a sudden quench. This research is
motivated in part by recent experimental developments in the physics of
ultracold atoms with potential applications in the adiabatic quantum state
preparation and quantum computation.Comment: 117 pages; review accepted in Advances in Physic
Angular and Current-Target Correlations in Deep Inelastic Scattering at HERA
Correlations between charged particles in deep inelastic ep scattering have
been studied in the Breit frame with the ZEUS detector at HERA using an
integrated luminosity of 6.4 pb-1. Short-range correlations are analysed in
terms of the angular separation between current-region particles within a cone
centred around the virtual photon axis. Long-range correlations between the
current and target regions have also been measured. The data support
predictions for the scaling behaviour of the angular correlations at high Q2
and for anti-correlations between the current and target regions over a large
range in Q2 and in the Bjorken scaling variable x. Analytic QCD calculations
and Monte Carlo models correctly describe the trends of the data at high Q2,
but show quantitative discrepancies. The data show differences between the
correlations in deep inelastic scattering and e+e- annihilation.Comment: 26 pages including 10 figures (submitted to Eur. J. Phys. C
Thymic development beyond ÎČ-selection requires phosphatidylinositol 3-kinase activation by CXCR4
T cell development requires phosphatidylinositol 3-kinase (PI3K) signaling with contributions from both the class IA, p110ÎŽ, and class IB, p110Îł catalytic subunits. However, the receptors on immature T cells by which each of these PI3Ks are activated have not been identified, nor has the mechanism behind their functional redundancy in the thymus. Here, we show that PI3K signaling from the preTCR requires p110ÎŽ, but not p110Îł. Mice deficient for the class IB regulatory subunit p101 demonstrated the requirement for p101 in T cell development, implicating G proteinâcoupled receptor signaling in ÎČ-selection. We found evidence of a role for CXCR4 using small molecule antagonists in an in vitro model of ÎČ-selection and demonstrated a requirement for CXCR4 during thymic development in CXCR4-deficient embryos. Finally, we demonstrate that CXCL12, the ligand for CXCR4, allows for Notch-dependent differentiation of DN3 thymocytes in the absence of supporting stromal cells. These findings establish a role for CXCR4-mediated PI3K signaling that, together with signals from Notch and the preTCR, contributes to continued T cell development beyond ÎČ-selection
Heterochronic faecal transplantation boosts gut germinal centres in aged mice
Ageing is a complex multifactorial process associated with a plethora of disorders, which contribute significantly to morbidity worldwide. One of the organs significantly affected by age is the gut. Age-dependent changes of the gut-associated microbiome have been linked to increased frailty and systemic inflammation. This change in microbial composition with age occurs in parallel with a decline in function of the gut immune system, however it is not clear if there is a causal link between the two. Here we report that the defective germinal centre reaction in Peyerâs patches of aged mice can be rescued by faecal transfers from younger adults into aged mice and by immunisations with cholera toxin, without affecting germinal centre reactions in peripheral lymph nodes. This demonstrates that the poor germinal centre reaction in aged animals is not irreversible, and that it is possible to improve this response in older individuals by providing appropriate stimuli
Cell Therapy of Congenital Corneal Diseases with Umbilical Mesenchymal Stem Cells: Lumican Null Mice
BACKGROUND: Keratoplasty is the most effective treatment for corneal blindness, but suboptimal medical conditions and lack of qualified medical personnel and donated cornea often prevent the performance of corneal transplantation in developing countries. Our study aims to develop alternative treatment regimens for congenital corneal diseases of genetic mutation. METHODOLOGY/PRINCIPAL FINDINGS: Human mesenchymal stem cells isolated from neonatal umbilical cords were transplanted to treat thin and cloudy corneas of lumican null mice. Transplantation of umbilical mesenchymal stem cells significantly improved corneal transparency and increased stromal thickness of lumican null mice, but human umbilical hematopoietic stem cells failed to do the same. Further studies revealed that collagen lamellae were re-organized in corneal stroma of lumican null mice after mesenchymal stem cell transplantation. Transplanted umbilical mesenchymal stem cells survived in the mouse corneal stroma for more than 3 months with little or no graft rejection. In addition, these cells assumed a keratocyte phenotype, e.g., dendritic morphology, quiescence, expression of keratocyte unique keratan sulfated keratocan and lumican, and CD34. Moreover, umbilical mesenchymal stem cell transplantation improved host keratocyte functions, which was verified by enhanced expression of keratocan and aldehyde dehydrogenase class 3A1 in lumican null mice. CONCLUSIONS/SIGNIFICANCE: Umbilical mesenchymal stem cell transplantation is a promising treatment for congenital corneal diseases involving keratocyte dysfunction. Unlike donated corneas, umbilical mesenchymal stem cells are easily isolated, expanded, stored, and can be quickly recovered from liquid nitrogen when a patient is in urgent need
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