285 research outputs found

    Surfing the edge: Finding nonlinear solutions using feedback control

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    Many transitional wall-bounded shear flows are characterised by the coexistence in state-space of laminar and turbulent regimes. Probing the edge boundarz between the two attractors has led in the last decade to the numerical discovery of new (unstable) solutions to the incompressible Navier--Stokes equations. However, the iterative bisection method used to achieve this can become prohibitively costly for large systems. Here we suggest a simple feedback control strategy to stabilise edge states, hence accelerating their numerical identification by several orders of magnitude. The method is illustrated for several configurations of cylindrical pipe flow. Traveling waves solutions are identified as edge states, and can be isolated rapidly in only one short numerical run. A new branch of solutions is also identified. When the edge state is a periodic orbit or chaotic state, the feedback control does not converge precisely to solutions of the uncontrolled system, but nevertheless brings the dynamics very close to the original edge manifold in a single run. We discuss the opportunities offered by the speed and simplicity of this new method to probe the structure of both state space and parameter space

    Relative periodic orbits in transitional pipe flow

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    A dynamical system description of the transition process in shear flows with no linear instability starts with a knowledge of exact coherent solutions, among them travelling waves (TWs) and relative periodic orbits (RPOs). We describe a numerical method to find such solutions in pipe flow and apply it in the vicinity of a Hopf bifurcation from a TW which looks to be especially relevant for transition. The dominant structural feature of the RPO solution is the presence of weakly modulated streaks. This RPO, like the TW from which it bifurcates, sits on the laminar-turbulent boundary separating initial conditions which lead to turbulence from those which immediately relaminarise

    Respective roles of organic and mineral components of human cortical bone matrix in micromechanical behavior: An instrumented indentation study

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    International audienceBone is a multiscale composite material made of both a type I collagen matrix and a poorly crystalline apatite mineral phase. Due to remodeling activity, cortical bone is made of Bone Structural Units (BSUs) called osteons. Since osteon represents a fundamental level of structural hierarchy, it is important to investigate the relationship between mechanical behavior and tissue composition at this scale for a better understanding of the mechanisms of bone fragility. The aim of this study is to analyze the links between ultrastructural properties and the mechanical behavior of bone tissue at the scale of osteon. Iliac bone biopsies were taken from untreated postmenopausal osteoporotic women, embedded, sectioned and microradiographed to assess the degree of mineralization of bone (DMB). On each section, BSUs of known DMB were indented with relatively high load (∌500 mN) to determine local elastic modulus (E), contact hardness (Hc) and true hardness(H) of several bone lamellae. Crystallinity and collagen maturity were measured by Fourier Transform InfraRed Microspectroscopy (FTIRM) on the same BSUs. Inter-relationships between mechanical properties and ultrastructural components were analyzed using multiple regression analysis. This study showed that elastic deformation was only explained by DMB whereas plastic deformation was more correlated with collagen maturity. Contact hardness, reflecting both elastic and plastic behaviors, was correlated with both DMB and collagen maturity. Norelationship was found between crystallinity and mechanical properties at the osteon level

    OVERTONE VIBRATIONAL SPECTROSCOPY AND DYNAMICS IN H2_2-H2_2O COMPLEXES: A COMBINED THEORETICAL AND EXPERIMENTAL STUDY

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    Author Institution: JILA, University of Colorado and National Institute of; Standards and Technology, Boulder, Colorado; CNRS-Universite de Bourgogne, Dijon, France; CNRS, Institut de Planetologie et d'Astrophysique de Grenoble, France; Radboud University, 6525 AJ Nijmegen, The NetherlandsH2_2 is the most abundant molecule in the universe and also H2_2O occurs in relatively high concentrations in various interstellar environments. Processes that occur through the interaction of these molecules may, for example, play a role in the mechanism producing the observed H2_2O maser activity. Spectroscopic studies of the H2_2-H2_2O complex in different stable and metastable states will be reported in the accompanying talk; theoretical studies will be presented here. The latter involve calculations of the bound rovibrational levels of the complex with both monomers in their vibrational ground state, as well as of the metastable levels with H2_2O in its OH stretch overtone state, on the appropriate \textit{ab initio} five-dimensional intermolecular potential surfaces. Also the line strengths of all the allowed transitions between these levels that may occur in combination with the vOH=2←0v_{\rm OH} = 2 \leftarrow 0 overtone transition were computed, for all four ortho/para H2_2 and ortho/para H2_2O variants of the complex. The spectrum simulated with these data agrees very well with the measured spectrum and was used to assign this spectrum. In addition, the information obtained from the theory was useful to understand the observed predissociation dynamics of the complex

    Experiment design and bacterial abundance control extracellular H2O2 concentrations during four series of mesocosm experiments

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    The extracellular concentration of H2O2 in surface aquatic environments is controlled by a balance between photochemical production and the microbial synthesis of catalase and peroxidase enzymes to remove H2O2 from solution. In any kind of incubation experiment, the formation rates and equilibrium concentrations of reactive oxygen species (ROSs) such as H2O2 may be sensitive to both the experiment design, particularly to the regulation of incident light, and the abundance of different microbial groups, as both cellular H2O2 production and catalase–peroxidase enzyme production rates differ between species. Whilst there are extensive measurements of photochemical H2O2 formation rates and the distribution of H2O2 in the marine environment, it is poorly constrained how different microbial groups affect extracellular H2O2 concentrations, how comparable extracellular H2O2 concentrations within large-scale incubation experiments are to those observed in the surface-mixed layer, and to what extent a mismatch with environmentally relevant concentrations of ROS in incubations could influence biological processes differently to what would be observed in nature. Here we show that both experiment design and bacterial abundance consistently exert control on extracellular H2O2 concentrations across a range of incubation experiments in diverse marine environments. During four large-scale (>1000 L) mesocosm experiments (in Gran Canaria, the Mediterranean, Patagonia and Svalbard) most experimental factors appeared to exert only minor, or no, direct effect on H2O2 concentrations. For example, in three of four experiments where pH was manipulated to 0.4–0.5 below ambient pH, no significant change was evident in extracellular H2O2 concentrations relative to controls. An influence was sometimes inferred from zooplankton density, but not consistently between different incubation experiments, and no change in H2O2 was evident in controlled experiments using different densities of the copepod Calanus finmarchicus grazing on the diatom Skeletonema costatum (<1 % change in [H2O2] comparing copepod densities from 1 to 10 L−1). Instead, the changes in H2O2 concentration contrasting high- and low-zooplankton incubations appeared to arise from the resulting changes in bacterial activity. The correlation between bacterial abundance and extracellular H2O2 was stronger in some incubations than others (R2 range 0.09 to 0.55), yet high bacterial densities were consistently associated with low H2O2. Nonetheless, the main control on H2O2 concentrations during incubation experiments relative to those in ambient, unenclosed waters was the regulation of incident light. In an open (lidless) mesocosm experiment in Gran Canaria, H2O2 was persistently elevated (2–6-fold) above ambient concentrations; whereas using closed high-density polyethylene mesocosms in Crete, Svalbard and Patagonia H2O2 within incubations was always reduced (median 10 %–90 %) relative to ambient waters

    Erdafitinib in BCG-treated high risk non-muscle invasive bladder cancer

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    © 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette–GuĂ©rin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. Patients and methods: Patients aged ≄18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. Results: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2: 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. Conclusions: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.Peer reviewe

    Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

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    Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts

    Flavaglines Alleviate Doxorubicin Cardiotoxicity: Implication of Hsp27

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    Background: Despite its effectiveness in the treatment of various cancers, the use of doxorubicin is limited by a potentially fatal cardiomyopathy. Prevention of this cardiotoxicity remains a critical issue in clinical oncology. We hypothesized that flavaglines, a family of natural compounds that display potent neuroprotective effects, may also alleviate doxorubicininduced cardiotoxicity. Methodology/Principal Findings: Our in vitro data established that a pretreatment with flavaglines significantly increased viability of doxorubicin-injured H9c2 cardiomyocytes as demonstrated by annexin V, TUNEL and active caspase-3 assays. We demonstrated also that phosphorylation of the small heat shock protein Hsp27 is involved in the mechanism by which flavaglines display their cardioprotective effect. Furthermore, knocking-down Hsp27 in H9c2 cardiomyocytes completely reversed this cardioprotection. Administration of our lead compound (FL3) to mice attenuated cardiomyocyte apoptosis and cardiac fibrosis, as reflected by a 50 % decrease of mortality. Conclusions/Significance: These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induce

    Tight Regulation of the intS Gene of the KplE1 Prophage: A New Paradigm for Integrase Gene Regulation

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    Temperate phages have the ability to maintain their genome in their host, a process called lysogeny. For most, passive replication of the phage genome relies on integration into the host's chromosome and becoming a prophage. Prophages remain silent in the absence of stress and replicate passively within their host genome. However, when stressful conditions occur, a prophage excises itself and resumes the viral cycle. Integration and excision of phage genomes are mediated by regulated site-specific recombination catalyzed by tyrosine and serine recombinases. In the KplE1 prophage, site-specific recombination is mediated by the IntS integrase and the TorI recombination directionality factor (RDF). We previously described a sub-family of temperate phages that is characterized by an unusual organization of the recombination module. Consequently, the attL recombination region overlaps with the integrase promoter, and the integrase and RDF genes do not share a common activated promoter upon lytic induction as in the lambda prophage. In this study, we show that the intS gene is tightly regulated by its own product as well as by the TorI RDF protein. In silico analysis revealed that overlap of the attL region with the integrase promoter is widely encountered in prophages present in prokaryotic genomes, suggesting a general occurrence of negatively autoregulated integrase genes. The prediction that these integrase genes are negatively autoregulated was biologically assessed by studying the regulation of several integrase genes from two different Escherichia coli strains. Our results suggest that the majority of tRNA-associated integrase genes in prokaryotic genomes could be autoregulated and that this might be correlated with the recombination efficiency as in KplE1. The consequences of this unprecedented regulation for excisive recombination are discussed

    The Involvement of SMILE/TMTC3 in Endoplasmic Reticulum Stress Response

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    The state of operational tolerance has been detected sporadically in some renal transplanted patients that stopped immunosuppressive drugs, demonstrating that allograft tolerance might exist in humans. Several years ago, a study by Brouard et al. identified a molecular signature of several genes that were significantly differentially expressed in the blood of such patients compared with patients with other clinical situations. The aim of the present study is to analyze the role of one of these molecules over-expressed in the blood of operationally tolerant patients, SMILE or TMTC3, a protein whose function is still unknown.We first confirmed that SMILE mRNA is differentially expressed in the blood of operationally tolerant patients with drug-free long term graft function compared to stable and rejecting patients. Using a yeast two-hybrid approach and a colocalization study by confocal microscopy we furthermore report an interaction of SMILE with PDIA3, a molecule resident in the endoplasmic reticulum (ER). In accordance with this observation, SMILE silencing in HeLa cells correlated with the modulation of several transcripts involved in proteolysis and a decrease in proteasome activity. Finally, SMILE silencing increased HeLa cell sensitivity to the proteasome inhibitor Bortezomib, a drug that induces ER stress via protein overload, and increased transcript expression of a stress response protein, XBP-1, in HeLa cells and keratinocytes.In this study we showed that SMILE is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP-1 transcript expression. This function of SMILE may influence immune cell behavior in the context of transplantation, and the analysis of endoplasmic reticulum stress in transplantation may reveal new pathways of regulation in long-term graft acceptance thereby increasing our understanding of tolerance
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