Response to ``Comment on `Bohmian mechanics with complex action: A new trajectory-based formulation of quantum mechanics' '' [J. Chem. Phys. 127, 197101 (2007)

NASA Astrophysics Data System (ADS)

Goldfarb, Yair; Degani, Ilan; Tannor, David J.

2007-11-01

In their comment, Sanz and Miret-Artés (SMA) describe previous trajectory-based formalisms based on the quantum Hamilton-Jacobi (QHJ) formalism. In this reply, we highlight our unique contributions: the identification of the smallness of the quantum force in the complex QHJ and its solution using complex trajectories. SMA also raise the question of how the term locality should be used in quantum mechanics. We suggest that at least certain aspects of nonlocality can depend on the method used to solve the problem.

Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response

PubMed Central

Shahin, Mohamed H; Johnson, Julie A

2016-01-01

Thiazide (TZD) diuretics are among the most commonly prescribed antihypertensives globally; however their chronic blood pressure (BP) lowering mechanism remains unclear. Herein we discuss the current evidence regarding specific mechanisms regulating the antihypertensive effects of TZDs, suggesting that TZDs act via multiple complex and interacting mechanisms, including natriuresis with short term use and direct vasodilatory effects chronically. Additionally, we review pharmacogenomics signals that have been associated with TZDs BP-response in several cohorts (i.e. NEDD4L, PRKCA, EDNRA-GNAS, and YEATS4) and discuss how these genes might be related to TZD BP-response mechanism. Understanding the association between these genes and TZD BP mechanism might facilitate the development of new drugs and therapeutic approaches based on a deeper understanding of the determinants of BP-response. PMID:26874237

Low- and high-spin iron (II) complexes studied by effective crystal field method combined with molecular mechanics.

PubMed

Darkhovskii, M B; Pletnev, I V; Tchougréeff, A L

2003-11-15

A computational method targeted to Werner-type complexes is developed on the basis of quantum mechanical effective Hamiltonian crystal field (EHCF) methodology (previously proposed for describing electronic structure of transition metal complexes) combined with the Gillespie-Kepert version of molecular mechanics (MM). It is a special version of the hybrid quantum/MM approach. The MM part is responsible for representing the whole molecule, including ligand atoms and metal ion coordination sphere, but leaving out the effects of the d-shell. The quantum mechanical EHCF part is limited to the metal ion d-shell. The method reproduces with reasonable accuracy geometry and spin states of the Fe(II) complexes with monodentate and polydentate aromatic ligands with nitrogen donor atoms. In this setting a single set of MM parameters set is shown to be sufficient for handling all spin states of the complexes under consideration. Copyright 2003 Wiley Periodicals, Inc.

Nonlinear mechanics of hybrid polymer networks that mimic the complex mechanical environment of cells

NASA Astrophysics Data System (ADS)

Jaspers, Maarten; Vaessen, Sarah L.; van Schayik, Pim; Voerman, Dion; Rowan, Alan E.; Kouwer, Paul H. J.

2017-05-01

The mechanical properties of cells and the extracellular environment they reside in are governed by a complex interplay of biopolymers. These biopolymers, which possess a wide range of stiffnesses, self-assemble into fibrous composite networks such as the cytoskeleton and extracellular matrix. They interact with each other both physically and chemically to create a highly responsive and adaptive mechanical environment that stiffens when stressed or strained. Here we show that hybrid networks of a synthetic mimic of biological networks and either stiff, flexible and semi-flexible components, even very low concentrations of these added components, strongly affect the network stiffness and/or its strain-responsive character. The stiffness (persistence length) of the second network, its concentration and the interaction between the components are all parameters that can be used to tune the mechanics of the hybrids. The equivalence of these hybrids with biological composites is striking.

Classification of Error Related Brain Activity in an Auditory Identification Task with Conditions of Varying Complexity

NASA Astrophysics Data System (ADS)

Kakkos, I.; Gkiatis, K.; Bromis, K.; Asvestas, P. A.; Karanasiou, I. S.; Ventouras, E. M.; Matsopoulos, G. K.

2017-11-01

The detection of an error is the cognitive evaluation of an action outcome that is considered undesired or mismatches an expected response. Brain activity during monitoring of correct and incorrect responses elicits Event Related Potentials (ERPs) revealing complex cerebral responses to deviant sensory stimuli. Development of accurate error detection systems is of great importance both concerning practical applications and in investigating the complex neural mechanisms of decision making. In this study, data are used from an audio identification experiment that was implemented with two levels of complexity in order to investigate neurophysiological error processing mechanisms in actors and observers. To examine and analyse the variations of the processing of erroneous sensory information for each level of complexity we employ Support Vector Machines (SVM) classifiers with various learning methods and kernels using characteristic ERP time-windowed features. For dimensionality reduction and to remove redundant features we implement a feature selection framework based on Sequential Forward Selection (SFS). The proposed method provided high accuracy in identifying correct and incorrect responses both for actors and for observers with mean accuracy of 93% and 91% respectively. Additionally, computational time was reduced and the effects of the nesting problem usually occurring in SFS of large feature sets were alleviated.

Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents.

PubMed

Yadav, N; Kumar, S; Marlowe, T; Chaudhary, A K; Kumar, R; Wang, J; O'Malley, J; Boland, P M; Jayanthi, S; Kumar, T K S; Yadava, N; Chandra, D

2015-11-05

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.

Investigating cell mechanics with atomic force microscopy

PubMed Central

Haase, Kristina; Pelling, Andrew E.

2015-01-01

Transmission of mechanical force is crucial for normal cell development and functioning. However, the process of mechanotransduction cannot be studied in isolation from cell mechanics. Thus, in order to understand how cells ‘feel’, we must first understand how they deform and recover from physical perturbations. Owing to its versatility, atomic force microscopy (AFM) has become a popular tool to study intrinsic cellular mechanical properties. Used to directly manipulate and examine whole and subcellular reactions, AFM allows for top-down and reconstitutive approaches to mechanical characterization. These studies show that the responses of cells and their components are complex, and largely depend on the magnitude and time scale of loading. In this review, we generally describe the mechanotransductive process through discussion of well-known mechanosensors. We then focus on discussion of recent examples where AFM is used to specifically probe the elastic and inelastic responses of single cells undergoing deformation. We present a brief overview of classical and current models often used to characterize observed cellular phenomena in response to force. Both simple mechanistic models and complex nonlinear models have been used to describe the observed cellular behaviours, however a unifying description of cell mechanics has not yet been resolved. PMID:25589563

Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response.

PubMed

Shahin, Mohamed H; Johnson, Julie A

2016-04-01

Thiazide (TZD) diuretics are among the most commonly prescribed antihypertensives globally; however their chronic blood pressure (BP) lowering mechanism remains unclear. Herein we discuss the current evidence regarding specific mechanisms regulating the antihypertensive effects of TZDs, suggesting that TZDs act via multiple complex and interacting mechanisms, including natriuresis with short term use and direct vasodilatory effects chronically. Additionally, we review pharmacogenomics signals that have been associated with TZDs BP-response in several cohorts (i.e. NEDD4L, PRKCA, EDNRA-GNAS, and YEATS4) and discuss how these genes might be related to TZD BP-response mechanism. Understanding the association between these genes and TZD BP mechanism might facilitate the development of new drugs and therapeutic approaches based on a deeper understanding of the determinants of BP-response. Copyright © 2016. Published by Elsevier Ltd.

Accelerated Disassembly of IgE:Receptor Complexes by a Disruptive Macromolecular Inhibitor

PubMed Central

Kim, Beomkyu; Eggel, Alexander; Tarchevskaya, Svetlana S.; Vogel, Monique; Prinz, Heino; Jardetzky, Theodore S.

2012-01-01

IgE antibodies bind the high affinity IgE Fc receptor (FcεRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response1,2. Inhibitors of IgE:FcεRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma3,4. However, preformed IgE:FcεRI complexes that prime cells prior to allergen exposure dissociate extremely slowly5 and cannot be disrupted by strictly competitive inhibitors. IgE-Fc conformational flexibility indicated that inhibition could be mediated by allosteric or other non-classical mechanisms6–8. Here we demonstrate that an engineered protein inhibitor, DARPin E2_799–11, acts through a non-classical inhibition mechanism, not only blocking IgE:FcεRI interactions, but actively stimulating the dissociation of preformed ligand-receptor complexes. The structure of the E2_79:IgE-Fc3-4 complex predicts the presence of two non-equivalent E2_79 sites in the asymmetric IgE:FcεRI complex, with Site 1 distant from the receptor and Site 2 exhibiting partial steric overlap. While the structure is suggestive of an allosteric inhibition mechanism, mutational studies and quantitative kinetic modeling indicate that E2_79 acts through a facilitated dissociation mechanism at Site 2 alone. These results demonstrate that high affinity IgE:FcεRI complexes can be actively dissociated to block the allergic response and suggest that protein:protein complexes may be more generally amenable to active disruption by macromolecular inhibitors. PMID:23103871

The RNA Polymerase-Associated Factor 1 Complex Is Required for Plant Touch Responses

PubMed Central

Jensen, Gregory S.; Fal, Kateryna; Hamant, Olivier

2017-01-01

Abstract Thigmomorphogenesis is a stereotypical developmental alteration in the plant body plan that can be induced by repeatedly touching plant organs. To unravel how plants sense and record multiple touch stimuli we performed a novel forward genetic screen based on the development of a shorter stem in response to repetitive touch. The touch insensitive (ths1) mutant identified in this screen is defective in some aspects of shoot and root thigmomorphogenesis. The ths1 mutant is an intermediate loss-of-function allele of VERNALIZATION INDEPENDENCE 3 (VIP3), a previously characterized gene whose product is part of the RNA polymerase II-associated factor 1 (Paf1) complex. The Paf1 complex is found in yeast, plants and animals, and has been implicated in histone modification and RNA processing. Several components of the Paf1 complex are required for reduced stem height in response to touch and normal root slanting and coiling responses. Global levels of histone H3K36 trimethylation are reduced in VIP3 mutants. In addition, THS1/VIP3 is required for wild type histone H3K36 trimethylation at the TOUCH3 (TCH3) and TOUCH4 (TCH4) loci and for rapid touch-induced upregulation of TCH3 and TCH4 transcripts. Thus, an evolutionarily conserved chromatin-modifying complex is required for both short- and long-term responses to mechanical stimulation, providing insight into how plants record mechanical signals for thigmomorphogenesis. PMID:28204553

Modulation of Specific and Allergy-Related Immune Responses by Helminths

PubMed Central

Daniłowicz-Luebert, Emilia; O'Regan, Noëlle L.; Steinfelder, Svenja; Hartmann, Susanne

2011-01-01

Helminths are master regulators of host immune responses utilising complex mechanisms to dampen host protective Th2-type responses and favour long-term persistence. Such evasion mechanisms ensure mutual survival of both the parasite and the host. In this paper, we present recent findings on the cells that are targeted by helminths and the molecules and mechanisms that are induced during infection. We discuss the impact of these factors on the host response as well as their effect in preventing the development of aberrant allergic inflammation. We also examine recent findings on helminth-derived molecules that can be used as tools to pinpoint the underlying mechanisms of immune regulation or to determine new anti-inflammatory therapeutics. PMID:22219659

Molecular dynamics simulations of heterogeneous cell membranes in response to uniaxial membrane stretches at high loading rates.

PubMed

Zhang, Lili; Zhang, Zesheng; Jasa, John; Li, Dongli; Cleveland, Robin O; Negahban, Mehrdad; Jérusalem, Antoine

2017-08-16

The chemobiomechanical signatures of diseased cells are often distinctively different from that of healthy cells. This mainly arises from cellular structural/compositional alterations induced by disease development or therapeutic molecules. Therapeutic shock waves have the potential to mechanically destroy diseased cells and/or increase cell membrane permeability for drug delivery. However, the biomolecular mechanisms by which shock waves interact with diseased and healthy cellular components remain largely unknown. By integrating atomistic simulations with a novel multiscale numerical framework, this work provides new biomolecular mechanistic perspectives through which many mechanosensitive cellular processes could be quantitatively characterised. Here we examine the biomechanical responses of the chosen representative membrane complexes under rapid mechanical loadings pertinent to therapeutic shock wave conditions. We find that their rupture characteristics do not exhibit significant sensitivity to the applied strain rates. Furthermore, we show that the embedded rigid inclusions markedly facilitate stretch-induced membrane disruptions while mechanically stiffening the associated complexes under the applied membrane stretches. Our results suggest that the presence of rigid molecules in cellular membranes could serve as "mechanical catalysts" to promote the mechanical destructions of the associated complexes, which, in concert with other biochemical/medical considerations, should provide beneficial information for future biomechanical-mediated therapeutics.

A Five-Year Goal for Training Complexes.

ERIC Educational Resources Information Center

Cohen, Saul B.

The training complex is conceived as a new kind of mechanism within which teachers will be trained with the assistance of protocol and training materials. It is to be operated by a consortium of universities, schools, and other agencies. Each training complex would be the core of an Educational Service District, which would be responsible for…

Self-Healing and Thermo-Responsive Dual-Crosslinked Alginate Hydrogels based on Supramolecular Inclusion Complexes

PubMed Central

Miao, Tianxin; Fenn, Spencer L.; Charron, Patrick N.; Oldinski, Rachael A.

2015-01-01

β-cyclodextrin (β-CD), with a lipophilic inner cavity and hydrophilic outer surface, interacts with a large variety of non-polar guest molecules to form non-covalent inclusion complexes. Conjugation of β-CD onto biomacromolecules can form physically-crosslinked hydrogel networks upon mixing with a guest molecule. Herein describes the development and characterization of self-healing, thermo-responsive hydrogels, based on host-guest inclusion complexes between alginate-graft-β-CD and Pluronic® F108 (poly(ethylene glycol)-b-poly(propylene glycol)-b-poly(ethylene glycol)). The mechanics, flow characteristics, and thermal response were contingent on the polymer concentrations, and the host-guest molar ratio. Transient and reversible physical crosslinking between host and guest polymers governed self-assembly, allowing flow under shear stress, and facilitating complete recovery of the material properties within a few seconds of unloading. The mechanical properties of the dual-crosslinked, multi-stimuli responsive hydrogels were tuned as high as 30 kPa at body temperature, and are advantageous for biomedical applications such as drug delivery and cell transplantation. PMID:26509214

Characterizing heterogeneous cellular responses to perturbations.

PubMed

Slack, Michael D; Martinez, Elisabeth D; Wu, Lani F; Altschuler, Steven J

2008-12-09

Cellular populations have been widely observed to respond heterogeneously to perturbation. However, interpreting the observed heterogeneity is an extremely challenging problem because of the complexity of possible cellular phenotypes, the large dimension of potential perturbations, and the lack of methods for separating meaningful biological information from noise. Here, we develop an image-based approach to characterize cellular phenotypes based on patterns of signaling marker colocalization. Heterogeneous cellular populations are characterized as mixtures of phenotypically distinct subpopulations, and responses to perturbations are summarized succinctly as probabilistic redistributions of these mixtures. We apply our method to characterize the heterogeneous responses of cancer cells to a panel of drugs. We find that cells treated with drugs of (dis-)similar mechanism exhibit (dis-)similar patterns of heterogeneity. Despite the observed phenotypic diversity of cells observed within our data, low-complexity models of heterogeneity were sufficient to distinguish most classes of drug mechanism. Our approach offers a computational framework for assessing the complexity of cellular heterogeneity, investigating the degree to which perturbations induce redistributions of a limited, but nontrivial, repertoire of underlying states and revealing functional significance contained within distinct patterns of heterogeneous responses.

The effects of the activation of the inner-hair-cell basolateral K+ channels on auditory nerve responses.

PubMed

Altoè, Alessandro; Pulkki, Ville; Verhulst, Sarah

2018-07-01

The basolateral membrane of the mammalian inner hair cell (IHC) expresses large voltage and Ca 2+ gated outward K + currents. To quantify how the voltage-dependent activation of the K + channels affects the functionality of the auditory nerve innervating the IHC, this study adopts a model of mechanical-to-neural transduction in which the basolateral K + conductances of the IHC can be made voltage-dependent or not. The model shows that the voltage-dependent activation of the K + channels (i) enhances the phase-locking properties of the auditory fiber (AF) responses; (ii) enables the auditory nerve to encode a large dynamic range of sound levels; (iii) enables the AF responses to synchronize precisely with the envelope of amplitude modulated stimuli; and (iv), is responsible for the steep offset responses of the AFs. These results suggest that the basolateral K + channels play a major role in determining the well-known response properties of the AFs and challenge the classical view that describes the IHC membrane as an electrical low-pass filter. In contrast to previous models of the IHC-AF complex, this study ascribes many of the AF response properties to fairly basic mechanisms in the IHC membrane rather than to complex mechanisms in the synapse. Copyright © 2018 Elsevier B.V. All rights reserved.

Insights into the species-specific TLR4 signaling mechanism in response to Rhodobacter sphaeroides lipid A detection

NASA Astrophysics Data System (ADS)

Anwar, Muhammad Ayaz; Panneerselvam, Suresh; Shah, Masaud; Choi, Sangdun

2015-01-01

TLR4 in complex with MD2 senses the presence of lipid A (LA) and initiates a signaling cascade that curb the infection. This complex is evolutionarily conserved and can initiate the immune system in response to a variety of LAs. In this study, molecular dynamics simulation (25 ns) was performed to elucidate the differential behavior of TLR4/MD2 complex in response to Rhodobacter sphaeroides lipid A (RsLA). Penta-acyl chain-containing RsLA is at the verge of agonist (6 acyl-chains) and antagonist (4 acyl-chains) structure, and activates the TLR4 pathway in horses and hamsters, while inhibiting in humans and murine. In the time-evolved coordinates, the promising factors that dictated the differential response included the local and global mobility pattern of complexes, solvent-accessible surface area of ligand, and surface charge distributions of TLR4 and MD2. We showed that the GlcN1-GlcN2 backbone acquires agonist (3FXI)-like configurations in horses and hamsters, while acquiring antagonist (2E59)-like configurations in humans and murine systems. Moreover, analysis of F126 behavior in the MD2 F126 loop (amino acids 123-129) and loop EF (81-89) suggested that certain sequence variations also contribute to species-specific response. This study underlines the TLR4 signaling mechanism and provides new therapeutic opportunities.

Blufensin1 Negatively Impacts Basal Defense in Response to Barley Powdery Mildew

USDA-ARS?s Scientific Manuscript database

Plants have evolved complex regulatory mechanisms to control the defense response against microbial attack. Both temporal and spatial gene expression are tightly regulated in response to pathogen ingress, modulating both positive and negative control of defense. BLUFENSIN1 (BLN1), a small peptide ...

Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yadav, N.; Kumar, S.; Marlowe, T.

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrialmore » biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.« less

Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

DOE PAGES

Yadav, N.; Kumar, S.; Marlowe, T.; ...

2015-11-05

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrialmore » biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.« less

Responses of antennal olfactory receptors in the yellow fever mosquito Aedes aegypti to human body odours.

PubMed

Pappenberger, B; Geier, M; Boeckh, J

1996-01-01

Recent behavioural studies have demonstrated that human body odours which female Aedes aegypti find attractive exert their effects as complex mixtures of synergistically acting components. We have attempted to clarify the sensory mechanisms underlying the perception of these complex host odours by studying the responses of sensory cells underneath the A3-type sensilla of the mosquito antenna to both a human skin wash extract and the extract's active chromatographic fractions. The reaction patterns show that the host stimuli elicit responses from several types of receptor cells in a typical across-fibre pattern mode. It seems as if this is another case where the essential message in a biologically significant odour consists of a complex pattern of compounds that is encoded in an according complex response pattern by a cooperating set of primary sensory neurons of different odour specificities.

Archaeal Genome Guardians Give Insights into Eukaryotic DNA Replication and Damage Response Proteins

PubMed Central

Shin, David S.; Pratt, Ashley J.; Tainer, John A.

2014-01-01

As the third domain of life, archaea, like the eukarya and bacteria, must have robust DNA replication and repair complexes to ensure genome fidelity. Archaea moreover display a breadth of unique habitats and characteristics, and structural biologists increasingly appreciate these features. As archaea include extremophiles that can withstand diverse environmental stresses, they provide fundamental systems for understanding enzymes and pathways critical to genome integrity and stress responses. Such archaeal extremophiles provide critical data on the periodic table for life as well as on the biochemical, geochemical, and physical limitations to adaptive strategies allowing organisms to thrive under environmental stress relevant to determining the boundaries for life as we know it. Specifically, archaeal enzyme structures have informed the architecture and mechanisms of key DNA repair proteins and complexes. With added abilities to temperature-trap flexible complexes and reveal core domains of transient and dynamic complexes, these structures provide insights into mechanisms of maintaining genome integrity despite extreme environmental stress. The DNA damage response protein structures noted in this review therefore inform the basis for genome integrity in the face of environmental stress, with implications for all domains of life as well as for biomanufacturing, astrobiology, and medicine. PMID:24701133

High fidelity computational characterization of the mechanical response of thermally aged polycarbonate

NASA Astrophysics Data System (ADS)

Zhang, Zesheng; Zhang, Lili; Jasa, John; Li, Wenlong; Gazonas, George; Negahban, Mehrdad

2017-07-01

A representative all-atom molecular dynamics (MD) system of polycarbonate (PC) is built and conditioned to capture and predict the behaviours of PC in response to a broad range of thermo-mechanical loadings for various thermal aging. The PC system is constructed to have a distribution of molecular weights comparable to a widely used commercial PC (LEXAN 9034), and thermally conditioned to produce models for aged and unaged PC. The MD responses of these models are evaluated through comparisons to existing experimental results carried out at much lower loading rates, but done over a broad range of temperatures and loading modes. These experiments include monotonic extension/compression/shear, unilaterally and bilaterally confined compression, and load-reversal during shear. It is shown that the MD simulations show both qualitative and quantitative similarity with the experimental response. The quantitative similarity is evaluated by comparing the dilatational response under bilaterally confined compression, the shear flow viscosity and the equivalent yield stress. The consistency of the in silico response to real laboratory experiments strongly suggests that the current PC models are physically and mechanically relevant and potentially can be used to investigate thermo-mechanical response to loading conditions that would not easily be possible. These MD models may provide valuable insight into the molecular sources of certain observations, and could possibly offer new perspectives on how to develop constitutive models that are based on better understanding the response of PC under complex loadings. To this latter end, the models are used to predict the response of PC to complex loading modes that would normally be difficult to do or that include characteristics that would be difficult to measure. These include the responses of unaged and aged PC to unilaterally confined extension/compression, cyclic uniaxial/shear loadings, and saw-tooth extension/compression/shear.

Phospholipase D and phosphatidic acid in plant defence response: from protein–protein and lipid–protein interactions to hormone signalling

PubMed Central

Zhao, Jian

2015-01-01

Phospholipase Ds (PLDs) and PLD-derived phosphatidic acids (PAs) play vital roles in plant hormonal and environmental responses and various cellular dynamics. Recent studies have further expanded the functions of PLDs and PAs into plant–microbe interaction. The molecular diversities and redundant functions make PLD–PA an important signalling complex regulating lipid metabolism, cytoskeleton dynamics, vesicle trafficking, and hormonal signalling in plant defence through protein–protein and protein–lipid interactions or hormone signalling. Different PLD–PA signalling complexes and their targets have emerged as fast-growing research topics for understanding their numerous but not yet established roles in modifying pathogen perception, signal transduction, and downstream defence responses. Meanwhile, advanced lipidomics tools have allowed researchers to reveal further the mechanisms of PLD–PA signalling complexes in regulating lipid metabolism and signalling, and their impacts on jasmonic acid/oxylipins, salicylic acid, and other hormone signalling pathways that essentially mediate plant defence responses. This review attempts to summarize the progress made in spatial and temporal PLD/PA signalling as well as PLD/PA-mediated modification of plant defence. It presents an in-depth discussion on the functions and potential mechanisms of PLD–PA complexes in regulating actin filament/microtubule cytoskeleton, vesicle trafficking, and hormonal signalling, and in influencing lipid metabolism-derived metabolites as critical signalling components in plant defence responses. The discussion puts PLD–PA in a broader context in order to guide future research. PMID:25680793

Light and oxygenic photosynthesis: energy dissipation as a protection mechanism against photo-oxidation

PubMed Central

Szabó, Ildikó; Bergantino, Elisabetta; Giacometti, Giorgio Mario

2005-01-01

Efficient photosynthesis is of fundamental importance for plant survival and fitness. However, in oxygenic photosynthesis, the complex apparatus responsible for the conversion of light into chemical energy is susceptible to photodamage. Oxygenic photosynthetic organisms have therefore evolved several protective mechanisms to deal with light energy. Rapidly inducible non-photochemical quenching (NPQ) is a short-term response by which plants and eukaryotic algae dissipate excitation energy as heat. This review focuses on recent advances in the elucidation of the molecular mechanisms underlying this protective quenching pathway in higher plants. PMID:15995679

Behavioural system identification of visual flight speed control in Drosophila melanogaster

PubMed Central

Rohrseitz, Nicola; Fry, Steven N.

2011-01-01

Behavioural control in many animals involves complex mechanisms with intricate sensory-motor feedback loops. Modelling allows functional aspects to be captured without relying on a description of the underlying complex, and often unknown, mechanisms. A wide range of engineering techniques are available for modelling, but their ability to describe time-continuous processes is rarely exploited to describe sensory-motor control mechanisms in biological systems. We performed a system identification of visual flight speed control in the fruitfly Drosophila, based on an extensive dataset of open-loop responses previously measured under free flight conditions. We identified a second-order under-damped control model with just six free parameters that well describes both the transient and steady-state characteristics of the open-loop data. We then used the identified control model to predict flight speed responses after a visual perturbation under closed-loop conditions and validated the model with behavioural measurements performed in free-flying flies under the same closed-loop conditions. Our system identification of the fruitfly's flight speed response uncovers the high-level control strategy of a fundamental flight control reflex without depending on assumptions about the underlying physiological mechanisms. The results are relevant for future investigations of the underlying neuromotor processing mechanisms, as well as for the design of biomimetic robots, such as micro-air vehicles. PMID:20525744

Behavioural system identification of visual flight speed control in Drosophila melanogaster.

PubMed

Rohrseitz, Nicola; Fry, Steven N

2011-02-06

Behavioural control in many animals involves complex mechanisms with intricate sensory-motor feedback loops. Modelling allows functional aspects to be captured without relying on a description of the underlying complex, and often unknown, mechanisms. A wide range of engineering techniques are available for modelling, but their ability to describe time-continuous processes is rarely exploited to describe sensory-motor control mechanisms in biological systems. We performed a system identification of visual flight speed control in the fruitfly Drosophila, based on an extensive dataset of open-loop responses previously measured under free flight conditions. We identified a second-order under-damped control model with just six free parameters that well describes both the transient and steady-state characteristics of the open-loop data. We then used the identified control model to predict flight speed responses after a visual perturbation under closed-loop conditions and validated the model with behavioural measurements performed in free-flying flies under the same closed-loop conditions. Our system identification of the fruitfly's flight speed response uncovers the high-level control strategy of a fundamental flight control reflex without depending on assumptions about the underlying physiological mechanisms. The results are relevant for future investigations of the underlying neuromotor processing mechanisms, as well as for the design of biomimetic robots, such as micro-air vehicles.

Laminar and orientation-dependent characteristics of spatial nonlinearities: implications for the computational architecture of visual cortex.

PubMed

Victor, Jonathan D; Mechler, Ferenc; Ohiorhenuan, Ifije; Schmid, Anita M; Purpura, Keith P

2009-12-01

A full understanding of the computations performed in primary visual cortex is an important yet elusive goal. Receptive field models consisting of cascades of linear filters and static nonlinearities may be adequate to account for responses to simple stimuli such as gratings and random checkerboards, but their predictions of responses to complex stimuli such as natural scenes are only approximately correct. It is unclear whether these discrepancies are limited to quantitative inaccuracies that reflect well-recognized mechanisms such as response normalization, gain controls, and cross-orientation suppression or, alternatively, imply additional qualitative features of the underlying computations. To address this question, we examined responses of V1 and V2 neurons in the monkey and area 17 neurons in the cat to two-dimensional Hermite functions (TDHs). TDHs are intermediate in complexity between traditional analytic stimuli and natural scenes and have mathematical properties that facilitate their use to test candidate models. By exploiting these properties, along with the laminar organization of V1, we identify qualitative aspects of neural computations beyond those anticipated from the above-cited model framework. Specifically, we find that V1 neurons receive signals from orientation-selective mechanisms that are highly nonlinear: they are sensitive to phase correlations, not just spatial frequency content. That is, the behavior of V1 neurons departs from that of linear-nonlinear cascades with standard modulatory mechanisms in a qualitative manner: even relatively simple stimuli evoke responses that imply complex spatial nonlinearities. The presence of these findings in the input layers suggests that these nonlinearities act in a feedback fashion.

Behavioral genetics and taste

PubMed Central

Boughter, John D; Bachmanov, Alexander A

2007-01-01

This review focuses on behavioral genetic studies of sweet, umami, bitter and salt taste responses in mammals. Studies involving mouse inbred strain comparisons and genetic analyses, and their impact on elucidation of taste receptors and transduction mechanisms are discussed. Finally, the effect of genetic variation in taste responsiveness on complex traits such as drug intake is considered. Recent advances in development of genomic resources make behavioral genetics a powerful approach for understanding mechanisms of taste. PMID:17903279

Mechanisms regulating skin immunity and inflammation.

PubMed

Pasparakis, Manolis; Haase, Ingo; Nestle, Frank O

2014-05-01

Immune responses in the skin are important for host defence against pathogenic microorganisms. However, dysregulated immune reactions can cause chronic inflammatory skin diseases. Extensive crosstalk between the different cellular and microbial components of the skin regulates local immune responses to ensure efficient host defence, to maintain and restore homeostasis, and to prevent chronic disease. In this Review, we discuss recent findings that highlight the complex regulatory networks that control skin immunity, and we provide new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation.

Paucity of attractors in nonlinear systems driven with complex signals.

PubMed

Pethel, Shawn D; Blakely, Jonathan N

2011-04-01

We study the probability of multistability in a quadratic map driven repeatedly by a random signal of length N, where N is taken as a measure of the signal complexity. We first establish analytically that the number of coexisting attractors is bounded above by N. We then numerically estimate the probability p of a randomly chosen signal resulting in a multistable response as a function of N. Interestingly, with increasing drive signal complexity the system exhibits a paucity of attractors. That is, almost any drive signal beyond a certain complexity level will result in a single attractor response (p=0). This mechanism may play a role in allowing sensitive multistable systems to respond consistently to external influences.

Advances in cardiovascular fluid mechanics: bench to bedside.

PubMed

Dasi, Lakshmi P; Sucosky, Philippe; de Zelicourt, Diane; Sundareswaran, Kartik; Jimenez, Jorge; Yoganathan, Ajit P

2009-04-01

This paper presents recent advances in cardiovascular fluid mechanics that define the current state of the art. These studies include complex multimodal investigations with advanced measurement and simulation techniques. We first discuss the complex flows within the total cavopulmonary connection in Fontan patients. We emphasize the quantification of energy losses by studying the importance of caval offsets as well as the differences among various Fontan surgical protocols. In our studies of the fluid mechanics of prosthetic heart valves, we reveal for the first time the full three-dimensional complexity of flow fields in the vicinity of bileaflet and trileaflet valves and the microscopic hinge flow dynamics. We also present results of these valves functioning in a patient-specific native aorta geometry. Our in vitro mitral valve studies show the complex mechanism of the native mitral valve apparatus. We demonstrate that the different components of the mitral valve have independent and synergistically complex functions that allow the valve to operate efficiently. We also show how valve mechanics change under pathological and repair conditions associated with enlarged ventricles. Finally, our ex vivo studies on the interactions between the aortic valve and its surrounding hemodynamic environment are aimed at providing insights into normal valve function and valve pathology. We describe the development of organ- and tissue-culture systems and the biological response of the tissue subjected to their respective simulated mechanical environment. The studies noted above have enhanced our understanding of the complex fluid mechanics associated with the cardiovascular system and have led to new translational technologies.

Numerical Study of the Complex Temporal Pattern of Spontaneous Oscillation in Bullfrog Saccular Hair Cells

NASA Astrophysics Data System (ADS)

Roongthumskul, Yuttana; Fredrickson-Hemsing, Lea; Kao, Albert; Bozovic, Dolores

2011-11-01

Hair bundles of the bullfrog sacculus display spontaneous oscillations that show complex temporal profiles. Quiescent intervals are typically interspersed with oscillations, analogous to bursting behavior observed in neural systems. By introducing slow calcium dynamics into the theoretical model of bundle mechanics, we reproduce numerically the multi-mode oscillations and explore the effects of internal parameters on the temporal profiles and the frequency tuning of their linear response functions. We also study the effects of mechanical overstimulation on the oscillatory behavior.

A Class of Multiresponsive Colorimetric and Fluorescent pH Probes via Three Different Reaction Mechanisms of Salen Complexes: A Selective and Accurate pH Measurement.

PubMed

Cheng, Jinghui; Gou, Fei; Zhang, Xiaohong; Shen, Guangyu; Zhou, Xiangge; Xiang, Haifeng

2016-09-19

We report a class of multiresponsive colorimetric and fluorescent pH probes based on three different reaction mechanisms including cation exchange, protonation, and hydrolysis reaction of K(I), Ca(II), Zn(II), Cu(II), Al(III), and Pd(II) Salen complexes. Compared with traditional pure organic pH probes, these complex-based pH probes exhibited a much better selectivity due to the shielding function of the filled-in metal ion in the complex. Their pH sensing performances were affected by the ligand structure and the central metal ion. This work is the first report of "off-on-on'-off" colorimetric and fluorescent pH probes that possess three different reaction mechanisms and should inspire the design of multiple-responsive probes for important analytes in biological systems.

Soil moisture controlled runoff mechanisms in a small agricultural catchment in Austria.

NASA Astrophysics Data System (ADS)

Vreugdenhil, Mariette; Szeles, Borbala; Silasari, Rasmiaditya; Hogan, Patrick; Oismueller, Markus; Strauss, Peter; Wagner, Wolfgang; Bloeschl, Guenter

2017-04-01

Understanding runoff generation mechanisms is pivotal for improved estimation of floods in small catchments. However, this requires in situ measurements with a high spatial and temporal resolution of different land surface parameters, which are rarely available distributed over the catchment scale and for a long period. The Hydrological Open Air Laboratory (HOAL) is a hydrological observatory which comprises a complex agricultural catchment, covering 66 ha. Due to the agricultural land use and low permeability of the soil part of the catchment was tile drained in the 1940s. The HOAL is equipped with an extensive soil moisture network measuring at 31 locations, 4 rain gauges and 12 stream gauges. By measuring with so many sensors in a complex catchment, the collected data enables the investigation of multiple runoff mechanisms which can be observed simultaneously in different parts of the catchment. The aim of this study is to identify and characterize different runoff mechanisms and the control soil moisture dynamics exert on them. As a first step 72 rainfall events were identified within the period 2014-2015. By analyzing event discharge response, measured at the different stream gauges, and root zone soil moisture, four different runoff mechanisms are identified. The four mechanisms exhibit contrasting soil moisture-discharge relationships. In the presented study we characterize the runoff response types by curve-fitting the discharge response to the soil moisture state. The analysis provides insights in the main runoff processes occurring in agricultural catchments. The results of this study a can be of assistance in other catchments to identify catchment hydrologic response.

The role and mechanics of dendritic cells in tumor antigen acquisition and presentation following laser immunotherapy

NASA Astrophysics Data System (ADS)

Laverty, Sean M.; Dawkins, Bryan A.; Chen, Wei R.

2018-02-01

We extend our model of the antitumor immune response initiated by laser-immunotherapy treatment to more closely examine key steps in the immune response 1) tumor antigen acquisition by antigen-presenting dendritic cells (DCs) and 2) cytotoxic T cell (CTL) priming by lymphatic DCs. Specifically we explore the formation of DC-CTL complexes that lead to CTL priming. We find that the bias in the dissociation rate of the complex influences the outcome of treatment. In particular, a bias towards priming favors a rapid activated CTL response and the clearance of tumors.

Modelling DC responses of 3D complex fracture networks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beskardes, Gungor Didem; Weiss, Chester Joseph

Here, the determination of the geometrical properties of fractures plays a critical role in many engineering problems to assess the current hydrological and mechanical states of geological media and to predict their future states. However, numerical modeling of geoelectrical responses in realistic fractured media has been challenging due to the explosive computational cost imposed by the explicit discretizations of fractures at multiple length scales, which often brings about a tradeoff between computational efficiency and geologic realism. Here, we use the hierarchical finite element method to model electrostatic response of realistically complex 3D conductive fracture networks with minimal computational cost.

Modelling DC responses of 3D complex fracture networks

DOE PAGES

Beskardes, Gungor Didem; Weiss, Chester Joseph

2018-03-01

Here, the determination of the geometrical properties of fractures plays a critical role in many engineering problems to assess the current hydrological and mechanical states of geological media and to predict their future states. However, numerical modeling of geoelectrical responses in realistic fractured media has been challenging due to the explosive computational cost imposed by the explicit discretizations of fractures at multiple length scales, which often brings about a tradeoff between computational efficiency and geologic realism. Here, we use the hierarchical finite element method to model electrostatic response of realistically complex 3D conductive fracture networks with minimal computational cost.

NF-κB activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer

PubMed Central

Blakely, Collin M.; Pazarentzos, Evangelos; Olivas, Victor; Asthana, Saurabh; Yan, Jenny Jiacheng; Tan, Irena; Hrustanovic, Gorjan; Chan, Elton; Lin, Luping; Neel, Dana S.; Newton, William; Bobb, Kathryn; Fouts, Timothy; Meshulam, Jeffrey; Gubens, Matthew A.; Jablons, David M.; Johnson, Jeffrey R.; Bandyopadhyay, Sourav; Krogan, Nevan J.; Bivona, Trever G.

2015-01-01

Summary Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR-mutant lung adenocarcinoma we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses. PMID:25843712

Metabolic responses in Candida tropicalis to complex inhibitors during xylitol bioconversion.

PubMed

Wang, Shizeng; Li, Hao; Fan, Xiaoguang; Zhang, Jingkun; Tang, Pingwah; Yuan, Qipeng

2015-09-01

During xylitol fermentation, Candida tropicalis is often inhibited by inhibitors in hemicellulose hydrolysate. The mechanisms involved in the metabolic responses to inhibitor stress and the resistances to inhibitors are still not clear. To understand the inhibition mechanisms and the metabolic responses to inhibitors, a GC/MS-based metabolomics approach was performed on C. tropicalis treated with and without complex inhibitors (CI, including furfural, phenol and acetic acid). Partial least squares discriminant analysis was used to determine the metabolic variability between CI-treated groups and control groups, and 25 metabolites were identified as possible entities responsible for the discrimination caused by inhibitors. We found that xylose uptake rate and xylitol oxidation rate were promoted by CI treatment. Metabolomics analysis showed that the flux from xylulose to pentose phosphate pathway increased, and tricarboxylic acid cycle was disturbed by CI. Moreover, the changes in levels of 1,3-propanediol, trehalose, saturated fatty acids and amino acids showed different mechanisms involved in metabolic responses to inhibitor stress. The increase of 1,3-propanediol was considered to be correlated with regulating redox balance and osmoregulation. The increase of trehalose might play a role in protein stabilization and cellular membranes protection. Saturated fatty acids could cause the decrease of membrane fluidity and make the plasma membrane rigid to maintain the integrity of plasma membrane. The deeper understanding of the inhibition mechanisms and the metabolic responses to inhibitors will provide us with more information on the metabolism regulation during xylitol bioconversion and the construction of industrial strains with inhibitor tolerance for better utilization of bioresource. Copyright © 2015 Elsevier Inc. All rights reserved.

Multiscale characterization and mechanical modeling of an Al-Zn-Mg electron beam weld

NASA Astrophysics Data System (ADS)

Puydt, Quentin; Flouriot, Sylvain; Ringeval, Sylvain; Parry, Guillaume; De Geuser, Frédéric; Deschamps, Alexis

Welding of precipitation hardening alloys results in multi-scale microstructural heterogeneities, from the hardening nano-scale precipitates to the micron-scale solidification structures and to the component geometry. This heterogeneity results in a complex mechanical response, with gradients in strength, stress triaxiality and damage initiation sites.

A Complex mTOR Response in Habituation Paradigms for a Social Signal in Adult Songbirds

ERIC Educational Resources Information Center

Ahmadiantehrani, Somayeh; Gores, Elisa O.; London, Sarah E.

2018-01-01

Nonassociative learning is considered simple because it depends on presentation of a single stimulus, but it likely reflects complex molecular signaling. To advance understanding of the molecular mechanisms of one form of nonassociative learning, habituation, for ethologically relevant signals we examined song recognition learning in adult zebra…

Unification of color postprocessing techniques for 3-dimensional computational mechanics

NASA Technical Reports Server (NTRS)

Bailey, Bruce Charles

1985-01-01

To facilitate the understanding of complex three-dimensional numerical models, advanced interactive color postprocessing techniques are introduced. These techniques are sufficiently flexible so that postprocessing difficulties arising from model size, geometric complexity, response variation, and analysis type can be adequately overcome. Finite element, finite difference, and boundary element models may be evaluated with the prototype postprocessor. Elements may be removed from parent models to be studied as independent subobjects. Discontinuous responses may be contoured including responses which become singular, and nonlinear color scales may be input by the user for the enhancement of the contouring operation. Hit testing can be performed to extract precise geometric, response, mesh, or material information from the database. In addition, stress intensity factors may be contoured along the crack front of a fracture model. Stepwise analyses can be studied, and the user can recontour responses repeatedly, as if he were paging through the response sets. As a system, these tools allow effective interpretation of complex analysis results.

Phospholipase D and phosphatidic acid in plant defence response: from protein-protein and lipid-protein interactions to hormone signalling.

PubMed

Zhao, Jian

2015-04-01

Phospholipase Ds (PLDs) and PLD-derived phosphatidic acids (PAs) play vital roles in plant hormonal and environmental responses and various cellular dynamics. Recent studies have further expanded the functions of PLDs and PAs into plant-microbe interaction. The molecular diversities and redundant functions make PLD-PA an important signalling complex regulating lipid metabolism, cytoskeleton dynamics, vesicle trafficking, and hormonal signalling in plant defence through protein-protein and protein-lipid interactions or hormone signalling. Different PLD-PA signalling complexes and their targets have emerged as fast-growing research topics for understanding their numerous but not yet established roles in modifying pathogen perception, signal transduction, and downstream defence responses. Meanwhile, advanced lipidomics tools have allowed researchers to reveal further the mechanisms of PLD-PA signalling complexes in regulating lipid metabolism and signalling, and their impacts on jasmonic acid/oxylipins, salicylic acid, and other hormone signalling pathways that essentially mediate plant defence responses. This review attempts to summarize the progress made in spatial and temporal PLD/PA signalling as well as PLD/PA-mediated modification of plant defence. It presents an in-depth discussion on the functions and potential mechanisms of PLD-PA complexes in regulating actin filament/microtubule cytoskeleton, vesicle trafficking, and hormonal signalling, and in influencing lipid metabolism-derived metabolites as critical signalling components in plant defence responses. The discussion puts PLD-PA in a broader context in order to guide future research. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Sorption Mechanisms of Antibiotic Cephapirin onto Quartz and Feldspar by Raman Spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peterson, Jonathan; Wang, Wei; Gu, Baohua

2009-01-01

Raman spectroscopy was used to investigate the sorption mechanisms of cephapirin (CHP), a veterinary antibiotic, onto quartz (SiO2) and feldspar (KAlSi3O8) at different pH values. Depending on the charge and surface properties of the mineral, different reaction mechanisms including electrostatic attraction, monodentate and bidentate complexation were found to be responsible for CHP sorption. The zwitterion (CHPo) adsorbs to a quartz(+) surface by electrostatic attraction of the carboxylate anion group ( COO-) at a low pH, but adsorbs to a quartz(-) surface through electrostatic attraction of the pyridinium cation and possibly COO- bridge complexes at relatively higher pH conditions. CHP- bondsmore » to a quartz(-) surface by bidentate complexation between one oxygen of COO- and oxygen from the carbonyl (C=O) of the acetoxymethyl group. On a feldspar surface of mixed charge, CHPo forms monodentate complexes between C=O as well as COO- bridging complexes or electrostatically attached to localized edge (hydr)oxy-Al surfaces. CHP- adsorbs to feldspar(-) through monodentate C=O complexation, and similar mechanisms may operate for the sorption of other cephalosporins. This research demonstrates, for the first time, that Raman spectroscopic techniques can be effective for evaluating the sorption processes and mechanisms of cephalosporin antibiotics even at relatively low sorbed concentrations (97-120 μmol/kg).« less

Biphasic responses in multi-site phosphorylation systems.

PubMed

Suwanmajo, Thapanar; Krishnan, J

2013-12-06

Multi-site phosphorylation systems are repeatedly encountered in cellular biology and multi-site modification is a basic building block of post-translational modification. In this paper, we demonstrate how distributive multi-site modification mechanisms by a single kinase/phosphatase pair can lead to biphasic/partial biphasic dose-response characteristics for the maximally phosphorylated substrate at steady state. We use simulations and analysis to uncover a hidden competing effect which is responsible for this and analyse how it may be accentuated. We build on this to analyse different variants of multi-site phosphorylation mechanisms showing that some mechanisms are intrinsically not capable of displaying this behaviour. This provides both a consolidated understanding of how and under what conditions biphasic responses are obtained in multi-site phosphorylation and a basis for discriminating between different mechanisms based on this. We also demonstrate how this behaviour may be combined with other behaviour such as threshold and bistable responses, demonstrating the capacity of multi-site phosphorylation systems to act as complex molecular signal processors.

Responses to olfactory signals reflect network structure of flower-visitor interactions.

PubMed

Junker, Robert R; Höcherl, Nicole; Blüthgen, Nico

2010-07-01

1. Network analyses provide insights into the diversity and complexity of ecological interactions and have motivated conclusions about community stability and co-evolution. However, biological traits and mechanisms such as chemical signals regulating the interactions between individual species--the microstructure of a network--are poorly understood. 2. We linked the responses of receivers (flower visitors) towards signals (flower scent) to the structure of a highly diverse natural flower-insect network. For each interaction, we define link temperature--a newly developed metric--as the deviation of the observed interaction strength from neutrality, assuming that animals randomly interact with flowers. 3. Link temperature was positively correlated to the specific visitors' responses to floral scents, experimentally examined in a mobile olfactometer. Thus, communication between plants and consumers via phytochemical signals reflects a significant part of the microstructure in a complex network. Negative as well as positive responses towards floral scents contributed to these results, where individual experience was important apart from innate behaviour. 4. Our results indicate that: (1) biological mechanisms have a profound impact on the microstructure of complex networks that underlies the outcome of aggregate statistics, and (2) floral scents act as a filter, promoting the visitation of some flower visitors, but also inhibiting the visitation of others.

RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma.

PubMed

Das, Arabinda; McDonald, Daniel G; Dixon-Mah, Yaenette N; Jacqmin, Dustin J; Samant, Vikram N; Vandergrift, William A; Lindhorst, Scott M; Cachia, David; Varma, Abhay K; Vanek, Kenneth N; Banik, Naren L; Jenrette, Joseph M; Raizer, Jeffery J; Giglio, Pierre; Patel, Sunil J

2016-06-01

Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK'872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma.

Adaptation of neuronal signaling and cell stress response pathways in a multigenic response of Drosophila melanogaster to DDT selection

USDA-ARS?s Scientific Manuscript database

The adaptation of insect populations to insecticidal control is a continual threat human health and sustainable agriculture practices, but many complex genomic mechanisms involved remain poorly understood. A systems approach was applied to investigate the interconnections between structural and func...

Evaluation and expression analysis of alfalfa genotypes in response to prolonged salt stress

USDA-ARS?s Scientific Manuscript database

Salinity is one of the most important abiotic stresses that adversely affect plant growth and productivity globally. In order to tackle this complex problem, it is important to link the biochemical and physiological responses with the underlying genetic mechanisms. In this study, we used 12 previous...

Endocrine Responses to Resistance Exercise,

DTIC Science & Technology

1987-08-30

resistance training responses of selected hormones related to acute stress and growth promoting actions. Hormonal mechanisms appear to be involved with ...an important determinant of hormonal response. Still. little is known with regard to other single and multiple factor variables (e.g.. rest period...hormone through a direct interaction with a cytoplasmic receptor leading to the typical migration of the hormone-receptor complex to the nucleus

Coordination of frontline defense mechanisms under severe oxidative stress.

PubMed

Kaur, Amardeep; Van, Phu T; Busch, Courtney R; Robinson, Courtney K; Pan, Min; Pang, Wyming Lee; Reiss, David J; DiRuggiero, Jocelyne; Baliga, Nitin S

2010-07-01

Complexity of cellular response to oxidative stress (OS) stems from its wide-ranging damage to nucleic acids, proteins, carbohydrates, and lipids. We have constructed a systems model of OS response (OSR) for Halobacterium salinarum NRC-1 in an attempt to understand the architecture of its regulatory network that coordinates this complex response. This has revealed a multi-tiered OS-management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, production of rhodopsins, carotenoids and gas vesicles, metal trafficking, and various other aspects of metabolism. Through experimental validation of interactions within the OSR regulatory network, we show that despite their inability to directly sense reactive oxygen species, general transcription factors have an important function in coordinating this response. Remarkably, a significant fraction of this OSR was accurately recapitulated by a model that was earlier constructed from cellular responses to diverse environmental perturbations--this constitutes the general stress response component. Notwithstanding this observation, comparison of the two models has identified the coordination of frontline defense and repair systems by regulatory mechanisms that are triggered uniquely by severe OS and not by other environmental stressors, including sub-inhibitory levels of redox-active metals, extreme changes in oxygen tension, and a sub-lethal dose of gamma rays.

Example of Good Practice of a Learning Environment with a Classroom Response System in a Mechanical Engineering Bachelor Course

ERIC Educational Resources Information Center

Arteaga, Ines Lopez; Vinken, Esther

2013-01-01

Results of a successful pilot study are presented, in which quizzes are introduced in a second year bachelor course for mechanical engineering students. The pilot study course entailed the basic concepts of mechanical vibrations in complex, realistic structures. The quiz is held weekly using a SharePoint application. The purpose of the quizzes is…

In vivo quantitative analysis of Talin turnover in response to force

PubMed Central

Hákonardóttir, Guðlaug Katrín; López-Ceballos, Pablo; Herrera-Reyes, Alejandra Donají; Das, Raibatak; Coombs, Daniel; Tanentzapf, Guy

2015-01-01

Cell adhesion to the extracellular matrix (ECM) allows cells to form and maintain three-dimensional tissue architecture. Cell–ECM adhesions are stabilized upon exposure to mechanical force. In this study, we used quantitative imaging and mathematical modeling to gain mechanistic insight into how integrin-based adhesions respond to increased and decreased mechanical forces. A critical means of regulating integrin-based adhesion is provided by modulating the turnover of integrin and its adhesion complex (integrin adhesion complex [IAC]). The turnover of the IAC component Talin, a known mechanosensor, was analyzed using fluorescence recovery after photobleaching. Experiments were carried out in live, intact flies in genetic backgrounds that increased or decreased the force applied on sites of adhesion. This analysis showed that when force is elevated, the rate of assembly of new adhesions increases such that cell–ECM adhesion is stabilized. Moreover, under conditions of decreased force, the overall rate of turnover, but not the proportion of adhesion complex components undergoing turnover, increases. Using point mutations, we identify the key functional domains of Talin that mediate its response to force. Finally, by fitting a mathematical model to the data, we uncover the mechanisms that mediate the stabilization of ECM-based adhesion during development. PMID:26446844

Drought-Responsive Mechanisms in Plant Leaves Revealed by Proteomics.

PubMed

Wang, Xiaoli; Cai, Xiaofeng; Xu, Chenxi; Wang, Quanhua; Dai, Shaojun

2016-10-18

Plant drought tolerance is a complex trait that requires a global view to understand its underlying mechanism. The proteomic aspects of plant drought response have been extensively investigated in model plants, crops and wood plants. In this review, we summarize recent proteomic studies on drought response in leaves to reveal the common and specialized drought-responsive mechanisms in different plants. Although drought-responsive proteins exhibit various patterns depending on plant species, genotypes and stress intensity, proteomic analyses show that dominant changes occurred in sensing and signal transduction, reactive oxygen species scavenging, osmotic regulation, gene expression, protein synthesis/turnover, cell structure modulation, as well as carbohydrate and energy metabolism. In combination with physiological and molecular results, proteomic studies in leaves have helped to discover some potential proteins and/or metabolic pathways for drought tolerance. These findings provide new clues for understanding the molecular basis of plant drought tolerance.

Drought-Responsive Mechanisms in Plant Leaves Revealed by Proteomics

PubMed Central

Wang, Xiaoli; Cai, Xiaofeng; Xu, Chenxi; Wang, Quanhua; Dai, Shaojun

2016-01-01

Plant drought tolerance is a complex trait that requires a global view to understand its underlying mechanism. The proteomic aspects of plant drought response have been extensively investigated in model plants, crops and wood plants. In this review, we summarize recent proteomic studies on drought response in leaves to reveal the common and specialized drought-responsive mechanisms in different plants. Although drought-responsive proteins exhibit various patterns depending on plant species, genotypes and stress intensity, proteomic analyses show that dominant changes occurred in sensing and signal transduction, reactive oxygen species scavenging, osmotic regulation, gene expression, protein synthesis/turnover, cell structure modulation, as well as carbohydrate and energy metabolism. In combination with physiological and molecular results, proteomic studies in leaves have helped to discover some potential proteins and/or metabolic pathways for drought tolerance. These findings provide new clues for understanding the molecular basis of plant drought tolerance. PMID:27763546

Mechanical and electrical tuning in a tonotopically organized insect ear

NASA Astrophysics Data System (ADS)

Hummel, Jennifer; Schöneich, Stefan; Hedwig, Berthold; Kössl, Manfred; Nowotny, Manuela

2015-12-01

The high-frequency hearing organ of bushcrickets - the crista acustica (CA) - is tonotopically organized. Details about the mechano-electrical transduction mechanisms within the sensory-cell complex, however, remain unknown. In the recent study, we investigated and compared the anatomical, mechanical and electrophysiological properties of the CA and reveal a strong correlation of the mechanical and neuronal frequency tuning, which is supported by an anatomical gradient along the CA. Only in the distal high-frequency region of the CA a discrepancy between a strong mechanical response to low frequencies <30 kHz and a neuronal response that was restricted to frequencies >30 kHz was found. Therefore, we suggest that there might be additional intrinsic tuning mechanisms in the sensory cells of the distal region to distinguish the frequency content of sound.

Origami-inspired building block and parametric design for mechanical metamaterials

NASA Astrophysics Data System (ADS)

Jiang, Wei; Ma, Hua; Feng, Mingde; Yan, Leilei; Wang, Jiafu; Wang, Jun; Qu, Shaobo

2016-08-01

An origami-based building block of mechanical metamaterials is proposed and explained by introducing a mechanism model based on its geometry. According to our model, this origami mechanism supports response to uniaxial tension that depends on structure parameters. Hence, its mechanical properties can be tunable by adjusting the structure parameters. Experiments for poly lactic acid (PLA) samples were carried out, and the results are in good agreement with those of finite element analysis (FEA). This work may be useful for designing building blocks of mechanical metamaterials or other complex mechanical structures.

Coordination of Satellite Cell Activation and Self-Renewal by Par-Complex-Dependent Asymmetric Activation of p38α/β MAPK

PubMed Central

Troy, Andrew; Cadwallader, Adam B.; Fedorov, Yuri; Tyner, Kristina; Tanaka, Kathleen Kelly; Olwin, Bradley B.

2014-01-01

SUMMARY In response to muscle injury, satellite cells activate the p38α/β MAPK pathway to exit quiescence, then proliferate, repair skeletal muscle, and self-renew, replenishing the quiescent satellite cell pool. Although satellite cells are capable of asymmetric division, the mechanisms regulating satellite cell self-renewal are not understood. We found that satellite cells, once activated, enter the cell cycle and a subset undergoes asymmetric division, renewing the satellite cell pool. Asymmetric localization of the Par complex activates p38α/β MAPK in only one daughter cell, inducing MyoD, which permits cell cycle entry and generates a proliferating myoblast. The absence of p38α/β MAPK signaling in the other daughter cell prevents MyoD induction, renewing the quiescent satellite cell. Thus, satellite cells employ a mechanism to generate distinct daughter cells, coupling the Par complex and p38α/β MAPK signaling to link the response to muscle injury with satellite cell self-renewal. PMID:23040480

Efficient approach to obtain free energy gradient using QM/MM MD simulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asada, Toshio; Koseki, Shiro; The Research Institute for Molecular Electronic Devices

2015-12-31

The efficient computational approach denoted as charge and atom dipole response kernel (CDRK) model to consider polarization effects of the quantum mechanical (QM) region is described using the charge response and the atom dipole response kernels for free energy gradient (FEG) calculations in the quantum mechanical/molecular mechanical (QM/MM) method. CDRK model can reasonably reproduce energies and also energy gradients of QM and MM atoms obtained by expensive QM/MM calculations in a drastically reduced computational time. This model is applied on the acylation reaction in hydrated trypsin-BPTI complex to optimize the reaction path on the free energy surface by means ofmore » FEG and the nudged elastic band (NEB) method.« less

Cell wall pectic arabinans influence the mechanical properties of Arabidopsis thaliana inflorescence stems and their response to mechanical stress.

PubMed

Verhertbruggen, Yves; Marcus, Susan E; Chen, Jianshe; Knox, J Paul

2013-08-01

Little is known of the dynamics of plant cell wall matrix polysaccharides in response to the impact of mechanical stress on plant organs. The capacity of the imposition of a mechanical stress (periodic brushing) to reduce the height of the inflorescence stem of Arabidopsis thaliana seedlings has been used to study the role of pectic arabinans in the mechanical properties and stress responsiveness of a plant organ. The arabinan-deficient-1 (arad1) mutation that affects arabinan structures in epidermal cell walls of inflorescence stems is demonstrated to reduce the impact on inflorescence stem heights caused by mechanical stress. The arabinan-deficient-2 (arad2) mutation, that does not have detectable impact on arabinan structures, is also shown to reduce the impact on stem heights caused by mechanical stress. The LM13 linear arabinan epitope is specifically detected in epidermal cell walls of the younger, flexible regions of inflorescence stems and increases in abundance at the base of inflorescence stems in response to an imposed mechanical stress. The strain (percentage deformation) of stem epidermal cells in the double mutant arad1 × arad2 is lower in unbrushed plants than in wild-type plants, but rises to wild-type levels in response to brushing. The study demonstrates the complexity of arabinan structures within plant cell walls and also that their contribution to cell wall mechanical properties is a factor influencing responsiveness to mechanical stress.

Apple (Malus H domestica Borkh.) responds to a simulated severe drought: genes common and unique to leaves and bark

USDA-ARS?s Scientific Manuscript database

Dehydration is feature of many abiotic stresses, but is more often an agricultural threat on its own. Plants have evolved numerous mechanisms for coping with dehydration, including morphological, biochemical, and molecular genetic responses. These mechanisms are complex and involve various combina...

Cellular Basis of Mechanotransduction

NASA Technical Reports Server (NTRS)

Ingber, Donald E.

1996-01-01

Physical forces, such as those due to gravity are fundamental regulators of tissue development. To influence morphogenesis, mechanical forces must alter growth and function. Yet little is known about how cells convert mechanical signals into a chemical response. This presentation attempts to place the potential molecular mediators of mechanotransduction within the context of the structural complexity of living cells.

Monitoring in real-time focal adhesion protein dynamics in response to a discrete mechanical stimulus

NASA Astrophysics Data System (ADS)

von Bilderling, Catalina; Caldarola, Martín; Masip, Martín E.; Bragas, Andrea V.; Pietrasanta, Lía I.

2017-01-01

The adhesion of cells to the extracellular matrix is a hierarchical, force-dependent, multistage process that evolves at several temporal scales. An understanding of this complex process requires a precise measurement of forces and its correlation with protein responses in living cells. We present a method to quantitatively assess live cell responses to a local and specific mechanical stimulus. Our approach combines atomic force microscopy with fluorescence imaging. Using this approach, we evaluated the recruitment of adhesion proteins such as vinculin, focal adhesion kinase, paxillin, and zyxin triggered by applying forces in the nN regime to live cells. We observed in real time the development of nascent adhesion sites, evident from the accumulation of early adhesion proteins at the position where the force was applied. We show that the method can be used to quantify the recruitment characteristic times for adhesion proteins in the formation of focal complexes. We also found a spatial remodeling of the mature focal adhesion protein zyxin as a function of the applied force. Our approach allows the study of a variety of complex biological processes involved in cellular mechanotransduction.

Monitoring in real-time focal adhesion protein dynamics in response to a discrete mechanical stimulus.

PubMed

von Bilderling, Catalina; Caldarola, Martín; Masip, Martín E; Bragas, Andrea V; Pietrasanta, Lía I

2017-01-01

The adhesion of cells to the extracellular matrix is a hierarchical, force-dependent, multistage process that evolves at several temporal scales. An understanding of this complex process requires a precise measurement of forces and its correlation with protein responses in living cells. We present a method to quantitatively assess live cell responses to a local and specific mechanical stimulus. Our approach combines atomic force microscopy with fluorescence imaging. Using this approach, we evaluated the recruitment of adhesion proteins such as vinculin, focal adhesion kinase, paxillin, and zyxin triggered by applying forces in the nN regime to live cells. We observed in real time the development of nascent adhesion sites, evident from the accumulation of early adhesion proteins at the position where the force was applied. We show that the method can be used to quantify the recruitment characteristic times for adhesion proteins in the formation of focal complexes. We also found a spatial remodeling of the mature focal adhesion protein zyxin as a function of the applied force. Our approach allows the study of a variety of complex biological processes involved in cellular mechanotransduction.

Characterization of the influence of external stimulus on protein-nucleic acid complex through multiscale computations

NASA Astrophysics Data System (ADS)

Gosai, Agnivo

The concomitant detection, monitoring and analysis of biomolecules have assumed utmost importance in the field of medical diagnostics as well as in different spheres of biotechnology research such as drug development, environmental hazard detection and biodefense. There is an increased demand for the modulation of the biological response for such detection / sensing schemes which will be facilitated by the sensitive and controllable transmission of external stimuli. Electrostatic actuation for the controlled release/capture of biomolecules through conformational transformations of bioreceptors provides an efficient and feasible mechanism to modulate biological response. In addition, electrostatic actuation mechanism has the advantage of allowing massively parallel schemes and measurement capabilities that could ultimately be essential for biomedical applications. Experiments have previously demonstrated the unbinding of thrombin from its aptamer in presence of small positive electrode potential whereas the complex remained associated in presence of small negative potentials / zero potential. However, the nanoscale physics/chemistry involved in this process is not clearly understood. In this thesis a combination of continuum mechanics based modeling and a variety of atomistic simulation techniques have been utilized to corroborate the aforementioned experimental observations. It is found that the computational approach can satisfactorily predict the dynamics of the electrically excited aptamer-thrombin complex as well as provide an analytical model to characterize the forced binding of the complex.

Fallen Angels or Risen Apes? A Tale of the Intricate Complexities of Imbalanced Immune Responses in the Pathogenesis and Progression of Immune-Mediated and Viral Cancers

PubMed Central

Ondondo, Beatrice Omusiro

2014-01-01

Excessive immune responses directed against foreign pathogens, self-antigens, or commensal microflora can cause cancer establishment and progression if the execution of tight immuno-regulatory mechanisms fails. On the other hand, induction of potent tumor antigen-specific immune responses together with stimulation of the innate immune system is a pre-requisite for effective anti-tumor immunity, and if suppressed by the strong immuno-regulatory mechanisms can lead to cancer progression. Therefore, it is crucial that the inevitable co-existence of these fundamental, yet conflicting roles of immune-regulatory cells is carefully streamlined as imbalances can be detrimental to the host. Infection with chronic persistent viruses is characterized by severe immune dysfunction resulting in T cell exhaustion and sometimes deletion of antigen-specific T cells. More often, this is due to increased immuno-regulatory processes, which are triggered to down-regulate immune responses and limit immunopathology. However, such heightened levels of immune disruption cause a concomitant loss of tumor immune-surveillance and create a permissive microenvironment for cancer establishment and progression, as demonstrated by increased incidences of cancer in immunosuppressed hosts. Paradoxically, while some cancers arise as a consequence of increased immuno-regulatory mechanisms that inhibit protective immune responses and impinge on tumor surveillance, other cancers arise due to impaired immuno-regulatory mechanisms and failure to limit pathogenic inflammatory responses. This intricate complexity, where immuno-regulatory cells can be beneficial in certain immune settings but detrimental in other settings underscores the need for carefully formulated interventions to equilibrate the balance between immuno-stimulatory and immuno-regulatory processes. PMID:24639678

The knottin-like Blufensin family regulates genes involved in nuclear import and the secretory pathway in barley-powdery mildew interactions

USDA-ARS?s Scientific Manuscript database

Plants have evolved complex regulatory mechanisms to control a multi-layered defense response to microbial attack. Both temporal and spatial gene expression are tightly regulated in response to pathogen ingress, modulating both positive and negative control of defense. BLUFENSINs, small knottin-like...

Ozone co-exposure modifies cardiac responses to fine and ultrafine ambient particulate matter in mice: concordance of electrocardiogram and mechanical responses

EPA Science Inventory

BackgroundStudies have shown a relationship between air pollution and increased risk of cardiovascular morbidity and mortality. Due to the complexity of ambient air pollution composition, recent studies have examined the effects of co-exposure, particularly particulate matter (PM...

Complex auditory behaviour emerges from simple reactive steering

NASA Astrophysics Data System (ADS)

Hedwig, Berthold; Poulet, James F. A.

2004-08-01

The recognition and localization of sound signals is fundamental to acoustic communication. Complex neural mechanisms are thought to underlie the processing of species-specific sound patterns even in animals with simple auditory pathways. In female crickets, which orient towards the male's calling song, current models propose pattern recognition mechanisms based on the temporal structure of the song. Furthermore, it is thought that localization is achieved by comparing the output of the left and right recognition networks, which then directs the female to the pattern that most closely resembles the species-specific song. Here we show, using a highly sensitive method for measuring the movements of female crickets, that when walking and flying each sound pulse of the communication signal releases a rapid steering response. Thus auditory orientation emerges from reactive motor responses to individual sound pulses. Although the reactive motor responses are not based on the song structure, a pattern recognition process may modulate the gain of the responses on a longer timescale. These findings are relevant to concepts of insect auditory behaviour and to the development of biologically inspired robots performing cricket-like auditory orientation.

Ultrastable cellulosome-adhesion complex tightens under load.

PubMed

Schoeler, Constantin; Malinowska, Klara H; Bernardi, Rafael C; Milles, Lukas F; Jobst, Markus A; Durner, Ellis; Ott, Wolfgang; Fried, Daniel B; Bayer, Edward A; Schulten, Klaus; Gaub, Hermann E; Nash, Michael A

2014-12-08

Challenging environments have guided nature in the development of ultrastable protein complexes. Specialized bacteria produce discrete multi-component protein networks called cellulosomes to effectively digest lignocellulosic biomass. While network assembly is enabled by protein interactions with commonplace affinities, we show that certain cellulosomal ligand-receptor interactions exhibit extreme resistance to applied force. Here, we characterize the ligand-receptor complex responsible for substrate anchoring in the Ruminococcus flavefaciens cellulosome using single-molecule force spectroscopy and steered molecular dynamics simulations. The complex withstands forces of 600-750 pN, making it one of the strongest bimolecular interactions reported, equivalent to half the mechanical strength of a covalent bond. Our findings demonstrate force activation and inter-domain stabilization of the complex, and suggest that certain network components serve as mechanical effectors for maintaining network integrity. This detailed understanding of cellulosomal network components may help in the development of biocatalysts for production of fuels and chemicals from renewable plant-derived biomass.

Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response.

PubMed

Zhang, Conggang; Liu, Zeyu; Bunker, Eric; Ramirez, Adrian; Lee, Schuyler; Peng, Yinghua; Tan, Aik-Choon; Eckhardt, S Gail; Chapnick, Douglas A; Liu, Xuedong

2017-09-08

Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m -chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

A history of cepstrum analysis and its application to mechanical problems

NASA Astrophysics Data System (ADS)

Randall, Robert B.

2017-12-01

It is not widely realised that the first paper on cepstrum analysis was published two years before the FFT algorithm, despite having Tukey as a common author, and its definition was such that it was not reversible even to the log spectrum. After publication of the FFT in 1965, the cepstrum was redefined so as to be reversible to the log spectrum, and shortly afterwards Oppenheim and Schafer defined the ;complex cepstrum;, which was reversible to the time domain. They also derived the analytical form of the complex cepstrum of a transfer function in terms of its poles and zeros. The cepstrum had been used in speech analysis for determining voice pitch (by accurately measuring the harmonic spacing), but also for separating the formants (transfer function of the vocal tract) from voiced and unvoiced sources, and this led quite early to similar applications in mechanics. The first was to gear diagnostics (Randall), where the cepstrum greatly simplified the interpretation of the sideband families associated with local faults in gears, and the second was to extraction of diesel engine cylinder pressure signals from acoustic response measurements (Lyon and Ordubadi). Later Polydoros defined the differential cepstrum, which had an analytical form similar to the impulse response function, and Gao and Randall used this and the complex cepstrum in the application of cepstrum analysis to modal analysis of mechanical structures. Antoni proposed the mean differential cepstrum, which gave a smoothed result. The cepstrum can be applied to MIMO systems if at least one SIMO response can be separated, and a number of blind source separation techniques have been proposed for this. Most recently it has been shown that even though it is not possible to apply the complex cepstrum to stationary signals, it is possible to use the real cepstrum to edit their (log) amplitude spectrum, and combine this with the original phase to obtain edited time signals. This has already been used for a wide range of mechanical applications. A very powerful processing tool is an exponential ;lifter; (window) applied to the cepstrum, which is shown to extract the modal part of the response (with a small extra damping of each mode corresponding to the window). This can then be used to repress or enhance the modal information in the response according to the application.

Fluid flow in the osteocyte mechanical environment: a fluid-structure interaction approach.

PubMed

Verbruggen, Stefaan W; Vaughan, Ted J; McNamara, Laoise M

2014-01-01

Osteocytes are believed to be the primary sensor of mechanical stimuli in bone, which orchestrate osteoblasts and osteoclasts to adapt bone structure and composition to meet physiological loading demands. Experimental studies to quantify the mechanical environment surrounding bone cells are challenging, and as such, computational and theoretical approaches have modelled either the solid or fluid environment of osteocytes to predict how these cells are stimulated in vivo. Osteocytes are an elastic cellular structure that deforms in response to the external fluid flow imposed by mechanical loading. This represents a most challenging multi-physics problem in which fluid and solid domains interact, and as such, no previous study has accounted for this complex behaviour. The objective of this study is to employ fluid-structure interaction (FSI) modelling to investigate the complex mechanical environment of osteocytes in vivo. Fluorescent staining of osteocytes was performed in order to visualise their native environment and develop geometrically accurate models of the osteocyte in vivo. By simulating loading levels representative of vigorous physiological activity ([Formula: see text] compression and 300 Pa pressure gradient), we predict average interstitial fluid velocities [Formula: see text] and average maximum shear stresses [Formula: see text] surrounding osteocytes in vivo. Interestingly, these values occur in the canaliculi around the osteocyte cell processes and are within the range of stimuli known to stimulate osteogenic responses by osteoblastic cells in vitro. Significantly our results suggest that the greatest mechanical stimulation of the osteocyte occurs in the cell processes, which, cell culture studies have indicated, is the most mechanosensitive area of the cell. These are the first computational FSI models to simulate the complex multi-physics mechanical environment of osteocyte in vivo and provide a deeper understanding of bone mechanobiology.

Systems Biology Approaches for Discovering Biomarkers for Traumatic Brain Injury

PubMed Central

Feala, Jacob D.; AbdulHameed, Mohamed Diwan M.; Yu, Chenggang; Dutta, Bhaskar; Yu, Xueping; Schmid, Kara; Dave, Jitendra; Tortella, Frank

2013-01-01

Abstract The rate of traumatic brain injury (TBI) in service members with wartime injuries has risen rapidly in recent years, and complex, variable links have emerged between TBI and long-term neurological disorders. The multifactorial nature of TBI secondary cellular response has confounded attempts to find cellular biomarkers for its diagnosis and prognosis or for guiding therapy for brain injury. One possibility is to apply emerging systems biology strategies to holistically probe and analyze the complex interweaving molecular pathways and networks that mediate the secondary cellular response through computational models that integrate these diverse data sets. Here, we review available systems biology strategies, databases, and tools. In addition, we describe opportunities for applying this methodology to existing TBI data sets to identify new biomarker candidates and gain insights about the underlying molecular mechanisms of TBI response. As an exemplar, we apply network and pathway analysis to a manually compiled list of 32 protein biomarker candidates from the literature, recover known TBI-related mechanisms, and generate hypothetical new biomarker candidates. PMID:23510232

Coherent Exciton Dynamics in the Presence of Underdamped Vibrations

DOE PAGES

Dijkstra, Arend G.; Wang, Chen; Cao, Jianshu; ...

2015-01-22

Recent ultrafast optical experiments show that excitons in large biological light-harvesting complexes are coupled to molecular vibration modes. These high-frequency vibrations will not only affect the optical response, but also drive the exciton transport. Here, using a model dimer system, the frequency of the underdamped vibration is shown to have a strong effect on the exciton dynamics such that quantum coherent oscillations in the system can be present even in the case of strong noise. Two mechanisms are identified to be responsible for the enhanced transport efficiency: critical damping due to the tunable effective strength of the coupling to themore » bath, and resonance coupling where the vibrational frequency coincides with the energy gap in the system. The interplay of these two mechanisms determines parameters responsible for the most efficient transport, and these optimal control parameters are comparable to those in realistic light-harvesting complexes. Interestingly, oscillations in the excitonic coherence at resonance are suppressed in comparison to the case of an off-resonant vibration.« less

Canonical and Non-Canonical Autophagy in HIV-1 Replication Cycle

PubMed Central

Leymarie, Olivier; Lepont, Leslie; Berlioz-Torrent, Clarisse

2017-01-01

Autophagy is a lysosomal-dependent degradative process essential for maintaining cellular homeostasis, and is a key player in innate and adaptive immune responses to intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). In HIV-1 target cells, autophagy mechanisms can (i) selectively direct viral proteins and viruses for degradation; (ii) participate in the processing and presentation of viral-derived antigens through major histocompatibility complexes; and (iii) contribute to interferon production in response to HIV-1 infection. As a consequence, HIV-1 has evolved different strategies to finely regulate the autophagy pathway to favor its replication and dissemination. HIV-1 notably encodes accessory genes encoding Tat, Nef and Vpu proteins, which are able to perturb and hijack canonical and non-canonical autophagy mechanisms. This review outlines the current knowledge on the complex interplay between autophagy and HIV-1 replication cycle, providing an overview of the autophagy-mediated molecular processes deployed both by infected cells to combat the virus and by HIV-1 to evade antiviral response. PMID:28946621

Mechanical Behavior of Additively Manufactured Uranium-6 wt. pct. Niobium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, A. S.; Wraith, M. W.; Burke, S. C.

This report describes an effort to process uranium-6 weight% niobium using laser powder bed fusion. The chemistry, crystallography, microstructure and mechanical response resulting from this process are discussed with particular emphasis on the effect of the laser powder bed fusion process on impurities. In an effort to achieve homogenization and uniform mechanical behavior from different builds, as well as to induce a more conventional loading response, we explore post-processing heat treatments on this complex alloy. Elevated temperature heat treatment for recrystallization is evaluated and the effect of recrystallization on mechanical behavior in laser powder bed fusion processed U-6Nb is discussed.more » Wrought-like mechanical behavior and grain sizes are achieved through post-processing and are reported herein.« less

Using Malus sieversii Ledeb., the wild apple progenitor of Malus H domestica Borkh., to identify genes contributing to water use efficiency and potential drought resistance

USDA-ARS?s Scientific Manuscript database

Dehydration is a feature of many abiotic stresses, but is more often an agricultural threat in its own right. Plants have evolved numerous mechanisms for coping with dehydration, including morphological, biochemical, and molecular biological responses. These mechanisms are complex and involve vari...

Cardiorespiratory interactions in neural circulatory control in humans.

PubMed

Shamsuzzaman, A S; Somers, V K

2001-06-01

The reflex mechanisms and interactions described in this overview provide some explanation for the range of neural circulatory responses evident during changes in breathing. The effects described represent the integrated responses to activation of several reflex mechanisms, including peripheral and central chemoreflexes, arterial baroreflexes, pulmonary stretch receptors, and ventricular mechanoreceptors. These interactions occur on a dynamic basis and the transfer characteristics of any single interaction are, in all likelihood, also highly dynamic. Nevertheless, it is only by attempting to understand individual reflexes and their modulating influences that a more thorough understanding of the responses to complex phenomena such as hyperventilation, apnea, and obstructive sleep apnea can be better understood.

Developmental control of integrin expression regulates Th2 effector homing

USDA-ARS?s Scientific Manuscript database

Integrin CD18, a component of the LFA-1 complex that also includes CD11a, is essential for Th2, but not Th1, cell homing, but the explanation for this phenomenon remains obscure. In this study, we investigate the mechanism by which Th2 effector responses require the LFA-1 complex. CD11a-deficient T ...

ERP Correlates of Pitch Error Detection in Complex Tone and Voice Auditory Feedback with Missing Fundamental

PubMed Central

Behroozmand, Roozbeh; Korzyukov, Oleg; Larson, Charles R.

2012-01-01

Previous studies have shown that the pitch of a sound is perceived in the absence of its fundamental frequency (F0), suggesting that a distinct mechanism may resolve pitch based on a pattern that exists between harmonic frequencies. The present study investigated whether such a mechanism is active during voice pitch control. ERPs were recorded in response to +200 cents pitch shifts in the auditory feedback of self-vocalizations and complex tones with and without the F0. The absence of the fundamental induced no difference in ERP latencies. However, a right-hemisphere difference was found in the N1 amplitudes with larger responses to complex tones that included the fundamental compared to when it was missing. The P1 and N1 latencies were shorter in the left hemisphere, and the N1 and P2 amplitudes were larger bilaterally for pitch shifts in voice and complex tones compared with pure tones. These findings suggest hemispheric differences in neural encoding of pitch in sounds with missing fundamental. Data from the present study suggest that the right cortical auditory areas, thought to be specialized for spectral processing, may utilize different mechanisms to resolve pitch in sounds with missing fundamental. The left hemisphere seems to perform faster processing to resolve pitch based on the rate of temporal variations in complex sounds compared with pure tones. These effects indicate that the differential neural processing of pitch in the left and right hemispheres may enable the audio-vocal system to detect temporal and spectral variations in the auditory feedback for vocal pitch control. PMID:22386045

Structure, function and regulation of plant photosystem I.

PubMed

Jensen, Poul Erik; Bassi, Roberto; Boekema, Egbert J; Dekker, Jan P; Jansson, Stefan; Leister, Dario; Robinson, Colin; Scheller, Henrik Vibe

2007-05-01

Photosystem I (PSI) is a multisubunit protein complex located in the thylakoid membranes of green plants and algae, where it initiates one of the first steps of solar energy conversion by light-driven electron transport. In this review, we discuss recent progress on several topics related to the functioning of the PSI complex, like the protein composition of the complex in the plant Arabidopsis thaliana, the function of these subunits and the mechanism by which nuclear-encoded subunits can be inserted into or transported through the thylakoid membrane. Furthermore, the structure of the native PSI complex in several oxygenic photosynthetic organisms and the role of the chlorophylls and carotenoids in the antenna complexes in light harvesting and photoprotection are reviewed. The special role of the 'red' chlorophylls (chlorophyll molecules that absorb at longer wavelength than the primary electron donor P700) is assessed. The physiology and mechanism of the association of the major light-harvesting complex of photosystem II (LHCII) with PSI during short term adaptation to changes in light quality and quantity is discussed in functional and structural terms. The mechanism of excitation energy transfer between the chlorophylls and the mechanism of primary charge separation is outlined and discussed. Finally, a number of regulatory processes like acclimatory responses and retrograde signalling is reviewed with respect to function of the thylakoid membrane. We finish this review by shortly discussing the perspectives for future research on PSI.

Progressive but Previously Untreated CLL Patients with Greater Array CGH Complexity Exhibit a Less Durable Response to Chemoimmunotherapy

PubMed Central

Kay, Neil E.; Eckel-Passow, Jeanette E.; Braggio, Esteban; VanWier, Scott; Shanafelt, Tait D.; Van Dyke, Daniel L.; Jelinek, Diane F.; Tschumper, Renee C.; Kipps, Thomas; Byrd, John C.; Fonseca, Rafael

2010-01-01

To better understand the implications of genomic instability and outcome in B-cell CLL, we sought to address genomic complexity as a predictor of chemosensitivity and ultimately clinical outcome in this disease. We employed array-based comparative genomic hybridization (aCGH), using a one-million probe array and identified gains and losses of genetic material in 48 patients treated on a chemoimmunotherapy (CIT) clinical trial. We identified chromosomal gain or loss in ≥6% of the patients on chromosomes 3, 8, 9, 10, 11, 12, 13, 14 and 17. Higher genomic complexity, as a mechanism favoring clonal selection, was associated with shorter progression-free survival and predicted a poor response to treatment. Of interest, CLL cases with loss of p53 surveillance showed more complex genomic features and were found both in patients with a 17p13.1 deletion and in the more favorable genetic subtype characterized by the presence of 13q14.1 deletion. This aCGH study adds information on the association between inferior trial response and increasing genetic complexity as CLL progresses. PMID:21156228

Cohesin and Human Disease

PubMed Central

Liu, Jinglan; Krantz, Ian D.

2016-01-01

Cornelia de Lange syndrome (CdLS) is a dominant multisystem disorder caused by a disruption of cohesin function. The cohesin ring complex is composed of four protein subunits and more than 25 additional proteins involved in its regulation. The discovery that this complex also has a fundamental role in long-range regulation of transcription in Drosophila has shed light on the mechanism likely responsible for its role in development. In addition to the three cohesin proteins involved in CdLS, a second multisystem, recessively inherited, developmental disorder, Roberts-SC phocomelia, is caused by mutations in another regulator of the cohesin complex, ESCO2. Here we review the phenotypes of these disorders, collectively termed cohesinopathies, as well as the mechanism by which cohesin disruption likely causes these diseases. PMID:18767966

Identifying partial topology of complex dynamical networks via a pinning mechanism

NASA Astrophysics Data System (ADS)

Zhu, Shuaibing; Zhou, Jin; Lu, Jun-an

2018-04-01

In this paper, we study the problem of identifying the partial topology of complex dynamical networks via a pinning mechanism. By using the network synchronization theory and the adaptive feedback controlling method, we propose a method which can greatly reduce the number of nodes and observers in the response network. Particularly, this method can also identify the whole topology of complex networks. A theorem is established rigorously, from which some corollaries are also derived in order to make our method more cost-effective. Several numerical examples are provided to verify the effectiveness of the proposed method. In the simulation, an approach is also given to avoid possible identification failure caused by inner synchronization of the drive network.

Coordination of frontline defense mechanisms under severe oxidative stress

PubMed Central

Kaur, Amardeep; Van, Phu T; Busch, Courtney R; Robinson, Courtney K; Pan, Min; Pang, Wyming Lee; Reiss, David J; DiRuggiero, Jocelyne; Baliga, Nitin S

2010-01-01

Complexity of cellular response to oxidative stress (OS) stems from its wide-ranging damage to nucleic acids, proteins, carbohydrates, and lipids. We have constructed a systems model of OS response (OSR) for Halobacterium salinarum NRC-1 in an attempt to understand the architecture of its regulatory network that coordinates this complex response. This has revealed a multi-tiered OS-management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, production of rhodopsins, carotenoids and gas vesicles, metal trafficking, and various other aspects of metabolism. Through experimental validation of interactions within the OSR regulatory network, we show that despite their inability to directly sense reactive oxygen species, general transcription factors have an important function in coordinating this response. Remarkably, a significant fraction of this OSR was accurately recapitulated by a model that was earlier constructed from cellular responses to diverse environmental perturbations—this constitutes the general stress response component. Notwithstanding this observation, comparison of the two models has identified the coordination of frontline defense and repair systems by regulatory mechanisms that are triggered uniquely by severe OS and not by other environmental stressors, including sub-inhibitory levels of redox-active metals, extreme changes in oxygen tension, and a sub-lethal dose of γ rays. PMID:20664639

Concentration-independent pH detection with a luminescent dimetallic Eu(III)-based probe.

PubMed

Moore, Jeremiah D; Lord, Richard L; Cisneros, G Andrés; Allen, Matthew J

2012-10-24

A pH-responsive, luminescent, dimetallic Eu(III)-containing complex has been synthesized and exhibits a unique mechanism of response. The luminescence-decay rate of the complex is slow, due to a lack of water molecules coordinated to the Eu(III) ions. However, the luminescence-decay rate decreases with increasing pH over a biologically relevant range of 4-8. Physical characterization and computational analysis suggest that the pH response is due to protonation of a bridging alkoxide at lower pH values. Modulation of the luminescence-decay rate is independent from the concentration of Eu(III), which we expect to be useful in the non-invasive imaging of in vivo pH.

Designer biomaterials for mechanobiology

NASA Astrophysics Data System (ADS)

Li, Linqing; Eyckmans, Jeroen; Chen, Christopher S.

2017-12-01

Biomaterials engineered with specific bioactive ligands, tunable mechanical properties and complex architecture have emerged as powerful tools to probe cell sensing and response to physical properties of their material surroundings, and ultimately provide designer approaches to control cell function.

Drugs meeting the molecular basis of diabetic kidney disease: bridging from molecular mechanism to personalized medicine.

PubMed

Lambers Heerspink, Hiddo J; Oberbauer, Rainer; Perco, Paul; Heinzel, Andreas; Heinze, Georg; Mayer, Gert; Mayer, Bernd

2015-08-01

Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Mechanobiology of the Meniscus

PubMed Central

McNulty, Amy L.; Guilak, Farshid

2015-01-01

The meniscus plays a critical biomechanical role in the knee, providing load support, joint stability, and congruity. Importantly, growing evidence indicates that the mechanobiologic response of meniscal cells plays a critical role in the physiologic, pathologic, and repair responses of the meniscus. Here we review experimental and theoretical studies that have begun to directly measure the biomechanical effects of joint loading on the meniscus under physiologic and pathologic conditions, showing that the menisci are exposed to high contact stresses, resulting in a complex and nonuniform stress-strain environment within the tissue. By combining microscale measurements of the mechanical properties of meniscal cells and their pericellular and extracellular matrix regions, theoretical and experimental models indicate that the cells in the meniscus are exposed to a complex and inhomogeneous environment of stress, strain, fluid pressure, fluid flow, and a variety of physicochemical factors. Studies across a range of culture systems from isolated cells to tissues have revealed that the biological response of meniscal cells is directly influenced by physical factors, such as tension, compression, and hydrostatic pressure. In addition, these studies have provided new insights into the mechanotransduction mechanisms by which physical signals are converted into metabolic or pro/anti-inflammatory responses. Taken together, these in vivo and in vitro studies show that mechanical factors play an important role in the health, degeneration, and regeneration of the meniscus. A more thorough understanding of the mechanobiologic responses of the meniscus will hopefully lead to therapeutic approaches to prevent degeneration and enhance repair of the meniscus. PMID:25731738

Identifying the myogenic and metabolic components of cerebral autoregulation.

PubMed

Payne, S J

2018-05-14

Cerebral autoregulation is the term used to describe a number of mechanisms that act together to maintain a near constant cerebral blood flow in response to changes in arterial blood pressure. These mechanisms are complex and known to be affected in a range of cerebrovascular diseases. However, it can be difficult to assign an alteration in cerebral autoregulation to one of the underlying physiological mechanisms without the use of a complex mathematical model. In this paper, we thus set out a new approach that enables these mechanisms to be related to the autoregulation behaviour and hence inferred from experimental measurements. We show that the arteriolar response is a function of just three parameters, which we term the elastic, the myogenic and the metabolic sensitivity coefficients, and that the full vascular response is dependent upon only seven parameters. The ratio of the strengths of the myogenic and the metabolic responses is found to be in the range 2.5 to 5 over a wide range of pressure, indicating that the balance between the two appears to lie within this range. We validate the model with existing experimental data both at the level of an individual vessel and across the whole vasculature, and show that the results are consistent with findings from the literature. We then conduct a sensitivity analysis of the model to demonstrate which parameters are most important in determining the strength of static autoregulation, showing that autoregulation strength is predominantly set by the arteriolar sensitivity coefficients. This new approach could be used in future studies to help to interpret the components of the autoregulation response and how they are affected under different conditions, providing a greater insight into the fundamental processes that govern autoregulation. Copyright © 2018. Published by Elsevier Ltd.

The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sato, Shoko, E-mail: satosho@rs.tus.ac.jp; Shirakawa, Hitoshi, E-mail: shirakah@m.tohoku.ac.jp; Tomita, Shuhei, E-mail: tomita@med.tottori-u.ac.jp

2013-11-15

Although the aryl hydrocarbon receptor (AHR) and glucocorticoid receptor (GR) play essential roles in mammalian development, stress responses, and other physiological events, crosstalk between these receptors has been the subject of much debate. Metallothioneins are classic glucocorticoid-inducible genes that were reported to increase upon treatment with AHR agonists in rodent tissues and cultured human cells. In this study, the mechanism of human metallothionein 2A (MT2A) gene transcription activation by AHR was investigated. Cotreatment with 3-methylcholanthrene and dexamethasone, agonists of AHR and GR respectively, synergistically increased MT2A mRNA levels in HepG2 cells. MT2A induction was suppressed by RNA interference against AHRmore » or GR. Coimmunoprecipitation experiments revealed a physical interaction between AHR and GR proteins. Moreover, chromatin immunoprecipitation assays indicated that AHR was recruited to the glucocorticoid response element in the MT2A promoter. Thus, we provide a novel mechanism whereby AHR modulates expression of human MT2A via the glucocorticoid response element and protein–protein interactions with GR. - Highlights: • Aryl hydrocarbon receptor forms a complex with glucocorticoid receptor in cells. • Human metallothionein gene is regulated by the AHR and GR interaction. • AHR–GR complex binds to glucocorticoid response element in metallothionein gene. • We demonstrated a novel transcriptional mechanism via AHR and GR interaction.« less

Synergism and Antagonism of Proximate Mechanisms Enable and Constrain the Response to Simultaneous Selection on Body Size and Development Time: An Empirical Test Using Experimental Evolution.

PubMed

Davidowitz, Goggy; Roff, Derek; Nijhout, H Frederik

2016-11-01

Natural selection acts on multiple traits simultaneously. How mechanisms underlying such traits enable or constrain their response to simultaneous selection is poorly understood. We show how antagonism and synergism among three traits at the developmental level enable or constrain evolutionary change in response to simultaneous selection on two focal traits at the phenotypic level. After 10 generations of 25% simultaneous directional selection on all four combinations of body size and development time in Manduca sexta (Sphingidae), the changes in the three developmental traits predict 93% of the response of development time and 100% of the response of body size. When the two focal traits were under synergistic selection, the response to simultaneous selection was enabled by juvenile hormone and ecdysteroids and constrained by growth rate. When the two focal traits were under antagonistic selection, the response to selection was due primarily to change in growth rate and constrained by the two hormonal traits. The approach used here reduces the complexity of the developmental and endocrine mechanisms to three proxy traits. This generates explicit predictions for the evolutionary response to selection that are based on biologically informed mechanisms. This approach has broad applicability to a diverse range of taxa, including algae, plants, amphibians, mammals, and insects.

Bacillus spores as building blocks for stimuli-responsive materials and nanogenerators

NASA Astrophysics Data System (ADS)

Sahin, Ozgur; Chen, Xi

2014-03-01

Materials that mechanically respond to external chemical stimuli have applications in a wide range of fields. Inspired by biological systems, stimuli-responsive materials that can oscillate, transport fluid, mimic homeostasis, and undergo complex changes in shape have been previously demonstrated. However, the effectiveness of synthetic stimuli-responsive materials in generating work is limited when compared to mechanical actuators. During studies of bacterial sporulation, we have found that the mechanical response of Bacillus spores to water gradients exhibits an energy density of more than 10 MJ/m3, which is two orders of magnitude higher than synthetic water-responsive materials. We also identified mutations that can approximately double the energy density of the spores, and found that spores can self-assemble into dense, submicron-thick monolayers on substrates such as silicon microcantilevers and elastomer sheets, creating self-assembled actuators that can remotely generate electrical power from an evaporating body of water. The energy conversion mechanism of Bacillus spores may facilitate synthetic stimuli-responsive materials with significantly higher energy densities. We acknowledge support from the U.S. Dept. of Energy Early Career Research Program, the Wyss Institute for Biologically Inspired Engineering, and the Rowland Institute at Harvard.

Complex computation in the retina

NASA Astrophysics Data System (ADS)

Deshmukh, Nikhil Rajiv

Elucidating the general principles of computation in neural circuits is a difficult problem requiring both a tractable model circuit as well as sophisticated measurement tools. This thesis advances our understanding of complex computation in the salamander retina and its underlying circuitry and furthers the development of advanced tools to enable detailed study of neural circuits. The retina provides an ideal model system for neural circuits in general because it is capable of producing complex representations of the visual scene, and both its inputs and outputs are accessible to the experimenter. Chapter 2 describes the biophysical mechanisms that give rise to the omitted stimulus response in retinal ganglion cells described in Schwartz et al., (2007) and Schwartz and Berry, (2008). The extra response to omitted flashes is generated at the input to bipolar cells, and is separable from the characteristic latency shift of the OSR apparent in ganglion cells, which must occur downstream in the circuit. Chapter 3 characterizes the nonlinearities at the first synapse of the ON pathway in response to high contrast flashes and develops a phenomenological model that captures the effect of synaptic activation and intracellular signaling dynamics on flash responses. This work is the first attempt to model the dynamics of the poorly characterized mGluR6 transduction cascade unique to ON bipolar cells, and explains the second lobe of the biphasic flash response. Complementary to the study of neural circuits, recent advances in wafer-scale photolithography have made possible new devices to measure the electrical and mechanical properties of neurons. Chapter 4 reports a novel piezoelectric sensor that facilitates the simultaneous measurement of electrical and mechanical signals in neural tissue. This technology could reveal the relationship between the electrical activity of neurons and their local mechanical environment, which is critical to the study of mechanoreceptors, neural development, and traumatic brain injury. Chapter 5 describes advances in the development, fabrication, and testing of a prototype silicon micropipette for patch clamp physiology. Nanoscale photolithography addresses some of the limitations of traditional glass patch electrodes, such as the rapid dialysis of the cell with internal solution, and provides a platform for integration of microfluidics and electronics into the device, which can enable novel experimental methodology.

Network analyses based on comprehensive molecular interaction maps reveal robust control structures in yeast stress response pathways

PubMed Central

Kawakami, Eiryo; Singh, Vivek K; Matsubara, Kazuko; Ishii, Takashi; Matsuoka, Yukiko; Hase, Takeshi; Kulkarni, Priya; Siddiqui, Kenaz; Kodilkar, Janhavi; Danve, Nitisha; Subramanian, Indhupriya; Katoh, Manami; Shimizu-Yoshida, Yuki; Ghosh, Samik; Jere, Abhay; Kitano, Hiroaki

2016-01-01

Cellular stress responses require exquisite coordination between intracellular signaling molecules to integrate multiple stimuli and actuate specific cellular behaviors. Deciphering the web of complex interactions underlying stress responses is a key challenge in understanding robust biological systems and has the potential to lead to the discovery of targeted therapeutics for diseases triggered by dysregulation of stress response pathways. We constructed large-scale molecular interaction maps of six major stress response pathways in Saccharomyces cerevisiae (baker’s or budding yeast). Biological findings from over 900 publications were converted into standardized graphical formats and integrated into a common framework. The maps are posted at http://www.yeast-maps.org/yeast-stress-response/ for browse and curation by the research community. On the basis of these maps, we undertook systematic analyses to unravel the underlying architecture of the networks. A series of network analyses revealed that yeast stress response pathways are organized in bow–tie structures, which have been proposed as universal sub-systems for robust biological regulation. Furthermore, we demonstrated a potential role for complexes in stabilizing the conserved core molecules of bow–tie structures. Specifically, complex-mediated reversible reactions, identified by network motif analyses, appeared to have an important role in buffering the concentration and activity of these core molecules. We propose complex-mediated reactions as a key mechanism mediating robust regulation of the yeast stress response. Thus, our comprehensive molecular interaction maps provide not only an integrated knowledge base, but also a platform for systematic network analyses to elucidate the underlying architecture in complex biological systems. PMID:28725465

Pellagra-like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit.

PubMed

Hijazi, H; Salih, M A; Hamad, M H A; Hassan, H H; Salih, S B M; Mohamed, K A; Mukhtar, M M; Karrar, Z A; Ansari, S; Ibrahim, N; Alkuraya, F S

2015-01-01

An extremely rare pellagra-like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra-like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet-induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The role of the parafascicular complex (CM-Pf) of the human thalamus in the neuronal mechanisms of selective attention.

PubMed

Raeva, S N

2006-03-01

The reactions of 93 neurons in the parafascicular complex (CM-Pf) of the human thalamus were studied by microelectrode recording during stereotaxic neurosurgical operations in patients with spastic torticollis. High reactivity was demonstrated for two previously classified types of neurons with identical irregular (type A) and bursting Ca2+ -dependent (type B) activities in response to presentation of relevant verbal stimuli evoking selective attention in humans. Concordant changes in the network activity of A and B neurons were observed, in the form of linked activatory-inhibitory patterns of responses and the appearance, at the moment of presentation of an imperative morpheme of the command stimulus, of rapidly occurring intercellular interactions consisting of local synchronization with simultaneously developing rhythmic oscillatory (3-4 Hz) activity. Data are presented on the existence of a direct connection between these neuronal rearrangements and activation of selective attention, providing evidence for the involvement of the thalamic parafascicular complex (CM-Pf) in the mechanisms of selective attention and processing of relevant verbal information during the preparative period of voluntary actions.

Receptor kinase complex transmits RALF peptide signal to inhibit root growth in Arabidopsis.

PubMed

Du, Changqing; Li, Xiushan; Chen, Jia; Chen, Weijun; Li, Bin; Li, Chiyu; Wang, Long; Li, Jianglin; Zhao, Xiaoying; Lin, Jianzhong; Liu, Xuanming; Luan, Sheng; Yu, Feng

2016-12-20

A number of hormones work together to control plant cell growth. Rapid Alkalinization Factor 1 (RALF1), a plant-derived small regulatory peptide, inhibits cell elongation through suppression of rhizosphere acidification in plants. Although a receptor-like kinase, FERONIA (FER), has been shown to act as a receptor for RALF1, the signaling mechanism remains unknown. In this study, we identified a receptor-like cytoplasmic kinase (RPM1-induced protein kinase, RIPK), a plasma membrane-associated member of the RLCK-VII subfamily, that is recruited to the receptor complex through interacting with FER in response to RALF1. RALF1 triggers the phosphorylation of both FER and RIPK in a mutually dependent manner. Genetic analysis of the fer-4 and ripk mutants reveals RIPK, as well as FER, to be required for RALF1 response in roots. The RALF1-FER-RIPK interactions may thus represent a mechanism for peptide signaling in plants.

Endocytosis and Endosomal Trafficking in Plants.

PubMed

Paez Valencia, Julio; Goodman, Kaija; Otegui, Marisa S

2016-04-29

Endocytosis and endosomal trafficking are essential processes in cells that control the dynamics and turnover of plasma membrane proteins, such as receptors, transporters, and cell wall biosynthetic enzymes. Plasma membrane proteins (cargo) are internalized by endocytosis through clathrin-dependent or clathrin-independent mechanism and delivered to early endosomes. From the endosomes, cargo proteins are recycled back to the plasma membrane via different pathways, which rely on small GTPases and the retromer complex. Proteins that are targeted for degradation through ubiquitination are sorted into endosomal vesicles by the ESCRT (endosomal sorting complex required for transport) machinery for degradation in the vacuole. Endocytic and endosomal trafficking regulates many cellular, developmental, and physiological processes, including cellular polarization, hormone transport, metal ion homeostasis, cytokinesis, pathogen responses, and development. In this review, we discuss the mechanisms that mediate the recognition and sorting of endocytic and endosomal cargos, the vesiculation processes that mediate their trafficking, and their connection to cellular and physiological responses in plants.

Presentation of lipid antigens to T cells.

PubMed

Mori, Lucia; De Libero, Gennaro

2008-04-15

T cells specific for lipid antigens participate in regulation of the immune response during infections, tumor immunosurveillance, allergy and autoimmune diseases. T cells recognize lipid antigens as complexes formed with CD1 antigen-presenting molecules, thus resembling recognition of MHC-peptide complexes. The biophysical properties of lipids impose unique mechanisms for their delivery, internalization into antigen-presenting cells, membrane trafficking, processing, and loading of CD1 molecules. Each of these steps is controlled at molecular and celular levels and determines lipid immunogenicity. Lipid antigens may derive from microbes and from the cellular metabolism, thus allowing the immune system to survey a large repertoire of immunogenic molecules. Recognition of lipid antigens facilitates the detection of infectious agents and the initiation of responses involved in immunoregulation and autoimmunity. This review focuses on the presentation mechanisms and specific recognition of self and bacterial lipid antigens and discusses the important open issues.

Water exchange in manganese-based water-oxidizing catalysts in photosynthetic systems: from the water-oxidizing complex in photosystem II to nano-sized manganese oxides.

PubMed

Najafpour, Mohammad Mahdi; Isaloo, Mohsen Abbasi; Eaton-Rye, Julian J; Tomo, Tatsuya; Nishihara, Hiroshi; Satoh, Kimiyuki; Carpentier, Robert; Shen, Jian-Ren; Allakhverdiev, Suleyman I

2014-09-01

The water-oxidizing complex (WOC), also known as the oxygen-evolving complex (OEC), of photosystem II in oxygenic photosynthetic organisms efficiently catalyzes water oxidation. It is, therefore, responsible for the presence of oxygen in the Earth's atmosphere. The WOC is a manganese-calcium (Mn₄CaO₅(H₂O)₄) cluster housed in a protein complex. In this review, we focus on water exchange chemistry of metal hydrates and discuss the mechanisms and factors affecting this chemical process. Further, water exchange rates for both the biological cofactor and synthetic manganese water splitting are discussed. The importance of fully unveiling the water exchange mechanism to understand the chemistry of water oxidation is also emphasized here. This article is part of a special issue entitled: photosynthesis research for sustainability: keys to produce clean energy. Copyright © 2014 Elsevier B.V. All rights reserved.

The response to inositol: regulation of glycerolipid metabolism and stress response signaling in yeast

PubMed Central

Henry, Susan A.; Gaspar, Maria L.; Jesch, Stephen A.

2014-01-01

This article focuses on discoveries of the mechanisms governing the regulation of glycerolipid metabolism and stress response signaling in response to the phospholipid precursor, inositol. The regulation of glycerolipid lipid metabolism in yeast in response to inositol is highly complex, but increasingly well understood, and the roles of individual lipids in stress response are also increasingly well characterized. Discoveries that have emerged over several decades of genetic, molecular and biochemical analyses of metabolic, regulatory and signaling responses of yeast cells, both mutant and wild type, to the availability of the phospholipid precursor, inositol are discussed. PMID:24418527

Ultrastable cellulosome-adhesion complex tightens under load

PubMed Central

Schoeler, Constantin; Malinowska, Klara H.; Bernardi, Rafael C.; Milles, Lukas F.; Jobst, Markus A.; Durner, Ellis; Ott, Wolfgang; Fried, Daniel B.; Bayer, Edward A.; Schulten, Klaus; Gaub, Hermann E.; Nash, Michael A.

2014-01-01

Challenging environments have guided nature in the development of ultrastable protein complexes. Specialized bacteria produce discrete multi-component protein networks called cellulosomes to effectively digest lignocellulosic biomass. While network assembly is enabled by protein interactions with commonplace affinities, we show that certain cellulosomal ligand–receptor interactions exhibit extreme resistance to applied force. Here, we characterize the ligand–receptor complex responsible for substrate anchoring in the Ruminococcus flavefaciens cellulosome using single-molecule force spectroscopy and steered molecular dynamics simulations. The complex withstands forces of 600–750 pN, making it one of the strongest bimolecular interactions reported, equivalent to half the mechanical strength of a covalent bond. Our findings demonstrate force activation and inter-domain stabilization of the complex, and suggest that certain network components serve as mechanical effectors for maintaining network integrity. This detailed understanding of cellulosomal network components may help in the development of biocatalysts for production of fuels and chemicals from renewable plant-derived biomass. PMID:25482395

Combing Chromosomal DNA Mediated by the SMC Complex: Structure and Mechanisms.

PubMed

Kamada, Katsuhiko; Barillà, Daniela

2018-02-01

Genome maintenance requires various nucleoid-associated factors in prokaryotes. Among them, the SMC (Structural Maintenance of Chromosomes) protein has been thought to play a static role in the organization and segregation of the chromosome during cell division. However, recent studies have shown that the bacterial SMC is required to align left and right arms of the emerging chromosome and that the protein dynamically travels from origin to Ter region. A rod form of the SMC complex mediates DNA bridging and has been recognized as a machinery responsible for DNA loop extrusion, like eukaryotic condensin or cohesin complexes, which act as chromosome organizers. Attention is now turning to how the prototype of the complex is loaded on the entry site and translocated on chromosomal DNA, explaining its overall conformational changes at atomic levels. Here, we review and highlight recent findings concerning the prokaryotic SMC complex and discuss possible mechanisms from the viewpoint of protein architecture. © 2017 The Authors. BioEssays Published by WILEY Periodicals, Inc.

How the nucleus and mitochondria communicate in energy production during stress: nuclear MtATP6, an early-stress responsive gene, regulates the mitochondrial F₁F₀-ATP synthase complex.

PubMed

Moghadam, Ali Asghar; Ebrahimie, Eemaeil; Taghavi, Seyed Mohsen; Niazi, Ali; Babgohari, Mahbobeh Zamani; Deihimi, Tahereh; Djavaheri, Mohammad; Ramezani, Amin

2013-07-01

A small number of stress-responsive genes, such as those of the mitochondrial F1F0-ATP synthase complex, are encoded by both the nucleus and mitochondria. The regulatory mechanism of these joint products is mysterious. The expression of 6-kDa subunit (MtATP6), a relatively uncharacterized nucleus-encoded subunit of F0 part, was measured during salinity stress in salt-tolerant and salt-sensitive cultivated wheat genotypes, as well as in the wild wheat genotypes, Triticum and Aegilops using qRT-PCR. The MtATP6 expression was suddenly induced 3 h after NaCl treatment in all genotypes, indicating an early inducible stress-responsive behavior. Promoter analysis showed that the MtATP6 promoter includes cis-acting elements such as ABRE, MYC, MYB, GTLs, and W-boxes, suggesting a role for this gene in abscisic acid-mediated signaling, energy metabolism, and stress response. It seems that 6-kDa subunit, as an early response gene and nuclear regulatory factor, translocates to mitochondria and completes the F1F0-ATP synthase complex to enhance ATP production and maintain ion homeostasis under stress conditions. These communications between nucleus and mitochondria are required for inducing mitochondrial responses to stress pathways. Dual targeting of 6-kDa subunit may comprise as a mean of inter-organelle communication and save energy for the cell. Interestingly, MtATP6 showed higher and longer expression in the salt-tolerant wheat and the wild genotypes compared to the salt-sensitive genotype. Apparently, salt-sensitive genotypes have lower ATP production efficiency and weaker energy management than wild genotypes; a stress tolerance mechanism that has not been transferred to cultivated genotypes.

The response of tropical rainforests to drought-lessons from recent research and future prospects.

PubMed

Bonal, Damien; Burban, Benoit; Stahl, Clément; Wagner, Fabien; Hérault, Bruno

We review the recent findings on the influence of drought on tree mortality, growth or ecosystem functioning in tropical rainforests. Drought plays a major role in shaping tropical rainforests and the response mechanisms are highly diverse and complex. The numerous gaps identified here require the international scientific community to combine efforts in order to conduct comprehensive studies in tropical rainforests on the three continents. These results are essential to simulate the future of these ecosystems under diverse climate scenarios and to predict the future of the global earth carbon balance. Tropical rainforest ecosystems are characterized by high annual rainfall. Nevertheless, rainfall regularly fluctuates during the year and seasonal soil droughts do occur. Over the past decades, a number of extreme droughts have hit tropical rainforests, not only in Amazonia but also in Asia and Africa. The influence of drought events on tree mortality and growth or on ecosystem functioning (carbon and water fluxes) in tropical rainforest ecosystems has been studied intensively, but the response mechanisms are complex. Herein, we review the recent findings related to the response of tropical forest ecosystems to seasonal and extreme droughts and the current knowledge about the future of these ecosystems. This review emphasizes the progress made over recent years and the importance of the studies conducted under extreme drought conditions or in through-fall exclusion experiments in understanding the response of these ecosystems. It also points to the great diversity and complexity of the response of tropical rainforest ecosystems to drought. The numerous gaps identified here require the international scientific community to combine efforts in order to conduct comprehensive studies in tropical forest regions. These results are essential to simulate the future of these ecosystems under diverse climate scenarios and to predict the future of the global earth carbon balance.

Response of a benzoxainone derivative linked to monoaza-15-crown-5 with divalent heavy metals.

PubMed

Addleman, R S; Bennett, J; Tweedy, S H; Elshani, S; Wai, C M

1998-08-01

The response of a monoaza-15-crown-5 with an optically active aminobenzoxazinone moiety to divalent cations was investigated. The crown ether was found to undergo a strong emission shift to the blue when complexed with specific divalent metals that have ionic diameters between 1.9-2.4 A. Consequently the photoactive macrocycle is responsive to Mg(2+), Ca(2+), Ba(2+), Sr(2+), Cd(2+), and particularly responsive to Hg(2+)and Pb(2+). Macrocycle emission spectra are shown to be a function of cation concentration. Alkaline metal cations and smaller transition metals ions such as Ni(2+), Co(2+)and Zn(2+)do not cause significant changes in the macrocycle emission spectra. Emission, absorption, and complex stability constants are determined. Mechanisms of cation selectivity and spectral emission shifts are discussed. Challenges involving immobilization of the macrocycle while preserving its spectral response to cations are explored.

Auditory evoked potentials to abrupt pitch and timbre change of complex tones: electrophysiological evidence of 'streaming'?

PubMed

Jones, S J; Longe, O; Vaz Pato, M

1998-03-01

Examination of the cortical auditory evoked potentials to complex tones changing in pitch and timbre suggests a useful new method for investigating higher auditory processes, in particular those concerned with 'streaming' and auditory object formation. The main conclusions were: (i) the N1 evoked by a sudden change in pitch or timbre was more posteriorly distributed than the N1 at the onset of the tone, indicating at least partial segregation of the neuronal populations responsive to sound onset and spectral change; (ii) the T-complex was consistently larger over the right hemisphere, consistent with clinical and PET evidence for particular involvement of the right temporal lobe in the processing of timbral and musical material; (iii) responses to timbral change were relatively unaffected by increasing the rate of interspersed changes in pitch, suggesting a mechanism for detecting the onset of a new voice in a constantly modulated sound stream; (iv) responses to onset, offset and pitch change of complex tones were relatively unaffected by interfering tones when the latter were of a different timbre, suggesting these responses must be generated subsequent to auditory stream segregation.

ATF1 Modulates the Heat Shock Response by Regulating the Stress-Inducible Heat Shock Factor 1 Transcription Complex

PubMed Central

Takii, Ryosuke; Fujimoto, Mitsuaki; Tan, Ke; Takaki, Eiichi; Hayashida, Naoki; Nakato, Ryuichiro; Shirahige, Katsuhiko

2014-01-01

The heat shock response is an evolutionally conserved adaptive response to high temperatures that controls proteostasis capacity and is regulated mainly by an ancient heat shock factor (HSF). However, the regulation of target genes by the stress-inducible HSF1 transcription complex has not yet been examined in detail in mammalian cells. In the present study, we demonstrated that HSF1 interacted with members of the ATF1/CREB family involved in metabolic homeostasis and recruited them on the HSP70 promoter in response to heat shock. The HSF1 transcription complex, including the chromatin-remodeling factor BRG1 and lysine acetyltransferases p300 and CREB-binding protein (CBP), was formed in a manner that was dependent on the phosphorylation of ATF1. ATF1-BRG1 promoted the establishment of an active chromatin state and HSP70 expression during heat shock, whereas ATF1-p300/CBP accelerated the shutdown of HSF1 DNA-binding activity during recovery from acute stress, possibly through the acetylation of HSF1. Furthermore, ATF1 markedly affected the resistance to heat shock. These results revealed the unanticipated complexity of the primitive heat shock response mechanism, which is connected to metabolic adaptation. PMID:25312646

Nanoscale Charge Balancing Mechanism in Calcium-Silicate-Hydrate Gels: Novel Complex Disordered Materials from First-principles

NASA Astrophysics Data System (ADS)

Ozcelik, Ongun; White, Claire

Alkali-activated materials which have augmented chemical compositions as compared to ordinary Portland cement are sustainable technologies that have the potential to lower CO2 emissions associated with the construction industry. In particular, calcium-silicate-hydrate (C-S-H) gel is altered at the atomic scale due to changes in its chemical composition. Here, based on first-principles calculations, we predict a charge balancing mechanism at the molecular level in C-S-H gels when alkali atoms are introduced into their structure. This charge balancing process is responsible for the formation of novel structures which possess superior mechanical properties compared to their charge unbalanced counterparts. Different structural representations are obtained depending on the level of substitution and the degree of charge balancing incorporated in the structures. The impact of these charge balancing effects on the structures is assessed by analyzing their formation energies, local bonding environments, diffusion barriers and mechanical properties. These results provide information on the phase stability of alkali/aluminum containing C-S-H gels, shedding light on the fundamental mechanisms that play a crucial role in these complex disordered materials. We acknowledge funding from the Princeton Center for Complex Materials, a MRSEC supported by NSF.

A Soft Parallel Kinematic Mechanism.

PubMed

White, Edward L; Case, Jennifer C; Kramer-Bottiglio, Rebecca

2018-02-01

In this article, we describe a novel holonomic soft robotic structure based on a parallel kinematic mechanism. The design is based on the Stewart platform, which uses six sensors and actuators to achieve full six-degree-of-freedom motion. Our design is much less complex than a traditional platform, since it replaces the 12 spherical and universal joints found in a traditional Stewart platform with a single highly deformable elastomer body and flexible actuators. This reduces the total number of parts in the system and simplifies the assembly process. Actuation is achieved through coiled-shape memory alloy actuators. State observation and feedback is accomplished through the use of capacitive elastomer strain gauges. The main structural element is an elastomer joint that provides antagonistic force. We report the response of the actuators and sensors individually, then report the response of the complete assembly. We show that the completed robotic system is able to achieve full position control, and we discuss the limitations associated with using responsive material actuators. We believe that control demonstrated on a single body in this work could be extended to chains of such bodies to create complex soft robots.

Exploration of the molecular basis of blast injury in a biofidelic model of traumatic brain injury

NASA Astrophysics Data System (ADS)

Thielen, P.; Mehoke, T.; Gleason, J.; Iwaskiw, A.; Paulson, J.; Merkle, A.; Wester, B.; Dymond, J.

2018-01-01

Biological response to blast overpressure is complex and results in various and potentially non-concomitant acute and long-term deficits to exposed individuals. Clinical links between blast severity and injury outcomes remain elusive and have yet to be fully described, resulting in a critical inability to develop associated protection and mitigation strategies. Further, experimental models frequently fail to reproduce observed physiological phenomena and/or introduce artifacts that confound analysis and reproducibility. New models are required that employ consistent mechanical inputs, scale with biological analogs and known clinical data, and permit high-throughput examination of biological responses for a range of environmental and battlefield- relevant exposures. Here we describe a novel, biofidelic headform capable of integrating complex biological samples for blast exposure studies. We additionally demonstrate its utility in detecting acute transcriptional responses in the model organism Caenorhabditis elegans after exposure to blast overpressure. This approach enables correlation between mechanical exposure and biological outcome, permitting both the enhancement of existing surrogate and computational models and the high-throughput biofidelic testing of current and future protection systems.

Effects of cyproterone acetate on sexual arousal patterns of pedophiles.

PubMed

Bradford, J M; Pawlak, A

1993-12-01

The antiandrogen treatment of sexual offenders has been shown to reduce the recidivism rate. The mechanism of action has been assumed to be through asexualization with its secondary effects on sexual behavior. This study shows that the mechanism may be more complex and may involve a differential effect on sexual arousal patterns. Treatment responses may differ in high and low plasma testosterone groups.

Smart responsive phosphorescent materials for data recording and security protection.

PubMed

Sun, Huibin; Liu, Shujuan; Lin, Wenpeng; Zhang, Kenneth Yin; Lv, Wen; Huang, Xiao; Huo, Fengwei; Yang, Huiran; Jenkins, Gareth; Zhao, Qiang; Huang, Wei

2014-04-07

Smart luminescent materials that are responsive to external stimuli have received considerable interest. Here we report ionic iridium (III) complexes simultaneously exhibiting mechanochromic, vapochromic and electrochromic phosphorescence. These complexes share the same phosphorescent iridium (III) cation with a N-H moiety in the N^N ligand and contain different anions, including hexafluorophosphate, tetrafluoroborate, iodide, bromide and chloride. The anionic counterions cause a variation in the emission colours of the complexes from yellow to green by forming hydrogen bonds with the N-H proton. The electronic effect of the N-H moiety is sensitive towards mechanical grinding, solvent vapour and electric field, resulting in mechanochromic, vapochromic and electrochromic phosphorescence. On the basis of these findings, we construct a data-recording device and demonstrate data encryption and decryption via fluorescence lifetime imaging and time-gated luminescence imaging techniques. Our results suggest that rationally designed phosphorescent complexes may be promising candidates for advanced data recording and security protection.

IGF-1 signaling mediated cell-specific skeletal mechano-transduction.

PubMed

Tian, Faming; Wang, Yongmei; Bikle, Daniel D

2018-02-01

Mechanical loading preserves bone mass and stimulates bone formation, whereas skeletal unloading leads to bone loss. In addition to osteocytes, which are considered the primary sensor of mechanical load, osteoblasts, and bone specific mesenchymal stem cells also are involved. The skeletal response to mechanical signals is a complex process regulated by multiple signaling pathways including that of insulin-like growth factor-1 (IGF-1). Conditional osteocyte deletion of IGF-1 ablates the osteogenic response to mechanical loading. Similarly, osteocyte IGF-1 receptor (IGF-1R) expression is necessary for reloading-induced periosteal bone formation. Transgenic overexpression of IGF-1 in osteoblasts results in enhanced responsiveness to in vivo mechanical loading in mice, a response which is eliminated by osteoblastic conditional disruption of IGF-1 in vivo. Bone marrow derived stem cells (BMSC) from unloaded bone fail to respond to IGF-1 in vitro. IGF-1R is required for the transduction of a mechanical stimulus to downstream effectors, transduction which is lost when the IGF-1R is deleted. Although the molecular mechanisms are not yet fully elucidated, the IGF signaling pathway and its interactions with potentially interlinked signaling cascades involving integrins, the estrogen receptor, and wnt/β-catenin play an important role in regulating adaptive response of cancer bone cells to mechanical stimuli. In this review, we discuss recent advances investigating how IGF-1 and other interlinked molecules and signaling pathways regulate skeletal mechano-transduction involving different bone cells, providing an overview of the IGF-1 signaling mediated cell-specific response to mechanical stimuli. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:576-583, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Transcriptional regulatory networks controlling woolliness in peach in response to preharvest gibberellin application and cold storage.

PubMed

Pegoraro, Camila; Tadiello, Alice; Girardi, César L; Chaves, Fábio C; Quecini, Vera; de Oliveira, Antonio Costa; Trainotti, Livio; Rombaldi, Cesar Valmor

2015-11-18

Postharvest fruit conservation relies on low temperatures and manipulations of hormone metabolism to maintain sensory properties. Peaches are susceptible to chilling injuries, such as 'woolliness' that is caused by juice loss leading to a 'wooly' fruit texture. Application of gibberellic acid at the initial stages of pit hardening impairs woolliness incidence, however the mechanisms controlling the response remain unknown. We have employed genome wide transcriptional profiling to investigate the effects of gibberellic acid application and cold storage on harvested peaches. Approximately half of the investigated genes exhibited significant differential expression in response to the treatments. Cellular and developmental process gene ontologies were overrepresented among the differentially regulated genes, whereas sequences in cell death and immune response categories were underrepresented. Gene set enrichment demonstrated a predominant role of cold storage in repressing the transcription of genes associated to cell wall metabolism. In contrast, genes involved in hormone responses exhibited a more complex transcriptional response, indicating an extensive network of crosstalk between hormone signaling and low temperatures. Time course transcriptional analyses demonstrate the large contribution of gene expression regulation on the biochemical changes leading to woolliness in peach. Overall, our results provide insights on the mechanisms controlling the complex phenotypes associated to postharvest textural changes in peach and suggest that hormone mediated reprogramming previous to pit hardening affects the onset of chilling injuries.

PIEZO channel protein naturally expressed in human breast cancer cell MDA-MB-231 as probed by atomic force microscopy

NASA Astrophysics Data System (ADS)

Weng, Yuanqi; Yan, Fei; Chen, Runkang; Qian, Ming; Ou, Yun; Xie, Shuhong; Zheng, Hairong; Li, Jiangyu

2018-05-01

Mechanical stimuli drives many physiological processes through mechanically activated channels, and the recent discovery of PIEZO channel has generated great interests in its mechanotransduction. Many previous researches investigated PIEZO proteins by transcribing them in cells that originally have no response to mechanical stimulation, or by forming PIEZO-combined complexes in vitro, and few studied PIEZO protein's natural characteristics in cells. In this study we show that MDA-MB-231, a malignant cell in human breast cancer cell line, expresses the mechanosensitive behavior of PIEZO in nature without extra treatment, and we report its characteristics in response to localized mechanical stimulation under an atomic force microscope, wherein a correlation between the force magnitude applied and the channel opening probability is observed. The results on PIEZO of MDA-MB-231 can help establish a basis of preventing and controlling of human breast cancer cell via mechanical forces.

Two mechanisms for dissipation of excess light in monomeric and trimeric light-harvesting complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dall'Osto, Luca; Cazzaniga, Stefano; Bressan, Mauro

Oxygenic photoautotrophs require mechanisms for rapidly matching the level of chlorophyll excited states from light harvesting with the rate of electron transport from water to carbon dioxide. These photoprotective reactions prevent formation of reactive excited states and photoinhibition. The fastest response to excess illumination is the so-called non-photochemical quenching which, in higher plants, requires the luminal pH sensor PsbS and other yet unidentified components of the photosystem II antenna. Both trimeric light-harvesting complex II (LHCII) and monomeric LHC proteins have been indicated as site(s) of the heat-dissipative reactions. Different mechanisms have been proposed: Energy transfer to a lutein quencher inmore » trimers, formation of a zeaxanthin radical cation in monomers. Here, we report on the construction of a mutant lacking all monomeric LHC proteins but retaining LHCII trimers. Its non-photochemical quenching induction rate was substantially slower with respect to the wild type. A carotenoid radical cation signal was detected in the wild type, although it was lost in the mutant. Here, we conclude that non-photochemical quenching is catalysed by two independent mechanisms, with the fastest activated response catalysed within monomeric LHC proteins depending on both zeaxanthin and lutein and on the formation of a radical cation. Trimeric LHCII was responsible for the slowly activated quenching component whereas inclusion in supercomplexes was not required. Finally, this latter activity does not depend on lutein nor on charge transfer events, whereas zeaxanthin was essential.« less

Effect of fiber distribution and realignment on the nonlinear and inhomogeneous mechanical properties of human supraspinatus tendon under longitudinal tensile loading.

PubMed

Lake, Spencer P; Miller, Kristin S; Elliott, Dawn M; Soslowsky, Louis J

2009-12-01

Tendon exhibits nonlinear stress-strain behavior that may be partly due to movement of collagen fibers through the extracellular matrix. While a few techniques have been developed to evaluate the fiber architecture of other soft tissues, the organizational behavior of tendon under load has not been determined. The supraspinatus tendon (SST) of the rotator cuff is of particular interest for investigation due to its complex mechanical environment and corresponding inhomogeneity. In addition, SST injury occurs frequently with limited success in treatment strategies, illustrating the need for a better understanding of SST properties. Therefore, the objective of this study was to quantitatively evaluate the inhomogeneous tensile mechanical properties, fiber organization, and fiber realignment under load of human SST utilizing a novel polarized light technique. Fiber distributions were found to become more aligned under load, particularly during the low stiffness toe-region, suggesting that fiber realignment may be partly responsible for observed nonlinear behavior. Fiber alignment was found to correlate significantly with mechanical parameters, providing evidence for strong structure-function relationships in tendon. Human SST exhibits complex, inhomogeneous mechanical properties and fiber distributions, perhaps due to its complex loading environment. Surprisingly, histological grade of degeneration did not correlate with mechanical properties.

Structural Basis for DNA Recognition by the Two-Component Response Regulator RcsB.

PubMed

Filippova, Ekaterina V; Zemaitaitis, Bozena; Aung, Theint; Wolfe, Alan J; Anderson, Wayne F

2018-02-27

RcsB is a highly conserved transcription regulator of the Rcs phosphorelay system, a complex two-component signal transduction system (N. Majdalani and S. Gottesman, Annu Rev Microbiol 59:379-405, 2005; A. J. Wolfe, Curr Opin Microbiol 13:204-209, 2010, https://doi.org/10.1016/j.mib.2010.01.002; D. J. Clarke, Future Microbiol 5:1173-1184, 2010, https://doi.org/10.2217/fmb.10.83). RcsB plays an important role in virulence and pathogenicity in human hosts by regulating biofilm formation. RcsB can regulate transcription alone or together with its auxiliary transcription regulators by forming heterodimers. This complexity allows RcsB to regulate transcription of more than 600 bacterial genes in response to different stresses (D. Wang et al., Mol Plant Microbe Interact 25:6-17, 2012, https://doi.org/10.1094/MPMI-08-11-0207). Despite increasing knowledge of RcsB importance, molecular mechanisms that drive the ability of RcsB to control transcription of a large number of genes remain unclear. Here, we present crystal structures of unphosphorylated RcsB in complex with the consensus DNA-binding sequence of 22-mer (DNA22) and 18-mer (DNA18) of the flhDC operon from Escherichia coli determined at 3.15- and 3.37-Å resolution, respectively. The results of our structural analysis combined with the results of in vitro binding assays provide valuable insights to the protein regulatory mechanism, demonstrate how RcsB recognizes target DNA sequences, and reveal a unique oligomeric state that allows RcsB to form homo- and heterodimers. This information will help us understand the complex mechanisms of transcriptional regulation by RcsB in bacteria. IMPORTANCE RcsB is a well-studied two-component response regulator of the Rcs phosphorelay system, conserved within the family Enterobacteriaceae , which includes many pathogens. It is a global regulator, controlling more than 5% of bacterial genes associated with capsule biosynthesis, flagellar biogenesis, cell wall biosynthesis, antibiotic resistance, biofilm formation, and virulence in pathogens. Knowledge of RcsB structure represents a unique opportunity to explore mechanisms that regulate the Rcs phosphorelay system and its role in the family Enterobacteriaceae . Copyright © 2018 Filippova et al.

Transcriptomic changes during maize roots development responsive to Cadmium (Cd) pollution using comparative RNAseq-based approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peng, Hua; Sichuan Tourism College, Chengdu, 610000, Sichuan; He, Xiujing

The heavy metal cadmium (Cd), acts as a widespread environmental contaminant, which has shown to adversely affect human health, food safety and ecosystem safety in recent years. However, research on how plant respond to various kinds of heavy metal stress is scarcely reported, especially for understanding of complex molecular regulatory mechanisms and elucidating the gene networks of plant respond to Cd stress. Here, transcriptomic changes during Mo17 and B73 seedlings development responsive to Cd pollution were investigated and comparative RNAseq-based approach in both genotypes were performed. 115 differential expression genes (DEGs) with significant alteration in expression were found co-modulated inmore » both genotypes during the maize seedling development; of those, most of DGEs were found comprised of stress and defense responses proteins, transporters, as well as transcription factors, such as thaumatin-like protein, ZmOPR2 and ZmOPR5. More interestingly, genotype-specific transcriptional factors changes induced by Cd stress were found contributed to the regulatory mechanism of Cd sensitivity in both different genotypes. Moreover, 12 co-expression modules associated with specific biological processes or pathways (M1 to M12) were identified by consensus co-expression network. These results will expand our understanding of complex molecular mechanism of response and defense to Cd exposure in maize seedling roots. - Highlights: • Transcriptomic changes responsive to Cd pollution using comparative RNAseq-based approach. • 115 differential expression genes (DEGs) were found co-modulated in both genotypes. • Most of DGEs belong to stress and defense responses proteins, transporters, transcription factors. • 12 co-expression modules associated with specific biological processes or pathways. • Genotype-specific transcriptional factors changes induced by Cd stress were found.« less

FY07 NRL DoD High Performance Computing Modernization Program Annual Reports

DTIC Science & Technology

2008-09-05

performed. Implicit and explicit solutions methods are used as appropriate. The primary finite element codes used are ABAQUS and ANSYS. User subroutines ...geometric complexities, loading path dependence, rate dependence, and interaction between loading types (electrical, thermal and mechanical). Work is not...are used for specialized material constitutive response. Coupled material responses, such as electrical- thermal for capacitor materials or electrical

Surgical inflammatory stress: the embryo takes hold of the reins again

PubMed Central

2013-01-01

The surgical inflammatory response can be a type of high-grade acute stress response associated with an increasingly complex trophic functional system for using oxygen. This systemic neuro-immune-endocrine response seems to induce the re-expression of 2 extraembryonic-like functional axes, i.e. coelomic-amniotic and trophoblastic-yolk-sac-related, within injured tissues and organs, thus favoring their re-development. Accordingly, through the up-regulation of two systemic inflammatory phenotypes, i.e. neurogenic and immune-related, a gestational-like response using embryonic functions would be induced in the patient’s injured tissues and organs, which would therefore result in their repair. Here we establish a comparison between the pathophysiological mechanisms that are produced during the inflammatory response and the physiological mechanisms that are expressed during early embryonic development. In this way, surgical inflammation could be a high-grade stress response whose pathophysiological mechanisms would be based on the recapitulation of ontogenic and phylogenetic-related functions. Thus, the ultimate objective of surgical inflammation, as a gestational process, is creating new tissues/organs for repairing the injured ones. Since surgical inflammation and early embryonic development share common production mechanisms, the factors that hamper the wound healing reaction in surgical patients could be similar to those that impair the gestational process. PMID:23374964

A combined experimental atomic force microscopy-based nanoindentation and computational modeling approach to unravel the key contributors to the time-dependent mechanical behavior of single cells.

PubMed

Florea, Cristina; Tanska, Petri; Mononen, Mika E; Qu, Chengjuan; Lammi, Mikko J; Laasanen, Mikko S; Korhonen, Rami K

2017-02-01

Cellular responses to mechanical stimuli are influenced by the mechanical properties of cells and the surrounding tissue matrix. Cells exhibit viscoelastic behavior in response to an applied stress. This has been attributed to fluid flow-dependent and flow-independent mechanisms. However, the particular mechanism that controls the local time-dependent behavior of cells is unknown. Here, a combined approach of experimental AFM nanoindentation with computational modeling is proposed, taking into account complex material behavior. Three constitutive models (porohyperelastic, viscohyperelastic, poroviscohyperelastic) in tandem with optimization algorithms were employed to capture the experimental stress relaxation data of chondrocytes at 5 % strain. The poroviscohyperelastic models with and without fluid flow allowed through the cell membrane provided excellent description of the experimental time-dependent cell responses (normalized mean squared error (NMSE) of 0.003 between the model and experiments). The viscohyperelastic model without fluid could not follow the entire experimental data that well (NMSE = 0.005), while the porohyperelastic model could not capture it at all (NMSE = 0.383). We also show by parametric analysis that the fluid flow has a small, but essential effect on the loading phase and short-term cell relaxation response, while the solid viscoelasticity controls the longer-term responses. We suggest that the local time-dependent cell mechanical response is determined by the combined effects of intrinsic viscoelasticity of the cytoskeleton and fluid flow redistribution in the cells, although the contribution of fluid flow is smaller when using a nanosized probe and moderate indentation rate. The present approach provides new insights into viscoelastic responses of chondrocytes, important for further understanding cell mechanobiological mechanisms in health and disease.

GATA Factor Regulation in Excess Nitrogen Occurs Independently of Gtr-Ego Complex-Dependent TorC1 Activation.

PubMed

Tate, Jennifer J; Georis, Isabelle; Rai, Rajendra; Vierendeels, Fabienne; Dubois, Evelyne; Cooper, Terrance G

2015-05-29

The TorC1 protein kinase complex is a central component in a eukaryotic cell's response to varying nitrogen availability, with kinase activity being stimulated in nitrogen excess by increased intracellular leucine. This leucine-dependent TorC1 activation requires functional Gtr1/2 and Ego1/3 complexes. Rapamycin inhibition of TorC1 elicits nuclear localization of Gln3, a GATA-family transcription activator responsible for the expression of genes encoding proteins required to transport and degrade poor nitrogen sources, e.g., proline. In nitrogen-replete conditions, Gln3 is cytoplasmic and Gln3-mediated transcription minimal, whereas in nitrogen limiting or starvation conditions, or after rapamycin treatment, Gln3 is nuclear and transcription greatly increased. Increasing evidence supports the idea that TorC1 activation may not be as central to nitrogen-responsive intracellular Gln3 localization as envisioned previously. To test this idea directly, we determined whether Gtr1/2- and Ego1/3-dependent TorC1 activation also was required for cytoplasmic Gln3 sequestration and repressed GATA factor-mediated transcription by abolishing the Gtr-Ego complex proteins. We show that Gln3 is sequestered in the cytoplasm of gtr1Δ, gtr2Δ, ego1Δ, and ego3Δ strains either long term in logarithmically glutamine-grown cells or short term after refeeding glutamine to nitrogen-limited or -starved cells; GATA factor-dependent transcription also was minimal. However, in all but a gtr1Δ, nuclear Gln3 localization in response to nitrogen limitation or starvation was adversely affected. Our data demonstrate: (i) Gtr-Ego-dependent TorC1 activation is not required for cytoplasmic Gln3 sequestration in nitrogen-rich conditions; (ii) a novel Gtr-Ego-TorC1 activation-independent mechanism sequesters Gln3 in the cytoplasm; (iii) Gtr and Ego complex proteins participate in nuclear Gln3-Myc(13) localization, heretofore unrecognized functions for these proteins; and (iv) the importance of searching for new mechanisms associated with TorC1 activation and/or the regulation of Gln3 localization/function in response to changes in the cells' nitrogen environment. Copyright © 2015 Tate et al.

GATA Factor Regulation in Excess Nitrogen Occurs Independently of Gtr-Ego Complex-Dependent TorC1 Activation

PubMed Central

Tate, Jennifer J.; Georis, Isabelle; Rai, Rajendra; Vierendeels, Fabienne; Dubois, Evelyne; Cooper, Terrance G.

2015-01-01

The TorC1 protein kinase complex is a central component in a eukaryotic cell’s response to varying nitrogen availability, with kinase activity being stimulated in nitrogen excess by increased intracellular leucine. This leucine-dependent TorC1 activation requires functional Gtr1/2 and Ego1/3 complexes. Rapamycin inhibition of TorC1 elicits nuclear localization of Gln3, a GATA-family transcription activator responsible for the expression of genes encoding proteins required to transport and degrade poor nitrogen sources, e.g., proline. In nitrogen-replete conditions, Gln3 is cytoplasmic and Gln3-mediated transcription minimal, whereas in nitrogen limiting or starvation conditions, or after rapamycin treatment, Gln3 is nuclear and transcription greatly increased. Increasing evidence supports the idea that TorC1 activation may not be as central to nitrogen-responsive intracellular Gln3 localization as envisioned previously. To test this idea directly, we determined whether Gtr1/2- and Ego1/3-dependent TorC1 activation also was required for cytoplasmic Gln3 sequestration and repressed GATA factor-mediated transcription by abolishing the Gtr-Ego complex proteins. We show that Gln3 is sequestered in the cytoplasm of gtr1Δ, gtr2Δ, ego1Δ, and ego3Δ strains either long term in logarithmically glutamine-grown cells or short term after refeeding glutamine to nitrogen-limited or -starved cells; GATA factor−dependent transcription also was minimal. However, in all but a gtr1Δ, nuclear Gln3 localization in response to nitrogen limitation or starvation was adversely affected. Our data demonstrate: (i) Gtr-Ego-dependent TorC1 activation is not required for cytoplasmic Gln3 sequestration in nitrogen-rich conditions; (ii) a novel Gtr-Ego-TorC1 activation-independent mechanism sequesters Gln3 in the cytoplasm; (iii) Gtr and Ego complex proteins participate in nuclear Gln3-Myc13 localization, heretofore unrecognized functions for these proteins; and (iv) the importance of searching for new mechanisms associated with TorC1 activation and/or the regulation of Gln3 localization/function in response to changes in the cells’ nitrogen environment. PMID:26024867

Pupil movements to light and accommodative stimulation - A comparative study.

NASA Technical Reports Server (NTRS)

Semmlow, J.; Stark, L.

1973-01-01

Isolation and definition of specific response components in pupil reflexes through comparison of the dynamic features of light-induced and accommodation-induced pupil movements. A quantitative analysis of the behavior of the complex nonlinear pupil responses reveals the presence of two independent nonlinear characteristics: a range-dependent gain and a direction dependence or movement asymmetry. These nonlinear properties are attributed to motor processes because they are observable in pupil responses to both light and accommodation stimuli. The possible mechanisms and consequences of these pupil response characteristics are quantitatively defined and discussed.

Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide.

PubMed

Yakimov, Alexander; Pobegalov, Georgii; Bakhlanova, Irina; Khodorkovskii, Mikhail; Petukhov, Michael; Baitin, Dmitry

2017-09-19

The RecX protein, a very active natural RecA protein inhibitor, can completely disassemble RecA filaments at nanomolar concentrations that are two to three orders of magnitude lower than that of RecA protein. Based on the structure of RecX protein complex with the presynaptic RecA filament, we designed a short first in class α-helical peptide that both inhibits RecA protein activities in vitro and blocks the bacterial SOS-response in vivo. The peptide was designed using SEQOPT, a novel method for global sequence optimization of protein α-helices. SEQOPT produces artificial peptide sequences containing only 20 natural amino acids with the maximum possible conformational stability at a given pH, ionic strength, temperature, peptide solubility. It also accounts for restrictions due to known amino acid residues involved in stabilization of protein complexes under consideration. The results indicate that a few key intermolecular interactions inside the RecA protein presynaptic complex are enough to reproduce the main features of the RecX protein mechanism of action. Since the SOS-response provides a major mechanism of bacterial adaptation to antibiotics, these results open new ways for the development of antibiotic co-therapy that would not cause bacterial resistance. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Metabolome Integrated Analysis of High-Temperature Response in Pinus radiata.

PubMed

Escandón, Mónica; Meijón, Mónica; Valledor, Luis; Pascual, Jesús; Pinto, Gloria; Cañal, María Jesús

2018-01-01

The integrative omics approach is crucial to identify the molecular mechanisms underlying high-temperature response in non-model species. Based on future scenarios of heat increase, Pinus radiata plants were exposed to a temperature of 40°C for a period of 5 days, including recovered plants (30 days after last exposure to 40°C) in the analysis. The analysis of the metabolome using complementary mass spectrometry techniques (GC-MS and LC-Orbitrap-MS) allowed the reliable quantification of 2,287 metabolites. The analysis of identified metabolites and highlighter metabolic pathways across heat time exposure reveal the dynamism of the metabolome in relation to high-temperature response in P. radiata , identifying the existence of a turning point (on day 3) at which P. radiata plants changed from an initial stress response program (shorter-term response) to an acclimation one (longer-term response). Furthermore, the integration of metabolome and physiological measurements, which cover from the photosynthetic state to hormonal profile, suggests a complex metabolic pathway interaction network related to heat-stress response. Cytokinins (CKs), fatty acid metabolism and flavonoid and terpenoid biosynthesis were revealed as the most important pathways involved in heat-stress response in P. radiata , with zeatin riboside (ZR) and isopentenyl adenosine (iPA) as the key hormones coordinating these multiple and complex interactions. On the other hand, the integrative approach allowed elucidation of crucial metabolic mechanisms involved in heat response in P. radiata , as well as the identification of thermotolerance metabolic biomarkers (L-phenylalanine, hexadecanoic acid, and dihydromyricetin), crucial metabolites which can reschedule the metabolic strategy to adapt to high temperature.

Metabolome Integrated Analysis of High-Temperature Response in Pinus radiata

PubMed Central

Escandón, Mónica; Meijón, Mónica; Valledor, Luis; Pascual, Jesús; Pinto, Gloria; Cañal, María Jesús

2018-01-01

The integrative omics approach is crucial to identify the molecular mechanisms underlying high-temperature response in non-model species. Based on future scenarios of heat increase, Pinus radiata plants were exposed to a temperature of 40°C for a period of 5 days, including recovered plants (30 days after last exposure to 40°C) in the analysis. The analysis of the metabolome using complementary mass spectrometry techniques (GC-MS and LC-Orbitrap-MS) allowed the reliable quantification of 2,287 metabolites. The analysis of identified metabolites and highlighter metabolic pathways across heat time exposure reveal the dynamism of the metabolome in relation to high-temperature response in P. radiata, identifying the existence of a turning point (on day 3) at which P. radiata plants changed from an initial stress response program (shorter-term response) to an acclimation one (longer-term response). Furthermore, the integration of metabolome and physiological measurements, which cover from the photosynthetic state to hormonal profile, suggests a complex metabolic pathway interaction network related to heat-stress response. Cytokinins (CKs), fatty acid metabolism and flavonoid and terpenoid biosynthesis were revealed as the most important pathways involved in heat-stress response in P. radiata, with zeatin riboside (ZR) and isopentenyl adenosine (iPA) as the key hormones coordinating these multiple and complex interactions. On the other hand, the integrative approach allowed elucidation of crucial metabolic mechanisms involved in heat response in P. radiata, as well as the identification of thermotolerance metabolic biomarkers (L-phenylalanine, hexadecanoic acid, and dihydromyricetin), crucial metabolites which can reschedule the metabolic strategy to adapt to high temperature. PMID:29719546

Mechanism and Regulation of Gene Expression by Androgen Receptor in Prostate Cancer

DTIC Science & Technology

2004-07-01

the nature, regulation and mechanism of action of these factors can facilitate the development of anti-prostatic cancer therapy. The general objective...response to other signal transduction pathways) during prostate cancer development . This approach might provide new drug development insights into...G. Roeder. 2000. Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action. Mol

The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy

DTIC Science & Technology

2017-07-01

microenvironmental factor promoting metastatic progression. A critical step in metastatic tumor progression is the ability of tumor cells to evade immune attack...Tumor cells utilize a complex set of mechanisms that prevent the immune system from mounting effective anti-tumor responses. Moreover, the hypoxic...promote the immunosuppressive phenotypes of both tumor cells as well as infiltrating immune cells . However, the mechanisms by which hypoxia promotes

A cellular and metabolic assessment of the thermal stress responses in the endemic gastropod Benedictia limnaeoides ongurensis from Lake Baikal.

PubMed

Axenov-Gribanov, Denis V; Bedulina, Daria S; Shatilina, Zhanna M; Lubyaga, Yulia A; Vereshchagina, Kseniya P; Timofeyev, Maxim A

2014-01-01

Our objective was to determine if the Lake Baikal endemic gastropod Benedictia limnaeoides ongurensis, which inhabits in stable cold waters expresses a thermal stress response. We hypothesized that the evolution of this species in the stable cold waters of Lake Baikal resulted in a reduction of its thermal stress-response mechanisms at the biochemical and cellular levels. Contrary to our hypothesis, our results show that exposure to a thermal challenge activates the cellular and biochemical mechanisms of thermal resistance, such as heat shock proteins and antioxidative enzymes, and alters energetic metabolism in B. limnaeoides ongurensis. Thermal stress caused the elevation of heat shock protein 70 and the products of anaerobic glycolysis together with the depletion of glucose and phosphagens in the studied species. Thus, a temperature increase activates the complex biochemical system of stress response and alters the energetic metabolism in this endemic Baikal gastropod. It is concluded that the deepwater Lake Baikal endemic gastropod B. limnaeoides ongurensis retains the ability to activate well-developed biochemical stress-response mechanisms when exposed to a thermal challenge. © 2013.

Structure and mechanics of aegagropilae fiber network.

PubMed

Verhille, Gautier; Moulinet, Sébastien; Vandenberghe, Nicolas; Adda-Bedia, Mokhtar; Le Gal, Patrice

2017-05-02

Fiber networks encompass a wide range of natural and manmade materials. The threads or filaments from which they are formed span a wide range of length scales: from nanometers, as in biological tissues and bundles of carbon nanotubes, to millimeters, as in paper and insulation materials. The mechanical and thermal behavior of these complex structures depends on both the individual response of the constituent fibers and the density and degree of entanglement of the network. A question of paramount importance is how to control the formation of a given fiber network to optimize a desired function. The study of fiber clustering of natural flocs could be useful for improving fabrication processes, such as in the paper and textile industries. Here, we use the example of aegagropilae that are the remains of a seagrass ( Posidonia oceanica ) found on Mediterranean beaches. First, we characterize different aspects of their structure and mechanical response, and second, we draw conclusions on their formation process. We show that these natural aggregates are formed in open sea by random aggregation and compaction of fibers held together by friction forces. Although formed in a natural environment, thus under relatively unconstrained conditions, the geometrical and mechanical properties of the resulting fiber aggregates are quite robust. This study opens perspectives for manufacturing complex fiber network materials.

Mechanisms of Geomagnetic Field Influence on Gene Expression Using Influenza as a Model System: Basics of Physical Epidemiology

PubMed Central

Zaporozhan, Valeriy; Ponomarenko, Andriy

2010-01-01

Recent studies demonstrate distinct changes in gene expression in cells exposed to a weak magnetic field (MF). Mechanisms of this phenomenon are not understood yet. We propose that proteins of the Cryptochrome family (CRY) are “epigenetic sensors” of the MF fluctuations, i.e., magnetic field-sensitive part of the epigenetic controlling mechanism. It was shown that CRY represses activity of the major circadian transcriptional complex CLOCK/BMAL1. At the same time, function of CRY, is apparently highly responsive to weak MF because of radical pairs that periodically arise in the functionally active site of CRY and mediate the radical pair mechanism of magnetoreception. It is known that the circadian complex influences function of every organ and tissue, including modulation of both NF-κB- and glucocorticoids- dependent signaling pathways. Thus, MFs and solar cycles-dependent geomagnetic field fluctuations are capable of altering expression of genes related to function of NF-κB, hormones and other biological regulators. Notably, NF-κB, along with its significant role in immune response, also participates in differential regulation of influenza virus RNA synthesis. Presented data suggests that in the case of global application (example—geomagnetic field), MF-mediated regulation may have epidemiological and other consequences. PMID:20617011

SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex.

PubMed

Chen, Xiaojuan; Yang, Xingxing; Zheng, Yang; Yang, Yudong; Xing, Yaling; Chen, Zhongbin

2014-05-01

SARS coronavirus (SARS-CoV) develops an antagonistic mechanism by which to evade the antiviral activities of interferon (IFN). Previous studies suggested that SARS-CoV papain-like protease (PLpro) inhibits activation of the IRF3 pathway, which would normally elicit a robust IFN response, but the mechanism(s) used by SARS PLpro to inhibit activation of the IRF3 pathway is not fully known. In this study, we uncovered a novel mechanism that may explain how SARS PLpro efficiently inhibits activation of the IRF3 pathway. We found that expression of the membrane-anchored PLpro domain (PLpro-TM) from SARS-CoV inhibits STING/TBK1/IKKε-mediated activation of type I IFNs and disrupts the phosphorylation and dimerization of IRF3, which are activated by STING and TBK1. Meanwhile, we showed that PLpro-TM physically interacts with TRAF3, TBK1, IKKε, STING, and IRF3, the key components that assemble the STING-TRAF3-TBK1 complex for activation of IFN expression. However, the interaction between the components in STING-TRAF3-TBK1 complex is disrupted by PLpro-TM. Furthermore, SARS PLpro-TM reduces the levels of ubiquitinated forms of RIG-I, STING, TRAF3, TBK1, and IRF3 in the STING-TRAF3-TBK1 complex. These results collectively point to a new mechanism used by SARS-CoV through which PLpro negatively regulates IRF3 activation by interaction with STING-TRAF3-TBK1 complex, yielding a SARS-CoV countermeasure against host innate immunity.

Receptor-mediated protein kinase activation and the mechanism of transmembrane signaling in bacterial chemotaxis.

PubMed Central

Liu, Y; Levit, M; Lurz, R; Surette, M G; Stock, J B

1997-01-01

Chemotaxis responses of Escherichia coli and Salmonella are mediated by type I membrane receptors with N-terminal extracytoplasmic sensing domains connected by transmembrane helices to C-terminal signaling domains in the cytoplasm. Receptor signaling involves regulation of an associated protein kinase, CheA. Here we show that kinase activation by a soluble signaling domain construct involves the formation of a large complex, with approximately 14 receptor signaling domains per CheA dimer. Electron microscopic examination of these active complexes indicates a well defined bundle composed of numerous receptor filaments. Our findings suggest a mechanism for transmembrane signaling whereby stimulus-induced changes in lateral packing interactions within an array of receptor-sensing domains at the cell surface perturb an equilibrium between active and inactive receptor-kinase complexes within the cytoplasm. PMID:9405352

Thermo-Mechanical Methodology for Stabilizing Shape Memory Alloy Response

NASA Technical Reports Server (NTRS)

Padula, Santo

2013-01-01

This innovation is capable of significantly reducing the amount of time required to stabilize the strain-temperature response of a shape memory alloy (SMA). Unlike traditional stabilization processes that take days to weeks to achieve stabilized response, this innovation accomplishes stabilization in a matter of minutes, thus making it highly useful for the successful and practical implementation of SMA-based technologies in real-world applications. The innovation can also be applied to complex geometry components, not just simple geometries like wires or rods.

Immune evasion by pathogens of bovine respiratory disease complex.

PubMed

Srikumaran, Subramaniam; Kelling, Clayton L; Ambagala, Aruna

2007-12-01

Bovine respiratory tract disease is a multi-factorial disease complex involving several viruses and bacteria. Viruses that play prominent roles in causing the bovine respiratory disease complex include bovine herpesvirus-1, bovine respiratory syncytial virus, bovine viral diarrhea virus and parinfluenza-3 virus. Bacteria that play prominent roles in this disease complex are Mannheimia haemolytica and Mycoplasma bovis. Other bacteria that infect the bovine respiratory tract of cattle are Histophilus (Haemophilus) somni and Pasteurella multocida. Frequently, severe respiratory tract disease in cattle is associated with concurrent infections of these pathogens. Like other pathogens, the viral and bacterial pathogens of this disease complex have co-evolved with their hosts over millions of years. As much as the hosts have diversified and fine-tuned the components of their immune system, the pathogens have also evolved diverse and sophisticated strategies to evade the host immune responses. These pathogens have developed intricate mechanisms to thwart both the innate and adaptive arms of the immune responses of their hosts. This review presents an overview of the strategies by which the pathogens suppress host immune responses, as well as the strategies by which the pathogens modify themselves or their locations in the host to evade host immune responses. These immune evasion strategies likely contribute to the failure of currently-available vaccines to provide complete protection to cattle against these pathogens.

A calcium-driven mechanochemical model for prediction of force generation in smooth muscle.

PubMed

Murtada, Sae-Il; Kroon, Martin; Holzapfel, Gerhard A

2010-12-01

A new model for the mechanochemical response of smooth muscle is presented. The focus is on the response of the actin-myosin complex and on the related generation of force (or stress). The chemical (kinetic) model describes the cross-bridge interactions with the thin filament in which the calcium-dependent myosin phosphorylation is the only regulatory mechanism. The new mechanical model is based on Hill's three-component model and it includes one internal state variable that describes the contraction/relaxation of the contractile units. It is characterized by a strain-energy function and an evolution law incorporating only a few material parameters with clear physical meaning. The proposed model satisfies the second law of thermodynamics. The results of the combined coupled model are broadly consistent with isometric and isotonic experiments on smooth muscle tissue. The simulations suggest that the matrix in which the actin-myosin complex is embedded does have a viscous property. It is straightforward for implementation into a finite element program in order to solve more complex boundary-value problems such as the control of short-term changes in lumen diameter of arteries due to mechanochemical signals.

Membrane microdomains and the cytoskeleton constrain AtHIR1 dynamics and facilitate the formation of an AtHIR1-associated immune complex.

PubMed

Lv, Xueqin; Jing, Yanping; Xiao, Jianwei; Zhang, Yongdeng; Zhu, Yingfang; Julian, Russell; Lin, Jinxing

2017-04-01

Arabidopsis hypersensitive-induced reaction (AtHIR) proteins function in plant innate immunity. However, the underlying mechanisms by which AtHIRs participate in plant immunity remain elusive. Here, using VA-TIRFM and FLIM-FRET, we revealed that AtHIR1 is present in membrane microdomains and co-localizes with the membrane microdomain marker REM1.3. Single-particle tracking analysis revealed that membrane microdomains and the cytoskeleton, especially microtubules, restrict the lateral mobility of AtHIR1 at the plasma membrane and facilitate its oligomerization. Furthermore, protein proximity index measurements, fluorescence cross-correlation spectroscopy, and biochemical experiments demonstrated that the formation of the AtHIR1 complex upon pathogen perception requires intact microdomains and cytoskeleton. Taken together, these findings suggest that microdomains and the cytoskeleton constrain AtHIR1 dynamics, promote AtHIR1 oligomerization, and increase the efficiency of the interactions of AtHIR1 with components of the AtHIR1 complex in response to pathogens, thus providing valuable insight into the mechanisms of defense-related responses in plants. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Risk assessment and adaptive runoff utilization in water resource system considering the complex relationship among water supply, electricity generation and environment

NASA Astrophysics Data System (ADS)

Zhou, J.; Zeng, X.; Mo, L.; Chen, L.; Jiang, Z.; Feng, Z.; Yuan, L.; He, Z.

2017-12-01

Generally, the adaptive utilization and regulation of runoff in the source region of China's southwest rivers is classified as a typical multi-objective collaborative optimization problem. There are grim competitions and incidence relation in the subsystems of water supply, electricity generation and environment, which leads to a series of complex problems represented by hydrological process variation, blocked electricity output and water environment risk. Mathematically, the difficulties of multi-objective collaborative optimization focus on the description of reciprocal relationships and the establishment of evolving model of adaptive systems. Thus, based on the theory of complex systems science, this project tries to carry out the research from the following aspects: the changing trend of coupled water resource, the covariant factor and driving mechanism, the dynamic evolution law of mutual feedback dynamic process in the supply-generation-environment coupled system, the environmental response and influence mechanism of coupled mutual feedback water resource system, the relationship between leading risk factor and multiple risk based on evolutionary stability and dynamic balance, the transfer mechanism of multiple risk response with the variation of the leading risk factor, the multidimensional coupled feedback system of multiple risk assessment index system and optimized decision theory. Based on the above-mentioned research results, the dynamic method balancing the efficiency of multiple objectives in the coupled feedback system and optimized regulation model of water resources is proposed, and the adaptive scheduling mode considering the internal characteristics and external response of coupled mutual feedback system of water resource is established. In this way, the project can make a contribution to the optimal scheduling theory and methodology of water resource management under uncertainty in the source region of Southwest River.

Multistructure index in revealing complexity of regulatory mechanisms of human cardiovascular system at rest and orthostatic stress in healthy humans

NASA Astrophysics Data System (ADS)

Makowiec, Danuta; Graff, Beata; Struzik, Zbigniew R.

2017-02-01

Biological regulation is sufficiently complex to pose an enduring challenge for characterization of both its equilibrium and transient non-equilibrium dynamics. Two univariate but coupled observables, heart rate and systolic blood pressure, are commonly characterized in the benchmark example of the human cardiovascular regulatory system. Asymmetric distributions of accelerations and decelerations of heart rate, as well as rises and falls in systolic blood pressure, recorded in humans during a head-up tilt test provide insights into the dynamics of cardiovascular response to a rapid, controlled deregulation of the system's homeostasis. The baroreflex feedback loop is assumed to be the fundamental physiological mechanism for ensuring homeostatic blood supply to distant organs at rest and during orthostatic stress, captured in a classical beat-to-beat autoregressive model of baroreflex by de Boer et al. (1987). For model corroboration, a multistructure index statistic is proposed, seamlessly evaluating the size spectrum of magnitudes of neural reflexes such as baroreflex, responsible for maintaining the homeostatic dynamics. The multistructure index exposes a distinctly different dynamics of multiscale asymmetry between results obtained from real-life signals recorded from healthy subjects and those simulated using both the classical and perturbed versions of the model. Nonlinear effects observed suggest the pronounced presence of complex mechanisms resulting from baroreflex regulation when a human is at rest, which is aggravated in the system's response to orthostatic stress. Using our methodology of multistructure index, we therefore show a marked difference between model and real-life scenarios, which we attribute to multiscale asymmetry of non-linear origin in real-life signals, which we are not reproducible by the classical model.

Conflict Resolution in the Genome: How Transcription and Replication Make It Work.

PubMed

Hamperl, Stephan; Cimprich, Karlene A

2016-12-01

The complex machineries involved in replication and transcription translocate along the same DNA template, often in opposing directions and at different rates. These processes routinely interfere with each other in prokaryotes, and mounting evidence now suggests that RNA polymerase complexes also encounter replication forks in higher eukaryotes. Indeed, cells rely on numerous mechanisms to avoid, tolerate, and resolve such transcription-replication conflicts, and the absence of these mechanisms can lead to catastrophic effects on genome stability and cell viability. In this article, we review the cellular responses to transcription-replication conflicts and highlight how these inevitable encounters shape the genome and impact diverse cellular processes. Copyright © 2016 Elsevier Inc. All rights reserved.

Thermoviscoplastic nonlinear constitutive relationships for structural analysis of high temperature metal matrix composites

NASA Technical Reports Server (NTRS)

Chamis, C. C.; Hopkins, D. A.

1985-01-01

A set of thermoviscoplastic nonlinear constitutive relationships (1VP-NCR) is presented. The set was developed for application to high temperature metal matrix composites (HT-MMC) and is applicable to thermal and mechanical properties. Formulation of the TVP-NCR is based at the micromechanics level. The TVP-NCR are of simple form and readily integrated into nonlinear composite structural analysis. It is shown that the set of TVP-NCR is computationally effective. The set directly predicts complex materials behavior at all levels of the composite simulation, from the constituent materials, through the several levels of composite mechanics, and up to the global response of complex HT-MMC structural components.

On the dimension of complex responses in nonlinear structural vibrations

NASA Astrophysics Data System (ADS)

Wiebe, R.; Spottswood, S. M.

2016-07-01

The ability to accurately model engineering systems under extreme dynamic loads would prove a major breakthrough in many aspects of aerospace, mechanical, and civil engineering. Extreme loads frequently induce both nonlinearities and coupling which increase the complexity of the response and the computational cost of finite element models. Dimension reduction has recently gained traction and promises the ability to distill dynamic responses down to a minimal dimension without sacrificing accuracy. In this context, the dimensionality of a response is related to the number of modes needed in a reduced order model to accurately simulate the response. Thus, an important step is characterizing the dimensionality of complex nonlinear responses of structures. In this work, the dimensionality of the nonlinear response of a post-buckled beam is investigated. Significant detail is dedicated to carefully introducing the experiment, the verification of a finite element model, and the dimensionality estimation algorithm as it is hoped that this system may help serve as a benchmark test case. It is shown that with minor modifications, the method of false nearest neighbors can quantitatively distinguish between the response dimension of various snap-through, non-snap-through, random, and deterministic loads. The state-space dimension of the nonlinear system in question increased from 2-to-10 as the system response moved from simple, low-level harmonic to chaotic snap-through. Beyond the problem studied herein, the techniques developed will serve as a prescriptive guide in developing fast and accurate dimensionally reduced models of nonlinear systems, and eventually as a tool for adaptive dimension-reduction in numerical modeling. The results are especially relevant in the aerospace industry for the design of thin structures such as beams, panels, and shells, which are all capable of spatio-temporally complex dynamic responses that are difficult and computationally expensive to model.

The Spin-Lattice Relaxation of Hyperpolarized 89Y Complexes

NASA Astrophysics Data System (ADS)

Jindal, Ashish; Lumata, Lloyd; Xing, Yixun; Merritt, Matthew; Zhao, Piyu; Malloy, Craig; Sherry, Dean; Kovacs, Zoltan

2011-03-01

The low sensitivity of NMR can be overcome by dynamic nuclear polarization (DNP). However, a limitation to the use of hyperpolarized materials is the signal decay due to T1 relaxation. Among NMR-active nuclei, 89 Y is potentially valuable in medical imaging because in chelated form, pH-sensitive agents can be developed. 89 Y also offers many attractive features -- 100 % abundance, a 1/2 spin, and a long T1 , up to 10 min. Yet, developing new 89 Y complexes with even longer T1 values is desirable. Designing such complexes relies upon understanding the mechanism(s) responsible for T1 relaxation. We report an approach to hyperpolarized T1 measurements that enabled an analysis of relaxation mechanisms by selective deuteration of the ligand backbone, the solvent or both. Hyperpolarized 89 Y -- DTPA, DOTA, EDTA, and deuterated EDTA complexes were studied. Results suggest that substitution of low-gamma nuclei on the ligand backbone as opposed to that of the solvent most effectively increase the 89 Y T1 . These results are encouraging for in vivo applications as the presence of bound water may not dramatically affect the T1 .

PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena

PubMed Central

Hughes, Shannon K.; Oudin, Madeleine J.; Tadros, Jenny; Neil, Jason; Del Rosario, Amanda; Joughin, Brian A.; Ritsma, Laila; Wyckoff, Jeff; Vasile, Eliza; Eddy, Robert; Philippar, Ulrike; Lussiez, Alisha; Condeelis, John S.; van Rheenen, Jacco; White, Forest; Lauffenburger, Douglas A.; Gertler, Frank B.

2015-01-01

During breast cancer progression, alternative mRNA splicing produces functionally distinct isoforms of Mena, an actin regulator with roles in cell migration and metastasis. Aggressive tumor cell subpopulations express MenaINV, which promotes tumor cell invasion by potentiating EGF responses. However, the mechanism by which this occurs is unknown. Here we report that Mena associates constitutively with the tyrosine phosphatase PTP1B and mediates a novel negative feedback mechanism that attenuates receptor tyrosine kinase signaling. On EGF stimulation, complexes containing Mena and PTP1B are recruited to the EGFR, causing receptor dephosphorylation and leading to decreased motility responses. Mena also interacts with the 5′ inositol phosphatase SHIP2, which is important for the recruitment of the Mena-PTP1B complex to the EGFR. When MenaINV is expressed, PTP1B recruitment to the EGFR is impaired, providing a mechanism for growth factor sensitization to EGF, as well as HGF and IGF, and increased resistance to EGFR and Met inhibitors in signaling and motility assays. In sum, we demonstrate that Mena plays an important role in regulating growth factor–induced signaling. Disruption of this attenuation by MenaINV sensitizes tumor cells to low–growth factor concentrations, thereby increasing the migration and invasion responses that contribute to aggressive, malignant cell phenotypes. PMID:26337385

Non-self recognition, transcriptional reprogramming, and secondary metabolite accumulation during plant/pathogen interactions

PubMed Central

Hahlbrock, Klaus; Bednarek, Pawel; Ciolkowski, Ingo; Hamberger, Björn; Heise, Andreas; Liedgens, Hiltrud; Logemann, Elke; Nürnberger, Thorsten; Schmelzer, Elmon; Somssich, Imre E.; Tan, Jianwen

2003-01-01

Disease resistance of plants involves two distinct forms of chemical communication with the pathogen: recognition and defense. Both are essential components of a highly complex, multifaceted defense response, which begins with non-self recognition through the perception of pathogen-derived signal molecules and results in the production, inter alia, of antibiotically active compounds (phytoalexins) and cell wall-reinforcing material around the infection site. To elucidate the molecular details and the genomic basis of the underlying chains of events, we used two different experimental systems: suspension-cultured cells of Petroselinum crispum (parsley) and wild-type as well as mutant plants of Arabidopsis thaliana. Particular emphasis was placed on the structural and functional identification of signal and defense molecules, and on the mechanisms of signal perception, intracellular signal transduction and transcriptional reprogramming, including the structural and functional characterization of the responsible cis-acting gene promoter elements and transacting regulatory proteins. Comparing P. crispum and A. thaliana allows us to distinguish species-specific defense mechanisms from more universal responses, and furthermore provides general insights into the nature of the interactions. Despite the complexity of the pathogen defense response, it is experimentally tractable, and knowledge gained so far has opened up a new realm of gene technology-assisted strategies for resistance breeding of crop plants. PMID:12704242

Probiotics and down-regulation of the allergic response.

PubMed

Kalliomäki, Marko A; Isolauri, Erika

2004-11-01

The first clinical trials with probiotics, especially in the treatment of atopic eczema, have yielded encouraging results. Experimental studies have found that probiotics exert strain-specific effects in the intestinal lumen and on epithelial cells and immune cells with anti-allergic potential. These effects include enhancement in antigen degradation and gut barrier function and induction of regulatory and proinflammatory immune responses, the latter of which occurs more likely beyond the intestinal epithelium. Future studies should address more accurately how these and other possible mechanisms operate in the complex gastrointestinal macroenvironment in vivo and how these mechanisms are related to the clinical effects in a dose-dependent manner.

The genetics of insomnia--evidence for epigenetic mechanisms?

PubMed

Palagini, Laura; Biber, Knut; Riemann, Dieter

2014-06-01

Sleep is a complex physiological process and still remains one of the great mysteries of science. Over the past 10 y, genetic research has provided a new avenue to address the regulation and function of sleep. Gene loci that contribute quantitatively to sleep characteristics and variability have already been identified. However, up to now, a genetic basis has been established only for a few sleep disorders. Little is yet known about the genetic background of insomnia, one of the most common sleep disorders. According to the conceptualisation of the 3P model of insomnia, predisposing, precipitating and perpetuating factors contribute to the development and maintenance of insomnia. Growing evidence from studies of predisposing factors suggests a certain degree of heritability for insomnia and for a reactivity of sleep patterns to stressful events, explaining the emergence of insomnia in response to stressful life events. While a genetic susceptibility may modulate the impact of stress on the brain, this finding does not provide us with a complete understanding of the capacity of stress to produce long-lasting perturbations of brain and behaviour. Epigenetic gene-environment interactions have been identified just recently and may provide a more complex understanding of the genetic control of sleep and its disorders. It was recently hypothesised that stress-response-related brain plasticity might be epigenetically controlled and, moreover, several epigenetic mechanisms have been assumed to be involved in the regulation of sleep. Hence, it might be postulated that insomnia may be influenced by an epigenetic control process of both sleep mechanisms and stress-response-related gene-environment interactions having an impact on brain plasticity. This paper reviews the evidence for the genetic basis of insomnia and recent theories about epigenetic mechanisms involved in both sleep regulation and brain-stress response, leading to the hypothesis of an involvement of epigenetic mechanisms in the development and maintenance of insomnia. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dynamic Plant-Plant-Herbivore Interactions Govern Plant Growth-Defence Integration.

PubMed

de Vries, Jorad; Evers, Jochem B; Poelman, Erik H

2017-04-01

Plants downregulate their defences against insect herbivores upon impending competition for light. This has long been considered a resource trade-off, but recent advances in plant physiology and ecology suggest this mechanism is more complex. Here we propose that to understand why plants regulate and balance growth and defence, the complex dynamics in plant-plant competition and plant-herbivore interactions needs to be considered. Induced growth-defence responses affect plant competition and herbivore colonisation in space and time, which has consequences for the adaptive value of these responses. Assessing these complex interactions strongly benefits from advanced modelling tools that can model multitrophic interactions in space and time. Such an exercise will allow a critical re-evaluation why and how plants integrate defence and competition for light. Copyright © 2016 Elsevier Ltd. All rights reserved.

TaABC1, a member of the activity of bc1 complex protein kinase family from common wheat, confers enhanced tolerance to abiotic stresses in Arabidopsis

PubMed Central

Wang, Caixiang; Jing, Ruilian; Mao, Xinguo; Chang, Xiaoping; Li, Ang

2011-01-01

Abiotic stresses such as drought, salinity, and low temperature have drastic effects on plant growth and development. However, the molecular mechanisms regulating biochemical and physiological changes in response to stresses are not well understood. Protein kinases are major signal transduction factors among the reported molecular mechanisms mediating acclimation to environmental changes. Protein kinase ABC1 (activity of bc1 complex) is involved in regulating coenzyme Q biosynthesis in mitochondria in yeast (Saccharomyces cersvisiae), and in balancing oxidative stress in chloroplasts in Arabidopsis thaliana. In the current study, TaABC1 (Triticum aestivum L. activity of bc1 complex) protein kinase was localized to the cell membrane, cytoplasm, and nucleus. The effects of overexpressing TaABC1 in transgenic Arabidopsis plants on responses to drought, salt, and cold stress were further investigated. Transgenic Arabidopsis overexpressing the TaABC1 protein showed lower water loss and higher osmotic potential, photochemistry efficiency, and chlorophyll content, while cell membrane stability and controlled reactive oxygen species homeostasis were maintained. In addition, overexpression of TaABC1 increased the expression of stress-responsive genes, such as DREB1A, DREB2A, RD29A, ABF3, KIN1, CBF1, LEA, and P5CS, detected by real-time PCR analysis. The results suggest that TaABC1 overexpression enhances drought, salt, and cold stress tolerance in Arabidopsis, and imply that TaABC1 may act as a regulatory factor involved in a multiple stress response pathways. PMID:21115661

Neural Markers of Responsiveness to the Environment in Human Sleep.

PubMed

Andrillon, Thomas; Poulsen, Andreas Trier; Hansen, Lars Kai; Léger, Damien; Kouider, Sid

2016-06-15

Sleep is characterized by a loss of behavioral responsiveness. However, recent research has shown that the sleeping brain is not completely disconnected from its environment. How neural activity constrains the ability to process sensory information while asleep is yet unclear. Here, we instructed human volunteers to classify words with lateralized hand responses while falling asleep. Using an electroencephalographic (EEG) marker of motor preparation, we show how responsiveness is modulated across sleep. These modulations are tracked using classic event-related potential analyses complemented by Lempel-Ziv complexity (LZc), a measure shown to track arousal in sleep and anesthesia. Neural activity related to the semantic content of stimuli was conserved in light non-rapid eye movement (NREM) sleep. However, these processes were suppressed in deep NREM sleep and, importantly, also in REM sleep, despite the recovery of wake-like neural activity in the latter. In NREM sleep, sensory activations were counterbalanced by evoked down states, which, when present, blocked further processing of external information. In addition, responsiveness markers correlated positively with baseline complexity, which could be related to modulation in sleep depth. In REM sleep, however, this relationship was reversed. We therefore propose that, in REM sleep, endogenously generated processes compete with the processing of external input. Sleep can thus be seen as a self-regulated process in which external information can be processed in lighter stages but suppressed in deeper stages. Last, our results suggest drastically different gating mechanisms in NREM and REM sleep. Previous research has tempered the notion that sleepers are isolated from their environment. Here, we pushed this idea forward and examined, across all sleep stages, the brain's ability to flexibly process sensory information, up to the decision level. We extracted an EEG marker of motor preparation to determine the completion of the sensory processing chain and explored how it is constrained by baseline and evoked neural activity. In NREM sleep, slow waves elicited by stimuli appeared to block response preparation. We also used a novel analytic approach (Lempel-Ziv complexity) and showed that the ability to process external information correlates with neural complexity. A reversal of the correlation between complexity and motor indices in REM sleep suggests drastically different gating mechanisms across sleep stages. Copyright © 2016 the authors 0270-6474/16/366583-14$15.00/0.

Neuromolecular responses to social challenge: common mechanisms across mouse, stickleback fish, and honey bee.

PubMed

Rittschof, Clare C; Bukhari, Syed Abbas; Sloofman, Laura G; Troy, Joseph M; Caetano-Anollés, Derek; Cash-Ahmed, Amy; Kent, Molly; Lu, Xiaochen; Sanogo, Yibayiri O; Weisner, Patricia A; Zhang, Huimin; Bell, Alison M; Ma, Jian; Sinha, Saurabh; Robinson, Gene E; Stubbs, Lisa

2014-12-16

Certain complex phenotypes appear repeatedly across diverse species due to processes of evolutionary conservation and convergence. In some contexts like developmental body patterning, there is increased appreciation that common molecular mechanisms underlie common phenotypes; these molecular mechanisms include highly conserved genes and networks that may be modified by lineage-specific mutations. However, the existence of deeply conserved mechanisms for social behaviors has not yet been demonstrated. We used a comparative genomics approach to determine whether shared neuromolecular mechanisms could underlie behavioral response to territory intrusion across species spanning a broad phylogenetic range: house mouse (Mus musculus), stickleback fish (Gasterosteus aculeatus), and honey bee (Apis mellifera). Territory intrusion modulated similar brain functional processes in each species, including those associated with hormone-mediated signal transduction and neurodevelopment. Changes in chromosome organization and energy metabolism appear to be core, conserved processes involved in the response to territory intrusion. We also found that several homologous transcription factors that are typically associated with neural development were modulated across all three species, suggesting that shared neuronal effects may involve transcriptional cascades of evolutionarily conserved genes. Furthermore, immunohistochemical analyses of a subset of these transcription factors in mouse again implicated modulation of energy metabolism in the behavioral response. These results provide support for conserved genetic "toolkits" that are used in independent evolutions of the response to social challenge in diverse taxa.

Revisiting Ionosphere-Thermosphere Responses to Solar Wind Driving in Superstorms of November 2003 and 2004

NASA Astrophysics Data System (ADS)

Verkhoglyadova, O. P.; Komjathy, A.; Mannucci, A. J.; Mlynczak, M. G.; Hunt, L. A.; Paxton, L. J.

2017-10-01

We revisit three complex superstorms of 19-20 November 2003, 7-8 November 2004, and 9-11 November 2004 to analyze ionosphere-thermosphere (IT) effects driven by different solar wind structures associated with complex interplanetary coronal mass ejections (ICMEs) and their upstream sheaths. The efficiency of the solar wind-magnetosphere connection throughout the storms is estimated by coupling functions. The daytime IT responses to the complex driving are characterized by combining and collocating (where possible) measurements of several physical parameters (total electron content or TEC, thermospheric infrared nitric oxide emission, and composition ratio) from multiple satellite platforms and ground-based measurements. A variety of metrics are utilized to examine global IT phenomena at 1 h timescales. The role of direct driving of IT dynamics by solar wind structures and the role of IT preconditioning in these storms, which feature complex unusual TEC responses, are examined and contrasted. Furthermore, IT responses to ICME magnetic clouds and upstream sheaths are separately characterized. We identify IT feedback effects that can be important for long-lasting strong storms. The role of the interplanetary magnetic field By component on ionospheric convection may not be well captured by existing coupling functions. Mechanisms of thermospheric overdamping and consequential ionospheric feedback need to be further studied.

CD3ζ-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

PubMed Central

Bridgeman, J S; Ladell, K; Sheard, V E; Miners, K; Hawkins, R E; Price, D A; Gilham, D E

2014-01-01

Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions. PMID:24116999

An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex.

PubMed

Zhang, Peng; Bai, Yan; Lu, Ling; Li, Yun; Duan, Cunming

2016-01-14

Hypoxia-inducible factors (HIFs), while best known for their roles in the hypoxic response, have oxygen-independent roles in early development with poorly defined mechanisms. Here, we report a novel Hif-3α variant, Hif-3α2, in zebrafish. Hif-3α2 lacks the bHLH, PAS, PAC, and ODD domains, and is expressed in embryonic and adult tissues independently of oxygen availability. Hif-3α2 is a nuclear protein with significant hypoxia response element (HRE)-dependent transcriptional activity. Hif-3α2 overexpression not only decreases embryonic growth and developmental timing but also causes left-right asymmetry defects. Genetic deletion of Hif-3α2 by CRISPR/Cas9 genome editing increases, while Hif-3α2 overexpression decreases, Wnt/β-catenin signaling. This action is independent of its HRE-dependent transcriptional activity. Mechanistically, Hif-3α2 binds to β-catenin and destabilizes the nuclear β-catenin complex. This mechanism is distinct from GSK3β-mediated β-catenin degradation and is conserved in humans. These findings provide new insights into the oxygen-independent actions of HIFs and uncover a novel mechanism regulating Wnt/β-catenin signaling.

The Cellular Building Blocks of Breathing

PubMed Central

Ramirez, J.M.; Doi, A.; Garcia, A.J.; Elsen, F.P.; Koch, H.; Wei, A.D.

2013-01-01

Respiratory brainstem neurons fulfill critical roles in controlling breathing: they generate the activity patterns for breathing and contribute to various sensory responses including changes in O2 and CO2. These complex sensorimotor tasks depend on the dynamic interplay between numerous cellular building blocks that consist of voltage-, calcium-, and ATP-dependent ionic conductances, various ionotropic and metabotropic synaptic mechanisms, as well as neuromodulators acting on G-protein coupled receptors and second messenger systems. As described in this review, the sensorimotor responses of the respiratory network emerge through the state-dependent integration of all these building blocks. There is no known respiratory function that involves only a small number of intrinsic, synaptic, or modulatory properties. Because of the complex integration of numerous intrinsic, synaptic, and modulatory mechanisms, the respiratory network is capable of continuously adapting to changes in the external and internal environment, which makes breathing one of the most integrated behaviors. Not surprisingly, inspiration is critical not only in the control of ventilation, but also in the context of “inspiring behaviors” such as arousal of the mind and even creativity. Far-reaching implications apply also to the underlying network mechanisms, as lessons learned from the respiratory network apply to network functions in general. PMID:23720262

Amygdala Response to Emotional Stimuli without Awareness: Facts and Interpretations

PubMed Central

Diano, Matteo; Celeghin, Alessia; Bagnis, Arianna; Tamietto, Marco

2017-01-01

Over the past two decades, evidence has accumulated that the human amygdala exerts some of its functions also when the observer is not aware of the content, or even presence, of the triggering emotional stimulus. Nevertheless, there is as of yet no consensus on the limits and conditions that affect the extent of amygdala’s response without focused attention or awareness. Here we review past and recent studies on this subject, examining neuroimaging literature on healthy participants as well as brain-damaged patients, and we comment on their strengths and limits. We propose a theoretical distinction between processes involved in attentional unawareness, wherein the stimulus is potentially accessible to enter visual awareness but fails to do so because attention is diverted, and in sensory unawareness, wherein the stimulus fails to enter awareness because its normal processing in the visual cortex is suppressed. We argue this distinction, along with data sampling amygdala responses with high temporal resolution, helps to appreciate the multiplicity of functional and anatomical mechanisms centered on the amygdala and supporting its role in non-conscious emotion processing. Separate, but interacting, networks relay visual information to the amygdala exploiting different computational properties of subcortical and cortical routes, thereby supporting amygdala functions at different stages of emotion processing. This view reconciles some apparent contradictions in the literature, as well as seemingly contrasting proposals, such as the dual stage and the dual route model. We conclude that evidence in favor of the amygdala response without awareness is solid, albeit this response originates from different functional mechanisms and is driven by more complex neural networks than commonly assumed. Acknowledging the complexity of such mechanisms can foster new insights on the varieties of amygdala functions without awareness and their impact on human behavior. PMID:28119645

Auxins and tropisms

NASA Technical Reports Server (NTRS)

Muday, G. K.; Brown, C. S. (Principal Investigator)

2001-01-01

Differential growth of plants in response to the changes in the light and gravity vectors requires a complex signal transduction cascade. Although many of the details of the mechanisms by which these differential growth responses are induced are as yet unknown, auxin has been implicated in both gravitropism and phototropism. Specifically, the redistribution of auxin across gravity or light-stimulated tissues has been detected and shown to be required for this process. The approaches by which auxin has been implicated in tropisms include isolation of mutants altered in auxin transport or response with altered gravitropic or phototropic response, identification of auxin gradients with radiolabeled auxin and auxin-inducible gene reporter systems, and by use of inhibitors of auxin transport that block gravitropism and phototropism. Proteins that transport auxin have been identified and the mechanisms which determine auxin transport polarity have been explored. In addition, recent evidence that reversible protein phosphorylation controls this process is summarized. Finally, the data in support of several hypotheses for mechanisms by which auxin transport could be differentially regulated during gravitropism are examined. Although many details of the mechanisms by which plants respond to gravity and light are not yet clear, numerous recent studies demonstrate the role of auxin in these processes.

Mechanics regulates ATP-stimulated collective calcium response in fibroblast cells

PubMed Central

Lembong, Josephine; Sabass, Benedikt; Sun, Bo; Rogers, Matthew E.; Stone, Howard A.

2015-01-01

Cells constantly sense their chemical and mechanical environments. We study the effect of mechanics on the ATP-induced collective calcium response of fibroblast cells in experiments that mimic various tissue environments. We find that closely packed two-dimensional cell cultures on a soft polyacrylamide gel (Young's modulus E = 690 Pa) contain more cells exhibiting calcium oscillations than cultures on a rigid substrate (E = 36 000 Pa). Calcium responses of cells on soft substrates show a slower decay of calcium level relative to those on rigid substrates. Actin enhancement and disruption experiments for the cell cultures allow us to conclude that actin filaments determine the collective Ca2+ oscillatory behaviour in the culture. Inhibition of gap junctions results in a decrease of the oscillation period and reduced correlation of calcium responses, which suggests additional complexity of signalling upon cell–cell contact. Moreover, the frequency of calcium oscillations is independent of the rigidity of the substrate but depends on ATP concentration. We compare our results with those from similar experiments on individual cells. Overall, our observations show that collective chemical signalling in cell cultures via calcium depends critically on the mechanical environment. PMID:26063818

Basic Fibroblast Growth Factor Activates Serum Response Factor Gene Expression by Multiple Distinct Signaling Mechanisms

PubMed Central

Spencer, Jeffrey A.; Major, Michael L.; Misra, Ravi P.

1999-01-01

Serum response factor (SRF) plays a central role in the transcriptional response of mammalian cells to a variety of extracellular signals. It is a key regulator of many cellular early response genes which are believed to be involved in cell growth and differentiation. The mechanism by which SRF activates transcription in response to mitogenic agents has been extensively studied; however, significantly less is known about regulation of the SRF gene itself. Previously, we identified distinct regulatory elements in the SRF promoter that play a role in activation, including a consensus ETS domain binding site, a consensus overlapping Sp/Egr-1 binding site, and two SRF binding sites. We further showed that serum induces SRF by a mechanism that requires an intact SRF binding site, also termed a CArG box. In the present study we demonstrate that in response to stimulation of cells by a purified growth factor, basic fibroblast growth factor (bFGF), the SRF promoter is upregulated by a complex pathway that involves at least two independent mechanisms: a CArG box-independent mechanism that is mediated by an ETS binding site, and a novel CArG box-dependent mechanism that requires both an Sp factor binding site and the CArG motifs for maximal stimulation. Our analysis indicates that the CArG/Sp element activation mechanism is mediated by distinct signaling pathways. The CArG box-dependent component is targeted by a Rho-mediated pathway, and the Sp binding site-dependent component is targeted by a Ras-mediated pathway. Both SRF and bFGF have been implicated in playing an important role in mediating cardiogenesis during development. The implications of our findings for SRF expression during development are discussed. PMID:10330138

FAST TRACK COMMUNICATION: Novel mechanism for nanoscale catalysis

NASA Astrophysics Data System (ADS)

Msezane, Alfred Z.; Felfli, Zineb; Sokolovski, Dmitri

2010-10-01

The interplay between Regge resonances and Ramsauer-Townsend minima in the electron elastic total cross sections for Au and Pd atoms along with their large electron affinities is proposed as the fundamental atomic mechanism responsible for the observed exceptional catalytic properties of Au nanoparticles and to explain why the combination Au-Pd possesses an even higher catalytic activity than Au or Pd separately when catalyzing H2O2, consistent with recent experiments. The investigation uses the recent complex angular momentum description of electron scattering from neutral atoms and the proposed mechanism in general.

Healthcare Reimbursement and Quality Improvement: Integration Using the Electronic Medical Record

PubMed Central

Britton, John R.

2015-01-01

Reimbursement for healthcare has utilized a variety of payment mechanisms with varying degrees of effectiveness. Whether these mechanisms are used singly or in combination, it is imperative that the resulting systems remunerate on the basis of the quantity, complexity, and quality of care provided. Expanding the role of the electronic medical record (EMR) to monitor provider practice, patient responsiveness, and functioning of the healthcare organization has the potential to not only enhance the accuracy and efficiency of reimbursement mechanisms but also to improve the quality of medical care. PMID:26340397

Improved response time of flexible microelectromechanical sensors employing eco-friendly nanomaterials.

PubMed

Fan, Shicheng; Dan, Li; Meng, Lingju; Zheng, Wei; Elias, Anastasia; Wang, Xihua

2017-11-09

Flexible force/pressure sensors are of interest for academia and industry and have applications in wearable technologies. Most of such sensors on the market or reported in journal publications are based on the operation mechanism of probing capacitance or resistance changes of the materials under pressure. Recently, we reported the microelectromechanical (MEM) sensors based on a different mechanism: mechanical switches. Multiples of such MEM sensors can be integrated to achieve the same function of regular force/pressure sensors while having the advantages of ease of fabrication and long-term stability in operation. Herein, we report the dramatically improved response time (more than one order of magnitude) of these MEM sensors by employing eco-friendly nanomaterials-cellulose nanocrystals. For instance, the incorporation of polydimethysiloxane filled with cellulose nanocrystals shortened the response time of MEM sensors from sub-seconds to several milliseconds, leading to the detection of both diastolic and systolic pressures in the radial arterial blood pressure measurement. Comprehensive mechanical and electrical characterization of the materials and the devices reveal that greatly enhanced storage modulus and loss modulus play key roles in this improved response time. The demonstrated fast-response flexible sensors enabled continuous monitoring of heart rate and complex cardiovascular signals using pressure sensors for future wearable sensing platforms.

Suppressor Mutation Analysis of the Sensory Rhodopsin I-Transducer Complex: Insights into the Color-Sensing Mechanism

PubMed Central

Jung, Kwang-Hwan; Spudich, John L.

1998-01-01

The molecular complex containing the phototaxis receptor sensory rhodopsin I (SRI) and transducer protein HtrI (halobacterial transducer for SRI) mediates color-sensitive phototaxis responses in the archaeon Halobacterium salinarum. One-photon excitation of the complex by orange light elicits attractant responses, while two-photon excitation (orange followed by near-UV light) elicits repellent responses in swimming cells. Several mutations in SRI and HtrI cause an unusual mutant phenotype, called orange-light-inverted signaling, in which the cell produces a repellent response to normally attractant light. We applied a selection procedure for intragenic and extragenic suppressors of orange-light-inverted mutants and identified 15 distinct second-site mutations that restore the attractant response. Two of the 3 suppressor mutations in SRI are positioned at the cytoplasmic ends of helices F and G, and 12 suppressor mutations in HtrI cluster at the cytoplasmic end of the second HtrI transmembrane helix (TM2). Nearly all suppressors invert the normally repellent response to two-photon stimulation to an attractant response when they are expressed with their suppressible mutant alleles or in an otherwise wild-type strain. The results lead to a model for control of flagellar reversal by the SRI-HtrI complex. The model invokes an equilibrium between the A (reversal-inhibiting) and R (reversal-stimulating) conformers of the signaling complex. Attractant light and repellent light shift the equilibrium toward the A and R conformers, respectively, and mutations are proposed to cause intrinsic shifts in the equilibrium in the dark form of the complex. Differences in the strength of the two-photon signal inversion and in the allele specificity of suppression are correlated, and this correlation can be explained in terms of different values of the equilibrium constant (Keq) for the conformational transition in different mutants and mutant-suppressor pairs. PMID:9555883

Sclerostin's role in bone's adaptive response to mechanical loading.

PubMed

Galea, Gabriel L; Lanyon, Lance E; Price, Joanna S

2017-03-01

Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The aryl hydrocarbon receptor repressor - More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer.

PubMed

Vogel, Christoph F A; Haarmann-Stemmann, Thomas

2017-02-01

The aryl hydrocarbon receptor repressor (AhRR) was first described as a specific competitive repressor of aryl hydrocarbon receptor (AhR) activity based on its ability to dimerize with the AhR nuclear translocator (ARNT) and through direct competition of AhR/ARNT and AhRR/ARNT complexes for binding to dioxin-responsive elements (DREs). Like AhR, AhRR belongs to the basic Helix-Loop-Helix/Per-ARNT-Sim (bHLH/PAS) protein family but lacks functional ligand-binding and transactivation domains. Transient transfection experiments with ARNT and AhRR mutants examining the inhibitory mechanism of AhRR suggested a more complex mechanism than the simple mechanism of negative feedback through sequestration of ARNT to regulate AhR signaling. Recently, AhRR has been shown to act as a tumor suppressor gene in several types of cancer cells. Furthermore, epidemiological studies have found epigenetic changes and silencing of AhRR associated with exposure to cigarette smoke and cancer development. Additional studies from our laboratories have demonstrated that AhRR represses other signaling pathways including NF-κB and is capable of regulating inflammatory responses. A better understanding of the regulatory mechanisms of AhRR in AhR signaling and adverse outcome pathways leading to deregulated inflammatory responses contributing to tumor promotion and other adverse health effects is expected from future studies. This review article summarizes the characteristics of AhRR as an inhibitor of AhR activity and highlights more recent findings pointing out the role of AhRR in inflammation and tumorigenesis.

First-Principles Studies of Structure-Property Relationships: Enabling Design of Functional Materials

NASA Astrophysics Data System (ADS)

Zhou, Qunfei

First-principles calculations based on quantum mechanics have been proved to be powerful for accurately regenerating experimental results, uncovering underlying myths of experimental phenomena, and accelerating the design of innovative materials. This work has been motivated by the demand to design next-generation thermionic emitting cathodes and techniques to allow for synthesis of photo-responsive polymers on complex surfaces with controlled thickness and patterns. For Os-coated tungsten thermionic dispenser cathodes, we used first-principles methods to explore the bulk and surface properties of W-Os alloys in order to explain the previously observed experimental phenomena that thermionic emission varies significantly with W-Os alloy composition. Meanwhile, we have developed a new quantum mechanical approach to quantitatively predict the thermionic emission current density from materials perspective without any semi-empirical approximations or complicated analytical models, which leads to better understanding of thermionic emission mechanism. The methods from this work could be used to accelerate the design of next-generation thermionic cathodes. For photoresponsive materials, we designed a novel type of azobenzene-containing monomer for light-mediated ring-opening metathesis polymerization (ROMP) toward the fabrication of patterned, photo-responsive polymers by controlling ring strain energy (RSE) of the monomer that drives ROMP. This allows for unprecedented remote, noninvasive, instantaneous spatial and temporal control of photo-responsive polymer deposition on complex surfaces.This work on the above two different materials systems showed the power of quantum mechanical calculations on predicting, understanding and discovering the structures and properties of both known and unknown materials in a fast, efficient and reliable way.

Quantitative analysis reveals crosstalk mechanisms of heat shock-induced attenuation of NF-κB signaling at the single cell level.

PubMed

Kardyńska, Małgorzata; Paszek, Anna; Śmieja, Jarosław; Spiller, David; Widłak, Wiesława; White, Michael R H; Paszek, Pawel; Kimmel, Marek

2018-04-01

Elevated temperature induces the heat shock (HS) response, which modulates cell proliferation, apoptosis, the immune and inflammatory responses. However, specific mechanisms linking the HS response pathways to major cellular signaling systems are not fully understood. Here we used integrated computational and experimental approaches to quantitatively analyze the crosstalk mechanisms between the HS-response and a master regulator of inflammation, cell proliferation, and apoptosis the Nuclear Factor κB (NF-κB) system. We found that populations of human osteosarcoma cells, exposed to a clinically relevant 43°C HS had an attenuated NF-κB p65 response to Tumor Necrosis Factor α (TNFα) treatment. The degree of inhibition of the NF-κB response depended on the HS exposure time. Mathematical modeling of single cells indicated that individual crosstalk mechanisms differentially encode HS-mediated NF-κB responses while being consistent with the observed population-level responses. In particular "all-or-nothing" encoding mechanisms were involved in the HS-dependent regulation of the IKK activity and IκBα phosphorylation, while others involving transport were "analogue". In order to discriminate between these mechanisms, we used live-cell imaging of nuclear translocations of the NF-κB p65 subunit. The single cell responses exhibited "all-or-nothing" encoding. While most cells did not respond to TNFα stimulation after a 60 min HS, 27% showed responses similar to those not receiving HS. We further demonstrated experimentally and theoretically that the predicted inhibition of IKK activity was consistent with the observed HS-dependent depletion of the IKKα and IKKβ subunits in whole cell lysates. However, a combination of "all-or-nothing" crosstalk mechanisms was required to completely recapitulate the single cell data. We postulate therefore that the heterogeneity of the single cell responses might be explained by the cell-intrinsic variability of HS-modulated IKK signaling. In summary, we show that high temperature modulates NF-κB responses in single cells in a complex and unintuitive manner, which needs to be considered in hyperthermia-based treatment strategies.

Glucose Modulates Respiratory Complex I Activity in Response to Acute Mitochondrial Dysfunction

PubMed Central

Cannino, Giuseppe; El-Khoury, Riyad; Pirinen, Marja; Hutz, Bettina; Rustin, Pierre; Jacobs, Howard T.; Dufour, Eric

2012-01-01

Proper coordination between glycolysis and respiration is essential, yet the regulatory mechanisms involved in sensing respiratory chain defects and modifying mitochondrial functions accordingly are unclear. To investigate the nature of this regulation, we introduced respiratory bypass enzymes into cultured human (HEK293T) cells and studied mitochondrial responses to respiratory chain inhibition. In the absence of respiratory chain inhibitors, the expression of alternative respiratory enzymes did not detectably alter cell physiology or mitochondrial function. However, in permeabilized cells NDI1 (alternative NADH dehydrogenase) bypassed complex I inhibition, whereas alternative oxidase (AOX) bypassed complex III or IV inhibition. In contrast, in intact cells the effects of the AOX bypass were suppressed by growth on glucose, whereas those produced by NDI1 were unaffected. Moreover, NDI1 abolished the glucose suppression of AOX-driven respiration, implicating complex I as the target of this regulation. Rapid Complex I down-regulation was partly released upon prolonged respiratory inhibition, suggesting that it provides an “emergency shutdown” system to regulate metabolism in response to dysfunctions of the oxidative phosphorylation. This system was independent of HIF1, mitochondrial superoxide, or ATP synthase regulation. Our findings reveal a novel pathway for adaptation to mitochondrial dysfunction and could provide new opportunities for combatting diseases. PMID:23007390

SCF(KMD) controls cytokinin signaling by regulating the degradation of type-B response regulators.

PubMed

Kim, Hyo Jung; Chiang, Yi-Hsuan; Kieber, Joseph J; Schaller, G Eric

2013-06-11

Cytokinins are plant hormones that play critical roles in growth and development. In Arabidopsis, the transcriptional response to cytokinin is regulated by action of type-B Arabidopsis response regulators (ARRs). Although central elements in the cytokinin signal transduction pathway have been identified, mechanisms controlling output remain to be elucidated. Here we demonstrate that a family of F-box proteins, called the kiss me deadly (KMD) family, targets type-B ARR proteins for degradation. KMD proteins form an S-phase kinase-associated PROTEIN1 (SKP1)/Cullin/F-box protein (SCF) E3 ubiquitin ligase complex and directly interact with type-B ARR proteins. Loss-of-function KMD mutants stabilize type-B ARRs and exhibit an enhanced cytokinin response. In contrast, plants with elevated KMD expression destabilize type-B ARR proteins leading to cytokinin insensitivity. Our results support a model in which an SCF(KMD) complex negatively regulates cytokinin responses by controlling levels of a key family of transcription factors.

The L-Z complexity of exercise-induced muscle fatigue based on acoustic myographye

NASA Astrophysics Data System (ADS)

Yijian, Min; Xinyuan, Liu; Tingting, Wang

2014-01-01

The mechanism of exercise fatigue was investigated during exercise using L-Z complexity of non-linear analysis. Muscle fatigue was induced in the sitting position by lifting the heel under a load. An acoustic myogram of the gastrocnemius was obtained until exhaustion. The different modes of the speed responses were calculated using the L-Z complexity method, which analyzes muscle fibers participation, while the exercise is in progress. The L-Z complexity decreased incrementally with decreases in muscle strength, reaching a minimum value when the muscle was exhausted. Our data indicate that the L-Z complexity method is easy to use and effective at revealing the dynamic characteristics and variations of exercise fatigue. This method could be used to monitor sports training.

Dielectric Rheo-SANS: An Instrument for the Simultaneous Interrogation of Rheology, Microstructure and Electronic Properties of Complex Fluids

NASA Astrophysics Data System (ADS)

Wagner, Norman; Richards, Jeffrey; Hipp, Julie; Butler, Paul

In situ measurements are an increasingly important tool to inform the complex relationship between nanoscale properties and macroscopic measurements. For conducting colloidal suspensions, we seek intrinsic relationships between the measured electrical and mechanical response of a material both in quiescence and under applied shear. These relationships can be used to inform the development of new materials with enhanced electrical and mechanical performance. In order to study these relationships, we have developed a dielectric rheology instrument that is compatible with small angle neutron scattering (SANS) experiments. This Dielectric RheoSANS instrument consists of a Couette geometry mounted on an ARES G2 strain controlled rheometer enclosed in a modified Forced Convection Oven (FCO). In this talk, we outline the development of the Dielectric RheoSANS instruments and demonstrate its operation using two systems - a suspension of carbon black particles in propylene carbonate and poly(3-hexylthiophene) organogel - where there is interest in how shear influences the microstructure state of the material. By monitoring the conductivity and rheological response of these materials at the same time, we can capture the entire evolution of the material response to an applied deformation. NCNR NIST Cooperative Agreement #70NANB12H239.

Suppression and Contrast Normalization in Motion Processing

PubMed Central

2017-01-01

Sensory neurons are activated by a range of stimuli to which they are said to be tuned. Usually, they are also suppressed by another set of stimuli that have little effect when presented in isolation. The interactions between preferred and suppressive stimuli are often quite complex and vary across neurons, even within a single area, making it difficult to infer their collective effect on behavioral responses mediated by activity across populations of neurons. Here, we investigated this issue by measuring, in human subjects (three males), the suppressive effect of static masks on the ocular following responses induced by moving stimuli. We found a wide range of effects, which depend in a nonlinear and nonseparable manner on the spatial frequency, contrast, and spatial location of both stimulus and mask. Under some conditions, the presence of the mask can be seen as scaling the contrast of the driving stimulus. Under other conditions, the effect is more complex, involving also a direct scaling of the behavioral response. All of this complexity at the behavioral level can be captured by a simple model in which stimulus and mask interact nonlinearly at two stages, one monocular and one binocular. The nature of the interactions is compatible with those observed at the level of single neurons in primates, usually broadly described as divisive normalization, without having to invoke any scaling mechanism. SIGNIFICANCE STATEMENT The response of sensory neurons to their preferred stimulus is often modulated by stimuli that are not effective when presented alone. Individual neurons can exhibit multiple modulatory effects, with considerable variability across neurons even in a single area. Such diversity has made it difficult to infer the impact of these modulatory mechanisms on behavioral responses. Here, we report the effects of a stationary mask on the reflexive eye movements induced by a moving stimulus. A model with two stages, each incorporating a divisive modulatory mechanism, reproduces our experimental results and suggests that qualitative variability of masking effects in cortical neurons might arise from differences in the extent to which such effects are inherited from earlier stages. PMID:29018158

Studies on the mechanism of action of 6-mercaptopurine. Interaction with copper and xanthine oxidase.

PubMed

Kela, U; Vijayvargiya, R

1981-03-01

Interaction between 6-mercaptopurine, Cu2+ and the enzyme xanthine oxidase (EC 1.2.3.2.) was examined. Whereas Cu2+ was found to inhibit the enzyme, 6-mercaptopurine could protect as well as reverse the enzyme inhibition produced by the metal ion. The formation of a complex between 6-mercaptopurine and Cu2+ seems to be responsible for the observed effect. Job's [(1928) Ann. Chem. 9, 113] method has shown the composition of the complex to be 1:1. The apparent stability constant (log K value), as determined by Subhrama Rao & Raghav Rao's [(1955) J. Sci. Chem. Ind. Res. 143, 278], method is found to be 6.74. It is suggested that the formation of a stable complex between 6-mercaptopurine molecules and Cu2+ may be an additional mechanism of action of 6-mercaptopurine, particularly with reference to its anti-inflammatory properties.

Mechanism of wavelength conversion in polystyrene doped with benzoxanthene: emergence of a complex.

PubMed

Nakamura, Hidehito; Shirakawa, Yoshiyuki; Kitamura, Hisashi; Sato, Nobuhiro; Shinji, Osamu; Saito, Katashi; Takahashi, Sentaro

2013-01-01

Fluorescent guest molecules doped in polymers have been used to convert ultraviolet light into visible light for applications ranging from optical fibres to filters for the cultivation of plants. The wavelength conversion process involves the absorption of light at short wavelengths followed by fluorescence emission at a longer wavelength. However, a precise understanding of the light conversion remains unclear. Here we show light responses for a purified polystyrene base substrates doped with fluorescent benzoxanthene in concentrations varied over four orders of magnitude. The shape of the excitation spectrum for fluorescence emission changes significantly with the concentration of the benzoxanthene, indicating formation of a base substrate/fluorescent molecule complex. Furthermore, the wavelength conversion light yield increases in three stages depending on the nature of the complex. These findings identify a mechanism that will have many applications in wavelength conversion materials.

Mechanism of wavelength conversion in polystyrene doped with benzoxanthene: emergence of a complex

PubMed Central

Nakamura, Hidehito; Shirakawa, Yoshiyuki; Kitamura, Hisashi; Sato, Nobuhiro; Shinji, Osamu; Saito, Katashi; Takahashi, Sentaro

2013-01-01

Fluorescent guest molecules doped in polymers have been used to convert ultraviolet light into visible light for applications ranging from optical fibres to filters for the cultivation of plants. The wavelength conversion process involves the absorption of light at short wavelengths followed by fluorescence emission at a longer wavelength. However, a precise understanding of the light conversion remains unclear. Here we show light responses for a purified polystyrene base substrates doped with fluorescent benzoxanthene in concentrations varied over four orders of magnitude. The shape of the excitation spectrum for fluorescence emission changes significantly with the concentration of the benzoxanthene, indicating formation of a base substrate/fluorescent molecule complex. Furthermore, the wavelength conversion light yield increases in three stages depending on the nature of the complex. These findings identify a mechanism that will have many applications in wavelength conversion materials. PMID:23974205

Studies on the mechanism of action of 6-mercaptopurine. Interaction with copper and xanthine oxidase.

PubMed Central

Kela, U; Vijayvargiya, R

1981-01-01

Interaction between 6-mercaptopurine, Cu2+ and the enzyme xanthine oxidase (EC 1.2.3.2.) was examined. Whereas Cu2+ was found to inhibit the enzyme, 6-mercaptopurine could protect as well as reverse the enzyme inhibition produced by the metal ion. The formation of a complex between 6-mercaptopurine and Cu2+ seems to be responsible for the observed effect. Job's [(1928) Ann. Chem. 9, 113] method has shown the composition of the complex to be 1:1. The apparent stability constant (log K value), as determined by Subhrama Rao & Raghav Rao's [(1955) J. Sci. Chem. Ind. Res. 143, 278], method is found to be 6.74. It is suggested that the formation of a stable complex between 6-mercaptopurine molecules and Cu2+ may be an additional mechanism of action of 6-mercaptopurine, particularly with reference to its anti-inflammatory properties. PMID:6895465

Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation

PubMed Central

Próchnicki, Tomasz; Mangan, Matthew S.; Latz, Eicke

2016-01-01

Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K + efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca 2+ fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation. PMID:27508077

Genotype-specific responses of apple roots to pathogenic infection by Pythium ultimum

USDA-ARS?s Scientific Manuscript database

Resistance mechanisms employed to defend against soilborne necrotrophic pathogens are poorly understood, particularly with respect to perennial tree fruit crops such as apple. Pythium ultimum is a component of the pathogen complex that incites apple replant disease (ARD). Different levels of tolera...

Moving Material into Space Without Rockets.

ERIC Educational Resources Information Center

Cheng, R. S.; Trefil, J. S.

1985-01-01

In response to conventional rocket demands on fuel supplies, electromagnetic launches were developed to give payloads high velocity using a stationary energy source. Several orbital mechanics problems are solved including a simple problem (radial launch with no rotation) and a complex problem involving air resistance and gravity. (DH)

An Elaborate Data Set Characterizing the Mechanical Response of the Foot

PubMed Central

Erdemir, Ahmet; Sirimamilla, Pavana A.; Halloran, Jason P.; van den Bogert, Antonie J.

2010-01-01

Background Mechanical properties of the foot are responsible for its normal function and play a role in various clinical problems. Specifically, we are interested in quantification of foot mechanical properties to assist the development of computational models for movement analysis and detailed simulations of tissue deformation. Current available data are specific to a foot region and the loading scenarios are limited to a single direction. A data set that incorporates regional response, to quantify individual function of foot components, as well as overall response, to illustrate their combined operation, does not exist. Furthermore, combined three-dimensional loading scenarios while measuring the complete three-dimensional deformation response are lacking. When combined with an anatomical image data set, development of anatomically realistic and mechanically validated models becomes possible. Therefore, the goal of this study was to record and disseminate the mechanical response of a foot specimen, supported by imaging data. Method of Approach Robotic testing was conducted at the rear foot, forefoot, metatarsal heads, and the foot as a whole. Complex foot deformations were induced by single mode loading, e.g. compression, and combined loading, e.g. compression and shear. Small and large indenters were used for heel and metatarsal head loading; an elevated platform was utilized to isolate the rear foot and forefoot; and a full platform compressed the whole foot. Three-dimensional tool movements and reaction loads were recorded simultaneously. Computed tomography scans of the same specimen were collected for anatomical reconstruction a-priori. Results Three-dimensional mechanical response of the specimen was nonlinear and viscoelastic. A low stiffness region was observed starting with contact between the tool and foot regions, increasing with loading. Loading and unloading response portrayed hysteresis. Loading range ensured capturing the toe and linear regions of the load deformation curves for the dominant loading direction, with the rates approximating those of walking. Conclusion A large data set was successfully obtained to characterize the overall as well as regional mechanical response of an intact foot specimen under single and combined loads. Medical imaging complemented the mechanical testing data to establish the potential relationship between the anatomical architecture and mechanical response, and for further development of foot models that are mechanically realistic and anatomically consistent. This combined data set has been documented and disseminated in the public domain to promote future development in foot biomechanics. PMID:19725699

Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP.

PubMed

Matheny, Sharon A; Chen, Chiyuan; Kortum, Robert L; Razidlo, Gina L; Lewis, Robert E; White, Michael A

2004-01-15

The signal transduction cascade comprising Raf, mitogen-activated protein (MAP) kinase kinase (MEK) and MAP kinase is a Ras effector pathway that mediates diverse cellular responses to environmental cues and contributes to Ras-dependent oncogenic transformation. Here we report that the Ras effector protein Impedes Mitogenic signal Propagation (IMP) modulates sensitivity of the MAP kinase cascade to stimulus-dependent activation by limiting functional assembly of the core enzymatic components through the inactivation of KSR, a scaffold/adaptor protein that couples activated Raf to its substrate MEK. IMP is a Ras-responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination, which releases the inhibition of Raf-MEK complex formation. Thus, Ras activates the MAP kinase cascade through simultaneous dual effector interactions: induction of Raf kinase activity and derepression of Raf-MEK complex formation. IMP depletion results in increased stimulus-dependent MEK activation without alterations in the timing or duration of the response. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus and providing a mechanism to allow adaptive behaviour of the cascade in chronic or complex signalling environments.

Chromatin modification and remodelling: a regulatory landscape for the control of Arabidopsis defence responses upon pathogen attack.

PubMed

Berr, Alexandre; Ménard, Rozenn; Heitz, Thierry; Shen, Wen-Hui

2012-06-01

Due to their sessile lifestyle, plants have to cope with an ever-changing environment and to defend themselves against a multitude of biotic aggressors that compromise their development and reproduction. Responses to various biotic stresses largely depend on the plant's capacity to modulate rapidly and specifically its transcriptome. In a stress type-dependent manner, external signals are translocated into the nucleus to activate transcription factors, resulting in the increased expression of particular sets of defence-related genes. Among mechanisms of transcriptional regulation, chromatin remodelling accomplished through the activity of histone-modifying enzymes and ATP-dependent chromatin-remodelling complexes is emerging as a key process in the orchestration of plant biotic stress responses. In this review, we summarize and discuss roles that chromatin-remodelling mechanisms may play in regulating Arabidopsis defence responses. © 2012 Blackwell Publishing Ltd.

Cd(II)-terpyridine-based complex as a ratiometric fluorescent probe for pyrophosphate detection in solution and as an imaging agent in living cells.

PubMed

Jiao, Shu-Yan; Li, Kun; Zhang, Wei; Liu, Yan-Hong; Huang, Zeng; Yu, Xiao-Qi

2015-01-21

The terpyridine anthracene ligand was synthesized and characterized. is a ratiometric fluorescent probe for Cd(2+) with a recognition mechanism based on intramolecular charge transfer (ICT). An complex was isolated, and its structure was established using single-crystal XRD. The complex was able to serve as a novel reversible chemosensing ensemble to allow ratiometric response to pyrophosphate (PPi) in aqueous media. Moreover, the fluorescence imaging in living cells from these two emission channels suggested that was a ratiometric probe for Cd(2+), and the in situ generated complex was also a ratiometric ensemble for PPi detection in living cells.

Recruitment of Fanconi Anemia and Breast Cancer Proteins to DNA Damage Sites is differentially Governed by Replication

PubMed Central

Shen, Xi; Do, Huong; Li, Yongjian; Chung, Woo-Hyun; Tomasz, Maria; de Winter, Johan P.; Xia, Bing; Elledge, Stephen J.; Wang, Weidong; Li, Lei

2009-01-01

Summary Fanconi anemia (FA) is characterized by cellular hypersensivity to DNA crosslinking agents, but how the Fanconi pathway protects cells from DNA crosslinks and whether FA proteins act directly on crosslinks remains unclear. We developed a chromatin-IP-based strategy termed eChIP and detected association of multiple FA proteins with DNA crosslinks in vivo. Inter-dependence analyses revealed that crosslink-specific enrichment of various FA proteins is controlled by distinct mechanisms. BRCA-related FA proteins (BRCA2, FANCJ/BACH1, and FANCN/PALB2), but not FA core and I/D2 complexes, require replication for their crosslink association. FANCD2, but not FANCJ and FANCN, requires the FA core complex for its recruitment. FA core complex requires nucleotide excision repair proteins XPA and XPC for its association. Consistent with the distinct recruitment mechanism, recombination-independent crosslink repair was inversely affected in cells deficient of FANC-core versus BRCA-related FA proteins. Thus, FA proteins participate in distinct DNA damage response mechanisms governed by DNA replication status. PMID:19748364

A viscoelastic analysis of the P56 mouse brain under large-deformation dynamic indentation.

PubMed

MacManus, David B; Pierrat, Baptiste; Murphy, Jeremiah G; Gilchrist, Michael D

2017-01-15

The brain is a complex organ made up of many different functional and structural regions consisting of different types of cells such as neurons and glia, as well as complex anatomical geometries. It is hypothesized that the different regions of the brain exhibit significantly different mechanical properties which may be attributed to the diversity of cells within individual brain regions. The regional viscoelastic properties of P56 mouse brain tissue, up to 70μm displacement, are presented and discussed in the context of traumatic brain injury, particularly how the different regions of the brain respond to mechanical loads. Force-relaxation data obtained from micro-indentation measurements were fit to both linear and quasi-linear viscoelastic models to determine the time and frequency domain viscoelastic response of the pons, cortex, medulla oblongata, cerebellum, and thalamus. The damping ratio of each region was also determined. Each region was found to have a unique mechanical response to the applied displacement, with the pons and thalamus exhibiting the largest and smallest force-response, respectively. All brain regions appear to have an optimal frequency for the dissipation of energies which lies between 1 and 10Hz. We present the first mechanical characterization of the viscoelastic response for different regions of mouse brain. Force-relaxation tests are performed under large strain dynamic micro-indentation, and viscoelastic models are used subsequently, providing time-dependent mechanical properties of brain tissue under loading conditions comparable to what is experienced in TBI. The unique mechanical properties of different brain regions are highlighted, with substantial variations in the viscoelastic properties and damping ratio of each region. Cortex and pons were the stiffest regions, while the thalamus and medulla were most compliant. The cerebellum and thalamus had highest damping ratio values and those of the medulla were lowest. The reported material parameters can be implemented into finite element computer models of the mouse to investigate the effects of trauma on individual brain regions. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Early T-cell activation biophysics

PubMed Central

Henry, Nelly; Hivroz, Claire

2009-01-01

The T-cell is one of the main players in the mammalian immune response. It ensures antigen recognition at the surface of antigen-presenting cells in a complex and highly sensitive and specific process, in which the encounter of the T-cell receptor with the agonist peptide associated with the major histocompatibility complex triggers T-cell activation. While signaling pathways have been elucidated in increasing detail, the mechanism of TCR triggering remains highly controversial despite active research published in the past 10 years. In this paper, we present a short overview of pending questions on critical initial events associated with T-cell triggering. In particular, we examine biophysical approaches already in use, as well as future directions. We suggest that the most recent advances in fluorescence super-resolution imaging, coupled with the new classes of genetic fluorescent probes, will play an important role in elucidation of the T-cell triggering mechanism. Beyond this aspect, we predict that exploration of mechanical cues in the triggering process will provide new clues leading to clarification of the entire mechanism. PMID:20514131

Mechanical Properties of β-Catenin Revealed by Single-Molecule Experiments

PubMed Central

Valbuena, Alejandro; Vera, Andrés Manuel; Oroz, Javier; Menéndez, Margarita; Carrión-Vázquez, Mariano

2012-01-01

β-catenin is a central component of the adaptor complex that links cadherins to the actin cytoskeleton in adherens junctions and thus, it is a good candidate to sense and transmit mechanical forces to trigger specific changes inside the cell. To fully understand its molecular physiology, we must first investigate its mechanical role in mechanotransduction within the cadherin system. We have studied the mechanical response of β-catenin to stretching using single-molecule force spectroscopy and molecular dynamics. Unlike most proteins analyzed to date, which have a fixed mechanical unfolding pathway, the β-catenin armadillo repeat region (ARM) displays low mechanostability and multiple alternative unfolding pathways that seem to be modulated by its unstructured termini. These results are supported by steered molecular dynamics simulations, which also predict its mechanical stabilization and unfolding pathway restrictions when the contiguous α-helix of the C-terminal unstructured region is included. Furthermore, simulations of the ARM/E-cadherin cytosolic tail complex emulating the most probable stress geometry occurring in vivo show a mechanical stabilization of the interaction whose magnitude correlates with the length of the stretch of the cadherin cytosolic tail that is in contact with the ARM region. PMID:23083718

Mechanical circulator for elastic waves by using the nonreciprocity of flexible rotating rings

NASA Astrophysics Data System (ADS)

Beli, Danilo; Silva, Priscilla Brandão; Arruda, José Roberto de França

2018-01-01

Circulators have a wide range of applications in wave manipulation. They provide a nonreciprocal response by breaking the time-reversal symmetry. In the mechanical field, nonlinear isolators and ferromagnetic circulators can be used for this objective. However, they require high power and high volumes. Herein, a flexible rotating ring is used to break the time-reversal symmetry as a result of the combined effect of Coriolis acceleration and material damping. Complete asymmetry of oscillating and evanescent components of wavenumbers is achieved. The elastic ring produces a nonreciprocal response that is used to design a three port mechanical circulator. The rotational speed for maximum transmission in one port and isolation in the other one is determined using analytical equations. A spectral element formulation is used to compute the complex dispersion diagrams and the forced response. Waveguides that support longitudinal and flexural waves are investigated. In this case, the ring nonreciprocity is modulated by the waveguide reciprocal response and the transmission coefficients can be affected. The proposed device is compact, nonferromagnetic, and may open new directions for elastic wave manipulation.

Identifying Stress Transcription Factors Using Gene Expression and TF-Gene Association Data

PubMed Central

Wu, Wei-Sheng; Chen, Bor-Sen

2007-01-01

Unicellular organisms such as yeasts have evolved to survive environmental stresses by rapidly reorganizing the genomic expression program to meet the challenges of harsh environments. The complex adaptation mechanisms to stress remain to be elucidated. In this study, we developed Stress Transcription Factor Identification Algorithm (STFIA), which integrates gene expression and TF-gene association data to identify the stress transcription factors (TFs) of six kinds of stresses. We identified some general stress TFs that are in response to various stresses, and some specific stress TFs that are in response to one specific stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs may be sufficient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the adaptation mechanisms to different stresses may have a bow-tie structure. Second, there may exist extensive regulatory cross-talk among different stress responses. In conclusion, this study proposes a network of the regulators of stress responses and their mechanism of action. PMID:20066130

A simple model of mechanotransduction in primate glabrous skin

PubMed Central

Dong, Yi; Mihalas, Stefan; Kim, Sung Soo; Yoshioka, Takashi; Niebur, Ernst

2013-01-01

Tactile stimulation of the hand evokes highly precise and repeatable patterns of activity in mechanoreceptive afferents; the strength (i.e., firing rate) and timing of these responses have been shown to convey stimulus information. To achieve an understanding of the mechanisms underlying the representation of tactile stimuli in the nerve, we developed a two-stage computational model consisting of a nonlinear mechanical transduction stage followed by a generalized integrate-and-fire mechanism. The model improves upon a recently published counterpart in two important ways. First, complexity is dramatically reduced (at least one order of magnitude fewer parameters). Second, the model comprises a saturating nonlinearity and therefore can be applied to a much wider range of stimuli. We show that both the rate and timing of afferent responses are predicted with remarkable precision and that observed adaptation patterns and threshold behavior are well captured. We conclude that the responses of mechanoreceptive afferents can be understood using a very parsimonious mechanistic model, which can then be used to accurately simulate the responses of afferent populations. PMID:23236001

Cartilage-like electrostatic stiffening of responsive cryogel scaffolds

NASA Astrophysics Data System (ADS)

Offeddu, G. S.; Mela, I.; Jeggle, P.; Henderson, R. M.; Smoukov, S. K.; Oyen, M. L.

2017-02-01

Cartilage is a structural tissue with unique mechanical properties deriving from its electrically-charged porous structure. Traditional three-dimensional environments for the culture of cells fail to display the complex physical response displayed by the natural tissue. In this work, the reproduction of the charged environment found in cartilage is achieved using polyelectrolyte hydrogels based on polyvinyl alcohol and polyacrylic acid. The mechanical response and morphology of microporous physically-crosslinked cryogels are compared to those of heat-treated chemical gels made from the same polymers, as a result of pH-dependent swelling. In contrast to the heat-treated chemically-crosslinked gels, the elastic modulus of the physical cryogels was found to increase with charge activation and swelling, explained by the occurrence of electrostatic stiffening of the polymer chains at large charge densities. At the same time, the permeability of both materials to fluid flow was impaired by the presence of electric charges. This cartilage-like mechanical behavior displayed by responsive cryogels can be reproduced in other polyelectrolyte hydrogel systems to fabricate biomimetic cellular scaffolds for the repair of the tissue.

Gibberellin DELLA signaling targets the retromer complex to redirect protein trafficking to the plasma membrane

PubMed Central

Salanenka, Yuliya; Verstraeten, Inge; Löfke, Christian; Tabata, Kaori; Naramoto, Satoshi; Glanc, Matouš; Friml, Jiří

2018-01-01

The plant hormone gibberellic acid (GA) is a crucial regulator of growth and development. The main paradigm of GA signaling puts forward transcriptional regulation via the degradation of DELLA transcriptional repressors. GA has also been shown to regulate tropic responses by modulation of the plasma membrane incidence of PIN auxin transporters by an unclear mechanism. Here we uncovered the cellular and molecular mechanisms by which GA redirects protein trafficking and thus regulates cell surface functionality. Photoconvertible reporters revealed that GA balances the protein traffic between the vacuole degradation route and recycling back to the cell surface. Low GA levels promote vacuolar delivery and degradation of multiple cargos, including PIN proteins, whereas high GA levels promote their recycling to the plasma membrane. This GA effect requires components of the retromer complex, such as Sorting Nexin 1 (SNX1) and its interacting, microtubule (MT)-associated protein, the Cytoplasmic Linker-Associated Protein (CLASP1). Accordingly, GA regulates the subcellular distribution of SNX1 and CLASP1, and the intact MT cytoskeleton is essential for the GA effect on trafficking. This GA cellular action occurs through DELLA proteins that regulate the MT and retromer presumably via their interaction partners Prefoldins (PFDs). Our study identified a branching of the GA signaling pathway at the level of DELLA proteins, which, in parallel to regulating transcription, also target by a nontranscriptional mechanism the retromer complex acting at the intersection of the degradation and recycling trafficking routes. By this mechanism, GA can redirect receptors and transporters to the cell surface, thus coregulating multiple processes, including PIN-dependent auxin fluxes during tropic responses. PMID:29463731

Driving mechanisms of passive and active transport across cellular membranes as the mechanisms of cell metabolism and development as well as the mechanisms of cellular distance reactions on hormonal expression and the immune response.

PubMed

Ponisovskiy, M R

2011-01-01

The article presents mechanisms of cell metabolism, cell development, cell activity, and maintenance of cellular stability. The literature is reviewed from the point of view of these concepts. The balance between anabolic and catabolic processes induces chemical potentials in the extracellular and intracellular media. The chemical potentials of these media are defined as the driving forces of both passive and active transport of substances across cellular membranes. The driving forces of substance transport across cellular membranes as in cellular metabolism and in immune responses and hormonal expressions are considered in the biochemical and biophysical models, reflecting the mechanisms for maintenance of stability of the internal medium and internal energy of an organism. The interactions of passive transport and active transport of substances across cellular walls promote cell proliferation, as well as the mechanism of cellular capacitors, promoting remote reactions across distance for hormonal expression and immune responses. The offered concept of cellular capacitors has given the possibility to explain the mechanism of remote responses of cells to new situations, resulting in the appearance of additional agents. The biophysical model develops an explanation of some cellular functions: cellular membrane action have been identified with capacitor action, based on the similarity of the structures and as well as on similarity of biophysical properties of electric data that confirm the action of the compound-specific interactions of cells within an organism, promoting hormonal expressions and immune responses to stabilize the thermodynamic system of an organism. Comparison of a cellular membrane action to a capacitor has given the possibility for the explanations of exocytosis and endocytosis mechanisms, internalization of the receptor-ligand complex, selection as a receptor reaction to a ligand by immune responses or hormonal effects, reflecting cellular distance reactions on the hormonal expressions, immune responses, and specificity of the mechanisms of immune reactions. Reviewing current research of cell activity, explanations are presented of mechanisms of apoptosis, autophagy, hormonal expression, and immune responses from the point of view of described cellular mechanisms. Thermodynamic laws are used to confirm the importance of the actions of these mechanisms for maintenance of stability of the internal medium and internal energy of an organism.

Involvement of Spearman's g in conceptualisation versus execution of complex tasks.

PubMed

Carroll, Ellen L; Bright, Peter

2016-10-01

Strong correlations between measures of fluid intelligence (or Spearman's g) and working memory are widely reported in the literature, but there is considerable controversy concerning the nature of underlying mechanisms driving this relationship. In the four experiments presented here we consider the role of response conflict and task complexity in the context of real-time task execution demands (Experiments 1-3) and also address recent evidence that g confers an advantage at the level of task conceptualisation rather than (or in addition to) task execution (Experiment 4). We observed increased sensitivity of measured fluid intelligence to task performance in the presence (vs. the absence) of response conflict, and this relationship remained when task complexity was reduced. Performance-g correlations were also observed in the absence of response conflict, but only in the context of high task complexity. Further, we present evidence that differences in conceptualisation or 'modelling' of task instructions prior to execution had an important mediating effect on observed correlations, but only when the task encompassed a strong element of response inhibition. Our results suggest that individual differences in ability reflect, in large part, variability in the efficiency with which the relational complexity of task constraints are held in mind. It follows that fluid intelligence may support successful task execution through the construction of effective action plans via optimal allocation of limited resources. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Genomic Methods for Clinical and Translational Pain Research

PubMed Central

Wang, Dan; Kim, Hyungsuk; Wang, Xiao-Min; Dionne, Raymond

2012-01-01

Pain is a complex sensory experience for which the molecular mechanisms are yet to be fully elucidated. Individual differences in pain sensitivity are mediated by a complex network of multiple gene polymorphisms, physiological and psychological processes, and environmental factors. Here, we present the methods for applying unbiased molecular-genetic approaches, genome-wide association study (GWAS), and global gene expression analysis, to help better understand the molecular basis of pain sensitivity in humans and variable responses to analgesic drugs. PMID:22351080

Age differences in the motor control of speech: An fMRI study of healthy aging.

PubMed

Tremblay, Pascale; Sato, Marc; Deschamps, Isabelle

2017-05-01

Healthy aging is associated with a decline in cognitive, executive, and motor processes that are concomitant with changes in brain activation patterns, particularly at high complexity levels. While speech production relies on all these processes, and is known to decline with age, the mechanisms that underlie these changes remain poorly understood, despite the importance of communication on everyday life. In this cross-sectional group study, we investigated age differences in the neuromotor control of speech production by combining behavioral and functional magnetic resonance imaging (fMRI) data. Twenty-seven healthy adults underwent fMRI while performing a speech production task consisting in the articulation of nonwords of different sequential and motor complexity. Results demonstrate strong age differences in movement time (MT), with longer and more variable MT in older adults. The fMRI results revealed extensive age differences in the relationship between BOLD signal and MT, within and outside the sensorimotor system. Moreover, age differences were also found in relation to sequential complexity within the motor and attentional systems, reflecting both compensatory and de-differentiation mechanisms. At very high complexity level (high motor complexity and high sequence complexity), age differences were found in both MT data and BOLD response, which increased in several sensorimotor and executive control areas. Together, these results suggest that aging of motor and executive control mechanisms may contribute to age differences in speech production. These findings highlight the importance of studying functionally relevant behavior such as speech to understand the mechanisms of human brain aging. Hum Brain Mapp 38:2751-2771, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Drug Intervention Response Predictions with PARADIGM (DIRPP) identifies drug resistant cancer cell lines and pathway mechanisms of resistance.

PubMed

Brubaker, Douglas; Difeo, Analisa; Chen, Yanwen; Pearl, Taylor; Zhai, Kaide; Bebek, Gurkan; Chance, Mark; Barnholtz-Sloan, Jill

2014-01-01

The revolution in sequencing techniques in the past decade has provided an extensive picture of the molecular mechanisms behind complex diseases such as cancer. The Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Project (CGP) have provided an unprecedented opportunity to examine copy number, gene expression, and mutational information for over 1000 cell lines of multiple tumor types alongside IC50 values for over 150 different drugs and drug related compounds. We present a novel pipeline called DIRPP, Drug Intervention Response Predictions with PARADIGM7, which predicts a cell line's response to a drug intervention from molecular data. PARADIGM (Pathway Recognition Algorithm using Data Integration on Genomic Models) is a probabilistic graphical model used to infer patient specific genetic activity by integrating copy number and gene expression data into a factor graph model of a cellular network. We evaluated the performance of DIRPP on endometrial, ovarian, and breast cancer related cell lines from the CCLE and CGP for nine drugs. The pipeline is sensitive enough to predict the response of a cell line with accuracy and precision across datasets as high as 80 and 88% respectively. We then classify drugs by the specific pathway mechanisms governing drug response. This classification allows us to compare drugs by cellular response mechanisms rather than simply by their specific gene targets. This pipeline represents a novel approach for predicting clinical drug response and generating novel candidates for drug repurposing and repositioning.

Aerodynamic instability: A case history

NASA Technical Reports Server (NTRS)

Eisenmann, R. C.

1985-01-01

The identification, diagnosis, and final correction of complex machinery malfunctions typically require the correlation of many parameters such as mechanical construction, process influence, maintenance history, and vibration response characteristics. The progression is reviewed of field testing, diagnosis, and final correction of a specific machinery instability problem. The case history presented addresses a unique low frequency instability problem on a high pressure barrel compressor. The malfunction was eventually diagnosed as a fluidic mechanism that manifested as an aerodynamic disturbance to the rotor assembly.

Solving Immunology?

PubMed Central

Vodovotz, Yoram; Xia, Ashley; Read, Elizabeth L.; Bassaganya-Riera, Josep; Hafler, David A.; Sontag, Eduardo; Wang, Jin; Tsang, John S.; Day, Judy D.; Kleinstein, Steven; Butte, Atul J.; Altman, Matthew C; Hammond, Ross; Sealfon, Stuart C.

2016-01-01

Emergent responses of the immune system result from integration of molecular and cellular networks over time and across multiple organs. High-content and high-throughput analysis technologies, concomitantly with data-driven and mechanistic modeling, hold promise for systematic interrogation of these complex pathways. However, connecting genetic variation and molecular mechanisms to individual phenotypes and health outcomes has proven elusive. Gaps remain in data, and disagreements persist about the value of mechanistic modeling for immunology. Here, we present the perspectives that emerged from the NIAID workshop “Complex Systems Science, Modeling and Immunity” and subsequent discussions regarding the potential synergy of high-throughput data acquisition, data-driven modeling and mechanistic modeling to define new mechanisms of immunological disease and to accelerate the translation of these insights into therapies. PMID:27986392

Therapies in inborn errors of oxidative metabolism

PubMed Central

Schiff, Manuel; Bénit, Paule; Jacobs, Howard T.; Vockley, Jerry; Rustin, Pierre

2014-01-01

Mitochondrial diseases encompass a wide range of presentations and mechanisms, dictating a need to consider both broad-based and disease-specific therapies. The manifestations of mitochondrial dysfunction and the response to therapy vary between individuals. This probably reflects the genetic complexity of mitochondrial biology, which requires an excess of 2000 genes for proper function, with numerous interfering epigenetic and environmental factors. Accordingly, we are increasingly aware of the complexity of these diseases which involve far more than merely decreased ATP supply. Indeed, recent therapeutic progress has addressed only specific disease entities. In this review present and prospective therapeutic approaches will be discussed on the basis of targets and mechanism of action, but with a broad outlook on their potential applications. PMID:22633959

New Insights into the Roles of Acidocalcisomes and the Contractile Vacuole Complex in Osmoregulation in Protists

PubMed Central

Docampo, Roberto; Jimenez, Veronica; Lander, Noelia; Li, Zhu-Hong; Niyogi, Sayantanee

2013-01-01

While free-living protists are usually subjected to hyposmotic environments, parasitic protists are also in contact with hyperosmotic habitats. Recent work in one of these parasites, Trypanosoma cruzi, has revealed that its contractile vacuole complex, which usually collects and expels excess water as a mechanism of regulatory volume decrease after hyposmotic stress, has also a role in cell shrinking when the cells are submitted to hyperosmotic stress. Trypanosomes also have an acidic calcium store rich in polyphosphate (polyP), named the acidocalcisome, which is involved in their response to osmotic stress. Here, we review newly emerging insights on the role of acidocalcisomes and the contractile vacuole complex in the cellular response to hyposmotic and hyperosmotic stresses. We also review the current state of knowledge on the composition of these organelles and their other roles in calcium homeostasis and protein trafficking. PMID:23890380

New insights into roles of acidocalcisomes and contractile vacuole complex in osmoregulation in protists.

PubMed

Docampo, Roberto; Jimenez, Veronica; Lander, Noelia; Li, Zhu-Hong; Niyogi, Sayantanee

2013-01-01

While free-living protists are usually subjected to hyposmotic environments, parasitic protists are also in contact with hyperosmotic habitats. Recent work in one of these parasites, Trypanosoma cruzi, has revealed that its contractile vacuole complex, which usually collects and expels excess water as a mechanism of regulatory volume decrease after hyposmotic stress, has also a role in cell shrinking when the cells are submitted to hyperosmotic stress. Trypanosomes also have an acidic calcium store rich in polyphosphate (polyP), named the acidocalcisome, which is involved in their response to osmotic stress. Here, we review newly emerging insights on the role of acidocalcisomes and the contractile vacuole complex in the cellular response to hyposmotic and hyperosmotic stresses. We also review the current state of knowledge on the composition of these organelles and their other roles in calcium homeostasis and protein trafficking. © 2013, Elsevier Inc. All Rights Reserved.

Microbiota as a mediator of cancer progression and therapy.

PubMed

Pope, Jillian L; Tomkovich, Sarah; Yang, Ye; Jobin, Christian

2017-01-01

Complex and intricate circuitries regulate cellular proliferation, survival, and growth, and alterations of this network through genetic and epigenetic events result in aberrant cellular behaviors, often leading to carcinogenesis. Although specific germline mutations have been recognized as cancer inducers, the vast majority of neoplastic changes in humans occur through environmental exposure, lifestyle, and diet. An emerging concept in cancer biology implicates the microbiota as a powerful environmental factor modulating the carcinogenic process. For example, the intestinal microbiota influences cancer development or therapeutic responses through specific activities (immune responses, metabolites, microbial structures, and toxins). The numerous effects of microbiota on carcinogenesis, ranging from promoting, preventing, or even influencing therapeutic outcomes, highlight the complex relationship between the biota and the host. In this review, we discuss the latest findings on this complex microbial interaction with the host and highlight potential mechanisms by which the microbiota mediates such a wide impact on carcinogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

Microbiota as a mediator of cancer progression and therapy

PubMed Central

Pope, Jillian L.; Tomkovich, Sarah; Yang, Ye; Jobin, Christian

2017-01-01

Complex and intricate circuitries regulate cellular proliferation, survival, and growth, and alterations of this network through genetic and epigenetic events result in aberrant cellular behaviors, often leading to carcinogenesis. Although specific germline mutations have been recognized as cancer inducers, the vast majority of neoplastic changes in humans occur through environmental exposure, lifestyle, and diet. An emerging concept in cancer biology implicates the microbiota as a powerful environmental factor modulating the carcinogenic process. For example, the intestinal microbiota influences cancer development or therapeutic responses through specific activities (immune responses, metabolites, microbial structures, and toxins). The numerous effects of microbiota on carcinogenesis, ranging from promoting, preventing, or even influencing therapeutic outcomes, highlight the complex relationship between the biota and the host. In this review, we discuss the latest findings on this complex microbial interaction with the host and highlight potential mechanisms by which the microbiota mediates such a wide impact on carcinogenesis. PMID:27554797

Next-Generation Pathology.

PubMed

Caie, Peter D; Harrison, David J

2016-01-01

The field of pathology is rapidly transforming from a semiquantitative and empirical science toward a big data discipline. Large data sets from across multiple omics fields may now be extracted from a patient's tissue sample. Tissue is, however, complex, heterogeneous, and prone to artifact. A reductionist view of tissue and disease progression, which does not take this complexity into account, may lead to single biomarkers failing in clinical trials. The integration of standardized multi-omics big data and the retention of valuable information on spatial heterogeneity are imperative to model complex disease mechanisms. Mathematical modeling through systems pathology approaches is the ideal medium to distill the significant information from these large, multi-parametric, and hierarchical data sets. Systems pathology may also predict the dynamical response of disease progression or response to therapy regimens from a static tissue sample. Next-generation pathology will incorporate big data with systems medicine in order to personalize clinical practice for both prognostic and predictive patient care.

Octopamine and tyramine modulate the thermoregulatory fanning response in honey bees (Apis mellifera L.)

USDA-ARS?s Scientific Manuscript database

Biogenic amines regulate the proximate mechanisms underlying most behavior, including those that contribute to the overall success of complex societies. For honey bees one critical set of behaviors contributing to the welfare of a colony are involved with nest thermoregulation. Worker honey bees co...

Critical role for CCAAT/Enhancer-binding protein beta in immune complex-induced acute lung injury

USDA-ARS?s Scientific Manuscript database

Although inflammation plays a central role in the pathogenesis of acute lung injury (ALI), the molecular mechanisms underlying inflammatory responses in ALI are poorly understood, and therapeutic options remain limited. The CCAAT/enhancer-binding protein (C/EBP) gamma and -gamma have been implicated...

Gene Expression Responses in Male Fathead Minnows Exposed to Binary Mixtures of an Estrogen and Antiestrogen

EPA Science Inventory

Aquatic organisms are continuously exposed to complex mixtures of chemicals, many of which can interfere with their endocrine system, resulting in impaired reproduction, development or survival, among others. In order to analyze the effects and mechanisms of action of estrogen...

Process Timing and Its Relation to the Coding of Tonal Harmony

ERIC Educational Resources Information Center

Aksentijevic, Aleksandar; Barber, Paul J.; Elliott, Mark A.

2011-01-01

Advances in auditory research suggest that gamma-band synchronization of frequency-specific cortical loci could be responsible for the integration of pure tones (harmonics) into harmonic complex tones. Thus far, evidence for such a mechanism has been revealed in neurophysiological studies, with little corroborative psychophysical evidence. In six…

EVALUATING HYDROLOGICAL RESPONSE TO FORECASTED LAND-USE CHANGE: SCENARIO TESTING WITH THE AUTOMATED GEOSPATIAL WATERSHED ASSESSMENT TOOL

EPA Science Inventory

Studies of future management and policy options based on different assumptions provide a mechanism to examine possible outcomes and especially their likely benefits or consequences. Planning and assessment in land and water resource management are evolving toward complex, spatia...

Transcriptional response of Leptospira interrogans to iron limitation and characterization of a PerR homolog

USDA-ARS?s Scientific Manuscript database

Leptospira interrogans is the causative agent of leptospirosis, a zoonosis of global significance. Iron is essential for growth of most bacterial species. Since availability of iron is low in the host, pathogens have evolved complex iron acquisition mechanisms to survive and establish infection. In ...

Genomic, transcriptomic and phenomic variation reveals the complex adaptation to stress response of modern maize breeding

USDA-ARS?s Scientific Manuscript database

Early maize adaptation to different agricultural environments was an important process associated with the creation of a stable food supply that allowed the evolution of human civilization in the Americas. To explore the mechanisms of maize adaptation, genomic, transcriptomic and phenomic data were ...

An account of co-ordination mechanisms for humanitarian assistance during the international response to the 1994 crisis in Rwanda.

PubMed

Borton, J

1996-12-01

This paper examines the co-ordination strategies developed to respond to the Great Lakes crisis following the events of April 1994. It analyses the different functions and mechanisms which sought to achieve a co-ordinated response--ranging from facilitation at one extreme to management and direction at the other. The different regimes developed to facilitate co-ordination within Rwanda and neighbouring countries, focusing on both inter-agency and inter-country co-ordination issues, are then analysed. Finally, the paper highlights the absence of mechanisms to achieve coherence between the humanitarian, political and security domains. It concludes that effective co-ordination is critical not only to achieve programme efficiency, but to ensure that the appropriate instruments and strategies to respond to complex political emergencies are in place. It proposes a radical re-shaping of international humanitarian, political and security institutions, particularly the United Nations, to improve the effectiveness of humanitarian and political responses to crises such as that in the Great Lakes.

Cooperation, conflict, and the evolution of queen pheromones.

PubMed

Kocher, Sarah D; Grozinger, Christina M

2011-11-01

While chemical communication regulates individual behavior in a wide variety of species, these communication systems are most elaborated in insect societies. In these complex systems, pheromones produced by the reproductive individuals (queens) are critical in establishing and maintaining dominant reproductive status over hundreds to thousands of workers. The proximate and ultimate mechanisms by which these intricate pheromone communication systems evolved are largely unknown, though there has been much debate over whether queen pheromones function as a control mechanism or as an honest signal facilitating cooperation. Here, we summarize results from recent studies in honey bees, bumble bees, wasps, ants and termites. We further discuss evolutionary mechanisms by which queen pheromone communication systems may have evolved. Overall, these studies suggest that queen-worker pheromone communication is a multi-component, labile dialog between the castes, rather than a simple, fixed signal-response system. We also discuss future approaches that can shed light on the proximate and ultimate mechanisms that underlie these complex systems by focusing on the development of increasingly sophisticated genomic tools and their potential applications to examine the molecular mechanisms that regulate pheromone production and perception.

Investigation of Stimulation-Response Relationships for Complex Fracture Systems in Enhanced Geothermal Reservoirs

DOE Data Explorer

Fu, Pengcheng; Johnson, Scott M.; Carrigan, Charles R.

2011-01-01

Hydraulic fracturing is currently the primary method for stimulating low-permeability geothermal reservoirs and creating Enhanced (or Engineered) Geothermal Systems (EGS) with improved permeability and heat production efficiency. Complex natural fracture systems usually exist in the formations to be stimulated and it is therefore critical to understand the interactions between existing fractures and newly created fractures before optimal stimulation strategies can be developed. Our study aims to improve the understanding of EGS stimulation-response relationships by developing and applying computer-based models that can effectively reflect the key mechanisms governing interactions between complex existing fracture networks and newly created hydraulic fractures. In this paper, we first briefly describe the key modules of our methodology, namely a geomechanics solver, a discrete fracture flow solver, a rock joint response model, an adaptive remeshing module, and most importantly their effective coupling. After verifying the numerical model against classical closed-form solutions, we investigate responses of reservoirs with different preexisting natural fractures to a variety of stimulation strategies. The factors investigated include: the in situ stress states (orientation of the principal stresses and the degree of stress anisotropy), pumping pressure, and stimulation sequences of multiple wells.

Mechanistic Basis for Plant Responses to Drought Stress : Regulatory Mechanism of Abscisic Acid Signaling

NASA Astrophysics Data System (ADS)

Miyakawa, Takuya; Tanokura, Masaru

The phytohormone abscisic acid (ABA) plays a key role in the rapid adaptation of plants to environmental stresses such as drought and high salinity. Accumulated ABA in plant cells promotes stomatal closure in guard cells and transcription of stress-tolerant genes. Our understanding of ABA responses dramatically improved by the discovery of both PYR/PYL/RCAR as a soluble ABA receptor and inhibitory complex of a protein phospatase PP2C and a protein kinase SnRK2. Moreover, several structural analyses of PYR/PYL/RCAR revealed the mechanistic basis for the regulatory mechanism of ABA signaling, which provides a rational framework for the design of alternative agonists in future.

Analytical solution for a class of network dynamics with mechanical and financial applications

NASA Astrophysics Data System (ADS)

Krejčí, P.; Lamba, H.; Melnik, S.; Rachinskii, D.

2014-09-01

We show that for a certain class of dynamics at the nodes the response of a network of any topology to arbitrary inputs is defined in a simple way by its response to a monotone input. The nodes may have either a discrete or continuous set of states and there is no limit on the complexity of the network. The results provide both an efficient numerical method and the potential for accurate analytic approximation of the dynamics on such networks. As illustrative applications, we introduce a quasistatic mechanical model with objects interacting via frictional forces and a financial market model with avalanches and critical behavior that are generated by momentum trading strategies.

Analysis of Stress-Responsive Gene Expression in Cultivated and Weedy Rice Differing in Cold Stress Tolerance

PubMed Central

Pereira, Andy; Tseng, Te-Ming; Zimmer, Paulo Dejalma; Burgos, Nilda Roma

2015-01-01

Rice (Oryza sativa L.) cultivars show impairment of growth in response to environmental stresses such as cold at the early seedling stage. Locally adapted weedy rice is able to survive under adverse environmental conditions, and can emerge in fields from greater soil depth. Cold-tolerant weedy rice can be a good genetic source for developing cold-tolerant, weed-competitive rice cultivars. An in-depth analysis is presented here of diverse indica and japonica rice genotypes, mostly weedy rice, for cold stress response to provide an understanding of different stress adaptive mechanisms towards improvement of the rice crop performance in the field. We have tested a collection of weedy rice genotypes to: 1) classify the subspecies (ssp.) grouping (japonica or indica) of 21 accessions; 2) evaluate their sensitivity to cold stress; and 3) analyze the expression of stress-responsive genes under cold stress and a combination of cold and depth stress. Seeds were germinated at 25°C at 1.5- and 10-cm sowing depth for 10d. Seedlings were then exposed to cold stress at 10°C for 6, 24 and 96h, and the expression of cold-, anoxia-, and submergence-inducible genes was analyzed. Control plants were seeded at 1.5cm depth and kept at 25°C. The analysis revealed that cold stress signaling in indica genotypes is more complex than that of japonica as it operates via both the CBF-dependent and CBF-independent pathways, implicated through induction of transcription factors including OsNAC2, OsMYB46 and OsF-BOX28. When plants were exposed to cold + sowing depth stress, a complex signaling network was induced that involved cross talk between stresses mediated by CBF-dependent and CBF-independent pathways to circumvent the detrimental effects of stresses. The experiments revealed the importance of the CBF regulon for tolerance to both stresses in japonica and indica ssp. The mechanisms for cold tolerance differed among weedy indica genotypes and also between weedy indica and cultivated japonica ssp. as indicated by the up/downregulation of various stress-responsive pathways identified from gene expression analysis. The cold-stress response is described in relation to the stress signaling pathways, showing complex adaptive mechanisms in different genotypes. PMID:26230579

Study of Effects on Mechanical Properties of PLA Filament which is blended with Recycled PLA Materials

NASA Astrophysics Data System (ADS)

Babagowda; Kadadevara Math, R. S.; Goutham, R.; Srinivas Prasad, K. R.

2018-02-01

Fused deposition modeling is a rapidly growing additive manufacturing technology due to its ability to build functional parts having complex geometry. The mechanical properties of the build part is depends on several process parameters and build material of the printed specimen. The aim of this study is to characterize and optimize the parameters such as layer thickness and PLA build material which is mixed with recycled PLA material. Tensile and flexural or bending test are carried out to determine the mechanical response characteristics of the printed specimen. Taguchi method is used for number of experiments and Taguchi S/N ratio is used to identify the set of parameters which give good results for respective response characteristics, effectiveness of each parameters is investigated by using analysis of variance (ANOVA).

Mechanosensitive channels in bacteria as membrane tension reporters

NASA Technical Reports Server (NTRS)

Sukharev, S.

1999-01-01

The purpose of this short review is to discuss recent data on the molecular structure and mechanism of gating of MscL, a mechanosensitive channel of large conductance from Escherichia coli. MscL is the first isolated molecule shown to convert mechanical stress of the membrane into a simple response, the opening of a large aqueous pore. The functional complex appears to be a stable homo-pentamer of 15-kDa subunits, the gating transitions in which are driven by stretch forces conveyed through the lipid bilayer. We have measured the open probability of MscL and the kinetics of transitions as a function of membrane tension. The parameters extracted from the single-channel current recordings and dose-response curves such as the energy difference between the closed, open, and intermediate conducting states, and the transition-related changes in protein dimensions suggest a large conformational rearrangement of the channel complex. The estimations show that in native conditions MscL openings could be driven primarily by forces of osmotic nature. The thermodynamic and spatial parameters reasonably correlate with the available data on the structure of a single MscL subunit and multimeric organization of the complex. Combined with the functional analysis of mutations, these data give grounds to hypotheses on the nature of the channel mechanosensitivity.

Cancer cell: using inflammation to invade the host

PubMed Central

Arias, José-Ignacio; Aller, María-Angeles; Arias, Jaime

2007-01-01

Background Inflammation is increasingly recognized as an important component of tumorigenesis, although the mechanisms involved are not fully characterized. The invasive capacity of cancers is reflected in the classic metastatic cascade: tumor (T), node (N) and metastasis (M). However, this staging system for cancer would also have a tumoral biological significance. Presentation of the hypothesis To integrate the mechanisms that control the inflammatory response in the actual staging system of cancer. It is considered that in both processes of inflammation and cancer, three successive phenotypes are presented that represent the expression of trophic functional systems of increasing metabolic complexity for using oxygen. Testing the hypothesis While a malignant tumor develops it express phenotypes that also share the inflammatory response such as: an ischemic phenotype (anoxic-hypoxic), a leukocytic phenotype with anaerobic glycolysis and migration, and an angiogenic phenotype with hyperactivity of glycolytic enzymes, tumor proliferation and metastasis, and cachexia of the host. The increasing metabolic complexity of the tumor cell to use oxygen allows for it to be released, migrate and proliferate, thus creating structures of growing complexity. Implication of the hypothesis One aim of cancer gene therapy could be the induction of oxidative phosphorylation, the last metabolic step required by inflammation in order to differentiate the tissue that it produces. PMID:17437633

Complex and extensive post-transcriptional regulation revealed by integrative proteomic and transcriptomic analysis of metabolite stress response in Clostridium acetobutylicum.

PubMed

Venkataramanan, Keerthi P; Min, Lie; Hou, Shuyu; Jones, Shawn W; Ralston, Matthew T; Lee, Kelvin H; Papoutsakis, E Terry

2015-01-01

Clostridium acetobutylicum is a model organism for both clostridial biology and solvent production. The organism is exposed to its own toxic metabolites butyrate and butanol, which trigger an adaptive stress response. Integrative analysis of proteomic and RNAseq data may provide novel insights into post-transcriptional regulation. The identified iTRAQ-based quantitative stress proteome is made up of 616 proteins with a 15 % genome coverage. The differentially expressed proteome correlated poorly with the corresponding differential RNAseq transcriptome. Up to 31 % of the differentially expressed proteins under stress displayed patterns opposite to those of the transcriptome, thus suggesting significant post-transcriptional regulation. The differential proteome of the translation machinery suggests that cells employ a different subset of ribosomal proteins under stress. Several highly upregulated proteins but with low mRNA levels possessed mRNAs with long 5'UTRs and strong RBS scores, thus supporting the argument that regulatory elements on the long 5'UTRs control their translation. For example, the oxidative stress response rubrerythrin was upregulated only at the protein level up to 40-fold without significant mRNA changes. We also identified many leaderless transcripts, several displaying different transcriptional start sites, thus suggesting mRNA-trimming mechanisms under stress. Downregulation of Rho and partner proteins pointed to changes in transcriptional elongation and termination under stress. The integrative proteomic-transcriptomic analysis demonstrated complex expression patterns of a large fraction of the proteome. Such patterns could not have been detected with one or the other omic analyses. Our analysis proposes the involvement of specific molecular mechanisms of post-transcriptional regulation to explain the observed complex stress response.

Interaction of Nectarin 4 with a fungal protein triggers a microbial surveillance and defense mechanism in nectar.

PubMed

Harper, April D; Stalnaker, Stephanie H; Wells, Lance; Darvill, Alan; Thornburg, Robert; York, William S

2010-12-01

Understanding the biochemical mechanisms by which plants respond to microbial infection is a fundamental goal of plant science. Extracellular dermal glycoproteins (EDGPs) are widely expressed in plant tissues and have been implicated in plant defense responses. Although EDGPs are known to interact with fungal proteins, the downstream effects of these interactions are poorly understood. To gain insight into these phenomena, we used tobacco floral nectar as a model system to identify a mechanism by which the EDGP known as Nectarin IV (NEC4) functions as pathogen surveillance molecule. Our data demonstrates that the interaction of NEC4 with a fungal endoglucanase (XEG) promotes the catalytic activity of Nectarin V (NEC5), which catalyzes the conversion of glucose and molecular oxygen to gluconic acid and H(2)O(2). Significantly enhanced NEC5 activity was observed when XEG was added to nectar or nectarin solutions that contain NEC4. This response was also observed when the purified NEC4:XEG complex was added to NEC4-depleted nectarin solutions, which did not respond to XEG alone. These results indicate that formation of the NEC4:XEG complex is a key step leading to induction of NEC5 activity in floral nectar, resulting in an increase in concentrations of reactive oxygen species (ROS), which are known to inhibit microbial growth directly and activate signal transduction pathways that induce innate immunity responses in the plant. Copyright © 2010. Published by Elsevier Ltd.

Application of Δ- and λ-isomerism of octahedral metal complexes for inducing chiral nematic phases.

PubMed

Sato, Hisako; Yamagishi, Akihiko

2009-11-20

The Delta- and Lambda-isomerism of octahedral metal complexes is employed as a source of chirality for inducing chiral nematic phases. By applying a wide range of chiral metal complexes as a dopant, it has been found that tris(beta-diketonato)metal(III) complexes exhibit an extremely high value of helical twisting power. The mechanism of induction of the chiral nematic phase is postulated on the basis of a surface chirality model. The strategy for designing an efficient dopant is described, together with the results using a number of examples of Co(III), Cr(III) and Ru(III) complexes with C(2) symmetry. The development of photo-responsive dopants to achieve the photo-induced structural change of liquid crystal by use of photo-isomerization of chiral metal complexes is also described.

Application of Δ- and Λ-Isomerism of Octahedral Metal Complexes for Inducing Chiral Nematic Phases

PubMed Central

Sato, Hisako; Yamagishi, Akihiko

2009-01-01

The Δ- and Λ-isomerism of octahedral metal complexes is employed as a source of chirality for inducing chiral nematic phases. By applying a wide range of chiral metal complexes as a dopant, it has been found that tris(β-diketonato)metal(III) complexes exhibit an extremely high value of helical twisting power. The mechanism of induction of the chiral nematic phase is postulated on the basis of a surface chirality model. The strategy for designing an efficient dopant is described, together with the results using a number of examples of Co(III), Cr(III) and Ru(III) complexes with C2 symmetry. The development of photo-responsive dopants to achieve the photo-induced structural change of liquid crystal by use of photo-isomerization of chiral metal complexes is also described. PMID:20057959

Single-molecule spectroscopy reveals photosynthetic LH2 complexes switch between emissive states

PubMed Central

Schlau-Cohen, Gabriela S.; Wang, Quan; Southall, June; Cogdell, Richard J.; Moerner, W. E.

2013-01-01

Photosynthetic organisms flourish under low light intensities by converting photoenergy to chemical energy with near unity quantum efficiency and under high light intensities by safely dissipating excess photoenergy and deleterious photoproducts. The molecular mechanisms balancing these two functions remain incompletely described. One critical barrier to characterizing the mechanisms responsible for these processes is that they occur within proteins whose excited-state properties vary drastically among individual proteins and even within a single protein over time. In ensemble measurements, these excited-state properties appear only as the average value. To overcome this averaging, we investigate the purple bacterial antenna protein light harvesting complex 2 (LH2) from Rhodopseudomonas acidophila at the single-protein level. We use a room-temperature, single-molecule technique, the anti-Brownian electrokinetic trap, to study LH2 in a solution-phase (nonperturbative) environment. By performing simultaneous measurements of fluorescence intensity, lifetime, and spectra of single LH2 complexes, we identify three distinct states and observe transitions occurring among them on a timescale of seconds. Our results reveal that LH2 complexes undergo photoactivated switching to a quenched state, likely by a conformational change, and thermally revert to the ground state. This is a previously unobserved, reversible quenching pathway, and is one mechanism through which photosynthetic organisms can adapt to changes in light intensities. PMID:23776245

Single-molecule spectroscopy reveals photosynthetic LH2 complexes switch between emissive states.

PubMed

Schlau-Cohen, Gabriela S; Wang, Quan; Southall, June; Cogdell, Richard J; Moerner, W E

2013-07-02

Photosynthetic organisms flourish under low light intensities by converting photoenergy to chemical energy with near unity quantum efficiency and under high light intensities by safely dissipating excess photoenergy and deleterious photoproducts. The molecular mechanisms balancing these two functions remain incompletely described. One critical barrier to characterizing the mechanisms responsible for these processes is that they occur within proteins whose excited-state properties vary drastically among individual proteins and even within a single protein over time. In ensemble measurements, these excited-state properties appear only as the average value. To overcome this averaging, we investigate the purple bacterial antenna protein light harvesting complex 2 (LH2) from Rhodopseudomonas acidophila at the single-protein level. We use a room-temperature, single-molecule technique, the anti-Brownian electrokinetic trap, to study LH2 in a solution-phase (nonperturbative) environment. By performing simultaneous measurements of fluorescence intensity, lifetime, and spectra of single LH2 complexes, we identify three distinct states and observe transitions occurring among them on a timescale of seconds. Our results reveal that LH2 complexes undergo photoactivated switching to a quenched state, likely by a conformational change, and thermally revert to the ground state. This is a previously unobserved, reversible quenching pathway, and is one mechanism through which photosynthetic organisms can adapt to changes in light intensities.

Salt-Sensitive Hypertension: Perspectives on Intrarenal Mechanisms

PubMed Central

Majid, Dewan S.A.; Prieto, Minolfa C.; Navar, L Gabriel

2015-01-01

Salt sensitive hypertension is characterized by increases in blood pressure in response to increases in dietary salt intake and is associated with an enhanced risk of cardiovascular and renal morbidity. Although researchers have sought for decades to understand how salt sensitivity develops in humans, the mechanisms responsible for the increases in blood pressure in response to high salt intake are complex and only partially understood. Until now, scientists have been unable to explain why some individuals are salt sensitive and others are salt resistant. Although a central role for the kidneys in the development of salt sensitivity and hypertension has been generally accepted, it is also recognized that hypertension is of multifactorial origin and a variety of factors can induce, or prevent, blood pressure responsiveness to the manipulation of salt intake. Excess salt intake in susceptible persons may also induce inappropriate central and sympathetic nervous system responses and increase the production of intrarenal angiotensin II, catecholamines and other factors such as oxidative stress and inflammatory cytokines. One key factor is the concomitant inappropriate or paradoxical activation of the intrarenal renin-angiotensin system, by high salt intake. This is reflected by the increases in urinary angiotensinogen during high salt intake in salt sensitive models. A complex interaction between neuroendocrine factors and the kidney may underlie the propensity for some individuals to retain salt and develop salt-dependent hypertension. In this review, we focus mainly on the renal contributions that provide the mechanistic link between chronic salt intake and the development of hypertension. PMID:26028244

Mechanical compression and hydrostatic pressure induce reversible changes in actin cytoskeletal organisation in chondrocytes in agarose.

PubMed

Knight, M M; Toyoda, T; Lee, D A; Bader, D L

2006-01-01

In numerous cell types, the cytoskeleton has been widely implicated in mechanotransduction pathways involving stretch-activated ion channels, integrins and deformation of intracellular organelles. Studies have also demonstrated that the cytoskeleton can undergo remodelling in response to mechanical stimuli such as tensile strain or fluid flow. In articular chondrocytes, the mechanotransduction pathways are complex, inter-related and as yet, poorly understood. Furthermore, little is known of how the chondrocyte cytoskeleton responds to physiological mechanical loading. This study utilises the well-characterised chondrocyte-agarose model and an established confocal image-analysis technique to demonstrate that both static and cyclic, compressive strain and hydrostatic pressure all induce remodelling of actin microfilaments. This remodelling was characterised by a change from a uniform to a more punctate distribution of cortical actin around the cell periphery. For some loading regimes, this remodelling was reversed over a subsequent 1h unloaded period. This reversible remodelling of actin cytoskeleton may therefore represent a mechanism through which the chondrocyte alters its mechanical properties and mechanosensitivity in response to physiological mechanical loading.

The Effect of Water Molecules on Mechanical Properties of Bamboo Microfibrils

NASA Astrophysics Data System (ADS)

Rahbar, Nima

Bamboo fibers have higher strength-to-weight ratios than steel and concrete. The unique properties of bamboo fibers come from their natural composite structures that comprise mainly cellulose nanofibrils in a matrix of intertwined hemicellulose and lignin called lignin-carbohydrate complex (LCC). Here, we have utilized atomistic simulations to investigate the mechanical properties and mechanisms of interactions between these materials, in the presence of water molecules. Our results suggest that hemicellulose exhibits better mechanical properties and lignin shows greater tendency to adhere to cellulose nanofibrils. Consequently, the role of hemicellulose found to be enhancing the mechanical properties and lignin found to be providing the strength of bamboo fibers. The abundance of Hbonds in hemicellulose chains is responsible for improving the mechanical behavior of LCC. The strong van der Waals forces between lignin molecules and cellulose nanofibrils is responsible for higher adhesion energy between LCC/cellulose nanofibrils. We also found out that the amorphous regions of cellulose nanofibrils is the weakest interface in bamboo Microfibrils. In presence of water, the elastic modulus of lignin increases at low water content (less than 10 NSF CAREER Grant No. 1261284.

Pathophysiology of chest trauma.

PubMed

Calhoon, J H; Trinkle, J K

1997-05-01

Recent information indicates that there is a complex cellular and molecular generic response to injury that can lead to multi-organ failure. For many years, basic physiology and biochemistry were considered to be the systemic mechanisms to injury, but now it is known that subcellular and molecular events are the keys to unlocking the secrets of the body's response to trauma. The interaction of the endothelial cell with neutrophils and platelets to produce cytokines, free radicals, and upregulating adhesion molecules is especially significant.

Comparative transcriptomics and proteomics analysis of citrus fruit, to improve understanding of the effect of low temperature on maintaining fruit quality during lengthy post-harvest storage

PubMed Central

Yun, Ze; Jin, Shuai; Ding, Yuduan; Wang, Zhuang; Gao, Huijun; Pan, Zhiyong; Xu, Juan; Cheng, Yunjiang; Deng, Xiuxin

2012-01-01

Fruit quality is a very complex trait that is affected by both genetic and non-genetic factors. Generally, low temperature (LT) is used to delay fruit senescence and maintain fruit quality during post-harvest storage but the molecular mechanisms involved are poorly understood. Hirado Buntan Pummelo (HBP; Citrus grandis × C. paradis) fruit were chosen to explore the mechanisms that maintain citrus fruit quality during lengthy LT storage using transcriptome and proteome studies based on digital gene expression (DGE) profiling and two-dimensional gel electrophoresis (2-DE), respectively. Results showed that LT up-regulated stress-responsive genes, arrested signal transduction, and inhibited primary metabolism, secondary metabolism and the transportation of metabolites. Calcineurin B-like protein (CBL)–CBL-interacting protein kinase complexes might be involved in the signal transduction of LT stress, and fruit quality is likely to be regulated by sugar-mediated auxin and abscisic acid (ABA) signalling. Furthermore, ABA was specific to the regulation of citrus fruit senescence and was not involved in the LT stress response. In addition, the accumulation of limonin, nomilin, methanol, and aldehyde, together with the up-regulated heat shock proteins, COR15, and cold response-related genes, provided a comprehensive proteomics and transcriptomics view on the coordination of fruit LT stress responses. PMID:22323274

Molecular Assembly of Clostridium botulinum progenitor M complex of type E.

PubMed

Eswaramoorthy, Subramaniam; Sun, Jingchuan; Li, Huilin; Singh, Bal Ram; Swaminathan, Subramanyam

2015-12-07

Clostridium botulinum neurotoxin (BoNT) is released as a progenitor complex, in association with a non-toxic-non-hemagglutinin protein (NTNH) and other associated proteins. We have determined the crystal structure of M type Progenitor complex of botulinum neurotoxin E [PTC-E(M)], a heterodimer of BoNT and NTNH. The crystal structure reveals that the complex exists as a tight, interlocked heterodimer of BoNT and NTNH. The crystal structure explains the mechanism of molecular assembly of the complex and reveals several acidic clusters at the interface responsible for association at low acidic pH and disassociation at basic/neutral pH. The similarity of the general architecture between the PTC-E(M) and the previously determined PTC-A(M) strongly suggests that the progenitor M complexes of all botulinum serotypes may have similar molecular arrangement, although the neurotoxins apparently can take very different conformation when they are released from the M complex.

Interaction of plasticity and circuit organization during the acquisition of cerebellum-dependent motor learning

PubMed Central

Yang, Yan; Lisberger, Stephen G

2013-01-01

Motor learning occurs through interactions between the cerebellar circuit and cellular plasticity at different sites. Previous work has established plasticity in brain slices and suggested plausible sites of behavioral learning. We now reveal what actually happens in the cerebellum during short-term learning. We monitor the expression of plasticity in the simple-spike firing of cerebellar Purkinje cells during trial-over-trial learning in smooth pursuit eye movements of monkeys. Our findings imply that: 1) a single complex-spike response driven by one instruction for learning causes short-term plasticity in a Purkinje cell’s mossy fiber/parallel-fiber input pathways; 2) complex-spike responses and simple-spike firing rate are correlated across the Purkinje cell population; and 3) simple-spike firing rate at the time of an instruction for learning modulates the probability of a complex-spike response, possibly through a disynaptic feedback pathway to the inferior olive. These mechanisms may participate in long-term motor learning. DOI: http://dx.doi.org/10.7554/eLife.01574.001 PMID:24381248

The Effect of Crosslinking on the Microscale Stress Response and Molecular Deformations in Actin Networks

NASA Astrophysics Data System (ADS)

Gurmessa, Bekele; Fitzpatrick, Robert; Valdivia, Jonathon; Anderson, Rae M. R.

Actin, the most abundant protein in eukaryotic cells, is a semi-flexible biopolymer in the cytoskeleton that plays a crucial structural and mechanical role in cell stability, motion and replication, as well as muscle contraction. Most of these mechanically driven structural changes in cells stem from the complex viscoelastic nature of entangled actin networks and the presence of a myriad of proteins that cross-link actin filaments. Despite their importance, the mechanical response of actin networks is not yet well understood, particularly at the molecular level. Here, we use optical trapping - coupled with fluorescence microscopy - to characterize the microscale stress response and induced filament deformations in entangled and cross-linked actin networks subject to localized mechanical perturbations. In particular, we actively drive a microsphere 10 microns through an entangled or cross- linked actin network at a constant speed and measure the resistive force that the deformed actin filaments exert on the bead during and following strain. We simultaneously visualize and track individual sparsely-labeled actin filaments to directly link force response to molecular deformations, and map the propagation of the initially localized perturbation field throughout the rest of the network (~100 um). By varying the concentration of actin and cross-linkers we directly determine the role of crosslinking and entanglements on the length and time scales of stress propagation, molecular deformation and relaxation mechanisms in actin networks.

Biochemical and immunological mechanisms by which sickle cell trait protects against malaria.

PubMed

Gong, Lauren; Parikh, Sunil; Rosenthal, Philip J; Greenhouse, Bryan

2013-09-11

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.

Biochemical and immunological mechanisms by which sickle cell trait protects against malaria

PubMed Central

2013-01-01

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria. PMID:24025776

Interrelations between hydraulic and mechanical stress adaptations in woody plants

PubMed Central

Ennos, A Roland; Fournier, Meriem

2008-01-01

The fields of plant water relations and plant biomechanics have traditionally been studied separately even though often the same tissues are responsible for water transport and mechanical support. There is now increasing evidence that hydraulic and mechanical adaptations may influence one another. We studied the changes in the hydraulic and mechanical properties of the wood along lateral roots of two species of buttressed trees. In these roots, the mechanical contstraints quantified by strain measurements are known to decrease distally. Further, we investigated the effect of mechanical loading on the vessel anatomy in these and four other species of tropical trees. We found that as the strain decreased, the wood became progressively less stiff and strong but the conductivity increased exponentially. This was reflected in that adaptations towards re-enforcing mechanically loaded areas resulted in xylem with fewer and smaller vessels. In addition a controlled growth experiment on three tree species showed that drought adaptation may results in plants with stronger and stiffer tissue. Our results indicate that hydraulic and mechanical stress adaptations may be interrelated, and so support recent studied suggesting that physiological responses are complex balances rather than pure optimisations. PMID:19704486

The NBS1-Treacle complex controls ribosomal RNA transcription in response to DNA damage

PubMed Central

Larsen, Dorthe H; Hari, Flurina; Clapperton, Julie A; Gwerder, Myriam; Gutsche, Katrin; Altmeyer, Matthias; Jungmichel, Stephanie; Toledo, Luis I; Fink, Daniel; Rask, Maj-Britt; Grøfte, Merete; Lukas, Claudia; Nielsen, Michael L; Smerdon, Stephen J; Lukas, Jiri; Stucki, Manuel

2016-01-01

Chromosome breakage elicits transient silencing of ribosomal RNA synthesis, but the mechanisms involved remained elusive. Here we discover an in-trans signaling mechanism that triggers pan-nuclear silencing of rRNA transcription in response to DNA damage. This is associated with transient recruitment of the Nijmegen breakage syndrome protein 1 (NBS1), a central regulator of DNA damage responses, into the nucleoli. We further identified TCOF1-Treacle, a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle-dependent. Finally, we provide evidence that Treacle-mediated NBS1 recruitment into the nucleoli regulates rRNA silencing in-trans in the presence of distant chromosome breaks. PMID:25064736

The NBS1-Treacle complex controls ribosomal RNA transcription in response to DNA damage.

PubMed

Larsen, Dorthe H; Hari, Flurina; Clapperton, Julie A; Gwerder, Myriam; Gutsche, Katrin; Altmeyer, Matthias; Jungmichel, Stephanie; Toledo, Luis I; Fink, Daniel; Rask, Maj-Britt; Grøfte, Merete; Lukas, Claudia; Nielsen, Michael L; Smerdon, Stephen J; Lukas, Jiri; Stucki, Manuel

2014-08-01

Chromosome breakage elicits transient silencing of ribosomal RNA synthesis, but the mechanisms involved remained elusive. Here we discover an in trans signalling mechanism that triggers pan-nuclear silencing of rRNA transcription in response to DNA damage. This is associated with transient recruitment of the Nijmegen breakage syndrome protein 1 (NBS1), a central regulator of DNA damage responses, into the nucleoli. We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent. Finally, we provide evidence that Treacle-mediated NBS1 recruitment into the nucleoli regulates rRNA silencing in trans in the presence of distant chromosome breaks.

Diabetic Retinopathy: Vascular and Inflammatory Disease

PubMed Central

Semeraro, F.; Cancarini, A.; dell'Omo, R.; Rezzola, S.; Romano, M. R.; Costagliola, C.

2015-01-01

Diabetic retinopathy (DR) is the leading cause of visual impairment in the working-age population of the Western world. The pathogenesis of DR is complex and several vascular, inflammatory, and neuronal mechanisms are involved. Inflammation mediates structural and molecular alterations associated with DR. However, the molecular mechanisms underlying the inflammatory pathways associated with DR are not completely characterized. Previous studies indicate that tissue hypoxia and dysregulation of immune responses associated with diabetes mellitus can induce increased expression of numerous vitreous mediators responsible for DR development. Thus, analysis of vitreous humor obtained from diabetic patients has made it possible to identify some of the mediators (cytokines, chemokines, and other factors) responsible for DR pathogenesis. Further studies are needed to better understand the relationship between inflammation and DR. Herein the main vitreous-related factors triggering the occurrence of retinal complication in diabetes are highlighted. PMID:26137497

Force transmission in epithelial tissues.

PubMed

Vasquez, Claudia G; Martin, Adam C

2016-03-01

In epithelial tissues, cells constantly generate and transmit forces between each other. Forces generated by the actomyosin cytoskeleton regulate tissue shape and structure and also provide signals that influence cells' decisions to divide, die, or differentiate. Forces are transmitted across epithelia because cells are mechanically linked through junctional complexes, and forces can propagate through the cell cytoplasm. Here, we review some of the molecular mechanisms responsible for force generation, with a specific focus on the actomyosin cortex and adherens junctions. We then discuss evidence for how these mechanisms promote cell shape changes and force transmission in tissues. © 2016 Wiley Periodicals, Inc.

Nipah Virus V Protein Evades Alpha and Gamma Interferons by Preventing STAT1 and STAT2 Activation and Nuclear Accumulation

PubMed Central

Rodriguez, Jason J.; Parisien, Jean-Patrick; Horvath, Curt M.

2002-01-01

Characterization of recent outbreaks of fatal encephalitis in southeast Asia identified the causative agent to be a previously unrecognized enveloped negative-strand RNA virus of the Paramyxoviridae family, Nipah virus. One feature linking Nipah virus to this family is a conserved cysteine-rich domain that is the hallmark of paramyxovirus V proteins. The V proteins of other paramyxovirus species have been linked with evasion of host cell interferon (IFN) signal transduction and subsequent antiviral responses by inducing proteasomal degradation of the IFN-responsive transcription factors, STAT1 or STAT2. Here we demonstrate that Nipah virus V protein escapes IFN by a distinct mechanism involving direct inhibition of STAT protein function. Nipah virus V protein differs from other paramyxovirus V proteins in its subcellular distribution but not in its ability to inhibit cellular IFN responses. Nipah virus V protein does not induce STAT degradation but instead inhibits IFN responses by forming high-molecular-weight complexes with both STAT1 and STAT2. We demonstrate that Nipah virus V protein accumulates in the cytoplasm by a Crm1-dependent mechanism, alters the STAT protein subcellular distribution in the steady state, and prevents IFN-stimulated STAT redistribution. Consistent with the formation of complexes, STAT protein tyrosine phosphorylation is inhibited in cells expressing the Nipah virus V protein. As a result, Nipah virus V protein efficiently prevents STAT1 and STAT2 nuclear translocation in response to IFN, inhibiting cellular responses to both IFN-α and IFN-γ. PMID:12388709

A Comparative Proteome Approach Reveals Metabolic Changes Associated with Flammulina velutipes Mycelia in Response to Cold and Light Stress.

PubMed

Liu, Jing-Yu; Chang, Ming-Chang; Meng, Jun-Long; Feng, Cui-Ping; Wang, Yu

2018-04-11

In some industrial processes, cold and light stresses are recognized as two important environmental triggers for the transformation of mycelia into fruit-bodies via intermediate primordia in Flammulina velutipes cultivation. To gain insights into the mechanism of regulation of F. velutipes mycelia in response to cold and light stress, proteins expressed abundantly and characteristically at particular stress states were investigated by using the isobaric tags for the relative and absolute quantitation labeling technique. Among the 1046 nonredundant proteins identified with a high degree of confidence, 264 proteins, which were detected as differentially expressed proteins, were associated with 176 specific KEGG pathways. In-depth data analysis revealed that the regulatory network underlying the cold and light response mechanisms of F. velutipes mycelia was complex and multifaceted, as it included varied functions such as rapid energy supply, the biosynthesis of lysine, phenylalanine, tyrosine, and γ-aminobutyric acid, the calcium signal transduction process, dynein-dependent actin and microtubule cytoskeleton formation, autolysis, oxidative stress adaptation, pigment secretion, tissue and organ morphogenesis, and other interesting stress-related processes. Insights into the proteins might shed light on an intuitive understanding of the cold and light stress response mechanism underlying the fruiting processes of F. velutipes. Furthermore, the data might also provide further insights into the stress response mechanism of macro-fungi and valuable information for scientific improvement of some mushroom cultivation techniques in practice.

Altered Topology in Information Processing of a Narrated Story in Older Adults with Mild Cognitive Impairment.

PubMed

Yogev-Seligmann, Galit; Oren, Noga; Ash, Elissa L; Hendler, Talma; Giladi, Nir; Lerner, Yulia

2016-05-03

The ability to store, integrate, and manipulate information declines with aging. These changes occur earlier, faster, and to a greater degree as a result of neurodegeneration. One of the most common and early characteristics of cognitive decline is difficulty with comprehension of information. The neural mechanisms underlying this breakdown of information processing are poorly understood. Using functional MRI and natural stimuli (e.g., stories), we mapped the neural mechanisms by which the human brain accumulates and processes information with increasing duration and complexity in participants with amnestic mild cognitive impairment (aMCI) and healthy older adults. To explore the mechanisms of information processing, we measured the reliability of brain responses elicited by listening to different versions of a narrated story created by segmenting the story into words, sentences, and paragraphs and then scrambling the segments. Comparing healthy older adults and participants with aMCI revealed that in both groups, all types of stimuli similarly recruited primary auditory areas. However, prominent differences between groups were found at the level of processing long and complex stimuli. In healthy older adults, parietal and frontal regions demonstrated highly synchronized responses in both the paragraph and full story conditions, as has been previously reported in young adults. Participants with aMCI, however, exhibited a robust functional shift of long time scale processing to the pre- and post-central sulci. Our results suggest that participants with aMCI experienced a functional shift of higher order auditory information processing, possibly reflecting a functional response to concurrent or impending neuronal or synaptic loss. This observation might assist in understanding mechanisms of cognitive decline in aMCI.

Processing of Communication Sounds: Contributions of Learning, Memory, and Experience

PubMed Central

Bigelow, James; Rossi, Breein

2013-01-01

Abundant evidence from both field and lab studies has established that conspecific vocalizations (CVs) are of critical ecological significance for a wide variety of species, including humans, nonhuman primates, rodents, and other mammals and birds. Correspondingly, a number of experiments have demonstrated behavioral processing advantages for CVs, such as in discrimination and memory tasks. Further, a wide range of experiments have described brain regions in many species that appear to be specialized for processing CVs. For example, several neural regions have been described in both mammals and birds wherein greater neural responses are elicited by CVs than by comparison stimuli such as heterospecific vocalizations, nonvocal complex sounds, and artificial stimuli. These observations raise the question of whether these regions reflect domain-specific neural mechanisms dedicated to processing CVs, or alternatively, if these regions reflect domain-general neural mechanisms for representing complex sounds of learned significance. Inasmuch as CVs can be viewed as complex combinations of basic spectrotemporal features, the plausibility of the latter position is supported by a large body of literature describing modulated cortical and subcortical representation of a variety of acoustic features that have been experimentally associated with stimuli of natural behavioral significance (such as food rewards). Herein, we review a relatively small body of existing literature describing the roles of experience, learning, and memory in the emergence of species-typical neural representations of CVs and auditory system plasticity. In both songbirds and mammals, manipulations of auditory experience as well as specific learning paradigms are shown to modulate neural responses evoked by CVs, either in terms of overall firing rate or temporal firing patterns. In some cases, CV-sensitive neural regions gradually acquire representation of non-CV stimuli with which subjects have training and experience. These results parallel literature in humans describing modulation of responses in face-sensitive neural regions through learning and experience. Thus, although many questions remain, the available evidence is consistent with the notion that CVs may acquire distinct neural representation through domain-general mechanisms for representing complex auditory objects that are of learned importance to the animal. PMID:23792078

Host-pathogen interplay in the respiratory environment of Cystic Fibrosis

PubMed Central

Hurley, Bryan P.; Bragonzi, Alessandra

2015-01-01

Significant advances have been made in the understanding of disease progression in cystic fibrosis (CF), revealing a complex interplay between host and pathogenic organisms. The diverse CF microbiota within the airway activates an aberrant immune response that is ineffective in clearing infection. An appreciation of how the CF host immune system interacts with these organisms is crucial to understanding the pathogenesis of CF pulmonary disease. Here we discuss the microbial complexity present in the lungs of individuals with CF, review emerging concepts of innate and adaptive immune responses to pathogens that chronically inhabit the CF lung, and discuss therapies that target the aberrant inflammatory response that characterizes CF. A greater understanding of the underlying mechanisms will shed light on pathogenesis and guide more targeted therapies in the future that serve to reduce infection, minimize lung pathology, and improve the quality of life for patients with CF. PMID:25800687

Constitutive Models Based on Compressible Plastic Flows

NASA Technical Reports Server (NTRS)

Rajendran, A. M.

1983-01-01

The need for describing materials under time or cycle dependent loading conditions has been emphasized in recent years by several investigators. In response to the need, various constitutive models describing the nonlinear behavior of materials under creep, fatigue, or other complex loading conditions were developed. The developed models for describing the fully dense (non-porous) materials were mostly based on uncoupled plasticity theory. The improved characterization of materials provides a better understanding of the structual response under complex loading conditions. The pesent studies demonstrate that the rate or time dependency of the response of a porous aggregate can be incorporated into the nonlinear constitutive behavior of a porous solid by appropriately modeling the incompressible matrix behavior. It is also sown that the yield function which wads determined by a continuum mechanics approach must be verified by appropriate experiments on void containing sintered materials in order to obtain meaningful numbers for the constants that appear in the yield function.

Learning to Link Visual Contours

PubMed Central

Li, Wu; Piëch, Valentin; Gilbert, Charles D.

2008-01-01

SUMMARY In complex visual scenes, linking related contour elements is important for object recognition. This process, thought to be stimulus driven and hard wired, has substrates in primary visual cortex (V1). Here, however, we find contour integration in V1 to depend strongly on perceptual learning and top-down influences that are specific to contour detection. In naive monkeys the information about contours embedded in complex backgrounds is absent in V1 neuronal responses, and is independent of the locus of spatial attention. Training animals to find embedded contours induces strong contour-related responses specific to the trained retinotopic region. These responses are most robust when animals perform the contour detection task, but disappear under anesthesia. Our findings suggest that top-down influences dynamically adapt neural circuits according to specific perceptual tasks. This may serve as a general neuronal mechanism of perceptual learning, and reflect top-down mediated changes in cortical states. PMID:18255036

Mechanical reinforcement and environmental effects on a nylon-6/clay nanocomposite

NASA Astrophysics Data System (ADS)

Shelley, J. Stebbins

2000-10-01

Hybridization, or modifying the organic polymers with inorganic constituents, is one method of achieving mechanical property improvements in polymeric materials while preserving processing characteristics. Toyota Central Research developed, and Ube Industries commercialized, one such hybrid nanocomposite: nylon-6/montmorillonite clay. This dissertation explores mechanisms of reinforcement in these nylon-6/clay nanocomposites and studies their degradation by atmospheric pollutants. A 100% improvement in modulus, 77% improvement in yield stress, and 54°C improvement in heat distortion temperature over nylon-6 were observed in extruded 5 wt% clay nanocomposite sheets. Infrared absorption spectrography and dynamic mechanical analysis were used to investigate the mechanisms of reinforcement in these nanocomposites. The improved mechanical properties, increased heat distortion temperature, reduced diffusion rate, and lower susceptibility to degradation in NO x observed where attributed to constraint of polymer chain motion by interaction with clay lamellae. Changes in the loss tangent peak in the glass transition region of the dynamic mechanical data provide an estimate of the volume of chains constrained by complexation of their mid-chain amide oxygen groups with the charged clay lamellae. X-ray analysis, optical microscopy, and light scattering were used to study changes in crystallization due to this complexation. Photomicrographs indicate that the morphology of the crystallites change from spherulitic to planar with the addition of clay. Decreases in diffusion rates of water and total water absorption were demonstrated in immersion experiments. Complexation of nylon-6 with 5 wt% clay reduces the total absorption of water by over 16%. The plane stress fracture toughness of extruded 5 wt% clay nanocomposite was 46% greater than that of nylon-6. The degradation of the nanocomposites in calcium chloride solution and NOx was examined through post exposure residual tensile and stress cracking experiments. CaCl 2 solution degraded the mechanical responses of the nanocomposite materials in proportion to the amount of water absorbed. NOx exposure degraded the mechanical performance regardless of the constraining effect of clay lamellae and the reduced diffusion rate in the nanocomposites. The stress cracking response of the nanocomposite in NOx (apparently not diffusion driven) resulted in a 650% increase in the time to failure of 5 wt% clay nanocomposites over unmodified nylon-6 for the same normalized stress intensity factor.

Structural, electronic, and optical properties of representative Cu-flavonoid complexes.

PubMed

Lekka, Ch E; Ren, Jun; Meng, Sheng; Kaxiras, Efthimios

2009-05-07

We present density functional theory (DFT) results on the structural, electronic, and optical properties of Cu-flavonoid complexes for molar ratios 1:1, 1:2, and 1:3. We find that the preferred chelating site is close to the 4-oxo group and in particular the 3-4 site followed by the 3'-4' dihydroxy group in ring B. For the Cu-quercetin complexes, the large bathochromic shift of the first absorbance band upon complexation, which is in good agreement with experimental UV-vis spectra, results from the reduction of the electronic energy gap. The HOMO states for these complexes are characterized by pi-bonding between the Cu d orbitals and the C, O p orbitals except for the case of 1:1 complex (spin minority), which corresponds to sigma-type bonds. The LUMO states are attributed to the contribution of Cu p(z) orbitals. Consequently, the main features of the first optical absorption maxima are essentially due to pi --> pi transitions, while the 1:1 complex exhibits also sigma --> pi transitions. Our optical absorption calculations based on time-dependent DFT demonstrate that the 1:1 complex is responsible for the spectroscopic features at pH 5.5, whereas the 1:2 complex is mainly the one responsible for the characteristic spectra at pH 7.4. These theoretical predictions explain in detail the behavior of the optical absorption for the Cu-flavonoid complexes observed in experiments and are thus useful in elucidating the complexation mechanism and antioxidant activity of flavonoids.

Essential hypertension: racial/ethnic differences in pathophysiology.

PubMed

Douglas, J G; Thibonnier, M; Wright, J T

1996-01-01

Essential hypertension is a complex polygenetic disorder with different "intermediate phenotypes" among diverse racial/ethnic groups. Differences have been identified in the renin-angiotensin system, prevalence of salt sensitivity, ion-transport mechanisms, and calcium homeostasis, yet no unifying hypothesis as to the genetic mechanisms responsible for the excess prevalence and severity of hypertension among African Americans has emerged. Environmental factors, such as access to health care, socioeconomic status, stress, diet, and obesity, account for some of the differences in the prevalence of hypertension worldwide.

Vaccinia virus decreases major histocompatibility complex (MHC) class II antigen presentation, T-cell priming, and peptide association with MHC class II

PubMed Central

Rehm, Kristina E; Connor, Ramsey F; Jones, Gwendolyn J B; Yimbu, Kenneth; Mannie, Mark D; Roper, Rachel L

2009-01-01

Vaccinia virus (VACV) is the current live virus vaccine used to protect humans against smallpox and monkeypox, but its use is contraindicated in several populations because of its virulence. It is therefore important to elucidate the immune evasion mechanisms of VACV. We found that VACV infection of antigen-presenting cells (APCs) significantly decreased major histocompatibility complex (MHC) II antigen presentation and decreased synthesis of 13 chemokines and cytokines, suggesting a potent viral mechanism for immune evasion. In these model systems, responding T cells were not directly affected by virus, indicating that VACV directly affects the APC. VACV significantly decreased nitric oxide production by peritoneal exudate cells and the RAW macrophage cell line in response to lipopolysaccharide (LPS) and interferon (IFN)-γ, decreased class II MHC expression on APCs, and induced apoptosis in macrophages and dendritic cells. However, VACV decreased antigen presentation by 1153 B cells without apparent apoptosis induction, indicating that VACV differentially affects B lymphocytes and other APCs. We show that the key mechanism of VACV inhibition of antigen presentation may be its reduction of antigenic peptide loaded into the cleft of MHC class II molecules. These data indicate that VACV evades the host immune response by impairing critical functions of the APC. PMID:20067538

A review of visual perception mechanisms that regulate rapid adaptive camouflage in cuttlefish.

PubMed

Chiao, Chuan-Chin; Chubb, Charles; Hanlon, Roger T

2015-09-01

We review recent research on the visual mechanisms of rapid adaptive camouflage in cuttlefish. These neurophysiologically complex marine invertebrates can camouflage themselves against almost any background, yet their ability to quickly (0.5-2 s) alter their body patterns on different visual backgrounds poses a vexing challenge: how to pick the correct body pattern amongst their repertoire. The ability of cuttlefish to change appropriately requires a visual system that can rapidly assess complex visual scenes and produce the motor responses-the neurally controlled body patterns-that achieve camouflage. Using specifically designed visual backgrounds and assessing the corresponding body patterns quantitatively, we and others have uncovered several aspects of scene variation that are important in regulating cuttlefish patterning responses. These include spatial scale of background pattern, background intensity, background contrast, object edge properties, object contrast polarity, object depth, and the presence of 3D objects. Moreover, arm postures and skin papillae are also regulated visually for additional aspects of concealment. By integrating these visual cues, cuttlefish are able to rapidly select appropriate body patterns for concealment throughout diverse natural environments. This sensorimotor approach of studying cuttlefish camouflage thus provides unique insights into the mechanisms of visual perception in an invertebrate image-forming eye.

Mediator, SWI/SNF and SAGA complexes regulate Yap8-dependent transcriptional activation of ACR2 in response to arsenate.

PubMed

Menezes, Regina Andrade; Pimentel, Catarina; Silva, Ana Rita Courelas; Amaral, Catarina; Merhej, Jawad; Devaux, Frédéric; Rodrigues-Pousada, Claudina

2017-04-01

Response to arsenic stress in Saccharomyces cerevisiae is orchestrated by the regulatory protein Yap8, which mediates transcriptional activation of ACR2 and ACR3. This study contributes to the state of art knowledge of the molecular mechanisms underlying yeast stress response to arsenate as it provides the genetic and biochemical evidences that Yap8, through cysteine residues 132, 137, and 274, is the sensor of presence of arsenate in the cytosol. Moreover, it is here reported for the first time the essential role of the Mediator complex in the transcriptional activation of ACR2 by Yap8. Based on our data, we propose an order-of-function map to recapitulate the sequence of events taking place in cells injured with arsenate. Modification of the sulfhydryl state of these cysteines converts Yap8 in its activated form, triggering the recruitment of the Mediator complex to the ACR2/ACR3 promoter, through the interaction with the tail subunit Med2. The Mediator complex then transfers the regulatory signals conveyed by Yap8 to the core transcriptional machinery, which culminates with TBP occupancy, ACR2 upregulation and cell adaptation to arsenate stress. Additional co-factors are required for the transcriptional activation of ACR2 by Yap8, particularly the nucleosome remodeling activity of SWI/SNF and SAGA complexes. Copyright © 2017. Published by Elsevier B.V.

Restoration of Tamoxifen Sensitivity in Estrogen Receptor–Negative Breast Cancer Cells: Tamoxifen-Bound Reactivated ER Recruits Distinctive Corepressor Complexes

PubMed Central

Sharma, Dipali; Saxena, Neeraj K.; Davidson, Nancy E.; Vertino, Paula M.

2010-01-01

Breast tumors expressing estrogen receptor-α (ER) respond well to therapeutic strategies using selective ER modulators, such as tamoxifen. However, ~ 30% of invasive breast cancers are hormone independent because they lack ER expression due to hypermethylation of ER promoter. Treatment of ER-negative breast cancer cells with demethylating agents [5-aza-2′-deoxycytidine (5-aza-dC)] and histone deacetylase (HDAC) inhibitors (trichostatin A) leads to expression of ER mRNA and functional protein. Here, we examined whether epigenetically reactivated ER is a target for tamoxifen therapy. Following treatment with trichostatin A and 5-aza-dC, the formerly unresponsive ER-negative MDA-MB-231 breast cancer cells became responsive to tamoxifen. Tamoxifen-mediated inhibition of cell growth in these cells is mediated at least in part by the tamoxifen-bound ER. Tamoxifen-bound reactivated ER induces transcriptional repression at estrogen-responsive genes by ordered recruitment of multiple distinct chromatin-modifying complexes. Using chromatin immunoprecipitation, we show recruitment of two different corepressor complexes to ER-responsive promoters in a mutually exclusive and sequential manner: the nuclear receptor corepressor-HDAC3 complex followed by nucleosome remodeling and histone deacetylation complex. The mechanistic insight provided by this study might help in designing therapeutic strategies directed toward epigenetic mechanisms in the prevention or treatment of breast cancer. PMID:16778215

Intracellular delivery of universal proteins using a lysine headgroup containing cationic liposomes: deciphering the uptake mechanism.

PubMed

Sarker, Satya Ranjan; Hokama, Ryosuke; Takeoka, Shinji

2014-01-06

An amino acid-based cationic lipid having a TFA counterion (trifluoroacetic acid counterion) in the lysine headgroup was used to deliver functional proteins into human cervical cancer cells, HeLa, in the presence of serum. Proteins used in the study were fluorescein isothiocyanate (FITC) labeled bovine serum albumin, mouse anti-F actin antibody [NH3], and goat anti mouse IgG conjugated with FITC. The formation of liposome/protein complexes was confirmed using native polyacrylamide gel electrophoresis. Furthermore, the complexes were characterized in terms of their size and zeta potential at different pH values and found to be responsive to changes in pH. The highest delivery efficiency of the liposome/albumin complexes was 99% at 37 °C. The liposomes effectively delivered albumin and antibodies as confirmed by confocal laser scanning microscopy (CLSM). Inhibition studies showed that the cellular uptake mechanism of the complexes was via caveolae-mediated endocytosis, and the proteins were subsequently released from either the early endosomes or the caveosomes as suggested by CLSM. Thus, lysine-based cationic liposomes can be a useful tool for intracellular protein delivery.

Topics in Complexity: From Physical to Life Science Systems

NASA Astrophysics Data System (ADS)

Charry, Pedro David Manrique

Complexity seeks to unwrap the mechanisms responsible for collective phenomena across the physical, biological, chemical, economic and social sciences. This thesis investigates real-world complex dynamical systems ranging from the quantum/natural domain to the social domain. The following novel understandings are developed concerning these systems' out-of-equilibrium and nonlinear behavior. Standard quantum techniques show divergent outcomes when a quantum system comprising more than one subunit is far from thermodynamic equilibrium. Abnormal photon inter-arrival times help fulfill the metabolic needs of a terrestrial photosynthetic bacterium. Spatial correlations within incident light can act as a driving mechanism for an organism's adaptation toward more ordered structures. The group dynamics of non-identical objects, whose assembly rules depend on mutual heterogeneity, yield rich transition dynamics between isolation and cohesion, with the cohesion regime reproducing a particular universal pattern commonly found in many real-world systems. Analyses of covert networks reveal collective gender superiority in the connectivity that provides benefits for system robustness and survival. Nodal migration in a network generates complex contagion profiles that lie beyond traditional approaches and yet resemble many modern-day outbreaks.

Cell Cycle Regulators Guide Mitochondrial Activity in Radiation-Induced Adaptive Response

PubMed Central

Alexandrou, Aris T.

2014-01-01

Abstract Significance: There are accruing concerns on potential genotoxic agents present in the environment including low-dose ionizing radiation (LDIR) that naturally exists on earth's surface and atmosphere and is frequently used in medical diagnosis and nuclear industry. Although its long-term health risk is being evaluated and remains controversial, LDIR is shown to induce temporary but significant adaptive responses in mammalian cells and animals. The mechanisms guiding the mitochondrial function in LDIR-induced adaptive response represent a unique communication between DNA damage and cellular metabolism. Elucidation of the LDIR-regulated mitochondrial activity may reveal new mechanisms adjusting cellular function to cope with hazardous environmental stress. Recent Advances: Key cell cycle regulators, including Cyclin D1/CDK4 and Cyclin B1/cyclin-dependent kinase 1 (CDK1) complexes, are actively involved in the regulation of mitochondrial functions via phosphorylation of their mitochondrial targets. Accumulating new evidence supports a concept that the Cyclin B1/CDK1 complex acts as a mediator in the cross talk between radiation-induced DNA damage and mitochondrial functions to coordinate cellular responses to low-level genotoxic stresses. Critical Issues: The LDIR-mediated mitochondrial activity via Cyclin B1/CDK1 regulation is an irreplaceable network that is able to harmonize vital cellular functions with adjusted mitochondrial metabolism to enhance cellular homeostasis. Future Directions: Further investigation of the coordinative mechanism that regulates mitochondrial activities in sublethal stress conditions, including LDIR, will reveal new insights of how cells cope with genotoxic injury and will be vital for future targeted therapeutic interventions that reduce environmental injury and cancer risk. Antioxid. Redox Signal. 20, 1463–1480. PMID:24180340

Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish

PubMed Central

Goodale, Britton C.; Tilton, Susan C.; Wilson, Glenn; Corvi, Margaret M.; Janszen, Derek B.; Anderson, Kim A.; Waters, Katrina M.; Tanguay, Robert L.

2014-01-01

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. These multi-ring chemicals differentially activate the Aryl Hydrocarbon Receptor (AHR) in a structurally dependent manner, and induce toxicity via both AHR-dependent and-independent mechanisms. PAH exposure is known to induce developmental malformations in zebrafish embryos, and recent studies have shown cardiac toxicity induced by compounds with low AHR affinity. Unraveling the potentially diverse molecular mechanisms of PAH toxicity is essential for understanding the hazard posed by complex PAH mixtures present in the environment. We analyzed transcriptional responses to PAH exposure in zebrafish embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR) at concentrations that induced developmental malformations by 120 hours post-fertilization (hpf). Whole genome microarray analysis of mRNA expression at 24 and 48 hpf identified genes that were differentially regulated over time and in response to the three PAH structures. PAH body burdens were analyzed at both time points using GC-MS, and demonstrated differences in PAH uptake into the embryos. This was important for discerning dose-related differences from those that represented unique molecular mechanisms. While BAA misregulated the least number of transcripts, it caused strong induction of cyp1a and other genes known to be downstream of the AHR, which were not induced by the other two PAHs. Analysis of functional roles of misregulated genes and their predicted regulatory transcription factors also distinguished the BAA response from regulatory networks disrupted by DBT and PYR exposure. These results indicate that systems approaches can be used to classify the toxicity of PAHs based on the networks perturbed following exposure, and may provide a path for unraveling the toxicity of complex PAH mixtures. PMID:23656968

Genome-wide analysis of ABA-responsive elements ABRE and CE3 reveals divergent patterns in Arabidopsis and rice

PubMed Central

Gómez-Porras, Judith L; Riaño-Pachón, Diego Mauricio; Dreyer, Ingo; Mayer, Jorge E; Mueller-Roeber, Bernd

2007-01-01

Background In plants, complex regulatory mechanisms are at the core of physiological and developmental processes. The phytohormone abscisic acid (ABA) is involved in the regulation of various such processes, including stomatal closure, seed and bud dormancy, and physiological responses to cold, drought and salinity stress. The underlying tissue or plant-wide control circuits often include combinatorial gene regulatory mechanisms and networks that we are only beginning to unravel with the help of new molecular tools. The increasing availability of genomic sequences and gene expression data enables us to dissect ABA regulatory mechanisms at the individual gene expression level. In this paper we used an in-silico-based approach directed towards genome-wide prediction and identification of specific features of ABA-responsive elements. In particular we analysed the genome-wide occurrence and positional arrangements of two well-described ABA-responsive cis-regulatory elements (CREs), ABRE and CE3, in thale cress (Arabidopsis thaliana) and rice (Oryza sativa). Results Our results show that Arabidopsis and rice use the ABA-responsive elements ABRE and CE3 distinctively. Earlier reports for various monocots have identified CE3 as a coupling element (CE) associated with ABRE. Surprisingly, we found that while ABRE is equally abundant in both species, CE3 is practically absent in Arabidopsis. ABRE-ABRE pairs are common in both genomes, suggesting that these can form functional ABA-responsive complexes (ABRCs) in Arabidopsis and rice. Furthermore, we detected distinct combinations, orientation patterns and DNA strand preferences of ABRE and CE3 motifs in rice gene promoters. Conclusion Our computational analyses revealed distinct recruitment patterns of ABA-responsive CREs in upstream sequences of Arabidopsis and rice. The apparent absence of CE3s in Arabidopsis suggests that another CE pairs with ABRE to establish a functional ABRC capable of interacting with transcription factors. Further studies will be needed to test whether the observed differences are extrapolatable to monocots and dicots in general, and to understand how they contribute to the fine-tuning of the hormonal response. The outcome of our investigation can now be used to direct future experimentation designed to further dissect the ABA-dependent regulatory networks. PMID:17672917

Genome-wide analysis of ABA-responsive elements ABRE and CE3 reveals divergent patterns in Arabidopsis and rice.

PubMed

Gómez-Porras, Judith L; Riaño-Pachón, Diego Mauricio; Dreyer, Ingo; Mayer, Jorge E; Mueller-Roeber, Bernd

2007-08-01

In plants, complex regulatory mechanisms are at the core of physiological and developmental processes. The phytohormone abscisic acid (ABA) is involved in the regulation of various such processes, including stomatal closure, seed and bud dormancy, and physiological responses to cold, drought and salinity stress. The underlying tissue or plant-wide control circuits often include combinatorial gene regulatory mechanisms and networks that we are only beginning to unravel with the help of new molecular tools. The increasing availability of genomic sequences and gene expression data enables us to dissect ABA regulatory mechanisms at the individual gene expression level. In this paper we used an in-silico-based approach directed towards genome-wide prediction and identification of specific features of ABA-responsive elements. In particular we analysed the genome-wide occurrence and positional arrangements of two well-described ABA-responsive cis-regulatory elements (CREs), ABRE and CE3, in thale cress (Arabidopsis thaliana) and rice (Oryza sativa). Our results show that Arabidopsis and rice use the ABA-responsive elements ABRE and CE3 distinctively. Earlier reports for various monocots have identified CE3 as a coupling element (CE) associated with ABRE. Surprisingly, we found that while ABRE is equally abundant in both species, CE3 is practically absent in Arabidopsis. ABRE-ABRE pairs are common in both genomes, suggesting that these can form functional ABA-responsive complexes (ABRCs) in Arabidopsis and rice. Furthermore, we detected distinct combinations, orientation patterns and DNA strand preferences of ABRE and CE3 motifs in rice gene promoters. Our computational analyses revealed distinct recruitment patterns of ABA-responsive CREs in upstream sequences of Arabidopsis and rice. The apparent absence of CE3s in Arabidopsis suggests that another CE pairs with ABRE to establish a functional ABRC capable of interacting with transcription factors. Further studies will be needed to test whether the observed differences are extrapolatable to monocots and dicots in general, and to understand how they contribute to the fine-tuning of the hormonal response. The outcome of our investigation can now be used to direct future experimentation designed to further dissect the ABA-dependent regulatory networks.

Dynamics of the DNA damage response: insights from live-cell imaging

PubMed Central

Karanam, Ketki; Loewer, Alexander

2013-01-01

All organisms have to safeguard the integrity of their genome to prevent malfunctioning and oncogenic transformation. Sophisticated DNA damage response mechanisms have evolved to detect and repair genomic lesions. With the emergence of live-cell microscopy of individual cells, we now begin to appreciate the complex spatiotemporal kinetics of the DNA damage response and can address the causes and consequences of the heterogeneity in the responses of genetically identical cells. Here, we highlight key discoveries where live-cell imaging has provided unprecedented insights into how cells respond to DNA double-strand breaks and discuss the main challenges and promises in using this technique. PMID:23292635

CD1d-restricted immunoglobulin G formation to GPI-anchored antigens mediated by NKT cells.

PubMed

Schofield, L; McConville, M J; Hansen, D; Campbell, A S; Fraser-Reid, B; Grusby, M J; Tachado, S D

1999-01-08

Immunoglobulin G (IgG) responses require major histocompatibility complex (MHC)-restricted recognition of peptide fragments by conventional CD4(+) helper T cells. Immunoglobulin G responses to glycosylphosphatidylinositol (GPI)- anchored protein antigens, however, were found to be regulated in part through CD1d-restricted recognition of the GPI moiety by thymus-dependent, interleukin-4-producing CD4(+), natural killer cell antigen 1.1 [(NK1.1)+] helper T cells. The CD1-NKT cell pathway regulated immunogobulin G responses to the GPI-anchored surface antigens of Plasmodium and Trypanosoma and may be a general mechanism for rapid, MHC-unrestricted antibody responses to diverse pathogens.

Normalization of cell responses in cat striate cortex

NASA Technical Reports Server (NTRS)

Heeger, D. J.

1992-01-01

Simple cells in the striate cortex have been depicted as half-wave-rectified linear operators. Complex cells have been depicted as energy mechanisms, constructed from the squared sum of the outputs of quadrature pairs of linear operators. However, the linear/energy model falls short of a complete explanation of striate cell responses. In this paper, a modified version of the linear/energy model is presented in which striate cells mutually inhibit one another, effectively normalizing their responses with respect to stimulus contrast. This paper reviews experimental measurements of striate cell responses, and shows that the new model explains a significantly larger body of physiological data.

Psp Stress Response Proteins Form a Complex with Mislocalized Secretins in the Yersinia enterocolitica Cytoplasmic Membrane.

PubMed

Srivastava, Disha; Moumene, Amal; Flores-Kim, Josué; Darwin, Andrew J

2017-09-12

The bacterial phage shock protein system (Psp) is a conserved extracytoplasmic stress response that is essential for the virulence of some pathogens, including Yersinia enterocolitica It is induced by events that can compromise inner membrane (IM) integrity, including the mislocalization of outer membrane pore-forming proteins called secretins. In the absence of the Psp system, secretin mislocalization permeabilizes the IM and causes rapid cell death. The Psp proteins PspB and PspC form an integral IM complex with two independent roles. First, the PspBC complex is required to activate the Psp response in response to some inducing triggers, including a mislocalized secretin. Second, PspBC are sufficient to counteract mislocalized secretin toxicity. Remarkably, secretin mislocalization into the IM induces psp gene expression without significantly affecting the expression of any other genes. Furthermore, psp null strains are killed by mislocalized secretins, whereas no other null mutants have been found to share this specific secretin sensitivity. This suggests an exquisitely specific relationship between secretins and the Psp system, but there has been no mechanism described to explain this. In this study, we addressed this deficiency by using a coimmunoprecipitation approach to show that the Psp proteins form a specific complex with mislocalized secretins in the Y. enterocolitica IM. Importantly, analysis of different secretin mutant proteins also revealed that this interaction is absolutely dependent on a secretin adopting a multimeric state. Therefore, the Psp system has evolved with the ability to detect and detoxify dangerous secretin multimers while ignoring the presence of innocuous monomers. IMPORTANCE The phage shock protein (Psp) response has been linked to important phenotypes in diverse bacteria, including those related to antibiotic resistance, biofilm formation, and virulence. This has generated widespread interest in understanding various aspects of its function. Outer membrane secretin proteins are essential components of export systems required for the virulence of many bacterial pathogens. However, secretins can mislocalize into the inner membrane, and this induces the Psp response in a highly specific manner and kills Psp-defective strains with similar specificity. There has been no mechanism described to explain this exquisitely specific relationship between secretins and the Psp system. Therefore, this study provides a critical advance by discovering that Psp effector proteins form a complex with secretins in the Yersinia enterocolitica inner membrane. Remarkably, this interaction is absolutely dependent on a secretin adopting its multimeric state. Therefore, the Psp system detects and detoxifies dangerous secretin multimers, while ignoring the presence of innocuous secretin monomers. Copyright © 2017 Srivastava et al.

Employability and Higher Education: Contextualising Female Students' Workplace Experiences to Enhance Understanding of Employability Development

ERIC Educational Resources Information Center

Gracia, Louise

2009-01-01

Current political and economic discourses position employability as a responsibility of higher education, which deploys mechanisms such as supervised work experience (SWE) to embed employability skills development into the undergraduate curriculum. However, workplaces are socially constructed complex arenas of embodied knowledge that are gendered.…

Divergent Electrocardiographic Responses to Whole and Particle-Free Diesel Exhaust Inhalation in Spontaneously Hypertensive Rats

EPA Science Inventory

Diesel exhaust (DE) is a major contributor to traffic-related fine PM2.5. While inroads have been made in understanding the mechanisms of PM related health effects, DE’s complex mixture of PM, gases and volatile organics makes it difficult to determine how the constituents contri...

Single Event Effects (SEE) for Power Metal-Oxide-Semiconductor Field-Effect Transistors (MOSFETs)

NASA Technical Reports Server (NTRS)

Lauenstein, Jean-Marie

2011-01-01

Single-event gate rupture (SEGR) continues to be a key failure mode in power MOSFETs. (1) SEGR is complex, making rate prediction difficult SEGR mechanism has two main components: (1) Oxide damage-- Reduces field required for rupture (2) Epilayer response -- Creates transient high field across the oxide.

Cross-linking staphylococcal enterotoxin A bound to major histocompatibility complex class I is required for TNF-alpha secretion

NASA Technical Reports Server (NTRS)

Wright, A. D.; Chapes, S. K.

1999-01-01

The mechanism of how superantigens function to activate cells has been linked to their ability to bind and cross-link the major histocompatibility complex class II (MHCII) molecule. Cells that lack the MHCII molecule also respond to superantigens, however, with much less efficiency. Therefore, the purpose of this study was to confirm that staphylococcal enterotoxin A (SEA) could bind the MHCI molecule and to test the hypothesis that cross-linking SEA bound to MHCII-deficient macrophages would induce a more robust cytokine response than without cross-linking. We used a capture enzyme-linked immunosorbent assay and an immunprecipitation assay to directly demonstrate that MHCI molecules bind SEA. Directly cross-linking MHCI using monoclonal antibodies or cross-linking bound SEA with an anti-SEA antibody or biotinylated SEA with avidin increased TNF-alpha and IL-6 secretion by MHCII(-/-) macrophages. The induction of a vigorous macrophage cytokine response by SEA/anti-SEA cross-linking of MHCI offers a mechanism to explain how MHCI could play an important role in superantigen-mediated pathogenesis. Copyright 1999 Academic Press.

3D-Printing of Meso-structurally Ordered Carbon Fiber/Polymer Composites with Unprecedented Orthotropic Physical Properties

NASA Astrophysics Data System (ADS)

Lewicki, James P.; Rodriguez, Jennifer N.; Zhu, Cheng; Worsley, Marcus A.; Wu, Amanda S.; Kanarska, Yuliya; Horn, John D.; Duoss, Eric B.; Ortega, Jason M.; Elmer, William; Hensleigh, Ryan; Fellini, Ryan A.; King, Michael J.

2017-03-01

Here we report the first example of a class of additively manufactured carbon fiber reinforced composite (AMCFRC) materials which have been achieved through the use of a latent thermal cured aromatic thermoset resin system, through an adaptation of direct ink writing (DIW) 3D-printing technology. We have developed a means of printing high performance thermoset carbon fiber composites, which allow the fiber component of a resin and carbon fiber fluid to be aligned in three dimensions via controlled micro-extrusion and subsequently cured into complex geometries. Characterization of our composite systems clearly show that we achieved a high order of fiber alignment within the composite microstructure, which in turn allows these materials to outperform equivalently filled randomly oriented carbon fiber and polymer composites. Furthermore, our AM carbon fiber composite systems exhibit highly orthotropic mechanical and electrical responses as a direct result of the alignment of carbon fiber bundles in the microscale which we predict will ultimately lead to the design of truly tailorable carbon fiber/polymer hybrid materials having locally programmable complex electrical, thermal and mechanical response.

The regulations and role of circadian clock and melatonin in uterine receptivity and pregnancy-An immunological perspective.

PubMed

Man, Gene Chi Wai; Zhang, Tao; Chen, Xiaoyan; Wang, Jianzhang; Wu, Fangrong; Liu, Yingyu; Wang, Chi Chiu; Cheong, Ying; Li, Tin Chiu

2017-08-01

During normal pregnancy, the mechanism by which the fetus escapes immunological rejection by the maternal womb remains elusive. Given the biological complexities, the immunological mechanism is unlikely to be simply an allograft response in acceptance or rejection of the early pregnancy. Circadian clock responsible for the mammalian circadian rhythm is an endogenously generated rhythm associated with almost all physiological processes including reproduction. There is now growing evidence to suggest that the circadian clocks are intricately linked to the immune system and pregnancy. When perturbed, the role of immune cells can be affected on maintaining the enriched vascular system needed for placentation. This alteration can be triggered by the irregular production of maternal and placental melatonin. Hence, the role of circadian rhythm modulators such as melatonin offers intriguing opportunities for therapy. In this review, we evaluate the complex interaction between the circadian clock and melatonin within the immune system and their roles in the circadian regulation and maintenance of normal pregnancy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

3D-Printing of Meso-structurally Ordered Carbon Fiber/Polymer Composites with Unprecedented Orthotropic Physical Properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewicki, James P.; Rodriguez, Jennifer N.; Zhu, Cheng

Here we report the first example of a class of additively manufactured carbon fiber reinforced composite (AMCFRC) materials which have been achieved through the use of a latent thermal cured aromatic thermoset resin system, through an adaptation of direct ink writing (DIW) 3D-printing technology. We have developed a means of printing high performance thermoset carbon fiber composites, which allow the fiber component of a resin and carbon fiber fluid to be aligned in three dimensions via controlled micro-extrusion and subsequently cured into complex geometries. Characterization of our composite systems clearly show that we achieved a high order of fiber alignmentmore » within the composite microstructure, which in turn allows these materials to outperform equivalently filled randomly oriented carbon fiber and polymer composites. Moreover, our AM carbon fiber composite systems exhibit highly orthotropic mechanical and electrical responses as a direct result of the alignment of carbon fiber bundles in the microscale which we predict will ultimately lead to the design of truly tailorable carbon fiber/polymer hybrid materials having locally programmable complex electrical, thermal and mechanical response.« less

A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

NASA Astrophysics Data System (ADS)

Xu, Hui; Li, Zhongyu; Yu, Yue; Sizdahkhani, Saman; Ho, Winson S.; Yin, Fangchao; Wang, Li; Zhu, Guoli; Zhang, Min; Jiang, Lei; Zhuang, Zhengping; Qin, Jianhua

2016-11-01

The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes-permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research.

3D-Printing of Meso-structurally Ordered Carbon Fiber/Polymer Composites with Unprecedented Orthotropic Physical Properties

DOE PAGES

Lewicki, James P.; Rodriguez, Jennifer N.; Zhu, Cheng; ...

2017-03-06

Here we report the first example of a class of additively manufactured carbon fiber reinforced composite (AMCFRC) materials which have been achieved through the use of a latent thermal cured aromatic thermoset resin system, through an adaptation of direct ink writing (DIW) 3D-printing technology. We have developed a means of printing high performance thermoset carbon fiber composites, which allow the fiber component of a resin and carbon fiber fluid to be aligned in three dimensions via controlled micro-extrusion and subsequently cured into complex geometries. Characterization of our composite systems clearly show that we achieved a high order of fiber alignmentmore » within the composite microstructure, which in turn allows these materials to outperform equivalently filled randomly oriented carbon fiber and polymer composites. Moreover, our AM carbon fiber composite systems exhibit highly orthotropic mechanical and electrical responses as a direct result of the alignment of carbon fiber bundles in the microscale which we predict will ultimately lead to the design of truly tailorable carbon fiber/polymer hybrid materials having locally programmable complex electrical, thermal and mechanical response.« less

The informativity of sound modulates crossmodal facilitation of visual discrimination: a fMRI study.

PubMed

Li, Qi; Yu, Hongtao; Li, Xiujun; Sun, Hongzan; Yang, Jingjing; Li, Chunlin

2017-01-18

Many studies have investigated behavioral crossmodal facilitation when a visual stimulus is accompanied by a concurrent task-irrelevant sound. Lippert and colleagues reported that a concurrent task-irrelevant sound reduced the uncertainty of the timing of the visual display and improved perceptional responses (informative sound). However, the neural mechanism by which the informativity of sound affected crossmodal facilitation of visual discrimination remained unclear. In this study, we used event-related functional MRI to investigate the neural mechanisms underlying the role of informativity of sound in crossmodal facilitation of visual discrimination. Significantly faster reaction times were observed when there was an informative relationship between auditory and visual stimuli. The functional MRI results showed sound informativity-induced activation enhancement including the left fusiform gyrus and the right lateral occipital complex. Further correlation analysis showed that the right lateral occipital complex was significantly correlated with the behavioral benefit in reaction times. This suggests that this region was modulated by the informative relationship within audiovisual stimuli that was learnt during the experiment, resulting in late-stage multisensory integration and enhanced behavioral responses.

3D-Printing of Meso-structurally Ordered Carbon Fiber/Polymer Composites with Unprecedented Orthotropic Physical Properties.

PubMed

Lewicki, James P; Rodriguez, Jennifer N; Zhu, Cheng; Worsley, Marcus A; Wu, Amanda S; Kanarska, Yuliya; Horn, John D; Duoss, Eric B; Ortega, Jason M; Elmer, William; Hensleigh, Ryan; Fellini, Ryan A; King, Michael J

2017-03-06

Here we report the first example of a class of additively manufactured carbon fiber reinforced composite (AMCFRC) materials which have been achieved through the use of a latent thermal cured aromatic thermoset resin system, through an adaptation of direct ink writing (DIW) 3D-printing technology. We have developed a means of printing high performance thermoset carbon fiber composites, which allow the fiber component of a resin and carbon fiber fluid to be aligned in three dimensions via controlled micro-extrusion and subsequently cured into complex geometries. Characterization of our composite systems clearly show that we achieved a high order of fiber alignment within the composite microstructure, which in turn allows these materials to outperform equivalently filled randomly oriented carbon fiber and polymer composites. Furthermore, our AM carbon fiber composite systems exhibit highly orthotropic mechanical and electrical responses as a direct result of the alignment of carbon fiber bundles in the microscale which we predict will ultimately lead to the design of truly tailorable carbon fiber/polymer hybrid materials having locally programmable complex electrical, thermal and mechanical response.

3D-Printing of Meso-structurally Ordered Carbon Fiber/Polymer Composites with Unprecedented Orthotropic Physical Properties

PubMed Central

Lewicki, James P.; Rodriguez, Jennifer N.; Zhu, Cheng; Worsley, Marcus A.; Wu, Amanda S.; Kanarska, Yuliya; Horn, John D.; Duoss, Eric B.; Ortega, Jason M.; Elmer, William; Hensleigh, Ryan; Fellini, Ryan A.; King, Michael J.

2017-01-01

Here we report the first example of a class of additively manufactured carbon fiber reinforced composite (AMCFRC) materials which have been achieved through the use of a latent thermal cured aromatic thermoset resin system, through an adaptation of direct ink writing (DIW) 3D-printing technology. We have developed a means of printing high performance thermoset carbon fiber composites, which allow the fiber component of a resin and carbon fiber fluid to be aligned in three dimensions via controlled micro-extrusion and subsequently cured into complex geometries. Characterization of our composite systems clearly show that we achieved a high order of fiber alignment within the composite microstructure, which in turn allows these materials to outperform equivalently filled randomly oriented carbon fiber and polymer composites. Furthermore, our AM carbon fiber composite systems exhibit highly orthotropic mechanical and electrical responses as a direct result of the alignment of carbon fiber bundles in the microscale which we predict will ultimately lead to the design of truly tailorable carbon fiber/polymer hybrid materials having locally programmable complex electrical, thermal and mechanical response. PMID:28262669

Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes

PubMed Central

Cheng, Tsing; Orlow, Seth J.; Manga, Prashiela

2013-01-01

Summary Accumulation of proteins in the endoplasmic reticulum (ER) typically induces stress and initiates the unfolded protein response (UPR) to facilitate recovery. If homeostasis is not restored, apoptosis is induced. However, adaptation to chronic UPR activation can increase resistance to subsequent acute ER stress. We therefore investigated adaptive mechanisms in Oculocutaneous albinism type 2 (Oca2)-null melanocytes where UPR signaling is arrested despite continued tyrosinase accumulation leading to resistance to the chemical ER stressor thapsigargin. Although thapsigargin triggers UPR activation, instead of Perk-mediated phosphorylation of eIF2α, in Oca2-null melanocytes, eIF2α was rapidly dephosphorylated upon treatment. Dephosphorylation was mediated by the Gadd34-PP1α phosphatase complex. Gadd34-complex inhibition blocked eIF2α dephosphorylation and significantly increased Oca2-null melanocyte sensitivity to thapsigargin. Thus, Oca2-null melanocytes adapt to acute ER stress by disruption of proapoptotic Perk signaling, which promotes cell survival. This is the first study to demonstrate rapid eIF2α dephosphorylation as an adaptive mechanism to ER stress. PMID:23962237

Multiscale mechanical integrity of human supraspinatus tendon in shear after elastin depletion.

PubMed

Fang, Fei; Lake, Spencer P

2016-10-01

Human supraspinatus tendon (SST) exhibits region-specific nonlinear mechanical properties under tension, which have been attributed to its complex multiaxial physiological loading environment. However, the mechanical response and underlying multiscale mechanism regulating SST behavior under other loading scenarios are poorly understood. Furthermore, little is known about the contribution of elastin to tendon mechanics. We hypothesized that (1) SST exhibits region-specific shear mechanical properties, (2) fiber sliding is the predominant mode of local matrix deformation in SST in shear, and (3) elastin helps maintain SST mechanical integrity by facilitating force transfer among collagen fibers. Through the use of biomechanical testing and multiphoton microscopy, we measured the multiscale mechanical behavior of human SST in shear before and after elastase treatment. Three distinct SST regions showed similar stresses and microscale deformation. Collagen fiber reorganization and sliding were physical mechanisms observed as the SST response to shear loading. Measures of microscale deformation were highly variable, likely due to a high degree of extracellular matrix heterogeneity. After elastase treatment, tendon exhibited significantly decreased stresses under shear loading, particularly at low strains. These results show that elastin contributes to tendon mechanics in shear, further complementing our understanding of multiscale tendon structure-function relationships. Copyright © 2016 Elsevier Ltd. All rights reserved.

Possible role of interference, protein noise, and sink effects in nonphotochemical quenching in photosynthetic complexes.

PubMed

Berman, Gennady P; Nesterov, Alexander I; Gurvitz, Shmuel; Sayre, Richard T

2017-01-01

We analyze theoretically a simple and consistent quantum mechanical model that reveals the possible role of quantum interference, protein noise, and sink effects in the nonphotochemical quenching (NPQ) in light-harvesting complexes (LHCs). The model consists of a network of five interconnected sites (excitonic states of light-sensitive molecules) responsible for the NPQ mechanism. The model also includes the "damaging" and the dissipative channels. The damaging channel is responsible for production of singlet oxygen and other destructive outcomes. In our model, both damaging and "dissipative" charge transfer channels are described by discrete electron energy levels attached to their sinks, that mimic the continuum part of electron energy spectrum. All five excitonic sites interact with the protein environment that is modeled using a stochastic process. Our approach allowed us to derive the exact and closed system of linear ordinary differential equations for the reduced density matrix and its first momentums. These equations are solved numerically including for strong interactions between the light-sensitive molecules and protein environment. As an example, we apply our model to demonstrate possible contributions of quantum interference, protein noise, and sink effects in the NPQ mechanism in the CP29 minor LHC. The numerical simulations show that using proper combination of quantum interference effects, properties of noise, and sinks, one can significantly suppress the damaging channel. Our findings demonstrate the possible role of interference, protein noise, and sink effects for modeling, engineering, and optimizing the performance of the NPQ processes in both natural and artificial light-harvesting complexes.

Possible role of interference, protein noise, and sink effects in nonphotochemical quenching in photosynthetic complexes

DOE PAGES

Berman, Gennady P.; Nesterov, Alexander I.; Gurvitz, Shmuel; ...

2016-04-30

Here, we analyze theoretically a simple and consistent quantum mechanical model that reveals the possible role of quantum interference, protein noise, and sink effects in the nonphotochemical quenching (NPQ) in light-harvesting complexes (LHCs). The model consists of a network of five interconnected sites (excitonic states of light-sensitive molecules) responsible for the NPQ mechanism. The model also includes the “damaging” and the dissipative channels. The damaging channel is responsible for production of singlet oxygen and other destructive outcomes. In this model, both damaging and “dissipative” charge transfer channels are described by discrete electron energy levels attached to their sinks, that mimicmore » the continuum part of electron energy spectrum. All five excitonic sites interact with the protein environment that is modeled using a stochastic process. Our approach allowed us to derive the exact and closed system of linear ordinary differential equations for the reduced density matrix and its first momentums. Moreover, these equations are solved numerically including for strong interactions between the light-sensitive molecules and protein environment. As an example, we apply our model to demonstrate possible contributions of quantum interference, protein noise, and sink effects in the NPQ mechanism in the CP29 minor LHC. The numerical simulations show that using proper combination of quantum interference effects, properties of noise, and sinks, one can significantly suppress the damaging channel. Finally, our findings demonstrate the possible role of interference, protein noise, and sink effects for modeling, engineering, and optimizing the performance of the NPQ processes in both natural and artificial light-harvesting complexes.« less

Parasitoids select plants more heavily infested with their caterpillar hosts: a new approach to aid interpretation of plant headspace volatiles

PubMed Central

Girling, Robbie D.; Stewart-Jones, Alex; Dherbecourt, Julie; Staley, Joanna T.; Wright, Denis J.; Poppy, Guy M.

2011-01-01

Plants produce volatile organic compounds (VOCs) in response to herbivore attack, and these VOCs can be used by parasitoids of the herbivore as host location cues. We investigated the behavioural responses of the parasitoid Cotesia vestalis to VOCs from a plant–herbivore complex consisting of cabbage plants (Brassica oleracea) and the parasitoids host caterpillar, Plutella xylostella. A Y-tube olfactometer was used to compare the parasitoids' responses to VOCs produced as a result of different levels of attack by the caterpillar and equivalent levels of mechanical damage. Headspace VOC production by these plant treatments was examined using gas chromatography–mass spectrometry. Cotesia vestalis were able to exploit quantitative and qualitative differences in volatile emissions, from the plant–herbivore complex, produced as a result of different numbers of herbivores feeding. Cotesia vestalis showed a preference for plants with more herbivores and herbivore damage, but did not distinguish between different levels of mechanical damage. Volatile profiles of plants with different levels of herbivores/herbivore damage could also be separated by canonical discriminant analyses. Analyses revealed a number of compounds whose emission increased significantly with herbivore load, and these VOCs may be particularly good indicators of herbivore number, as the parasitoid processes cues from its external environment. PMID:21270031

Have we been asking the right questions when assessing response inhibition in go/no-go tasks with fMRI? A meta-analysis and critical review.

PubMed

Criaud, Marion; Boulinguez, Philippe

2013-01-01

The popular go/no-go paradigm is supposed to ensure a reliable probing of response inhibition mechanisms. Functional magnetic resonance imaging (fMRI) studies have repeatedly found a large number of structures, usually including a right lateralized parieto-frontal network and the pre-supplementary motor area (pre-SMA). However, it is unlikely that all these regions are directly related to the mechanism that actively suppresses the motor command. Since most go/no-go designs involve complex stimulus identification/detection processes, these activations may rather reflect the engagement of different cognitive processes that are intrinsically related and quite difficult to disentangle. The current critical review is based on repeated meta-analyses of 30 go/no-go fMRI experiments using the Activation Likelihood Estimate method to contrast studies using simple vs. complex stimuli. The results show that most of the activity typically elicited by no-go signals, including pre-SMA hemodynamic response, is actually driven by the engagement of high attentional or working memory resources, not by inhibitory processes per se. Implications for current methods and theories of inhibitory control are discussed, and new lines of inquiry are proposed. Copyright © 2012 Elsevier Ltd. All rights reserved.

PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy.

PubMed

Dong, Lijie; Nian, Hong; Shao, Yan; Zhang, Yan; Li, Qiutang; Yi, Yue; Tian, Fang; Li, Wenbo; Zhang, Hong; Zhang, Xiaomin; Wang, Fei; Li, Xiaorong

2015-05-01

Pathological retinal neovascularization, including retinopathy of prematurity and age-related macular degeneration, is the most common cause of blindness worldwide. Insulin-like growth factor-1 (IGF-1) has a direct mitogenic effect on endothelial cells, which is the basis of angiogenesis. Vascular endothelial growth factor (VEGF) activation in response to IGF-1 is well documented; however, the molecular mechanisms responsible for the termination of IGF-1 signaling are still not completely elucidated. Here, we show that the polypyrimidine tract-binding protein-associated splicing factor (PSF) is a potential negative regulator of VEGF expression induced by IGF stimulation. Functional analysis demonstrated that ectopic expression of PSF inhibits IGF-1-stimulated transcriptional activation and mRNA expression of the VEGF gene, whereas knockdown of PSF increased IGF-1-stimulated responses. PSF recruited Hakai to the VEGF transcription complex, resulting in inhibition of IGF-1-mediated transcription. Transfection with Hakai siRNA reversed the PSF-mediated transcriptional repression of VEGF gene transcription. In summary, these results show that PSF can repress the transcriptional activation of VEGF stimulated by IGF-1 via recruitment of the Hakai complex and delineate a novel regulatory mechanism of IGF-1/VEGF signaling that may have implications in the pathogenesis of neovascularization in ocular diseases.

Holonomy, quantum mechanics and the signal-tuned Gabor approach to the striate cortex

NASA Astrophysics Data System (ADS)

Torreão, José R. A.

2016-02-01

It has been suggested that an appeal to holographic and quantum properties will be ultimately required for the understanding of higher brain functions. On the other hand, successful quantum-like approaches to cognitive and behavioral processes bear witness to the usefulness of quantum prescriptions as applied to the analysis of complex non-quantum systems. Here, we show that the signal-tuned Gabor approach for modeling cortical neurons, although not based on quantum assumptions, also admits a quantum-like interpretation. Recently, the equation of motion for the signal-tuned complex cell response has been derived and proven equivalent to the Schrödinger equation for a dissipative quantum system whose solutions come under two guises: as plane-wave and Airy-packet responses. By interpreting the squared magnitude of the plane-wave solution as a probability density, in accordance with the quantum mechanics prescription, we arrive at a Poisson spiking probability — a common model of neuronal response — while spike propagation can be described by the Airy-packet solution. The signal-tuned approach is also proven consistent with holonomic brain theories, as it is based on Gabor functions which provide a holographic representation of the cell’s input, in the sense that any restricted subset of these functions still allows stimulus reconstruction.

Unraveling the Root Proteome Changes and Its Relationship to Molecular Mechanism Underlying Salt Stress Response in Radish (Raphanus sativus L.)

PubMed Central

Sun, Xiaochuan; Wang, Yan; Xu, Liang; Li, Chao; Zhang, Wei; Luo, Xiaobo; Jiang, Haiyan; Liu, Liwang

2017-01-01

To understand the molecular mechanism underlying salt stress response in radish, iTRAQ-based proteomic analysis was conducted to investigate the differences in protein species abundance under different salt treatments. In total, 851, 706, and 685 differential abundance protein species (DAPS) were identified between CK vs. Na100, CK vs. Na200, and Na100 vs. Na200, respectively. Functional annotation analysis revealed that salt stress elicited complex proteomic alterations in radish roots involved in carbohydrate and energy metabolism, protein metabolism, signal transduction, transcription regulation, stress and defense and transport. Additionally, the expression levels of nine genes encoding DAPS were further verified using RT-qPCR. The integrative analysis of transcriptomic and proteomic data in conjunction with miRNAs was further performed to strengthen the understanding of radish response to salinity. The genes responsible for signal transduction, ROS scavenging and transport activities as well as several key miRNAs including miR171, miR395, and miR398 played crucial roles in salt stress response in radish. Based on these findings, a schematic genetic regulatory network of salt stress response was proposed. This study provided valuable insights into the molecular mechanism underlying salt stress response in radish roots and would facilitate developing effective strategies toward genetically engineered salt-tolerant radish and other root vegetable crops. PMID:28769938

Trans-Homolog Interactions Facilitating Paramutation in Maize

PubMed Central

2015-01-01

Paramutations represent locus-specific trans-homolog interactions affecting the heritable silencing properties of endogenous alleles. Although examples of paramutation are well studied in maize (Zea mays), the responsible mechanisms remain unclear. Genetic analyses indicate roles for plant-specific DNA-dependent RNA polymerases that generate small RNAs, and current working models hypothesize that these small RNAs direct heritable changes at sequences often acting as transcriptional enhancers. Several studies have defined specific sequences that mediate paramutation behaviors, and recent results identify a diversity of DNA-dependent RNA polymerase complexes operating in maize. Other reports ascribe broader roles for some of these complexes in normal genome function. This review highlights recent research to understand the molecular mechanisms of paramutation and examines evidence relevant to small RNA-based modes of transgenerational epigenetic inheritance. PMID:26149572

Linking definitions, mechanisms, and modeling of drought-induced tree death.

PubMed

Anderegg, William R L; Berry, Joseph A; Field, Christopher B

2012-12-01

Tree death from drought and heat stress is a critical and uncertain component in forest ecosystem responses to a changing climate. Recent research has illuminated how tree mortality is a complex cascade of changes involving interconnected plant systems over multiple timescales. Explicit consideration of the definitions, dynamics, and temporal and biological scales of tree mortality research can guide experimental and modeling approaches. In this review, we draw on the medical literature concerning human death to propose a water resource-based approach to tree mortality that considers the tree as a complex organism with a distinct growth strategy. This approach provides insight into mortality mechanisms at the tree and landscape scales and presents promising avenues into modeling tree death from drought and temperature stress. Copyright © 2012 Elsevier Ltd. All rights reserved.

Chimpanzees and Bonobos Exhibit Emotional Responses to Decision Outcomes

PubMed Central

Rosati, Alexandra G.; Hare, Brian

2013-01-01

The interface between cognition, emotion, and motivation is thought to be of central importance in understanding complex cognitive functions such as decision-making and executive control in humans. Although nonhuman apes have complex repertoires of emotional expression, little is known about the role of affective processes in ape decision-making. To illuminate the evolutionary origins of human-like patterns of choice, we investigated decision-making in humans' closest phylogenetic relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). In two studies, we examined these species' temporal and risk preferences, and assessed whether apes show emotional and motivational responses in decision-making contexts. We find that (1) chimpanzees are more patient and more risk-prone than are bonobos, (2) both species exhibit affective and motivational responses following the outcomes of their decisions, and (3) some emotional and motivational responses map onto species-level and individual-differences in decision-making. These results indicate that apes do exhibit emotional responses to decision-making, like humans. We explore the hypothesis that affective and motivational biases may underlie the psychological mechanisms supporting value-based preferences in these species. PMID:23734175

Dissecting genetic architecture of startle response in Drosophila melanogaster using multi-omics information.

PubMed

Xue, Angli; Wang, Hongcheng; Zhu, Jun

2017-09-28

Startle behavior is important for survival, and abnormal startle responses are related to several neurological diseases. Drosophila melanogaster provides a powerful system to investigate the genetic underpinnings of variation in startle behavior. Since mechanically induced, startle responses and environmental conditions can be readily quantified and precisely controlled. The 156 wild-derived fully sequenced lines of the Drosophila Genetic Reference Panel (DGRP) were used to identify SNPs and transcripts associated with variation in startle behavior. The results validated highly significant effects of 33 quantitative trait SNPs (QTSs) and 81 quantitative trait transcripts (QTTs) directly associated with phenotypic variation of startle response. We also detected QTT variation controlled by 20 QTSs (tQTSs) and 73 transcripts (tQTTs). Association mapping based on genomic and transcriptomic data enabled us to construct a complex genetic network that underlies variation in startle behavior. Based on principles of evolutionary conservation, human orthologous genes could be superimposed on this network. This study provided both genetic and biological insights into the variation of startle response behavior of Drosophila melanogaster, and highlighted the importance of genetic network to understand the genetic architecture of complex traits.

Current perspectives on behavioural and cellular mechanisms of illness anorexia.

PubMed

Asarian, Lori; Langhans, Wolfgang

2005-12-01

Here we review our current understanding of the integration of immune, neural, metabolic and endocrine signals involved in the generation of anorexia during acute infection, with the focus on anorexia elicited by peripheral administration of bacterial lipopolysaccharide (LPS). We chose to limit this review to peripheral LPS-anorexia because the mechanisms underlying this response may also be valid for anorexia during other types of acute or chronic infections, with slight differences in the duration of anorexia, levels of circulating concentrations of pro-inflammatory cytokines and hypermetabolism. Evidence so far indicates that LPS-anorexia is a complex response beneficial to host defence that involves both peripheral and central action of pro-inflammatory cytokines, other immune factors, such as prostanoids, and neurotransmitters, such as serotonin. One interesting characteristic of LPS-anorexia is its sexual differentiation, an aspect mainly mediated by the gonadal hormone estradiol. Understanding the behavioural and molecular mechanisms of LPS-anorexia may even provide useful leads for identifying mechanisms of eating disorders in humans.

Effect of microstructure on the coupled electromagnetic-thermo-mechanical response of cyclotrimethylenetrinitramine-estane energetic aggregates to infrared laser radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Judith A.; Zikry, M. A., E-mail: zikry@ncsu.edu

2015-09-28

The coupled electromagnetic (EM)-thermo-mechanical response of cyclotrimethylenetrinitramine-estane energetic aggregates under laser irradiation and high strain rate loads has been investigated for various aggregate sizes and binder volume fractions. The cyclotrimethylenetrinitramine (RDX) crystals are modeled with a dislocation density-based crystalline plasticity formulation and the estane binder is modeled with finite viscoelasticity through a nonlinear finite element approach that couples EM wave propagation with laser heat absorption, thermal conduction, and inelastic deformation. Material property and local behavior mismatch at the crystal-binder interfaces resulted in geometric scattering of the EM wave, electric field and laser heating localization, high stress gradients, dislocation density, andmore » crystalline shear slip accumulation. Viscous sliding in the binder was another energy dissipation mechanism that reduced stresses in aggregates with thicker binder ligaments and larger binder volume fractions. This investigation indicates the complex interactions between EM waves and mechanical behavior, for accurate predictions of laser irradiation of heterogeneous materials.« less

In-vivo evaluation of the response of Galleria mellonella larvae to novel copper(II) phenanthroline-phenazine complexes.

PubMed

Rochford, Garret; Molphy, Zara; Browne, Niall; Surlis, Carla; Devereux, Michael; McCann, Malachy; Kellett, Andrew; Howe, Orla; Kavanagh, Kevin

2018-06-01

Herein we report the in-vivo characterisation and metabolic changes in Galleria mellonella larvae to a series of bis-chelate copper(II) phenanthroline-phenazine cationic complexes of [Cu(phen) 2 ] 2+ (Cu-Phen), [Cu(DPQ)(Phen)] 2+ (Cu-DPQ-Phen) and [Cu(DPPZ)(Phen)] 2+ (Cu-DPPZ-Phen) (where phen = 1,10-phenanthroline, DPQ = dipyrido[3,2-ƒ:2',3'-h]quinoxaline and DPPZ = dipyrido[3,2-a:2',3'-c]phenazine). Our aim was to investigate the influence of the systematic extension of the ligated phenazine ligand in the G. mellonella model as a first step towards assessing the in-vivo tolerance and mode of action of the complex series with respect to the well-studied oxidative chemical nuclease, Cu-Phen. The Lethal Dose 50 (LD 50 ) values were established over dose ranges of 2 - 30 μg at 4-, 24-, 48- and 72 h by mortality assessment, with Cu-Phen eliciting the highest mortality at 4 h (Cu-Phen, 12.62 μg < Cu-DPQ-Phen, 21.53 μg < Cu-DPPZ-Phen, 26.07 μg). At other timepoints, a similar profile was observed as the phenazine π-backbone within the complex scaffold was extended. Assessment of both cellular response and related gene expression demonstrated that the complexes did not initiate an immune response. However, Label-Free Quantification proteomic data indicated the larval response was associated with upregulation of key proteins such as Glutathione S-transferase, purine synthesis and glycolysis/gluconeogenesis (e.g. fructose-bisphosphate aldolase and glyceraldehyde-3-phosphate). Both Cu-Phen and Cu-DPQ-Phen elicited a similar in-vivo response in contrast to Cu-DPPZ-Phen, which displayed a substantial increase in nitrogen detoxification proteins and proteins with calcium binding sites. Overall, the response of G. mellonella larvae exposure to the complex series is dominated by detoxification and metabolic proteome response mechanisms. Copyright © 2018 Elsevier Inc. All rights reserved.

Biological mechanisms of non-linear dose-response for respirable mineral fibers.

PubMed

Cox, Louis Anthony Tony

2018-06-19

Sufficiently high and prolonged inhalation exposures to some respirable elongated mineral particles (REMPs), notably including amphibole asbestos fibers, can increase risk of inflammation-mediated diseases including malignant mesothelioma, pleural diseases, fibrosis, and lung cancer. Chronic inflammation involves ongoing activation of the NLRP3 inflammasome, which enables immune cells to produce potent proinflammatory cytokines IL-1β and IL-18. Reactive oxygen species (ROS) (in particular, mitochondrial ROS) contribute to NRLP3 activation via a well-elucidated mechanism involving oxidation of reduced thioredoxin and association of thioredoxin-interacting protein with NLRP3. Lysosomal destabilization, efflux of cytosolic potassium ions and influx of calcium ions, signals from damaged mitochondria, both translational and post-translational controls, and prion-like polymerization have increasingly clear roles in regulating NLRP3 activation. As the molecular biology of inflammation-mediated responses to REMP exposure becomes clearer, a practical question looms: What do these mechanisms imply for the shape of the dose-response function relating exposure concentrations and durations for EMPs to risk of pathological responses? Dose-response thresholds or threshold-like nonlinearities can arise from (a) Cooperativity in assembly of supramolecular signaling complexes; (b) Positive feedback loops and bistability in regulatory networks; (c) Overwhelming of defensive barriers maintaining homeostasis; and (d) Damage thresholds, as in lysosome destabilization-induced activation of NLRP3. Each of these mechanisms holds for NLRP3 activation in response to stimuli such as REMP exposures. It is therefore timely to consider the implications of these advances in biological understanding for human health risk assessment with dose-response thresholds. Copyright © 2018. Published by Elsevier Inc.

Mast Cell Interactions and Crosstalk in Regulating Allergic Inflammation.

PubMed

Velez, Tania E; Bryce, Paul J; Hulse, Kathryn E

2018-04-17

This review summarizes recent findings on mast cell biology with a focus on IgE-independent roles of mast cells in regulating allergic responses. Recent studies have described novel mast cell-derived molecules, both secreted and membrane-bound, that facilitate cross-talk with a variety of immune effector cells to mediate type 2 inflammatory responses. Mast cells are complex and dynamic cells that are persistent in allergy and are capable of providing signals that lead to the initiation and persistence of allergic mechanisms.

Cell-wall recovery after irreversible deformation of wood

NASA Astrophysics Data System (ADS)

Keckes, Jozef; Burgert, Ingo; Frühmann, Klaus; Müller, Martin; Kölln, Klaas; Hamilton, Myles; Burghammer, Manfred; Roth, Stephan V.; Stanzl-Tschegg, Stefanie; Fratzl, Peter

2003-12-01

The remarkable mechanical properties of biological materials reside in their complex hierarchical architecture and in specific molecular mechanistic phenomena. The fundamental importance of molecular interactions and bond recovery has been suggested by studies on deformation and fracture of bone and nacre. Like these mineral-based materials, wood also represents a complex nanocomposite with excellent mechanical performance, despite the fact that it is mainly based on polymers. In wood, however, the mechanistic contribution of processes in the cell wall is not fully understood. Here we have combined tensile tests on individual wood cells and on wood foils with simultaneous synchrotron X-ray diffraction analysis in order to separate deformation mechanisms inside the cell wall from those mediated by cell-cell interactions. We show that tensile deformation beyond the yield point does not deteriorate the stiffness of either individual cells or foils. This indicates that there is a dominant recovery mechanism that re-forms the amorphous matrix between the cellulose microfibrils within the cell wall, maintaining its mechanical properties. This stick-slip mechanism, rather like Velcro operating at the nanometre level, provides a 'plastic response' similar to that effected by moving dislocations in metals. We suggest that the molecular recovery mechanism in the cell matrix is a universal phenomenon dominating the tensile deformation of different wood tissue types.

The Immune Response and the Pathogenesis of Idiopathic Inflammatory Myositis: a Critical Review.

PubMed

Ceribelli, Angela; De Santis, Maria; Isailovic, Natasa; Gershwin, M Eric; Selmi, Carlo

2017-02-01

The pathogenesis of idiopathic inflammatory myositis (IIMs, including polymyositis and dermatomyositis) remains largely enigmatic, despite advances in the study of the role played by innate immunity, adaptive immunity, genetic predisposition, and environmental factors in an orchestrated response. Several factors are involved in the inflammatory state that characterizes the different forms of IIMs which share features and mechanisms but are clearly different with respect to the involved sites and characteristics of the inflammation. Cellular and non-cellular mechanisms of both the immune and non-immune systems have been identified as key regulators of inflammation in polymyositis/dermatomyositis, particularly at different stages of disease, leading to the fibrotic state that characterizes the end stage. Among these, a special role is played by an interferon signature and complement cascade with different mechanisms in polymyositis and dermatomyositis; these differences can be identified also histologically in muscle biopsies. Numerous cellular components of the adaptive and innate immune response are present in the site of tissue inflammation, and the complexity of idiopathic inflammatory myositis is further supported by the involvement of non-immune mechanisms such as hypoxia and autophagy. The aim of this comprehensive review is to describe the major pathogenic mechanisms involved in the onset of idiopathic inflammatory myositis and to report on the major working hypothesis with therapeutic implications.

Rapid analytical assessment of the mechanical perturbations induced by non-isothermal injection into a subsurface formation.

NASA Astrophysics Data System (ADS)

De Simone, Silvia; Carrera, Jesús; María Gómez Castro, Berta

2016-04-01

Fluid injection into geological formations is required for several engineering operations, e.g. geothermal energy production, hydrocarbon production and storage, CO2 storage, wastewater disposal, etc. Non-isothermal fluid injection causes alterations of the pressure and temperature fields, which affect the mechanical stability of the reservoir. This coupled thermo-hydro-mechanical behavior has become a matter of special interest because of public concern about induced seismicity. The response is complex and its evaluation often requires numerical modeling. Nevertheless, analytical solutions are useful in improving our understanding of interactions, identifying the controlling parameters, testing codes and in providing a rapid assessment of the system response to an alteration. We present an easy-to-use solution to the transient advection-conduction heat transfer problem for parallel and radial flow. The solution is then applied to derive analytical expressions for hydraulic and thermal driven displacements and stresses. The validity is verified by comparison with numerical simulations and yields fairly accurate results. The solution is then used to illustrate some features of the poroelastic and thermoelastic response and, in particular, the sensitivity to the external mechanical constraints and to the reservoir dimension.

Understanding the mechanism of catalytic fast pyrolysis by unveiling reactive intermediates in heterogeneous catalysis

NASA Astrophysics Data System (ADS)

Hemberger, Patrick; Custodis, Victoria B. F.; Bodi, Andras; Gerber, Thomas; van Bokhoven, Jeroen A.

2017-06-01

Catalytic fast pyrolysis is a promising way to convert lignin into fine chemicals and fuels, but current approaches lack selectivity and yield unsatisfactory conversion. Understanding the pyrolysis reaction mechanism at the molecular level may help to make this sustainable process more economic. Reactive intermediates are responsible for product branching and hold the key to unveiling these mechanisms, but are notoriously difficult to detect isomer-selectively. Here, we investigate the catalytic pyrolysis of guaiacol, a lignin model compound, using photoelectron photoion coincidence spectroscopy with synchrotron radiation, which allows for isomer-selective detection of reactive intermediates. In combination with ambient pressure pyrolysis, we identify fulvenone as the central reactive intermediate, generated by catalytic demethylation to catechol and subsequent dehydration. The fulvenone ketene is responsible for the phenol formation. This technique may open unique opportunities for isomer-resolved probing in catalysis, and holds the potential for achieving a mechanistic understanding of complex, real-life catalytic processes.

Impaired complex IV activity in response to loss of LRPPRC function can be compensated by mitochondrial hyperfusion

PubMed Central

Rolland, Stéphane G.; Motori, Elisa; Memar, Nadin; Hench, Jürgen; Frank, Stephan; Winklhofer, Konstanze F.; Conradt, Barbara

2013-01-01

Mitochondrial morphology changes in response to various stimuli but the significance of this is unclear. In a screen for mutants with abnormal mitochondrial morphology, we identified MMA-1, the Caenorhabditis elegans homolog of the French Canadian Leigh Syndrome protein LRPPRC (leucine-rich pentatricopeptide repeat containing). We demonstrate that reducing mma-1 or LRPPRC function causes mitochondrial hyperfusion. Reducing mma-1/LRPPRC function also decreases the activity of complex IV of the electron transport chain, however without affecting cellular ATP levels. Preventing mitochondrial hyperfusion in mma-1 animals causes larval arrest and embryonic lethality. Furthermore, prolonged LRPPRC knock-down in mammalian cells leads to mitochondrial fragmentation and decreased levels of ATP. These findings indicate that in a mma-1/LRPPRC–deficient background, hyperfusion allows mitochondria to maintain their functions despite a reduction in complex IV activity. Our data reveal an evolutionary conserved mechanism that is triggered by reduced complex IV function and that induces mitochondrial hyperfusion to transiently compensate for a drop in the activity of the electron transport chain. PMID:23878239

Immune effector mechanisms against schistosomiasis: looking for a chink in the parasite's armour

PubMed Central

Wilson, R Alan; Coulson, Patricia S

2009-01-01

A recombinant antigen vaccine against Schistosoma mansoni remains elusive, in part because the parasite deploys complex defensive and offensive strategies to combat immune attack. Nevertheless, research on rodent and primate models has shown that schistosomes can be defeated when appropriate responses are elicited. Acquired protection appears to involve protracted inhibition of larval migration or key molecular processes at the adult surfaces, not rapid cytolytic killing mechanisms. A successful vaccine will likely require a cocktail of antigens rather than a single recombinant protein. In addition, ways need to be found of keeping the immune system on permanent alert, either to achieve adequate inhibition of protein function in adults, or because a trickle of incoming parasites does not amplify the secondary response. PMID:19717340

Induced antiviral innate immunity in Drosophila.

PubMed

Lamiable, Olivier; Imler, Jean-Luc

2014-08-01

Immunity to viral infections in the model organism Drosophila melanogaster involves both RNA interference and additional induced responses. The latter include not only cellular mechanisms such as programmed cell death and autophagy, but also the induction of a large set of genes, some of which contribute to the control of viral replication and resistance to infection. This induced response to infection is complex and involves both virus-specific and cell-type specific mechanisms. We review here recent developments, from the sensing of viral infection to the induction of signaling pathways and production of antiviral effector molecules. Our current understanding, although still partial, validates the Drosophila model of antiviral induced immunity for insect pests and disease vectors, as well as for mammals. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Rice E3-Ubiquitin Ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE1 Modulates the Expression of ROOT MEANDER CURLING, a Gene Involved in Root Mechanosensing, through the Interaction with Two ETHYLENE-RESPONSE FACTOR Transcription Factors1

PubMed Central

Lourenço, Tiago F.; Serra, Tânia S.; Cordeiro, André M.; Swanson, Sarah J.; Gilroy, Simon; Saibo, Nelson J.M.; Oliveira, M. Margarida

2015-01-01

Plant roots can sense and respond to a wide diversity of mechanical stimuli, including touch and gravity. However, little is known about the signal transduction pathways involved in mechanical stimuli responses in rice (Oryza sativa). This work shows that rice root responses to mechanical stimuli involve the E3-ubiquitin ligase rice HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE1 (OsHOS1), which mediates protein degradation through the proteasome complex. The morphological analysis of the roots in transgenic RNA interference::OsHOS1 and wild-type plants, exposed to a mechanical barrier, revealed that the OsHOS1 silencing plants keep a straight root in contrast to wild-type plants that exhibit root curling. Moreover, it was observed that the absence of root curling in response to touch can be reverted by jasmonic acid. The straight root phenotype of the RNA interference::OsHOS1 plants was correlated with a higher expression rice ROOT MEANDER CURLING (OsRMC), which encodes a receptor-like kinase characterized as a negative regulator of rice root curling mediated by jasmonic acid. Using the yeast two-hybrid system and bimolecular fluorescence complementation assays, we showed that OsHOS1 interacts with two ETHYLENE-RESPONSE FACTOR transcription factors, rice ETHYLENE-RESPONSIVE ELEMENT BINDING PROTEIN1 (OsEREBP1) and rice OsEREBP2, known to regulate OsRMC gene expression. In addition, we showed that OsHOS1 affects the stability of both transcription factors in a proteasome-dependent way, suggesting that this E3-ubiquitin ligase targets OsEREBP1 and OsEREBP2 for degradation. Our results highlight the function of the proteasome in rice response to mechanical stimuli and in the integration of these signals, through hormonal regulation, into plant growth and developmental programs. PMID:26381316

Analysis of stimulus-related activity in rat auditory cortex using complex spectral coefficients

PubMed Central

Krause, Bryan M.

2013-01-01

The neural mechanisms of sensory responses recorded from the scalp or cortical surface remain controversial. Evoked vs. induced response components (i.e., changes in mean vs. variance) are associated with bottom-up vs. top-down processing, but trial-by-trial response variability can confound this interpretation. Phase reset of ongoing oscillations has also been postulated to contribute to sensory responses. In this article, we present evidence that responses under passive listening conditions are dominated by variable evoked response components. We measured the mean, variance, and phase of complex time-frequency coefficients of epidurally recorded responses to acoustic stimuli in rats. During the stimulus, changes in mean, variance, and phase tended to co-occur. After the stimulus, there was a small, low-frequency offset response in the mean and modest, prolonged desynchronization in the alpha band. Simulations showed that trial-by-trial variability in the mean can account for most of the variance and phase changes observed during the stimulus. This variability was state dependent, with smallest variability during periods of greatest arousal. Our data suggest that cortical responses to auditory stimuli reflect variable inputs to the cortical network. These analyses suggest that caution should be exercised when interpreting variance and phase changes in terms of top-down cortical processing. PMID:23657279

[A complex interplay of hormones, neuro-transmitters, neuropeptides and immunity cells is responsible for the control of eating].

PubMed

Rondanelli, M

1997-09-01

Food-seeking behaviour is a complex mechanism which involves an interplay of hormones, neurotransmitters, neuropeptides and immunity cells. In this review the important role of the cooperation between the SNC system, the endocrine system and in particular the immune system in the control of eating is underlined. Like stress and depression, in fact the regulation of eating represents another example of the interplay between these three systems and it is secondary to a bidirectional dialogue between the center and the periphery.

Engineering a pH-Regulated Switch in the Major Light-Harvesting Complex of Plants (LHCII): Proof of Principle.

PubMed

Liguori, Nicoletta; Natali, Alberto; Croce, Roberta

2016-12-15

Under excess light, photosynthetic organisms employ feedback mechanisms to avoid photodamage. Photoprotection is triggered by acidification of the lumen of the photosynthetic membrane following saturation of the metabolic activity. A low pH triggers thermal dissipation of excess absorbed energy by the light-harvesting complexes (LHCs). LHCs are not able to sense pH variations, and their switch to a dissipative mode depends on stress-related proteins and allosteric cofactors. In green algae the trigger is the pigment-protein complex LHCSR3. Its C-terminus is responsible for a pH-driven conformational change from a light-harvesting to a quenched state. Here, we show that by replacing the C-terminus of the main LHC of plants with that of LHCSR3, it is possible to regulate its excited-state lifetime solely via protonation, demonstrating that the protein template of LHCs can be modified to activate reversible quenching mechanisms independent of external cofactors and triggers.

Comparative proteomics illustrates the complexity of drought resistance mechanisms in two wheat (Triticum aestivum L.) cultivars under dehydration and rehydration.

PubMed

Cheng, Lixiang; Wang, Yuping; He, Qiang; Li, Huijun; Zhang, Xiaojing; Zhang, Feng

2016-08-31

Drought stress is one of the most adverse environmental constraints to plant growth and productivity. Comparative proteomics of drought-tolerant and sensitive wheat genotypes is a strategy to understand the complexity of molecular mechanism of wheat in response to drought. This study attempted to extend findings regarding the potential proteomic dynamics in wheat under drought stress and to enrich the research content of drought tolerance mechanism. A comparative proteomics approach was applied to analyze proteome change of Xihan No. 2 (a drought-tolerant cultivar) and Longchun 23 (a drought-sensitive cultivar) subjected to a range of dehydration treatments (18 h, 24 h and 48 h) and rehydration treatment (R24 h) using 2-DE, respectively. Quantitative image analysis showed a total of 172 protein spots in Xihan No. 2 and 215 spots from Longchun 23 with their abundance significantly altered (p < 0.05) more than 2.5-fold. Out of these spots, a total of 84 and 64 differentially abundant proteins were identified by MALDI-TOF/TOF MS in Xihan No. 2 and Longchun 23, respectively. Most of these identified proteins were involved in metabolism, photosynthesis, defence and protein translation/processing/degradation in both two cultivars. In addition, the proteins involved in redox homeostasis, energy, transcription, cellular structure, signalling and transport were also identified. Furthermore, the comparative analysis of drought-responsive proteome allowed for the general elucidation of the major mechanisms associated with differential responses to drought of both two cultivars. These cellular processes work more cooperatively to re-establish homeostasis in Xihan No. 2 than Longchun 23. The resistance mechanisms of Xihan No. 2 mainly included changes in the metabolism of carbohydrates and amino acids as well as in the activation of more antioxidation and defense systems and in the levels of proteins involved in ATP synthesis and protein degradation/refolding. This study revealed that the levels of a number of proteins involved in various cellular processes were affected by drought stress in two wheat cultivars with different drought tolerance. The results showed that there exist specific responses to drought in Xihan No. 2 and Longchun 23. The proposed hypothetical model would explain the interaction of these identified proteins that are associated with drought-responses in two cultivars, and help in developing strategies to improve drought tolerance in wheat.

Role of integrin-linked kinase in regulating phosphorylation of Akt and fibroblast survival in type I collagen matrices through a beta1 integrin viability signaling pathway.

PubMed

Nho, Richard Seonghun; Xia, Hong; Kahm, Judy; Kleidon, Jill; Diebold, Deanna; Henke, Craig A

2005-07-15

A beta1 integrin phosphatidylinositol 3-kinase/Akt pathway regulates fibroblast survival in collagen matrices. When fibroblasts attach to collagen, Akt becomes phosphorylated, providing a survival signal. In contrast, in response to mechanical forces generated during collagen contraction, Akt is dephosphorylated and fibroblasts undergo apoptosis. The kinase(s) responsible for regulating Akt phosphorylation in response to matrix-derived mechanical signals are unclear. Integrin-linked kinase (ILK) is associated with the beta1 integrin in the focal adhesion complex and as such is a candidate kinase that may regulate Akt phosphorylation and fibroblast viability. Nevertheless, there is no direct evidence that matrix-derived mechanical forces regulate cell viability by modulating ILK activity. Here, we show that ILK activity decreased in response to collagen matrix contraction, which correlated with Akt dephosphorylation and induction of fibroblast apoptosis. In contrast, enforced activation of beta1 integrin by activating antibody preserved ILK and Akt activity during collagen matrix contraction, and this is associated with protection from collagen contraction-induced apoptosis. Knock-down of ILK by small, interfering RNA (siRNA) attenuated Akt phosphorylation in response to ligation of beta1 integrin by collagen or activating antibody and enhanced fibroblast apoptosis in response to collagen contraction. Kinase dead ILK attenuated Akt phosphorylation and enhanced fibroblast apoptosis, whereas hyperactive and wild type ILK augmented Akt phosphorylation and protected fibroblasts from apoptosis. Constitutively active Akt preserved Akt activity and rescued ILK siRNA-treated fibroblasts from collagen contraction-induced apoptosis. These data establish that matrix-derived mechanical forces sensed by beta1 integrin are capable of modulating ILK activity which regulates fibroblast viability via an Akt-dependent mechanism.

Environment-dependent regulation of spliceosome activity by the LSM2-8 complex in Arabidopsis.

PubMed

Carrasco-López, Cristian; Hernández-Verdeja, Tamara; Perea-Resa, Carlos; Abia, David; Catalá, Rafael; Salinas, Julio

2017-07-07

Spliceosome activity is tightly regulated to ensure adequate splicing in response to internal and external cues. It has been suggested that core components of the spliceosome, such as the snRNPs, would participate in the control of its activity. The experimental indications supporting this proposition, however, remain scarce, and the operating mechanisms poorly understood. Here, we present genetic and molecular evidence demonstrating that the LSM2-8 complex, the protein moiety of the U6 snRNP, regulates the spliceosome activity in Arabidopsis, and that this regulation is controlled by the environmental conditions. Our results show that the complex ensures the efficiency and accuracy of constitutive and alternative splicing of selected pre-mRNAs, depending on the conditions. Moreover, miss-splicing of most targeted pre-mRNAs leads to the generation of nonsense mediated decay signatures, indicating that the LSM2-8 complex also guarantees adequate levels of the corresponding functional transcripts. Interestingly, the selective role of the complex has relevant physiological implications since it is required for adequate plant adaptation to abiotic stresses. These findings unveil an unanticipated function for the LSM2-8 complex that represents a new layer of posttranscriptional regulation in response to external stimuli in eukaryotes. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

What's Special about Human Imitation? A Comparison with Enculturated Apes.

PubMed

Subiaul, Francys

2016-07-07

What, if anything, is special about human imitation? An evaluation of enculturated apes' imitation skills, a "best case scenario" of non-human apes' imitation performance, reveals important similarities and differences between this special population of apes and human children. Candidates for shared imitation mechanisms include the ability to imitate various familiar transitive responses and object-object actions that involve familiar tools. Candidates for uniquely derived imitation mechanisms include: imitating novel transitive actions and novel tool-using responses as well as imitating opaque or intransitive gestures, regardless of familiarity. While the evidence demonstrates that enculturated apes outperform non-enculturated apes and perform more like human children, all apes, regardless of rearing history, generally excel at imitating familiar, over-rehearsed responses and are poor, relative to human children, at imitating novel, opaque or intransitive responses. Given the similarities between the sensory and motor systems of preschool age human children and non-human apes, it is unlikely that differences in sensory input and/or motor-output alone explain the observed discontinuities in imitation performance. The special rearing history of enculturated apes-including imitation-specific training-further diminishes arguments suggesting that differences are experience-dependent. Here, it is argued that such differences are best explained by distinct, specialized mechanisms that have evolved for copying rules and responses in particular content domains. Uniquely derived social and imitation learning mechanisms may represent adaptations for learning novel communicative gestures and complex tool-use. Given our species' dependence on both language and tools, mechanisms that accelerated learning in these domains are likely to have faced intense selective pressures, starting with the earliest of human ancestors.

Do advanced glycation end-products play a role in malaria susceptibility?

PubMed Central

Traoré, Karim; Arama, Charles; Médebielle, Maurice; Doumbo, Ogobara; Picot, Stéphane

2016-01-01

There are growing data supporting the differences in susceptibility to malaria described between sympatric populations with different lifestyles. Evidence has also been growing for some time that nutritional status and the host’s metabolism are part of the complex mechanisms underlying these differences. The role of dietary advanced glycation end-products (AGEs) in the modulation of immune responses (innate and adaptive responses) and chronic oxidative stress has been established. But less is known about AGE implication in naturally acquired immunity and susceptibility to malaria. Since inflammatory immune responses and oxidative events have been demonstrated as the hallmark of malaria infection, it seems crucial to investigate the role of AGE in susceptibility or resistance to malaria. This review provides new insight into the relationship between nutrition, metabolic disorders, and infections, and how this may influence the mechanisms of susceptibility or resistance to malaria in endemic areas. PMID:27012162

Translation Control: A Multifaceted Regulator of Inflammatory Response

PubMed Central

Mazumder, Barsanjit; Li, Xiaoxia; Barik, Sailen

2010-01-01

A robust innate immune response is essential to the protection of all vertebrates from infection, but it often comes with the price tag of acute inflammation. If unchecked, a runaway inflammatory response can cause significant tissue damage, resulting in myriad disorders, such as dermatitis, toxicshock, cardiovascular disease, acute pelvic and arthritic inflammatory diseases, and various infections. To prevent such pathologies, cells have evolved mechanisms to rapidly and specifically shut off these beneficial inflammatory activities before they become detrimental. Our review of recent literature, including our own work, reveals that the most dominant and common mechanism is translational silencing, in which specific regulatory proteins or complexes are recruited to cis-acting RNA structures in the untranslated regions of single or multiple mRNAs that code for the inflammatory protein(s). Enhancement of the silencing function may constitute a novel pharmacological approach to prevent immunity-related inflammation. PMID:20304832

Translation control: a multifaceted regulator of inflammatory response.

PubMed

Mazumder, Barsanjit; Li, Xiaoxia; Barik, Sailen

2010-04-01

A robust innate immune response is essential to the protection of all vertebrates from infection, but it often comes with the price tag of acute inflammation. If unchecked, a runaway inflammatory response can cause significant tissue damage, resulting in myriad disorders, such as dermatitis, toxic shock, cardiovascular disease, acute pelvic and arthritic inflammatory diseases, and various infections. To prevent such pathologies, cells have evolved mechanisms to rapidly and specifically shut off these beneficial inflammatory activities before they become detrimental. Our review of recent literature, including our own work, reveals that the most dominant and common mechanism is translational silencing, in which specific regulatory proteins or complexes are recruited to cis-acting RNA structures in the untranslated regions of single or multiple mRNAs that code for the inflammatory protein(s). Enhancement of the silencing function may constitute a novel pharmacological approach to prevent immunity-related inflammation.

Nonlinear frequency response based adaptive vibration controller design for a class of nonlinear systems

NASA Astrophysics Data System (ADS)

Thenozhi, Suresh; Tang, Yu

2018-01-01

Frequency response functions (FRF) are often used in the vibration controller design problems of mechanical systems. Unlike linear systems, the FRF derivation for nonlinear systems is not trivial due to their complex behaviors. To address this issue, the convergence property of nonlinear systems can be studied using convergence analysis. For a class of time-invariant nonlinear systems termed as convergent systems, the nonlinear FRF can be obtained. The present paper proposes a nonlinear FRF based adaptive vibration controller design for a mechanical system with cubic damping nonlinearity and a satellite system. Here the controller gains are tuned such that a desired closed-loop frequency response for a band of harmonic excitations is achieved. Unlike the system with cubic damping, the satellite system is not convergent, therefore an additional controller is utilized to achieve the convergence property. Finally, numerical examples are provided to illustrate the effectiveness of the proposed controller.

Enhanced Respiratory Chain Supercomplex Formation in Response to Exercise in Human Skeletal Muscle.

PubMed

Greggio, Chiara; Jha, Pooja; Kulkarni, Sameer S; Lagarrigue, Sylviane; Broskey, Nicholas T; Boutant, Marie; Wang, Xu; Conde Alonso, Sonia; Ofori, Emmanuel; Auwerx, Johan; Cantó, Carles; Amati, Francesca

2017-02-07

Mitochondrial dysfunction is a hallmark of multiple metabolic complications. Physical activity is known to increase mitochondrial content in skeletal muscle, counteracting age-related decline in muscle function and protecting against metabolic and cardiovascular complications. Here, we investigated the effect of 4 months of exercise training on skeletal muscle mitochondria electron transport chain complexes and supercomplexes in 26 healthy, sedentary older adults. Exercise differentially modulated respiratory complexes. Complex I was the most upregulated complex and not stoichiometrically associated to the other complexes. In contrast to the other complexes, complex I was almost exclusively found assembled in supercomplexes in muscle mitochondria. Overall, supercomplex content was increased after exercise. In particular, complexes I, III, and IV were redistributed to supercomplexes in the form of I+III 2 +IV. Taken together, our results provide the first evidence that exercise affects the stoichiometry of supercomplex formation in humans and thus reveal a novel adaptive mechanism for increased energy demand. Copyright © 2017 Elsevier Inc. All rights reserved.

Nonlinear optical properties and excited state dynamics of sandwich-type mixed (phthalocyaninato)(Schiff-base) triple-decker complexes: Effect of rare earth atom

NASA Astrophysics Data System (ADS)

Li, Zhongguo; Gao, Feng; Xiao, Zhengguo; Wu, Xingzhi; Zuo, Jinglin; Song, Yinglin

2018-07-01

The third-order nonlinear optical properties of two di-lanthanide (Ln = Tb and Dy) sandwich complexes with mixed phthalocyanine and Schiff-base ligands were studied using Z-scan technique at 532 nm with 20 ps and 4 ns pulses. Both complexes exhibit reverse saturable absorption and self-focusing effect in ps regime, while the second-order hyperpolarizability decreases from Dy to Tb. Interestingly, the Tb triple-decker complexes show larger nonlinear absorption than Dy complexes on ns timescale. The time-resolved pump-probe measurements demonstrate that the nonlinear optical response was caused by excited-state mechanism related to the five-level model, while the singlet state lifetime of Dy complexes is 3 times shorter than that of Tb complexes. Our results indicate the lanthanide ions play a critical role in the photo-physical properties of triple-decker phthalocyanine complexes for their application as optical limiting materials.

Smoking and nonsmoking asthma: differences in clinical outcome and pathogenesis.

PubMed

Fattahi, Fatemeh; Hylkema, Machteld N; Melgert, Barbro N; Timens, Wim; Postma, Dirkje S; ten Hacken, Nick H T

2011-02-01

Cigarette smoking in asthma is frequently present and is associated with worsening of symptoms, accelerated lung-function decline, a higher frequency of hospital admissions, a higher degree of asthma severity, poorer asthma control and reduced responsiveness to corticosteroids. Furthermore, it is associated with reduced numbers of eosinophils and higher numbers of mast cells in the submucosa of the airway wall. Airway remodeling is increased as evidenced by increased epithelial thickness and goblet cell hyperplasia in smoking asthmatics. The pathogenesis responsible for smoking-induced changes in airway inflammation and remodeling in asthma is complex and largely unknown. The underlying mechanism of reduced corticosteroid responsiveness is also unknown. This article discusses differences between smoking and nonsmoking asthmatics regarding the clinical expression of asthma, lung function, response to corticosteroids, airway inflammation and remodeling processes. Possible pathogenetic mechanisms that may explain the links between cigarette smoking and changes in the clinical expression of asthma will be discussed, as well as the beneficial effects of smoking cessation.

Fatigue in isometric contraction in a single muscle fibre: a compartmental calcium ion flow model.

PubMed

Kothiyal, K P; Ibramsha, M

1986-01-01

Fatigue in muscle is a complex biological phenomenon which has so far eluded a definite explanation. Many biochemical and physiological models have been suggested in the literature to account for the decrement in the ability of muscle to sustain a given level of force for a long time. Some of these models have been critically analysed in this paper and are shown to be not able to explain all the experimental observations. A new compartmental model based on the intracellular calcium ion movement in muscle is proposed to study the mechanical responses of a muscle fibre. Computer simulation is performed to obtain model responses in isometric contraction to an impulse and a train of stimuli of long duration. The simulated curves have been compared with experimentally observed mechanical responses of the semitendinosus muscle fibre of Rana pipiens. The comparison of computed and observed responses indicates that the proposed calcium ion model indeed accounts very well for the muscle fatigue.

Mechanical injury and repair of cells

NASA Technical Reports Server (NTRS)

Miyake, Katsuya; McNeil, Paul L.

2003-01-01

OBJECTIVE: To concisely review the field of cell plasma membrane disruption (torn cell surface) and repair. MAIN POINTS: Plasma membrane disruption is a common form of cell injury under physiologic conditions, after trauma, in certain muscular dystrophies, and during certain forms of clinical intervention. Rapid repair of a disruption is essential to cell survival and involves a complex and active cell response that includes membrane fusion and cytoskeletal activation. Tissues, such as cardiac and skeletal muscle, adapt to a disruption injury by hypertrophying. Cells adapt by increasing the efficiency of their resealing response. CONCLUSION: Plasma membrane disruption is an important cellular event in both health and disease. The disruption repair mechanism is now well understood at the cellular level, but much remains to be learned at the molecular level. Cell and tissue level adaptational responses to the disruption either prevent its further occurrence or facilitate future repairs. Therapeutically useful drugs might result if, using this accumulating knowledge, chemical agents can be developed that can enhance repair or adaptive responses.

Report for MaRIE Drivers Workshop on needs for energetic material's studies.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Specht, Paul Elliott

Energetic materials (i.e. explosives, propellants, and pyrotechnics) have complex mesoscale features that influence their dynamic response. Direct measurement of the complex mechanical, thermal, and chemical response of energetic materials is critical for improving computational models and enabling predictive capabilities. Many of the physical phenomena of interest in energetic materials cover time and length scales spanning several orders of magnitude. Examples include chemical interactions in the reaction zone, the distribution and evolution of temperature fields, mesoscale deformation in heterogeneous systems, and phase transitions. This is particularly true for spontaneous phenomena, like thermal cook-off. The ability for MaRIE to capture multiple lengthmore » scales and stochastic phenomena can significantly advance our understanding of energetic materials and yield more realistic, predictive models.« less

Meeting Report: Structural Determination of Environmentally Responsive Proteins

PubMed Central

Reinlib, Leslie

2005-01-01

The three-dimensional structure of gene products continues to be a missing lynchpin between linear genome sequences and our understanding of the normal and abnormal function of proteins and pathways. Enhanced activity in this area is likely to lead to better understanding of how discrete changes in molecular patterns and conformation underlie functional changes in protein complexes and, with it, sensitivity of an individual to an exposure. The National Institute of Environmental Health Sciences convened a workshop of experts in structural determination and environmental health to solicit advice for future research in structural resolution relative to environmentally responsive proteins and pathways. The highest priorities recommended by the workshop were to support studies of structure, analysis, control, and design of conformational and functional states at molecular resolution for environmentally responsive molecules and complexes; promote understanding of dynamics, kinetics, and ligand responses; investigate the mechanisms and steps in posttranslational modifications, protein partnering, impact of genetic polymorphisms on structure/function, and ligand interactions; and encourage integrated experimental and computational approaches. The workshop participants also saw value in improving the throughput and purity of protein samples and macromolecular assemblies; developing optimal processes for design, production, and assembly of macromolecular complexes; encouraging studies on protein–protein and macromolecular interactions; and examining assemblies of individual proteins and their functions in pathways of interest for environmental health. PMID:16263521

Vascular response of ruthenium tetraamines in aortic ring from normotensive rats.

PubMed

Conceição-Vertamatti, Ana Gabriela; Ramos, Luiz Alberto Ferreira; Calandreli, Ivy; Chiba, Aline Nunes; Franco, Douglas Wagner; Tfouni, Elia; Grassi-Kassisse, Dora Maria

2015-03-01

Ruthenium (Ru) tetraamines are being increasingly used as nitric oxide (NO) carriers. In this context, pharmacological studies have become highly relevant to better understand the mechanism of action involved. To evaluate the vascular response of the tetraamines trans-[Ru(II)(NH3)4(Py)(NO)](3+), trans-[Ru(II)(Cl)(NO) (cyclan)](PF6)2, and trans-[Ru(II)(NH3)4(4-acPy)(NO)](3+). Aortic rings were contracted with noradrenaline (10(-6) M). After voltage stabilization, a single concentration (10(-6) M) of the compounds was added to the assay medium. The responses were recorded during 120 min. Vascular integrity was assessed functionally using acetylcholine at 10(-6) M and sodium nitroprusside at 10(-6) M as well as by histological examination. Histological analysis confirmed the presence or absence of endothelial cells in those tissues. All tetraamine complexes altered the contractile response induced by norepinephrine, resulting in increased tone followed by relaxation. In rings with endothelium, the inhibition of endothelial NO caused a reduction of the contractile effect caused by pyridine NO. No significant responses were observed in rings with endothelium after treatment with cyclan NO. In contrast, in rings without endothelium, the inhibition of guanylate cyclase significantly reduced the contractile response caused by the pyridine NO and cyclan NO complexes, and both complexes caused a relaxing effect. The results indicate that the vascular effect of the evaluated complexes involved a decrease in the vascular tone induced by norepinephrine (10(-6) M) at the end of the incubation period in aortic rings with and without endothelium, indicating the slow release of NO from these complexes and suggesting that the ligands promoted chemical stability to the molecule. Moreover, we demonstrated that the association of Ru with NO is more stable when the ligands pyridine and cyclan are used in the formulation of the compound.

Responses of the pulp, periradicular and soft tissues following trauma to the permanent teeth.

PubMed

Yu, C Y; Abbott, P V

2016-03-01

Trauma to the permanent teeth involves not only the teeth but also the pulp, the periodontal ligament, alveolar bone, gingiva and other associated structures. There are many variations in the types of injuries with varying severity and often a tooth may sustain more than one injury at the same time. In more severe trauma cases, there are many different cellular systems of mineralized hard and unmineralized soft tissues involved, each with varying potential for healing. Furthermore, the responses of the different tissues may be interrelated and dependent on each other. Hence, healing subsequent to dental trauma has long been known to be very complex. Because of this complexity, tissue responses and the consequences following dental trauma have been confusing and puzzling for many clinicians. In this review, the tissue responses are described under the tissue compartments typically involved following dental trauma: the pulp, periradicular and associated soft tissues. The factors involved in the mechanisms of trauma are analysed for their effects on the tissue responses. A thorough understanding of the possible tissue responses is imperative for clinicians to overcome the confusion and manage dental trauma adequately and conservatively in order to minimize the consequences following trauma. © 2016 Australian Dental Association.

Establishing an unusual cell type: How to make a dikaryon

PubMed Central

Kruzel, Emilia K.; Hull, Christina M.

2010-01-01

Summary The dikaryons of basidiomycete fungi represent an unusual cell type required for complete sexual development. Dikaryon formation occurs via the activities of cell type-specific homeodomain transcription factors, which form regulatory complexes to establish the dikaryotic state. Decades of classical genetic and cell biological studies in mushrooms have provided a foundation for more recent molecular studies in the pathogenic species Ustilago maydis and Cryptococcus neoformans. Studies in these systems have revealed novel mechanisms of regulation that function downstream of classic homeodomain complexes to ensure that dikaryons are established and propagated. Comparisons of these dikaryon-specific networks promise to reveal the nature of regulatory network evolution and the adaptations responsible for driving complex eukaryotic development. PMID:21036099

Complex chromatid-isochromatid exchanges following irradiation with heavy ions?

PubMed

Loucas, B D; Eberle, R L; Durante, M; Cornforth, M N

2004-01-01

We describe a peculiar and relatively rare type of chromosomal rearrangement induced in human peripheral lymphocytes that were ostensibly irradiated in G(0) phase of the cell cycle by accelerated heavy ions, and which, to the best of our knowledge, have not been previously described. The novel rearrangements which were detected using mFISH following exposure to 500 MeV/nucleon and 5 GeV/n 56Fe particles, but were not induced by either 137Cs gamma rays or 238Pu alpha particles, can alternatively be described as either complex chromatid-isochromatid or complex chromatid-chromosome exchanges. Different mechanisms potentially responsible for their formation are discussed. Copyright 2003 S. Karger AG, Basel

Identification of diverse nerve growth factor-regulated genes by serial analysis of gene expression (SAGE) profiling

PubMed Central

Angelastro, James M.; Klimaschewski, Lars; Tang, Song; Vitolo, Ottavio V.; Weissman, Tamily A.; Donlin, Laura T.; Shelanski, Michael L.; Greene, Lloyd A.

2000-01-01

Neurotrophic factors such as nerve growth factor (NGF) promote a wide variety of responses in neurons, including differentiation, survival, plasticity, and repair. Such actions often require changes in gene expression. To identify the regulated genes and thereby to more fully understand the NGF mechanism, we carried out serial analysis of gene expression (SAGE) profiling of transcripts derived from rat PC12 cells before and after NGF-promoted neuronal differentiation. Multiple criteria supported the reliability of the profile. Approximately 157,000 SAGE tags were analyzed, representing at least 21,000 unique transcripts. Of these, nearly 800 were regulated by 6-fold or more in response to NGF. Approximately 150 of the regulated transcripts have been matched to named genes, the majority of which were not previously known to be NGF-responsive. Functional categorization of the regulated genes provides insight into the complex, integrated mechanism by which NGF promotes its multiple actions. It is anticipated that as genomic sequence information accrues the data derived here will continue to provide information about neurotrophic factor mechanisms. PMID:10984536

Dynamics driving function: new insights from electron transferring flavoproteins and partner complexes.

PubMed

Toogood, Helen S; Leys, David; Scrutton, Nigel S

2007-11-01

Electron transferring flavoproteins (ETFs) are soluble heterodimeric FAD-containing proteins that function primarily as soluble electron carriers between various flavoprotein dehydrogenases. ETF is positioned at a key metabolic branch point, responsible for transferring electrons from up to 10 primary dehydrogenases to the membrane-bound respiratory chain. Clinical mutations of ETF result in the often fatal disease glutaric aciduria type II. Structural and biophysical studies of ETF in complex with partner proteins have shown that ETF partitions the functions of partner binding and electron transfer between (a) a 'recognition loop', which acts as a static anchor at the ETF-partner interface, and (b) a highly mobile redox-active FAD domain. Together, this enables the FAD domain of ETF to sample a range of conformations, some compatible with fast interprotein electron transfer. This 'conformational sampling' enables ETF to recognize structurally distinct partners, whilst also maintaining a degree of specificity. Complex formation triggers mobility of the FAD domain, an 'induced disorder' mechanism contrasting with the more generally accepted models of protein-protein interaction by induced fit mechanisms. We discuss the implications of the highly dynamic nature of ETFs in biological interprotein electron transfer. ETF complexes point to mechanisms of electron transfer in which 'dynamics drive function', a feature that is probably widespread in biology given the modular assembly and flexible nature of biological electron transfer systems.

Particle size affects Brassica seed meal-induced pathogen suppression of Rhizoctonia solani AG-5

USDA-ARS?s Scientific Manuscript database

R. solani AG-5 is a component of the pathogen complex that incites apple replant disease, and is suppressed via multiple mechanisms in response to B. juncea seed meal (SM) amendment. Allyl isothiocyanate (AITC) functions in suppression of this pathogen during the initial 24 h period post-seed meal a...

Northeast Artificial Intelligence Consortium Annual Report. Volume 6. 1988 Building an Intelligent Assistant: The Acquisition, Integration, and Maintenance of Complex Distributed Tasks

DTIC Science & Technology

1989-10-01

of.ezpertiae Seymour. Wright (or artificisi. intelligence distributed. ai planning robo tics computer.vsion))." Implementation: (replace-values-in-constraint...by mechanical partners or advisors that customize the system’s response to the idiosyncrasies of the student. This paper describes the initial

Perceptual conflict during sensorimotor integration processes - a neurophysiological study in response inhibition.

PubMed

Chmielewski, Witold X; Beste, Christian

2016-05-25

A multitude of sensory inputs needs to be processed during sensorimotor integration. A crucial factor for detecting relevant information is its complexity, since information content can be conflicting at a perceptual level. This may be central to executive control processes, such as response inhibition. This EEG study aims to investigate the system neurophysiological mechanisms behind effects of perceptual conflict on response inhibition. We systematically modulated perceptual conflict by integrating a Global-local task with a Go/Nogo paradigm. The results show that conflicting perceptual information, in comparison to non-conflicting perceptual information, impairs response inhibition performance. This effect was evident regardless of whether the relevant information for response inhibition is displayed on the global, or local perceptual level. The neurophysiological data suggests that early perceptual/ attentional processing stages do not underlie these modulations. Rather, processes at the response selection level (P3), play a role in changed response inhibition performance. This conflict-related impairment of inhibitory processes is associated with activation differences in (inferior) parietal areas (BA7 and BA40) and not as commonly found in the medial prefrontal areas. This suggests that various functional neuroanatomical structures may mediate response inhibition and that the functional neuroanatomical structures involved depend on the complexity of sensory integration processes.

Preface: cardiac control pathways: signaling and transport phenomena.

PubMed

Sideman, Samuel

2008-03-01

Signaling is part of a complex system of communication that governs basic cellular functions and coordinates cellular activity. Transfer of ions and signaling molecules and their interactions with appropriate receptors, transmembrane transport, and the consequent intracellular interactions and functional cellular response represent a complex system of interwoven phenomena of transport, signaling, conformational changes, chemical activation, and/or genetic expression. The well-being of the cell thus depends on a harmonic orchestration of all these events and the existence of control mechanisms that assure the normal behavior of the various parameters involved and their orderly expression. The ability of cells to sustain life by perceiving and responding correctly to their microenvironment is the basis for development, tissue repair, and immunity, as well as normal tissue homeostasis. Natural deviations, or human-induced interference in the signaling pathways and/or inter- and intracellular transport and information transfer, are responsible for the generation, modulation, and control of diseases. The present overview aims to highlight some major topics of the highly complex cellular information transfer processes and their control mechanisms. Our goal is to contribute to the understanding of the normal and pathophysiological phenomena associated with cardiac functions so that more efficient therapeutic modalities can be developed. Our objective in this volume is to identify and enhance the study of some basic passive and active physical and chemical transport phenomena, physiological signaling pathways, and their biological consequences.

[Mechanistic modelling allows to assess pathways of DNA lesion interactions underlying chromosome aberration formation].

PubMed

Eĭdel'man, Iu A; Slanina, S V; Sal'nikov, I V; Andreev, S G

2012-12-01

The knowledge of radiation-induced chromosomal aberration (CA) mechanisms is required in many fields of radiation genetics, radiation biology, biodosimetry, etc. However, these mechanisms are yet to be quantitatively characterised. One of the reasons is that the relationships between primary lesions of DNA/chromatin/chromosomes and dose-response curves for CA are unknown because the pathways of lesion interactions in an interphase nucleus are currently inaccessible for direct experimental observation. This article aims for the comparative analysis of two principally different scenarios of formation of simple and complex interchromosomal exchange aberrations: by lesion interactions at chromosome territories' surface vs. in the whole space of the nucleus. The analysis was based on quantitative mechanistic modelling of different levels of structures and processes involved in CA formation: chromosome structure in an interphase nucleus, induction, repair and interactions of DNA lesions. It was shown that the restricted diffusion of chromosomal loci, predicted by computational modelling of chromosome organization, results in lesion interactions in the whole space of the nucleus being impossible. At the same time, predicted features of subchromosomal dynamics agrees well with in vivo observations and does not contradict the mechanism of CA formation at the surface of chromosome territories. On the other hand, the "surface mechanism" of CA formation, despite having certain qualities, proved to be insufficient to explain high frequency of complex exchange aberrations observed by mFISH technique. The alternative mechanism, CA formation on nuclear centres is expected to be sufficient to explain frequent complex exchanges.

Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology

NASA Technical Reports Server (NTRS)

Ingber, Donald E.

2002-01-01

Great advances have been made in the identification of the soluble angiogenic factors, insoluble extracellular matrix (ECM) molecules, and receptor signaling pathways that mediate control of angiogenesis--the growth of blood capillaries. This review focuses on work that explores how endothelial cells integrate these chemical signals with mechanical cues from their local tissue microenvironment so as to produce functional capillary networks that exhibit specialized form as well as function. These studies have revealed that ECM governs whether an endothelial cell will switch between growth, differentiation, motility, or apoptosis programs in response to a soluble stimulus based on its ability to mechanically resist cell tractional forces and thereby produce cell and cytoskeletal distortion. Transmembrane integrin receptors play a key role in this mechanochemical transduction process because they both organize a cytoskeletal signaling complex within the focal adhesion and preferentially focus mechanical forces on this site. Molecular filaments within the internal cytoskeleton--microfilaments, microtubules, and intermediate filaments--also contribute to the cell's structural and functional response to mechanical stress through their role as discrete support elements within a tensegrity-stabilized cytoskeletal array. Importantly, a similar form of mechanical control also has been shown to be involved in the regulation of contractility in vascular smooth muscle cells and cardiac myocytes. Thus, the mechanism by which cells perform mechanochemical transduction and the implications of these findings for morphogenetic control are discussed in the wider context of vascular development and cardiovascular physiology.

Molecular genetic analysis of plant gravitropism

NASA Technical Reports Server (NTRS)

Lomax, T. L.

1997-01-01

The analysis of mutants is a powerful approach for elucidating the components of complex biological processes. A growing number of mutants have been isolated which affect plant gravitropism and the classes of mutants found thus far provide important information about the gravity response mechanism. The wide variety of mutants isolated, especially in Arabidopsis, indicates that gravitropism is a complex, multi-step process. The existence of mutants altered in either root gravitropism alone, shoot gravitropism alone, or both indicates that the root and shoot gravitropic mechanisms have both separate and common steps. Reduced starch mutants have confirmed the role of amyloplasts in sensing the gravity signal. The hormone auxin is thought to act as the transducing signal between the sites of gravity perception (the starch parenchyma cells surrounding the vascular tissue in shoots and the columella cells of root caps) and asymmetric growth (the epidermal cells of the elongation zone(s) of each organ). To date, all mutants that are resistant to high concentrations of auxin have also been found to exhibit a reduced gravitropic response, thus supporting the role of auxin. Not all gravitropic mutants are auxin-resistant, however, indicating that there are additional steps which do not involve auxin. Studies with mutants of tomato which exhibit either reduced or reversed gravitropic responses further support the role of auxin redistribution in gravitropism and suggest that both red light and cytokinin interact with gravitropism through controlling lateral auxin transport. Plant responses to gravity thus likely involve changes in both auxin transport and sensitivity.

Why individual thermo sensation and pain perception varies? Clue of disruptive mutations in TRPVs from 2504 human genome data.

PubMed

Ghosh, Arijit; Kaur, Navneet; Kumar, Abhishek; Goswami, Chandan

2016-09-02

Every individual varies in character and so do their sensory functions and perceptions. The molecular mechanism and the molecular candidates involved in these processes are assumed to be similar if not same. So far several molecular factors have been identified which are fairly conserved across the phylogenetic tree and are involved in these complex sensory functions. Among all, members belonging to Transient Receptor Potential (TRP) channels have been widely characterized for their involvement in thermo-sensation. These include TRPV1 to TRPV4 channels which reveal complex thermo-gating behavior in response to changes in temperature. The molecular evolution of these channels is highly correlative with the thermal response of different species. However, recent 2504 human genome data suggest that these thermo-sensitive TRPV channels are highly variable and carry possible deleterious mutations in human population. These unexpected findings may explain the individual differences in terms of complex sensory functions.

A functionally conserved Polycomb response element from mouse HoxD complex responds to heterochromatin factors

NASA Astrophysics Data System (ADS)

Vasanthi, Dasari; Nagabhushan, A.; Matharu, Navneet Kaur; Mishra, Rakesh K.

2013-10-01

Anterior-posterior body axis in all bilaterians is determined by the Hox gene clusters that are activated in a spatio-temporal order. This expression pattern of Hox genes is established and maintained by regulatory mechanisms that involve higher order chromatin structure and Polycomb group (PcG) and trithorax group (trxG) proteins. We identified earlier a Polycomb response element (PRE) in the mouse HoxD complex that is functionally conserved in flies. We analyzed the molecular and genetic interactions of mouse PRE using Drosophila melanogaster and vertebrate cell culture as the model systems. We demonstrate that the repressive activity of this PRE depends on PcG/trxG genes as well as the heterochromatin components. Our findings indicate that a wide range of factors interact with the HoxD PRE that can contribute to establishing the expression pattern of homeotic genes in the complex early during development and maintain that pattern at subsequent stages.

Control of cell respiration by nitric oxide in Ataxia Telangiectasia lymphoblastoid cells.

PubMed

Masci, Alessandra; Mastronicola, Daniela; Arese, Marzia; Piane, Maria; De Amicis, Andrea; Blanck, Thomas J J; Chessa, Luciana; Sarti, Paolo

2008-01-01

Ataxia Telangiectasia (AT) patients are particularly sensitive to oxidative-nitrosative stress. Nitric oxide (NO) controls mitochondrial respiration via the reversible inhibition of complex IV. The mitochondrial response to NO of AT lymphoblastoid cells was investigated. Cells isolated from three patients and three intrafamilial healthy controls were selected showing within each group a normal diploid karyotype and homogeneous telomere length. Different complex IV NO-inhibition patterns were induced by varying the electron flux through the respiratory chain, using exogenous cell membrane permeable electron donors. Under conditions of high electron flux the mitochondrial NO inhibition of respiration was greater in AT than in control cells (P< or =0.05). This property appears peculiar to AT, and correlates well to the higher concentration of cytochrome c detected in the AT cells. This finding is discussed on the basis of the proposed mechanism of reaction of NO with complex IV. It is suggested that the peculiar response of AT mitochondria to NO stress may be relevant to the mitochondrial metabolism of AT patients.

Specific excitatory connectivity for feature integration in mouse primary visual cortex

PubMed Central

Molina-Luna, Patricia; Roth, Morgane M.

2017-01-01

Local excitatory connections in mouse primary visual cortex (V1) are stronger and more prevalent between neurons that share similar functional response features. However, the details of how functional rules for local connectivity shape neuronal responses in V1 remain unknown. We hypothesised that complex responses to visual stimuli may arise as a consequence of rules for selective excitatory connectivity within the local network in the superficial layers of mouse V1. In mouse V1 many neurons respond to overlapping grating stimuli (plaid stimuli) with highly selective and facilitatory responses, which are not simply predicted by responses to single gratings presented alone. This complexity is surprising, since excitatory neurons in V1 are considered to be mainly tuned to single preferred orientations. Here we examined the consequences for visual processing of two alternative connectivity schemes: in the first case, local connections are aligned with visual properties inherited from feedforward input (a ‘like-to-like’ scheme specifically connecting neurons that share similar preferred orientations); in the second case, local connections group neurons into excitatory subnetworks that combine and amplify multiple feedforward visual properties (a ‘feature binding’ scheme). By comparing predictions from large scale computational models with in vivo recordings of visual representations in mouse V1, we found that responses to plaid stimuli were best explained by assuming feature binding connectivity. Unlike under the like-to-like scheme, selective amplification within feature-binding excitatory subnetworks replicated experimentally observed facilitatory responses to plaid stimuli; explained selective plaid responses not predicted by grating selectivity; and was consistent with broad anatomical selectivity observed in mouse V1. Our results show that visual feature binding can occur through local recurrent mechanisms without requiring feedforward convergence, and that such a mechanism is consistent with visual responses and cortical anatomy in mouse V1. PMID:29240769

Interferons and Interferon Regulatory Factors in Malaria

PubMed Central

Claser, Carla; Tan, Kevin Shyong Wei; Rénia, Laurent

2014-01-01

Malaria is one of the most serious infectious diseases in humans and responsible for approximately 500 million clinical cases and 500 thousand deaths annually. Acquired adaptive immune responses control parasite replication and infection-induced pathologies. Most infections are clinically silent which reflects on the ability of adaptive immune mechanisms to prevent the disease. However, a minority of these can become severe and life-threatening, manifesting a range of overlapping syndromes of complex origins which could be induced by uncontrolled immune responses. Major players of the innate and adaptive responses are interferons. Here, we review their roles and the signaling pathways involved in their production and protection against infection and induced immunopathologies. PMID:25157202

Role of various hormones in photosynthetic responses of green plants under environmental stresses.

PubMed

Poonam; Bhardwaj, Renu; Kaur, Ravdeep; Bali, Shagun; Kaur, Parminder; Sirhindi, Geetika; Thukral, Ashwani K; Ohri, Puja; Vig, Adarsh P

2015-01-01

Environmental stress includes adverse factors like water deficit, high salinity, enhanced temperature and heavy metals etc. These stresses alter the normal growth and metabolic processes of plants including photosynthesis. Major photosynthetic responses under various stresses include inhibition of photosystems (I and II), changes in thylakoid complexes, decreased photosynthetic activity and modifications in structure and functions of chloroplasts etc. Various defense mechanisms are triggered inside the plants in response to these stresses that are regulated by plant hormones or plant growth regulators. These phytohormones include abscisic acid, auxins, cytokinins, ethylene, brassinosteroids, jasmonates and salicylic acid etc. The present review focuses on stress protective effects of plants hormones on the photosynthetic responses.

Specificity and multiplicity in the recognition of individuals: implications for the evolution of social behaviour.

PubMed

Wiley, R H

2013-02-01

Recognition of conspecifics occurs when individuals classify sets of conspecifics based on sensory input from them and associate these sets with different responses. Classification of conspecifics can vary in specificity (the number of individuals included in a set) and multiplicity (the number of sets differentiated). In other words, the information transmitted varies in complexity. Although recognition of conspecifics has been reported in a wide variety of organisms, few reports have addressed the specificity or multiplicity of this capability. This review discusses examples of these patterns, the mechanisms that can produce them, and the evolution of these mechanisms. Individual recognition is one end of a spectrum of specificity, and binary classification of conspecifics is one end of a spectrum of multiplicity. In some cases, recognition requires no more than simple forms of learning, such as habituation, yet results in individually specific recognition. In other cases, recognition of individuals involves complex associations of multiple cues with multiple previous experiences in particular contexts. Complex mechanisms for recognition are expected to evolve only when simpler mechanisms do not provide sufficient specificity and multiplicity to obtain the available advantages. In particular, the evolution of cooperation and deception is always promoted by specificity and multiplicity in recognition. Nevertheless, there is only one demonstration that recognition of specific individuals contributes to cooperation in animals other than primates. Human capacities for individual recognition probably have a central role in the evolution of complex forms of human cooperation and deception. Although relatively little studied, this capability probably rivals cognitive abilities for language. © 2012 The Author. Biological Reviews © 2012 Cambridge Philosophical Society.

A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications.

PubMed

Pillay, Viness; Tsai, Tong-Sheng; Choonara, Yahya E; du Toit, Lisa C; Kumar, Pradeep; Modi, Girish; Naidoo, Dinesh; Tomar, Lomas K; Tyagi, Charu; Ndesendo, Valence M K

2014-06-01

Electroactive polymers (EAPs) are promising candidate materials for the design of drug delivery technologies, especially in conditions where an "on-off" drug release mechanism is required. To achieve this, EAPs such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene may be blended into responsive hydrogels in conjunction with the desired drug to obtain a patient-controlled drug release system. The "on-off" drug release mechanism can be achieved through the environmental-responsive nature of the interpenetrating hydrogel-EAP complex via (i) charged ions initiated diffusion of drug molecules; (ii) conformational changes that occur during redox switching of EAPs; or (iii) electroerosion. These release mechanisms are not exhaustive and new release mechanisms are still under investigation. Therefore, this review seeks to provide a concise incursion and critical overview of EAPs and responsive hydrogels as a strategy for advanced drug delivery, for example, controlled release of neurotransmitters, sulfosalicyclic acid from cross-linked hydrogel, and vaccine delivery. The review further discusses techniques such as linear sweep voltammetry, cyclic voltammetry, impedance spectroscopy, and chronoamperometry for the determination of the redox capability of EAPs. The future implications of the hydrogel-EAP composites include, but not limited to, application toward biosensors, DNA hybridizations, microsurgical tools, and miniature bioreactors and may be utilized to their full potential in the form of injectable devices as nanorobots or nanobiosensors. Copyright © 2013 Wiley Periodicals, Inc.

Depression as a systemic syndrome: mapping the feedback loops of major depressive disorder.

PubMed

Wittenborn, A K; Rahmandad, H; Rick, J; Hosseinichimeh, N

2016-02-01

Depression is a complex public health problem with considerable variation in treatment response. The systemic complexity of depression, or the feedback processes among diverse drivers of the disorder, contribute to the persistence of depression. This paper extends prior attempts to understand the complex causal feedback mechanisms that underlie depression by presenting the first broad boundary causal loop diagram of depression dynamics. We applied qualitative system dynamics methods to map the broad feedback mechanisms of depression. We used a structured approach to identify candidate causal mechanisms of depression in the literature. We assessed the strength of empirical support for each mechanism and prioritized those with support from validation studies. Through an iterative process, we synthesized the empirical literature and created a conceptual model of major depressive disorder. The literature review and synthesis resulted in the development of the first causal loop diagram of reinforcing feedback processes of depression. It proposes candidate drivers of illness, or inertial factors, and their temporal functioning, as well as the interactions among drivers of depression. The final causal loop diagram defines 13 key reinforcing feedback loops that involve nine candidate drivers of depression. Future research is needed to expand upon this initial model of depression dynamics. Quantitative extensions may result in a better understanding of the systemic syndrome of depression and contribute to personalized methods of evaluation, prevention and intervention.

Depression as a systemic syndrome: mapping the feedback loops of major depressive disorder

PubMed Central

Wittenborn, A. K.; Rahmandad, H.; Rick, J.; Hosseinichimeh, N.

2016-01-01

Background Depression is a complex public health problem with considerable variation in treatment response. The systemic complexity of depression, or the feedback processes among diverse drivers of the disorder, contribute to the persistence of depression. This paper extends prior attempts to understand the complex causal feedback mechanisms that underlie depression by presenting the first broad boundary causal loop diagram of depression dynamics. Method We applied qualitative system dynamics methods to map the broad feedback mechanisms of depression. We used a structured approach to identify candidate causal mechanisms of depression in the literature. We assessed the strength of empirical support for each mechanism and prioritized those with support from validation studies. Through an iterative process, we synthesized the empirical literature and created a conceptual model of major depressive disorder. Results The literature review and synthesis resulted in the development of the first causal loop diagram of reinforcing feedback processes of depression. It proposes candidate drivers of illness, or inertial factors, and their temporal functioning, as well as the interactions among drivers of depression. The final causal loop diagram defines 13 key reinforcing feedback loops that involve nine candidate drivers of depression. Conclusions Future research is needed to expand upon this initial model of depression dynamics. Quantitative extensions may result in a better understanding of the systemic syndrome of depression and contribute to personalized methods of evaluation, prevention and intervention. PMID:26621339

Physical mechanisms of solar activity effects in the middle atmosphere

NASA Technical Reports Server (NTRS)

Ebel, A.

1989-01-01

A great variety of physical mechanisms of possibly solar induced variations in the middle atmosphere has been discussed in the literature during the last decades. The views which have been put forward are often controversial in their physical consequences. The reason may be the complexity and non-linearity of the atmospheric response to comparatively weak forcing resulting from solar activity. Therefore this review focuses on aspects which seem to indicate nonlinear processes in the development of solar induced variations. Results from observations and numerical simulations are discussed.

Special Considerations in Neonatal Mechanical Ventilation.

PubMed

Dalgleish, Stacey; Kostecky, Linda; Charania, Irina

2016-12-01

Care of infants supported with mechanical ventilation is complex, time intensive, and requires constant vigilance by an expertly prepared health care team. Current evidence must guide nursing practice regarding ventilated neonates. This article highlights the importance of common language to establish a shared mental model and enhance clear communication among the interprofessional team. Knowledge regarding the underpinnings of an open lung strategy and the interplay between the pathophysiology and individual infant's response to a specific ventilator strategy is most likely to result in a positive clinical outcome. Copyright © 2016 Elsevier Inc. All rights reserved.

Polaron conductivity mechanism in oxalic acid dihydrate: ac conductivity experiment

NASA Astrophysics Data System (ADS)

Levstik, Adrijan; Filipič, Cene; Bobnar, Vid; Levstik, Iva; Hadži, Dušan

2006-10-01

The ac electrical conductivity of the oxalic acid dihydrate ( α -POX) was investigated as a function of the frequency and temperature. The real part of the complex ac electrical conductivity was found to follow the universal dielectric response σ'∝νs , indicating that hopping or tunneling of localized charge carriers governs the electrical transport. A detailed analysis of the temperature dependence of the exponent s revealed that in a broad temperature range 50-200K the tunneling of polarons is the dominating charge transport mechanism.

Enhancement of sensitivity using hybrid stimulus for the diagnosis of prostate cancer based on polydiacetylene (PDA) supramolecules.

PubMed

Kwon, Il Kyoung; Kim, Jun Pyo; Sim, Sang Jun

2010-12-15

In this study, hybrid stimulus was initially introduced to improve the sensitivity of PDA vesicle chip for detection of prostate-specific antigen-α1-antichymotrypsin (PSA-ACT) complex. The strategy of hybrid stimulus on PDA vesicle chip offers the amplification method of fluorescent signal which combines a primary response by the immune reaction of antigen-antibody and a secondary response by the mechanical pressure of pAb-conjugated magnetic beads. As the primary response result on PDA vesicle chip, the PSA-ACT complex in PBS buffer was detected at 10 ng/mL. However, this detection sensitivity was insufficient for diagnosis of prostate cancer because the normal human PSA concentration is less than 4.0 ng/mL. To solve this problem, polyclonal PSA antibody-conjugated magnetic beads were used as an amplifying agent after primary immunoresponse. As a result, the PSA-ACT complex concentrations (as low as 0.1 ng/mL) could be detected in the PBS buffer sample. Therefore, this result can be applied to various fields, such as the detection of cells, proteins, and DNA for sensitive and specific biosensing based on PDA supramolecules. Copyright © 2010 Elsevier B.V. All rights reserved.

Solving Immunology?

PubMed

Vodovotz, Yoram; Xia, Ashley; Read, Elizabeth L; Bassaganya-Riera, Josep; Hafler, David A; Sontag, Eduardo; Wang, Jin; Tsang, John S; Day, Judy D; Kleinstein, Steven H; Butte, Atul J; Altman, Matthew C; Hammond, Ross; Sealfon, Stuart C

2017-02-01

Emergent responses of the immune system result from the integration of molecular and cellular networks over time and across multiple organs. High-content and high-throughput analysis technologies, concomitantly with data-driven and mechanistic modeling, hold promise for the systematic interrogation of these complex pathways. However, connecting genetic variation and molecular mechanisms to individual phenotypes and health outcomes has proven elusive. Gaps remain in data, and disagreements persist about the value of mechanistic modeling for immunology. Here, we present the perspectives that emerged from the National Institute of Allergy and Infectious Disease (NIAID) workshop 'Complex Systems Science, Modeling and Immunity' and subsequent discussions regarding the potential synergy of high-throughput data acquisition, data-driven modeling, and mechanistic modeling to define new mechanisms of immunological disease and to accelerate the translation of these insights into therapies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Assessing field-scale biogeophysical signatures of bioremediation over a mature crude oil spill

USGS Publications Warehouse

Slater, Lee; Ntarlagiannis, Dimitrios; Atekwana, Estella; Mewafy, Farag; Revil, Andre; Skold, Magnus; Gorby, Yuri; Day-Lewis, Frederick D.; Lane, John W.; Trost, Jared J.; Werkema, Dale D.; Delin, Geoffrey N.; Herkelrath, William N.; Rectanus, H.V.; Sirabian, R.

2011-01-01

We conducted electrical geophysical measurements at the National Crude Oil Spill Fate and Natural Attenuation Research Site (Bemidji, MN). Borehole and surface self-potential measurements do not show evidence for the existence of a biogeobattery mechanism in response to the redox gradient resulting from biodegradation of oil. The relatively small self potentials recorded are instead consistent with an electrodiffusion mechanism driven by differences in the mobility of charge carriers associated with biodegradation byproducts. Complex resistivity measurements reveal elevated electrical conductivity and interfacial polarization at the water table where oil contamination is present, extending into the unsaturated zone. This finding implies that the effect of microbial cell growth/attachment, biofilm formation, and mineral weathering accompanying hydrocarbon biodegradation on complex interfacial conductivity imparts a sufficiently large electrical signal to be measured using field-scale geophysical techniques.

Molecular assembly of Clostridium botulinum progenitor M complex of type E

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eswaramoorthy, Subramaniam; Sun, Jingchuan; Li, Huilin

2015-12-07

Clostridium botulinum neurotoxin (BoNT) is released as a progenitor complex, in association with a non-toxic-non-hemagglutinin protein (NTNH) and other associated proteins. We have determined the crystal structure of M type Progenitor complex of botulinum neurotoxin E [PTC-E(M)], a heterodimer of BoNT and NTNH. The crystal structure reveals that the complex exists as a tight, interlocked heterodimer of BoNT and NTNH. The crystal structure explains the mechanism of molecular assembly of the complex and reveals several acidic clusters at the interface responsible for association at low acidic pH and disassociation at basic/neutral pH. Furthermore, the similarity of the general architecture betweenmore » the PTC-E(M) and the previously determined PTC-A(M) strongly suggests that the progenitor M complexes of all botulinum serotypes may have similar molecular arrangement, although the neurotoxins apparently can take very different conformation when they are released from the M complex.« less

Mechanical responses, texture evolution, and yield loci of extruded AZ31 magnesium alloy under various loading conditions: Experiment and modeling

NASA Astrophysics Data System (ADS)

Kabirian, Farhoud

Mechanical responses and texture evolution of extruded AZ31 Mg are measured under uniaxial (tension-compression) and multiaxial (free-end torsion) loadings. Compression loading is carried out in three different directions at temperature and strain rate ranges of 77-423 K and 10-4 -3000 s -1, respectively. Texture evolution at different intermediate strains reveals that crystal reorientation is exhausted at smaller strains with increase in strain rate while increase in temperature retards twinning. In addition to the well-known tension-compression yield asymmetry, a strong anisotropy in strain hardening response is observed. Strain hardening during the compression experiment is intensified with decreasing and increasing temperature and strain rate, respectively. This complex behavior is explained through understanding the roles of deformation mechanisms using the Visco-Plastic Self Consistent (VPSC) model. In order to calibrate the VPSC model's constants as accurate as possible, a vast number of mechanical responses including stress-strain curves in tension, compression in three directions, and free-end torsion, texture evolution at different strains, lateral strains of compression samples, twin volume fraction, and axial strain during the torsion experiment. Modeling results show that depending on the number of measurements used for calibration, roles of different mechanisms in plastic deformation change significantly. In addition, a precise definition of yield is established for the extruded AZ31magnesium alloy after it is subjected to different loading conditions (uniaxial to multiaxial) at four different plastic strains. The yield response is measured in ?-? space. Several yield criteria are studied to predict yield response of extruded AZ31. This study proposes an asymmetrical fourth-order polynomial yield function. Material constants in this model can be directly calculated using mechanical measurements. Convexity of the proposed model is discussed, and domains of constants where convexity holds are determined. Effects of grain refinement induced by Equal Channel Angular Pressing, ECAP, on mechanical responses and texture evolution are investigated. Yield strength in compression increases after ECAP, however, strain-hardening rate drops with number of ECAP passes while failure strain increases. Texture measurements reveal the higher propensity to twinning in the extruded material compared with ECAPed magnesium. Calculated Schmid factor maps are utilized to connect the observed mechanical responses to the texture.

Overlearned responses hinder S-R binding.

PubMed

Moeller, Birte; Frings, Christian

2017-01-01

Two mechanisms that are important for human action control are the integration of individual action plans (see Hommel, Müsseler, Aschersleben, & Prinz, 2001) and the automatization of overlearned actions to familiar stimuli (see Logan, 1988). In the present study, we analyzed the influence of automatization on action plan integration. Integration with pronunciation responses were compared for response incompatible word and nonword stimuli. Stimulus-response binding effects were observed for nonwords. In contrast, words that automatically triggered an overlearned pronunciation response were not integrated with pronunciation of a different word. That is, automatized response retrieval hindered binding effects regarding the retrieving stimulus and a new response. The results are a first indication of the way that binding and learning processes interact, and might also be a first step to understanding the more complex interdependency of the processes responsible for stimulus-response binding in action control and stimulus-response associations in learning research. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Relationship between mechanical-property and energy-absorption trends for composite tubes

NASA Technical Reports Server (NTRS)

Farley, Gary L.

1992-01-01

U.S. Army helicopters are designed to dissipate prescribed levels of crash impact kinetic energy without compromising the integrity of the fuselage. Because of the complexity of the energy-absorption process it is imperative for designers of energy-absorbing structures to develop an in-depth understanding of how and why composite structures absorb energy. A description of the crushing modes and mechanisms of energy absorption for composite tubes and beams is presented. Three primary crushing modes of composite structures including transverse shearing, lamina bending, and local buckling are described. The experimental data presented show that fiber and matrix mechanical properties and laminate stiffness and strength mechanical properties cannot reliably predict the energy-absorption response of composite tubes.

Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo.

PubMed

Cuende, Julia; Liénart, Stéphanie; Dedobbeleer, Olivier; van der Woning, Bas; De Boeck, Gitte; Stockis, Julie; Huygens, Caroline; Colau, Didier; Somja, Joan; Delvenne, Philippe; Hannon, Muriel; Baron, Frédéric; Dumoutier, Laure; Renauld, Jean-Christophe; De Haard, Hans; Saunders, Michael; Coulie, Pierre G; Lucas, Sophie

2015-04-22

Regulatory T cells (Tregs) are essential to prevent autoimmunity, but excessive Treg function contributes to cancer progression by inhibiting antitumor immune responses. Tregs exert contact-dependent inhibition of immune cells through the production of active transforming growth factor-β1 (TGF-β1). On the Treg cell surface, TGF-β1 is in an inactive form bound to membrane protein GARP and then activated by an unknown mechanism. We demonstrate that GARP is involved in this activation mechanism. Two anti-GARP monoclonal antibodies were generated that block the production of active TGF-β1 by human Tregs. These antibodies recognize a conformational epitope that requires amino acids GARP137-139 within GARP/TGF-β1 complexes. A variety of antibodies recognizing other GARP epitopes did not block active TGF-β1 production by Tregs. In a model of xenogeneic graft-versus-host disease in NSG mice, the blocking antibodies inhibited the immunosuppressive activity of human Tregs. These antibodies may serve as therapeutic tools to boost immune responses to infection or cancer via a mechanism of action distinct from that of currently available immunomodulatory antibodies. Used alone or in combination with tumor vaccines or antibodies targeting the CTLA4 or PD1/PD-L1 pathways, blocking anti-GARP antibodies may improve the efficiency of cancer immunotherapy. Copyright © 2015, American Association for the Advancement of Science.

Analytical Modelling and Optimization of the Temperature-Dependent Dynamic Mechanical Properties of Fused Deposition Fabricated Parts Made of PC-ABS.

PubMed

Mohamed, Omar Ahmed; Masood, Syed Hasan; Bhowmik, Jahar Lal

2016-11-04

Fused deposition modeling (FDM) additive manufacturing has been intensively used for many industrial applications due to its attractive advantages over traditional manufacturing processes. The process parameters used in FDM have significant influence on the part quality and its properties. This process produces the plastic part through complex mechanisms and it involves complex relationships between the manufacturing conditions and the quality of the processed part. In the present study, the influence of multi-level manufacturing parameters on the temperature-dependent dynamic mechanical properties of FDM processed parts was investigated using IV-optimality response surface methodology (RSM) and multilayer feed-forward neural networks (MFNNs). The process parameters considered for optimization and investigation are slice thickness, raster to raster air gap, deposition angle, part print direction, bead width, and number of perimeters. Storage compliance and loss compliance were considered as response variables. The effect of each process parameter was investigated using developed regression models and multiple regression analysis. The surface characteristics are studied using scanning electron microscope (SEM). Furthermore, performance of optimum conditions was determined and validated by conducting confirmation experiment. The comparison between the experimental values and the predicted values by IV-Optimal RSM and MFNN was conducted for each experimental run and results indicate that the MFNN provides better predictions than IV-Optimal RSM.

High-potential defense mechanisms of neocortex in a rat model of transient asphyxia induced cardiac arrest.

PubMed

Keilhoff, Gerburg; Esser, Torben; Titze, Maximilian; Ebmeyer, Uwe; Schild, Lorenz

2017-11-01

Cardiac arrest (CA) is a common cause of disability and mortality and thus an important risk for human health. Circulatory failure has dramatic consequences for the brain as one of the most oxygen-consuming organs. Hippocampus, striatum and neocortex rate among the most vulnerable brain regions. The neocortex is less sensitive to hypoxia/reperfusion in comparison with the hippocampal CA1 region. That implicates the existence of efficient defense mechanisms in the neocortex against hypoxia/reperfusion injury, which we analyzed in a well-established CA rat model. We explored different immunohistochemical markers (NeuN, MAP2, GFAP, IBA1, NOX4, MnSOD, Bax, caspase 3, cfos, nNOS, eNOS, iNOS, TUNEL), amount of mitochondria, activities of respiratory chain complexes and amount/composition of cardiolipin. CA induced a moderate degeneration of cortical neurons. As possible defense mechanisms the study revealed: (i) increased activities of respiratory chain complexes of cortical mitochondria as response to increased energy demand after ACA-induced cell stress; (ii) increase of cardiolipin content as cellular stress response, which might contribute to the promotion of mitochondrial ATP synthesis; (iii) strengthening of the fast, effective and long-lasting mitochondrial MnSOD defense system; (iv) ACA-induced increase in expression of eNOS and nNOS in vasculature being able to reduce ischemic injury by vasodilation. Copyright © 2017 Elsevier B.V. All rights reserved.

Analytical Modelling and Optimization of the Temperature-Dependent Dynamic Mechanical Properties of Fused Deposition Fabricated Parts Made of PC-ABS

PubMed Central

Mohamed, Omar Ahmed; Masood, Syed Hasan; Bhowmik, Jahar Lal

2016-01-01

Fused deposition modeling (FDM) additive manufacturing has been intensively used for many industrial applications due to its attractive advantages over traditional manufacturing processes. The process parameters used in FDM have significant influence on the part quality and its properties. This process produces the plastic part through complex mechanisms and it involves complex relationships between the manufacturing conditions and the quality of the processed part. In the present study, the influence of multi-level manufacturing parameters on the temperature-dependent dynamic mechanical properties of FDM processed parts was investigated using IV-optimality response surface methodology (RSM) and multilayer feed-forward neural networks (MFNNs). The process parameters considered for optimization and investigation are slice thickness, raster to raster air gap, deposition angle, part print direction, bead width, and number of perimeters. Storage compliance and loss compliance were considered as response variables. The effect of each process parameter was investigated using developed regression models and multiple regression analysis. The surface characteristics are studied using scanning electron microscope (SEM). Furthermore, performance of optimum conditions was determined and validated by conducting confirmation experiment. The comparison between the experimental values and the predicted values by IV-Optimal RSM and MFNN was conducted for each experimental run and results indicate that the MFNN provides better predictions than IV-Optimal RSM. PMID:28774019

Nonlinear oscillatory rheology and structure of wormlike micellar solutions and colloidal suspensions

NASA Astrophysics Data System (ADS)

Gurnon, Amanda Kate

The complex, nonlinear flow behavior of soft materials transcends industrial applications, smart material design and non-equilibrium thermodynamics. A long-standing, fundamental challenge in soft-matter science is establishing a quantitative connection between the deformation field, local microstructure and macroscopic dynamic flow properties i.e., the rheology. Soft materials are widely used in consumer products and industrial processes including energy recovery, surfactants for personal healthcare (e.g. soap and shampoo), coatings, plastics, drug delivery, medical devices and therapeutics. Oftentimes, these materials are processed by, used during, or exposed to non-equilibrium conditions for which the transient response of the complex fluid is critical. As such, designing new dynamic experiments is imperative to testing these materials and further developing micromechanical models to predict their transient response. Two of the most common classes of these soft materials stand as the focus of the present research; they are: solutions of polymer-like micelles (PLM or also known as wormlike micelles, WLM) and concentrated colloidal suspensions. In addition to their varied applications these two different classes of soft materials are also governed by different physics. In contrast, to the shear thinning behavior of the WLMs at high shear rates, the near hard-sphere colloidal suspensions are known to display increases, sometimes quite substantial, in viscosity (known as shear thickening). The stress response of these complex fluids derive from the shear-induced microstructure, thus measurements of the microstructure under flow are critical for understanding the mechanisms underlying the complex, nonlinear rheology of these complex fluids. A popular micromechanical model is reframed from its original derivation for predicting steady shear rheology of polymers and WLMs to be applicable to weakly nonlinear oscillatory shear flow. The validity, utility and limits of this constitutive model are tested by comparison with experiments on model WLM solutions. Further comparisons to the nonlinear oscillatory shear responses measured from colloidal suspensions establishes this analysis as a promising, quantitative method for understanding the underlying mechanisms responsible for the nonlinear dynamic response of complex fluids. A new experimental technique is developed to measure the microstructure of complex fluids during steady and transient shear flow using small-angle neutron scattering (SANS). The Flow-SANS experimental method is now available to the broader user communities at the NIST Center for Neutron Research, Gaithersburg, MD and the Institut Laue-Langevin, Grenoble, France. Using this new method, a model shear banding WLM solution is interrogated under steady and oscillatory shear. For the first time, the flow-SANS methods identify new metastable states for shear banding WLM solutions, thus establishing the method as capable of probing new states not accessible using traditional steady or linear oscillatory shear methods. The flow-induced three-dimensional microstructure of a colloidal suspension under steady and dynamic oscillatory shear is also measured using these rheo- and flow-SANS methods. A new structure state is identified in the shear thickening regime that proves critical for defining the "hydrocluster" microstructure state of the suspension that is responsible for shear thickening. For both the suspensions and the WLM solutions, stress-SANS rules with the measured microstructures define the individual stress components arising separately from conservative and hydrodynamic forces and these are compared with the macroscopic rheology. Analysis of these results defines the crucial length- and time-scales of the transient microstructure response. The novel dynamic microstructural measurements presented in this dissertation provide new insights into the complexities of shear thickening and shear banding flow phenomena, which are effects observed more broadly across many different types of soft materials. Consequently, the microstructure-rheology property relationships developed for these two classes of complex fluids will aid in the testing and advancement of micromechanical constitutive model development, smart material design, industrial processing and fundamental non-equilibrium thermodynamic research of a broad range of soft materials.

Functional compartmentalization of Rad9 and Hus1 reveals diverse assembly of the 9‐1‐1 complex components during the DNA damage response in Leishmania

PubMed Central

Damasceno, Jeziel D.; Obonaga, Ricardo; Santos, Elaine V.; Scott, Alan; McCulloch, Richard

2016-01-01

Summary The Rad9‐Rad1‐Hus1 (9‐1‐1) complex is a key component in the coordination of DNA damage sensing, cell cycle progression and DNA repair pathways in eukaryotic cells. This PCNA‐related trimer is loaded onto RPA‐coated single stranded DNA and interacts with ATR kinase to mediate effective checkpoint signaling to halt the cell cycle and to promote DNA repair. Beyond these core activities, mounting evidence suggests that a broader range of functions can be provided by 9‐1‐1 structural diversification. The protozoan parasite Leishmania is an early‐branching eukaryote with a remarkably plastic genome, which hints at peculiar genome maintenance mechanisms. Here, we investigated the existence of homologs of the 9‐1‐1 complex subunits in L. major and found that LmRad9 and LmRad1 associate with chromatin in response to replication stress and form a complex in vivo with LmHus1. Similar to LmHus1, LmRad9 participates in telomere homeostasis and in the response to both replication stress and double strand breaks. However, LmRad9 and LmHus1‐deficient cells present markedly opposite phenotypes, which suggest their functional compartmentalization. We show that some of the cellular pool of LmRad9 forms an alternative complex and that some of LmHus1 exists as a monomer. We propose that the diverse assembly of the Leishmania 9‐1‐1 subunits mediates functional compartmentalization, which has a direct impact on the response to genotoxic stress. PMID:27301589

The Candida albicans Inhibitory Activity of the Extract from Papaya (Carica papaya L.) Seed Relates to Mitochondria Dysfunction.

PubMed

Zhang, Tao; Chen, Weijun

2017-08-25

The inhibitory activity of the papaya seed extract (PSE) on Candida albicans ( C. albicans ) was determined by turbidimetry method. The inhibitory mechanisms were also evaluated from the prospective of reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) decrease, and the activities of four complex enzymes in mitochondria respiratory chain. Results obtained from this study indicated that the PSE exhibited an effective inhibitory activity on C. albicans and induced significant accumulation of ROS and collapse of MMP. The Complex I and Complex III exhibited continues significant decrease in mitochondrial enzyme activity assays, but the Complex II and Complex IV activities were not positively correlated. Furthermore, the GC-MS analysis demonstrated that the PSE represents a rich and high-purity source of benzyl isothiocyanate (BITC), which indicated the BITC may be responsible for the mitochondrial dysfunction.

Kinetics of the iodine- and bromine-mediated transport of halide ions: demonstration of an interfacial complexation mechanism.

PubMed Central

Klotz, K H; Benz, R

1993-01-01

Stationary and kinetic experiments were performed on lipid bilayer membranes to study the mechanism of iodine- and bromine-mediated halide transport in detail. The stationary conductance data suggested that four different 1:1 complexes between I2 and Br2 and the halides I- and Br- were responsible for the observed conductance increase by iodine and bromine (I3-, I2Br-, Br2I-, and Br3-). Charge pulse experiments allowed the further elucidation of the transport mechanism. Only two of three exponential voltage relaxations predicted by the Läuger model could be resolved under all experimental conditions. This means that either the heterogeneous complexation reactions kR (association) and kD (dissociation) were too fast to be resolved or that the neutral carriers were always in equilibrium within the membrane. Experiments at different carrier and halide concentrations suggested that the translocation of the neutral carrier is much faster than the other processes involved in carrier-mediated ion transport. The model was modified accordingly. From the charge pulse data at different halide concentrations, the translocation rate constant of the complexed carriers, kAS, the dissociation constant, kD, and the total surface concentration of charged carriers, NAS, could be evaluated from one single charge pulse experiment. The association rate of the complex, kR, could be obtained in some cases from the plot of the stationary conductance data as a function of the halide concentration in the aqueous phase. The translocation rate constant, kAS, of the different complexes is a function of the image force and of the Born charging energy. It increases 5000-fold from Br3- to I3- because of an enlarged ion radius. PMID:8312500

Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype

PubMed Central

Tsuda, Takeshi; Fitzgerald, Kristi K.

2017-01-01

Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts. PMID:29367543

Role of Microenvironment in Glioma Invasion: What We Learned from In Vitro Models

PubMed Central

Manini, Ivana; Caponnetto, Federica; Bartolini, Anna; Ius, Tamara; Mariuzzi, Laura; Di Loreto, Carla; Cesselli, Daniela

2018-01-01

The invasion properties of glioblastoma hamper a radical surgery and are responsible for its recurrence. Understanding the invasion mechanisms is thus critical to devise new therapeutic strategies. Therefore, the creation of in vitro models that enable these mechanisms to be studied represents a crucial step. Since in vitro models represent an over-simplification of the in vivo system, in these years it has been attempted to increase the level of complexity of in vitro assays to create models that could better mimic the behaviour of the cells in vivo. These levels of complexity involved: 1. The dimension of the system, moving from two-dimensional to three-dimensional models; 2. The use of microfluidic systems; 3. The use of mixed cultures of tumour cells and cells of the tumour micro-environment in order to mimic the complex cross-talk between tumour cells and their micro-environment; 4. And the source of cells used in an attempt to move from commercial lines to patient-based models. In this review, we will summarize the evidence obtained exploring these different levels of complexity and highlighting advantages and limitations of each system used. PMID:29300332

Micromechanical response of articular cartilage to tensile load measured using nonlinear microscopy.

PubMed

Bell, J S; Christmas, J; Mansfield, J C; Everson, R M; Winlove, C P

2014-06-01

Articular cartilage (AC) is a highly anisotropic biomaterial, and its complex mechanical properties have been a topic of intense investigation for over 60 years. Recent advances in the field of nonlinear optics allow the individual constituents of AC to be imaged in living tissue without the need for exogenous contrast agents. Combining mechanical testing with nonlinear microscopy provides a wealth of information about microscopic responses to load. This work investigates the inhomogeneous distribution of strain in loaded AC by tracking the movement and morphological changes of individual chondrocytes using point pattern matching and Bayesian modeling. This information can be used to inform models of mechanotransduction and pathogenesis, and is readily extendable to various other connective tissues. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Pulse oximeter as a sensor of fluid responsiveness: do we have our finger on the best solution?

PubMed Central

Monnet, Xavier; Lamia, Bouchra; Teboul, Jean-Louis

2005-01-01

The pulse oximetry plethysmographic signal resembles the peripheral arterial pressure waveform, and the degree of respiratory variation in the pulse oximetry wave is close to the degree of respiratory arterial pulse pressure variation. Thus, it is tempting to speculate that pulse oximetry can be used to assess preload responsiveness in mechanically ventilated patients. In this commentary we briefly review the complex meaning of the pulse oximetry plethysmographic signal and highlight the advantages, limitations and pitfalls of the pulse oximetry method. Future studies including volume challenge must be performed to test whether the pulse oximetry waveform can really serve as a nonivasive tool for the guidance of fluid therapy in patients receiving mechanical ventilation in intensive care units and in operating rooms. PMID:16277729

Flexibility of centromere and kinetochore structures

PubMed Central

Burrack, Laura S.; Berman, Judith

2012-01-01

Centromeres, and the kinetochores that assemble on them, are essential for accurate chromosome segregation. Diverse centromere organization patterns and kinetochore structures have evolved in eukaryotes ranging from yeast to humans. In addition, centromere DNA and kinetochore position can vary even within individual cells. This flexibility manifests in several ways: centromere DNA sequences evolve rapidly, kinetochore positions shift in response to altered chromosome structure, and kinetochore complex numbers change in response to fluctuations in kinetochore protein levels. Despite their differences, all of these diverse structures promote efficient chromosome segregation. This robustness is inherent to chromosome segregation mechanisms and balances genome stability with adaptability. In this review, we explore the mechanisms and consequences of centromere and kinetochore flexibility as well as the benefits and limitations of different experimental model systems for studying them. PMID:22445183

Recent advances in understanding neurotrophin signaling

PubMed Central

Bothwell, Mark

2016-01-01

The nerve growth factor family of growth factors, collectively known as neurotrophins, are evolutionarily ancient regulators with an enormous range of biological functions. Reflecting this long history and functional diversity, mechanisms for cellular responses to neurotrophins are exceptionally complex. Neurotrophins signal through p75 NTR, a member of the TNF receptor superfamily member, and through receptor tyrosine kinases (TrkA, TrkB, TrkC), often with opposite functional outcomes. The two classes of receptors are activated preferentially by proneurotrophins and mature processed neurotrophins, respectively. However, both receptor classes also possess neurotrophin-independent signaling functions. Signaling functions of p75 NTR and Trk receptors are each influenced by the other class of receptors. This review focuses on the mechanisms responsible for the functional interplay between the two neurotrophin receptor signaling systems. PMID:27540475

Recent advances in understanding neurotrophin signaling.

PubMed

Bothwell, Mark

2016-01-01

The nerve growth factor family of growth factors, collectively known as neurotrophins, are evolutionarily ancient regulators with an enormous range of biological functions. Reflecting this long history and functional diversity, mechanisms for cellular responses to neurotrophins are exceptionally complex. Neurotrophins signal through p75 (NTR), a member of the TNF receptor superfamily member, and through receptor tyrosine kinases (TrkA, TrkB, TrkC), often with opposite functional outcomes. The two classes of receptors are activated preferentially by proneurotrophins and mature processed neurotrophins, respectively. However, both receptor classes also possess neurotrophin-independent signaling functions. Signaling functions of p75 (NTR) and Trk receptors are each influenced by the other class of receptors. This review focuses on the mechanisms responsible for the functional interplay between the two neurotrophin receptor signaling systems.

Recrystallization and superplasticity at 300 C in an aluminum-magnesium alloy

NASA Technical Reports Server (NTRS)

Hales, S. J.; Mcnelley, T. R.; Mcqueen, H. J.

1991-01-01

Variations in thermomechanical processing (TMP) which regulate the microstructural characteristics and superplastic response of an Al-10Mg-0.1Zr alloy at 300 C were evaluated. Mechanical property data revealed that the superplastic ductility can be enhanced by simultaneously increasing the total rolling strain, the reduction per pass, and the duration of reheating intervals between passes during isothermal rolling. Texture and microscopy data were consistent with the development of a refined microstructure by recovery-dominated processes, i.e., continuous recrystallization, during the processing. The mechanisms by which a refined substructure can be progressively converted into a fine-grained structure during repeated cycles of deformation and annealing are addressed. A qualitative description of the complex sequence of developments leading to a microstructure better suited to support superplastic response is presented.

Electric foot shock stress adaptation: Does it exist or not?

PubMed

Bali, Anjana; Jaggi, Amteshwar Singh

2015-06-01

Stress adaptation is a protective phenomenon against repeated stress exposure and is characterized by a decreased responsiveness to a repeated stress stimulus. The adaptation is associated with a complex cascade of events, including the changes in behavior, neurotransmitter and gene expression levels. The non-adaptation or maladaptation to stress may underlie the affective disorders, such as anxiety, depression and post-traumatic stress disorder (PTSD). Electric foot shock is a complex stressor, which includes both physical and emotional components. Unlike immobilization, restraint and cold immersion stress, the phenomenon of stress adaptation is not very well defined in response to electric foot shock. A number of preclinical studies have reported the development of adaptation to electric foot shock stress. However, evidence also reveals the non-adaptive behavior in response to foot shocks. The distinct adaptive/non-adaptive responses may be possibly influenced by the type, intensity, and duration of the stress. The present review discusses the existence or non-existence of adaptation to electric foot shock stress along with possible mechanism. Copyright © 2015 Elsevier Inc. All rights reserved.

Age-related differences in reaction time task performance in young children.

PubMed

Kiselev, Sergey; Espy, Kimberly Andrews; Sheffield, Tiffany

2009-02-01

Performance of reaction time (RT) tasks was investigated in young children and adults to test the hypothesis that age-related differences in processing speed supersede a "global" mechanism and are a function of specific differences in task demands and processing requirements. The sample consisted of 54 4-year-olds, 53 5-year-olds, 59 6-year-olds, and 35 adults from Russia. Using the regression approach pioneered by Brinley and the transformation method proposed by Madden and colleagues and Ridderinkhoff and van der Molen, age-related differences in processing speed differed among RT tasks with varying demands. In particular, RTs differed between children and adults on tasks that required response suppression, discrimination of color or spatial orientation, reversal of contingencies of previously learned stimulus-response rules, and greater stimulus-response complexity. Relative costs of these RT task differences were larger than predicted by the global difference hypothesis except for response suppression. Among young children, age-related differences larger than predicted by the global difference hypothesis were evident when tasks required color or spatial orientation discrimination and stimulus-response rule complexity, but not for response suppression or reversal of stimulus-response contingencies. Process-specific, age-related differences in processing speed that support heterochronicity of brain development during childhood were revealed.

[Systemic immunological response in children with chronic gingivitis and gastro-intestinal pathology].

PubMed

Romanenko, E G

2014-01-01

Study of the immune system mechanisms in chronic catarrhal gingivitis in children with gastrointestinal pathology was performed in 102 children (49 with chronic gastritis and duodenitis and 53 with no signs of gastrointestinal pathology). Forty-eight children with healthy periodontium constituted control group. Generalized chronic catarrhal gingivitis in children with gastroduodenal pathology is characterized by intense humoral response by simultaneous T-cell immunity suppression. Detection of high serum titers of circulating immune complexes in patients with chronic catarrhal gingivitis suggests a role of immune response in the pathogenesis of periodontal disease increases with concomitant diseases of the upper gastrointestinal tract.

Abiotic Stress Responses and Microbe-Mediated Mitigation in Plants: The Omics Strategies

PubMed Central

Meena, Kamlesh K.; Sorty, Ajay M.; Bitla, Utkarsh M.; Choudhary, Khushboo; Gupta, Priyanka; Pareek, Ashwani; Singh, Dhananjaya P.; Prabha, Ratna; Sahu, Pramod K.; Gupta, Vijai K.; Singh, Harikesh B.; Krishanani, Kishor K.; Minhas, Paramjit S.

2017-01-01

Abiotic stresses are the foremost limiting factors for agricultural productivity. Crop plants need to cope up adverse external pressure created by environmental and edaphic conditions with their intrinsic biological mechanisms, failing which their growth, development, and productivity suffer. Microorganisms, the most natural inhabitants of diverse environments exhibit enormous metabolic capabilities to mitigate abiotic stresses. Since microbial interactions with plants are an integral part of the living ecosystem, they are believed to be the natural partners that modulate local and systemic mechanisms in plants to offer defense under adverse external conditions. Plant-microbe interactions comprise complex mechanisms within the plant cellular system. Biochemical, molecular and physiological studies are paving the way in understanding the complex but integrated cellular processes. Under the continuous pressure of increasing climatic alterations, it now becomes more imperative to define and interpret plant-microbe relationships in terms of protection against abiotic stresses. At the same time, it also becomes essential to generate deeper insights into the stress-mitigating mechanisms in crop plants for their translation in higher productivity. Multi-omics approaches comprising genomics, transcriptomics, proteomics, metabolomics and phenomics integrate studies on the interaction of plants with microbes and their external environment and generate multi-layered information that can answer what is happening in real-time within the cells. Integration, analysis and decipherization of the big-data can lead to a massive outcome that has significant chance for implementation in the fields. This review summarizes abiotic stresses responses in plants in-terms of biochemical and molecular mechanisms followed by the microbe-mediated stress mitigation phenomenon. We describe the role of multi-omics approaches in generating multi-pronged information to provide a better understanding of plant–microbe interactions that modulate cellular mechanisms in plants under extreme external conditions and help to optimize abiotic stresses. Vigilant amalgamation of these high-throughput approaches supports a higher level of knowledge generation about root-level mechanisms involved in the alleviation of abiotic stresses in organisms. PMID:28232845

Abiotic Stress Responses and Microbe-Mediated Mitigation in Plants: The Omics Strategies.

PubMed

Meena, Kamlesh K; Sorty, Ajay M; Bitla, Utkarsh M; Choudhary, Khushboo; Gupta, Priyanka; Pareek, Ashwani; Singh, Dhananjaya P; Prabha, Ratna; Sahu, Pramod K; Gupta, Vijai K; Singh, Harikesh B; Krishanani, Kishor K; Minhas, Paramjit S

2017-01-01

Abiotic stresses are the foremost limiting factors for agricultural productivity. Crop plants need to cope up adverse external pressure created by environmental and edaphic conditions with their intrinsic biological mechanisms, failing which their growth, development, and productivity suffer. Microorganisms, the most natural inhabitants of diverse environments exhibit enormous metabolic capabilities to mitigate abiotic stresses. Since microbial interactions with plants are an integral part of the living ecosystem, they are believed to be the natural partners that modulate local and systemic mechanisms in plants to offer defense under adverse external conditions. Plant-microbe interactions comprise complex mechanisms within the plant cellular system. Biochemical, molecular and physiological studies are paving the way in understanding the complex but integrated cellular processes. Under the continuous pressure of increasing climatic alterations, it now becomes more imperative to define and interpret plant-microbe relationships in terms of protection against abiotic stresses. At the same time, it also becomes essential to generate deeper insights into the stress-mitigating mechanisms in crop plants for their translation in higher productivity. Multi-omics approaches comprising genomics, transcriptomics, proteomics, metabolomics and phenomics integrate studies on the interaction of plants with microbes and their external environment and generate multi-layered information that can answer what is happening in real-time within the cells. Integration, analysis and decipherization of the big-data can lead to a massive outcome that has significant chance for implementation in the fields. This review summarizes abiotic stresses responses in plants in-terms of biochemical and molecular mechanisms followed by the microbe-mediated stress mitigation phenomenon. We describe the role of multi-omics approaches in generating multi-pronged information to provide a better understanding of plant-microbe interactions that modulate cellular mechanisms in plants under extreme external conditions and help to optimize abiotic stresses. Vigilant amalgamation of these high-throughput approaches supports a higher level of knowledge generation about root-level mechanisms involved in the alleviation of abiotic stresses in organisms.

Cellular and molecular specificity of pituitary gland physiology.

PubMed

Perez-Castro, Carolina; Renner, Ulrich; Haedo, Mariana R; Stalla, Gunter K; Arzt, Eduardo

2012-01-01

The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.

Mapping magnetoelastic response of terfenol-D ring structure

NASA Astrophysics Data System (ADS)

Youssef, George; Newacheck, Scott; Lopez, Mario

2017-05-01

The magneto-elastic response of a Terfenol-D (Tb.3Dy.7Fe1.92) ring has been experimentally investigated and analyzed. Ring structures give rise to complex behavior based on the interaction of the magnetic field with the material, which is further compounded with anisotropies associated with mechanical and magnetic properties. Discrete strain measurements were used to construct magnetostriction maps, which are used to elucidate the non-uniformity of the strain distribution due to geometrical factors and magnetic field interactions, namely, magnetic shielding and stable onion state in the ring structure.

Challenges for Super-Resolution Localization Microscopy and Biomolecular Fluorescent Nano-Probing in Cancer Research

PubMed Central

Ilić, Nataša; Pilarczyk, Götz; Lee, Jin-Ho; Logeswaran, Abiramy; Borroni, Aurora Paola; Krufczik, Matthias; Theda, Franziska; Waltrich, Nadine; Bestvater, Felix; Hildenbrand, Georg; Cremer, Christoph; Blank, Michael

2017-01-01

Understanding molecular interactions and regulatory mechanisms in tumor initiation, progression, and treatment response are key requirements towards advanced cancer diagnosis and novel treatment procedures in personalized medicine. Beyond decoding the gene expression, malfunctioning and cancer-related epigenetic pathways, investigations of the spatial receptor arrangements in membranes and genome organization in cell nuclei, on the nano-scale, contribute to elucidating complex molecular mechanisms in cells and tissues. By these means, the correlation between cell function and spatial organization of molecules or molecular complexes can be studied, with respect to carcinogenesis, tumor sensitivity or tumor resistance to anticancer therapies, like radiation or antibody treatment. Here, we present several new applications for bio-molecular nano-probes and super-resolution, laser fluorescence localization microscopy and their potential in life sciences, especially in biomedical and cancer research. By means of a tool-box of fluorescent antibodies, green fluorescent protein (GFP) tagging, or specific oligonucleotides, we present tumor relevant re-arrangements of Erb-receptors in membranes, spatial organization of Smad specific ubiquitin protein ligase 2 (Smurf2) in the cytosol, tumor cell characteristic heterochromatin organization, and molecular re-arrangements induced by radiation or antibody treatment. The main purpose of this article is to demonstrate how nano-scaled distance measurements between bio-molecules, tagged by appropriate nano-probes, can be applied to elucidate structures and conformations of molecular complexes which are characteristic of tumorigenesis and treatment responses. These applications open new avenues towards a better interpretation of the spatial organization and treatment responses of functionally relevant molecules, at the single cell level, in normal and cancer cells, offering new potentials for individualized medicine. PMID:28956810

Identical phosphatase mechanisms achieved through distinct modes of binding phosphoprotein substrate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pazy, Y.; Motaleb, M.A.; Guarnieri, M.T.

2010-04-05

Two-component signal transduction systems are widespread in prokaryotes and control numerous cellular processes. Extensive investigation of sensor kinase and response regulator proteins from many two-component systems has established conserved sequence, structural, and mechanistic features within each family. In contrast, the phosphatases which catalyze hydrolysis of the response regulator phosphoryl group to terminate signal transduction are poorly understood. Here we present structural and functional characterization of a representative of the CheC/CheX/FliY phosphatase family. The X-ray crystal structure of Borrelia burgdorferi CheX complexed with its CheY3 substrate and the phosphoryl analogue BeF{sub 3}{sup -} reveals a binding orientation between a response regulatormore » and an auxiliary protein different from that shared by every previously characterized example. The surface of CheY3 containing the phosphoryl group interacts directly with a long helix of CheX which bears the conserved (E - X{sub 2} - N) motif. Conserved CheX residues Glu96 and Asn99, separated by a single helical turn, insert into the CheY3 active site. Structural and functional data indicate that CheX Asn99 and CheY3 Thr81 orient a water molecule for hydrolytic attack. The catalytic residues of the CheX-CheY3 complex are virtually superimposable on those of the Escherichia coli CheZ phosphatase complexed with CheY, even though the active site helices of CheX and CheZ are oriented nearly perpendicular to one other. Thus, evolution has found two structural solutions to achieve the same catalytic mechanism through different helical spacing and side chain lengths of the conserved acid/amide residues in CheX and CheZ.« less

Challenges for Super-Resolution Localization Microscopy and Biomolecular Fluorescent Nano-Probing in Cancer Research.

PubMed

Hausmann, Michael; Ilić, Nataša; Pilarczyk, Götz; Lee, Jin-Ho; Logeswaran, Abiramy; Borroni, Aurora Paola; Krufczik, Matthias; Theda, Franziska; Waltrich, Nadine; Bestvater, Felix; Hildenbrand, Georg; Cremer, Christoph; Blank, Michael

2017-09-28

Understanding molecular interactions and regulatory mechanisms in tumor initiation, progression, and treatment response are key requirements towards advanced cancer diagnosis and novel treatment procedures in personalized medicine. Beyond decoding the gene expression, malfunctioning and cancer-related epigenetic pathways, investigations of the spatial receptor arrangements in membranes and genome organization in cell nuclei, on the nano-scale, contribute to elucidating complex molecular mechanisms in cells and tissues. By these means, the correlation between cell function and spatial organization of molecules or molecular complexes can be studied, with respect to carcinogenesis, tumor sensitivity or tumor resistance to anticancer therapies, like radiation or antibody treatment. Here, we present several new applications for bio-molecular nano-probes and super-resolution, laser fluorescence localization microscopy and their potential in life sciences, especially in biomedical and cancer research. By means of a tool-box of fluorescent antibodies, green fluorescent protein (GFP) tagging, or specific oligonucleotides, we present tumor relevant re-arrangements of Erb-receptors in membranes, spatial organization of Smad specific ubiquitin protein ligase 2 (Smurf2) in the cytosol, tumor cell characteristic heterochromatin organization, and molecular re-arrangements induced by radiation or antibody treatment. The main purpose of this article is to demonstrate how nano-scaled distance measurements between bio-molecules, tagged by appropriate nano-probes, can be applied to elucidate structures and conformations of molecular complexes which are characteristic of tumorigenesis and treatment responses. These applications open new avenues towards a better interpretation of the spatial organization and treatment responses of functionally relevant molecules, at the single cell level, in normal and cancer cells, offering new potentials for individualized medicine.

Ants determine their next move at rest: motor planning and causality in complex systems.

PubMed

Hunt, Edmund R; Baddeley, Roland J; Worley, Alan; Sendova-Franks, Ana B; Franks, Nigel R

2016-01-01

To find useful work to do for their colony, individual eusocial animals have to move, somehow staying attentive to relevant social information. Recent research on individual Temnothorax albipennis ants moving inside their colony's nest found a power-law relationship between a movement's duration and its average speed; and a universal speed profile for movements showing that they mostly fluctuate around a constant average speed. From this predictability it was inferred that movement durations are somehow determined before the movement itself. Here, we find similar results in lone T. albipennis ants exploring a large arena outside the nest, both when the arena is clean and when it contains chemical information left by previous nest-mates. This implies that these movement characteristics originate from the same individual neural and/or physiological mechanism(s), operating without immediate regard to social influences. However, the presence of pheromones and/or other cues was found to affect the inter-event speed correlations. Hence we suggest that ants' motor planning results in intermittent response to the social environment: movement duration is adjusted in response to social information only between movements, not during them. This environmentally flexible, intermittently responsive movement behaviour points towards a spatially allocated division of labour in this species. It also prompts more general questions on collective animal movement and the role of intermittent causation from higher to lower organizational levels in the stability of complex systems.

Integrated Physiological, Proteomic, and Metabolomic Analysis of Ultra Violet (UV) Stress Responses and Adaptation Mechanisms in Pinus radiata*

PubMed Central

Pascual, Jesús; Cañal, María Jesús; Escandón, Mónica; Meijón, Mónica; Weckwerth, Wolfram

2017-01-01

Globally expected changes in environmental conditions, especially the increase of UV irradiation, necessitate extending our knowledge of the mechanisms mediating tree species adaptation to this stress. This is crucial for designing new strategies to maintain future forest productivity. Studies focused on environmentally realistic dosages of UV irradiation in forest species are scarce. Pinus spp. are commercially relevant trees and not much is known about their adaptation to UV. In this work, UV treatment and recovery of Pinus radiata plants with dosages mimicking future scenarios, based on current models of UV radiation, were performed in a time-dependent manner. The combined metabolome and proteome analysis were complemented with measurements of + physiological parameters and gene expression. Sparse PLS analysis revealed complex molecular interaction networks of molecular and physiological data. Early responses prevented phototoxicity by reducing photosystem activity and the electron transfer chain together with the accumulation of photoprotectors and photorespiration. Apart from the reduction in photosynthesis as consequence of the direct UV damage on the photosystems, the primary metabolism was rearranged to deal with the oxidative stress while minimizing ROS production. New protein kinases and proteases related to signaling, coordination, and regulation of UV stress responses were revealed. All these processes demonstrate a complex molecular interaction network extending the current knowledge on UV-stress adaptation in pine. PMID:28096192

Neu1 sialidase and matrix metalloproteinase-9 cross-talk regulates nucleic acid-induced endosomal TOLL-like receptor-7 and -9 activation, cellular signaling and pro-inflammatory responses.

PubMed

Abdulkhalek, Samar; Szewczuk, Myron R

2013-11-01

The precise mechanism(s) by which intracellular TOLL-like receptors (TLRs) become activated by their ligands remains unclear. Here, we report a molecular organizational G-protein coupled receptor (GPCR) signaling platform to potentiate a novel mammalian neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B GPCR, all of which form a tripartite complex with TLR-7 and -9. siRNA silencing Neu1, MMP-9 and neuromedin-B GPCR in RAW-blue macrophage cells significantly reduced TLR7 imiquimod- and TLR9 ODN1826-induced NF-κB (NF-κB-pSer(536)) activity. Tamiflu, specific MMP-9 inhibitor, neuromedin B receptor specific antagonist BIM23127, and the selective inhibitor of whole heterotrimeric G-protein complex BIM-46174 significantly block nucleic acid-induced TLR-7 and -9 MyD88 recruitment, NF-κB activation and proinflammatory TNFα and MCP-1 cytokine responses. For the first time, Neu1 clearly plays a central role in mediating nucleic acid-induced intracellular TLR activation, and the interactions involving NMBR-MMP9-Neu1 cross-talk constitute a novel intracellular TLR signaling platform that is essential for NF-κB activation and pro-inflammatory responses. © 2013. Published by Elsevier Inc. All rights reserved.

Dual personality of Mad1: regulation of nuclear import by a spindle assembly checkpoint protein.

PubMed

Cairo, Lucas V; Ptak, Christopher; Wozniak, Richard W

2013-01-01

Nuclear transport is a dynamic process that can be modulated in response to changes in cellular physiology. We recently reported that the transport activity of yeast nuclear pore complexes (NPCs) is altered in response to kinetochore-microtubule (KT-MT) interaction defects. Specifically, KT detachment from MTs activates a signaling pathway that prevents the nuclear import of cargos by the nuclear transport factor Kap121p. This loss of Kap121p-mediated import is thought to influence the nuclear environment, including the phosphorylation state of nuclear proteins. A key regulator of this process is the spindle assembly checkpoint protein Mad1p. In response to unattached KTs, Mad1p dynamically cycles between NPCs and KTs. This cycling appears to induce NPC molecular rearrangements that prevent the nuclear import of Kap121p-cargo complexes. Here, we discuss the underlying mechanisms and the physiological relevance of Mad1p cycling and the inhibition of Kap121p-mediated nuclear import, focusing on outstanding questions within the pathway.

The Disordered C-Terminus of Yeast Hsf1 Contains a Cryptic Low-Complexity Amyloidogenic Region.

PubMed

Pujols, Jordi; Santos, Jaime; Pallarès, Irantzu; Ventura, Salvador

2018-05-06

Response mechanisms to external stress rely on networks of proteins able to activate specific signaling pathways to ensure the maintenance of cell proteostasis. Many of the proteins mediating this kind of response contain intrinsically disordered regions, which lack a defined structure, but still are able to interact with a wide range of clients that modulate the protein function. Some of these interactions are mediated by specific short sequences embedded in the longer disordered regions. Because the physicochemical properties that promote functional and abnormal interactions are similar, it has been shown that, in globular proteins, aggregation-prone and binding regions tend to overlap. It could be that the same principle applies for disordered protein regions. In this context, we show here that a predicted low-complexity interacting region in the disordered C-terminus of the stress response master regulator heat shock factor 1 (Hsf1) protein corresponds to a cryptic amyloid region able to self-assemble into fibrillary structures resembling those found in neurodegenerative disorders.

Host-pathogen interplay in the respiratory environment of cystic fibrosis.

PubMed

Yonker, Lael M; Cigana, Cristina; Hurley, Bryan P; Bragonzi, Alessandra

2015-07-01

Significant advances have been made in the understanding of disease progression in cystic fibrosis (CF), revealing a complex interplay between host and pathogenic organisms. The diverse CF microbiota within the airway activates an aberrant immune response that is ineffective in clearing infection. An appreciation of how the CF host immune system interacts with these organisms is crucial to understanding the pathogenesis of CF pulmonary disease. Here we discuss the microbial complexity present in the lungs of individuals with CF, review emerging concepts of innate and adaptive immune responses to pathogens that chronically inhabit the CF lung, and discuss therapies that target the aberrant inflammatory response that characterizes CF. A greater understanding of the underlying mechanisms will shed light on pathogenesis and guide more targeted therapies in the future that serve to reduce infection, minimize lung pathology, and improve the quality of life for patients with CF. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex.

PubMed

Zhao, Bo; Zhang, Weidao; Cun, Yixian; Li, Jingzheng; Liu, Yan; Gao, Jing; Zhu, Hongwen; Zhou, Hu; Zhang, Rugang; Zheng, Ping

2018-01-01

Pluripotent stem cells (PSCs) harbor constitutive DNA replication stress during their rapid proliferation and the consequent genome instability hampers their applications in regenerative medicine. It is therefore important to understand the regulatory mechanisms of replication stress response in PSCs. Here, we report that mouse embryonic stem cells (ESCs) are superior to differentiated cells in resolving replication stress. Specifically, ESCs utilize a unique Filia-Floped protein complex-dependent mechanism to efficiently promote the restart of stalled replication forks, therefore maintaining genomic stability. The ESC-specific Filia-Floped complex resides on replication forks under normal conditions. Replication stress stimulates their recruitment to stalling forks and the serine 151 residue of Filia is phosphorylated in an ATR-dependent manner. This modification enables the Filia-Floped complex to act as a functional scaffold, which then promotes the stalling fork restart through a dual mechanism: both enhancing recruitment of the replication fork restart protein, Blm, and stimulating ATR kinase activation. In the Blm pathway, the scaffolds recruit the E3 ubiquitin ligase, Trim25, to the stalled replication forks, and in turn Trim25 tethers and concentrates Blm at stalled replication forks through ubiquitination. In differentiated cells, the recruitment of the Trim25-Blm complex to replication forks and the activation of ATR signaling are much less robust due to lack of the ESC-specific Filia-Floped scaffold. Thus, our study reveals that ESCs utilize an additional and unique regulatory layer to efficiently promote the stalled fork restart and maintain genomic stability.

Surface structural ion adsorption modeling of competitive binding of oxyanions by metal (hydr)oxides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiemstra, T.; Riemsdijk, W.H. van

1999-02-01

An important challenge in surface complexation models (SCM) is to connect the molecular microscopic reality to macroscopic adsorption phenomena. This study elucidates the primary factor controlling the adsorption process by analyzing the adsorption and competition of PO{sub 4}, AsO{sub 4}, and SeO{sub 3}. The authors show that the structure of the surface-complex acting in the dominant electrostatic field can be ascertained as the primary controlling adsorption factor. The surface species of arsenate are identical with those of phosphate and the adsorption behavior is very similar. On the basis of the selenite adsorption, The authors show that the commonly used 1pKmore » models are incapable to incorporate in the adsorption modeling the correct bidentate binding mechanism found by spectroscopy. The use of the bidentate mechanism leads to a proton-oxyanion ratio and corresponding pH dependence that are too large. The inappropriate intrinsic charge attribution to the primary surface groups and the condensation of the inner sphere surface complex to a point charge are responsible for this behavior of commonly used 2pK models. Both key factors are differently defined in the charge distributed multi-site complexation (CD-MUSIC) model and are based in this model on a surface structural approach. The CD-MUSIC model can successfully describe the macroscopic adsorption phenomena using the surface speciation and binding mechanisms as found by spectroscopy. The model is also able to predict the anion competition well. The charge distribution in the interface is in agreement with the observed structure of surface complexes.« less

Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation

PubMed Central

Ishise, Hisako; Larson, Barrett; Hirata, Yutaka; Fujiwara, Toshihiro; Nishimoto, Soh; Kubo, Tateki; Matsuda, Ken; Kanazawa, Shigeyuki; Sotsuka, Yohei; Fujita, Kazutoshi; Kakibuchi, Masao; Kawai, Kenichiro

2015-01-01

Wound healing process is a complex and highly orchestrated process that ultimately results in the formation of scar tissue. Hypertrophic scar contracture is considered to be a pathologic and exaggerated wound healing response that is known to be triggered by repetitive mechanical forces. We now show that Transient Receptor Potential (TRP) C3 regulates the expression of fibronectin, a key regulatory molecule involved in the wound healing process, in response to mechanical strain via the NFkB pathway. TRPC3 is highly expressed in human hypertrophic scar tissue and mechanical stimuli are known to upregulate TRPC3 expression in human skin fibroblasts in vitro. TRPC3 overexpressing fibroblasts subjected to repetitive stretching forces showed robust expression levels of fibronectin. Furthermore, mechanical stretching of TRPC3 overexpressing fibroblasts induced the activation of nuclear factor-kappa B (NFκB), a regulator fibronectin expression, which was able to be attenuated by pharmacologic blockade of either TRPC3 or NFκB. Finally, transplantation of TRPC3 overexpressing fibroblasts into mice promoted wound contraction and increased fibronectin levels in vivo. These observations demonstrate that mechanical stretching drives fibronectin expression via the TRPC3-NFkB axis, leading to intractable wound contracture. This model explains how mechanical strain on cutaneous wounds might contribute to pathologic scarring. PMID:26108359

Mechanical Regulation of Signaling Pathways in Bone

PubMed Central

Thompson, William R.; Rubin, Clinton T.; Rubin, Janet

2012-01-01

A wide range of cell types depend on mechanically induced signals to enable appropriate physiological responses. The skeleton is particularly dependent on mechanical information to guide the resident cell population towards adaptation, maintenance and repair. Research at the organ, tissue, cell and molecular levels has improved our understanding of how the skeleton can recognize the functional environment, and how these challenges are translated into cellular information that can site-specifically alter phenotype. This review first considers those cells within the skeleton that are responsive to mechanical signals, including osteoblasts, osteoclasts, osteocytes and osteoprogenitors. This is discussed in light of a range of experimental approaches that can vary parameters such as strain, fluid shear stress, and pressure. The identity of mechanoreceptor candidates is approached, with consideration of integrins, pericellular tethers, focal adhesions, ion channels, cadherins, connexins, and the plasma membrane including caveolar and non-caveolar lipid rafts and their influence on integral signaling protein interactions. Several mechanically regulated intracellular signaling cascades are detailed including activation of kinases (Akt, MAPK, FAK), β-catenin, GTPases, and calcium signaling events. While the interaction of bone cells with their mechanical environment is complex, an understanding of mechanical regulation of bone signaling is crucial to understanding bone physiology, the etiology of diseases such as osteoporosis, and to the development of interventions to improve bone strength. PMID:22575727

Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction.

PubMed

Sotomayor, Marcos; Weihofen, Wilhelm A; Gaudet, Rachelle; Corey, David P

2012-12-06

Hearing and balance use hair cells in the inner ear to transform mechanical stimuli into electrical signals. Mechanical force from sound waves or head movements is conveyed to hair-cell transduction channels by tip links, fine filaments formed by two atypical cadherins known as protocadherin 15 and cadherin 23 (refs 4, 5). These two proteins are involved in inherited deafness and feature long extracellular domains that interact tip-to-tip in a Ca(2+)-dependent manner. However, the molecular architecture of this complex is unknown. Here we combine crystallography, molecular dynamics simulations and binding experiments to characterize the protocadherin 15-cadherin 23 bond. We find a unique cadherin interaction mechanism, in which the two most amino-terminal cadherin repeats (extracellular cadherin repeats 1 and 2) of each protein interact to form an overlapped, antiparallel heterodimer. Simulations predict that this tip-link bond is mechanically strong enough to resist forces in hair cells. In addition, the complex is shown to become unstable in response to Ca(2+) removal owing to increased flexure of Ca(2+)-free cadherin repeats. Finally, we use structures and biochemical measurements to study the molecular mechanisms by which deafness mutations disrupt tip-link function. Overall, our results shed light on the molecular mechanics of hair-cell sensory transduction and on new interaction mechanisms for cadherins, a large protein family implicated in tissue and organ morphogenesis, neural connectivity and cancer.

What’s Special about Human Imitation? A Comparison with Enculturated Apes

PubMed Central

Subiaul, Francys

2016-01-01

What, if anything, is special about human imitation? An evaluation of enculturated apes’ imitation skills, a “best case scenario” of non-human apes’ imitation performance, reveals important similarities and differences between this special population of apes and human children. Candidates for shared imitation mechanisms include the ability to imitate various familiar transitive responses and object–object actions that involve familiar tools. Candidates for uniquely derived imitation mechanisms include: imitating novel transitive actions and novel tool-using responses as well as imitating opaque or intransitive gestures, regardless of familiarity. While the evidence demonstrates that enculturated apes outperform non-enculturated apes and perform more like human children, all apes, regardless of rearing history, generally excel at imitating familiar, over-rehearsed responses and are poor, relative to human children, at imitating novel, opaque or intransitive responses. Given the similarities between the sensory and motor systems of preschool age human children and non-human apes, it is unlikely that differences in sensory input and/or motor-output alone explain the observed discontinuities in imitation performance. The special rearing history of enculturated apes—including imitation-specific training—further diminishes arguments suggesting that differences are experience-dependent. Here, it is argued that such differences are best explained by distinct, specialized mechanisms that have evolved for copying rules and responses in particular content domains. Uniquely derived social and imitation learning mechanisms may represent adaptations for learning novel communicative gestures and complex tool-use. Given our species’ dependence on both language and tools, mechanisms that accelerated learning in these domains are likely to have faced intense selective pressures, starting with the earliest of human ancestors. PMID:27399786

Model verification of mixed dynamic systems. [POGO problem in liquid propellant rockets

NASA Technical Reports Server (NTRS)

Chrostowski, J. D.; Evensen, D. A.; Hasselman, T. K.

1978-01-01

A parameter-estimation method is described for verifying the mathematical model of mixed (combined interactive components from various engineering fields) dynamic systems against pertinent experimental data. The model verification problem is divided into two separate parts: defining a proper model and evaluating the parameters of that model. The main idea is to use differences between measured and predicted behavior (response) to adjust automatically the key parameters of a model so as to minimize response differences. To achieve the goal of modeling flexibility, the method combines the convenience of automated matrix generation with the generality of direct matrix input. The equations of motion are treated in first-order form, allowing for nonsymmetric matrices, modeling of general networks, and complex-mode analysis. The effectiveness of the method is demonstrated for an example problem involving a complex hydraulic-mechanical system.

Simulations of Instabilities in Complex Valve and Feed Systems

NASA Technical Reports Server (NTRS)

Ahuja, Vineet; Hosangadi, Ashvin; Shipman, Jeremy; Cavallo, Peter A.

2006-01-01

CFD analyses are playing an increasingly important role in identifying and characterizing flow induced instabilities in rocket engine test facilities and flight systems. In this paper, we analyze instability mechanisms that range from turbulent pressure fluctuations due to vortex shedding in structurally complex valve systems to flow resonance in plug cavities to large scale pressure fluctuations due to collapse of cavitation induced vapor clouds. Furthermore, we discuss simulations of transient behavior related to valve motion that can serve as guidelines for valve scheduling. Such predictions of valve response to varying flow conditions is of crucial importance to engine operation and testing.

Emotional contagion and proto-organizing in human interaction dynamics

PubMed Central

Hazy, James K.; Boyatzis, Richard E.

2015-01-01

This paper combines the complexity notions of phase transitions and tipping points with recent advances in cognitive neuroscience to propose a general theory of human proto-organizing. It takes as a premise that a necessary prerequisite for organizing, or “proto-organizing,” occurs through emotional contagion in subpopulations of human interaction dynamics in complex ecosystems. Emotional contagion is posited to engender emotional understanding and identification with others, a social process that acts as a mechanism that enables (or precludes) cooperative responses to opportunities and risks. Propositions are offered and further research is suggested. PMID:26124736

Minimal influence of G-protein null mutations on ozone-induced changes in gene expression, foliar injury, gas-exchange and peroxidase activity in Arabidopsis thaliana L

USDA-ARS?s Scientific Manuscript database

Ozone uptake by plants leads to an increase in reactive oxygen species (ROS) in the intercellular space of leaves and induces signalling processes reported to involve the membrane-bound heterotrimeric G-protein complex. Therefore, potential G-protein-mediated response mechanisms to ozone were compar...

Computational Modeling of Shape Memory Polymer Origami that Responds to Light

NASA Astrophysics Data System (ADS)

Mailen, Russell William

Shape memory polymers (SMPs) transform in response to external stimuli, such as infrared (IR) light. Although SMPs have many applications, this investigation focuses on their use as actuators in self-folding origami structures. Ink patterned on the surface of the SMP sheet absorbs thermal energy from the IR light, which produces localized heating. The material shrinks wherever the activation temperature is exceeded and can produce out-of-plane deformation. The time and temperature dependent response of these SMPs provides unique opportunities for developing complex three-dimensional (3D) structures from initially flat sheets through self-folding origami, but the application of this technique requires predicting accurately the final folded or deformed shape. Furthermore, current computational approaches for SMPs do not fully couple the thermo-mechanical response of the material. Hence, a proposed nonlinear, 3D, thermo-viscoelastic finite element framework was formulated to predict deformed shapes for different self-folding systems and compared to experimental results for self-folding origami structures. A detailed understanding of the shape memory response and the effect of controllable design parameters, such as the ink pattern, pre-strain conditions, and applied thermal and mechanical fields, allows for a predictive understanding and design of functional, 3D structures. The proposed modeling framework was used to obtain a fundamental understanding of the thermo-mechanical behavior of SMPs and the impact of the material behavior on hinged self-folding. These predictions indicated how the thermal and mechanical conditions during pre-strain significantly affect the shrinking and folding response of the SMP. Additionally, the externally applied thermal loads significantly influenced the folding rate and maximum bending angle. The computational framework was also adapted to understand the effects of fully coupling the thermal and mechanical response of the material. This updated framework accounted for external heat sources, such as ambient temperature and incident surface heat flux, as well as internal temperature changes due to conduction and viscous heat generation. Viscous heating during the pre-strain sequence affected the residual stresses after cooling due to accelerated viscoelastic relaxation. This resulted in a delayed shrinking and folding response. Other factors that affected the folding response include sheet thickness, hinge width, degree of pre-strain, and hinge temperature. The predicted results indicated that the maximum bending angle can be increased for a folded structure by increasing the hinge width, degree of pre-strain, and hinge surface temperature. Folding time can be reduced by decreasing the sheet thickness, increasing the hinge width, and increasing the hinge temperature. The coupled thermo-mechanical approach was also extended to investigate both curved and folded structures by varying the ink pattern and the substrate geometry. With this approach, two continuous curvature mechanisms were obtained. One was an indirect curvature mechanism which resulted from internal stresses that evolved from the shrinking of activated regions of the material relative to unactivated regions. The second was a direct curvature mechanism that resulted from ink distributed in gradients across the surface of the material. Furthermore, the effects of hinge orientation, proximity of multiple hinges, sheet aspect ratio, and axisymmetric ink patterns were characterized for other shapes, such as rectangles and discs. The findings of this investigation clearly indicate that this validated computational approach can be used to predict and understand the myriad mechanisms of self-folding origami structures. By varying the location of ink on the polymer surface and making changes to the substrate geometry, complex 3D structures can be obtained. The developed thermo-mechanical framework can be used to design optimized origami structures for biomedical devices, space telescopes, and functional, engineered origami devices.

Antigen Cross-Presentation of Immune Complexes

PubMed Central

Platzer, Barbara; Stout, Madeleine; Fiebiger, Edda

2014-01-01

The ability of dendritic cells (DCs) to cross-present tumor antigens has long been a focus of interest to physicians, as well as basic scientists, that aim to establish efficient cell-based cancer immune therapy. A prerequisite for exploiting this pathway for therapeutic purposes is a better understanding of the mechanisms that underlie the induction of tumor-specific cytotoxic T-lymphocyte (CTL) responses when initiated by DCs via cross-presentation. The ability of humans DC to perform cross-presentation is of utmost interest, as this cell type is a main target for cell-based immunotherapy in humans. The outcome of a cross-presentation event is guided by the nature of the antigen, the form of antigen uptake, and the subpopulation of DCs that performs presentation. Generally, CD8α+ DCs are considered to be the most potent cross-presenting DCs. This paradigm, however, only applies to soluble antigens. During adaptive immune responses, immune complexes form when antibodies interact with their specific epitopes on soluble antigens. Immunoglobulin G (IgG) immune complexes target Fc-gamma receptors on DCs to shuttle exogenous antigens efficiently into the cross-presentation pathway. This receptor-mediated cross-presentation pathway is a well-described route for the induction of strong CD8+ T cell responses. IgG-mediated cross-presentation is intriguing because it permits the CD8− DCs, which are commonly considered to be weak cross-presenters, to efficiently cross-present. Engaging multiple DC subtypes for cross-presentation might be a superior strategy to boost CTL responses in vivo. We here summarize our current understanding of how DCs use IgG-complexed antigens for the efficient induction of CTL responses. Because of its importance for human cell therapy, we also review the recent advances in the characterization of cross-presentation properties of human DC subsets. PMID:24744762

Heavy Metal Stress and Some Mechanisms of Plant Defense Response

PubMed Central

Emamverdian, Abolghassem; Ding, Yulong; Mokhberdoran, Farzad; Xie, Yinfeng

2015-01-01

Unprecedented bioaccumulation and biomagnification of heavy metals (HMs) in the environment have become a dilemma for all living organisms including plants. HMs at toxic levels have the capability to interact with several vital cellular biomolecules such as nuclear proteins and DNA, leading to excessive augmentation of reactive oxygen species (ROS). This would inflict serious morphological, metabolic, and physiological anomalies in plants ranging from chlorosis of shoot to lipid peroxidation and protein degradation. In response, plants are equipped with a repertoire of mechanisms to counteract heavy metal (HM) toxicity. The key elements of these are chelating metals by forming phytochelatins (PCs) or metallothioneins (MTs) metal complex at the intra- and intercellular level, which is followed by the removal of HM ions from sensitive sites or vacuolar sequestration of ligand-metal complex. Nonenzymatically synthesized compounds such as proline (Pro) are able to strengthen metal-detoxification capacity of intracellular antioxidant enzymes. Another important additive component of plant defense system is symbiotic association with arbuscular mycorrhizal (AM) fungi. AM can effectively immobilize HMs and reduce their uptake by host plants via binding metal ions to hyphal cell wall and excreting several extracellular biomolecules. Additionally, AM fungi can enhance activities of antioxidant defense machinery of plants. PMID:25688377

A novel mechanism for regulation of the type I IFN response by herpesvirus deconjugases.

PubMed

Gupta, Soham; Ylä-Anttila, Päivi; Masucci, Maria G

2018-04-11

Upon infection, viral nucleic acids are recognized by germline-encoded pattern-recognition receptors (PRRs), and cytosolic retinoic acid-inducible gene I (RIG-I)-like helicases (RLHs) that initiate signaling pathways resulting in the production of type I IFN and pro-inflammatory cytokines. Binding of RIG-I to viral nucleic acids triggers the formation of the RIG-I signalosome where RIG-I is ubiquitinated by the TRIM25 ligase and, with the help of 14-3-3 scaffolds, further translocated to mitochondrial anti-viral signalling proteins (MAVS). Subsequent ubiquitination-mediated events trigger transcriptional activation of the effectors of innate immunity. We have found a new mechanism by which herpesviruses interfere with this signalling pathway to favour the establishment of latency and promote virus replication. The cysteine protease encoded in the conserved N-terminal domain of the herpesvirus large tegument protein binds to 14-3-3 proteins and forms a tri-molecular complex with TRIM25, promoting the activation and autoubiquitination of the ligase. RIG-I is recruited to the complex but its ubiquitination is drastically reduced, which effectively inactivates downstream signalling and blocks the type I IFN response.

Deciphering the Magainin Resistance Process of Escherichia coli Strains in Light of the Cytosolic Proteome

PubMed Central

Maria-Neto, Simone; Cândido, Elizabete de Souza; Rodrigues, Diana Ribas; de Sousa, Daniel Amaro; da Silva, Ezequiel Marcelino; de Moraes, Lidia Maria Pepe; Otero-Gonzalez, Anselmo de Jesus; Magalhães, Beatriz Simas; Dias, Simoni Campos

2012-01-01

Antimicrobial peptides (AMPs) are effective antibiotic agents commonly found in plants, animals, and microorganisms, and they have been suggested as the future of antimicrobial chemotherapies. It is vital to understand the molecular details that define the mechanism of action of resistance to AMPs for a rational planning of the next antibiotic generation and also to shed some light on the complex AMP mechanism of action. Here, the antibiotic resistance of Escherichia coli ATCC 8739 to magainin I was evaluated in the cytosolic subproteome. Magainin-resistant strains were selected after 10 subsequent spreads at subinhibitory concentrations of magainin I (37.5 mg · liter−1), and their cytosolic proteomes were further compared to those of magainin-susceptible strains through two-dimensional electrophoresis analysis. As a result, 41 differentially expressed proteins were detected by in silico analysis and further identified by tandem mass spectrometry de novo sequencing. Functional categorization indicated an intense metabolic response mainly in energy and nitrogen uptake, stress response, amino acid conversion, and cell wall thickness. Indeed, data reported here show that resistance to cationic antimicrobial peptides possesses a greater molecular complexity than previously supposed, resulting in cell commitment to several metabolic pathways. PMID:22290970

Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes.

PubMed

Cheng, Tsing; Orlow, Seth J; Manga, Prashiela

2013-11-01

Accumulation of proteins in the endoplasmic reticulum (ER) typically induces stress and initiates the unfolded protein response (UPR) to facilitate recovery. If homeostasis is not restored, apoptosis is induced. However, adaptation to chronic UPR activation can increase resistance to subsequent acute ER stress. We therefore investigated adaptive mechanisms in Oculocutaneous albinism type 2 (Oca2)-null melanocytes where UPR signaling is arrested despite continued tyrosinase accumulation leading to resistance to the chemical ER stressor thapsigargin. Although thapsigargin triggers UPR activation, instead of Perk-mediated phosphorylation of eIF2α, in Oca2-null melanocytes, eIF2α was rapidly dephosphorylated upon treatment. Dephosphorylation was mediated by the Gadd34-PP1α phosphatase complex. Gadd34-complex inhibition blocked eIF2α dephosphorylation and significantly increased Oca2-null melanocyte sensitivity to thapsigargin. Thus, Oca2-null melanocytes adapt to acute ER stress by disruption of pro-apoptotic Perk signaling, which promotes cell survival. This is the first study to demonstrate rapid eIF2α dephosphorylation as an adaptive mechanism to ER stress. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

NOTCH1 Inhibits Activation of ATM by Impairing the Formation of an ATM-FOXO3a-KAT5/Tip60 Complex.

PubMed

Adamowicz, Marek; Vermezovic, Jelena; d'Adda di Fagagna, Fabrizio

2016-08-23

The DNA damage response (DDR) signal transduction pathway is responsible for sensing DNA damage and further relaying this signal into the cell. ATM is an apical DDR kinase that orchestrates the activation and the recruitment of downstream DDR factors to induce cell-cycle arrest and repair. We have previously shown that NOTCH1 inhibits ATM activation upon DNA damage, but the underlying mechanism remains unclear. Here, we show that NOTCH1 does not impair ATM recruitment to DNA double-strand breaks (DSBs). Rather, NOTCH1 prevents binding of FOXO3a and KAT5/Tip60 to ATM through a mechanism in which NOTCH1 competes with FOXO3a for ATM binding. Lack of FOXO3a binding to ATM leads to the loss of KAT5/Tip60 association with ATM. Moreover, expression of NOTCH1 or depletion of ATM impairs the formation of the FOXO3a-KAT5/Tip60 protein complex. Finally, we show that pharmacological induction of FOXO3a nuclear localization sensitizes NOTCH1-driven cancers to DNA-damage-induced cell death. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The endocrine and paracrine control of menstruation.

PubMed

Henriet, Patrick; Gaide Chevronnay, Héloïse P; Marbaix, Etienne

2012-07-25

During the reproductive life, the human endometrium undergoes cycles of substantial remodeling including, at menstruation, a massive but delimited tissue breakdown immediately followed by scarless repair. The present review aims at summarizing the current knowledge on the endocrine and paracrine control of menstruation in the light of recent observations that undermine obsolete dogmas. Menstruation can be globally considered as a response to falling progesterone concentration. However, tissue breakdown is heterogeneous and tightly controlled in space and time by a complex network of regulators and effectors, including cytokines, chemokines, proteases and various components of an inflammatory response. Moreover, menstruation must be regarded as part of a complex and integrated mechanism of tissue remodeling including features that precede and follow tissue lysis, i.e. decidualization and immediate post-menstrual regeneration. The understanding of the regulation of menstruation is of major basic and clinical interest. Indeed, these mechanisms largely overlap with those controlling other histopathological occurrences of tissue remodeling, such as development and cancer, and inappropriate control of menstrual features is a major potential cause of two frequent endometrial pathologies (i.e. abnormal uterine bleeding and endometriosis). Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A statistical image analysis framework for pore-free islands derived from heterogeneity distribution of nuclear pore complexes.

PubMed

Mimura, Yasuhiro; Takemoto, Satoko; Tachibana, Taro; Ogawa, Yutaka; Nishimura, Masaomi; Yokota, Hideo; Imamoto, Naoko

2017-11-24

Nuclear pore complexes (NPCs) maintain cellular homeostasis by mediating nucleocytoplasmic transport. Although cyclin-dependent kinases (CDKs) regulate NPC assembly in interphase, the location of NPC assembly on the nuclear envelope is not clear. CDKs also regulate the disappearance of pore-free islands, which are nuclear envelope subdomains; this subdomain gradually disappears with increase in homogeneity of the NPC in response to CDK activity. However, a causal relationship between pore-free islands and NPC assembly remains unclear. Here, we elucidated mechanisms underlying NPC assembly from a new perspective by focusing on pore-free islands. We proposed a novel framework for image-based analysis to automatically determine the detailed 'landscape' of pore-free islands from a large quantity of images, leading to the identification of NPC intermediates that appear in pore-free islands with increased frequency in response to CDK activity. Comparison of the spatial distribution between simulated and the observed NPC intermediates within pore-free islands showed that their distribution was spatially biased. These results suggested that the disappearance of pore-free islands is highly related to de novo NPC assembly and indicated the existence of specific regulatory mechanisms for the spatial arrangement of NPC assembly on nuclear envelopes.

Inhibition of the NEMO/IKKβ association complex formation, a novel mechanism associated with the NF-κB activation suppression by Withania somnifera's key metabolite withaferin A.

PubMed

Grover, Abhinav; Shandilya, Ashutosh; Punetha, Ankita; Bisaria, Virendra S; Sundar, Durai

2010-12-02

Nuclear Factor kappa B (NF-κB) is a transcription factor involved in the regulation of cell signaling responses and is a key regulator of cellular processes involved in the immune response, differentiation, cell proliferation, and apoptosis. The constitutive activation of NF-κB contributes to multiple cellular outcomes and pathophysiological conditions such as rheumatoid arthritis, asthma, inflammatory bowel disease, AIDS and cancer. Thus there lies a huge therapeutic potential beneath inhibition of NF-κB signalling pathway for reducing these chronic ailments. Withania somnifera, a reputed herb in ayurvedic medicine, comprises a large number of steroidal lactones known as withanolides which show plethora of pharmacological activities like anti- inflammatory, antitumor, antibacterial, antioxidant, anticonvulsive, and immunosuppressive. Though a few studies have been reported depicting the effect of WA (withaferin A) on suppression of NF-κB activation, the mechanism behind this is still eluding the researchers. The study conducted here is an attempt to explore NF-κB signalling pathway modulating capability of Withania somnifera's major constituent WA and to elucidate its possible mode of action using molecular docking and molecular dynamics simulations studies. Formation of active IKK (IκB kinase) complex comprising NEMO (NF-κB Essential Modulator) and IKKβ subunits is one of the essential steps for NF-κB signalling pathway, non-assembly of which can lead to prevention of the above mentioned vulnerable disorders. As observed from our semi-flexible docking analysis, WA forms strong intermolecular interactions with the NEMO chains thus building steric as well as thermodynamic barriers to the incoming IKKβ subunits, which in turn pave way to naive complex formation capability of NEMO with IKKβ. Docking of WA into active NEMO/IKKβ complex using flexible docking in which key residues of the complex were kept flexible also suggest the disruption of the active complex. Thus the molecular docking analysis of WA into NEMO and active NEMO/IKKβ complex conducted in this study provides significant evidence in support of the proposed mechanism of NF-κB activation suppression by inhibition or disruption of active NEMO/IKKβ complex formation being accounted by non-assembly of the catalytically active NEMO/IKKβ complex. Results from the molecular dynamics simulations in water show that the trajectories of the native protein and the protein complexed with WA are stable over a considerably long time period of 2.6 ns. NF-κB is one of the most attractive topics in current biological, biochemical, and pharmacological research, and in the recent years the number of studies focusing on its inhibition/regulation has increased manifolds. Small ligands (both natural and synthetic) are gaining particular attention in this context. Our computational analysis provided a rationalization of the ability of naturally occurring withaferin A to alter the NF-κB signalling pathway along with its proposed mode of inhibition of the pathway. The absence of active IKK multisubunit complex would prevent degradation of IκB proteins, as the IκB proteins would not get phosphorylated by IKK. This would ultimately lead to non-release of NF-κB and its further translocation to the nucleus thus arresting its nefarious acts. Conclusively our results strongly suggest that withaferin A is a potent anticancer agent as ascertained by its potent NF-κB modulating capability. Moreover the present MD simulations made clear the dynamic structural stability of NEMO/IKKβ in complex with the drug WA, together with the inhibitory mechanism.

Involvement of heme oxygenase-1 in β-cyclodextrin-hemin complex-induced cucumber adventitious rooting process.

PubMed

Lin, Yuting; Li, Meiyue; Huang, Liqin; Shen, Wenbiao; Ren, Yong

2012-09-01

Our previous results showed that β-cyclodextrin-hemin complex (CDH) exhibited a vital protective role against cadmium-induced oxidative damage and toxicity in alfalfa seedling roots by the regulation of heme oxygenase-1 (HO-1) gene expression. In this report, we further test whether CDH exhibited the hormonal-like response. The application of CDH and an inducer of HO-1, hemin, were able to induce the up-regulation of cucumber HO-1 gene (CsHO1) expression and thereafter the promotion of adventitious rooting in cucumber explants. The effect is specific for HO-1 since the potent HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blocked the above responses triggered by CDH, and the inhibitory effects were reversed further when 30% saturation of CO aqueous solution was added together. Further, molecular evidence showed that CDH triggered the increases of the HO-1-mediated target genes responsible for adventitious rooting, including one DnaJ-like gene (CsDNAJ-1) and two calcium-dependent protein kinase (CDPK) genes (CsCDPK1 and CsCDPK5), and were inhibited by ZnPP and reversed by CO. The calcium (Ca2+) chelator ethylene glycol-bis (2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) and the Ca2+ channel blocker lanthanum chloride (LaCl3) not only compromised the induction of adventitious rooting induced by CDH but also decreased the transcripts of above three target genes. However, the application of ascorbic acid (AsA), a well-known antioxidant in plants, failed to exhibit similar inducible effect on adventitious root formation. In short, above results illustrated that the response of CDH in the induction of cucumber adventitious rooting might be through HO-1-dependent mechanism and calcium signaling. Physiological, pharmacological and molecular evidence showed that β-cyclodextrin-hemin complex (CDH) was able to induce cucumber adventitious rooting through heme oxygenase-1 (HO-1)-dependent mechanism and calcium signaling.

Transcriptomic responses of a simplified soil microcosm to a plant pathogen and its biocontrol agent reveal a complex reaction to harsh habitat.

PubMed

Perazzolli, Michele; Herrero, Noemí; Sterck, Lieven; Lenzi, Luisa; Pellegrini, Alberto; Puopolo, Gerardo; Van de Peer, Yves; Pertot, Ilaria

2016-10-27

Soil microorganisms are key determinants of soil fertility and plant health. Soil phytopathogenic fungi are one of the most important causes of crop losses worldwide. Microbial biocontrol agents have been extensively studied as alternatives for controlling phytopathogenic soil microorganisms, but molecular interactions between them have mainly been characterised in dual cultures, without taking into account the soil microbial community. We used an RNA sequencing approach to elucidate the molecular interplay of a soil microbial community in response to a plant pathogen and its biocontrol agent, in order to examine the molecular patterns activated by the microorganisms. A simplified soil microcosm containing 11 soil microorganisms was incubated with a plant root pathogen (Armillaria mellea) and its biocontrol agent (Trichoderma atroviride) for 24 h under controlled conditions. More than 46 million paired-end reads were obtained for each replicate and 28,309 differentially expressed genes were identified in total. Pathway analysis revealed complex adaptations of soil microorganisms to the harsh conditions of the soil matrix and to reciprocal microbial competition/cooperation relationships. Both the phytopathogen and its biocontrol agent were specifically recognised by the simplified soil microcosm: defence reaction mechanisms and neutral adaptation processes were activated in response to competitive (T. atroviride) or non-competitive (A. mellea) microorganisms, respectively. Moreover, activation of resistance mechanisms dominated in the simplified soil microcosm in the presence of both A. mellea and T. atroviride. Biocontrol processes of T. atroviride were already activated during incubation in the simplified soil microcosm, possibly to occupy niches in a competitive ecosystem, and they were not further enhanced by the introduction of A. mellea. This work represents an additional step towards understanding molecular interactions between plant pathogens and biocontrol agents within a soil ecosystem. Global transcriptional analysis of the simplified soil microcosm revealed complex metabolic adaptation in the soil environment and specific responses to antagonistic or neutral intruders.

Diabetes Alters Mechanical Properties and Collagen Fiber Re-Alignment in Multiple Mouse Tendons

PubMed Central

Connizzo, Brianne K.; Bhatt, Pankti R.; Liechty, Kenneth W.; Soslowsky, Louis J.

2014-01-01

Tendons function to transfer load from muscle to bone through their complex composition and hierarchical structure, consisting mainly of type I collagen. Recent evidence suggests that type II diabetes may cause alterations in collagen structure, such as irregular fibril morphology and density, which could play a role in the mechanical function of tendons. Using the db/db mouse model of type II diabetes, the diabetic skin was found to have impaired biomechanical properties when compared to the non-diabetic group. The purpose of this study was to assess the effect of diabetes on biomechanics, collagen fiber re-alignment, and biochemistry in three functionally different tendons (Achilles, supraspinatus, patellar) using the db/db mouse model. Results showed that cross-sectional area and stiffness, but not modulus, were significantly reduced in all three tendons. However, the tendon response to load (transition strain, collagen fiber re-alignment) occurred earlier in the mechanical test, contrary to expectations. In addition, the patellar tendon had an altered response to diabetes when compared to the other two tendons, with no changes in fiber realignment and decreased collagen content at the midsubstance of the tendon. Overall, type II diabetes alters tendon mechanical properties and the dynamic response to load. PMID:24833253

Sensory Processing Dysfunction in the Personal Experience and Neuronal Machinery of Schizophrenia

PubMed Central

Javitt, Daniel C.; Freedman, Robert

2015-01-01

Sensory processing deficits, first investigated by Kraeplin and Bleuler as possible pathophysiological mechanisms in schizophrenia, are now being re-characterized in the context of modern understanding of the involved molecular and neurobiological brain mechanisms. The National Institute of Mental Health Research Domain Criteria position these deficits as intermediaries between molecular and cellular mechanisms and clinical symptoms of schizophrenia such as hallucinations. The pre-pulse inhibition of startle responses by a weaker preceding tone, the inhibitory gating of response to paired sensory stimuli characterized using the auditory P50 evoked response, and the detection of slightly different stimuli that elicits the cortical Mismatch Negativity potential demonstrate deficits in early sensory processing mechanisms, whose molecular and neurobiological bases are increasingly well understood. Deficits in sensory processing underlie more complex cognitive dysfunction and, vice versa, are affected by higher-level cognitive difficulties. These deficits are now being used to identify genes involved in familial transmission of the illness and to monitor potentially therapeutic drug effects for both treatment and prevention. This research also provides a clinical reminder that patients’ sensory perception of the surrounding world, even during treatment sessions, may differ considerable from others’ perceptions. A person’s ability to understand and interact effectively with surrounding world ultimately depends upon an underlying sensory experience of it. PMID:25553496

Single and collective cell migration: the mechanics of adhesions

PubMed Central

De Pascalis, Chiara; Etienne-Manneville, Sandrine

2017-01-01

Chemical and physical properties of the environment control cell proliferation, differentiation, or apoptosis in the long term. However, to be able to move and migrate through a complex three-dimensional environment, cells must quickly adapt in the short term to the physical properties of their surroundings. Interactions with the extracellular matrix (ECM) occur through focal adhesions or hemidesmosomes via the engagement of integrins with fibrillar ECM proteins. Cells also interact with their neighbors, and this involves various types of intercellular adhesive structures such as tight junctions, cadherin-based adherens junctions, and desmosomes. Mechanobiology studies have shown that cell–ECM and cell–cell adhesions participate in mechanosensing to transduce mechanical cues into biochemical signals and conversely are responsible for the transmission of intracellular forces to the extracellular environment. As they migrate, cells use these adhesive structures to probe their surroundings, adapt their mechanical properties, and exert the appropriate forces required for their movements. The focus of this review is to give an overview of recent developments showing the bidirectional relationship between the physical properties of the environment and the cell mechanical responses during single and collective cell migration. PMID:28684609

Fibre reinforced concrete exposed to elevated temperature

NASA Astrophysics Data System (ADS)

Novák, J.; Kohoutková, A.

2017-09-01

Although concrete when subject to fire performs very well, its behaviour and properties change dramatically under high temperature due to damaged microstructure and mesostructure. As fibre reinforced concrete (FRC) represents a complex material composed of various components with different response to high temperature, to determine its behaviour and mechanical properties in fire is a demanding task. The presented paper provides a summary of findings on the fire response of fibre FRC. Namely, the information on steel fibre reinforced concrete (SFRC), synthetic fibre reinforced concrete and hybrid (steel + synthetic) fibre reinforced concrete have been gathered from various contributions published up to date. The mechanical properties including the melting point and ignition point of fibres affect significantly the properties of concrete composites with addition of fibres. The combination of steel and synthetic fibres represents a promising alternative how to ensure good toughness of a concrete composite before heating and improve its residual mechanical behaviour and spalling resistance as well as the ductility after heating. While synthetic fibres increase concrete spalling resistance, steel fibres in a concrete mix leads to an improvement in both mechanical properties and resistance to heating effects.

Complex networks analysis of obstructive nephropathy data

NASA Astrophysics Data System (ADS)

Zanin, M.; Boccaletti, S.

2011-09-01

Congenital obstructive nephropathy (ON) is one of the most frequent and complex diseases affecting children, characterized by an abnormal flux of the urine, due to a partial or complete obstruction of the urinary tract; as a consequence, urine may accumulate in the kidney and disturb the normal operation of the organ. Despite important advances, pathological mechanisms are not yet fully understood. In this contribution, the topology of complex networks, based on vectors of features of control and ON subjects, is related with the severity of the pathology. Nodes in these networks represent genetic and metabolic profiles, while connections between them indicate an abnormal relation between their expressions. Resulting topologies allow discriminating ON subjects and detecting which genetic or metabolic elements are responsible for the malfunction.

Environmentally-relevant concentrations of Al(III) and Fe(III) cations induce aggregation of free DNA by complexation with phosphate group.

PubMed

Qin, Chao; Kang, Fuxing; Zhang, Wei; Shou, Weijun; Hu, Xiaojie; Gao, Yanzheng

2017-10-15

Environmental persistence of free DNA is influenced by its complexation with other chemical species and its aggregation mechanisms. However, it is not well-known how naturally-abundant metal ions, e.g., Al(III) and Fe(III), influence DNA aggregation. This study investigated aggregation behaviors of model DNA from salmon testes as influenced by metal cations, and elucidated the predominant mechanism responsible for DNA aggregation. Compared to monovalent (K + and Na + ) and divalent (Ca 2+ and Mg 2+ ) cations, Al(III) and Fe(III) species in aqueous solution caused rapid DNA aggregations. The maximal DNA aggregation occurred at 0.05 mmol/L Al(III) or 0.075 mmol/L Fe(III), respectively. A combination of atomic force microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy revealed that Al(III) and Fe(III) complexed with negatively charged phosphate groups to neutralize DNA charges, resulting in decreased electrostatic repulsion and subsequent DNA aggregation. Zeta potential measurements and molecular computation further support this mechanism. Furthermore, DNA aggregation was enhanced at higher temperature and near neutral pH. Therefore, DNA aggregation is collectively determined by many environmental factors such as ion species, temperature, and solution pH. Copyright © 2017 Elsevier Ltd. All rights reserved.

Multi-omics approach identifies molecular mechanisms of plant-fungus mycorrhizal interaction

DOE PAGES

Larsen, Peter E.; Sreedasyam, Avinash; Trivedi, Geetika; ...

2016-01-19

In mycorrhizal symbiosis, plant roots form close, mutually beneficial interactions with soil fungi. Before this mycorrhizal interaction can be established however, plant roots must be capable of detecting potential beneficial fungal partners and initiating the gene expression patterns necessary to begin symbiosis. To predict a plant root – mycorrhizal fungi sensor systems, we analyzed in vitro experiments of Populus tremuloides (aspen tree) and Laccaria bicolor (mycorrhizal fungi) interaction and leveraged over 200 previously published transcriptomic experimental data sets, 159 experimentally validated plant transcription factor binding motifs, and more than 120-thousand experimentally validated protein-protein interactions to generate models of pre-mycorrhizal sensormore » systems in aspen root. These sensor mechanisms link extracellular signaling molecules with gene regulation through a network comprised of membrane receptors, signal cascade proteins, transcription factors, and transcription factor biding DNA motifs. Modeling predicted four pre-mycorrhizal sensor complexes in aspen that interact with fifteen transcription factors to regulate the expression of 1184 genes in response to extracellular signals synthesized by Laccaria. Predicted extracellular signaling molecules include common signaling molecules such as phenylpropanoids, salicylate, and, jasmonic acid. Lastly, this multi-omic computational modeling approach for predicting the complex sensory networks yielded specific, testable biological hypotheses for mycorrhizal interaction signaling compounds, sensor complexes, and mechanisms of gene regulation.« less

Multi-omics approach identifies molecular mechanisms of plant-fungus mycorrhizal interaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Larsen, Peter E.; Sreedasyam, Avinash; Trivedi, Geetika

In mycorrhizal symbiosis, plant roots form close, mutually beneficial interactions with soil fungi. Before this mycorrhizal interaction can be established however, plant roots must be capable of detecting potential beneficial fungal partners and initiating the gene expression patterns necessary to begin symbiosis. To predict a plant root – mycorrhizal fungi sensor systems, we analyzed in vitro experiments of Populus tremuloides (aspen tree) and Laccaria bicolor (mycorrhizal fungi) interaction and leveraged over 200 previously published transcriptomic experimental data sets, 159 experimentally validated plant transcription factor binding motifs, and more than 120-thousand experimentally validated protein-protein interactions to generate models of pre-mycorrhizal sensormore » systems in aspen root. These sensor mechanisms link extracellular signaling molecules with gene regulation through a network comprised of membrane receptors, signal cascade proteins, transcription factors, and transcription factor biding DNA motifs. Modeling predicted four pre-mycorrhizal sensor complexes in aspen that interact with fifteen transcription factors to regulate the expression of 1184 genes in response to extracellular signals synthesized by Laccaria. Predicted extracellular signaling molecules include common signaling molecules such as phenylpropanoids, salicylate, and, jasmonic acid. Lastly, this multi-omic computational modeling approach for predicting the complex sensory networks yielded specific, testable biological hypotheses for mycorrhizal interaction signaling compounds, sensor complexes, and mechanisms of gene regulation.« less

Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury.

PubMed

Chandrakesan, Parthasarathy; May, Randal; Weygant, Nathaniel; Qu, Dongfeng; Berry, William L; Sureban, Sripathi M; Ali, Naushad; Rao, Chinthalapally; Huycke, Mark; Bronze, Michael S; Houchen, Courtney W

2016-11-23

Crypt epithelial survival and regeneration after injury require highly coordinated complex interplay between resident stem cells and diverse cell types. The function of Dclk1 expressing tuft cells regulating intestinal epithelial DNA damage response for cell survival/self-renewal after radiation-induced injury is unclear. Intestinal epithelial cells (IECs) were isolated and purified and utilized for experimental analysis. We found that small intestinal crypts of Villin Cre ;Dclk1 f/f mice were hypoplastic and more apoptotic 24 h post-total body irradiation, a time when stem cell survival is p53-independent. Injury-induced ATM mediated DNA damage response, pro-survival genes, stem cell markers, and self-renewal ability for survival and restitution were reduced in the isolated intestinal epithelial cells. An even greater reduction in these signaling pathways was observed 3.5 days post-TBI, when peak crypt regeneration occurs. We found that interaction with Dclk1 is critical for ATM and COX2 activation in response to injury. We determined that Dclk1 expressing tuft cells regulate the whole intestinal epithelial cells following injury through paracrine mechanism. These findings suggest that intestinal tuft cells play an important role in regulating the ATM mediated DNA damage response, for epithelial cell survival/self-renewal via a Dclk1 dependent mechanism, and these processes are indispensable for restitution and function after severe radiation-induced injury.

BAG3 regulates formation of the SNARE complex and insulin secretion

PubMed Central

Iorio, V; Festa, M; Rosati, A; Hahne, M; Tiberti, C; Capunzo, M; De Laurenzi, V; Turco, M C

2015-01-01

Insulin release in response to glucose stimulation requires exocytosis of insulin-containing granules. Glucose stimulation of beta cells leads to focal adhesion kinase (FAK) phosphorylation, which acts on the Rho family proteins (Rho, Rac and Cdc42) that direct F-actin remodeling. This process requires docking and fusion of secretory vesicles to the release sites at the plasma membrane and is a complex mechanism that is mediated by SNAREs. This transiently disrupts the F-actin barrier and allows the redistribution of the insulin-containing granules to more peripheral regions of the β cell, hence facilitating insulin secretion. In this manuscript, we show for the first time that BAG3 plays an important role in this process. We show that BAG3 downregulation results in increased insulin secretion in response to glucose stimulation and in disruption of the F-actin network. Moreover, we show that BAG3 binds to SNAP-25 and syntaxin-1, two components of the t-SNARE complex preventing the interaction between SNAP-25 and syntaxin-1. Upon glucose stimulation BAG3 is phosphorylated by FAK and dissociates from SNAP-25 allowing the formation of the SNARE complex, destabilization of the F-actin network and insulin release. PMID:25766323

Reconstitution of actin-based motility of Listeria and Shigella using pure proteins

NASA Astrophysics Data System (ADS)

Loisel, Thomas P.; Boujemaa, Rajaa; Pantaloni, Dominique; Carlier, Marie-France

1999-10-01

Actin polymerization is essential for cell locomotion and is thought to generate the force responsible for cellular protrusions. The Arp2/3 complex is required to stimulate actin assembly at the leading edge in response to signalling. The bacteria Listeria and Shigella bypass the signalling pathway and harness the Arp2/3 complex to induce actin assembly and to propel themselves in living cells. However, the Arp2/3 complex alone is insufficient to promote movement. Here we have used pure components of the actin cytoskeleton to reconstitute sustained movement in Listeria and Shigella in vitro. Actin-based propulsion is driven by the free energy released by ATP hydrolysis linked to actin polymerization, and does not require myosin. In addition to actin and activated Arp2/3 complex, actin depolymerizing factor (ADF, or cofilin) and capping protein are also required for motility as they maintain a high steady-state level of G-actin, which controls the rate of unidirectional growth of actin filaments at the surface of the bacterium. The movement is more effective when profilin, α-actinin and VASP (for Listeria) are also included. These results have implications for our understanding of the mechanism of actin-based motility in cells.

Mechanisms and strategies of plant defense against Botrytis cinerea.

PubMed

AbuQamar, Synan; Moustafa, Khaled; Tran, Lam Son

2017-03-01

Biotic factors affect plant immune responses and plant resistance to pathogen infections. Despite the considerable progress made over the past two decades in manipulating genes, proteins and their levels from diverse sources, no complete genetic tolerance to environmental stresses has been developed so far in any crops. Plant defense response to pathogens, including Botrytis cinerea, is a complex biological process involving various changes at the biochemical, molecular (i.e. transcriptional) and physiological levels. Once a pathogen is detected, effective plant resistance activates signaling networks through the generation of small signaling molecules and the balance of hormonal signaling pathways to initiate defense mechanisms to the particular pathogen. Recently, studies using Arabidopsis thaliana and crop plants have shown that many genes are involved in plant responses to B. cinerea infection. In this article, we will review our current understanding of mechanisms regulating plant responses to B. cinerea with a particular interest on hormonal regulatory networks involving phytohormones salicylic acid (SA), jasmonic acid (JA), ethylene (ET) and abscisic acid (ABA). We will also highlight some potential gene targets that are promising for improving crop resistance to B. cinerea through genetic engineering and breeding programs. Finally, the role of biological control as a complementary and alternative disease management will be overviewed.

Healthcare Reimbursement and Quality Improvement: Integration Using the Electronic Medical Record Comment on "Fee-for-Service Payment--an Evil Practice That Must Be Stamped Out?".

PubMed

Britton, John R

2015-05-08

Reimbursement for healthcare has utilized a variety of payment mechanisms with varying degrees of effectiveness. Whether these mechanisms are used singly or in combination, it is imperative that the resulting systems remunerate on the basis of the quantity, complexity, and quality of care provided. Expanding the role of the electronic medical record (EMR) to monitor provider practice, patient responsiveness, and functioning of the healthcare organization has the potential to not only enhance the accuracy and efficiency of reimbursement mechanisms but also to improve the quality of medical care. © 2015 by Kerman University of Medical Sciences.

Biophysics of cancer progression and high-throughput mechanical characterization of biomaterials

NASA Astrophysics Data System (ADS)

Osborne, Lukas Dylan

Cancer metastasis involves a series of events known as the metastatic cascade. In this complex progression, cancer cells detach from the primary tumor, invade the surrounding stromal space, transmigrate the vascular system, and establish secondary tumors at distal sites. Specific mechanical phenotypes are likely adopted to enable cells to successfully navigate the mechanical environments encountered during metastasis. To examine the role of cell mechanics in cancer progression, I employed force-consistent biophysical and biochemical assays to characterize the mechanistic links between stiffness, stiffness response and cell invasion during the epithelial to mesenchymal transition (EMT). EMT is an essential physiological process, whose abnormal reactivation has been implicated in the detachment of cancer cells from epithelial tissue and their subsequent invasion into stromal tissue. I demonstrate that epithelial-state cells respond to force by evoking a stiffening response, and that after EMT, mesenchymal-state cells have reduced stiffness but also lose the ability to increase their stiffness in response to force. Using loss and gain of function studies, two proteins are established as functional connections between attenuated stiffness and stiffness response and the increased invasion capacity acquired after EMT. To enable larger scale assays to more fully explore the connection between biomechanics and cancer, I discuss the development of an automated array high throughput (AHT) microscope. The AHT system is shown to implement passive microbead rheology to accurately characterize the mechanical properties of biomaterials. Compared to manually performed mechanical characterizations, the AHT system executes experiments in two orders of magnitude less time. Finally, I use the AHT microscope to study the effect of gain of function oncogenic molecules on cell stiffness. I find evidence that our assay can identify alterations in cell stiffness due to constitutive activation of cancer pathways.

Mechanical response tissue analyzer for estimating bone strength

NASA Technical Reports Server (NTRS)

Arnaud, Sara B.; Steele, Charles; Mauriello, Anthony

1991-01-01

One of the major concerns for extended space flight is weakness of the long bones of the legs, composed primarily of cortical bone, that functions to provide mechanical support. The strength of cortical bone is due to its complex structure, described simplistically as cylinders of parallel osteons composed of layers of mineralized collagen. The reduced mechanical stresses during space flight or immobilization of bone on Earth reduces the mineral content, and changes the components of its matrix and structure so that its strength is reduced. Currently, the established clinical measures of bone strength are indirect. The measures are based on determinations of mineral density by means of radiography, photon absorptiometry, and quantitative computer tomography. While the mineral content of bone is essential to its strength, there is growing awareness of the limitations of the measurement as the sole predictor of fracture risk in metabolic bone diseases, especially limitations of the measurement as the sole predictor of fracture risk in metabolic bone diseases, especially osteoporosis. Other experimental methods in clinical trials that more directly evaluate the physical properties of bone, and do not require exposure to radiation, include ultrasound, acoustic emission, and low-frequency mechanical vibration. The last method can be considered a direct measure of the functional capacity of a long bone since it quantifies the mechanical response to a stimulus delivered directly to the bone. A low frequency vibration induces a response (impedance) curve with a minimum at the resonant frequency, that a few investigators use for the evaluation of the bone. An alternative approach, the method under consideration, is to use the response curve as the basis for determination of the bone bending stiffness EI (E is the intrinsic material property and I is the cross-sectional moment of inertia) and mass, fundamental mechanical properties of bone.

Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise

PubMed Central

Gundermann, David M.; Fry, Christopher S.; Dickinson, Jared M.; Walker, Dillon K.; Timmerman, Kyle L.; Drummond, Micah J.; Volpi, Elena

2012-01-01

Blood flow restriction (BFR) to contracting skeletal muscle during low-intensity resistance exercise training increases muscle strength and size in humans. However, the mechanism(s) underlying these effects are largely unknown. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis (MPS) are stimulated following an acute bout of BFR exercise. The purpose of this study was to test the hypothesis that reactive hyperemia is the mechanism responsible for stimulating mTORC1 signaling and MPS following BFR exercise. Six young men (24 ± 2 yr) were used in a randomized crossover study consisting of two exercise trials: low-intensity resistance exercise with BFR (BFR trial) and low-intensity resistance exercise with sodium nitroprusside (SNP), a pharmacological vasodilator infusion into the femoral artery immediately after exercise to simulate the reactive hyperemia response after BFR exercise (SNP trial). Postexercise mixed-muscle fractional synthetic rate from the vastus lateralis increased by 49% in the BFR trial (P < 0.05) with no change in the SNP trial (P > 0.05). BFR exercise increased the phosphorylation of mTOR, S6 kinase 1, ribosomal protein S6, ERK1/2, and Mnk1-interacting kinase 1 (P < 0.05) with no changes in mTORC1 signaling in the SNP trial (P > 0.05). We conclude that reactive hyperemia is not a primary mechanism for BFR exercise-induced mTORC1 signaling and MPS. Further research is necessary to elucidate the cellular mechanism(s) responsible for the increase in mTOR signaling, MPS, and hypertrophy following acute and chronic BFR exercise. PMID:22362401

Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise.

PubMed

Gundermann, David M; Fry, Christopher S; Dickinson, Jared M; Walker, Dillon K; Timmerman, Kyle L; Drummond, Micah J; Volpi, Elena; Rasmussen, Blake B

2012-05-01

Blood flow restriction (BFR) to contracting skeletal muscle during low-intensity resistance exercise training increases muscle strength and size in humans. However, the mechanism(s) underlying these effects are largely unknown. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis (MPS) are stimulated following an acute bout of BFR exercise. The purpose of this study was to test the hypothesis that reactive hyperemia is the mechanism responsible for stimulating mTORC1 signaling and MPS following BFR exercise. Six young men (24 ± 2 yr) were used in a randomized crossover study consisting of two exercise trials: low-intensity resistance exercise with BFR (BFR trial) and low-intensity resistance exercise with sodium nitroprusside (SNP), a pharmacological vasodilator infusion into the femoral artery immediately after exercise to simulate the reactive hyperemia response after BFR exercise (SNP trial). Postexercise mixed-muscle fractional synthetic rate from the vastus lateralis increased by 49% in the BFR trial (P < 0.05) with no change in the SNP trial (P > 0.05). BFR exercise increased the phosphorylation of mTOR, S6 kinase 1, ribosomal protein S6, ERK1/2, and Mnk1-interacting kinase 1 (P < 0.05) with no changes in mTORC1 signaling in the SNP trial (P > 0.05). We conclude that reactive hyperemia is not a primary mechanism for BFR exercise-induced mTORC1 signaling and MPS. Further research is necessary to elucidate the cellular mechanism(s) responsible for the increase in mTOR signaling, MPS, and hypertrophy following acute and chronic BFR exercise.

Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli

PubMed Central

Gat-Viks, Irit; Chevrier, Nicolas; Wilentzik, Roni; Eisenhaure, Thomas; Raychowdhury, Raktima; Steuerman, Yael; Shalek, Alex; Hacohen, Nir; Amit, Ido; Regev, Aviv

2013-01-01

Individual genetic variation affects gene expression in response to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness QTLs; reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant acts as an activator of the antiviral response; using RNAi, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli. PMID:23503680

Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli.

PubMed

Gat-Viks, Irit; Chevrier, Nicolas; Wilentzik, Roni; Eisenhaure, Thomas; Raychowdhury, Raktima; Steuerman, Yael; Shalek, Alex K; Hacohen, Nir; Amit, Ido; Regev, Aviv

2013-04-01

Individual genetic variation affects gene responsiveness to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness quantitative trait loci or reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant responds as an activator of the antiviral response; using RNA interference, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli.

The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis.

PubMed

Fu, Junjiang; Qin, Li; He, Tao; Qin, Jun; Hong, Jun; Wong, Jiemin; Liao, Lan; Xu, Jianming

2011-02-01

The epithelial-mesenchymal transition (EMT) converts epithelial tumor cells into invasive and metastatic cancer cells, leading to mortality in cancer patients. Although TWIST is a master regulator of EMT and metastasis for breast and other cancers, the mechanisms responsible for TWIST-mediated gene transcription remain unknown. In this study, purification and characterization of the TWIST protein complex revealed that TWIST interacts with several components of the Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) complex, MTA2, RbAp46, Mi2 and HDAC2, and recruits them to the proximal regions of the E-cadherin promoter for transcriptional repression. Depletion of these TWIST complex components from cancer cell lines that depend on TWIST for metastasis efficiently suppresses cell migration and invasion in culture and lung metastasis in mice. These findings not only provide novel mechanistic and functional links between TWIST and the Mi2/NuRD complex but also establish new essential roles for the components of Mi2/NuRD complex in cancer metastasis.

Characterizing Feedback Control Mechanisms in Nonlinear Microbial Models of Soil Organic Matter Decomposition by Stability Analysis

NASA Astrophysics Data System (ADS)

Georgiou, K.; Tang, J.; Riley, W. J.; Torn, M. S.

2014-12-01

Soil organic matter (SOM) decomposition is regulated by biotic and abiotic processes. Feedback interactions between such processes may act to dampen oscillatory responses to perturbations from equilibrium. Indeed, although biological oscillations have been observed in small-scale laboratory incubations, the overlying behavior at the plot-scale exhibits a relatively stable response to disturbances in input rates and temperature. Recent studies have demonstrated the ability of microbial models to capture nonlinear feedbacks in SOM decomposition that linear Century-type models are unable to reproduce, such as soil priming in response to increased carbon input. However, these microbial models often exhibit strong oscillatory behavior that is deemed unrealistic. The inherently nonlinear dynamics of SOM decomposition have important implications for global climate-carbon and carbon-concentration feedbacks. It is therefore imperative to represent these dynamics in Earth System Models (ESMs) by introducing sub-models that accurately represent microbial and abiotic processes. In the present study we explore, both analytically and numerically, four microbe-enabled model structures of varying levels of complexity. The most complex model combines microbial physiology, a non-linear mineral sorption isotherm, and enzyme dynamics. Based on detailed stability analysis of the nonlinear dynamics, we calculate the system modes as functions of model parameters. This dependence provides insight into the source of state oscillations. We find that feedback mechanisms that emerge from careful representation of enzyme and mineral interactions, with parameter values in a prescribed range, are critical for both maintaining system stability and capturing realistic responses to disturbances. Corroborating and expanding upon the results of recent studies, we explain the emergence of oscillatory responses and discuss the appropriate microbe-enabled model structure for inclusion in ESMs.

Mechanical response of stainless steel subjected to biaxial load path changes: Cruciform experiments and multi-scale modeling

DOE PAGES

Upadhyay, Manas V.; Patra, Anirban; Wen, Wei; ...

2018-05-08

In this paper, we propose a multi-scale modeling approach that can simulate the microstructural and mechanical behavior of metal or alloy parts with complex geometries subjected to multi-axial load path changes. The model is used to understand the biaxial load path change behavior of 316L stainless steel cruciform samples. At the macroscale, a finite element approach is used to simulate the cruciform geometry and numerically predict the gauge stresses, which are difficult to obtain analytically. At each material point in the finite element mesh, the anisotropic viscoplastic self-consistent model is used to simulate the role of texture evolution on themore » mechanical response. At the single crystal level, a dislocation density based hardening law that appropriately captures the role of multi-axial load path changes on slip activity is used. The combined approach is experimentally validated using cruciform samples subjected to uniaxial load and unload followed by different biaxial reloads in the angular range [27º, 90º]. Polycrystalline yield surfaces before and after load path changes are generated using the full-field elasto-viscoplastic fast Fourier transform model to study the influence of the deformation history and reloading direction on the mechanical response, including the Bauschinger effect, of these cruciform samples. Results reveal that the Bauschinger effect is strongly dependent on the first loading direction and strain, intergranular and macroscopic residual stresses after first load, and the reloading angle. The microstructural origins of the mechanical response are discussed.« less

Mechanical response of stainless steel subjected to biaxial load path changes: Cruciform experiments and multi-scale modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Upadhyay, Manas V.; Patra, Anirban; Wen, Wei

In this paper, we propose a multi-scale modeling approach that can simulate the microstructural and mechanical behavior of metal or alloy parts with complex geometries subjected to multi-axial load path changes. The model is used to understand the biaxial load path change behavior of 316L stainless steel cruciform samples. At the macroscale, a finite element approach is used to simulate the cruciform geometry and numerically predict the gauge stresses, which are difficult to obtain analytically. At each material point in the finite element mesh, the anisotropic viscoplastic self-consistent model is used to simulate the role of texture evolution on themore » mechanical response. At the single crystal level, a dislocation density based hardening law that appropriately captures the role of multi-axial load path changes on slip activity is used. The combined approach is experimentally validated using cruciform samples subjected to uniaxial load and unload followed by different biaxial reloads in the angular range [27º, 90º]. Polycrystalline yield surfaces before and after load path changes are generated using the full-field elasto-viscoplastic fast Fourier transform model to study the influence of the deformation history and reloading direction on the mechanical response, including the Bauschinger effect, of these cruciform samples. Results reveal that the Bauschinger effect is strongly dependent on the first loading direction and strain, intergranular and macroscopic residual stresses after first load, and the reloading angle. The microstructural origins of the mechanical response are discussed.« less

Thyroid hormone effects on mitochondrial energetics.

PubMed

Harper, Mary-Ellen; Seifert, Erin L

2008-02-01

Thyroid hormones are the major endocrine regulators of metabolic rate, and their hypermetabolic effects are widely recognized. The cellular mechanisms underlying these metabolic effects have been the subject of much research. Thyroid hormone status has a profound impact on mitochondria, the organelles responsible for the majority of cellular adenosine triphosphate (ATP) production. However, mechanisms are not well understood. We review the effects of thyroid hormones on mitochondrial energetics and principally oxidative phosphorylation. Genomic and nongenomic mechanisms have been studied. Through the former, thyroid hormones stimulate mitochondriogenesis and thereby augment cellular oxidative capacity. Thyroid hormones induce substantial modifications in mitochondrial inner membrane protein and lipid compositions. Results are consistent with the idea that thyroid hormones activate the uncoupling of oxidative phosphorylation through various mechanisms involving inner membrane proteins and lipids. Increased uncoupling appears to be responsible for some of the hypermetabolic effects of thyroid hormones. ATP synthesis and turnover reactions are also affected. There appear to be complex relationships between mitochondrial proton leak mechanisms, reactive oxygen species production, and thyroid status. As the majority of studies have focused on the effects of thyroid status on rat liver preparations, there is still a need to address fundamental questions regarding thyroid hormone effects in other tissues and species.

3D multiphysics modeling of superconducting cavities with a massively parallel simulation suite

NASA Astrophysics Data System (ADS)

Kononenko, Oleksiy; Adolphsen, Chris; Li, Zenghai; Ng, Cho-Kuen; Rivetta, Claudio

2017-10-01

Radiofrequency cavities based on superconducting technology are widely used in particle accelerators for various applications. The cavities usually have high quality factors and hence narrow bandwidths, so the field stability is sensitive to detuning from the Lorentz force and external loads, including vibrations and helium pressure variations. If not properly controlled, the detuning can result in a serious performance degradation of a superconducting accelerator, so an understanding of the underlying detuning mechanisms can be very helpful. Recent advances in the simulation suite ace3p have enabled realistic multiphysics characterization of such complex accelerator systems on supercomputers. In this paper, we present the new capabilities in ace3p for large-scale 3D multiphysics modeling of superconducting cavities, in particular, a parallel eigensolver for determining mechanical resonances, a parallel harmonic response solver to calculate the response of a cavity to external vibrations, and a numerical procedure to decompose mechanical loads, such as from the Lorentz force or piezoactuators, into the corresponding mechanical modes. These capabilities have been used to do an extensive rf-mechanical analysis of dressed TESLA-type superconducting cavities. The simulation results and their implications for the operational stability of the Linac Coherent Light Source-II are discussed.

The Role of Immunogenicity in Cardiovascular Disease

PubMed Central

Jan, Michael; Virtue, Anthony T.; Pansuria, Meghanaben; Liu, Jingshan; Xiong, Xinyu; Fang, Pu; Meng, Shu; Wang, Hong; Yang, Xiao-Feng

2012-01-01

Recently, many of the complexities associated with cardiovascular diseases (CVD) have been unlocked. However, despite these breakthroughs, CVD and its related complications are the leading contributors of morbidity and mortality worldwide, which indicates the shortcomings of current treatment regimens and the need for continued research. Published data within the field clearly indicates that CVD are built on inflammation and autoimmune platforms, though a strong, fundamental understanding of the mechanisms remains elusive. Areas such as the mechanisms underlying increased immunogenicity of self-proteins in the cardiovascular system, the roles of immunogenic auto-antigens in eliciting inflammatory autoimmune responses, and the immunosuppressive mechanisms involved in controlling inflammatory and autoimmune cardiovascular diseases remain to be well-understood. We will delve into these topics and the advancements made within the field in this review. Specifically, we will concentrate on the innate and adaptive immune responses mediating immunogenicity; the mechanisms of inflammation and autoimmunity in atherogenesis; the mechanisms of inflammation and autoimmunity in diabetic atherosclerosis; immunogenicity and stem cell therapy; as well as immunogenicity and immunosuppression. In depth examination and comprehension of these topics will provide insight into the recent progress of the field and bring to the forefront potentially novel therapeutic avenues. PMID:24511305

Modeling Composite Laminate Crushing for Crash Analysis

NASA Technical Reports Server (NTRS)

Fleming, David C.; Jones, Lisa (Technical Monitor)

2002-01-01

Crash modeling of composite structures remains limited in application and has not been effectively demonstrated as a predictive tool. While the global response of composite structures may be well modeled, when composite structures act as energy-absorbing members through direct laminate crushing the modeling accuracy is greatly reduced. The most efficient composite energy absorbing structures, in terms of energy absorbed per unit mass, are those that absorb energy through a complex progressive crushing response in which fiber and matrix fractures on a small scale dominate the behavior. Such failure modes simultaneously include delamination of plies, failure of the matrix to produce fiber bundles, and subsequent failure of fiber bundles either in bending or in shear. In addition, the response may include the significant action of friction, both internally (between delaminated plies or fiber bundles) or externally (between the laminate and the crushing surface). A figure shows the crushing damage observed in a fiberglass composite tube specimen, illustrating the complexity of the response. To achieve a finite element model of such complex behavior is an extremely challenging problem. A practical crushing model based on detailed modeling of the physical mechanisms of crushing behavior is not expected in the foreseeable future. The present research describes attempts to model composite crushing behavior using a novel hybrid modeling procedure. Experimental testing is done is support of the modeling efforts, and a test specimen is developed to provide data for validating laminate crushing models.

PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena.

PubMed

Hughes, Shannon K; Oudin, Madeleine J; Tadros, Jenny; Neil, Jason; Del Rosario, Amanda; Joughin, Brian A; Ritsma, Laila; Wyckoff, Jeff; Vasile, Eliza; Eddy, Robert; Philippar, Ulrike; Lussiez, Alisha; Condeelis, John S; van Rheenen, Jacco; White, Forest; Lauffenburger, Douglas A; Gertler, Frank B

2015-11-01

During breast cancer progression, alternative mRNA splicing produces functionally distinct isoforms of Mena, an actin regulator with roles in cell migration and metastasis. Aggressive tumor cell subpopulations express Mena(INV), which promotes tumor cell invasion by potentiating EGF responses. However, the mechanism by which this occurs is unknown. Here we report that Mena associates constitutively with the tyrosine phosphatase PTP1B and mediates a novel negative feedback mechanism that attenuates receptor tyrosine kinase signaling. On EGF stimulation, complexes containing Mena and PTP1B are recruited to the EGFR, causing receptor dephosphorylation and leading to decreased motility responses. Mena also interacts with the 5' inositol phosphatase SHIP2, which is important for the recruitment of the Mena-PTP1B complex to the EGFR. When Mena(INV) is expressed, PTP1B recruitment to the EGFR is impaired, providing a mechanism for growth factor sensitization to EGF, as well as HGF and IGF, and increased resistance to EGFR and Met inhibitors in signaling and motility assays. In sum, we demonstrate that Mena plays an important role in regulating growth factor-induced signaling. Disruption of this attenuation by Mena(INV) sensitizes tumor cells to low-growth factor concentrations, thereby increasing the migration and invasion responses that contribute to aggressive, malignant cell phenotypes. © 2015 Hughes, Oudin, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Systems biology-based approaches toward understanding drought tolerance in food crops.

PubMed

Jogaiah, Sudisha; Govind, Sharathchandra Ramsandra; Tran, Lam-Son Phan

2013-03-01

Economically important crops, such as maize, wheat, rice, barley, and other food crops are affected by even small changes in water potential at important growth stages. Developing a comprehensive understanding of host response to drought requires a global view of the complex mechanisms involved. Research on drought tolerance has generally been conducted using discipline-specific approaches. However, plant stress response is complex and interlinked to a point where discipline-specific approaches do not give a complete global analysis of all the interlinked mechanisms. Systems biology perspective is needed to understand genome-scale networks required for building long-lasting drought resistance. Network maps have been constructed by integrating multiple functional genomics data with both model plants, such as Arabidopsis thaliana, Lotus japonicus, and Medicago truncatula, and various food crops, such as rice and soybean. Useful functional genomics data have been obtained from genome-wide comparative transcriptome and proteome analyses of drought responses from different crops. This integrative approach used by many groups has led to identification of commonly regulated signaling pathways and genes following exposure to drought. Combination of functional genomics and systems biology is very useful for comparative analysis of other food crops and has the ability to develop stable food systems worldwide. In addition, studying desiccation tolerance in resurrection plants will unravel how combination of molecular genetic and metabolic processes interacts to produce a resurrection phenotype. Systems biology-based approaches have helped in understanding how these individual factors and mechanisms (biochemical, molecular, and metabolic) "interact" spatially and temporally. Signaling network maps of such interactions are needed that can be used to design better engineering strategies for improving drought tolerance of important crop species.

Experimental Study of the Effects of EIPA, Losartan, and BQ-123 on Electrophysiological Changes Induced by Myocardial Stretch.

PubMed

Chorro, Francisco J; Canto, Irene Del; Brines, Laia; Such-Miquel, Luis; Calvo, Conrado; Soler, Carlos; Zarzoso, Manuel; Trapero, Isabel; Tormos, Álvaro; Such, Luis

2015-12-01

Mechanical response to myocardial stretch has been explained by various mechanisms, which include Na(+)/H(+) exchanger activation by autocrine-paracrine system activity. Drug-induced changes were analyzed to investigate the role of these mechanisms in the electrophysiological responses to acute myocardial stretch. Multiple epicardial electrodes and mapping techniques were used to analyze changes in ventricular fibrillation induced by acute myocardial stretch in isolated perfused rabbit hearts. Four series were studied: control (n = 9); during perfusion with the angiotensin receptor blocker losartan (1 μM, n = 8); during perfusion with the endothelin A receptor blocker BQ-123 (0.1 μM, n = 9), and during perfusion with the Na(+)/H(+) exchanger inhibitor EIPA (5-[N-ethyl-N-isopropyl]-amiloride) (1 μM, n = 9). EIPA attenuated the increase in the dominant frequency of stretch-induced fibrillation (control=40.4%; losartan=36% [not significant]; BQ-123=46% [not significant]; and EIPA=22% [P<.001]). During stretch, the activation maps were less complex (P<.0001) and the spectral concentration of the arrhythmia was greater (greater regularity) in the EIPA series: control=18 (3%); EIPA = 26 (9%) (P < .02); losartan=18 (5%) (not significant); and BQ-123=18 (4%) (not significant). The Na(+)/H(+) exchanger inhibitor EIPA attenuated the electrophysiological effects responsible for the acceleration and increased complexity of ventricular fibrillation induced by acute myocardial stretch. The angiotensin II receptor antagonist losartan and the endothelin A receptor blocker BQ-123 did not modify these effects. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex

PubMed Central

Wan, Pin; Pan, Pan; Zhang, Yecheng; Wu, Kailang; Liu, Yingle; Wu, Jianguo

2017-01-01

Activation of NLRP3 inflammasome is important for effective host defense against invading pathogen. Together with apoptosis-associated speck-like protein containing CARD domain (ASC), NLRP3 induces the cleavage of caspase-1 to facilitate the maturation of interleukin-1beta (IL-1β), an important pro-inflammatory cytokine. IL-1β subsequently plays critical roles in inflammatory responses by activating immune cells and inducing many secondary pro-inflammatory cytokines. Although the role of NLRP3 inflammasome in immune response is well defined, the mechanism underlying its assembly modulated by pathogen infection remains largely unknown. Here, we identified a novel mechanism by which enterovirus 71 (EV71) facilitates the assembly of NLRP3 inflammasome. Our results show that EV71 induces production and secretion of IL-1β in macrophages and peripheral blood mononuclear cells (PBMCs) through activation of NLRP3 inflammasome. EV71 replication and protein synthesis are required for NLRP3-mediated activation of IL-1β. Interestingly, EV71 3D protein, a RNA-dependent RNA polymerase (RdRp) was found to stimulate the activation of NLRP3 inflammasome, the cleavage of pro-caspase-1, and the release of IL-1β through direct binding to NLRP3. More importantly, 3D interacts with NLRP3 to facilitate the assembly of inflammasome complex by forming a 3D-NLRP3-ASC ring-like structure, resulting in the activation of IL-1β. These findings demonstrate a new role of 3D as an important player in the activation of inflammatory response, and identify a novel mechanism underlying the modulation of inflammasome assembly and function induced by pathogen invasion. PMID:28060938

Mixed mechanisms of multi-site phosphorylation

PubMed Central

Suwanmajo, Thapanar; Krishnan, J.

2015-01-01

Multi-site phosphorylation is ubiquitous in cell biology and has been widely studied experimentally and theoretically. The underlying chemical modification mechanisms are typically assumed to be distributive or processive. In this paper, we study the behaviour of mixed mechanisms that can arise either because phosphorylation and dephosphorylation involve different mechanisms or because phosphorylation and/or dephosphorylation can occur through a combination of mechanisms. We examine a hierarchy of models to assess chemical information processing through different mixed mechanisms, using simulations, bifurcation analysis and analytical work. We demonstrate how mixed mechanisms can show important and unintuitive differences from pure distributive and processive mechanisms, in some cases resulting in monostable behaviour with simple dose–response behaviour, while in other cases generating new behaviour-like oscillations. Our results also suggest patterns of information processing that are relevant as the number of modification sites increases. Overall, our work creates a framework to examine information processing arising from complexities of multi-site modification mechanisms and their impact on signal transduction. PMID:25972433

A flame burning within.

PubMed

Ferrucci, Luigi; Ble, Alessandro; Bandinelli, Stefania; Lauretani, Fulvio; Suthers, Kristen; Guralnik, Jack M

2004-06-01

Inflammation is a human being's primary defense against threats to homeostasis that are encountered every day. Especially in old age, when regulatory mechanisms responsible for inflammatory responses may be ineffective or damaged, the result can be adverse pathological conditions, and an increased risk of morbidity and mortality. The inflammation response is a plastic network composed of redundant signaling among several different mediators. These mediators have a reciprocal relationship with other biological sub-systems, including hormone regulation, the autonomic nervous system, and oxidative/anti-oxidant balance. Studying this complex architecture requires parallel and multiple research strategies from epidemiological to biochemical level, from observational studies to innovative intervention approaches. Given that the inflammatory response is a critical age-related process, understanding its regulatory action is essential in avoiding hazardous consequences in old age.

Crystal structure of an EfPDF complex with Met-Ala-Ser based on crystallographic packing.

PubMed

Nam, Ki Hyun; Kim, Kook-Han; Kim, Eunice Eun Kyeong; Hwang, Kwang Yeon

2009-04-17

PDF (peptide deformylase) plays a critical role in the production of mature proteins by removing the N-formyl polypeptide of nascent proteins in the prokaryote cell system. This protein is essential for bacterial growth, making it an attractive target for the design of new antibiotics. Accordingly, PDF has been evaluated as a drug target; however, architectural mechanism studies of PDF have not yet fully elucidated its molecular function. We recently reported the crystal structure of PDF produced by Enterococcus faecium [K.H. Nam, J.I. Ham, A. Priyadarshi, E.E. Kim, N. Chung, K.Y. Hwang, "Insight into the antibacterial drug design and architectural mechanism of peptide recognition from the E. faecium peptide deformylase structure", Proteins 74 (2009) 261-265]. Here, we present the crystal structure of the EfPDF complex with MAS (Met-Ser-Ala), thereby not only delineating the architectural mechanism for the recognition of mimic-peptides by N-terminal cleaved expression peptide, but also suggesting possible targets for rational design of antibacterial drugs. In addition to their implications for drug design, these structural studies will facilitate elucidation of the architectural mechanism responsible for the peptide recognition of PDF.

Evasion Mechanisms Used by Pathogens to Escape the Lectin Complement Pathway.

PubMed

Rosbjerg, Anne; Genster, Ninette; Pilely, Katrine; Garred, Peter

2017-01-01

The complement system is a crucial defensive network that protects the host against invading pathogens. It is part of the innate immune system and can be initiated via three pathways: the lectin, classical and alternative activation pathway. Overall the network compiles a group of recognition molecules that bind specific patterns on microbial surfaces, a group of associated proteases that initiates the complement cascade, and a group of proteins that interact in proteolytic complexes or the terminal pore-forming complex. In addition, various regulatory proteins are important for controlling the level of activity. The result is a pro-inflammatory response meant to combat foreign microbes. Microbial elimination is, however, not a straight forward procedure; pathogens have adapted to their environment by evolving a collection of evasion mechanisms that circumvent the human complement system. Complement evasion strategies features different ways of exploiting human complement proteins and moreover features different pathogen-derived proteins that interfere with the normal processes. Accumulated, these mechanisms target all three complement activation pathways as well as the final common part of the cascade. This review will cover the currently known lectin pathway evasion mechanisms and give examples of pathogens that operate these to increase their chance of invasion, survival and dissemination.

In vitro selection of DNA elements highly responsive to the human T-cell lymphotropic virus type I transcriptional activator, Tax.

PubMed

Paca-Uccaralertkun, S; Zhao, L J; Adya, N; Cross, J V; Cullen, B R; Boros, I M; Giam, C Z

1994-01-01

The human T-cell lymphotropic virus type I (HTLV-I) transactivator, Tax, the ubiquitous transcriptional factor cyclic AMP (cAMP) response element-binding protein (CREB protein), and the 21-bp repeats in the HTLV-I transcriptional enhancer form a ternary nucleoprotein complex (L. J. Zhao and C. Z. Giam, Proc. Natl. Acad. Sci. USA 89:7070-7074, 1992). Using an antibody directed against the COOH-terminal region of Tax along with purified Tax and CREB proteins, we selected DNA elements bound specifically by the Tax-CREB complex in vitro. Two distinct but related groups of sequences containing the cAMP response element (CRE) flanked by long runs of G and C residues in the 5' and 3' regions, respectively, were preferentially recognized by Tax-CREB. In contrast, CREB alone binds only to CRE motifs (GNTGACG[T/C]) without neighboring G- or C-rich sequences. The Tax-CREB-selected sequences bear a striking resemblance to the 5' or 3' two-thirds of the HTLV-I 21-bp repeats and are highly inducible by Tax. Gel electrophoretic mobility shift assays, DNA transfection, and DNase I footprinting analyses indicated that the G- and C-rich sequences flanking the CRE motif are crucial for Tax-CREB-DNA ternary complex assembly and Tax transactivation but are not in direct contact with the Tax-CREB complex. These data show that Tax recruits CREB to form a multiprotein complex that specifically recognizes the viral 21-bp repeats. The expanded DNA binding specificity of Tax-CREB and the obligatory role the ternary Tax-CREB-DNA complex plays in transactivation reveal a novel mechanism for regulating the transcriptional activity of leucine zipper proteins like CREB.

High-performance graphdiyne-based electrochemical actuators.

PubMed

Lu, Chao; Yang, Ying; Wang, Jian; Fu, Ruoping; Zhao, Xinxin; Zhao, Lei; Ming, Yue; Hu, Ying; Lin, Hongzhen; Tao, Xiaoming; Li, Yuliang; Chen, Wei

2018-02-21

Electrochemical actuators directly converting electrical energy to mechanical energy are critically important for artificial intelligence. However, their energy transduction efficiency is always lower than 1.0% because electrode materials lack active units in microstructure, and their assembly systems can hardly express the intrinsic properties. Here, we report a molecular-scale active graphdiyne-based electrochemical actuator with a high electro-mechanical transduction efficiency of up to 6.03%, exceeding that of the best-known piezoelectric ceramic, shape memory alloy and electroactive polymer reported before, and its energy density (11.5 kJ m -3 ) is comparable to that of mammalian skeletal muscle (~8 kJ m -3 ). Meanwhile, the actuator remains responsive at frequencies from 0.1 to 30 Hz with excellent cycling stability over 100,000 cycles. Furthermore, we verify the alkene-alkyne complex transition effect responsible for the high performance through in situ sum frequency generation spectroscopy. This discovery sheds light on our understanding of actuation mechanisms and will accelerate development of smart actuators.

DNA Damage and Repair in Human Cancer: Molecular Mechanisms and Contribution to Therapy-Related Leukemias

PubMed Central

Casorelli, Ida; Bossa, Cecilia; Bignami, Margherita

2012-01-01

Most antitumour therapies damage tumour cell DNA either directly or indirectly. Without repair, damage can result in genetic instability and eventually cancer. The strong association between the lack of DNA damage repair, mutations and cancer is dramatically demonstrated by a number of cancer-prone human syndromes, such as xeroderma pigmentosum, ataxia-telangiectasia and Fanconi anemia. Notably, DNA damage responses, and particularly DNA repair, influence the outcome of therapy. Because DNA repair normally excises lethal DNA lesions, it is intuitive that efficient repair will contribute to intrinsic drug resistance. Unexpectedly, a paradoxical relationship between DNA mismatch repair and drug sensitivity has been revealed by model studies in cell lines. This suggests that connections between DNA repair mechanism efficiency and tumour therapy might be more complex. Here, we review the evidence for the contribution of carcinogenic properties of several drugs as well as of alterations in specific mechanisms involved in drug-induced DNA damage response and repair in the pathogenesis of therapy-related cancers. PMID:23066388

Understanding the mechanism of catalytic fast pyrolysis by unveiling reactive intermediates in heterogeneous catalysis

PubMed Central

Hemberger, Patrick; Custodis, Victoria B. F.; Bodi, Andras; Gerber, Thomas; van Bokhoven, Jeroen A.

2017-01-01

Catalytic fast pyrolysis is a promising way to convert lignin into fine chemicals and fuels, but current approaches lack selectivity and yield unsatisfactory conversion. Understanding the pyrolysis reaction mechanism at the molecular level may help to make this sustainable process more economic. Reactive intermediates are responsible for product branching and hold the key to unveiling these mechanisms, but are notoriously difficult to detect isomer-selectively. Here, we investigate the catalytic pyrolysis of guaiacol, a lignin model compound, using photoelectron photoion coincidence spectroscopy with synchrotron radiation, which allows for isomer-selective detection of reactive intermediates. In combination with ambient pressure pyrolysis, we identify fulvenone as the central reactive intermediate, generated by catalytic demethylation to catechol and subsequent dehydration. The fulvenone ketene is responsible for the phenol formation. This technique may open unique opportunities for isomer-resolved probing in catalysis, and holds the potential for achieving a mechanistic understanding of complex, real-life catalytic processes. PMID:28660882

Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: etiological contribution to complex regional pain syndromes (Part II).

PubMed

Wang, Fuzhou; Stefano, George B; Kream, Richard M

2014-07-12

Cumulating evidence indicated that nerve injury-associated cellular and molecular changes play an essential role in contributing to the development of pathological pain, and more recent findings implicated the critical role of epigenetic mechanisms in pain-related sensitization in the DRG subsequent to nerve injury. In this part of the dyad review (Part II), we reviewed and paid special attention on the etiological contribution of DGR gene expression modulated by epigenetic mechanisms of CRPS. As essential effectors to different molecular activation, we first discussed the activation of various signaling pathways that subsequently from nerve injury, and in further illustrated the fundamental and functional underpinnings of nerve injury-induced pain, in which we argued for the potential epigenetic mechanisms in response to sensitizing stimuli or injury. Therefore, understanding the specific mediating factors that influence individual epigenetic differences contributing to pain sensitivity and responsiveness to analgesics possesses crucial clinical implications.

Simple models for rope substructure mechanics: application to electro-mechanical lifts

NASA Astrophysics Data System (ADS)

Herrera, I.; Kaczmarczyk, S.

2016-05-01

Mechanical systems modelled as rigid mass elements connected by tensioned slender structural members such as ropes and cables represent quite common substructures used in lift engineering and hoisting applications. Special interest is devoted by engineers and researchers to the vibratory response of such systems for optimum performance and durability. This paper presents simplified models that can be employed to determine the natural frequencies of systems having substructures of two rigid masses constrained by tensioned rope/cable elements. The exact solution for free un-damped longitudinal displacement response is discussed in the context of simple two-degree-of-freedom models. The results are compared and the influence of characteristics parameters such as the ratio of the average mass of the two rigid masses with respect to the rope mass and the deviation ratio of the two rigid masses with respect to the average mass is analyzed. This analysis gives criteria for the application of such simplified models in complex elevator and hoisting system configurations.

Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors

PubMed Central

Chatzigeorgiou, Marios; Yoo, Sungjae; Watson, Joseph D.; Lee, Wei-Hsiang; Spencer, W. Clay; Kindt, Katie S.; Hwang, Sun Wook; Miller, David M.; Treinin, Millet; Driscoll, Monica; Schafer, William R.

2010-01-01

Summary Polymodal nociceptors detect noxious stimuli including harsh touch, toxic chemicals, and extremes of heat and cold. The molecular mechanisms by which nociceptors are able to sense multiple qualitatively distinct stimuli are not well-understood. We show here that the C. elegans PVD neurons are mulitidendritic nociceptors that respond to harsh touch as well as cold temperatures. The harsh touch modality specifically requires the DEG/ENaC proteins MEC-10 and DEGT-1, which represent putative components of a harsh touch mechanotransduction complex. By contrast, responses to cold require the TRPA-1 channel and are MEC-10- and DEGT-1-independent. Heterologous expression of C. elegans TRPA-1 can confer cold responsiveness to other C. elegans neurons or to mammalian cells, indicating that TRPA-1 is itself a cold sensor. These results show that C. elegans nociceptors respond to thermal and mechanical stimuli using distinct sets of molecules, and identify DEG/ENaC channels as potential receptors for mechanical pain. PMID:20512132

Neurological consequences of systemic inflammation in the premature neonate.

PubMed

Patra, Aparna; Huang, Hong; Bauer, John A; Giannone, Peter J

2017-06-01

Despite substantial progress in neonatal care over the past two decades leading to improved survival of extremely premature infants, extreme prematurity continues to be associated with long term neurodevelopmental impairments. Cerebral white matter injury is the predominant form of insult in preterm brain leading to adverse neurological consequences. Such brain injury pattern and unfavorable neurologic sequelae is commonly encountered in premature infants exposed to systemic inflammatory states such as clinical or culture proven sepsis with or without evidence of meningitis, prolonged mechanical ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis and chorioamnionitis. Underlying mechanisms may include cytokine mediated processes without direct entry of pathogens into the brain, developmental differences in immune response and complex neurovascular barrier system that play a critical role in regulating the cerebral response to various systemic inflammatory insults in premature infants. Understanding of these pathologic mechanisms and clinical correlates of such injury based on serum biomarkers or brain imaging findings on magnetic resonance imaging will pave way for future research and translational therapeutic opportunities for the developing brain.

Molecular and Epigenetic Mechanisms for the Complex Effects of Stress on Synaptic Physiology and Cognitive Functions

PubMed Central

Yuen, Eunice Y.; Wei, Jing

2017-01-01

Abstract Evidence over the past decades has found that stress, particularly through the corticosterone stress hormones, produces complex changes in glutamatergic signaling in prefrontal cortex, which leads to the alteration of cognitive processes medicated by this brain region. Interestingly, the effects of stress on glutamatergic transmission appear to be “U-shaped,” depending upon the duration and severity of the stressor. These biphasic effects of acute vs chronic stress represent the adaptive vs maladaptive responses to stressful stimuli. Animal studies suggest that the stress-induced modulation of excitatory synaptic transmission involves changes in presynaptic glutamate release, postsynaptic glutamate receptor membrane trafficking and degradation, spine structure and cytoskeleton network, and epigenetic control of gene expression. This review will discuss current findings on the key molecules involved in the stress-induced regulation of prefrontal cortex synaptic physiology and prefrontal cortex-mediated functions. Understanding the molecular and epigenetic mechanisms that underlie the complex effects of stress will help to develop novel strategies to cope with stress-related mental disorders. PMID:29016816

Molecular and Epigenetic Mechanisms for the Complex Effects of Stress on Synaptic Physiology and Cognitive Functions.

PubMed

Yuen, Eunice Y; Wei, Jing; Yan, Zhen

2017-11-01

Evidence over the past decades has found that stress, particularly through the corticosterone stress hormones, produces complex changes in glutamatergic signaling in prefrontal cortex, which leads to the alteration of cognitive processes medicated by this brain region. Interestingly, the effects of stress on glutamatergic transmission appear to be "U-shaped," depending upon the duration and severity of the stressor. These biphasic effects of acute vs chronic stress represent the adaptive vs maladaptive responses to stressful stimuli. Animal studies suggest that the stress-induced modulation of excitatory synaptic transmission involves changes in presynaptic glutamate release, postsynaptic glutamate receptor membrane trafficking and degradation, spine structure and cytoskeleton network, and epigenetic control of gene expression. This review will discuss current findings on the key molecules involved in the stress-induced regulation of prefrontal cortex synaptic physiology and prefrontal cortex-mediated functions. Understanding the molecular and epigenetic mechanisms that underlie the complex effects of stress will help to develop novel strategies to cope with stress-related mental disorders. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Networked buffering: a basic mechanism for distributed robustness in complex adaptive systems.

PubMed

Whitacre, James M; Bender, Axel

2010-06-15

A generic mechanism--networked buffering--is proposed for the generation of robust traits in complex systems. It requires two basic conditions to be satisfied: 1) agents are versatile enough to perform more than one single functional role within a system and 2) agents are degenerate, i.e. there exists partial overlap in the functional capabilities of agents. Given these prerequisites, degenerate systems can readily produce a distributed systemic response to local perturbations. Reciprocally, excess resources related to a single function can indirectly support multiple unrelated functions within a degenerate system. In models of genome:proteome mappings for which localized decision-making and modularity of genetic functions are assumed, we verify that such distributed compensatory effects cause enhanced robustness of system traits. The conditions needed for networked buffering to occur are neither demanding nor rare, supporting the conjecture that degeneracy may fundamentally underpin distributed robustness within several biotic and abiotic systems. For instance, networked buffering offers new insights into systems engineering and planning activities that occur under high uncertainty. It may also help explain recent developments in understanding the origins of resilience within complex ecosystems.

Aub and Ago3 are recruited to nuage through two mechanisms to form a ping-pong complex assembled by Krimper

PubMed Central

Webster, Alexandre; Li, Sisi; Hur, Junho K.; Wachsmuth, Malte; Bois, Justin S.; Perkins, Edward M.; Patel, Dinshaw J.; Aravin, Alexei A.

2015-01-01

In Drosophila, two Piwi proteins, Aubergine (Aub) and Argonaute-3 (Ago3) localize to perinuclear ‘nuage’ granules and use guide piRNAs to target and destroy transposable element transcripts. We find that Aub and Ago3 are recruited to nuage by two different mechanisms. Aub requires a piRNA guide for nuage recruitment, indicating that its localization depends on recognition of RNA targets. Ago3 is recruited to nuage independently of a piRNA cargo and relies on interaction with Krimper, a stable component of nuage that is able to aggregate in the absence of other nuage proteins. We show that Krimper interacts directly with Aub and Ago3 to coordinate the assembly of the ping-pong piRNA processing (4P) complex. Symmetrical dimethylated arginines are required for Aub to interact with Krimper, but are dispensable for Ago3 to bind Krimper. Our study reveals a multi-step process responsible for the assembly and function of nuage complexes in piRNA-guided transposon repression. PMID:26295961

Prediction in the service of comprehension: modulated early brain responses to omitted speech segments.

PubMed

Bendixen, Alexandra; Scharinger, Mathias; Strauß, Antje; Obleser, Jonas

2014-04-01

Speech signals are often compromised by disruptions originating from external (e.g., masking noise) or internal (e.g., inaccurate articulation) sources. Speech comprehension thus entails detecting and replacing missing information based on predictive and restorative neural mechanisms. The present study targets predictive mechanisms by investigating the influence of a speech segment's predictability on early, modality-specific electrophysiological responses to this segment's omission. Predictability was manipulated in simple physical terms in a single-word framework (Experiment 1) or in more complex semantic terms in a sentence framework (Experiment 2). In both experiments, final consonants of the German words Lachs ([laks], salmon) or Latz ([lats], bib) were occasionally omitted, resulting in the syllable La ([la], no semantic meaning), while brain responses were measured with multi-channel electroencephalography (EEG). In both experiments, the occasional presentation of the fragment La elicited a larger omission response when the final speech segment had been predictable. The omission response occurred ∼125-165 msec after the expected onset of the final segment and showed characteristics of the omission mismatch negativity (MMN), with generators in auditory cortical areas. Suggestive of a general auditory predictive mechanism at work, this main observation was robust against varying source of predictive information or attentional allocation, differing between the two experiments. Source localization further suggested the omission response enhancement by predictability to emerge from left superior temporal gyrus and left angular gyrus in both experiments, with additional experiment-specific contributions. These results are consistent with the existence of predictive coding mechanisms in the central auditory system, and suggestive of the general predictive properties of the auditory system to support spoken word recognition. Copyright © 2014 Elsevier Ltd. All rights reserved.

BATMAN-TCM: a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine.

PubMed

Liu, Zhongyang; Guo, Feifei; Wang, Yong; Li, Chun; Zhang, Xinlei; Li, Honglei; Diao, Lihong; Gu, Jiangyong; Wang, Wei; Li, Dong; He, Fuchu

2016-02-16

Traditional Chinese Medicine (TCM), with a history of thousands of years of clinical practice, is gaining more and more attention and application worldwide. And TCM-based new drug development, especially for the treatment of complex diseases is promising. However, owing to the TCM's diverse ingredients and their complex interaction with human body, it is still quite difficult to uncover its molecular mechanism, which greatly hinders the TCM modernization and internationalization. Here we developed the first online Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM). Its main functions include 1) TCM ingredients' target prediction; 2) functional analyses of targets including biological pathway, Gene Ontology functional term and disease enrichment analyses; 3) the visualization of ingredient-target-pathway/disease association network and KEGG biological pathway with highlighted targets; 4) comparison analysis of multiple TCMs. Finally, we applied BATMAN-TCM to Qishen Yiqi dripping Pill (QSYQ) and combined with subsequent experimental validation to reveal the functions of renin-angiotensin system responsible for QSYQ's cardioprotective effects for the first time. BATMAN-TCM will contribute to the understanding of the "multi-component, multi-target and multi-pathway" combinational therapeutic mechanism of TCM, and provide valuable clues for subsequent experimental validation, accelerating the elucidation of TCM's molecular mechanism. BATMAN-TCM is available at http://bionet.ncpsb.org/batman-tcm.

Deciphering the kinetic mechanisms controlling selected plant ADP-glucose pyrophosphorylases.

PubMed

Boehlein, Susan K; Shaw, Janine R; Hwang, Seon K; Stewart, Jon D; Curtis Hannah, L

2013-07-15

ADP-Glc pyrophosphorylase (AGPase), a rate-limiting enzyme in starch biosynthesis, is controlled by thermostability and allosteric regulation. Previous studies suggested that redox affects turnover number and heat stability of AGPases. Here, we investigated how allostery and redox state affect kinetic mechanisms of the reduced, heat labile and the oxidized, heat stable potato tuber enzymes; the heat labile maize endosperm enzyme and a chimeric maize/potato heat stable enzyme that lacks the cysteine responsible for redox changes. With 3-PGA, all AGPases followed a Theorell-Chance Bi Bi mechanism with ATP binding first and ADP-Glc releasing last. 3-PGA increases the binding affinity for both substrates with little effect on velocity for the maize and MP isoforms. By contrast, 3-PGA increases the velocity and the affinity for G-1-P for the potato enzymes. Redox state does not affect kcat of the two potato isoforms. Without 3-PGA the oxidized potato enzyme exhibits a rapid equilibrium random Bi Bi mechanism with a dead end ternary complex. This fundamental change from rapid, ordered binding with little buildup of intermediates to a mechanism featuring relatively slow, random binding is unique to the oxidized potato tuber enzyme. Finally, ADP-Glc the physiologically relevant product of this enzyme has complex, isoform-specific effects on catalysis. Copyright © 2013 Elsevier Inc. All rights reserved.

Probabilistic structural mechanics research for parallel processing computers

NASA Technical Reports Server (NTRS)

Sues, Robert H.; Chen, Heh-Chyun; Twisdale, Lawrence A.; Martin, William R.

1991-01-01

Aerospace structures and spacecraft are a complex assemblage of structural components that are subjected to a variety of complex, cyclic, and transient loading conditions. Significant modeling uncertainties are present in these structures, in addition to the inherent randomness of material properties and loads. To properly account for these uncertainties in evaluating and assessing the reliability of these components and structures, probabilistic structural mechanics (PSM) procedures must be used. Much research has focused on basic theory development and the development of approximate analytic solution methods in random vibrations and structural reliability. Practical application of PSM methods was hampered by their computationally intense nature. Solution of PSM problems requires repeated analyses of structures that are often large, and exhibit nonlinear and/or dynamic response behavior. These methods are all inherently parallel and ideally suited to implementation on parallel processing computers. New hardware architectures and innovative control software and solution methodologies are needed to make solution of large scale PSM problems practical.

Interfacial complexation in microfluidic droplets for single-step fabrication of microcapsule

NASA Astrophysics Data System (ADS)

Kaufman, Gilad; Nejati, Siamak; Sarfati, Raphael; Boltyanskiy, Rostislav; Williams, Danielle; Liu, Wei; Schloss, Ashley; Regan, Lynn; Yan, Elsa; Dufrense, Eric; Loewenberg, Michael; Osuji, Chinedum

We present microfluidic interfacial complexation in emulsion droplets as a simple single-step approach for fabricating a large variety of stable monodisperse microcapsules with tailored mechanical properties, protein binding and controlled release behavior. We rely on electrostatic interactions and hydrogen bonding to direct the assembly of complementary species at oil-water droplet interfaces to form microcapsules with polyelectrolyte shells, composite polyelectrolyte-nanoparticle shells, and copolymer-nanofiber shells. Additionally, we demonstrate the formation of microcapsules by adsorption of an amphiphilic bacterial hydrophobin, BslA, at oil-in-water and water-in-oil droplets, and protein capture on these capsules using engineered variants of the hydrophobin. We discuss the composition dependence of mechanical properties, shell thickness and release behavior, and regimes of stability for microcapsule fabrication. Nanoparticle based microcapsules display an intriguing plastic deformation response which enables the formation of large aspect ratio asperities by pipette aspiration of the shell.

Accidental versus operational oil spills from shipping in the Baltic Sea: risk governance and management strategies.

PubMed

Hassler, Björn

2011-03-01

Marine governance of oil transportation is complex. Due to difficulties in effectively monitoring procedures on vessels en voyage, incentives to save costs by not following established regulations on issues such as cleaning of tanks, crew size, and safe navigation may be substantial. The issue of problem structure is placed in focus, that is, to what degree the specific characteristics and complexity of intentional versus accidental oil spill risks affect institutional responses. It is shown that whereas the risk of accidental oil spills primarily has been met by technical requirements on the vessels in combination with Port State control, attempts have been made to curb intentional pollution by for example increased surveillance and smart governance mechanisms such as the No-Special-Fee system. It is suggested that environmental safety could be improved by increased use of smart governance mechanisms tightly adapted to key actors' incentives to alter behavior in preferable directions.

Genome-Wide Investigation of MicroRNAs and Their Targets in Response to Freezing Stress in Medicago sativa L., Based on High-Throughput Sequencing

PubMed Central

Shu, Yongjun; Liu, Ying; Li, Wei; Song, Lili; Zhang, Jun; Guo, Changhong

2016-01-01

Winter damage, especially in northern climates, is a major limitation of the utilization of perennial forages such as alfalfa. Therefore, improving freezing tolerance is imperative in alfalfa genetic breeding. However, freezing tolerance is a complex trait that is determined by many genes. To understand the complex regulation mechanisms of freezing tolerance in alfalfa, we performed small RNA sequencing analysis under cold (4°) and freezing (−8°) stress. The sequencing results revealed that 173 known, and 24 novel miRNAs were expressed, and that the expression of 35 miRNAs was affected by cold and/or freezing stress. Meanwhile, 105 target genes cleaved by these miRNAs were characterized by degradome sequencing. These targets were associated with biological regulation, cellular processes, metabolic processes, and response to stress. Interestingly, most of them were characterized as transcription factors (TFs), including auxin response factors, SBP, NAC, AP2/ERF, and GRF, which play important roles in plant abiotic responses. In addition, important miRNAs and mRNAs involved in nodulation were also identified, for example, the relationship between miR169 and the TF CCAAT (also named as NF-YA/HAP2), which suggested that nodulation has an important function in freezing tolerance in alfalfa. Our results provide valuable information to help determine the molecular mechanisms of freezing tolerance in alfalfa, which will aid the application of these miRNAs and their targets in the improvement of freezing tolerance in alfalfa and related plants. PMID:26801649

The transcriptomic responses of the eastern oyster, Crassostrea virginica, to environmental conditions.

PubMed

Chapman, Robert W; Mancia, Annalaura; Beal, Marion; Veloso, Artur; Rathburn, Charles; Blair, Anne; Holland, A F; Warr, G W; Didinato, Guy; Sokolova, Inna M; Wirth, Edward F; Duffy, Edward; Sanger, Denise

2011-04-01

Understanding the mechanisms by which organisms adapt to environmental conditions is a fundamental question for ecology and evolution. In this study, we evaluate changes in gene expression of a marine mollusc, the eastern oyster Crassostrea virginica, associated with the physico-chemical conditions and the levels of metals and other contaminants in their environment. The results indicate that transcript signatures can effectively disentangle the complex interactive gene expression responses to the environment and are also capable of disentangling the complex dynamic effects of environmental factors on gene expression. In this context, the mapping of environment to gene and gene to environment is reciprocal and mutually reinforcing. In general, the response of transcripts to the environment is driven by major factors known to affect oyster physiology such as temperature, pH, salinity, and dissolved oxygen, with pollutant levels playing a relatively small role, at least within the range of concentrations found in the studied oyster habitats. Further, the two environmental factors that dominate these effects (temperature and pH) interact in a dynamic and nonlinear fashion to impact gene expression. Transcriptomic data obtained in our study provide insights into the mechanisms of physiological responses to temperature and pH in oysters that are consistent with the known effects of these factors on physiological functions of ectotherms and indicate important linkages between transcriptomics and physiological outcomes. Should these linkages hold in further studies and in other organisms, they may provide a novel integrated approach for assessing the impacts of climate change, ocean acidification and anthropogenic contaminants on aquatic organisms via relatively inexpensive microarray platforms. © 2011 Blackwell Publishing Ltd.

The gammaTuRC Nanomachine Mechanism and Future Applications

NASA Astrophysics Data System (ADS)

Riehlman, Timothy D.

The complexity and precision of the eukaryotic cell's cytoskeletal network is unrivaled by any man-made systems, perfected by billions of years of evolution, mastering elegant processes of self-assembly, error correction, and self-repair. Understanding the capabilities of these networks will have important and far reaching applications in human medicine by aiding our understanding of developmental processes, cellular division, and disease mechanisms, and through biomimicry will provide insights for biosynthetic manufacturing at the nanoscale and across scales. My research utilizes cross species techniques from Human to the model organism of Fission Yeast to investigate the structure and mechanisms of the g-tubulin ring complex (gTuRC). The gTuRC is a highly conserved eukaryotic multiprotein complex serving as a microtubule organizing center (MTOC) responsible for microtubule nucleation through templating, regulation of dynamics, and establishment of microtubule polarity. Microtubules are 25 nm diameter dynamic flexible polymers of a/b-tubulin heterodimers that function as scaffolds, force generators, distributors, and intracellular highways. The microtubule cytoskeleton is essential for numerous fundamental cellular processes such as mitotic division of chromosomes and cell division, organelle distribution within the cell, cell signaling, and cell shape. This incredible diversity in functions is made possible in part due to molecular motor Kinesin-like proteins (Klps), which allow expansion into more specialized neural, immune, and ciliated cell functions. Combined, the MTOC, microtubules, and Klps represent ideal microtubule cytoskeleton protein (MCP) modular components for in vitro biomimicry towards generation of adaptable patterned networks for human designed applications. My research investigates the hypothesis that a mechanistic understanding of conserved MTOC gTuRC mechanisms will help us understand dynamic cellular nanomachines and their ability to self-assemble complex structures for applications in biomedicine and new roles in biomimetic nanotechnologies.

Initiation of DNA replication: functional and evolutionary aspects

PubMed Central

Bryant, John A.; Aves, Stephen J.

2011-01-01

Background The initiation of DNA replication is a very important and highly regulated step in the cell division cycle. It is of interest to compare different groups of eukaryotic organisms (a) to identify the essential molecular events that occur in all eukaryotes, (b) to start to identify higher-level regulatory mechanisms that are specific to particular groups and (c) to gain insights into the evolution of initiation mechanisms. Scope This review features a wide-ranging literature survey covering replication origins, origin recognition and usage, modification of origin usage (especially in response to plant hormones), assembly of the pre-replication complex, loading of the replisome, genomics, and the likely origin of these mechanisms and proteins in Archaea. Conclusions In all eukaryotes, chromatin is organized for DNA replication as multiple replicons. In each replicon, replication is initiated at an origin. With the exception of those in budding yeast, replication origins, including the only one to be isolated so far from a plant, do not appear to embody a specific sequence; rather, they are AT-rich, with short tracts of locally bent DNA. The proteins involved in initiation are remarkably similar across the range of eukaryotes. Nevertheless, their activity may be modified by plant-specific mechanisms, including regulation by plant hormones. The molecular features of initiation are seen in a much simpler form in the Archaea. In particular, where eukaryotes possess a number of closely related proteins that form ‘hetero-complexes’ (such as the origin recognition complex and the MCM complex), archaeans typically possess one type of protein (e.g. one MCM) that forms a homo-complex. This suggests that several eukaryotic initiation proteins have evolved from archaeal ancestors by gene duplication and divergence. PMID:21508040

The Defense Metabolite, Allyl Glucosinolate, Modulates Arabidopsis thaliana Biomass Dependent upon the Endogenous Glucosinolate Pathway

PubMed Central

Francisco, Marta; Joseph, Bindu; Caligagan, Hart; Li, Baohua; Corwin, Jason A.; Lin, Catherine; Kerwin, Rachel; Burow, Meike; Kliebenstein, Daniel J.

2016-01-01

Glucosinolates (GSLs) play an important role in plants as direct mediators of biotic and abiotic stress responses. Recent work is beginning to show that the GSLs can also inducing complex defense and growth networks. However, the physiological significance of these GSL-induced responses and the molecular mechanisms by which GSLs are sensed and/or modulate these responses are not understood. To identify these potential mechanisms within the plant and how they may relate to the endogenous GSLs, we tested the regulatory effect of exogenous allyl GSL application on growth and defense metabolism across sample of Arabidopsis thaliana accessions. We found that application of exogenous allyl GSL had the ability to initiate changes in plant biomass and accumulation of defense metabolites that genetically varied across accessions. This growth effect was related to the allyl GSL side-chain structure. Utilizing this natural variation and mutants in genes within the GSL pathway we could show that the link between allyl GSL and altered growth responses are dependent upon the function of known genes controlling the aliphatic GSL pathway. PMID:27313596

Hormesis as a mechanistic approach to understanding herbal treatments in traditional Chinese medicine.

PubMed

Wang, Dali; Calabrese, Edward J; Lian, Baoling; Lin, Zhifen; Calabrese, Vittorio

2018-04-01

Traditional Chinese medicine (TCM) has been long practiced and is becoming ever more widely recognized as providing curative and/or healing treatments for a number of diseases and physiological conditions. This paper posits that herbal medicines used in TCM treatments may act through hormetic dose-response mechanisms. It is proposed that the stimulatory (i.e., low dose) and inhibitory (i.e., high dose) components of the hormetic dose response correspond to respective "regulating" and "curing" aspects of TCM herbal treatments. Specifically, the "regulating" functions promote adaptive or preventive responses, while "curing" treatments alleviate the clinical symptoms. Patterns of hormetic responses are described, and the applicability of these processes to herbal medicines of TCM are explicated. It is noted that a research agenda aimed at elucidating these mechanisms and patterns would be expansive and complex. However, we argue its value, in that hormesis may afford something akin to a Rosetta Stone with which to interpret, translate, and explain TCM herbology in ways that are aligned with biomedical perspectives that could enable a more integrative approach to medicine. Copyright © 2017 Elsevier Inc. All rights reserved.

The Defense Metabolite, Allyl Glucosinolate, Modulates Arabidopsis thaliana Biomass Dependent upon the Endogenous Glucosinolate Pathway.

PubMed

Francisco, Marta; Joseph, Bindu; Caligagan, Hart; Li, Baohua; Corwin, Jason A; Lin, Catherine; Kerwin, Rachel; Burow, Meike; Kliebenstein, Daniel J

2016-01-01

Glucosinolates (GSLs) play an important role in plants as direct mediators of biotic and abiotic stress responses. Recent work is beginning to show that the GSLs can also inducing complex defense and growth networks. However, the physiological significance of these GSL-induced responses and the molecular mechanisms by which GSLs are sensed and/or modulate these responses are not understood. To identify these potential mechanisms within the plant and how they may relate to the endogenous GSLs, we tested the regulatory effect of exogenous allyl GSL application on growth and defense metabolism across sample of Arabidopsis thaliana accessions. We found that application of exogenous allyl GSL had the ability to initiate changes in plant biomass and accumulation of defense metabolites that genetically varied across accessions. This growth effect was related to the allyl GSL side-chain structure. Utilizing this natural variation and mutants in genes within the GSL pathway we could show that the link between allyl GSL and altered growth responses are dependent upon the function of known genes controlling the aliphatic GSL pathway.

Role for Human Mediator Subunit MED25 in Recruitment of Mediator to Promoters by Endoplasmic Reticulum Stress-responsive Transcription Factor ATF6α*

PubMed Central

Sela, Dotan; Conkright, Juliana J.; Chen, Lu; Gilmore, Joshua; Washburn, Michael P.; Florens, Laurence; Conaway, Ronald C.; Conaway, Joan Weliky

2013-01-01

Transcription factor ATF6α functions as a master regulator of endoplasmic reticulum (ER) stress response genes. In response to ER stress, ATF6α translocates from its site of latency in the ER membrane to the nucleus, where it activates RNA polymerase II transcription of ER stress response genes upon binding sequence-specifically to ER stress response enhancer elements (ERSEs) in their promoter-regulatory regions. In a recent study, we demonstrated that ATF6α activates transcription of ER stress response genes by a mechanism involving recruitment to ERSEs of the multisubunit Mediator and several histone acetyltransferase (HAT) complexes, including Spt-Ada-Gcn5 (SAGA) and Ada-Two-A-containing (ATAC) (Sela, D., Chen, L., Martin-Brown, S., Washburn, M.P., Florens, L., Conaway, J.W., and Conaway, R.C. (2012) J. Biol. Chem. 287, 23035–23045). In this study, we extend our investigation of the mechanism by which ATF6α supports recruitment of Mediator to ER stress response genes. We present findings arguing that Mediator subunit MED25 plays a critical role in this process and identify a MED25 domain that serves as a docking site on Mediator for the ATF6α transcription activation domain. PMID:23864652

Proton Order-Disorder Phenomena in a Hydrogen-Bonded Rhodium-η(5)-Semiquinone Complex: A Possible Dielectric Response Mechanism.

PubMed

Mitsumi, Minoru; Ezaki, Kazunari; Komatsu, Yuuki; Toriumi, Koshiro; Miyatou, Tatsuya; Mizuno, Motohiro; Azuma, Nobuaki; Miyazaki, Yuji; Nakano, Motohiro; Kitagawa, Yasutaka; Hanashima, Takayasu; Kiyanagi, Ryoji; Ohhara, Takashi; Nakasuji, Kazuhiro

2015-06-26

A newly synthesized one-dimensional (1D) hydrogen-bonded (H-bonded) rhodium(II)-η(5)-semiquinone complex, [Cp*Rh(η(5)-p-HSQ-Me4)]PF6 ([1]PF6; Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl; HSQ = semiquinone) exhibits a paraelectric-antiferroelectric second-order phase transition at 237.1 K. Neutron and X-ray crystal structure analyses reveal that the H-bonded proton is disordered over two sites in the room-temperature (RT) phase. The phase transition would arise from this proton disorder together with rotation or libration of the Cp* ring and PF6(-) ion. The relative permittivity εb' along the H-bonded chains reaches relatively high values (ca., 130) in the RT phase. The temperature dependence of (13)C CP/MAS NMR spectra demonstrates that the proton is dynamically disordered in the RT phase and that the proton exchange has already occurred in the low-temperature (LT) phase. Rate constants for the proton exchange are estimated to be 10(-4)-10(-6) s in the temperature range of 240-270 K. DFT calculations predict that the protonation/deprotonation of [1](+) leads to interesting hapticity changes of the semiquinone ligand accompanied by reduction/oxidation by the π-bonded rhodium fragment, producing the stable η(6)-hydroquinone complex, [Cp*Rh(3+)(η(6)-p-H2Q-Me4)](2+) ([2](2+)), and η(4)-benzoquinone complex, [Cp*Rh(+)(η(4)-p-BQ-Me4)] ([3]), respectively. Possible mechanisms leading to the dielectric response are discussed on the basis of the migration of the protonic solitons comprising of [2](2+) and [3], which would be generated in the H-bonded chain. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Resilience and tipping points of an exploited fish population over six decades.

PubMed

Vasilakopoulos, Paraskevas; Marshall, C Tara

2015-05-01

Complex natural systems with eroded resilience, such as populations, ecosystems and socio-ecological systems, respond to small perturbations with abrupt, discontinuous state shifts, or critical transitions. Theory of critical transitions suggests that such systems exhibit fold bifurcations featuring folded response curves, tipping points and alternate attractors. However, there is little empirical evidence of fold bifurcations occurring in actual complex natural systems impacted by multiple stressors. Moreover, resilience of complex systems to change currently lacks clear operational measures with generic application. Here, we provide empirical evidence for the occurrence of a fold bifurcation in an exploited fish population and introduce a generic measure of ecological resilience based on the observed fold bifurcation attributes. We analyse the multivariate development of Barents Sea cod (Gadus morhua), which is currently the world's largest cod stock, over six decades (1949-2009), and identify a population state shift in 1981. By plotting a multivariate population index against a multivariate stressor index, the shift mechanism was revealed suggesting that the observed population shift was a nonlinear response to the combined effects of overfishing and climate change. Annual resilience values were estimated based on the position of each year in relation to the fitted attractors and assumed tipping points of the fold bifurcation. By interpolating the annual resilience values, a folded stability landscape was fit, which was shaped as predicted by theory. The resilience assessment suggested that the population may be close to another tipping point. This study illustrates how a multivariate analysis, supported by theory of critical transitions and accompanied by a quantitative resilience assessment, can clarify shift mechanisms in data-rich complex natural systems. © 2014 John Wiley & Sons Ltd.

Growth condition dependency is the major cause of non-responsiveness upon genetic perturbation

PubMed Central

Amini, Saman; Holstege, Frank C. P.

2017-01-01

Investigating the role and interplay between individual proteins in biological processes is often performed by assessing the functional consequences of gene inactivation or removal. Depending on the sensitivity of the assay used for determining phenotype, between 66% (growth) and 53% (gene expression) of Saccharomyces cerevisiae gene deletion strains show no defect when analyzed under a single condition. Although it is well known that this non-responsive behavior is caused by different types of redundancy mechanisms or by growth condition/cell type dependency, it is not known what the relative contribution of these different causes is. Understanding the underlying causes of and their relative contribution to non-responsive behavior upon genetic perturbation is extremely important for designing efficient strategies aimed at elucidating gene function and unraveling complex cellular systems. Here, we provide a systematic classification of the underlying causes of and their relative contribution to non-responsive behavior upon gene deletion. The overall contribution of redundancy to non-responsive behavior is estimated at 29%, of which approximately 17% is due to homology-based redundancy and 12% is due to pathway-based redundancy. The major determinant of non-responsiveness is condition dependency (71%). For approximately 14% of protein complexes, just-in-time assembly can be put forward as a potential mechanistic explanation for how proteins can be regulated in a condition dependent manner. Taken together, the results underscore the large contribution of growth condition requirement to non-responsive behavior, which needs to be taken into account for strategies aimed at determining gene function. The classification provided here, can also be further harnessed in systematic analyses of complex cellular systems. PMID:28257504

Mechanical response of common millet (Panicum miliaceum) seeds under quasi-static compression: Experiments and modeling.

PubMed

Hasseldine, Benjamin P J; Gao, Chao; Collins, Joseph M; Jung, Hyun-Do; Jang, Tae-Sik; Song, Juha; Li, Yaning

2017-09-01

The common millet (Panicum miliaceum) seedcoat has a fascinating complex microstructure, with jigsaw puzzle-like epidermis cells articulated via wavy intercellular sutures to form a compact layer to protect the kernel inside. However, little research has been conducted on linking the microstructure details with the overall mechanical response of this interesting biological composite. To this end, an integrated experimental-numerical-analytical investigation was conducted to both characterize the microstructure and ascertain the microscale mechanical properties and to test the overall response of kernels and full seeds under macroscale quasi-static compression. Scanning electron microscopy (SEM) was utilized to examine the microstructure of the outer seedcoat and nanoindentation was performed to obtain the material properties of the seedcoat hard phase material. A multiscale computational strategy was applied to link the microstructure to the macroscale response of the seed. First, the effective anisotropic mechanical properties of the seedcoat were obtained from finite element (FE) simulations of a microscale representative volume element (RVE), which were further verified from sophisticated analytical models. Then, macroscale FE models of the individual kernel and full seed were developed. Good agreement between the compression experiments and FE simulations were obtained for both the kernel and the full seed. The results revealed the anisotropic property and the protective function of the seedcoat, and showed that the sutures of the seedcoat play an important role in transmitting and distributing loads in responding to external compression. Copyright © 2017 Elsevier Ltd. All rights reserved.