Comparative transcriptome analysis reveals distinct ethylene-independent regulation of ripening in response to low temperature in kiwifruit.

Science.gov (United States)

Asiche, William O; Mitalo, Oscar W; Kasahara, Yuka; Tosa, Yasuaki; Mworia, Eric G; Owino, Willis O; Ushijima, Koichiro; Nakano, Ryohei; Yano, Kentaro; Kubo, Yasutaka

2018-03-21

endogenous ethylene production, and coincided with increased expression of low temperature-responsive DEGs as well as the decrease in environmental temperature. These results indicate that kiwifruit possess both ethylene-dependent and low temperature-modulated ripening mechanisms that are distinct and independent of each other. The current work provides a foundation for elaborating the control of these two ripening mechanisms in kiwifruit.

Distinct timing mechanisms produce discrete and continuous movements.

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Raoul Huys

2008-04-01

Full Text Available The differentiation of discrete and continuous movement is one of the pillars of motor behavior classification. Discrete movements have a definite beginning and end, whereas continuous movements do not have such discriminable end points. In the past decade there has been vigorous debate whether this classification implies different control processes. This debate up until the present has been empirically based. Here, we present an unambiguous non-empirical classification based on theorems in dynamical system theory that sets discrete and continuous movements apart. Through computational simulations of representative modes of each class and topological analysis of the flow in state space, we show that distinct control mechanisms underwrite discrete and fast rhythmic movements. In particular, we demonstrate that discrete movements require a time keeper while fast rhythmic movements do not. We validate our computational findings experimentally using a behavioral paradigm in which human participants performed finger flexion-extension movements at various movement paces and under different instructions. Our results demonstrate that the human motor system employs different timing control mechanisms (presumably via differential recruitment of neural subsystems to accomplish varying behavioral functions such as speed constraints.

Latent memory facilitates relearning through molecular signaling mechanisms that are distinct from original learning.

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Menges, Steven A; Riepe, Joshua R; Philips, Gary T

2015-09-01

A highly conserved feature of memory is that it can exist in a latent, non-expressed state which is revealed during subsequent learning by its ability to significantly facilitate (savings) or inhibit (latent inhibition) subsequent memory formation. Despite the ubiquitous nature of latent memory, the mechanistic nature of the latent memory trace and its ability to influence subsequent learning remains unclear. The model organism Aplysia californica provides the unique opportunity to make strong links between behavior and underlying cellular and molecular mechanisms. Using Aplysia, we have studied the mechanisms of savings due to latent memory for a prior, forgotten experience. We previously reported savings in the induction of three distinct temporal domains of memory: short-term (10min), intermediate-term (2h) and long-term (24h). Here we report that savings memory formation utilizes molecular signaling pathways that are distinct from original learning: whereas the induction of both original intermediate- and long-term memory in naïve animals requires mitogen activated protein kinase (MAPK) activation and ongoing protein synthesis, 2h savings memory is not disrupted by inhibitors of MAPK or protein synthesis, and 24h savings memory is not dependent on MAPK activation. Collectively, these findings reveal that during forgetting, latent memory for the original experience can facilitate relearning through molecular signaling mechanisms that are distinct from original learning. Copyright © 2015 Elsevier Inc. All rights reserved.

Brain alterations and clinical symptoms of dementia in diabetes: Abeta/tau-dependent and independent mechanisms

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Naoyuki eSato

2014-09-01

Full Text Available Emerging evidence suggests that diabetes affects cognitive function and increases the incidence of dementia. However, the mechanisms by which diabetes modifies cognitive function still remains unclear. Morphologically, diabetes is associated with neuronal loss in the frontal and temporal lobes including the hippocampus, and aberrant functional connectivity of the posterior cingulate cortex and medial frontal/temporal gyrus. Clinically, diabetic patients show decreased executive function, information processing, planning, visuospatial construction, and visual memory. Therefore, in comparison with the characteristics of AD brain structure and cognition, diabetes seems to affect cognitive function through not only simple AD pathological feature-dependent mechanisms, but also independent mechanisms. As an Abeta/tau-independent mechanism, diabetes compromises cerebrovascular function, increases subcortical infarction and might alter the blood brain barrier (BBB. Diabetes also affects glucose metabolism, insulin signaling and mitochondrial function in the brain. Diabetes also modifies metabolism of Abeta and tau and causes Abeta/tau-dependent pathological changes. Moreover, there is evidence that suggests an interaction between Abeta/tau-dependent and independent mechanisms. Therefore, diabetes modifies cognitive function through Abeta/tau-dependent and independent mechanisms. Interaction between these two mechanisms forms a vicious cycle.

Learning Similar Actions by Reinforcement or Sensory-Prediction Errors Rely on Distinct Physiological Mechanisms.

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Uehara, Shintaro; Mawase, Firas; Celnik, Pablo

2017-09-14

Humans can acquire knowledge of new motor behavior via different forms of learning. The two forms most commonly studied have been the development of internal models based on sensory-prediction errors (error-based learning) and success-based feedback (reinforcement learning). Human behavioral studies suggest these are distinct learning processes, though the neurophysiological mechanisms that are involved have not been characterized. Here, we evaluated physiological markers from the cerebellum and the primary motor cortex (M1) using noninvasive brain stimulations while healthy participants trained finger-reaching tasks. We manipulated the extent to which subjects rely on error-based or reinforcement by providing either vector or binary feedback about task performance. Our results demonstrated a double dissociation where learning the task mainly via error-based mechanisms leads to cerebellar plasticity modifications but not long-term potentiation (LTP)-like plasticity changes in M1; while learning a similar action via reinforcement mechanisms elicited M1 LTP-like plasticity but not cerebellar plasticity changes. Our findings indicate that learning complex motor behavior is mediated by the interplay of different forms of learning, weighing distinct neural mechanisms in M1 and the cerebellum. Our study provides insights for designing effective interventions to enhance human motor learning. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Remembering to learn: independent place and journey coding mechanisms contribute to memory transfer.

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Bahar, Amir S; Shapiro, Matthew L

2012-02-08

The neural mechanisms that integrate new episodes with established memories are unknown. When rats explore an environment, CA1 cells fire in place fields that indicate locations. In goal-directed spatial memory tasks, some place fields differentiate behavioral histories ("journey-dependent" place fields) while others do not ("journey-independent" place fields). To investigate how these signals inform learning and memory for new and familiar episodes, we recorded CA1 and CA3 activity in rats trained to perform a "standard" spatial memory task in a plus maze and in two new task variants. A "switch" task exchanged the start and goal locations in the same environment; an "altered environment" task contained unfamiliar local and distal cues. In the switch task, performance was mildly impaired, new firing maps were stable, but the proportion and stability of journey-dependent place fields declined. In the altered environment, overall performance was strongly impaired, new firing maps were unstable, and stable proportions of journey-dependent place fields were maintained. In both tasks, memory errors were accompanied by a decline in journey codes. The different dynamics of place and journey coding suggest that they reflect separate mechanisms and contribute to distinct memory computations. Stable place fields may represent familiar relationships among environmental features that are required for consistent memory performance. Journey-dependent activity may correspond with goal-directed behavioral sequences that reflect expectancies that generalize across environments. The complementary signals could help link current events with established memories, so that familiarity with either a behavioral strategy or an environment can inform goal-directed learning.

Density-dependence as a size-independent regulatory mechanism.

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de Vladar, Harold P

2006-01-21

The growth function of populations is central in biomathematics. The main dogma is the existence of density-dependence mechanisms, which can be modelled with distinct functional forms that depend on the size of the population. One important class of regulatory functions is the theta-logistic, which generalizes the logistic equation. Using this model as a motivation, this paper introduces a simple dynamical reformulation that generalizes many growth functions. The reformulation consists of two equations, one for population size, and one for the growth rate. Furthermore, the model shows that although population is density-dependent, the dynamics of the growth rate does not depend either on population size, nor on the carrying capacity. Actually, the growth equation is uncoupled from the population size equation, and the model has only two parameters, a Malthusian parameter rho and a competition coefficient theta. Distinct sign combinations of these parameters reproduce not only the family of theta-logistics, but also the van Bertalanffy, Gompertz and Potential Growth equations, among other possibilities. It is also shown that, except for two critical points, there is a general size-scaling relation that includes those appearing in the most important allometric theories, including the recently proposed Metabolic Theory of Ecology. With this model, several issues of general interest are discussed such as the growth of animal population, extinctions, cell growth and allometry, and the effect of environment over a population.

Relational quantum mechanics

International Nuclear Information System (INIS)

Rovelli, C.

1996-01-01

I suggest that the common unease with taking quantum mechanics as a fundamental description of nature (the open-quotes measurement problemclose quotes) could derive from the use of an incorrect notion, as the unease with the Lorentz transformations before Einstein derived from the notion of observer-independent time. I suggest that this incorrect notion that generates the unease with quantum mechanics is the notion of open-quotes observer-independent stateclose quotes of a system, or open-quotes observer-independent values of physical quantities.close quotes I reformulate the problem of the open-quotes interpretation of quantum mechanicsclose quotes as the problem of deriving the formalism from a set of simple physical postulates. I consider a reformulation of quantum mechanics in terms of information theory. All systems are assumed to be equivalent, there is no observer-observed distinction, and the theory describes only the information that systems have about each other; nevertheless, the theory is complete

TLR2-dependent inhibition of macrophage responses to IFN-gamma is mediated by distinct, gene-specific mechanisms.

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Sarah A Benson

2009-07-01

Full Text Available Mycobacterium tuberculosis uses multiple mechanisms to avoid elimination by the immune system. We have previously shown that M. tuberculosis can inhibit selected macrophage responses to IFN-gamma through TLR2-dependent and -independent mechanisms. To specifically address the role of TLR2 signaling in mediating this inhibition, we stimulated macrophages with the specific TLR2/1 ligand Pam(3CSK(4 and assayed responses to IFN-gamma. Pam(3CSK(4 stimulation prior to IFN-gamma inhibited transcription of the unrelated IFN-gamma-inducible genes, CIITA and CXCL11. Surface expression of MHC class II and secretion of CXCL11 were greatly reduced as well, indicating that the reduction in transcripts had downstream effects. Inhibition of both genes required new protein synthesis. Using chromatin immunoprecipitation, we found that TLR2 stimulation inhibited IFN-gamma-induced RNA polymerase II binding to the CIITA and CXCL11 promoters. Furthermore, TATA binding protein was unable to bind the TATA box of the CXCL11 promoter, suggesting that assembly of transcriptional machinery was disrupted. However, TLR2 stimulation affected chromatin modifications differently at each of the inhibited promoters. Histone H3 and H4 acetylation was reduced at the CIITA promoter but unaffected at the CXCL11 promoter. In addition, NF-kappaB signaling was required for inhibition of CXCL11 transcription, but not for inhibition of CIITA. Taken together, these results indicate that TLR2-dependent inhibition of IFN-gamma-induced gene expression is mediated by distinct, gene-specific mechanisms that disrupt binding of the transcriptional machinery to the promoters.

Astragalus polysaccharides lowers plasma cholesterol through mechanisms distinct from statins.

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Yunjiu Cheng

Full Text Available To determine the efficacy and underlying mechanism of Astragalus polysaccharides (APS on plasma lipids in hypercholesterolemia hamsters. The effect of APS (0.25 g/kg/d on plasma and liver lipids, fecal bile acids and neutral sterol, cholesterol absorption and synthesis, HMG-CoA reductase activity, and gene and protein expressions in the liver and small intestine was investigated in twenty-four hypercholesterolemia hamsters. Treatment periods lasted for three months. APS significantly lowered plasma total cholesterol by 45.8%, triglycerides by 30%, and low-density lipoprotein-cholesterol by 47.4%, comparable to simvastatin. Further examinations revealed that APS reduced total cholesterol and triglycerides in the liver, increased fecal bile acid and neutral sterol excretion, inhibited cholesterol absorption, and by contrast, increased hepatic cholesterol synthesis and HMG-CoA reductase activity. Plasma total cholesterol or low-density lipoprotein-cholesterol levels were significantly correlated with cholesterol absorption rates. APS up-regulated cholesterol-7α-hydroxylase and LDL-receptor gene expressions. These new findings identify APS as a potential natural cholesterol lowering agent, working through mechanisms distinct from statins.

Thick filament mechano-sensing is a calcium-independent regulatory mechanism in skeletal muscle.

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Fusi, L; Brunello, E; Yan, Z; Irving, M

2016-10-31

Recent X-ray diffraction studies on actively contracting fibres from skeletal muscle showed that the number of myosin motors available to interact with actin-containing thin filaments is controlled by the stress in the myosin-containing thick filaments. Those results suggested that thick filament mechano-sensing might constitute a novel regulatory mechanism in striated muscles that acts independently of the well-known thin filament-mediated calcium signalling pathway. Here we test that hypothesis using probes attached to the myosin regulatory light chain in demembranated muscle fibres. We show that both the extent and kinetics of thick filament activation depend on thick filament stress but are independent of intracellular calcium concentration in the physiological range. These results establish direct control of myosin motors by thick filament mechano-sensing as a general regulatory mechanism in skeletal muscle that is independent of the canonical calcium signalling pathway.

Distinct mechanisms act in concert to mediate cell cycle arrest.

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Toettcher, Jared E; Loewer, Alexander; Ostheimer, Gerard J; Yaffe, Michael B; Tidor, Bruce; Lahav, Galit

2009-01-20

In response to DNA damage, cells arrest at specific stages in the cell cycle. This arrest must fulfill at least 3 requirements: it must be activated promptly; it must be sustained as long as damage is present to prevent loss of genomic information; and after the arrest, cells must re-enter into the appropriate cell cycle phase to ensure proper ploidy. Multiple molecular mechanisms capable of arresting the cell cycle have been identified in mammalian cells; however, it is unknown whether each mechanism meets all 3 requirements or whether they act together to confer specific functions to the arrest. To address this question, we integrated mathematical models describing the cell cycle and the DNA damage signaling networks and tested the contributions of each mechanism to cell cycle arrest and re-entry. Predictions from this model were then tested with quantitative experiments to identify the combined action of arrest mechanisms in irradiated cells. We find that different arrest mechanisms serve indispensable roles in the proper cellular response to DNA damage over time: p53-independent cyclin inactivation confers immediate arrest, whereas p53-dependent cyclin downregulation allows this arrest to be sustained. Additionally, p21-mediated inhibition of cyclin-dependent kinase activity is indispensable for preventing improper cell cycle re-entry and endoreduplication. This work shows that in a complex signaling network, seemingly redundant mechanisms, acting in a concerted fashion, can achieve a specific cellular outcome.

The Meritocratic Ideal in Education Systems: The Mechanisms of Academic Distinction in the International Context

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Maria Luisa Quaresma

2017-07-01

Full Text Available The state school lives immersed in the tension between democratic purposes and the ideals of merit and selectivity. In this context, state schools establish instruments of public praise for students who stand out academically or in other dimensions. We propose to map the rituals of academic distinction in Portuguese state schools and to discuss the widespread adoption of these mechanisms by secondary schools. However, neither their configuration nor the selection criteria are homogeneous, which points to the existence of distinct conceptualisations of excellence and margins of freedom for each school to define their own criteria for success.

Mechanical stimulation induces mTOR signaling via an ERK-independent mechanism: implications for a direct activation of mTOR by phosphatidic acid.

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Jae Sung You

Full Text Available Signaling by mTOR is a well-recognized component of the pathway through which mechanical signals regulate protein synthesis and muscle mass. However, the mechanisms involved in the mechanical regulation of mTOR signaling have not been defined. Nevertheless, recent studies suggest that a mechanically-induced increase in phosphatidic acid (PA may be involved. There is also evidence which suggests that mechanical stimuli, and PA, utilize ERK to induce mTOR signaling. Hence, we reasoned that a mechanically-induced increase in PA might promote mTOR signaling via an ERK-dependent mechanism. To test this, we subjected mouse skeletal muscles to mechanical stimulation in the presence or absence of a MEK/ERK inhibitor, and then measured several commonly used markers of mTOR signaling. Transgenic mice expressing a rapamycin-resistant mutant of mTOR were also used to confirm the validity of these markers. The results demonstrated that mechanically-induced increases in p70(s6k T389 and 4E-BP1 S64 phosphorylation, and unexpectedly, a loss in total 4E-BP1, were fully mTOR-dependent signaling events. Furthermore, we determined that mechanical stimulation induced these mTOR-dependent events, and protein synthesis, through an ERK-independent mechanism. Similar to mechanical stimulation, exogenous PA also induced mTOR-dependent signaling via an ERK-independent mechanism. Moreover, PA was able to directly activate mTOR signaling in vitro. Combined, these results demonstrate that mechanical stimulation induces mTOR signaling, and protein synthesis, via an ERK-independent mechanism that potentially involves a direct interaction of PA with mTOR. Furthermore, it appears that a decrease in total 4E-BP1 may be part of the mTOR-dependent mechanism through which mechanical stimuli activate protein synthesis.

Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.

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Kristina Kirschner

2015-03-01

Full Text Available The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage and chronically activated (in senescent or pro-apoptotic conditions p53. Compared to the classical 'acute' p53 binding profile, 'chronic' p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory 'p53 hubs' where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the 'lipogenic phenotype', a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms.

Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively.

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Nowak, Jakub Stanislaw; Hobor, Fruzsina; Downie Ruiz Velasco, Angela; Choudhury, Nila Roy; Heikel, Gregory; Kerr, Alastair; Ramos, Andres; Michlewski, Gracjan

2017-03-01

Lin28a inhibits the biogenesis of let-7 miRNAs by triggering the polyuridylation and degradation of their precursors by terminal uridylyltransferases TUT4/7 and 3'-5' exoribonuclease Dis3l2, respectively. Previously, we showed that Lin28a also controls the production of neuro-specific miRNA-9 via a polyuridylation-independent mechanism. Here we reveal that the sequences and structural characteristics of pre-let-7 and pre-miRNA-9 are eliciting two distinct modes of binding to Lin28a. We present evidence that Dis3l2 controls miRNA-9 production. Finally, we show that the constitutive expression of untagged Lin28a during neuronal differentiation in vitro positively and negatively affects numerous other miRNAs. Our findings shed light on the role of Lin28a in differentiating cells and on the ways in which one RNA-binding protein can perform multiple roles in the regulation of RNA processing. © 2017 Nowak et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

COX-independent mechanisms of cancer chemoprevention by anti-inflammatory drugs

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Evrim eGurpinar

2013-07-01

Full Text Available Epidemiological and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs, including cyclooxygenase (COX-2 selective inhibitors, reduce the risk of developing cancer. Experimental studies in human cancer cell lines and rodent models of carcinogenesis support these observations by providing strong evidence for the antineoplastic properties of NSAIDs. The involvement of COX-2 in tumorigenesis and its overexpression in various cancer tissues suggest that inhibition of COX-2 is responsible for the chemopreventive efficacy of these agents. However, the precise mechanisms by which NSAIDs exert their antiproliferative effects are still a matter of debate. Numerous other studies have shown that NSAIDs can act through COX-independent mechanisms. This review provides a detailed description of the major COX-independent molecular targets of NSAIDs and discusses how these targets may be involved in their anticancer effects. Toxicities resulting from COX inhibition and the suppression of prostaglandin synthesis preclude the long-term use of NSAIDs for cancer chemoprevention. Furthermore, chemopreventive efficacy is incomplete and treatment often leads to the development of resistance. Identification of alternative NSAID targets and elucidation of the biochemical processes by which they inhibit tumor growth could lead to the development of safer and more efficacious drugs for cancer chemoprevention.

The Biology of Atherosclerosis: General Paradigms and Distinct Pathogenic Mechanisms Among HIV-Infected Patients

OpenAIRE

Lo, Janet; Plutzky, Jorge

2012-01-01

Complications of atherosclerosis, including myocardial infarction and stroke, are the leading cause of death and disability worldwide. Recent data strongly implicate cardiovascular death as a contributor to mortality among patients with human immunodeficiency virus (HIV) infection, with evidence suggesting increased incidence of atherosclerosis among these patients. Therefore, greater understanding of atherosclerotic mechanisms and how these responses may be similar or distinct in HIV-infecte...

Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells

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Juan Liu

2016-04-01

Full Text Available Although dasatinib is effective in most imatinib mesylate (IMT-resistant chronic myeloid leukemia (CML patients, the underlying mechanism of its effectiveness in eliminating imatinib-resistant cells is only partially understood. This study investigated the effects of dasatinib on signaling mechanisms driving-resistance in imatinib-resistant CML cell line K562 (K562RIMT. Compared with K562 control cells, exsomal release, the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt/ mammalian target of rapamycin (mTOR signaling and autophagic activity were increased significantly in K562RIMT cells and mTOR-independent beclin-1/Vps34 signaling was shown to be involved in exosomal release in these cells. We found that Notch1 activation-mediated reduction of phosphatase and tensin homolog (PTEN was responsible for the increased Akt/mTOR activities in K562RIMT cells and treatment with Notch1 γ-secretase inhibitor prevented activation of Akt/mTOR. In addition, suppression of mTOR activity by rapamycin decreased the level of activity of p70S6K, induced upregulation of p53 and caspase 3, and led to increase of apoptosis in K562RIMT cells. Inhibition of autophagy by spautin-1 or beclin-1 knockdown decreased exosomal release, but did not affect apoptosis in K562RIMT cells. In summary, in K562RIMT cells dasatinib promoted apoptosis through downregulation of Akt/mTOR activities, while preventing exosomal release and inhibiting autophagy by downregulating expression of beclin-1 and Vps34. Our findings reveal distinct dasatinib-induced mechanisms of apoptotic response and exosomal release in imatinib-resistant CML cells.

Circuit mechanisms of sensorimotor learning

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Makino, Hiroshi; Hwang, Eun Jung; Hedrick, Nathan G.; Komiyama, Takaki

2016-01-01

SUMMARY The relationship between the brain and the environment is flexible, forming the foundation for our ability to learn. Here we review the current state of our understanding of the modifications in the sensorimotor pathway related to sensorimotor learning. We divide the process in three hierarchical levels with distinct goals: 1) sensory perceptual learning, 2) sensorimotor associative learning, and 3) motor skill learning. Perceptual learning optimizes the representations of important sensory stimuli. Associative learning and the initial phase of motor skill learning are ensured by feedback-based mechanisms that permit trial-and-error learning. The later phase of motor skill learning may primarily involve feedback-independent mechanisms operating under the classic Hebbian rule. With these changes under distinct constraints and mechanisms, sensorimotor learning establishes dedicated circuitry for the reproduction of stereotyped neural activity patterns and behavior. PMID:27883902

A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality

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Noël, Emily S.; Verhoeven, Manon; Lagendijk, Anne Karine; Tessadori, Federico; Smith, Kelly; Choorapoikayil, Suma; den Hertog, Jeroen; Bakkers, Jeroen

2013-11-01

Breaking left-right symmetry in bilateria is a major event during embryo development that is required for asymmetric organ position, directional organ looping and lateralized organ function in the adult. Asymmetric expression of Nodal-related genes is hypothesized to be the driving force behind regulation of organ laterality. Here we identify a Nodal-independent mechanism that drives asymmetric heart looping in zebrafish embryos. In a unique mutant defective for the Nodal-related southpaw gene, preferential dextral looping in the heart is maintained, whereas gut and brain asymmetries are randomized. As genetic and pharmacological inhibition of Nodal signalling does not abolish heart asymmetry, a yet undiscovered mechanism controls heart chirality. This mechanism is tissue intrinsic, as explanted hearts maintain ex vivo retain chiral looping behaviour and require actin polymerization and myosin II activity. We find that Nodal signalling regulates actin gene expression, supporting a model in which Nodal signalling amplifies this tissue-intrinsic mechanism of heart looping.

Antibody-mediated neutralization of Ebola virus can occur by two distinct mechanisms

International Nuclear Information System (INIS)

Shedlock, Devon J.; Bailey, Michael A.; Popernack, Paul M.; Cunningham, James M.; Burton, Dennis R.; Sullivan, Nancy J.

2010-01-01

Human Ebola virus causes severe hemorrhagic fever disease with high mortality and there is no vaccine or treatment. Antibodies in survivors occur early, are sustained, and can delay infection when transferred into nonhuman primates. Monoclonal antibodies (mAbs) from survivors exhibit potent neutralizing activity in vitro and are protective in rodents. To better understand targets and mechanisms of neutralization, we investigated a panel of mAbs shown previously to react with the envelope glycoprotein (GP). While one non-neutralizing mAb recognized a GP epitope in the nonessential mucin-like domain, the rest were specific for GP1, were neutralizing, and could be further distinguished by reactivity with secreted GP. We show that survivor antibodies, human KZ52 and monkey JP3K11, were specific for conformation-dependent epitopes comprising residues in GP1 and GP2 and that neutralization occurred by two distinct mechanisms; KZ52 inhibited cathepsin cleavage of GP whereas JP3K11 recognized the cleaved, fusion-active form of GP.

Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

Science.gov (United States)

Camberlein, Emilie; Cohen, Jonathan M.; José, Ricardo; Hyams, Catherine J.; Callard, Robin; Chimalapati, Suneeta; Yuste, Jose; Edwards, Lindsey A.; Marshall, Helina; van Rooijen, Nico; Noursadeghi, Mahdad

2015-01-01

Although the importance of alveolar macrophages for host immunity during early Streptococcus pneumoniae lung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model of S. pneumoniae early lung infection with wild-type, unencapsulated, and para-amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulated S. pneumoniae, alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimated S. pneumoniae doubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and the S. pneumoniae alveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection with S. pneumoniae. PMID:25583525

Distinct cortical areas for names of numbers and body parts independent of language and input modality.

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Le Clec'H, G; Dehaene, S; Cohen, L; Mehler, J; Dupoux, E; Poline, J B; Lehéricy, S; van de Moortele, P F; Le Bihan, D

2000-10-01

Some models of word comprehension postulate that the processing of words presented in different modalities and languages ultimately converges toward common cerebral systems associated with semantic-level processing and that the localization of these systems may vary with the category of semantic knowledge being accessed. We used functional magnetic resonance imaging to investigate this hypothesis with two categories of words, numerals, and body parts, for which the existence of distinct category-specific areas is debated in neuropsychology. Across two experiments, one with a blocked design and the other with an event-related design, a reproducible set of left-hemispheric parietal and prefrontal areas showed greater activation during the manipulation of topographical knowledge about body parts and a right-hemispheric parietal network during the manipulation of numerical quantities. These results complement the existing neuropsychological and brain-imaging literature by suggesting that within the extensive network of bilateral parietal regions active during both number and body-part processing, a subset shows category-specific responses independent of the language and modality of presentation. Copyright 2000 Academic Press.

Two independent mechanisms for motion-in-depth perception: evidence from individual differences

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Harold T Nefs

2010-10-01

Full Text Available Our forward-facing eyes allow us the advantage of binocular visual information: using the tiny differences between right and left eye views to learn about depth and location in three dimensions. Our visual systems also contain specialized mechanisms to detect motion-in-depth from binocular vision, but the nature of these mechanisms remains controversial. Binocular motion-in-depth perception could theoretically be based on first detecting binocular disparity and then monitoring how it changes over time. The alternative is to monitor the motion in the right and left eye separately and then compare these motion signals. Here we used an individual differences approach to test whether the two sources of information are processed via dissociated mechanisms, and to measure the relative importance of those mechanisms. Our results suggest the existence of two distinct mechanisms, each contributing to the perception of motion in depth in most observers. Additionally, for the first time, we demonstrate the relative prevalence of the two mechanisms within a normal population. In general, visual systems appear to rely mostly on the mechanism sensitive to changing binocular disparity, but perception of motion in depth is augmented by the presence of a less sensitive mechanism that uses interocular velocity differences. Occasionally, we find observers with the opposite pattern of sensitivity. More generally this work showcases the power of the individual differences approach in studying the functional organisation of cognitive systems.

Inflexibility and independence: Phase transitions in the majority-rule model.

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Crokidakis, Nuno; de Oliveira, Paulo Murilo Castro

2015-12-01

In this work we study opinion formation in a population participating in a public debate with two distinct choices. We consider three distinct mechanisms of social interactions and individuals' behavior: conformity, nonconformity, and inflexibility. The conformity is ruled by the majority-rule dynamics, whereas the nonconformity is introduced in the population as an independent behavior, implying the failure of attempted group influence. Finally, the inflexible agents are introduced in the population with a given density. These individuals present a singular behavior, in a way that their stubbornness makes them reluctant to change their opinions. We consider these effects separately and all together, with the aim to analyze the critical behavior of the system. We perform numerical simulations in some lattice structures and for distinct population sizes. Our results suggest that the different formulations of the model undergo order-disorder phase transitions in the same universality class as the Ising model. Some of our results are complemented by analytical calculations.

Distinct mechanisms eliminate mother and daughter centrioles in meiosis of starfish oocytes.

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Borrego-Pinto, Joana; Somogyi, Kálmán; Karreman, Matthia A; König, Julia; Müller-Reichert, Thomas; Bettencourt-Dias, Mónica; Gönczy, Pierre; Schwab, Yannick; Lénárt, Péter

2016-03-28

Centriole elimination is an essential process that occurs in female meiosis of metazoa to reset centriole number in the zygote at fertilization. How centrioles are eliminated remains poorly understood. Here we visualize the entire elimination process live in starfish oocytes. Using specific fluorescent markers, we demonstrate that the two older, mother centrioles are selectively removed from the oocyte by extrusion into polar bodies. We show that this requires specific positioning of the second meiotic spindle, achieved by dynein-driven transport, and anchorage of the mother centriole to the plasma membrane via mother-specific appendages. In contrast, the single daughter centriole remaining in the egg is eliminated before the first embryonic cleavage. We demonstrate that these distinct elimination mechanisms are necessary because if mother centrioles are artificially retained, they cannot be inactivated, resulting in multipolar zygotic spindles. Thus, our findings reveal a dual mechanism to eliminate centrioles: mothers are physically removed, whereas daughters are eliminated in the cytoplasm, preparing the egg for fertilization. © 2016 Borrego-Pinto et al.

Prickle isoforms control the direction of tissue polarity by microtubule independent and dependent mechanisms

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Katherine A. Sharp

2016-03-01

Full Text Available Planar cell polarity signaling directs the polarization of cells within the plane of many epithelia. While these tissues exhibit asymmetric localization of a set of core module proteins, in Drosophila, more than one mechanism links the direction of core module polarization to the tissue axes. One signaling system establishes a polarity bias in the parallel, apical microtubules upon which vesicles containing core proteins traffic. Swapping expression of the differentially expressed Prickle isoforms, Prickle and Spiny-legs, reverses the direction of core module polarization. Studies in the proximal wing and the anterior abdomen indicated that this results from their differential control of microtubule polarity. Prickle and Spiny-legs also control the direction of polarization in the distal wing (D-wing and the posterior abdomen (P-abd. We report here that this occurs without affecting microtubule polarity in these tissues. The direction of polarity in the D-wing is therefore likely determined by a novel mechanism independent of microtubule polarity. In the P-abd, Prickle and Spiny-legs interpret at least two directional cues through a microtubule-polarity-independent mechanism.

Independent Evolution of Six Families of Halogenating Enzymes.

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Xu, Gangming; Wang, Bin-Gui

2016-01-01

Halogenated natural products are widespread in the environment, and the halogen atoms are typically vital to their bioactivities. Thus far, six families of halogenating enzymes have been identified: cofactor-free haloperoxidases (HPO), vanadium-dependent haloperoxidases (V-HPO), heme iron-dependent haloperoxidases (HI-HPO), non-heme iron-dependent halogenases (NI-HG), flavin-dependent halogenases (F-HG), and S-adenosyl-L-methionine (SAM)-dependent halogenases (S-HG). However, these halogenating enzymes with similar biological functions but distinct structures might have evolved independently. Phylogenetic and structural analyses suggest that the HPO, V-HPO, HI-HPO, NI-HG, F-HG, and S-HG enzyme families may have evolutionary relationships to the α/β hydrolases, acid phosphatases, peroxidases, chemotaxis phosphatases, oxidoreductases, and SAM hydroxide adenosyltransferases, respectively. These halogenating enzymes have established sequence homology, structural conservation, and mechanistic features within each family. Understanding the distinct evolutionary history of these halogenating enzymes will provide further insights into the study of their catalytic mechanisms and halogenation specificity.

DeltaFosB induces osteosclerosis and decreases adipogenesis by two independent cell-autonomous mechanisms

DEFF Research Database (Denmark)

Kveiborg, Marie; Sabatakos, George; Chiusaroli, Riccardo

2004-01-01

establishes that the skeletal phenotype is cell autonomous to the osteoblast lineage and independent of adipocyte formation. It also strongly suggests that the decreased fat phenotype of NSE-DeltaFosB mice is independent of the changes in the osteoblast lineage. In vitro, overexpression of Delta......Osteoblasts and adipocytes may develop from common bone marrow mesenchymal precursors. Transgenic mice overexpressing DeltaFosB, an AP-1 transcription factor, under the control of the neuron-specific enolase (NSE) promoter show both markedly increased bone formation and decreased adipogenesis...... of DeltaFosB on adipocyte differentiation appears to occur at early stages of stem cell commitment, affecting C/EBPbeta functions. It is concluded that the changes in osteoblast and adipocyte differentiation in DeltaFosB transgenic mice result from independent cell-autonomous mechanisms....

Breast cancer oestrogen independence mediated by BCAR1 or BCAR3 genes is transmitted through mechanisms distinct from the oestrogen receptor signalling pathway or the epidermal growth factor receptor signalling pathway

International Nuclear Information System (INIS)

Dorssers, Lambert CJ; Agthoven, Ton van; Brinkman, Arend; Veldscholte, Jos; Smid, Marcel; Dechering, Koen J

2005-01-01

Tamoxifen is effective for endocrine treatment of oestrogen receptor-positive breast cancers but ultimately fails due to the development of resistance. A functional screen in human breast cancer cells identified two BCAR genes causing oestrogen-independent proliferation. The BCAR1 and BCAR3 genes both encode components of intracellular signal transduction, but their direct effect on breast cancer cell proliferation is not known. The aim of this study was to investigate the growth control mediated by these BCAR genes by gene expression profiling. We have measured the expression changes induced by overexpression of the BCAR1 or BCAR3 gene in ZR-75-1 cells and have made direct comparisons with the expression changes after cell stimulation with oestrogen or epidermal growth factor (EGF). A comparison with published gene expression data of cell models and breast tumours is made. Relatively few changes in gene expression were detected in the BCAR-transfected cells, in comparison with the extensive and distinct differences in gene expression induced by oestrogen or EGF. Both BCAR1 and BCAR3 regulate discrete sets of genes in these ZR-75-1-derived cells, indicating that the proliferation signalling proceeds along distinct pathways. Oestrogen-regulated genes in our cell model showed general concordance with reported data of cell models and gene expression association with oestrogen receptor status of breast tumours. The direct comparison of the expression profiles of BCAR transfectants and oestrogen or EGF-stimulated cells strongly suggests that anti-oestrogen-resistant cell proliferation is not caused by alternative activation of the oestrogen receptor or by the epidermal growth factor receptor signalling pathway

The biology of atherosclerosis: general paradigms and distinct pathogenic mechanisms among HIV-infected patients.

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Lo, Janet; Plutzky, Jorge

2012-06-01

Complications of atherosclerosis, including myocardial infarction and stroke, are the leading cause of death and disability worldwide. Recent data strongly implicate cardiovascular death as a contributor to mortality among patients with human immunodeficiency virus (HIV) infection, with evidence suggesting increased incidence of atherosclerosis among these patients. Therefore, greater understanding of atherosclerotic mechanisms and how these responses may be similar or distinct in HIV-infected patients is needed. Key concepts in atherosclerosis are reviewed, including the evidence that inflammation and abnormal metabolism are major drivers of atherosclerosis, and connected to the current literature regarding atherosclerosis in the context of HIV.

Amphetamine and cocaine suppress social play behavior in rats through distinct mechanisms.

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Achterberg, E J Marijke; Trezza, Viviana; Siviy, Stephen M; Schrama, Laurens; Schoffelmeer, Anton N M; Vanderschuren, Louk J M J

2014-04-01

Social play behavior is a characteristic form of social behavior displayed by juvenile and adolescent mammals. This social play behavior is highly rewarding and of major importance for social and cognitive development. Social play is known to be modulated by neurotransmitter systems involved in reward and motivation. Interestingly, psychostimulant drugs, such as amphetamine and cocaine, profoundly suppress social play, but the neural mechanisms underlying these effects remain to be elucidated. In this study, we investigated the pharmacological underpinnings of amphetamine- and cocaine-induced suppression of social play behavior in rats. The play-suppressant effects of amphetamine were antagonized by the alpha-2 adrenoreceptor antagonist RX821002 but not by the dopamine receptor antagonist alpha-flupenthixol. Remarkably, the effects of cocaine on social play were not antagonized by alpha-2 noradrenergic, dopaminergic, or serotonergic receptor antagonists, administered either alone or in combination. The effects of a subeffective dose of cocaine were enhanced by a combination of subeffective doses of the serotonin reuptake inhibitor fluoxetine, the dopamine reuptake inhibitor GBR12909, and the noradrenaline reuptake inhibitor atomoxetine. Amphetamine, like methylphenidate, exerts its play-suppressant effect through alpha-2 noradrenergic receptors. On the other hand, cocaine reduces social play by simultaneous increases in dopamine, noradrenaline, and serotonin neurotransmission. In conclusion, psychostimulant drugs with different pharmacological profiles suppress social play behavior through distinct mechanisms. These data contribute to our understanding of the neural mechanisms of social behavior during an important developmental period, and of the deleterious effects of psychostimulant exposure thereon.

A genetic screen for anchorage-independent proliferation in mammalian cells identifies a membrane-bound neuregulin.

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Davide Danovi

2010-07-01

Full Text Available Anchorage-independent proliferation is a hallmark of oncogenic transformation and is thought to be conducive to proliferation of cancer cells away from their site of origin. We have previously reported that primary Schwann cells expressing the SV40 Large T antigen (LT are not fully transformed in that they maintain a strict requirement for attachment, requiring a further genetic change, such as oncogenic Ras, to gain anchorage-independence. Using the LT-expressing cells, we performed a genetic screen for anchorage-independent proliferation and identified Sensory and Motor Neuron Derived Factor (SMDF, a transmembrane class III isoform of Neuregulin 1. In contrast to oncogenic Ras, SMDF induced enhanced proliferation in normal primary Schwann cells but did not trigger cellular senescence. In cooperation with LT, SMDF drove anchorage-independent proliferation, loss of contact inhibition and tumourigenicity. This transforming ability was shared with membrane-bound class III but not secreted class I isoforms of Neuregulin, indicating a distinct mechanism of action. Importantly, we show that despite being membrane-bound signalling molecules, class III neuregulins transform via a cell intrinsic mechanism, as a result of constitutive, elevated levels of ErbB signalling at high cell density and in anchorage-free conditions. This novel transforming mechanism may provide new targets for cancer therapy.

Pyridine-pyrimidine amides that prevent HGF-induced epithelial scattering by two distinct mechanisms.

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Siddiqui-Jain, Adam; Hoj, Jacob P; Hargiss, J Blade; Hoj, Taylor H; Payne, Carter J; Ritchie, Collin A; Herron, Steven R; Quinn, Colette; Schuler, Jeffrey T; Hansen, Marc D H

2017-09-01

Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in individual cells detaching and assuming a migratory and invasive phenotype. Epithelial scattering recapitulates cancer progression and studies have implicated HGF signaling as a driver of cancer metastasis. Inhibitors of HGF signaling have been proposed to act as anti-cancer agents. We previously screened a small molecule library for compounds that block HGF-induced epithelial scattering. Most hits identified in this screen exhibit anti-mitotic properties. Here we assess the biological mechanism of a compound that blocks HGF-induced scattering with limited anti-mitotic activity. Analogs of this compound have one of two distinct activities: inhibiting either cell migration or cell proliferation with cell cycle arrest in G2/M. Each activity bears unique structure-activity relationships. The mechanism of action of anti-mitotic compounds is by inhibition of microtubule polymerization; these compounds entropically and enthalpically bind tubulin in the colchicine binding site, generating a conformational change in the tubulin dimer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ibuprofen and Diclofenac Restrict Migration and Proliferation of Human Glioma Cells by Distinct Molecular Mechanisms

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Leidgens, Verena; Seliger, Corinna; Jachnik, Birgit; Welz, Tobias; Leukel, Petra; Vollmann-Zwerenz, Arabel; Bogdahn, Ulrich; Kreutz, Marina; Grauer, Oliver M.; Hau, Peter

2015-01-01

Background Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with anti-tumorigenic effects in different tumor entities. For glioma, research has generally focused on diclofenac; however data on other NSAIDs, such as ibuprofen, is limited. Therefore, we performed a comprehensive investigation of the cellular, molecular, and metabolic effects of ibuprofen and diclofenac on human glioblastoma cells. Methods Glioma cell lines were treated with ibuprofen or diclofenac to investigate functional effects on proliferation and cell motility. Cell cycle, extracellular lactate levels, lactate dehydrogenase-A (LDH-A) expression and activity, as well as inhibition of the Signal Transducer and Activator of Transcription 3 (STAT-3) signaling pathway, were determined. Specific effects of diclofenac and ibuprofen on STAT-3 were investigated by comparing their effects with those of the specific STAT-3 inhibitor STATTIC. Results Ibuprofen treatment led to a stronger inhibition of cell growth and migration than treatment with diclofenac. Proliferation was affected by cell cycle arrest at different checkpoints by both agents. In addition, diclofenac, but not ibuprofen, decreased lactate levels in all concentrations used. Both decreased STAT-3 phosphorylation; however, diclofenac led to decreased c-myc expression and subsequent reduction in LDH-A activity, whereas treatment with ibuprofen in higher doses induced c-myc expression and less LDH-A alteration. Conclusions This study indicates that both ibuprofen and diclofenac strongly inhibit glioma cells, but the subsequent metabolic responses of both agents are distinct. We postulate that ibuprofen may inhibit tumor cells also by COX- and lactate-independent mechanisms after long-term treatment in physiological dosages, whereas diclofenac mainly acts by inhibition of STAT-3 signaling and downstream modulation of glycolysis. PMID:26485029

The Independent and Shared Mechanisms of Intrinsic Brain Dynamics: Insights From Bistable Perception

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Teng Cao

2018-04-01

Full Text Available In bistable perception, constant input leads to alternating perception. The dynamics of the changing perception reflects the intrinsic dynamic properties of the “unconscious inferential” process in the brain. Under the same condition, individuals differ in how fast they experience the perceptual alternation. In this study, testing many forms of bistable perception in a large number of observers, we investigated the key question of whether there is a general and common mechanism or multiple and independent mechanisms that control the dynamics of the inferential brain. Bistable phenomena tested include binocular rivalry, vase-face, Necker cube, moving plaid, motion induced blindness, biological motion, spinning dancer, rotating cylinder, Lissajous-figure, rolling wheel, and translating diamond. Switching dynamics for each bistable percept was measured in 100 observers. Results show that the switching rates of subsets of bistable percept are highly correlated. The clustering of dynamic properties of some bistable phenomena but not an overall general control of switching dynamics implies that the brain’s inferential processes are both shared and independent – faster in constructing 3D structure from motion does not mean faster in integrating components into an objects.

NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies.

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Wallace, John L

2012-01-01

The mechanisms underlying the ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to cause ulceration in the stomach and proximal duodenum are well understood, and this injury can largely be prevented through suppression of gastric acid secretion (mainly with proton pump inhibitors). In contrast, the pathogenesis of small intestinal injury induced by NSAIDs is less well understood, involving more complex mechanisms than those in the stomach and proximal duodenum. There is clear evidence for important contributions to NSAID enteropathy of enteric bacteria, bile and enterohepatic recirculation of the NSAID. There is no evidence that suppression of gastric acid secretion will reduce the incidence or severity of NSAID enteropathy. Indeed, clinical data suggest little, if any, benefit. Animal studies suggest a significant exacerbation of NSAID enteropathy when proton pump inhibitors are co-administered with the NSAID. This worsening of damage appears to be linked to changes in the number and types of bacteria in the small intestine during proton pump inhibitor therapy. The distinct mechanisms of NSAID-induced injury in the stomach/proximal duodenum versus the more distal small intestine likely dictate distinct strategies for prevention. © 2011 The Author. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Vaccine and Wild-Type Strains of Yellow Fever Virus Engage Distinct Entry Mechanisms and Differentially Stimulate Antiviral Immune Responses.

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Fernandez-Garcia, Maria Dolores; Meertens, Laurent; Chazal, Maxime; Hafirassou, Mohamed Lamine; Dejarnac, Ophélie; Zamborlini, Alessia; Despres, Philippe; Sauvonnet, Nathalie; Arenzana-Seisdedos, Fernando; Jouvenet, Nolwenn; Amara, Ali

2016-02-09

The live attenuated yellow fever virus (YFV) vaccine 17D stands as a "gold standard" for a successful vaccine. 17D was developed empirically by passaging the wild-type Asibi strain in mouse and chicken embryo tissues. Despite its immense success, the molecular determinants for virulence attenuation and immunogenicity of the 17D vaccine are poorly understood. 17D evolved several mutations in its genome, most of which lie within the envelope (E) protein. Given the major role played by the YFV E protein during virus entry, it has been hypothesized that the residues that diverge between the Asibi and 17D E proteins may be key determinants of attenuation. In this study, we define the process of YFV entry into target cells and investigate its implication in the activation of the antiviral cytokine response. We found that Asibi infects host cells exclusively via the classical clathrin-mediated endocytosis, while 17D exploits a clathrin-independent pathway for infectious entry. We demonstrate that the mutations in the 17D E protein acquired during the attenuation process are sufficient to explain the differential entry of Asibi versus 17D. Interestingly, we show that 17D binds to and infects host cells more efficiently than Asibi, which culminates in increased delivery of viral RNA into the cytosol and robust activation of the cytokine-mediated antiviral response. Overall, our study reveals that 17D vaccine and Asibi enter target cells through distinct mechanisms and highlights a link between 17D attenuation, virus entry, and immune activation. The yellow fever virus (YFV) vaccine 17D is one of the safest and most effective live virus vaccines ever developed. The molecular determinants for virulence attenuation and immunogenicity of 17D are poorly understood. 17D was generated by serially passaging the virulent Asibi strain in vertebrate tissues. Here we examined the entry mechanisms engaged by YFV Asibi and the 17D vaccine. We found the two viruses use different entry

COGNITIVE COMPETENCE COMPARED TO COGNITIVE INDEPENDENCE AND COGNITIVE ACTIVITY

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Irina B. Shmigirilova

2014-01-01

Full Text Available The research is aimed at identifying the essence of the cognitive competence concept in comparison with the concepts of cognitive independence and activity.Methods: The methodology implies a theoretical analysis of psychopedagogical and methodological materials on the cognitive competence formation; generalized teaching experience; empirical methods of direct observations of educational process in the secondary school classrooms; interviews with school teachers and pupils.Results: The research outcomes reveal a semantic intersection between the cognitive competence, independence and activity, and their distinctive features. The paper emphasizes the importance of cognitive competence as an adaptive mechanism in situations of uncertainty and instability.Scientific novelty: The author clarifies the concept of cognitive competence regarding it as a multi-component and systematic characteristic of a personality.Practical significance: The research findings can be used by specialists in didactics developing the teaching techniques of cognitive competence formation for schoolchildren.

Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

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Chapuy, Bjoern; Stewart, Chip; Dunford, Andrew J; Kim, Jaegil; Kamburov, Atanas; Redd, Robert A; Lawrence, Mike S; Roemer, Margaretha G M; Li, Amy J; Ziepert, Marita; Staiger, Annette M; Wala, Jeremiah A; Ducar, Matthew D; Leshchiner, Ignaty; Rheinbay, Ester; Taylor-Weiner, Amaro; Coughlin, Caroline A; Hess, Julian M; Pedamallu, Chandra S; Livitz, Dimitri; Rosebrock, Daniel; Rosenberg, Mara; Tracy, Adam A; Horn, Heike; van Hummelen, Paul; Feldman, Andrew L; Link, Brian K; Novak, Anne J; Cerhan, James R; Habermann, Thomas M; Siebert, Reiner; Rosenwald, Andreas; Thorner, Aaron R; Meyerson, Matthew L; Golub, Todd R; Beroukhim, Rameen; Wulf, Gerald G; Ott, German; Rodig, Scott J; Monti, Stefano; Neuberg, Donna S; Loeffler, Markus; Pfreundschuh, Michael; Trümper, Lorenz; Getz, Gad; Shipp, Margaret A

2018-04-30

Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.

Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms.

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Carlin, Jesse Lea; Jain, Shalini; Gizewski, Elizabeth; Wan, Tina C; Tosh, Dilip K; Xiao, Cuiying; Auchampach, John A; Jacobson, Kenneth A; Gavrilova, Oksana; Reitman, Marc L

2017-03-01

Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1 -/- , Adora3 -/- ) mice. Confirming prior data, stimulation of the A 3 adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H 1 receptors. In contrast, A 1 AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A 1 AR agonists, including N 6 -cyclopentyladenosine (CPA), N 6 -cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A 1 AR and A 3 AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of Cl-ENBA [(±)-5'-chloro-5'-deoxy-N 6 -endo-norbornyladenosine], or using Adora3 -/- mice allowed selective stimulation of A 1 AR. AMP-stimulated hypothermia can occur independently of A 1 AR, A 3 AR, and mast cells. A 1 AR and A 3 AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A 1 AR nor A 3 AR was required for fasting-induced torpor. A 1 AR and A 3 AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms. Published by Elsevier Ltd.

Distinct signaling mechanisms in multiple developmental pathways by the SCRAMBLED receptor of Arabidopsis.

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Kwak, Su-Hwan; Woo, Sooah; Lee, Myeong Min; Schiefelbein, John

2014-10-01

SCRAMBLED (SCM), a leucine-rich repeat receptor-like kinase in Arabidopsis (Arabidopsis thaliana), is required for positional signaling in the root epidermis and for tissue/organ development in the shoot. To further understand SCM action, we generated a series of kinase domain variants and analyzed their ability to complement scm mutant defects. We found that the SCM kinase domain, but not kinase activity, is required for its role in root epidermal patterning, supporting the view that SCM is an atypical receptor kinase. We also describe a previously uncharacterized role for SCM in fruit dehiscence, because mature siliques from scm mutants fail to open properly. Interestingly, the kinase domain of SCM appears to be dispensable for this developmental process. Furthermore, we found that most of the SCM kinase domain mutations dramatically inhibit inflorescence development. Because this process is not affected in scm null mutants, it is likely that SCM acts redundantly to regulate inflorescence size. The importance of distinct kinase residues for these three developmental processes provides an explanation for the maintenance of the conserved kinase domain in the SCM protein, and it may generally explain its conservation in other atypical kinases. Furthermore, these results indicate that individual leucine-rich repeat receptor-like kinases may participate in multiple pathways using distinct signaling mechanisms to mediate diverse cellular communication events. © 2014 American Society of Plant Biologists. All Rights Reserved.

Affirming independence: Exploring mechanisms underlying a values affirmation intervention for first-generation students.

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Tibbetts, Yoi; Harackiewicz, Judith M; Canning, Elizabeth A; Boston, Jilana S; Priniski, Stacy J; Hyde, Janet S

2016-05-01

First-generation college students (students for whom neither parent has a 4-year college degree) earn lower grades and worry more about whether they belong in college, compared with continuing-generation students (who have at least 1 parent with a 4-year college degree). We conducted a longitudinal follow-up of participants from a study in which a values-affirmation intervention improved performance in a biology course for first-generation college students, and found that the treatment effect on grades persisted 3 years later. First-generation students in the treatment condition obtained a GPA that was, on average, .18 points higher than first-generation students in the control condition, 3 years after values affirmation was implemented (Study 1A). We explored mechanisms by testing whether the values-affirmation effects were predicated on first-generation students reflecting on interdependent values (thus affirming their values that are consistent with working-class culture) or independent values (thus affirming their values that are consistent with the culture of higher education). We found that when first-generation students wrote about their independence, they obtained higher grades (both in the semester in which values affirmation was implemented and in subsequent semesters) and felt less concerned about their background. In a separate laboratory experiment (Study 2) we manipulated the extent to which participants wrote about independence and found that encouraging first-generation students to write more about their independence improved their performance on a math test. These studies highlight the potential of having FG students focus on their own independence. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles

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Hoang, David T; Iczkowski, Kenneth A; Kilari, Deepak; See, William; Nevalainen, Marja T

2017-01-01

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms. PMID:27741508

Fab-based inhibitors reveal ubiquitin independent functions for HIV Vif neutralization of APOBEC3 restriction factors.

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Jennifer M Binning

2018-01-01

Full Text Available The lentiviral protein Viral Infectivity Factor (Vif counteracts the antiviral effects of host APOBEC3 (A3 proteins and contributes to persistent HIV infection. Vif targets A3 restriction factors for ubiquitination and proteasomal degradation by recruiting them to a multi-protein ubiquitin E3 ligase complex. Here, we describe a degradation-independent mechanism of Vif-mediated antagonism that was revealed through detailed structure-function studies of antibody antigen-binding fragments (Fabs to the Vif complex. Two Fabs were found to inhibit Vif-mediated A3 neutralization through distinct mechanisms: shielding A3 from ubiquitin transfer and blocking Vif E3 assembly. Combined biochemical, cell biological and structural studies reveal that disruption of Vif E3 assembly inhibited A3 ubiquitination but was not sufficient to restore its packaging into viral particles and antiviral activity. These observations establish that Vif can neutralize A3 family members in a degradation-independent manner. Additionally, this work highlights the potential of Fabs as functional probes, and illuminates how Vif uses a multi-pronged approach involving both degradation dependent and independent mechanisms to suppress A3 innate immunity.

Mouse Mammary Tumor Virus Signal Peptide Uses a Novel p97-Dependent and Derlin-Independent Retrotranslocation Mechanism To Escape Proteasomal Degradation

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Hyewon Byun

2017-03-01

Full Text Available Multiple pathogens, including viruses and bacteria, manipulate endoplasmic reticulum-associated degradation (ERAD to avoid the host immune response and promote their replication. The betaretrovirus mouse mammary tumor virus (MMTV encodes Rem, which is a precursor protein that is cleaved into a 98-amino-acid signal peptide (SP and a C-terminal protein (Rem-CT. SP uses retrotranslocation for ER membrane extraction and yet avoids ERAD by an unknown mechanism to enter the nucleus and function as a Rev-like protein. To determine how SP escapes ERAD, we used a ubiquitin-activated interaction trap (UBAIT screen to trap and identify transient protein interactions with SP, including the ERAD-associated p97 ATPase, but not E3 ligases or Derlin proteins linked to retrotranslocation, polyubiquitylation, and proteasomal degradation of extracted proteins. A dominant negative p97 ATPase inhibited both Rem and SP function. Immunoprecipitation experiments indicated that Rem, but not SP, is polyubiquitylated. Using both yeast and mammalian expression systems, linkage of a ubiquitin-like domain (UbL to SP or Rem induced degradation by the proteasome, whereas SP was stable in the absence of the UbL. ERAD-associated Derlin proteins were not required for SP activity. Together, these results suggested that Rem uses a novel p97-dependent, Derlin-independent retrotranslocation mechanism distinct from other pathogens to avoid SP ubiquitylation and proteasomal degradation.

Choosing the rules: distinct and overlapping frontoparietal representations of task rules for perceptual decisions.

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Zhang, Jiaxiang; Kriegeskorte, Nikolaus; Carlin, Johan D; Rowe, James B

2013-07-17

Behavior is governed by rules that associate stimuli with responses and outcomes. Human and monkey studies have shown that rule-specific information is widely represented in the frontoparietal cortex. However, it is not known how establishing a rule under different contexts affects its neural representation. Here, we use event-related functional MRI (fMRI) and multivoxel pattern classification methods to investigate the human brain's mechanisms of establishing and maintaining rules for multiple perceptual decision tasks. Rules were either chosen by participants or specifically instructed to them, and the fMRI activation patterns representing rule-specific information were compared between these contexts. We show that frontoparietal regions differ in the properties of their rule representations during active maintenance before execution. First, rule-specific information maintained in the dorsolateral and medial frontal cortex depends on the context in which it was established (chosen vs specified). Second, rule representations maintained in the ventrolateral frontal and parietal cortex are independent of the context in which they were established. Furthermore, we found that the rule-specific coding maintained in anticipation of stimuli may change with execution of the rule: representations in context-independent regions remain invariant from maintenance to execution stages, whereas rule representations in context-dependent regions do not generalize to execution stage. The identification of distinct frontoparietal systems with context-independent and context-dependent task rule representations, and the distinction between anticipatory and executive rule representations, provide new insights into the functional architecture of goal-directed behavior.

Distinctive Correspondence Between Separable Visual Attention Functions and Intrinsic Brain Networks.

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Ruiz-Rizzo, Adriana L; Neitzel, Julia; Müller, Hermann J; Sorg, Christian; Finke, Kathrin

2018-01-01

Separable visual attention functions are assumed to rely on distinct but interacting neural mechanisms. Bundesen's "theory of visual attention" (TVA) allows the mathematical estimation of independent parameters that characterize individuals' visual attentional capacity (i.e., visual processing speed and visual short-term memory storage capacity) and selectivity functions (i.e., top-down control and spatial laterality). However, it is unclear whether these parameters distinctively map onto different brain networks obtained from intrinsic functional connectivity, which organizes slowly fluctuating ongoing brain activity. In our study, 31 demographically homogeneous healthy young participants performed whole- and partial-report tasks and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Report accuracy was modeled using TVA to estimate, individually, the four TVA parameters. Networks encompassing cortical areas relevant for visual attention were derived from independent component analysis of rs-fMRI data: visual, executive control, right and left frontoparietal, and ventral and dorsal attention networks. Two TVA parameters were mapped on particular functional networks. First, participants with higher (vs. lower) visual processing speed showed lower functional connectivity within the ventral attention network. Second, participants with more (vs. less) efficient top-down control showed higher functional connectivity within the dorsal attention network and lower functional connectivity within the visual network. Additionally, higher performance was associated with higher functional connectivity between networks: specifically, between the ventral attention and right frontoparietal networks for visual processing speed, and between the visual and executive control networks for top-down control. The higher inter-network functional connectivity was related to lower intra-network connectivity. These results demonstrate that separable visual attention

Distinctive Correspondence Between Separable Visual Attention Functions and Intrinsic Brain Networks

Science.gov (United States)

Ruiz-Rizzo, Adriana L.; Neitzel, Julia; Müller, Hermann J.; Sorg, Christian; Finke, Kathrin

2018-01-01

Separable visual attention functions are assumed to rely on distinct but interacting neural mechanisms. Bundesen's “theory of visual attention” (TVA) allows the mathematical estimation of independent parameters that characterize individuals' visual attentional capacity (i.e., visual processing speed and visual short-term memory storage capacity) and selectivity functions (i.e., top-down control and spatial laterality). However, it is unclear whether these parameters distinctively map onto different brain networks obtained from intrinsic functional connectivity, which organizes slowly fluctuating ongoing brain activity. In our study, 31 demographically homogeneous healthy young participants performed whole- and partial-report tasks and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Report accuracy was modeled using TVA to estimate, individually, the four TVA parameters. Networks encompassing cortical areas relevant for visual attention were derived from independent component analysis of rs-fMRI data: visual, executive control, right and left frontoparietal, and ventral and dorsal attention networks. Two TVA parameters were mapped on particular functional networks. First, participants with higher (vs. lower) visual processing speed showed lower functional connectivity within the ventral attention network. Second, participants with more (vs. less) efficient top-down control showed higher functional connectivity within the dorsal attention network and lower functional connectivity within the visual network. Additionally, higher performance was associated with higher functional connectivity between networks: specifically, between the ventral attention and right frontoparietal networks for visual processing speed, and between the visual and executive control networks for top-down control. The higher inter-network functional connectivity was related to lower intra-network connectivity. These results demonstrate that separable visual attention

Distinctive Correspondence Between Separable Visual Attention Functions and Intrinsic Brain Networks

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Adriana L. Ruiz-Rizzo

2018-03-01

Full Text Available Separable visual attention functions are assumed to rely on distinct but interacting neural mechanisms. Bundesen's “theory of visual attention” (TVA allows the mathematical estimation of independent parameters that characterize individuals' visual attentional capacity (i.e., visual processing speed and visual short-term memory storage capacity and selectivity functions (i.e., top-down control and spatial laterality. However, it is unclear whether these parameters distinctively map onto different brain networks obtained from intrinsic functional connectivity, which organizes slowly fluctuating ongoing brain activity. In our study, 31 demographically homogeneous healthy young participants performed whole- and partial-report tasks and underwent resting-state functional magnetic resonance imaging (rs-fMRI. Report accuracy was modeled using TVA to estimate, individually, the four TVA parameters. Networks encompassing cortical areas relevant for visual attention were derived from independent component analysis of rs-fMRI data: visual, executive control, right and left frontoparietal, and ventral and dorsal attention networks. Two TVA parameters were mapped on particular functional networks. First, participants with higher (vs. lower visual processing speed showed lower functional connectivity within the ventral attention network. Second, participants with more (vs. less efficient top-down control showed higher functional connectivity within the dorsal attention network and lower functional connectivity within the visual network. Additionally, higher performance was associated with higher functional connectivity between networks: specifically, between the ventral attention and right frontoparietal networks for visual processing speed, and between the visual and executive control networks for top-down control. The higher inter-network functional connectivity was related to lower intra-network connectivity. These results demonstrate that separable

Distinct mechanisms of a phosphotyrosyl peptide binding to two SH2 domains.

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Pang, Xiaodong; Zhou, Huan-Xiang

2014-05-01

Protein phosphorylation is very common post-translational modification, catalyzed by kinases, for signaling and regulation. Phosphotyrosines frequently target SH2 domains. The spleen tyrosine kinase (Syk) is critical for tyrosine phosphorylation of multiple proteins and for regulation of important pathways. Phosphorylation of both Y342 and Y346 in Syk linker B is required for optimal signaling. The SH2 domains of Vav1 and PLC-γ both bind this doubly phosphorylated motif. Here we used a recently developed method to calculate the effects of Y342 and Y346 phosphorylation on the rate constants of a peptide from Syk linker B binding to the SH2 domains of Vav1 and PLC-γ. The predicted effects agree well with experimental observations. Moreover, we found that the same doubly phosphorylated peptide binds the two SH2 domains via distinct mechanisms, with apparent rigid docking for Vav1 SH2 and dock-and-coalesce for PLC-γ SH2.

Independent Attention Mechanisms Control the Activation of Tactile and Visual Working Memory Representations.

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Katus, Tobias; Eimer, Martin

2018-05-01

Working memory (WM) is limited in capacity, but it is controversial whether these capacity limitations are domain-general or are generated independently within separate modality-specific memory systems. These alternative accounts were tested in bimodal visual/tactile WM tasks. In Experiment 1, participants memorized the locations of simultaneously presented task-relevant visual and tactile stimuli. Visual and tactile WM load was manipulated independently (one, two, or three items per modality), and one modality was unpredictably tested after each trial. To track the activation of visual and tactile WM representations during the retention interval, the visual contralateral delay activity (CDA) and tactile CDA (tCDA) were measured over visual and somatosensory cortex, respectively. CDA and tCDA amplitudes were selectively affected by WM load in the corresponding (tactile or visual) modality. The CDA parametrically increased when visual load increased from one to two and to three items. The tCDA was enhanced when tactile load increased from one to two items and showed no further enhancement for three tactile items. Critically, these load effects were strictly modality-specific, as substantiated by Bayesian statistics. Increasing tactile load did not affect the visual CDA, and increasing visual load did not modulate the tCDA. Task performance at memory test was also unaffected by WM load in the other (untested) modality. This was confirmed in a second behavioral experiment where tactile and visual loads were either two or four items, unimodal baseline conditions were included, and participants performed a color change detection task in the visual modality. These results show that WM capacity is not limited by a domain-general mechanism that operates across sensory modalities. They suggest instead that WM storage is mediated by distributed modality-specific control mechanisms that are activated independently and in parallel during multisensory WM.

REMEMBERING TO LEARN: INDEPENDENT PLACE AND JOURNEY CODING MECHANISMS CONTRIBUTE TO MEMORY TRANSFER

OpenAIRE

Bahar, Amir S.; Shapiro, Matthew L.

2012-01-01

The neural mechanisms that integrate new episodes with established memories are unknown. When rats explore an environment, CA1 cells fire in place fields that indicate locations. In goal-directed spatial memory tasks, some place fields differentiate behavioral histories (journey-dependent place fields) while others do not (journey-independent place fields). To investigate how these signals inform learning and memory for new and familiar episodes, we recorded CA1 and CA3 activity in rats train...

Distinct mechanisms underlying tolerance to intermittent and constant hypoxia in Drosophila melanogaster.

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Priti Azad

Full Text Available BACKGROUND: Constant hypoxia (CH and intermittent hypoxia (IH occur during several pathological conditions such as asthma and obstructive sleep apnea. Our research is focused on understanding the molecular mechanisms that lead to injury or adaptation to hypoxic stress using Drosophila as a model system. Our current genome-wide study is designed to investigate gene expression changes and identify protective mechanism(s in D. melanogaster after exposure to severe (1% O(2 intermittent or constant hypoxia. METHODOLOGY/PRINCIPAL FINDINGS: Our microarray analysis has identified multiple gene families that are up- or down-regulated in response to acute CH or IH. We observed distinct responses to IH and CH in gene expression that varied in the number of genes and type of gene families. We then studied the role of candidate genes (up-or down-regulated in hypoxia tolerance (adult survival for longer periods (CH-7 days, IH-10 days under severe CH or IH. Heat shock proteins up-regulation (specifically Hsp23 and Hsp70 led to a significant increase in adult survival (as compared to controls of P-element lines during CH. In contrast, during IH treatment the up-regulation of Mdr49 and l(208717 genes (P-element lines provided survival advantage over controls. This suggests that the increased transcript levels following treatment with either paradigm play an important role in tolerance to severe hypoxia. Furthermore, by over-expressing Hsp70 in specific tissues, we found that up-regulation of Hsp70 in heart and brain play critical role in tolerance to CH in flies. CONCLUSIONS/SIGNIFICANCE: We observed that the gene expression response to IH or CH is specific and paradigm-dependent. We have identified several genes Hsp23, Hsp70, CG1600, l(208717 and Mdr49 that play an important role in hypoxia tolerance whether it is in CH or IH. These data provide further clues about the mechanisms by which IH or CH lead to cell injury and morbidity or adaptation and survival.

How space-number associations may be created in preliterate children: six distinct mechanisms

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Hans-Christoph eNuerk

2015-03-01

Full Text Available The directionality of space-number association (SNA is shaped by cultural experiences. It usually follows the culturally dominant reading direction. Smaller numbers are generally associated with the starting side for reading (left side in Western cultures, while larger numbers are associated with the right endpoint side. However, SNAs consistent with cultural reading directions are present before children can actually read and write. Therefore, these SNAs cannot only be shaped by the direction of children’s own reading/writing behavior. We propose six distinct processes - one biological and five cultural/educational - underlying directional space-number associations before formal reading acquisition: (i Brain lateralization (ii Monitoring adult reading behavior, (iii Pretend reading and writing, and rudimentary reading and writing skills, (iv Dominant attentional directional preferences in a society, not directly related to reading direction, (v Direct spatial-numerical learning, (vi Other spatial-directional processes independent of reading direction. In this mini-review, we will differentiate between these processes, elaborate when in development they might emerge, discuss how they may create the space-number associations observed in preliterate children and propose how they can be studied in the future.

PPARγ-Independent Mechanism

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Christopher M. Hogan

2011-01-01

Full Text Available Acute and chronic lung inflammation is associated with numerous important disease pathologies including asthma, chronic obstructive pulmonary disease and silicosis. Lung fibroblasts are a novel and important target of anti-inflammatory therapy, as they orchestrate, respond to, and amplify inflammatory cascades and are the key cell in the pathogenesis of lung fibrosis. Peroxisome proliferator-activated receptor gamma (PPARγ ligands are small molecules that induce anti-inflammatory responses in a variety of tissues. Here, we report for the first time that PPARγ ligands have potent anti-inflammatory effects on human lung fibroblasts. 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2 inhibit production of the inflammatory mediators interleukin-6 (IL-6, monocyte chemoattractant protein-1 (MCP-1, COX-2, and prostaglandin (PGE2 in primary human lung fibroblasts stimulated with either IL-1β or silica. The anti-inflammatory properties of these molecules are not blocked by the PPARγ antagonist GW9662 and thus are largely PPARγ independent. However, they are dependent on the presence of an electrophilic carbon. CDDO and 15d-PGJ2, but not rosiglitazone, inhibited NF-κB activity. These results demonstrate that CDDO and 15d-PGJ2 are potent attenuators of proinflammatory responses in lung fibroblasts and suggest that these molecules should be explored as the basis for novel, targeted anti-inflammatory therapies in the lung and other organs.

Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts.

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Michael E Johnson

Full Text Available Genome-wide expression profiling in systemic sclerosis (SSc has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like, each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFNα signaling showed a strong association with early disease, while TGFβ signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-κB. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGFβ and TNFα. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFNα is involved in early disease pathology, and disease severity is associated with active TGFβ signaling.

DNA-histone complexes as ligands amplify cell penetration and nuclear targeting of anti-DNA antibodies via energy-independent mechanisms.

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Zannikou, Markella; Bellou, Sofia; Eliades, Petros; Hatzioannou, Aikaterini; Mantzaris, Michael D; Carayanniotis, George; Avrameas, Stratis; Lymberi, Peggy

2016-01-01

We have generated three monoclonal cell-penetrating antibodies (CPAbs) from a non-immunized lupus-prone (NZB × NZW)F1 mouse that exhibited high anti-DNA serum titres. These CPAbs are polyreactive because they bind to DNA and other cellular components, and localize mainly in the nucleus of HeLa cells, albeit with a distinct nuclear labelling profile. Herein, we have examined whether DNA-histone complexes (DHC) binding to CPAbs, before cell entry, could modify the cell penetration of CPAbs or their nuclear staining properties. By applying confocal microscopy and image analysis, we found that extracellular binding of purified CPAbs to DHC significantly enhanced their subsequent cell-entry, both in terms of percentages of positively labelled cells and fluorescence intensity (internalized CPAb amount), whereas there was a variable effect on their nuclear staining profile. Internalization of CPAbs, either alone or bound to DHC, remained unaltered after the addition of endocytosis-specific inhibitors at 37° or assay performance at 4°, suggesting the involvement of energy-independent mechanisms in the internalization process. These findings assign to CPAbs a more complex pathogenetic role in systemic lupus erythematosus where both CPAbs and nuclear components are abundant. © 2015 John Wiley & Sons Ltd.

Coincident In Vitro Analysis of DNA-PK-Dependent and -Independent Nonhomologous End Joining

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Cynthia L. Hendrickson

2010-01-01

Full Text Available In mammalian cells, DNA double-strand breaks (DSBs are primarily repaired by nonhomologous end joining (NHEJ. The current model suggests that the Ku 70/80 heterodimer binds to DSB ends and recruits DNA-PKcs to form the active DNA-dependent protein kinase, DNA-PK. Subsequently, XRCC4, DNA ligase IV, XLF and most likely, other unidentified components participate in the final DSB ligation step. Therefore, DNA-PK plays a key role in NHEJ due to its structural and regulatory functions that mediate DSB end joining. However, recent studies show that additional DNA-PK-independent NHEJ pathways also exist. Unfortunately, the presence of DNA-PKcs appears to inhibit DNA-PK-independent NHEJ, and in vitro analysis of DNA-PK-independent NHEJ in the presence of the DNA-PKcs protein remains problematic. We have developed an in vitro assay that is preferentially active for DNA-PK-independent DSB repair based solely on its reaction conditions, facilitating coincident differential biochemical analysis of the two pathways. The results indicate the biochemically distinct nature of the end-joining mechanisms represented by the DNA-PK-dependent and -independent NHEJ assays as well as functional differences between the two pathways.

Performance pressure and caffeine both affect cognitive performance, but likely through independent mechanisms.

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Boere, Julia J; Fellinger, Lizz; Huizinga, Duncan J H; Wong, Sebastiaan F; Bijleveld, Erik

2016-02-01

A prevalent combination in daily life, performance pressure and caffeine intake have both been shown to impact people's cognitive performance. Here, we examined the possibility that pressure and caffeine affect cognitive performance via a shared pathway. In an experiment, participants performed a modular arithmetic task. Performance pressure and caffeine intake were orthogonally manipulated. Findings indicated that pressure and caffeine both negatively impacted performance. However, (a) pressure vs. caffeine affected performance on different trial types, and (b) there was no hint of an interactive effect. So, though the evidence is indirect, findings suggest that pressure and caffeine shape performance via distinct mechanisms, rather than a shared one. Copyright © 2015 Elsevier Inc. All rights reserved.

Cue-independent forgetting by intentional suppression - Evidence for inhibition as the mechanism of intentional forgetting.

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Wang, Yingying; Cao, Zhijun; Zhu, Zijian; Cai, Huaqian; Wu, Yanhong

2015-10-01

People are able to intentionally forget unwanted memories through voluntary suppression, as revealed by the Think/No-think (TNT) paradigm. However, the nature of intentional forgetting is controversial. Findings that forgetting is independent of retrieval cues suggest that inhibitory control underlies intentional forgetting, but this result is also in line with an interference account. To resolve this controversy, we have directly contrasted the cue-independent characteristic of suppression versus interference. A double-cue paradigm was used, in which two different cues were associated with the same target during initial memory formation. Only one cue-target association received further interference/suppression training. In the test phase, when both cues were used to retrieve the target, we found that interference caused memory impairment that was restricted to the trained cue-target association, while suppression induced forgetting that generalized to the independent cue-target association. Therefore, the effect of suppression differs from that of interference. The cue-independent forgetting by voluntary suppression indicates that the target memory itself is inhibited, providing evidence that the underlying mechanism of suppression-induced forgetting is inhibitory control. Copyright © 2015 Elsevier B.V. All rights reserved.

Defining and Selecting Independent Directors

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Eric Pichet

2017-10-01

Full Text Available Drawing from the Enlightened Shareholder Theory that the author first developed in 2011, this theoretical paper with practical and normative ambitions achieves a better definition of independent director, while improving the understanding of the roles he fulfils on boards of directors. The first part defines constructs like firms, Governance system and Corporate governance, offering a clear distinction between the latter two concepts before explaining the four main missions of a board. The second part defines the ideal independent director by outlining the objective qualities that are necessary and adding those subjective aspects that have turned this into a veritable profession. The third part defines the ideal process for selecting independent directors, based on nominating committees that should themselves be independent. It also includes ways of assessing directors who are currently in function, as well as modalities for renewing their mandates. The paper’s conclusion presents the Paradox of the Independent Director.

Reliability for systems of degrading components with distinct component shock sets

International Nuclear Information System (INIS)

Song, Sanling; Coit, David W.; Feng, Qianmei

2014-01-01

This paper studies reliability for multi-component systems subject to dependent competing risks of degradation wear and random shocks, with distinct shock sets. In practice, many systems are exposed to distinct and different types of shocks that can be categorized according to their sizes, function, affected components, etc. Previous research primarily focuses on simple systems with independent failure processes, systems with independent component time-to-failure, or components that share the same shock set or type of shocks. In our new model, we classify random shocks into different sets based on their sizes or function. Shocks with specific sizes or function can selectively affect one or more components in the system but not necessarily all components. Additionally the shocks from the different shock sets can arrive at different rates and have different relative magnitudes. Preventive maintenance (PM) optimization is conducted for the system with different component shock sets. Decision variables for two different maintenance scheduling problems, the PM replacement time interval, and the PM inspection time interval, are determined by minimizing a defined system cost rate. Sensitivity analysis is performed to provide insight into the behavior of the proposed maintenance policies. These models can be applied directly or customized for many complex systems that experience dependent competing failure processes with different component shock sets. A MEMS (Micro-electro mechanical systems) oscillator is a typical system subject to dependent and competing failure processes, and it is used as a numerical example to illustrate our new reliability and maintenance models

Beta2- and beta3-adrenoceptors activate glucose uptake in chick astrocytes by distinct mechanisms: a mechanism for memory enhancement?

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Hutchinson, Dana S; Summers, Roger J; Gibbs, Marie E

2007-11-01

Isoprenaline, acting at beta-adrenoceptors (ARs), enhances memory formation in single trial discriminated avoidance learning in day-old chicks by mechanisms involving alterations in glucose and glycogen metabolism. Earlier studies of memory consolidation in chicks indicated that beta3-ARs enhanced memory by increasing glucose uptake, whereas beta2-ARs enhance memory by increasing glycogenolysis. This study examines the ability of beta-ARs to increase glucose uptake in chick forebrain astrocytes. The beta-AR agonist isoprenaline increased glucose uptake in a concentration-dependent manner, as did insulin. Glucose uptake was increased by the beta2-AR agonist zinterol and the beta3-AR agonist CL316243, but not by the beta1-AR agonist RO363. In chick astrocytes, reverse transcription-polymerase chain reaction studies showed that beta1-, beta2-, and beta3-AR mRNA were present, whereas radioligand-binding studies showed the presence of only beta2- and beta3-ARs. beta-AR or insulin-mediated glucose uptake was inhibited by phosphatidylinositol-3 kinase and protein kinase C inhibitors, suggesting a possible interaction between the beta-AR and insulin pathways. However beta2- and beta3-ARs increase glucose uptake by two different mechanisms: beta2-ARs via a Gs-cAMP-protein kinase A-dependent pathway, while beta3-ARs via interactions with Gi. These results indicate that activation of beta2- and beta3-ARs causes glucose uptake in chick astrocytes by distinct mechanisms, which may be relevant for memory enhancement.

Independent risk of mechanical ventilation for AIDS-related Pneumocystis carinii pneumonia associated with bronchoalveolar lavage neutrophilia

DEFF Research Database (Denmark)

Bang, D.; Emborg, J.; Elkjaer, J.

2001-01-01

The use of mechanical ventilation (MV) for AIDS-related Pneumocystis carinii pneumonia (PCP) has varied over time. The introduction of adjunctive corticosteroid therapy has changed the pathophysiology of PCP. In the present study, we attempted to identify factors predictive of severe respiratory......%). In a logistic regression analysis, higher age, increased bronchoalveolar lavage (BAL) neutrophilia and a positive BAL cytomegalovirus CMV culture were associated with the need of MV. In multivariate analyses, only BAL neutrophilia remained independently predictive of mechanical ventilation. In conclusion, short......-term mortality remained high after the introduction of adjunctive corticosteroid therapy. BAL neutrophilia may be a useful prognostic marker to identify patients at high risk of requiring mechanical ventilation Udgivelsesdato: 2001/8...

Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome

DEFF Research Database (Denmark)

Morselli, Eugenia; Mariño, Guillermo; Bennetzen, Martin V

2011-01-01

Autophagy protects organelles, cells, and organisms against several stress conditions. Induction of autophagy by resveratrol requires the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1). In this paper, we show that the acetylase inhibitor spermidine stimulates autophagy...... independent of SIRT1 in human and yeast cells as well as in nematodes. Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome. Both agents favor convergent deacetylation...... and acetylation reactions in the cytosol and in the nucleus, respectively. Both resveratrol and spermidine were able to induce autophagy in cytoplasts (enucleated cells). Moreover, a cytoplasm-restricted mutant of SIRT1 could stimulate autophagy, suggesting that cytoplasmic deacetylation reactions dictate...

Vertebrate-like CRYPTOCHROME 2 from monarch regulates circadian transcription via independent repression of CLOCK and BMAL1 activity.

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Zhang, Ying; Markert, Matthew J; Groves, Shayna C; Hardin, Paul E; Merlin, Christine

2017-09-05

Circadian repression of CLOCK-BMAL1 by PERIOD and CRYPTOCHROME (CRY) in mammals lies at the core of the circadian timekeeping mechanism. CRY repression of CLOCK-BMAL1 and regulation of circadian period are proposed to rely primarily on competition for binding with coactivators on an α-helix located within the transactivation domain (TAD) of the BMAL1 C terminus. This model has, however, not been tested in vivo. Here, we applied CRISPR/Cas9-mediated mutagenesis in the monarch butterfly ( Danaus plexippus ), which possesses a vertebrate-like CRY (dpCRY2) and an ortholog of BMAL1, to show that insect CRY2 regulates circadian repression through TAD α-helix-dependent and -independent mechanisms. Monarch mutants lacking the BMAL1 C terminus including the TAD exhibited arrhythmic eclosion behavior. In contrast, mutants lacking the TAD α-helix but retaining the most distal C-terminal residues exhibited robust rhythms during the first day of constant darkness (DD1), albeit with a delayed peak of eclosion. Phase delay in this mutant on DD1 was exacerbated in the presence of a single functional allele of dpCry2 , and rhythmicity was abolished in the absence of dpCRY2. Reporter assays in Drosophila S2 cells further revealed that dpCRY2 represses through two distinct mechanisms: a TAD-dependent mechanism that involves the dpBMAL1 TAD α-helix and dpCLK W328 and a TAD-independent mechanism involving dpCLK E333. Together, our results provide evidence for independent mechanisms of vertebrate-like CRY circadian regulation on the BMAL1 C terminus and the CLK PAS-B domain and demonstrate the importance of a BMAL1 TAD-independent mechanism for generating circadian rhythms in vivo.

Distinct Signaling Mechanisms in Multiple Developmental Pathways by the SCRAMBLED Receptor of Arabidopsis1[OPEN

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Kwak, Su-Hwan; Woo, Sooah; Lee, Myeong Min; Schiefelbein, John

2014-01-01

SCRAMBLED (SCM), a leucine-rich repeat receptor-like kinase in Arabidopsis (Arabidopsis thaliana), is required for positional signaling in the root epidermis and for tissue/organ development in the shoot. To further understand SCM action, we generated a series of kinase domain variants and analyzed their ability to complement scm mutant defects. We found that the SCM kinase domain, but not kinase activity, is required for its role in root epidermal patterning, supporting the view that SCM is an atypical receptor kinase. We also describe a previously uncharacterized role for SCM in fruit dehiscence, because mature siliques from scm mutants fail to open properly. Interestingly, the kinase domain of SCM appears to be dispensable for this developmental process. Furthermore, we found that most of the SCM kinase domain mutations dramatically inhibit inflorescence development. Because this process is not affected in scm null mutants, it is likely that SCM acts redundantly to regulate inflorescence size. The importance of distinct kinase residues for these three developmental processes provides an explanation for the maintenance of the conserved kinase domain in the SCM protein, and it may generally explain its conservation in other atypical kinases. Furthermore, these results indicate that individual leucine-rich repeat receptor-like kinases may participate in multiple pathways using distinct signaling mechanisms to mediate diverse cellular communication events. PMID:25136062

Trimethylamine N-oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine

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Liao, Yi-Ting; Manson, Anthony C.; DeLyser, Michael R.; Noid, William G.; Cremer, Paul S.

2017-01-01

We report experimental and computational studies investigating the effects of three osmolytes, trimethylamine N-oxide (TMAO), betaine, and glycine, on the hydrophobic collapse of an elastin-like polypeptide (ELP). All three osmolytes stabilize collapsed conformations of the ELP and reduce the lower critical solution temperature (LSCT) linearly with osmolyte concentration. As expected from conventional preferential solvation arguments, betaine and glycine both increase the surface tension at the air–water interface. TMAO, however, reduces the surface tension. Atomically detailed molecular dynamics (MD) simulations suggest that TMAO also slightly accumulates at the polymer–water interface, whereas glycine and betaine are strongly depleted. To investigate alternative mechanisms for osmolyte effects, we performed FTIR experiments that characterized the impact of each cosolvent on the bulk water structure. These experiments showed that TMAO red-shifts the OH stretch of the IR spectrum via a mechanism that was very sensitive to the protonation state of the NO moiety. Glycine also caused a red shift in the OH stretch region, whereas betaine minimally impacted this region. Thus, the effects of osmolytes on the OH spectrum appear uncorrelated with their effects upon hydrophobic collapse. Similarly, MD simulations suggested that TMAO disrupts the water structure to the least extent, whereas glycine exerts the greatest influence on the water structure. These results suggest that TMAO stabilizes collapsed conformations via a mechanism that is distinct from glycine and betaine. In particular, we propose that TMAO stabilizes proteins by acting as a surfactant for the heterogeneous surfaces of folded proteins. PMID:28228526

Tissue inhibitor of metalloproteinase-3 (TIMP3) promotes endothelial apoptosis via a caspase-independent mechanism.

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Qi, Jian Hua; Anand-Apte, Bela

2015-04-01

Tissue inhibitor of metalloproteinases-3 (TIMP3) is a tumor suppressor and a potent inhibitor of angiogenesis. TIMP3 exerts its anti-angiogenic effect via a direct interaction with vascular endothelial growth factor (VEGF) receptor-2 (KDR) and inhibition of proliferation, migration and tube formation of endothelial cells (ECs). TIMP3 has also been shown to induce apoptosis in some cancer cells and vascular smooth muscle cells via MMP inhibition and caspase-dependent mechanisms. In this study, we examined the molecular mechanisms of TIMP3-mediated apoptosis in endothelial cells. We have previously demonstrated that mice developed smaller tumors with decreased vascularity when injected with breast carcinoma cells overexpressing TIMP3, than with control breast carcinoma cells. TIMP3 overexpression resulted in increased apoptosis in human breast carcinoma (MDA-MB435) in vivo but not in vitro. However, TIMP3 could induce apoptosis in ECs in vitro. The apoptotic activity of TIMP3 in ECs appears to be independent of MMP inhibitory activity. Furthermore, the equivalent expression of functional TIMP3 promoted apoptosis and caspase activation in ECs expressing KDR (PAE/KDR), but not in ECs expressing PDGF beta-receptor (PAE/β-R). Surprisingly, the apoptotic activity of TIMP3 appears to be independent of caspases. TIMP3 inhibited matrix-induced focal adhesion kinase (FAK) tyrosine phosphorylation and association with paxillin and disrupted the incorporation of β3 integrin, FAK and paxillin into focal adhesion contacts on the matrix, which were not affected by caspase inhibitors. Thus, TIMP3 may induce apoptosis in ECs by triggering a caspase-independent cell death pathway and targeting a FAK-dependent survival pathway.

Social conformity despite individual preferences for distinctiveness.

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Smaldino, Paul E; Epstein, Joshua M

2015-03-01

We demonstrate that individual behaviours directed at the attainment of distinctiveness can in fact produce complete social conformity. We thus offer an unexpected generative mechanism for this central social phenomenon. Specifically, we establish that agents who have fixed needs to be distinct and adapt their positions to achieve distinctiveness goals, can nevertheless self-organize to a limiting state of absolute conformity. This seemingly paradoxical result is deduced formally from a small number of natural assumptions and is then explored at length computationally. Interesting departures from this conformity equilibrium are also possible, including divergence in positions. The effect of extremist minorities on these dynamics is discussed. A simple extension is then introduced, which allows the model to generate and maintain social diversity, including multimodal distinctiveness distributions. The paper contributes formal definitions, analytical deductions and counterintuitive findings to the literature on individual distinctiveness and social conformity.

Different Selection Pressures Give Rise to Distinct Ethnic Phenomena

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Moya, Cristina; Boyd, Robert

2015-01-01

Many accounts of ethnic phenomena imply that processes such as stereotyping, essentialism, ethnocentrism, and intergroup hostility stem from a unitary adaptation for reasoning about groups. This is partly justified by the phenomena’s co-occurrence in correlational studies. Here we argue that these behaviors are better modeled as functionally independent adaptations that arose in response to different selection pressures throughout human evolution. As such, different mechanisms may be triggered by different group boundaries within a single society. We illustrate this functionalist framework using ethnographic work from the Quechua-Aymara language boundary in the Peruvian Altiplano. We show that different group boundaries motivate different ethnic phenomena. For example, people have strong stereotypes about socioeconomic categories, which are not cooperative units, whereas they hold fewer stereotypes about communities, which are the primary focus of cooperative activity. We also show that, despite the cross-cultural importance of ethnolinguistic boundaries, the Quechua-Aymara linguistic distinction does not strongly motivate any of these intergroup processes. PMID:25731969

Vaccine and Wild-Type Strains of Yellow Fever Virus Engage Distinct Entry Mechanisms and Differentially Stimulate Antiviral Immune Responses

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Maria Dolores Fernandez-Garcia

2016-02-01

Full Text Available The live attenuated yellow fever virus (YFV vaccine 17D stands as a “gold standard” for a successful vaccine. 17D was developed empirically by passaging the wild-type Asibi strain in mouse and chicken embryo tissues. Despite its immense success, the molecular determinants for virulence attenuation and immunogenicity of the 17D vaccine are poorly understood. 17D evolved several mutations in its genome, most of which lie within the envelope (E protein. Given the major role played by the YFV E protein during virus entry, it has been hypothesized that the residues that diverge between the Asibi and 17D E proteins may be key determinants of attenuation. In this study, we define the process of YFV entry into target cells and investigate its implication in the activation of the antiviral cytokine response. We found that Asibi infects host cells exclusively via the classical clathrin-mediated endocytosis, while 17D exploits a clathrin-independent pathway for infectious entry. We demonstrate that the mutations in the 17D E protein acquired during the attenuation process are sufficient to explain the differential entry of Asibi versus 17D. Interestingly, we show that 17D binds to and infects host cells more efficiently than Asibi, which culminates in increased delivery of viral RNA into the cytosol and robust activation of the cytokine-mediated antiviral response. Overall, our study reveals that 17D vaccine and Asibi enter target cells through distinct mechanisms and highlights a link between 17D attenuation, virus entry, and immune activation.

Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.

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Beck, Michael W; Derrick, Jeffrey S; Kerr, Richard A; Oh, Shin Bi; Cho, Woo Jong; Lee, Shin Jung C; Ji, Yonghwan; Han, Jiyeon; Tehrani, Zahra Aliakbar; Suh, Nayoung; Kim, Sujeong; Larsen, Scott D; Kim, Kwang S; Lee, Joo-Yong; Ruotolo, Brandon T; Lim, Mi Hee

2016-10-13

The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.

TCRs Used in Cancer Gene Therapy Cross-React with MART-1/Melan-A Tumor Antigens via Distinct Mechanisms

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Borbulevych, Oleg Y.; Santhanagopolan, Sujatha M.; Hossain, Moushumi; Baker, Brian M. (Notre)

2013-09-18

T cells engineered to express TCRs specific for tumor Ags can drive cancer regression. The first TCRs used in cancer gene therapy, DMF4 and DMF5, recognize two structurally distinct peptide epitopes of the melanoma-associated MART-1/Melan-A protein, both presented by the class I MHC protein HLA-A*0201. To help understand the mechanisms of TCR cross-reactivity and provide a foundation for the further development of immunotherapy, we determined the crystallographic structures of DMF4 and DMF5 in complex with both of the MART-1/Melan-A epitopes. The two TCRs use different mechanisms to accommodate the two ligands. Although DMF4 binds the two with a different orientation, altering its position over the peptide/MHC, DMF5 binds them both identically. The simpler mode of cross-reactivity by DMF5 is associated with higher affinity toward both ligands, consistent with the superior functional avidity of DMF5. More generally, the observation of two diverging mechanisms of cross-reactivity with the same Ags and the finding that TCR-binding orientation can be determined by peptide alone extend our understanding of the mechanisms underlying TCR cross-reactivity.

Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways

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Lewis D. Evans

2018-03-01

Full Text Available Summary: In Alzheimer’s disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of microtubule-binding protein tau MAPT. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia or reflects a constitutive biological process. We report two entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons. These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon. : In contrast with predictions that transfer of the microtubule-associated protein tau between neurons is a toxic gain-of-function process in dementia, Evans et al. show that healthy human neurons efficiently take up both normal and aggregated tau, by distinct but overlapping uptake mechanisms. Keywords: Alzheimer’s disease, frontotemporal dementia, Tau, MAPT, iPSC, endocytosis, human neurons, intracellular transport

Degree of handedness and priming: Further evidence for a distinction between production and identification priming mechanisms.

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Donna J. LaVoie

2015-02-01

Full Text Available The distinction between implicit and explicit forms of memory retrieval is long-standing, and important to the extent it reveals how different neural architecture supports different aspects of memory function. Similarly, distinctions have been made between kinds of repetition priming, a form of implicit memory retrieval. This study focuses on the production-identification priming distinction, which delineates priming tasks involving verification of stimulus features as compared to priming tasks that require use of a cue to guide response retrieval. Studies investigating this dissociation in dementia or similar patient populations indicate that these forms of priming may differ in their neural bases. The current study looks at degree of handedness as a way of investigating inferred neural architecture supporting these two forms of priming. A growing body of research indicates that degree of handedness (consistent, or CH, versus inconsistent, or ICH is associated with greater interhemispheric interaction and functional access to right hemisphere processing in ICH, with superior performance seen in ICH on memory tasks reliant on this processing. Arguments about the theoretical mechanisms underlying identification and production forms of perceptual priming tasks suggest that performance on these tasks will differ as a function of degree of handedness. We tested this question in a group of CH and ICH young adults, who were asked to study lists of words prior to performing a production priming task (word stem completion, a perceptual word identification task, and a word stem cued recall task. While both handedness groups exhibited reliable priming across tasks, word stem completion priming was greater in ICH than CH participants, with identification priming not differing between groups. This dissociation supports the argument that production and identification forms of priming have different underlying neural bases.

Establishment of neurovascular congruency in the mouse whisker system by an independent patterning mechanism.

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Oh, Won-Jong; Gu, Chenghua

2013-10-16

Nerves and vessels often run parallel to one another, a phenomenon that reflects their functional interdependency. Previous studies have suggested that neurovascular congruency in planar tissues such as skin is established through a "one-patterns-the-other" model, in which either the nervous system or the vascular system precedes developmentally and then instructs the other system to form using its established architecture as a template. Here, we find that, in tissues with complex three-dimensional structures such as the mouse whisker system, neurovascular congruency does not follow the previous model but rather is established via a mechanism in which nerves and vessels are patterned independently. Given the diversity of neurovascular structures in different tissues, guidance signals emanating from a central organizer in the specific target tissue may act as an important mechanism to establish neurovascular congruency patterns that facilitate unique target tissue function. Copyright © 2013 Elsevier Inc. All rights reserved.

Hippocampus duality: Memory and novelty detection are subserved by distinct mechanisms.

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Barbeau, Emmanuel J; Chauvel, Patrick; Moulin, Christopher J A; Regis, Jean; Liégeois-Chauvel, Catherine

2017-04-01

The hippocampus plays a pivotal role both in novelty detection and in long-term memory. The physiological mechanisms underlying these behaviors have yet to be understood in humans. We recorded intracerebral evoked potentials within the hippocampus of epileptic patients (n = 10) during both memory and novelty detection tasks (targets in oddball tasks). We found that memory and detection tasks elicited late local field potentials in the hippocampus during the same period, but of opposite polarity (negative during novelty detection tasks, positive during memory tasks, ∼260-600 ms poststimulus onset, P < 0.05). Critically, these potentials had maximal amplitude on the same contact in the hippocampus for each patient. This pattern did not depend on the task as different types of memory and novelty detection tasks were used. It did not depend on the novelty of the stimulus or the difficulty of the task either. Two different hypotheses are discussed to account for this result: it is either due to the activation of CA1 pyramidal neurons by two different pathways such as the monosynaptic and trisynaptic entorhinal-hippocampus pathways, or to the activation of different neuronal populations, that is, differing either functionally (e.g., novelty/familiarity neurons) or located in different regions of the hippocampus (e.g., CA1/subiculum). In either case, these activities may integrate the activity of two distinct large-scale networks implementing externally or internally oriented, mutually exclusive, brain states. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Common and distinct neural mechanisms of attentional switching and response conflict.

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Kim, Chobok; Johnson, Nathan F; Gold, Brian T

2012-08-21

The human capacities for overcoming prepotent actions and flexibly switching between tasks represent cornerstones of cognitive control. Functional neuroimaging has implicated a diverse set of brain regions contributing to each of these cognitive control processes. However, the extent to which attentional switching and response conflict draw on shared or distinct neural mechanisms remains unclear. The current study examined the neural correlates of response conflict and attentional switching using event-related functional magnetic resonance imaging (fMRI) and a fully randomized 2×2 design. We manipulated an arrow-word version of the Stroop task to measure conflict and switching in the context of a single task decision, in response to a common set of stimuli. Under these common conditions, both behavioral and imaging data showed significant main effects of conflict and switching but no interaction. However, conjunction analyses identified frontal regions involved in both switching and response conflict, including the dorsal anterior cingulate cortex (dACC) and left inferior frontal junction. In addition, connectivity analyses demonstrated task-dependent functional connectivity patterns between dACC and inferior temporal cortex for attentional switching and between dACC and posterior parietal cortex for response conflict. These results suggest that the brain makes use of shared frontal regions, but can dynamically modulate the connectivity patterns of some of those regions, to deal with attentional switching and response conflict. Copyright © 2012 Elsevier B.V. All rights reserved.

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

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Zanos, Panos; Moaddel, Ruin; Morris, Patrick J.; Georgiou, Polymnia; Fischell, Jonathan; Elmer, Greg I.; Alkondon, Manickavasagom; Yuan, Peixiong; Pribut, Heather J.; Singh, Nagendra S.; Dossou, Katina S.S.; Fang, Yuhong; Huang, Xi-Ping; Mayo, Cheryl L.; Wainer, Irving W.; Albuquerque, Edson X.; Thompson, Scott M.; Thomas, Craig J.; Zarate, Carlos A.; Gould, Todd D.

2016-01-01

Major depressive disorder afflicts ~16 percent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients. Here we show that the metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant actions in vivo. Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side-effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition. These findings have relevance for the development of next generation, rapid-acting antidepressants. PMID:27144355

Suppressive versus augmenting effect of the same pretreatment regimen in two murine tumor systems with distinct effector mechanisms

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Fujiwara, Hiromi; Hamaoka, Toshiyuki; Kitagawa, Masayasu

1978-01-01

The effect of presensitization with x-irradiated tumor cells on the development of host's immune resistance against the tumor-associated transplantation antigens (TATA) was investigated in two syngeneic tumor systems with distinct effector mechanisms. When X5563 plasmacytoma, to which immune resistance was mediated exclusively by killer T lymphocytes, was intravenously inoculated into syngeneic C3H/He mice with lower number after 7000 R x-irradiation, the mice failed to exhibit any protective immunity against the subsequent challenge with viable tumor cells. Moreover, these mice lost their capability to develop any immune resistance even after an appropriate immunization procedure. The immunodepression induced by such a pretreatment regimen was specific for X5563 tumor. While no suppressor cell activity was detected in the above pretreated mice, serum factor(s) from these mice was virtually responsible for this suppression. When the serum factor mediating this tumor-specific suppression was fractionated on the Sephadex G-200 column, the suppressive activity was found in albumin-corresponding fraction, free of any immunoglobulin component. In contrast, in MM102 mammary tumor system, in which immune resistance is solely mediated by tumor-specific antibody, the pretreatment with x-irradiated MM102 cells augmented the induction of anti-tumor immunity. These results indicate that while tumor antigens given in the form of x-irradiated tumor cells suppress the induction of killer T cell-mediated immunity in one system, the same presensitization regimen of tumor antigens augments the antibody-mediated immunity in another system, thus giving a divergent effect on the distinct effector mechanisms of syngeneic tumor immunity. (author)

Two Silene vulgaris copper transporters residing in different cellular compartments confer copper hypertolerance by distinct mechanisms when expressed in Arabidopsis thaliana.

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Li, Yanbang; Iqbal, Mazhar; Zhang, Qianqian; Spelt, Cornelis; Bliek, Mattijs; Hakvoort, Henk W J; Quattrocchio, Francesca M; Koes, Ronald; Schat, Henk

2017-08-01

Silene vulgaris is a metallophyte of calamine, cupriferous and serpentine soils all over Europe. Its metallicolous populations are hypertolerant to zinc (Zn), cadmium (Cd), copper (Cu) or nickel (Ni), compared with conspecific nonmetallicolous populations. These hypertolerances are metal-specific, but the underlying mechanisms are poorly understood. We investigated the role of HMA5 copper transporters in Cu-hypertolerance of a S. vulgaris copper mine population. Cu-hypertolerance in Silene is correlated and genetically linked with enhanced expression of two HMA5 paralogs, SvHMA5I and SvHMA5II, each of which increases Cu tolerance when expressed in Arabidopsis thaliana. Most Spermatophytes, except Brassicaceae, possess homologs of SvHMA5I and SvHMA5II, which originate from an ancient duplication predating the appearance of spermatophytes. SvHMA5II and the A. thaliana homolog AtHMA5 localize in the endoplasmic reticulum and upon Cu exposure move to the plasma membrane, from where they are internalized and degraded in the vacuole. This resembles trafficking of mammalian homologs and is apparently an extremely ancient mechanism. SvHMA5I, instead, neofunctionalized and always resides on the tonoplast, likely sequestering Cu in the vacuole. Adaption of Silene to a Cu-polluted soil is at least in part due to upregulation of two distinct HMA5 transporters, which contribute to Cu hypertolerance by distinct mechanisms. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Isolation of TRPV1 independent mechanisms of spontaneous and asynchronous glutamate release at primary afferent to NTS synapses.

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Axel J. Fenwick

2014-01-01

Full Text Available Cranial visceral afferents contained within the solitary tract (ST contact second-order neurons in the nucleus of the solitary tract (NTS and release the excitatory amino acid glutamate via three distinct exocytosis pathways; synchronous, asynchronous, and spontaneous release. The presence of TRPV1 in the central terminals of a majority of ST afferents conveys activity-dependent asynchronous glutamate release and provides a temperature sensitive calcium conductance which largely determines the rate of spontaneous vesicle fusion. TRPV1 is present in unmyelinated C-fiber afferents and these facilitated forms of glutamate release may underlie the relative strength of C-fibers in activating autonomic reflex pathways. However, pharmacological blockade of TRPV1 signaling eliminates only ~50% of the asynchronous profile and attenuates the temperature sensitivity of spontaneous release indicating additional thermosensitive calcium influx pathways may exist which mediate these forms of vesicle release. In the present study we isolate the contribution of TRPV1 independent forms of glutamate release at ST-NTS synapses. We found ST afferent innervation at NTS neurons and synchronous vesicle release from TRPV1 KO mice was not different to control animals; however, only half of TRPV1 KO ST afferents completely lacked asynchronous glutamate release. Further, temperature driven spontaneous rates of vesicle release were not different from 33˚ - 37˚C between control and TRPV1 KO afferents. These findings suggest additional temperature dependent mechanisms controlling asynchronous and thermosensitive spontaneous release at physiological temperatures, possibly mediated by additional thermosensitive TRP channels in primary afferent terminals.

Laboratory and 3-D-distinct element analysis of failure mechanism of slope under external surcharge

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Li, N.; Cheng, Y. M.

2014-09-01

Landslide is a major disaster resulting in considerable loss of human lives and property damages in hilly terrain in Hong Kong, China and many other countries. The factor of safety and the critical slip surface for slope stabilization are the main considerations for slope stability analysis in the past, while the detailed post-failure conditions of the slopes have not been considered in sufficient details. There are however increasing interest on the consequences after the initiation of failure which includes the development and propagation of the failure surfaces, the amount of failed mass and runoff and the affected region. To assess the development of slope failure in more details and to consider the potential danger of slopes after failure has initiated, the slope stability problem under external surcharge is analyzed by the distinct element method (DEM) and laboratory model test in the present research. A more refined study about the development of failure, microcosmic failure mechanism and the post-failure mechanism of slope will be carried out. The numerical modeling method and the various findings from the present work can provide an alternate method of analysis of slope failure which can give additional information not available from the classical methods of analysis.

Mechanistic insights into Mg2+-independent prenylation by CloQ from classical molecular mechanics and hybrid quantum mechanics/molecular mechanics molecular dynamics simulations.

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Bayse, Craig A; Merz, Kenneth M

2014-08-05

Understanding the mechanism of prenyltransferases is important to the design of engineered proteins capable of synthesizing derivatives of naturally occurring therapeutic agents. CloQ is a Mg(2+)-independent aromatic prenyltransferase (APTase) that transfers a dimethylallyl group to 4-hydroxyphenylpyruvate in the biosynthetic pathway for clorobiocin. APTases consist of a common ABBA fold that defines a β-barrel containing the reaction cavity. Positively charged basic residues line the inside of the β-barrel of CloQ to activate the pyrophosphate leaving group to replace the function of the Mg(2+) cofactor in other APTases. Classical molecular dynamics simulations of CloQ, its E281G and F68S mutants, and the related NovQ were used to explore the binding of the 4-hydroxyphenylpyruvate (4HPP) and dimethylallyl diphosphate substrates in the reactive cavity and the role of various conserved residues. Hybrid quantum mechanics/molecular mechanics potential of mean force (PMF) calculations show that the effect of the replacement of the Mg(2+) cofactor with basic residues yields a similar activation barrier for prenylation to Mg(2+)-dependent APTases like NphB. The topology of the binding pocket for 4HPP is important for selective prenylation at the ortho position of the ring. Methylation at this position alters the conformation of the substrate for O-prenylation at the phenol group. Further, a two-dimensional PMF scan shows that a "reverse" prenylation product may be a possible target for protein engineering.

Slicer-independent mechanism drives small-RNA strand separation during human RISC assembly.

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Park, June Hyun; Shin, Chanseok

2015-10-30

Small RNA silencing is mediated by the effector RNA-induced silencing complex (RISC) that consists of an Argonaute protein (AGOs 1-4 in humans). A fundamental step during RISC assembly involves the separation of two strands of a small RNA duplex, whereby only the guide strand is retained to form the mature RISC, a process not well understood. Despite the widely accepted view that 'slicer-dependent unwinding' via passenger-strand cleavage is a prerequisite for the assembly of a highly complementary siRNA into the AGO2-RISC, here we show by careful re-examination that 'slicer-independent unwinding' plays a more significant role in human RISC maturation than previously appreciated, not only for a miRNA duplex, but, unexpectedly, for a highly complementary siRNA as well. We discovered that 'slicer-dependency' for the unwinding was affected primarily by certain parameters such as temperature and Mg(2+). We further validate these observations in non-slicer AGOs (1, 3 and 4) that can be programmed with siRNAs at the physiological temperature of humans, suggesting that slicer-independent mechanism is likely a common feature of human AGOs. Our results now clearly explain why both miRNA and siRNA are found in all four human AGOs, which is in striking contrast to the strict small-RNA sorting system in Drosophila. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

SO2 photoexcitation mechanism links mass-independent sulfur isotopic fractionation in cryospheric sulfate to climate impacting volcanism

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Hattori, Shohei; Schmidt, Johan A.; Johnson, Matthew S.; Danielache, Sebastian O.; Yamada, Akinori; Ueno, Yuichiro; Yoshida, Naohiro

2013-01-01

Natural climate variation, such as that caused by volcanoes, is the basis for identifying anthropogenic climate change. However, knowledge of the history of volcanic activity is inadequate, particularly concerning the explosivity of specific events. Some material is deposited in ice cores, but the concentration of glacial sulfate does not distinguish between tropospheric and stratospheric eruptions. Stable sulfur isotope abundances contain additional information, and recent studies show a correlation between volcanic plumes that reach the stratosphere and mass-independent anomalies in sulfur isotopes in glacial sulfate. We describe a mechanism, photoexcitation of SO2, that links the two, yielding a useful metric of the explosivity of historic volcanic events. A plume model of S(IV) to S(VI) conversion was constructed including photochemistry, entrainment of background air, and sulfate deposition. Isotopologue-specific photoexcitation rates were calculated based on the UV absorption cross-sections of 32SO2, 33SO2, 34SO2, and 36SO2 from 250 to 320 nm. The model shows that UV photoexcitation is enhanced with altitude, whereas mass-dependent oxidation, such as SO2 + OH, is suppressed by in situ plume chemistry, allowing the production and preservation of a mass-independent sulfur isotope anomaly in the sulfate product. The model accounts for the amplitude, phases, and time development of Δ33S/δ34S and Δ36S/Δ33S found in glacial samples. We are able to identify the process controlling mass-independent sulfur isotope anomalies in the modern atmosphere. This mechanism is the basis of identifying the magnitude of historic volcanic events. PMID:23417298

Mechanisms of buffer therapy resistance.

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Bailey, Kate M; Wojtkowiak, Jonathan W; Cornnell, Heather H; Ribeiro, Maria C; Balagurunathan, Yoganand; Hashim, Arig Ibrahim; Gillies, Robert J

2014-04-01

Many studies have shown that the acidity of solid tumors contributes to local invasion and metastasis. Oral pH buffers can specifically neutralize the acidic pH of tumors and reduce the incidence of local invasion and metastatic formation in multiple murine models. However, this effect is not universal as we have previously observed that metastasis is not inhibited by buffers in some tumor models, regardless of buffer used. B16-F10 (murine melanoma), LL/2 (murine lung) and HCT116 (human colon) tumors are resistant to treatment with lysine buffer therapy, whereas metastasis is potently inhibited by lysine buffers in MDA-MB-231 (human breast) and PC3M (human prostate) tumors. In the current work, we confirmed that sensitive cells utilized a pH-dependent mechanism for successful metastasis supported by a highly glycolytic phenotype that acidifies the local tumor microenvironment resulting in morphological changes. In contrast, buffer-resistant cell lines exhibited a pH-independent metastatic mechanism involving constitutive secretion of matrix degrading proteases without elevated glycolysis. These results have identified two distinct mechanisms of experimental metastasis, one of which is pH-dependent (buffer therapy sensitive cells) and one which is pH-independent (buffer therapy resistant cells). Further characterization of these models has potential for therapeutic benefit. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms

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Weixiang Guo

2015-06-01

Full Text Available Fragile X mental retardation protein (FMRP and its autosomal paralog FXR2P are selective neuronal RNA-binding proteins, and mice that lack either protein exhibit cognitive deficits. Although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. In the present study, we discovered that FXR2P (also known as FXR2 is important for neuronal dendritic development. FMRP and FXR2P additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GluA1, but they do so via distinct mechanisms: FXR2P binds and stabilizes GluA1 mRNA and enhances subsequent protein expression, whereas FMRP promotes GluA1 membrane delivery. Our findings unveil important roles for FXR2P and GluA1 in neuronal development, uncover a regulatory mechanism of GluA1, and reveal a functional convergence between fragile X proteins in neuronal development.

Ire1 Has Distinct Catalytic Mechanisms for XBP1/HAC1 Splicing and RIDD

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Arvin B. Tam

2014-11-01

Full Text Available An evolutionarily conserved unfolded protein response (UPR component, IRE1, cleaves XBP1/HAC1 introns in order to generate spliced mRNAs that are translated into potent transcription factors. IRE1 also cleaves endoplasmic-reticulum-associated RNAs leading to their decay, an activity termed regulated IRE1-dependent decay (RIDD; however, the mechanism by which IRE1 differentiates intron cleavage from RIDD is not well understood. Using in vitro experiments, we found that IRE1 has two different modes of action: XBP1/HAC1 is cleaved by IRE1 subunits acting cooperatively within IRE1 oligomers, whereas a single subunit of IRE1 performs RIDD without cooperativity. Furthermore, these distinct activities can be separated by complementation of catalytically inactive IRE1 RNase and mutations at oligomerization interfaces. Using an IRE1 RNase inhibitor, STF-083010, selective inhibition of XBP1 splicing indicates that XBP1 promotes cell survival, whereas RIDD leads to cell death, revealing modulation of IRE1 activities as a drug-development strategy.

Deciding where to attend: Large-scale network mechanisms underlying attention and intention revealed by graph-theoretic analysis.

Science.gov (United States)

Liu, Yuelu; Hong, Xiangfei; Bengson, Jesse J; Kelley, Todd A; Ding, Mingzhou; Mangun, George R

2017-08-15

The neural mechanisms by which intentions are transformed into actions remain poorly understood. We investigated the network mechanisms underlying spontaneous voluntary decisions about where to focus visual-spatial attention (willed attention). Graph-theoretic analysis of two independent datasets revealed that regions activated during willed attention form a set of functionally-distinct networks corresponding to the frontoparietal network, the cingulo-opercular network, and the dorsal attention network. Contrasting willed attention with instructed attention (where attention is directed by external cues), we observed that the dorsal anterior cingulate cortex was allied with the dorsal attention network in instructed attention, but shifted connectivity during willed attention to interact with the cingulo-opercular network, which then mediated communications between the frontoparietal network and the dorsal attention network. Behaviorally, greater connectivity in network hubs, including the dorsolateral prefrontal cortex, the dorsal anterior cingulate cortex, and the inferior parietal lobule, was associated with faster reaction times. These results, shown to be consistent across the two independent datasets, uncover the dynamic organization of functionally-distinct networks engaged to support intentional acts. Copyright © 2017 Elsevier Inc. All rights reserved.

Antibody-independent mechanisms regulate the establishment of chronic Plasmodium infection

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Lin, Jingwen; Cunningham, Deirdre; Tumwine, Irene; Kushinga, Garikai; McLaughlin, Sarah; Spence, Philip; Böhme, Ulrike; Sanders, Mandy; Conteh, Solomon; Bushell, Ellen; Metcalf, Tom; Billker, Oliver; Duffy, Patrick E.; Newbold, Chris; Berriman, Matthew; Langhorne, Jean

2017-01-01

Malaria is caused by parasites of the genus Plasmodium. All human-infecting Plasmodium species can establish long-lasting chronic infections1–5, creating an infectious reservoir to sustain transmission1,6. It is widely accepted that maintenance of chronic infection involves evasion of adaptive immunity by antigenic variation7. However, genes involved in this process have been identified in only two of five human-infecting species: P. falciparum and P. knowlesi. Furthermore, little is understood about the early events in establishment of chronic infection in these species. Using a rodent model we demonstrate that only a minority of parasites from among the infecting population, expressing one of several clusters of virulence-associated pir genes, establishes a chronic infection. This process occurs in different species of parasite and in different hosts. Establishment of chronicity is independent of adaptive immunity and therefore different from the mechanism proposed for maintainance of chronic P. falciparum infections7–9. Furthermore, we show that the proportions of parasites expressing different types of pir genes regulate the time taken to establish a chronic infection. Since pir genes are common to most, if not all, species of Plasmodium10, this process may be a common way of regulating the establishment of chronic infections. PMID:28165471

Are anticoagulant independent mechanical valves within reach-fast prototype fabrication and in vitro testing of innovative bi-leaflet valve models.

Science.gov (United States)

Scotten, Lawrence N; Siegel, Rolland

2015-08-01

Exploration for causes of prosthetic valve thrombogenicity has frequently focused on forward or post-closure flow detail. In prior laboratory studies, we uncovered high amplitude flow velocities of short duration close to valve closure implying potential for substantial shear stress with subsequent initiation of blood coagulation pathways. This may be relevant to widely accepted clinical disparity between mechanical and tissue valves vis-à-vis thrombogenicity. With a series of prototype bi-leaflet mechanical valves, we attempt reduction of closure related velocities with the objective of identifying a prototype valve with thrombogenic potential similar to our tissue valve control. This iterative design approach may find application in preclinical assessment of valves for anticoagulation independence. Tested valves included: prototype mechanical bi-leaflet BVs (n=56), controls (n=2) and patented early prototype mechanicals (n=2) from other investigators. Pulsatile and quasi-steady flow systems were used for testing. Projected dynamic valve area (PDVA) was measured using previously described novel technology. Flow velocity over the open and closing periods was determined by volumetric flow rate/PDVA. For the closed valve interval, use was made of data obtained from quasi-steady back pressure/flow tests. Performance was ranked by a proposed thrombogenicity potential index (TPI) relative to tissue and mechanical control valves. Optimization of the prototype valve designs lead to a 3-D printed model (BV3D). For the mitral/aortic site, BV3D has lower TPI (1.10/1.47) relative to the control mechanical valve (3.44/3.93) and similar to the control tissue valve (ideal TPI ≤1.0). Using unique technology, rapid prototyping and thrombogenicity ranking, optimization of experimental valves for reduced thrombogenic potential was expedited and simplified. Innovative mechanical valve configurations were identified that merit consideration for further development which may bring

Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia induce distinct host responses.

Science.gov (United States)

McConnell, Kevin W; McDunn, Jonathan E; Clark, Andrew T; Dunne, W Michael; Dixon, David J; Turnbull, Isaiah R; Dipasco, Peter J; Osberghaus, William F; Sherman, Benjamin; Martin, James R; Walter, Michael J; Cobb, J Perren; Buchman, Timothy G; Hotchkiss, Richard S; Coopersmith, Craig M

2010-01-01

Pathogens that cause pneumonia may be treated in a targeted fashion by antibiotics, but if this therapy fails, then treatment involves only nonspecific supportive measures, independent of the inciting infection. The purpose of this study was to determine whether host response is similar after disparate infections with similar mortalities. Prospective, randomized controlled study. Animal laboratory in a university medical center. Pneumonia was induced in FVB/N mice by either Streptococcus pneumoniae or two different concentrations of Pseudomonas aeruginosa. Plasma and bronchoalveolar lavage fluid from septic animals was assayed by a microarray immunoassay measuring 18 inflammatory mediators at multiple time points. The host response was dependent on the causative organism as well as kinetics of mortality, but the pro-inflammatory and anti-inflammatory responses were independent of inoculum concentration or degree of bacteremia. Pneumonia caused by different concentrations of the same bacteria, Pseudomonas aeruginosa, also yielded distinct inflammatory responses; however, inflammatory mediator expression did not directly track the severity of infection. For all infections, the host response was compartmentalized, with markedly different concentrations of inflammatory mediators in the systemic circulation and the lungs. Hierarchical clustering analysis resulted in the identification of five distinct clusters of the host response to bacterial infection. Principal components analysis correlated pulmonary macrophage inflammatory peptide-2 and interleukin-10 with progression of infection, whereas elevated plasma tumor necrosis factor sr2 and macrophage chemotactic peptide-1 were indicative of fulminant disease with >90% mortality within 48 hrs. Septic mice have distinct local and systemic responses to Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia. Targeting specific host inflammatory responses induced by distinct bacterial infections could represent a

Motor learning in childhood reveals distinct mechanisms for memory retention and re-learning.

Science.gov (United States)

Musselman, Kristin E; Roemmich, Ryan T; Garrett, Ben; Bastian, Amy J

2016-05-01

Adults can easily learn and access multiple versions of the same motor skill adapted for different conditions (e.g., walking in water, sand, snow). Following even a single session of adaptation, adults exhibit clear day-to-day retention and faster re-learning of the adapted pattern. Here, we studied the retention and re-learning of an adapted walking pattern in children aged 6-17 yr. We found that all children, regardless of age, showed adult-like patterns of retention of the adapted walking pattern. In contrast, children under 12 yr of age did not re-learn faster on the next day after washout had occurred-they behaved as if they had never adapted their walking before. Re-learning could be improved in younger children when the adaptation time on day 1 was increased to allow more practice at the plateau of the adapted pattern, but never to adult-like levels. These results show that the ability to store a separate, adapted version of the same general motor pattern does not fully develop until adolescence, and furthermore, that the mechanisms underlying the retention and rapid re-learning of adapted motor patterns are distinct. © 2016 Musselman et al.; Published by Cold Spring Harbor Laboratory Press.

Mycobacterium tuberculosis Rho is an NTPase with distinct kinetic properties and a novel RNA-binding subdomain.

Directory of Open Access Journals (Sweden)

Anirban Mitra

Full Text Available Two mechanisms--factor independent and dependent termination--ensure the completion of RNA synthesis in eubacteria. Factor-dependent mechanism relies on the Rho protein to terminate transcription by interacting with RNA polymerase. Although well studied in Escherichia coli, the properties of the Rho homologs from most bacteria are not known. The rho gene is unusually large in genus Mycobacterium and other members of actinobacteria, having ∼150 additional residues towards the amino terminal end. We describe the distinct properties of Rho from Mycobacterium tuberculosis. It is an NTPase with a preference for purine nucleoside triphosphates with kinetic properties different from E. coli homolog and an ability to use various RNA substrates. The N-terminal subdomain of MtbRho can bind to RNA by itself, and appears to contribute to the interaction of the termination factor with RNAs. Furthermore, the interaction with RNA induces changes in conformation and oligomerization of MtbRho.

What History Tells Us about the Distinct Nature of Chemistry.

Science.gov (United States)

Chang, Hasok

2017-11-01

Attention to the history of chemistry can help us recognise the characteristics of chemistry that have helped to maintain it as a separate scientific discipline with a unique identity. Three such features are highlighted in this paper. First, chemistry has maintained a distinct type of theoretical thinking, independent from that of physics even in the era of quantum chemistry. Second, chemical research has always been shaped by its ineliminable practical relevance and usefulness. Third, the lived experience of chemistry, spanning the laboratory, the classroom and everyday life, is distinctive in its multidimensional sensuousness. Furthermore, I argue that the combination of these three features makes chemistry an exemplary science.

Feline immunodeficiency virus envelope glycoproteins antagonize tetherin through a distinctive mechanism that requires virion incorporation.

Science.gov (United States)

Morrison, James H; Guevara, Rebekah B; Marcano, Adriana C; Saenz, Dyana T; Fadel, Hind J; Rogstad, Daniel K; Poeschla, Eric M

2014-03-01

also its Env protein, but the mechanism is distinctive. Unlike other tetherin antagonists, FIV Env cannot act in trans to rescue vpu-deficient HIV-1. It must be incorporated specifically into FIV virions to be active. Also unlike other retroviral antagonists, but similar to Ebola virus Env, it does not act by downregulating or degrading tetherin. FIV Env might exclude tetherin locally or direct assembly to tetherin-negative membrane domains. Other distinctive features are apparent, including evidence that this virus evolved an equilibrium in which tetherin is both restriction factor and cofactor, as FIV requires tetherin for optimal particle release.

Quantum-mechanical few-body scattering equations with half-on-shell energy-independent subsystem input

International Nuclear Information System (INIS)

Zeiger, E.M.

1978-01-01

New equations are presented for three- and four-body scattering, within the context of nonrelativistic quantum mechanics and a Hamiltonian scattering theory. For the three-body case Faddeev-type equations are presented which, although obtained from the rigorous Faddeev theory, only require two-body bound state wave functions and half-off-shell transition amplitudes as input. In addition, their effective potentials are independent of the three-body energy, and can easily be made real after an angular momentum decomposition. The equations are formulated in terms of physical transition amplitudes for three-body processes, except that in the breakup case the partial-wave amplitudes differ from the corresponding full amplitudes by a Watson final-state-interaction factor. Also presented are new equations for four-body scattering, obtained by generalizing our three-body formalism to the four-body case. These equations, although equivalent to those of Faddeev--Yakubovskii, are expressed in terms of singularity-free transition amplitudes, and their energy-independent effective potentials require only half-on-shell subsystem transition amplitudes (and bound state wave functions) as input. However, due to the detailed index structure of the Faddeev--Yakubovskii formalsim, the result of the generalization is considerably more complicated than in the three-body case

Drawing the critical distinction between independent contractors and permanent employees : the tax implications

International Nuclear Information System (INIS)

Bodie, J.S.; Haymour, J.

1999-01-01

The many factors that should be considered when distinguishing between an independent contractor and an employee from the perspective of tax laws were discussed. Some of the major areas where disputes regarding relationships between the employee and the independent contractor arise were reviewed with particular emphasis on some of the dangers associated with a change in characterization of these types of relationships. Ways in which to guard against these dangers were also presented. The courts have established the following four tests to determine a contractor's status: (1) the control test, (2) the economic reality test, (3) the business integration test, and (4) the ownership of tools test. The control tests looks to the degree of control that an employer/recipient of services possesses over the work that is to be performed. The economic reality test looks to whether the contractor is actually in business for himself and is risking a loss. The business integration test examines the relationship between employer and contractor in terms of how economically dependent the contractor is on the employer and whether the task the contractor carries on forms an integral part of the business of the employer. The last test examines who owns the tools used by the contractor to carry out his duties. This presentation also reviewed how employers and contractors are responsible for adhering to Revenue Canada tax laws and certain liabilities regarding income taxes, Employment Insurance (EI) premiums, Canada Pension Plan (CPP) contributions and other amounts

Drawing the critical distinction between independent contractors and permanent employees : the tax implications

Energy Technology Data Exchange (ETDEWEB)

Bodie, J.S.; Haymour, J. [Fraser Milner, Calgary, AB (Canada)

1999-10-01

The many factors that should be considered when distinguishing between an independent contractor and an employee from the perspective of tax laws were discussed. Some of the major areas where disputes regarding relationships between the employee and the independent contractor arise were reviewed with particular emphasis on some of the dangers associated with a change in characterization of these types of relationships. Ways in which to guard against these dangers were also presented. The courts have established the following four tests to determine a contractor`s status: (1) the control test, (2) the economic reality test, (3) the business integration test, and (4) the ownership of tools test. The control tests looks to the degree of control that an employer/recipient of services possesses over the work that is to be performed. The economic reality test looks to whether the contractor is actually in business for himself and is risking a loss. The business integration test examines the relationship between employer and contractor in terms of how economically dependent the contractor is on the employer and whether the task the contractor carries on forms an integral part of the business of the employer. The last test examines who owns the tools used by the contractor to carry out his duties. This presentation also reviewed how employers and contractors are responsible for adhering to Revenue Canada tax laws and certain liabilities regarding income taxes, Employment Insurance (EI) premiums, Canada Pension Plan (CPP) contributions and other amounts.

Drawing the critical distinction between independent contractors and permanent employees : the tax implications

Energy Technology Data Exchange (ETDEWEB)

Bodie, J.S.; Haymour, J. [Fraser Milner, Calgary, AB (Canada)

1999-07-01

The many factors that should be considered when distinguishing between an independent contractor and an employee from the perspective of tax laws were discussed. Some of the major areas where disputes regarding relationships between the employee and the independent contractor arise were reviewed with particular emphasis on some of the dangers associated with a change in characterization of these types of relationships. Ways in which to guard against these dangers were also presented. The courts have established the following four tests to determine a contractor's status: (1) the control test, (2) the economic reality test, (3) the business integration test, and (4) the ownership of tools test. The control tests looks to the degree of control that an employer/recipient of services possesses over the work that is to be performed. The economic reality test looks to whether the contractor is actually in business for himself and is risking a loss. The business integration test examines the relationship between employer and contractor in terms of how economically dependent the contractor is on the employer and whether the task the contractor carries on forms an integral part of the business of the employer. The last test examines who owns the tools used by the contractor to carry out his duties. This presentation also reviewed how employers and contractors are responsible for adhering to Revenue Canada tax laws and certain liabilities regarding income taxes, Employment Insurance (EI) premiums, Canada Pension Plan (CPP) contributions and other amounts.

Amnesia, rehearsal, and temporal distinctiveness models of recall.

Science.gov (United States)

Brown, Gordon D A; Della Sala, Sergio; Foster, Jonathan K; Vousden, Janet I

2007-04-01

Classical amnesia involves selective memory impairment for temporally distant items in free recall (impaired primacy) together with relative preservation of memory for recency items. This abnormal serial position curve is traditionally taken as evidence for a distinction between different memory processes, with amnesia being associated with selectively impaired long-term memory. However recent accounts of normal serial position curves have emphasized the importance of rehearsal processes in giving rise to primacy effects and have suggested that a single temporal distinctiveness mechanism can account for both primacy and recency effects when rehearsal is considered. Here we explore the pattern of strategic rehearsal in a patient with very severe amnesia. When the patient's rehearsal pattern is taken into account, a temporal distinctiveness model can account for the serial position curve in both amnesic and control free recall. The results are taken as consistent with temporal distinctiveness models of free recall, and they motivate an emphasis on rehearsal patterns in understanding amnesic deficits in free recall.

HIV-1 Nef down-modulates C-C and C-X-C chemokine receptors via ubiquitin and ubiquitin-independent mechanism.

Directory of Open Access Journals (Sweden)

Prabha Chandrasekaran

Full Text Available Human and Simian Immunodeficiency virus (HIV-1, HIV-2, and SIV encode an accessory protein, Nef, which is a pathogenesis and virulence factor. Nef is a multivalent adapter that dysregulates the trafficking of many immune cell receptors, including chemokine receptors (CKRs. Physiological endocytic itinerary of agonist occupied CXCR4 involves ubiquitinylation of the phosphorylated receptor at three critical lysine residues and dynamin-dependent trafficking through the ESCRT pathway into lysosomes for degradation. Likewise, Nef induced CXCR4 degradation was critically dependent on the three lysines in the C-terminal -SSLKILSKGK- motif. Nef directly recruits the HECT domain E3 ligases AIP4 or NEDD4 to CXCR4 in the resting state. This mechanism was confirmed by ternary interactions of Nef, CXCR4 and AIP4 or NEDD4; by reversal of Nef effect by expression of catalytically inactive AIP4-C830A mutant; and siRNA knockdown of AIP4, NEDD4 or some ESCRT-0 adapters. However, ubiquitinylation dependent lysosomal degradation was not the only mechanism by which Nef downregulated CKRs. Agonist and Nef mediated CXCR2 (and CXCR1 degradation was ubiquitinylation independent. Nef also profoundly downregulated the naturally truncated CXCR4 associated with WHIM syndrome and engineered variants of CXCR4 that resist CXCL12 induced internalization via an ubiquitinylation independent mechanism.

A Novel Algorithm for the Generation of Distinct Kinematic Chain

Science.gov (United States)

Medapati, Sreenivasa Reddy; Kuchibhotla, Mallikarjuna Rao; Annambhotla, Balaji Srinivasa Rao

2016-07-01

Generation of distinct kinematic chains is an important topic in the design of mechanisms for various industrial applications i.e., robotic manipulator, tractor, crane etc. Many researchers have intently focused on this area and explained various processes of generating distinct kinematic chains which are laborious and complex. It is desirable to enumerate the kinematic chains systematically to know the inherent characteristics of a chain related to its structure so that all the distinct chains can be analyzed in depth, prior to the selection of a chain for a purpose. This paper proposes a novel and simple method with set of rules defined to eliminate isomorphic kinematic chains generating distinct kinematic chains. Also, this method simplifies the process of generating distinct kinematic chains even at higher levels i.e., 10-link, 11-link with single and multiple degree of freedom.

Distinct Circuits for Recovery of Eye Dominance and Acuity in Murine Amblyopia.

Science.gov (United States)

Stephany, Céleste-Élise; Ma, Xiaokuang; Dorton, Hilary M; Wu, Jie; Solomon, Alexander M; Frantz, Michael G; Qiu, Shenfeng; McGee, Aaron W

2018-05-24

Degrading vision by one eye during a developmental critical period yields enduring deficits in both eye dominance and visual acuity. A predominant model is that "reactivating" ocular dominance (OD) plasticity after the critical period is required to improve acuity in amblyopic adults. However, here we demonstrate that plasticity of eye dominance and acuity are independent and restricted by the nogo-66 receptor (ngr1) in distinct neuronal populations. Ngr1 mutant mice display greater excitatory synaptic input onto both inhibitory and excitatory neurons with restoration of normal vision. Deleting ngr1 in excitatory cortical neurons permits recovery of eye dominance but not acuity. Reciprocally, deleting ngr1 in thalamus is insufficient to rectify eye dominance but yields improvement of acuity to normal. Abolishing ngr1 expression in adult mice also promotes recovery of acuity. Together, these findings challenge the notion that mechanisms for OD plasticity contribute to the alterations in circuitry that restore acuity in amblyopia. Copyright © 2018 Elsevier Ltd. All rights reserved.

Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome.

Science.gov (United States)

Morselli, Eugenia; Mariño, Guillermo; Bennetzen, Martin V; Eisenberg, Tobias; Megalou, Evgenia; Schroeder, Sabrina; Cabrera, Sandra; Bénit, Paule; Rustin, Pierre; Criollo, Alfredo; Kepp, Oliver; Galluzzi, Lorenzo; Shen, Shensi; Malik, Shoaib Ahmad; Maiuri, Maria Chiara; Horio, Yoshiyuki; López-Otín, Carlos; Andersen, Jens S; Tavernarakis, Nektarios; Madeo, Frank; Kroemer, Guido

2011-02-21

Autophagy protects organelles, cells, and organisms against several stress conditions. Induction of autophagy by resveratrol requires the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1). In this paper, we show that the acetylase inhibitor spermidine stimulates autophagy independent of SIRT1 in human and yeast cells as well as in nematodes. Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome. Both agents favor convergent deacetylation and acetylation reactions in the cytosol and in the nucleus, respectively. Both resveratrol and spermidine were able to induce autophagy in cytoplasts (enucleated cells). Moreover, a cytoplasm-restricted mutant of SIRT1 could stimulate autophagy, suggesting that cytoplasmic deacetylation reactions dictate the autophagic cascade. At doses at which neither resveratrol nor spermidine stimulated autophagy alone, these agents synergistically induced autophagy. Altogether, these data underscore the importance of an autophagy regulatory network of antagonistic deacetylases and acetylases that can be pharmacologically manipulated.

Distinct cargo-specific response landscapes underpin the complex and nuanced role of galectin-glycan interactions in clathrin-independent endocytosis.

Science.gov (United States)

Mathew, Mohit P; Donaldson, Julie G

2018-05-11

Clathrin-independent endocytosis (CIE) is a form of endocytosis that lacks a defined cytoplasmic machinery. Here, we asked whether glycan interactions, acting from the outside, could be a part of that endocytic machinery. We show that the perturbation of global cellular patterns of protein glycosylation by modulation of metabolic flux affects CIE. Interestingly, these changes in glycosylation had cargo-specific effects. For example, in HeLa cells, GlcNAc treatment, which increases glycan branching, increased major histocompatibility complex class I (MHCI) internalization but inhibited CIE of the glycoprotein CD59 molecule (CD59). The effects of knocking down the expression of galectin 3, a carbohydrate-binding protein and an important player in galectin-glycan interactions, were also cargo-specific and stimulated CD59 uptake. By contrast, inhibition of all galectin-glycan interactions by lactose inhibited CIE of both MHCI and CD59. None of these treatments affected clathrin-mediated endocytosis, implying that glycosylation changes specifically affect CIE. We also found that the galectin lattice tailors membrane fluidity and cell spreading. Furthermore, changes in membrane dynamics mediated by the galectin lattice affected macropinocytosis, an altered form of CIE, in HT1080 cells. Our results suggest that glycans play an important and nuanced role in CIE, with each cargo being affected uniquely by alterations in galectin and glycan profiles and their interactions. We conclude that galectin-driven effects exist on a continuum from stimulatory to inhibitory, with distinct CIE cargo proteins having unique response landscapes and with different cell types starting at different positions on these conceptual landscapes.

Cap-independent translation of plant viral RNAs.

Science.gov (United States)

Kneller, Elizabeth L Pettit; Rakotondrafara, Aurélie M; Miller, W Allen

2006-07-01

The RNAs of many plant viruses lack a 5' cap and must be translated by a cap-independent mechanism. Here, we discuss the remarkably diverse cap-independent translation elements that have been identified in members of the Potyviridae, Luteoviridae, and Tombusviridae families, and genus Tobamovirus. Many other plant viruses have uncapped RNAs but their translation control elements are uncharacterized. Cap-independent translation elements of plant viruses differ strikingly from those of animal viruses: they are smaller (translation factors, and speculate on their mechanism of action and their roles in the virus replication cycle. Much remains to be learned about how these elements enable plant viruses to usurp the host translational machinery.

Binding of the cSH3 domain of Grb2 adaptor to two distinct RXXK motifs within Gab1 docker employs differential mechanisms.

Science.gov (United States)

McDonald, Caleb B; Seldeen, Kenneth L; Deegan, Brian J; Bhat, Vikas; Farooq, Amjad

2011-01-01

A ubiquitous component of cellular signaling machinery, Gab1 docker plays a pivotal role in routing extracellular information in the form of growth factors and cytokines to downstream targets such as transcription factors within the nucleus. Here, using isothermal titration calorimetry (ITC) in combination with macromolecular modeling (MM), we show that although Gab1 contains four distinct RXXK motifs, designated G1, G2, G3, and G4, only G1 and G2 motifs bind to the cSH3 domain of Grb2 adaptor and do so with distinct mechanisms. Thus, while the G1 motif strictly requires the PPRPPKP consensus sequence for high-affinity binding to the cSH3 domain, the G2 motif displays preference for the PXVXRXLKPXR consensus. Such sequential differences in the binding of G1 and G2 motifs arise from their ability to adopt distinct polyproline type II (PPII)- and 3(10) -helical conformations upon binding to the cSH3 domain, respectively. Collectively, our study provides detailed biophysical insights into a key protein-protein interaction involved in a diverse array of signaling cascades central to health and disease. Copyright © 2010 John Wiley & Sons, Ltd.

How multiple causes combine: independence constraints on causal inference.

Science.gov (United States)

Liljeholm, Mimi

2015-01-01

According to the causal power view, two core constraints-that causes occur independently (i.e., no confounding) and influence their effects independently-serve as boundary conditions for causal induction. This study investigated how violations of these constraints modulate uncertainty about the existence and strength of a causal relationship. Participants were presented with pairs of candidate causes that were either confounded or not, and that either interacted or exerted their influences independently. Consistent with the causal power view, uncertainty about the existence and strength of causal relationships was greater when causes were confounded or interacted than when unconfounded and acting independently. An elemental Bayesian causal model captured differences in uncertainty due to confounding but not those due to an interaction. Implications of distinct sources of uncertainty for the selection of contingency information and causal generalization are discussed.

Laboratory and 3-D distinct element analysis of the failure mechanism of a slope under external surcharge

Science.gov (United States)

Li, N.; Cheng, Y. M.

2015-01-01

Landslide is a major disaster resulting in considerable loss of human lives and property damages in hilly terrain in Hong Kong, China and many other countries. The factor of safety and the critical slip surface for slope stabilization are the main considerations for slope stability analysis in the past, while the detailed post-failure conditions of the slopes have not been considered in sufficient detail. There is however increasing interest in the consequences after the initiation of failure that includes the development and propagation of the failure surfaces, the amount of failed mass and runoff and the affected region. To assess the development of slope failure in more detail and to consider the potential danger of slopes after failure has initiated, the slope stability problem under external surcharge is analyzed by the distinct element method (DEM) and a laboratory model test in the present research. A more refined study about the development of failure, microcosmic failure mechanisms and the post-failure mechanisms of slopes will be carried out. The numerical modeling method and the various findings from the present work can provide an alternate method of analysis of slope failure, which can give additional information not available from the classical methods of analysis.

A new experiment-independent mechanism to persistify and serve the detector geometry of ATLAS

Science.gov (United States)

Bianchi, Riccardo Maria; Boudreau, Joseph; Vukotic, Ilija

2017-10-01

The complex geometry of the whole detector of the ATLAS experiment at LHC is currently stored only in custom online databases, from which it is built on-the-fly on request. Accessing the online geometry guarantees accessing the latest version of the detector description, but requires the setup of the full ATLAS software framework “Athena”, which provides the online services and the tools to retrieve the data from the database. This operation is cumbersome and slows down the applications that need to access the geometry. Moreover, all applications that need to access the detector geometry need to be built and run on the same platform as the ATLAS framework, preventing the usage of the actual detector geometry in stand-alone applications. Here we propose a new mechanism to persistify (in software development in general, and in HEP computing in particular, persistifying means taking an object which lives in memory only - for example because it was built on-the-fly while processing the experimental data, - serializing it and storing it on disk as a persistent object) and serve the geometry of HEP experiments. The new mechanism is composed by a new file format and the modules to make use of it. The new file format allows to store the whole detector description locally in a file, and it is especially optimized to describe large complex detectors with the minimum file size, making use of shared instances and storing compressed representations of geometry transformations. Then, the detector description can be read back in, to fully restore the in-memory geometry tree. Moreover, a dedicated REST API is being designed and developed to serve the geometry in standard exchange formats like JSON, to let users and applications download specific partial geometry information. With this new geometry persistification a new generation of applications could be developed, which can use the actual detector geometry while being platform-independent and experiment-independent.

The use of the J* integral for non-linear fracture mechanics

International Nuclear Information System (INIS)

Hellen, T.K.

1976-09-01

The Griffith energy balance criterion, first postulated over 50 years ago, is still the basis of linear elastic fracture mechanics. From this, accurate numerical methods for establishing stress intensity factors and energy release rates have been developed. One such method involves path independent contour integrals about the crack tip. An improved contour integral, designated J* is discussed, and shown to have distinct advantages over others in non-linear strain situations. A number of examples are shown including fractures in thermo-plastic and creep situations. (author)

A chimeric prokaryotic pentameric ligand–gated channel reveals distinct pathways of activation

Science.gov (United States)

Schmandt, Nicolaus; Velisetty, Phanindra; Chalamalasetti, Sreevatsa V.; Stein, Richard A.; Bonner, Ross; Talley, Lauren; Parker, Mark D.; Mchaourab, Hassane S.; Yee, Vivien C.; Lodowski, David T.

2015-01-01

Recent high resolution structures of several pentameric ligand–gated ion channels have provided unprecedented details of their molecular architecture. However, the conformational dynamics and structural rearrangements that underlie gating and allosteric modulation remain poorly understood. We used a combination of electrophysiology, double electron–electron resonance (DEER) spectroscopy, and x-ray crystallography to investigate activation mechanisms in a novel functional chimera with the extracellular domain (ECD) of amine-gated Erwinia chrysanthemi ligand–gated ion channel, which is activated by primary amines, and the transmembrane domain of Gloeobacter violaceus ligand–gated ion channel, which is activated by protons. We found that the chimera was independently gated by primary amines and by protons. The crystal structure of the chimera in its resting state, at pH 7.0 and in the absence of primary amines, revealed a closed-pore conformation and an ECD that is twisted with respect to the transmembrane region. Amine- and pH-induced conformational changes measured by DEER spectroscopy showed that the chimera exhibits a dual mode of gating that preserves the distinct conformational changes of the parent channels. Collectively, our findings shed light on both conserved and divergent features of gating mechanisms in this class of channels, and will facilitate the design of better allosteric modulators. PMID:26415570

The role of biofilms in persistent infections and factors involved in ica-independent biofilm development and gene regulation in Staphylococcus aureus.

Science.gov (United States)

Figueiredo, Agnes Marie Sá; Ferreira, Fabienne Antunes; Beltrame, Cristiana Ossaille; Côrtes, Marina Farrel

2017-09-01

Staphylococcus aureus biofilms represent a unique micro-environment that directly contribute to the bacterial fitness within hospital settings. The accumulation of this structure on implanted medical devices has frequently caused the development of persistent and chronic S. aureus-associated infections, which represent an important social and economic burden worldwide. ica-independent biofilms are composed of an assortment of bacterial products and modulated by a multifaceted and overlapping regulatory network; therefore, biofilm composition can vary among S. aureus strains. In the microniches formed by biofilms-produced by a number of bacterial species and composed by different structural components-drug refractory cell subpopulations with distinct physiological characteristics can emerge and result in therapeutic failures in patients with recalcitrant bacterial infections. In this review, we highlight the importance of biofilms in the development of persistence and chronicity in some S. aureus diseases, the main molecules associated with ica-independent biofilm development and the regulatory mechanisms that modulate ica-independent biofilm production, accumulation, and dispersion.

Different AMPA receptor subtypes mediate the distinct kinetic components of a biphasic EPSC in hippocampal interneurons

Directory of Open Access Journals (Sweden)

Todd eStincic

2015-05-01

Full Text Available CA1 hippocampal interneurons at the border between stratum radiatum and stratum lacunosum-moleculare have AMPA receptor (AMPAR-mediated excitatory postsynaptic currents (EPSCs that consist of two distinct phases: a typical fast component (FC, and a highly unusual slow component (SC that persists for hundreds of milliseconds. To determine whether these kinetically distinct components of the EPSC are mediated by distinct AMPAR subpopulations, we examined the relative contributions of GluA2-containing and –lacking AMPARs to the SC. GluA2-containing AMPARs mediated the majority of the FC whereas GluA2-lacking AMPARs preferentially generated the SC. When glutamate uptake through the glial glutamate transporter EAAT1 was inhibited, spill over-mediated AMPAR activation recruited an even slower third kinetic component that persisted for several seconds; however, this spillover-mediated current was mediated predominantly by GluA2-containing AMPARs and therefore was clearly distinct from the SC when uptake is intact. Thus, different AMPAR subpopulations that vary in GluA2 content mediate the distinct components of the AMPAR EPSC. The SC is developmentally downregulated in mice, declining after the second postnatal week. This downregulation affects both GluA2-containing and GluA2-lacking AMPARs mediating the SC, and is not accompanied by developmental changes in the GluA2 content of AMPARs underlying the FC. Thus, the downregulation of the SC appears to be independent of synaptic GluA2 expression, suggesting the involvement of another AMPAR subunit or an auxiliary protein. Our results therefore identify GluA2-dependent and GluA2-independent determinants of the SC: GluA2-lacking AMPARs preferentially contribute to the SC, while the developmental downregulation of the SC is independent of GluA2 content.

Commonalities and distinctions among mechanisms of addiction to alcohol and other drugs

Science.gov (United States)

Ozburn, Angela R.; Janowsky, Aaron J.; Crabbe, John C.

2015-01-01

Alcohol abuse is comorbid with abuse of many other drugs, some with similar pharmacology and others quite different. This leads to the hypothesis of an underlying, unitary dysfunctional neurobiological basis for substance abuse risk and consequences. In this review, we discuss commonalities and distinctions of addiction to alcohol and other drugs. We focus on recent advances in pre-clinical studies using rodent models of drug self-administration. While there are specific behavioral and molecular manifestations common to alcohol, psychostimulant, opioid, and nicotine dependence, attempts to propose a unifying theory of the addictions inevitably face details where distinctions are found among classes of drugs. For alcohol, versus other drugs of abuse, we discuss and compare advances in: 1) neurocircuitry important for the different stages of drug dependence; 2) transcriptomics and genetical genomics; and 3) enduring effects. We note in particular the contributions of behavioral genetics and animal models: discussions of progress specifically relevant to treatment development can be found in the accompanying review (Karoly et al, this issue). PMID:26431116

The Yin and Yang of SagS: Distinct Residues in the HmsP Domain of SagS Independently Regulate Biofilm Formation and Biofilm Drug Tolerance

Science.gov (United States)

Dingemans, Jozef; Poudyal, Bandita

2018-01-01

ABSTRACT The formation of inherently drug-tolerant biofilms by the opportunistic pathogen Pseudomonas aeruginosa requires the sensor-regulator hybrid SagS, with ΔsagS biofilms being unstructured and exhibiting increased antimicrobial susceptibility. Recent findings indicated SagS to function as a switch to control biofilm formation and drug tolerance independently. Moreover, findings suggested the periplasmic sensory HmsP domain of SagS is likely to be the control point in the regulation of biofilm formation and biofilm cells transitioning to a drug-tolerant state. We thus asked whether specific amino acid residues present in the HmsP domain contribute to the switch function of SagS. HmsP domain residues were therefore subjected to alanine replacement mutagenesis to identify substitutions that block the sensory function(s) of SagS, which is apparent by attached cells being unable to develop mature biofilms and/or prevent transition to an antimicrobial-resistant state. Mutant analyses revealed 32 residues that only contribute to blocking one sensory function. Moreover, amino acid residues affecting attachment and subsequent biofilm formation but not biofilm tolerance also impaired histidine kinase signaling via BfiS. In contrast, residues affecting biofilm drug tolerance but not attachment and subsequent biofilm formation negatively impacted BrlR transcription factor levels. Structure prediction suggested the two sets of residues affecting sensory functions are located in distinct areas that were previously described as being involved in ligand binding interactions. Taken together, these studies identify the molecular basis for the dual regulatory function of SagS. IMPORTANCE The membrane-bound sensory protein SagS plays a pivotal role in P. aeruginosa biofilm formation and biofilm cells gaining their heightened resistance to antimicrobial agents, with SagS being the control point at which both pathways diverge. Here, we demonstrate for the first time that the two

Hypocretin/Orexin Peptides Alter Spike Encoding by Serotonergic Dorsal Raphe Neurons through Two Distinct Mechanisms That Increase the Late Afterhyperpolarization.

Science.gov (United States)

Ishibashi, Masaru; Gumenchuk, Iryna; Miyazaki, Kenichi; Inoue, Takafumi; Ross, William N; Leonard, Christopher S

2016-09-28

Orexins (hypocretins) are neuropeptides that regulate multiple homeostatic processes, including reward and arousal, in part by exciting serotonergic dorsal raphe neurons, the major source of forebrain serotonin. Here, using mouse brain slices, we found that, instead of simply depolarizing these neurons, orexin-A altered the spike encoding process by increasing the postspike afterhyperpolarization (AHP) via two distinct mechanisms. This orexin-enhanced AHP (oeAHP) was mediated by both OX1 and OX2 receptors, required Ca(2+) influx, reversed near EK, and decayed with two components, the faster of which resulted from enhanced SK channel activation, whereas the slower component decayed like a slow AHP (sAHP), but was not blocked by UCL2077, an antagonist of sAHPs in some neurons. Intracellular phospholipase C inhibition (U73122) blocked the entire oeAHP, but neither component was sensitive to PKC inhibition or altered PKA signaling, unlike classical sAHPs. The enhanced SK current did not depend on IP3-mediated Ca(2+) release but resulted from A-current inhibition and the resultant spike broadening, which increased Ca(2+) influx and Ca(2+)-induced-Ca(2+) release, whereas the slower component was insensitive to these factors. Functionally, the oeAHP slowed and stabilized orexin-induced firing compared with firing produced by a virtual orexin conductance lacking the oeAHP. The oeAHP also reduced steady-state firing rate and firing fidelity in response to stimulation, without affecting the initial rate or fidelity. Collectively, these findings reveal a new orexin action in serotonergic raphe neurons and suggest that, when orexin is released during arousal and reward, it enhances the spike encoding of phasic over tonic inputs, such as those related to sensory, motor, and reward events. Orexin peptides are known to excite neurons via slow postsynaptic depolarizations. Here we elucidate a significant new orexin action that increases and prolongs the postspike

Distinctiveness enhances long-term event memory in non-human primates, irrespective of reinforcement.

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Lewis, Amy; Call, Josep; Berntsen, Dorthe

2017-08-01

Non-human primates are capable of recalling events that occurred as long as 3 years ago, and are able to distinguish between similar events; akin to human memory. In humans, distinctiveness enhances memory for events, however, it is unknown whether the same occurs in non-human primates. As such, we tested three great ape species on their ability to remember an event that varied in distinctiveness. Across three experiments, apes witnessed a baiting event in which one of three identical containers was baited with food. After a delay of 2 weeks, we tested their memory for the location of the baited container. Apes failed to recall the baited container when the event was undistinctive (Experiment 1), but were successful when it was distinctive (Experiment 2), although performance was equally good in a less-distinctive condition. A third experiment (Experiment 3) confirmed that distinctiveness, independent of reinforcement, was a consistent predictor of performance. These findings suggest that distinctiveness may enhance memory for events in non-human primates in the same way as in humans, and provides further evidence of basic similarities between the ways apes and humans remember past events. © 2017 Wiley Periodicals, Inc.

Partial discharge characteristics and mechanism in voids at impulse voltages

International Nuclear Information System (INIS)

Zhao, X F; Guo, Z F; Wang, Y Y; Li, J H; Li, Y M; Yao, X

2011-01-01

Partial discharge (PD) characteristics and mechanism in artificial cavities in an epoxy plate have been investigated for different void dimensions and impulse voltage waveforms. A differential measurement system was developed in order to detect PD current pulses effectively. Experimental results showed that the 50% probability PD inception voltage (PDIV 50 ) increases initially as the cavity diameter decreases at constant depth for double exponential impulses as well as oscillating impulses, but after aging, it becomes independent of the cavity diameter. Moreover, some distinctive characteristics of PD (e.g. main discharge and reverse discharge during the rise and fall phases of the applied voltage) were also investigated. The differences of the PD propagation and the mechanism between double exponential impulses and oscillating impulse were discussed

Understanding and imitating unfamiliar actions: distinct underlying mechanisms.

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Joana C Carmo

Full Text Available The human "mirror neuron system" has been proposed to be the neural substrate that underlies understanding and, possibly, imitating actions. However, since the brain activity with mirror properties seems insufficient to provide a good description for imitation of actions outside one's own repertoire, the existence of supplementary processes has been proposed. Moreover, it is unclear whether action observation requires the same neural mechanisms as the explicit access to their meaning. The aim of this study was two-fold as we investigated whether action observation requires different processes depending on 1 whether the ultimate goal is to imitate or understand the presented actions and 2 whether the to-be-imitated actions are familiar or unfamiliar to the subject. Participants were presented with both meaningful familiar actions and meaningless unfamiliar actions that they had to either imitate or discriminate later. Event-related Potentials were used as differences in brain activity could have been masked by the use of other techniques with lower temporal resolution. In the imitation task, a sustained left frontal negativity was more pronounced for meaningless actions than for meaningful ones, starting from an early time-window. Conversely, observing unfamiliar versus familiar actions with the intention of discriminating them led to marked differences over right centro-posterior scalp regions, in both middle and latest time-windows. These findings suggest that action imitation and action understanding may be sustained by dissociable mechanisms: while imitation of unfamiliar actions activates left frontal processes, that are likely to be related to learning mechanisms, action understanding involves dedicated operations which probably require right posterior regions, consistent with their involvement in social interactions.

Caenorhabditis elegans reveals a FxNPxY-independent low-density lipoprotein receptor internalization mechanism mediated by epsin1

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Kang, Yuan-Lin; Yochem, John; Bell, Leslie; Sorensen, Erika B.; Chen, Lihsia; Conner, Sean D.

2013-01-01

Low-density lipoprotein receptor (LDLR) internalization clears cholesterol-laden LDL particles from circulation in humans. Defects in clathrin-dependent LDLR endocytosis promote elevated serum cholesterol levels and can lead to atherosclerosis. However, our understanding of the mechanisms that control LDLR uptake remains incomplete. To identify factors critical to LDLR uptake, we pursued a genome-wide RNA interference screen using Caenorhabditis elegans LRP-1/megalin as a model for LDLR transport. In doing so, we discovered an unanticipated requirement for the clathrin-binding endocytic adaptor epsin1 in LDLR endocytosis. Epsin1 depletion reduced LDLR internalization rates in mammalian cells, similar to the reduction observed following clathrin depletion. Genetic and biochemical analyses of epsin in C. elegans and mammalian cells uncovered a requirement for the ubiquitin-interaction motif (UIM) as critical for receptor transport. As the epsin UIM promotes the internalization of some ubiquitinated receptors, we predicted LDLR ubiquitination as necessary for endocytosis. However, engineered ubiquitination-impaired LDLR mutants showed modest internalization defects that were further enhanced with epsin1 depletion, demonstrating epsin1-mediated LDLR endocytosis is independent of receptor ubiquitination. Finally, we provide evidence that epsin1-mediated LDLR uptake occurs independently of either of the two documented internalization motifs (FxNPxY or HIC) encoded within the LDLR cytoplasmic tail, indicating an additional internalization mechanism for LDLR. PMID:23242996

Progesterone modulates the LPS-induced nitric oxide production by a progesterone-receptor independent mechanism.

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Wolfson, Manuel Luis; Schander, Julieta Aylen; Bariani, María Victoria; Correa, Fernando; Franchi, Ana María

2015-12-15

Genital tract infections caused by Gram-negative bacteria induce miscarriage and are one of the most common complications of human pregnancy. LPS administration to 7-day pregnant mice induces embryo resorption after 24h, with nitric oxide playing a fundamental role in this process. We have previously shown that progesterone exerts protective effects on the embryo by modulating the inflammatory reaction triggered by LPS. Here we sought to investigate whether the in vivo administration of progesterone modulated the LPS-induced nitric oxide production from peripheral blood mononuclear cells from pregnant and non-pregnant mice. We found that progesterone downregulated LPS-induced nitric oxide production by a progesterone receptor-independent mechanism. Moreover, our results suggest a possible participation of glucocorticoid receptors in at least some of the anti-inflammatory effects of progesterone. Copyright © 2015 Elsevier B.V. All rights reserved.

Sleep apnea predicts distinct alterations in glucose homeostasis and biomarkers in obese adults with normal and impaired glucose metabolism

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Hill Nathan R

2010-12-01

Full Text Available Abstract Background Notwithstanding previous studies supporting independent associations between obstructive sleep apnea (OSA and prevalence of diabetes, the underlying pathogenesis of impaired glucose regulation in OSA remains unclear. We explored mechanisms linking OSA with prediabetes/diabetes and associated biomarker profiles. We hypothesized that OSA is associated with distinct alterations in glucose homeostasis and biomarker profiles in subjects with normal (NGM and impaired glucose metabolism (IGM. Methods Forty-five severely obese adults (36 women without certain comorbidities/medications underwent anthropometric measurements, polysomnography, and blood tests. We measured fasting serum glucose, insulin, selected cytokines, and calculated homeostasis model assessment estimates of insulin sensitivity (HOMA-IS and pancreatic beta-cell function (HOMA-B. Results Both increases in apnea-hypopnea index (AHI and the presence of prediabetes/diabetes were associated with reductions in HOMA-IS in the entire cohort even after adjustment for sex, race, age, and BMI (P = 0.003. In subjects with NGM (n = 30, OSA severity was associated with significantly increased HOMA-B (a trend towards decreased HOMA-IS independent of sex and adiposity. OSA-related oxyhemoglobin desaturations correlated with TNF-α (r=-0.76; P = 0.001 in women with NGM and with IL-6 (rho=-0.55; P = 0.035 in women with IGM (n = 15 matched individually for age, adiposity, and AHI. Conclusions OSA is independently associated with altered glucose homeostasis and increased basal beta-cell function in severely obese adults with NGM. The findings suggest that moderate to severe OSA imposes an excessive functional demand on pancreatic beta-cells, which may lead to their exhaustion and impaired secretory capacity over time. The two distinct biomarker profiles linking sleep apnea with NGM and IGM via TNF-α and IL-6 have been discerned in our study to suggest that sleep apnea and particularly

SOCIO-PEDAGOGICAL EVALUATION OF TEACHING STAFF ACTIVITIES IN COMPREHENSIVE SCHOOLS AS AN INDEPENDENT MECHANISM OF EDUCATION QUALITY ASSESSMENT

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Irina О. Antipina

2014-01-01

Full Text Available The aim of the research is to reveal various ways for developing the independent mechanisms of education quality assessment.Methods involve the analysis of the existing views concerning the quality assessment of teaching staff activities.Results: The research findings demonstrate functional specificity of comprehensive schools, the main phases of socio-pedagogic assessment of teaching staff activities, and the main criteria and indices of their monitoring. The author considers professional educational activity as a general assessment criterion. The main feature of socio-pedagogic assessment procedures involves participation of different categories of teaching and research staff, along with students’ parents and the neighboring society members.Scientific novelty: The author specifies the concept of socio-pedagogic assessment of teaching staff activities.Practical significance: Implementation of the research outcomes can stimulate professional activity of pedagogical society in developing the independent system of education quality assessment.

Mycobacteria exploit three genetically distinct DNA double-strand break repair pathways.

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Gupta, Richa; Barkan, Daniel; Redelman-Sidi, Gil; Shuman, Stewart; Glickman, Michael S

2011-01-01

Bacterial pathogens rely on their DNA repair pathways to resist genomic damage inflicted by the host. DNA double-strand breaks (DSBs) are especially threatening to bacterial viability. DSB repair by homologous recombination (HR) requires nucleases that resect DSB ends and a strand exchange protein that facilitates homology search. RecBCD and RecA perform these functions in Escherichia coli and constitute the major pathway of error-free DSB repair. Mycobacteria, including the human pathogen M. tuberculosis, elaborate an additional error-prone pathway of DSB repair via non-homologous end-joining (NHEJ) catalysed by Ku and DNA ligase D (LigD). Little is known about the relative contributions of HR and NHEJ to mycobacterial chromosome repair, the factors that dictate pathway choice, or the existence of additional DSB repair pathways. Here we demonstrate that Mycobacterium smegmatis has three DSB repair pathway options: HR, NHEJ and a novel mechanism of single-strand annealing (SSA). Inactivation of NHEJ or SSA is compensated by elevated HR. We find that mycobacterial RecBCD does not participate in HR or confer resistance to ionizing radiation (IR), but is required for the RecA-independent SSA pathway. In contrast, the mycobacterial helicase-nuclease AdnAB participates in the RecA-dependent HR pathway, and is a major determinant of resistance to IR and oxidative DNA damage. These findings reveal distinctive features of mycobacterial DSB repair, most notably the dedication of the RecBCD and AdnAB helicase-nuclease machines to distinct repair pathways. © 2010 Blackwell Publishing Ltd.

A DNA methylation-based definition of biologically distinct breast cancer subtypes.

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Stefansson, Olafur A; Moran, Sebastian; Gomez, Antonio; Sayols, Sergi; Arribas-Jorba, Carlos; Sandoval, Juan; Hilmarsdottir, Holmfridur; Olafsdottir, Elinborg; Tryggvadottir, Laufey; Jonasson, Jon G; Eyfjord, Jorunn; Esteller, Manel

2015-03-01

In cancer, epigenetic states are deregulated and thought to be of significance in cancer development and progression. We explored DNA methylation-based signatures in association with breast cancer subtypes to assess their impact on clinical presentation and patient prognosis. DNA methylation was analyzed using Infinium 450K arrays in 40 tumors and 17 normal breast samples, together with DNA copy number changes and subtype-specific markers by tissue microarrays. The identified methylation signatures were validated against a cohort of 212 tumors annotated for breast cancer subtypes by the PAM50 method (The Cancer Genome Atlas). Selected markers were pyrosequenced in an independent validation cohort of 310 tumors and analyzed with respect to survival, clinical stage and grade. The results demonstrate that DNA methylation patterns linked to the luminal-B subtype are characterized by CpG island promoter methylation events. In contrast, a large fraction of basal-like tumors are characterized by hypomethylation events occurring within the gene body. Based on these hallmark signatures, we defined two DNA methylation-based subtypes, Epi-LumB and Epi-Basal, and show that they are associated with unfavorable clinical parameters and reduced survival. Our data show that distinct mechanisms leading to changes in CpG methylation states are operative in different breast cancer subtypes. Importantly, we show that a few selected proxy markers can be used to detect the distinct DNA methylation-based subtypes thereby providing valuable information on disease prognosis. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Effects of frequency correlation in linear optical entangling gates operated with independent photons

International Nuclear Information System (INIS)

Barbieri, M.

2007-01-01

Bose-Einstein coalescence of independent photons at the surface of a beam splitter is the physical process that allows linear optical quantum gates to be built. When distinct parametric down-conversion events are used as an independent photon source, distinguishability arises form the energy correlation of each photon with its twin. We derive upper bound for the entanglement which can be generated under these conditions

Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease.

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Ihssane Bouybayoune

2015-04-01

Full Text Available Fatal familial insomnia (FFI and a genetic form of Creutzfeldt-Jakob disease (CJD178 are clinically different prion disorders linked to the D178N prion protein (PrP mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD mice modeling CJD178. No prion infectivity was detectable in Tg(FFI and Tg(CJD brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI and Tg(CJD neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms.

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Enculescu, Mihaela; Metzendorf, Christoph; Sparla, Richard; Hahnel, Maximilian; Bode, Johannes; Muckenthaler, Martina U; Legewie, Stefan

2017-01-01

ferroportin-independent homeostasis mechanisms.

Characterizing speed-independence of high-level designs

DEFF Research Database (Denmark)

Kishinevsky, Michael; Staunstrup, Jørgen

1994-01-01

This paper characterizes the speed-independence of high-level designs. The characterization is a condition on the design description ensuring that the behavior of the design is independent of the speeds of its components. The behavior of a circuit is modeled as a transition system, that allows data...... types, and internal as well as external non-determinism. This makes it possible to verify the speed-independence of a design without providing an explicit realization of the environment. The verification can be done mechanically. A number of experimental designs have been verified including a speed-independent...

Radial frequency stimuli and sine-wave gratings seem to be processed by distinct contrast brain mechanisms

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M.L.B. Simas

2005-03-01

Full Text Available An assumption commonly made in the study of visual perception is that the lower the contrast threshold for a given stimulus, the more sensitive and selective will be the mechanism that processes it. On the basis of this consideration, we investigated contrast thresholds for two classes of stimuli: sine-wave gratings and radial frequency stimuli (i.e., j0 targets or stimuli modulated by spherical Bessel functions. Employing a suprathreshold summation method, we measured the selectivity of spatial and radial frequency filters using either sine-wave gratings or j0 target contrast profiles at either 1 or 4 cycles per degree of visual angle (cpd, as the test frequencies. Thus, in a forced-choice trial, observers chose between a background spatial (or radial frequency alone and the given background stimulus plus the test frequency (1 or 4 cpd sine-wave grating or radial frequency. Contrary to our expectations, the results showed elevated thresholds (i.e., inhibition for sine-wave gratings and decreased thresholds (i.e., summation for radial frequencies when background and test frequencies were identical. This was true for both 1- and 4-cpd test frequencies. This finding suggests that sine-wave gratings and radial frequency stimuli are processed by different quasi-linear systems, one working at low luminance and contrast level (sine-wave gratings and the other at high luminance and contrast levels (radial frequency stimuli. We think that this interpretation is consistent with distinct foveal only and foveal-parafoveal mechanisms involving striate and/or other higher visual areas (i.e., V2 and V4.

Distinct evolutionary mechanisms for genomic imbalances in high-risk and low-risk neuroblastomas

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Gisselsson David

2007-09-01

Full Text Available Abstract Background Neuroblastoma (NB is the most common extracranial solid tumour of childhood. Several genomic imbalances correlate to prognosis in NB, with structural rearrangements, including gene amplification, in a near-diploid setting typically signifying high-risk tumours and numerical changes in a near-triploid setting signifying low-risk tumours. Little is known about the temporal sequence in which these imbalances occur during the carcinogenic process. Methods We have reconstructed the appearance of cytogenetic imbalances in 270 NBs by first grouping tumours and imbalances through principal component analysis and then using the number of imbalances in each tumour as an indicator of evolutionary progression. Results Tumours clustered in four sub-groups, dominated respectively by (1 gene amplification in double minute chromosomes and few other aberrations, (2 gene amplification and loss of 1p sequences, (3 loss of 1p and other structural aberrations including gain of 17q, and (4 whole-chromosome gains and losses. Temporal analysis showed that the structural changes in groups 1–3 were acquired in a step-wise fashion, with loss of 1p sequences and the emergence of double minute chromosomes as the earliest cytogenetic events. In contrast, the gains and losses of whole chromosomes in group 4 occurred through multiple simultaneous events leading to a near-triploid chromosome number. Conclusion The finding of different temporal patterns for the acquisition of genomic imbalances in high-risk and low-risk NBs lends strong support to the hypothesis that these tumours are biologically diverse entities, evolving through distinct genetic mechanisms.

History-independent cyclic response of nanotwinned metals

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Pan, Qingsong; Zhou, Haofei; Lu, Qiuhong; Gao, Huajian; Lu, Lei

2017-11-01

Nearly 90 per cent of service failures of metallic components and structures are caused by fatigue at cyclic stress amplitudes much lower than the tensile strength of the materials involved. Metals typically suffer from large amounts of cumulative, irreversible damage to microstructure during cyclic deformation, leading to cyclic responses that are unstable (hardening or softening) and history-dependent. Existing rules for fatigue life prediction, such as the linear cumulative damage rule, cannot account for the effect of loading history, and engineering components are often loaded by complex cyclic stresses with variable amplitudes, mean values and frequencies, such as aircraft wings in turbulent air. It is therefore usually extremely challenging to predict cyclic behaviour and fatigue life under a realistic load spectrum. Here, through both atomistic simulations and variable-strain-amplitude cyclic loading experiments at stress amplitudes lower than the tensile strength of the metal, we report a history-independent and stable cyclic response in bulk copper samples that contain highly oriented nanoscale twins. We demonstrate that this unusual cyclic behaviour is governed by a type of correlated ‘necklace’ dislocation consisting of multiple short component dislocations in adjacent twins, connected like the links of a necklace. Such dislocations are formed in the highly oriented nanotwinned structure under cyclic loading and help to maintain the stability of twin boundaries and the reversible damage, provided that the nanotwins are tilted within about 15 degrees of the loading axis. This cyclic deformation mechanism is distinct from the conventional strain localizing mechanisms associated with irreversible microstructural damage in single-crystal, coarse-grained, ultrafine-grained and nanograined metals.

An impossibility theorem for parameter independent hidden variable theories

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Leegwater, Gijs

2016-05-01

Recently, Roger Colbeck and Renato Renner (C&R) have claimed that '[n]o extension of quantum theory can have improved predictive power' (Colbeck & Renner, 2011, 2012b). If correct, this is a spectacular impossibility theorem for hidden variable theories, which is more general than the theorems of Bell (1964) and Leggett (2003). Also, C&R have used their claim in attempt to prove that a system's quantum-mechanical wave function is in a one-to-one correspondence with its 'ontic' state (Colbeck & Renner, 2012a). C&R's claim essentially means that in any hidden variable theory that is compatible with quantum-mechanical predictions, probabilities of measurement outcomes are independent of these hidden variables. This makes such variables otiose. On closer inspection, however, the generality and validity of the claim can be contested. First, it is based on an assumption called 'Freedom of Choice'. As the name suggests, this assumption involves the independence of an experimenter's choice of measurement settings. But in the way C&R define this assumption, a no-signalling condition is surreptitiously presupposed, making the assumption less innocent than it sounds. When using this definition, any hidden variable theory violating parameter independence, such as Bohmian Mechanics, is immediately shown to be incompatible with quantum-mechanical predictions. Also, the argument of C&R is hard to follow and their mathematical derivation contains several gaps, some of which cannot be closed in the way they suggest. We shall show that these gaps can be filled. The issue with the 'Freedom of Choice' assumption can be circumvented by explicitly assuming parameter independence. This makes the result less general, but better founded. We then obtain an impossibility theorem for hidden variable theories satisfying parameter independence only. As stated above, such hidden variable theories are impossible in the sense that any supplemental variables have no bearing on outcome probabilities

Singularities of robot mechanisms numerical computation and avoidance path planning

CERN Document Server

Bohigas, Oriol; Ros, Lluís

2017-01-01

This book presents the singular configurations associated with a robot mechanism, together with robust methods for their computation, interpretation, and avoidance path planning. Having such methods is essential as singularities generally pose problems to the normal operation of a robot, but also determine the workspaces and motion impediments of its underlying mechanical structure. A distinctive feature of this volume is that the methods are applicable to nonredundant mechanisms of general architecture, defined by planar or spatial kinematic chains interconnected in an arbitrary way. Moreover, singularities are interpreted as silhouettes of the configuration space when seen from the input or output spaces. This leads to a powerful image that explains the consequences of traversing singular configurations, and all the rich information that can be extracted from them. The problems are solved by means of effective branch-and-prune and numerical continuation methods that are of independent interest in themselves...

Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection*

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Haldiman, Tracy; Kim, Chae; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Qing, Liuting; Cohen, Mark L.; Langeveld, Jan; Telling, Glenn C.; Kong, Qingzhong; Safar, Jiri G.

2013-01-01

The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrPSc particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrPSc is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers. PMID:23974118

G protein-coupled estrogen receptor 1 (GPER1)/GPR30 increases ERK1/2 activity through PDZ motif-dependent and -independent mechanisms.

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Gonzalez de Valdivia, Ernesto; Broselid, Stefan; Kahn, Robin; Olde, Björn; Leeb-Lundberg, L M Fredrik

2017-06-16

G protein-coupled receptor 30 (GPR30), also called G protein-coupled estrogen receptor 1 (GPER1), is thought to play important roles in breast cancer and cardiometabolic regulation, but many questions remain about ligand activation, effector coupling, and subcellular localization. We showed recently that GPR30 interacts through the C-terminal type I PDZ motif with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, which anchor the receptor in the plasma membrane and mediate an apparently constitutive decrease in cAMP production independently of G i/o Here, we show that GPR30 also constitutively increases ERK1/2 activity. Removing the receptor PDZ motif or knocking down specifically AKAP5 inhibited the increase, showing that this increase also requires the PDZ interaction. However, the increase was inhibited by pertussis toxin as well as by wortmannin but not by AG1478, indicating that G i/o and phosphoinositide 3-kinase (PI3K) mediate the increase independently of epidermal growth factor receptor transactivation. FK506 and okadaic acid also inhibited the increase, implying that a protein phosphatase is involved. The proposed GPR30 agonist G-1 also increased ERK1/2 activity, but this increase was only observed at a level of receptor expression below that required for the constitutive increase. Furthermore, deleting the PDZ motif did not inhibit the G-1-stimulated increase. Based on these results, we propose that GPR30 increases ERK1/2 activity via two G i/o -mediated mechanisms, a PDZ-dependent, apparently constitutive mechanism and a PDZ-independent G-1-stimulated mechanism. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Mapping of genomic EGFRvIII deletions in glioblastoma: insight into rearrangement mechanisms and biomarker development.

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Koga, Tomoyuki; Li, Bin; Figueroa, Javier M; Ren, Bing; Chen, Clark C; Carter, Bob S; Furnari, Frank B

2018-04-12

Epidermal growth factor receptor (EGFR) variant III (vIII) is the most common oncogenic rearrangement in glioblastoma (GBM) generated by deletion of exons two to seven of EGFR. The proximal breakpoints occur in variable positions within the 123-kb intron one, presenting significant challenges in terms of PCR-based mapping. Molecular mechanisms underlying these deletions remain unclear. We determined the presence of EGFRvIII and its breakpoints for 29 GBM samples using quantitative polymerase chain reaction (qPCR), arrayed PCR mapping, Sanger sequencing, and whole genome sequencing (WGS). Patient-specific breakpoint PCR was performed on tumors, plasma and cerebrospinal fluid (CSF) samples. The breakpoint sequences and single nucleotide polymorphisms (SNPs) were analyzed to elucidate the underlying biogenic mechanism. PCR mapping and WGS independently unveiled eight EGFRvIII breakpoints in six tumors. Patient-specific primers yielded EGFRvIII PCR amplicons in matched tumors, and in cell-free DNA (cfDNA) from a CSF sample, but not in cfDNA or extracellular-vesicle DNA from plasma. The breakpoint analysis revealed nucleotide insertions in four, an insertion of a region outside of EGFR locus in one, microhomologies in three, as well as a duplication or an inversion accompanied by microhomologies in two, suggestive of distinct DNA repair mechanisms. In the GBM samples that harbored distinct breakpoints, the SNP compositions of EGFRvIII and amplified non-vIII EGFR were identical, suggesting that these rearrangements arose from amplified non-vIII EGFR. Our approach efficiently "fingerprints" each sample's EGFRvIII breakpoints. Breakpoint sequence analyses suggest that independent breakpoints arose from precursor amplified non-vIII EGFR through different DNA repair mechanisms.

Distinct mechanisms regulate Lck spatial organization in activated T cells

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Natasha eKapoor-Kaushik

2016-03-01

Full Text Available Phosphorylation of the T cell receptor (TCR by the kinase Lck is the first detectable signaling event upon antigen engagement. The distribution of Lck within the plasma membrane, its conformational state, kinase activity and protein interactions all contribute to determine how efficiently Lck phosphorylates the engaged TCR. Here we used cross-correlation raster image spectroscopy (ccRICS and photoactivated localization microscopy (PALM to identify two mechanisms of Lck clustering: an intrinsic mechanism of Lck clustering induced by locking Lck in its open conformation, and an extrinsic mechanism of clustering controlled by the phosphorylation of tyrosine 192, which regulates the affinity of Lck SH2 domain. Both mechanisms of clustering were differently affected by the absence of the kinase Zap70 or the adaptor Lat. We further observed that the adaptor TSAd bound to and promoted the diffusion of Lck when it is phosphorylated on tyrosine 192. Our data suggest that while Lck open conformation drives aggregation and clustering, the spatial organization of Lck is further controlled by signaling events downstream of TCR phosphorylation.

Motivation to hide emotion and children's understanding of the distinction between real and apparent emotions.

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Gosselin, Pierre; Warren, Madeleine; Diotte, Michèle

2002-12-01

The authors investigated the extent to which children's understanding of the distinction between real and apparent emotions varied according to the motivation to hide emotions. Children, aged 6-7 and 10-11 years, were read stories designed to elicit either prosocial or self-protective motivated display rules and were asked to predict the facial expressions the protagonists would make to hide felt emotions. Children were found to understand the distinction between real and apparent emotions very well, independently of the type of motivation. Contrary to predictions, boys understood this distinction better than did girls when the motivation to hide positive emotions was prosocial. Children perceived neutralization as the most appropriate strategy to hide felt emotions, followed by masking.

Is recursion language-specific? Evidence of recursive mechanisms in the structure of intentional action.

Science.gov (United States)

Vicari, Giuseppe; Adenzato, Mauro

2014-05-01

In their 2002 seminal paper Hauser, Chomsky and Fitch hypothesize that recursion is the only human-specific and language-specific mechanism of the faculty of language. While debate focused primarily on the meaning of recursion in the hypothesis and on the human-specific and syntax-specific character of recursion, the present work focuses on the claim that recursion is language-specific. We argue that there are recursive structures in the domain of motor intentionality by way of extending John R. Searle's analysis of intentional action. We then discuss evidence from cognitive science and neuroscience supporting the claim that motor-intentional recursion is language-independent and suggest some explanatory hypotheses: (1) linguistic recursion is embodied in sensory-motor processing; (2) linguistic and motor-intentional recursions are distinct and mutually independent mechanisms. Finally, we propose some reflections about the epistemic status of HCF as presenting an empirically falsifiable hypothesis, and on the possibility of testing recursion in different cognitive domains. Copyright © 2014 Elsevier Inc. All rights reserved.

Spermidine mediates degradation of ornithine decarboxylase by a non-lysosomal, ubiquitin-independent mechanism

International Nuclear Information System (INIS)

Glass, J.R.; Gerner, E.W.

1987-01-01

The mechanism of spermidine-induced ornithine decarboxylase (OCD, E.C. 4.1.1.17) inactivation was investigated using Chinese hamster ovary (CHO) cells, maintained in serum-free medium, which display a stabilization of ODC owing to the lack of accumulation of putrescine and spermidine. Treatment of cells with 10 μM exogenous spermidine leads to rapid decay of ODC activity accompanied by a parallel decrease in enzyme protein. Analysis of the decay of [ 35 S]methionine-labeled ODC and separation by two-dimensional electrophoresis revealed no detectable modification in ODC structure during enhanced degradation. Spermidine-mediated inactivation of ODC occurred in a temperature-dependent manner exhibiting pseudo-first-order kinetics over a temperature range of 22-37 0 C. In cultures treated continuously, an initial lag was observed after treatment with spermidine, followed by a rapid decline in activity as an apparent critical concentration of intracellular spermidine was achieved. Treating cells at 22 0 C for 3 hours with 10 μ M spermidine, followed by removal of exogenous polyamine, and then shifting to varying temperatures, resulted in rates of ODC inactivation identical with that determined with a continuous treatment. Arrhenius analysis showed that polyamine mediated inactivation of ODC occurred with an activation energy of approximately 16 kcal/mol. Treatment of cells with lysosomotrophic agents had no effect of ODC degradation. ODC turnover was not dependent on ubiquitin-dependent proteolysis. These data support the hypothesis that spermidine regulates ODC degradation via a mechanism requiring new protein synthesis, and that this occurs via a non-lysosomal, ubiquitin-independent pathway

Both differences in encoding processes and monitoring at retrieval reduce false alarms when distinctive information is studied.

Science.gov (United States)

Hanczakowski, Maciej; Mazzoni, Giuliana

2011-04-01

A reduction in false alarms to critical lures is observed in the DRM paradigm (Roediger & McDermott, 1995) when distinctive information is presented at encoding. Two mechanisms have been proposed to account for this reduction. According to the monitoring theory (e.g., the distinctiveness heuristic), lack of diagnostic recollection serves as a basis for discarding non-presented lures. According to the encoding theory, presenting distinctive information at study leads to impoverished relational processing, which results in a reduction in memorial information elicited by critical lures. In the present study a condition was created in which the use of the distinctiveness heuristic was precluded by associating, within the same study, lures with distinctive information in a context different from the study session. Under that condition reduction in false alarms to distinctive critical lures was still observed. This result supports the predictions of the encoding theory. However, when in the same study the use of the distinctiveness heuristic was not precluded, reductions in false alarms to unrelated lures were also observed when distinctive information was presented at study, indicating that both mechanisms are likely to contribute to the rejection of false memories.

Ubiquitination of Cdc20 by the APC occurs through an intramolecular mechanism

Science.gov (United States)

Foe, Ian T.; Foster, Scott A.; Cheung, Stephanie K.; DeLuca, Steven Z.; Morgan, David O.; Toczyski, David P.

2012-01-01

SUMMARY Background Cells control progression through late mitosis by regulating Cdc20 and Cdh1, the two mitotic activators of the Anaphase Promoting Complex (APC). The control of Cdc20 protein levels during the cell cycle is not well understood. Results Here, we demonstrate that Cdc20 is degraded in budding yeast by multiple APC-dependent mechanisms. We find that the majority of Cdc20 turnover does not involve a second activator molecule, but instead depends on in cis Cdc20 autoubiquitination while it is bound to its activator-binding site on the APC core. Unlike in trans ubiquitination of Cdc20 substrates, the APC ubiquitinates Cdc20 independent of APC activation by Cdc20’s C-box. Cdc20 turnover by this intramolecular mechanism is cell cycle-regulated, contributing to the decline in Cdc20 levels that occurs after anaphase. Interestingly, high substrate levels in vitro significantly reduce Cdc20 autoubiquitination. Conclusion We show here that Cdc20 fluctuates through the cell cycle via a distinct form of APC-mediated ubiquitination. This in cis autoubiquitination may preferentially occur in early anaphase, following depletion of Cdc20 substrates. This suggests that distinct mechanisms are able to target Cdc20 for ubiquitination at different points during the cell cycle. PMID:22079111

Alcohol-related biases in selective attention and action tendency make distinct contributions to dysregulated drinking behaviour.

Science.gov (United States)

Sharbanee, Jason M; Stritzke, Werner G K; Wiers, Reinout W; MacLeod, Colin

2013-10-01

To assess whether alcohol-related biases in selective-attention and action tendency uniquely or concurrently predict the ability to regulate alcohol consumption. Two groups of undergraduate social drinkers (total n = 55) who differed in their ability to regulate their alcohol consumption completed a novel Selective-Attention/Action-Tendency Task (SA/ATT), which assessed separately alcohol-related biases in selective attention and action tendency. University of Western Australia, Australia. Dysregulated drinking was operationalized as a self-reported high level of alcohol consumption on the Alcohol Consumption Questionnaire, and a high desire to reduce consumption on the Brief Readiness to Change Algorithm. Selective attention and action tendency were assessed using the SA/ATT, working memory was assessed using the operation-span task and participant characteristics were assessed using the Alcohol Use Disorders Identification Test (AUDIT) and Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Results indicated that (i) there was no significant association between alcohol-related biases in selective attention and action tendency, r = 0.16, P = 0.274, and (ii) biases towards alcohol, in both selective attention, β = 1.01, odds ratio = 2.74, P = 0.022, and action tendency, β = 1.24, odds ratio = 3.45, P = 0.015, predicted independent variance in dysregulated-drinker status. Biases in selective attention and action tendency appear to be distinct mechanisms that contribute independently to difficulty regulating alcohol consumption. Treatment components that could be combined to target both mechanisms could enhance treatment outcomes for alcohol-use disorders. © 2013 Society for the Study of Addiction.

Therapeutic γ-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms

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Dai, Yan; Sangerman, Jose; Hong, Yuan Luo; Fuchareon, Suthat; Chui, David H.K.; Faller, Douglas V.; Perrine, Susan P.

2015-01-01

Pharmacologic augmentation of γ-globin expression sufficient to reduce anemia and clinical severity in patients with diverse hemoglobinopathies has been challenging. In studies here, representative molecules from four chemical classes, representing several distinct primary mechanisms of action, were investigated for effects on γ-globin transcriptional repressors, including components of the NuRD complex (LSD1 and HDACs 2-3), and the downstream repressor BCL11A, in erythroid progenitors from hemoglobinopathy patients. Two HDAC inhibitors (MS-275 and SB939), a short-chain fatty acid derivative (sodium dimethylbutyrate [SDMB]), and an agent identified in high-throughput screening, Benserazide, were studied. These therapeutics induced γ globin mRNA in progenitors above same subject controls up to 20-fold, and increased F-reticulocytes up to 20%. Cellular protein levels of BCL11A, LSD-1, and KLF1 were suppressed by the compounds. Chromatin immunoprecipitation assays demonstrated a 3.6-fold reduction in LSD1 and HDAC3 occupancy in the γ-globin gene promoter with Benserazide exposure, 3-fold reduction in LSD-1 and HDAC2 occupancy in the γ-globin gene promoter with SDMB exposure, while markers of gene activation (histone H3K9 acetylation and H3K4 demethylation), were enriched 5.7-fold. These findings identify clinical-stage oral therapeutics which inhibit or displace major co-repressors of γ-globin gene transcription and may suggest a rationale for combination therapy to produce enhanced efficacy. PMID:26603726

Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain.

Science.gov (United States)

Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

2016-01-21

Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson's disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases.

Distinct Internalization Pathways of Human Amylin Monomers and Its Cytotoxic Oligomers in Pancreatic Cells

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Trikha, Saurabh; Jeremic, Aleksandar M.

2013-01-01

Toxic human amylin oligomers and aggregates are implicated in the pathogenesis of type 2 diabetes mellitus (TTDM). Although recent studies have shown that pancreatic cells can recycle amylin monomers and toxic oligomers, the exact uptake mechanism and trafficking routes of these molecular forms and their significance for amylin toxicity are yet to be determined. Using pancreatic rat insulinoma (RIN-m5F) beta (β)-cells and human islets as model systems we show that monomers and oligomers cross the plasma membrane (PM) through both endocytotic and non-endocytotic (translocation) mechanisms, the predominance of which is dependent on amylin concentrations and incubation times. At low (≤100 nM) concentrations, internalization of amylin monomers in pancreatic cells is completely blocked by the selective amylin-receptor (AM-R) antagonist, AC-187, indicating an AM-R dependent mechanism. In contrast at cytotoxic (µM) concentrations monomers initially (1 hour) enter pancreatic cells by two distinct mechanisms: translocation and macropinocytosis. However, during the late stage (24 hours) monomers internalize by a clathrin-dependent but AM-R and macropinocytotic independent pathway. Like monomers a small fraction of the oligomers initially enter cells by a non-endocytotic mechanism. In contrast a majority of the oligomers at both early (1 hour) and late times (24 hours) traffic with a fluid-phase marker, dextran, to the same endocytotic compartments, the uptake of which is blocked by potent macropinocytotic inhibitors. This led to a significant increase in extra-cellular PM accumulation, in turn potentiating amylin toxicity in pancreatic cells. Our studies suggest that macropinocytosis is a major but not the only clearance mechanism for both amylin’s molecular forms, thereby serving a cyto-protective role in these cells. PMID:24019897

Architecture-independent power bound for vibration energy harvesters

International Nuclear Information System (INIS)

Halvorsen, E; Le, C P; Mitcheson, P D; Yeatman, E M

2013-01-01

The maximum output power of energy harvesters driven by harmonic vibrations is well known for a range of specific harvester architectures. An architecture-independent bound based on the mechanical input-power also exists and gives a strict limit on achievable power with one mechanical degree of freedom, but is a least upper bound only for lossless devices. We report a new theoretical bound on the output power of vibration energy harvesters that includes parasitic, linear mechanical damping while still being architecture independent. This bound greatly improves the previous bound at moderate force amplitudes and is compared to the performance of established harvester architectures which are shown to agree with it in limiting cases. The bound is a hard limit on achievable power with one mechanical degree of freedom and can not be circumvented by transducer or power-electronic-interface design

Interaction of NMDA receptor and pacemaking mechanisms in the midbrain dopaminergic neuron.

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Joon Ha

Full Text Available Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR activation evokes high-frequency firing, whereas other tonic excitatory stimuli (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR activation or applied depolarization block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard nullcline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether-a-go-go current (ERG, which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations

Electroencephalographic dynamics of musical emotion perception revealed by independent spectral components.

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Lin, Yuan-Pin; Duann, Jeng-Ren; Chen, Jyh-Horng; Jung, Tzyy-Ping

2010-04-21

This study explores the electroencephalographic (EEG) correlates of emotional experience during music listening. Independent component analysis and analysis of variance were used to separate statistically independent spectral changes of the EEG in response to music-induced emotional processes. An independent brain process with equivalent dipole located in the fronto-central region exhibited distinct δ-band and θ-band power changes associated with self-reported emotional states. Specifically, the emotional valence was associated with δ-power decreases and θ-power increases in the frontal-central area, whereas the emotional arousal was accompanied by increases in both δ and θ powers. The resultant emotion-related component activations that were less interfered by the activities from other brain processes complement previous EEG studies of emotion perception to music.

Characterization of Na+-linked and Na+-independent Cl-/HCO3- exchange systems in Chinese hamster lung fibroblasts

International Nuclear Information System (INIS)

Cassel, D.; Scharf, O.; Rotman, M.; Cragoe, E.J. Jr.; Katz, M.

1988-01-01

The PS120 variant of Chinese hamster lung fibroblasts which lacks Na + /H + exchange activity was used to investigate bicarbonate transport systems and their role in intracellular pH (pH/sub i/) regulation. When pH/sub i/ was decreased by acid load, bicarbonate caused pH/sub i/ increase and stimulated 36 Cl - efflux from the cells, both in a Na + -dependent manner. These results together with previous findings that bicarbonate stimulates 22 Na + uptake in PS120 cells demonstrate the presence of a Na + -linked Cl - /HCO 3 - exchange system. In cells with normal initial pH/sub i/, bicarbonate caused Na + -independent pH/sub i/ increase in Cl - -free solutions and stimulated Na + -independent 36 Cl - efflux, indicating that a Na + -independent Cl - /HCO 3 - exchanger is also present in the cell. Na + -linked and Na + -independent Cl - /HCO 3- exchange is apparently mediated by two distinct systems, since a [(tetrahydrofluorene-7-yl)oxy]acetic acid derivative selectively inhibits the Na + -independent exchanger. An additional distinctive features is a 10-fold lower affinity for chloride of the Na + -linked exchanger. The Na + -linked and Na + -independent Cl - /HCO 3 - exchange systems are likely to protect the cell from acid and alkaline load, respectively

Distinct mechanisms of loss of IFN-gamma mediated HLA class I inducibility in two melanoma cell lines

International Nuclear Information System (INIS)

Rodríguez, Teresa; Méndez, Rosa; Del Campo, Ana; Jiménez, Pilar; Aptsiauri, Natalia; Garrido, Federico; Ruiz-Cabello, Francisco

2007-01-01

The inability of cancer cells to present antigen on the cell surface via MHC class I molecules is one of the mechanisms by which tumor cells evade anti-tumor immunity. Alterations of Jak-STAT components of interferon (IFN)-mediated signaling can contribute to the mechanism of cell resistance to IFN, leading to lack of MHC class I inducibility. Hence, the identification of IFN-γ-resistant tumors may have prognostic and/or therapeutic relevance. In the present study, we investigated a mechanism of MHC class I inducibility in response to IFN-γ treatment in human melanoma cell lines. Basal and IFN-induced expression of HLA class I antigens was analyzed by means of indirect immunofluorescence flow cytometry, Western Blot, RT-PCR, and quantitative real-time RT-PCR (TaqMan ® Gene Expression Assays). In demethylation studies cells were cultured with 5-aza-2'-deoxycytidine. Electrophoretic Mobility Shift Assay (EMSA) was used to assay whether IRF-1 promoter binding activity is induced in IFN-γ-treated cells. Altered IFN-γ mediated HLA-class I induction was observed in two melanoma cells lines (ESTDAB-004 and ESTDAB-159) out of 57 studied, while treatment of these two cell lines with IFN-α led to normal induction of HLA class I antigen expression. Examination of STAT-1 in ESTDAB-004 after IFN-γ treatment demonstrated that the STAT-1 protein was expressed but not phosphorylated. Interestingly, IFN-α treatment induced normal STAT-1 phosphorylation and HLA class I expression. In contrast, the absence of response to IFN-γ in ESTDAB-159 was found to be associated with alterations in downstream components of the IFN-γ signaling pathway. We observed two distinct mechanisms of loss of IFN-γ inducibility of HLA class I antigens in two melanoma cell lines. Our findings suggest that loss of HLA class I induction in ESTDAB-004 cells results from a defect in the earliest steps of the IFN-γ signaling pathway due to absence of STAT-1 tyrosine-phosphorylation, while absence

Independent effects of colour on object identification and memory.

Science.gov (United States)

Lloyd-Jones, Toby J; Nakabayashi, Kazuyo

2009-02-01

We examined the effects of colour on object identification and memory using a study-test priming procedure with a coloured-object decision task at test (i.e., deciding whether an object is correctly coloured). Objects were selected to have a single associated colour and were either correctly or incorrectly coloured. In addition, object shape and colour were either spatially integrated (i.e., colour fell on the object surface) or spatially separated (i.e., colour formed the background to the object). Transforming the colour of an object from study to test (e.g., from a yellow banana to a purple banana) reduced priming of response times, as compared to when the object was untransformed. This utilization of colour information in object memory was not contingent upon colour falling on the object surface or whether the resulting configuration was of a correctly or incorrectly coloured object. In addition, we observed independent effects of colour on response times, whereby coloured-object decisions were more efficient for correctly than for incorrectly coloured objects but only when colour fell on the object surface. These findings provide evidence for two distinct mechanisms of shape-colour binding in object processing.

Participation of Children with Disabilities in Taiwan: The Gap between Independence and Frequency

Science.gov (United States)

Hwang, Ai-Wen; Yen, Chia-Feng; Liou, Tsan-Hon; Simeonsson, Rune J.; Chi, Wen-Chou; Lollar, Donald J.; Liao, Hua-Fang; Kang, Lin-Ju; Wu, Ting-Fang; Teng, Sue-Wen; Chiu, Wen-Ta

2015-01-01

Background Independence and frequency are two distinct dimensions of participation in daily life. The gap between independence and frequency may reflect the role of the environment on participation, but this distinction has not been fully explored. Methods A total of 18,119 parents or primary caregivers of children with disabilities aged 6.0-17.9 years were interviewed in a cross-sectional nationwide survey with the Functioning Scale of the Disability Evaluation System - Child version (FUNDES-Child). A section consisting of 20 items measured the children’s daily participation in 4 environmental settings: home, neighborhood/community, school, and home/community. Higher independence and frequency restriction scores indicated greater limitation of participation in daily activities. Scores for independence, frequency and independence-frequency gaps were examined across ages along with trend analysis. ANOVA was used to compare the gaps across settings and diagnoses for children with mild levels of severity of impairment. Findings A negative independence-frequency gap (restriction of frequency was greater than that of independence) was found for children with mild to severe levels of impairment. A positive gap (restriction of independence was greater than that of frequency) was found for children with profound levels of severity. The gaps became wider with age in most settings of children with mild impairment and different diagnoses. Widest negative gaps were found for the neighborhood/community settings than for the other three settings for children with mild to severe impairment. Conclusions Children’s participation and independence-frequency gaps depend not only on the severity of their impairments or diagnoses, but also on their age, the setting and the support provided by their environment. In Taiwan, more frequency restrictions than ability restrictions were found for children with mild to moderate severity, especially in the neighborhood/community setting, and

Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways

Energy Technology Data Exchange (ETDEWEB)

Lund, Leif R; Romer, John; Thomasset, Nicole; Solberg, Helene; Pyke, Charles; Bissell, Mina J; Dano, Keld; Werb, Zena

1996-01-01

Postlactational involution of the mammary gland is characterized by two distinct physiological events: apoptosis of the secretory, epithelial cells undergoing programmed cell death, and proteolytic degradation of the mammary gland basement membrane. We examined the spatial and temporal patterns of apoptotic cells in relation to those of proteinases during involution of the BALB/c mouse mammary gland. Apoptosis was almost absent during lactation but became evident at day 2 of involution, when {beta}-casein gene expression was still high. Apoptotic cells were then seen at least up to day 8 of involution, when {beta}-casein gene expression was being extinguished. Expression of sulfated glycoprotein-2 (SGP-2), interleukin-1{beta} converting enzyme (ICE) and tissue inhibitor of metalloproteinases-1 was upregulated at day 2, when apoptotic cells were seen initially. Expression of the matrix metalloproteinases gelatinase A and stromelysin-1 and the serine proteinase urokinase-type plasminogen activator, which was low during lactation, was strongly upregulated in parallel starting at day 4 after weaning, coinciding with start of the collapse of the lobulo-alveolar structures and the intensive tissue remodeling in involution. The major sites of mRNA synthesis for these proteinases were fibroblast-like cells in the periductal stroma and stromal cells surrounding the collapsed alveoli, suggesting that the degradative phase of involution is due to a specialized mesenchymal-epithelial interaction. To elucidate the functional role of these proteinases during involution, at the onset of weaning we treated mice systemically with the glucocorticoid hydrocortisone, which is known to inhibit mammary gland involution. Although the initial wave of apoptotic cells appeared in the lumina of the gland, the dramatic regression and tissue remodeling usually evident by day 5 was substantially inhibited by systemic treatment with hydrocortisone. mRNA and protein for gelatinase A, stromelysin

The 11S Proteasomal Activator REGγ Impacts Polyglutamine-Expanded Androgen Receptor Aggregation and Motor Neuron Viability through Distinct Mechanisms

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Jill M. Yersak

2017-05-01

Full Text Available Spinal and bulbar muscular atrophy (SBMA is caused by expression of a polyglutamine (polyQ-expanded androgen receptor (AR. The inefficient nuclear proteasomal degradation of the mutant AR results in the formation of nuclear inclusions containing amino-terminal fragments of the mutant AR. PA28γ (also referred to as REGγ is a nuclear 11S-proteasomal activator with limited proteasome activation capabilities compared to its cytoplasmic 11S (PA28α, PA28β counterparts. To clarify the role of REGγ in polyQ-expanded AR metabolism, we carried out genetic and biochemical studies in cell models of SBMA. Overexpression of REGγ in a PC12 cell model of SBMA increased polyQ-expanded AR aggregation and contributed to polyQ-expanded AR toxicity in the presence of dihydrotestosterone (DHT. These effects of REGγ were independent of its association with the proteasome and may be due, in part, to the decreased binding of polyQ-expanded AR by the E3 ubiquitin-ligase MDM2. Unlike its effects in PC12 cells, REGγ overexpression rescued transgenic SBMA motor neurons from DHT-induced toxicity in a proteasome binding-dependent manner, suggesting that the degradation of a specific 11S proteasome substrate or substrates promotes motor neuron viability. One potential substrate that we found to play a role in mutant AR toxicity is the splicing factor SC35. These studies reveal that, depending on the cellular context, two biological roles for REGγ impact cell viability in the face of polyQ-expanded AR; a proteasome binding-independent mechanism directly promotes mutant AR aggregation while a proteasome binding-dependent mechanism promotes cell viability. The balance between these functions likely determines REGγ effects on polyQ-expanded AR-expressing cells.

How Do Physicians Become Medical Experts? A Test of Three Competing Theories: Distinct Domains, Independent Influence and Encapsulation Models

Science.gov (United States)

Violato, Claudio; Gao, Hong; O'Brien, Mary Claire; Grier, David; Shen, E.

2018-01-01

The distinction between basic sciences and clinical knowledge which has led to a theoretical debate on how medical expertise is developed has implications for medical school and lifelong medical education. This longitudinal, population based observational study was conducted to test the fit of three theories--knowledge encapsulation, independent…

The neural cell adhesion molecule L1 is distinct from the N-CAM related group of surface antigens BSP-2 and D2

DEFF Research Database (Denmark)

Faissner, A; Kruse, J; Goridis, C

1984-01-01

The neural cell adhesion molecule L1 and the group of N-CAM related molecules, BSP-2 and D2 antigen, are immunochemically distinct molecular species. The two groups of surface molecules are also functionally distinct entities, since inhibition of Ca2+-independent adhesion among early post-natal m...

Ego mechanisms of defense are associated with patients? preference of treatment modality independent of psychological distress in end-stage renal disease

OpenAIRE

Hyphantis, Thomas; Katsoudas, Spiros; Voudiclari, Sonia

2010-01-01

Several parameters mediate the selection of treatment modality in end-stage renal disease (ESRD). The nephrology community suggests that patient preference should be the prime determinant of modality choice. We aimed to test whether ego mechanisms of defense are associated with patients? treatment modality preferences, independent of psychological distress. In 58 eligible ESRD patients who had themselves chosen their treatment modality, we administered the Symptom Distress Checklist-90-R and ...

Quantum Distinction: Quantum Distinctiones!

OpenAIRE

Zeps, Dainis

2009-01-01

10 pages; How many distinctions, in Latin, quantum distinctiones. We suggest approach of anthropic principle based on anthropic reference system which should be applied equally both in theoretical physics and in mathematics. We come to principle that within reference system of life subject of mathematics (that of thinking) should be equated with subject of physics (that of nature). For this reason we enter notions of series of distinctions, quantum distinction, and argue that quantum distinct...

Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes

DEFF Research Database (Denmark)

Gual, Philippe; Gonzalez, Teresa; Grémeaux, Thierry

2003-01-01

. Furthermore, the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented the osmotic shock-induced phosphorylation of IRS-1 on Ser307. The inhibition of mTOR completely reversed the inhibitory effect of hyperosmotic stress on insulin-induced IRS-1 tyrosine phosphorylation and PI 3-kinase activation......In 3T3-L1 adipocytes, hyperosmotic stress was found to inhibit insulin signaling, leading to an insulin-resistant state. We show here that, despite normal activation of insulin receptor, hyperosmotic stress inhibits both tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1....... In addition, prolonged osmotic stress enhanced the degradation of IRS proteins through a rapamycin-insensitive pathway and a proteasome-independent process. These data support evidence of new mechanisms involved in osmotic stress-induced cellular insulin resistance. Short-term osmotic stress induces...

The origin of the distinction between microscopic formulas for stress and Cauchy stress

OpenAIRE

Chen, Youping

2016-01-01

Stress is calculated routinely in atomistic simulations. The widely used microscopic stress formulas derived from classical or quantum mechanics, however, are distinct from the concept of Cauchy stress, i.e., the true mechanical tress. This work examines various atomistic stress formulations and their inconsistencies. Using standard mathematic theorems and the law of mechanics, we show that Cauchy stress results unambiguously from the definition of internal force density, thereby removing the...

Common and distinct brain networks underlying panic and social anxiety disorders.

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Kim, Yong-Ku; Yoon, Ho-Kyoung

2018-01-03

Although panic disorder (PD) and phobic disorders are independent anxiety disorders with distinct sets of diagnostic criteria, there is a high level of overlap between them in terms of pathogenesis and neural underpinnings. Functional connectivity research using resting-state functional magnetic resonance imaging (rsfMRI) shows great potential in identifying the similarities and differences between PD and phobias. Understanding common and distinct networks between PD and phobic disorders is critical for identifying both specific and general neural characteristics of these disorders. We review recent rsfMRI studies and explore the clinical relevance of resting-state functional connectivity (rsFC) in PD and phobias. Although findings differ between studies, there are some meaningful, consistent findings. Social anxiety disorder (SAD) and PD share common default mode network alterations. Alterations within the sensorimotor network are observed primarily in PD. Increased connectivity in the salience network is consistently reported in SAD. This review supports hypotheses that PD and phobic disorders share common rsFC abnormalities and that the different clinical phenotypes between the disorders come from distinct brain functional network alterations. Copyright © 2017 Elsevier Inc. All rights reserved.

Rethinking Sovereignty. Independence-lite, devolutionmax and national accommodation

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Michael Keating

2012-10-01

Full Text Available National self-determination does not necessarily entail independence. Many nationality movements in Europe have historically called for a continued association with the host state. Non-nationalist parties, in turn, have often embraced various forms of devolution. This has opened up a middle ground, in the form of ‘independence-lite’ or ‘devolution max’, which would givenations control of most domestic policy. Proposals on these lines have been put forward in Quebec, Catalonia, the Basque Country and Scotland. These would allow stateless nations to strike distinct social and economic compromises. They would not give them control over the levers of macro-economic policy. They would entail a bilateral relationship with the state. Such proposals have not found favour with state majorities, and recent debates have been characterized by rather traditional assertions of sovereignty at oddswith our interdependent world.

Universality of State-Independent Violation of Correlation Inequalities for Noncontextual Theories

International Nuclear Information System (INIS)

Badziag, Piotr; Bengtsson, Ingemar; Cabello, Adan; Pitowsky, Itamar

2009-01-01

We show that the state-independent violation of inequalities for noncontextual hidden variable theories introduced in [Phys. Rev. Lett. 101, 210401 (2008)] is universal, i.e., occurs for any quantum mechanical system in which noncontextuality is meaningful. We describe a method to obtain state-independent violations for any system of dimension d≥3. This universality proves that, according to quantum mechanics, there are no 'classical' states.

Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism

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Hubbard, Basil P; Loh, Christine; Gomes, Ana P; Li, Jun; Lu, Quinn; Doyle, Taylor LG; Disch, Jeremy S; Armour, Sean M; Ellis, James L; Vlasuk, George P; Sinclair, David A

2013-01-01

SIRT1 is an NAD+-dependent deacetylase that counteracts multiple disease states associated with aging and may underlie some of the health benefits of calorie restriction. Understanding how SIRT1 is regulated in vivo could therefore lead to new strategies to treat age-related diseases. SIRT1 forms a stable complex with DBC1, an endogenous inhibitor. Little is known regarding the biochemical nature of SIRT1-DBC1 complex formation, how it is regulated and whether or not it is possible to block this interaction pharmacologically. In this study, we show that critical residues within the catalytic core of SIRT1 mediate binding to DBC1 via its N-terminal region, and that several carboxamide SIRT1 inhibitors, including EX-527, can completely block this interaction. We identify two acetylation sites on DBC1 that regulate its ability to bind SIRT1 and suppress its activity. Furthermore, we show that DBC1 itself is a substrate for SIRT1. Surprisingly, the effect of EX-527 on SIRT1-DBC1 binding is independent of DBC1 acetylation. Together, these data show that protein acetylation serves as an endogenous regulatory mechanism for SIRT1-DBC1 binding and illuminate a new path to developing small-molecule modulators of SIRT1. PMID:23892437

Nitration of naphthalene and remarks on the mechanism of electrophilic aromatic nitration*

Science.gov (United States)

Olah, George A.; Narang, Subhash C.; Olah, Judith A.

1981-01-01

Naphthalene was nitrated with a variety of nitrating agents. Comparison of data with Perrin's electrochemical nitration [Perrin, C. L. (1977) J. Am. Chem. Soc. 99, 5516-5518] shows that nitration of naphthalene gives an α-nitronaphthalene to β-nitronaphthalene ratio that varies between 9 and 29 and is thus not constant. Perrin's data, therefore, are considered to be inconclusive evidence for the proposed one-electron transfer mechanism for the nitration of naphthalene and other reactive aromatics. Moodie and Schoefield [Hoggett, J. G., Moodie, R. B., Penton, J. R. & Schoefield, K. (1971) Nitration and Aromatic Reactivity (Cambridge Univ. Press, London)], as well as Perrin, independently concluded that, in the general scheme of nitration of reactive aromatics, there is the necessity to introduce into the classical Ingold mechanism an additional step involving a distinct intermediate preceding the formation of the Wheland intermediate (σ complexes). This view coincides with our two-step mechanistic picture [Kuhn, S. J. & Olah, G. A. (1961) J. Am. Chem. Soc. 83, 4564-4571] of the nitronium salt nitration of aromatic hydrocarbons (including benzene and toluene), in which low substrate selectivity but high positional selectivity was found, indicating the independence of substrate from positional selectivity. PMID:16593026

Nitration of naphthalene and remarks on the mechanism of electrophilic aromatic nitration.

Science.gov (United States)

Olah, G A; Narang, S C; Olah, J A

1981-06-01

Naphthalene was nitrated with a variety of nitrating agents. Comparison of data with Perrin's electrochemical nitration [Perrin, C. L. (1977) J. Am. Chem. Soc. 99, 5516-5518] shows that nitration of naphthalene gives an alpha-nitronaphthalene to beta-nitronaphthalene ratio that varies between 9 and 29 and is thus not constant. Perrin's data, therefore, are considered to be inconclusive evidence for the proposed one-electron transfer mechanism for the nitration of naphthalene and other reactive aromatics. Moodie and Schoefield [Hoggett, J. G., Moodie, R. B., Penton, J. R. & Schoefield, K. (1971) Nitration and Aromatic Reactivity (Cambridge Univ. Press, London)], as well as Perrin, independently concluded that, in the general scheme of nitration of reactive aromatics, there is the necessity to introduce into the classical Ingold mechanism an additional step involving a distinct intermediate preceding the formation of the Wheland intermediate (sigma complexes). This view coincides with our two-step mechanistic picture [Kuhn, S. J. & Olah, G. A. (1961) J. Am. Chem. Soc. 83, 4564-4571] of the nitronium salt nitration of aromatic hydrocarbons (including benzene and toluene), in which low substrate selectivity but high positional selectivity was found, indicating the independence of substrate from positional selectivity.

Phylogeographic Evidence for 2 Genetically Distinct Zoonotic Plasmodium knowlesi Parasites, Malaysia.

Science.gov (United States)

Yusof, Ruhani; Ahmed, Md Atique; Jelip, Jenarun; Ngian, Hie Ung; Mustakim, Sahlawati; Hussin, Hani Mat; Fong, Mun Yik; Mahmud, Rohela; Sitam, Frankie Anak Thomas; Japning, J Rovie-Ryan; Snounou, Georges; Escalante, Ananias A; Lau, Yee Ling

2016-08-01

Infections of humans with the zoonotic simian malaria parasite Plasmodium knowlesi occur throughout Southeast Asia, although most cases have occurred in Malaysia, where P. knowlesi is now the dominant malaria species. This apparently skewed distribution prompted an investigation of the phylogeography of this parasite in 2 geographically separated regions of Malaysia, Peninsular Malaysia and Malaysian Borneo. We investigated samples collected from humans and macaques in these regions. Haplotype network analyses of sequences from 2 P. knowlesi genes, type A small subunit ribosomal 18S RNA and cytochrome c oxidase subunit I, showed 2 genetically distinct divergent clusters, 1 from each of the 2 regions of Malaysia. We propose that these parasites represent 2 distinct P. knowlesi types that independently became zoonotic. These types would have evolved after the sea-level rise at the end of the last ice age, which separated Malaysian Borneo from Peninsular Malaysia.

Implement of the Owner Distinction Function for Healing-Type Pet Robots

Science.gov (United States)

Nambo, Hidetaka; Kimura, Haruhiko; Hirose, Sadaki

In recent years, a robotics technology is extremely progressive, and robots are widely applied in many fields. One of the most typical robots is a pet robot. The pet robot is based on an animal pet, such as a dog or a cat. Also, it is known that an animal pet has a healing effect. Therefore, the study to apply pet robots to Animal Assisted Therapy instead of an animal pet has begun to be investigated. We, also, have investigated a method of an owner distinction for pet robot, to emphasize a healing effect of pet robots. In this paper, taking account of implementation into pet robots, a real-time owner distinction method is proposed. In the concrete, the method provides a real-time matching algorithm and an oblivion mechanism. The real-time matching means that a matching and a data acquisition are processed simultaneously. The oblivion mechanism is deleting features of owners in the database of the pet robots. Additionally, the mechanism enables to reduce matching costs or size of database and it enables to follow a change of owners. Furthermore, effectivity and a practicality of the method are evaluated by experiments.

Are Independent Probes Truly Independent?

Science.gov (United States)

Camp, Gino; Pecher, Diane; Schmidt, Henk G.; Zeelenberg, Rene

2009-01-01

The independent cue technique has been developed to test traditional interference theories against inhibition theories of forgetting. In the present study, the authors tested the critical criterion for the independence of independent cues: Studied cues not presented during test (and unrelated to test cues) should not contribute to the retrieval…

Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms.

Science.gov (United States)

Thiele, Frank; Cohrs, Christian M; Flor, Armando; Lisse, Thomas S; Przemeck, Gerhard K H; Horsch, Marion; Schrewe, Anja; Gailus-Durner, Valerie; Ivandic, Boris; Katus, Hugo A; Wurst, Wolfgang; Reisenberg, Catherine; Chaney, Hollis; Fuchs, Helmut; Hans, Wolfgang; Beckers, Johannes; Marini, Joan C; Hrabé de Angelis, Martin

2012-08-15

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with skeletal dysplasia of varying severity, predominantly caused by mutations in the collagen I genes (COL1A1/COL1A2). Extraskeletal findings such as cardiac and pulmonary complications are generally considered to be significant secondary features. Aga2, a murine model for human OI, was systemically analyzed in the German Mouse Clinic by means of in vivo and in vitro examinations of the cardiopulmonary system, to identify novel mechanisms accounting for perinatal lethality. Pulmonary and, especially, cardiac fibroblast of perinatal lethal Aga2/+ animals display a strong down-regulation of Col1a1 transcripts in vivo and in vitro, resulting in a loss of extracellular matrix integrity. In addition, dysregulated gene expression of Nppa, different types of collagen and Agt in heart and lung tissue support a bone-independent vicious cycle of heart dysfunction, including hypertrophy, loss of myocardial matrix integrity, pulmonary hypertension, pneumonia and hypoxia leading to death in Aga2. These murine findings are corroborated by a pediatric OI cohort study, displaying significant progressive decline in pulmonary function and restrictive pulmonary disease independent of scoliosis. Most participants show mild cardiac valvular regurgitation, independent of pulmonary and skeletal findings. Data obtained from human OI patients and the mouse model Aga2 provide novel evidence for primary effects of type I collagen mutations on the heart and lung. The findings will have potential benefits of anticipatory clinical exams and early intervention in OI patients.

Visuospatial Orientational Shifts: Evidence for Three Independent Mechanisms.

Science.gov (United States)

Noonan, Michael; Axelrod, Seymour

While it is often assumed that a single mechanism underlies varied experimental evidences of selectivity, Berlyne (1969) suggested that attention-like selectivity may take place in a number of quite separate neural systems. This study examined the issue of visuospatial attention by investigating covert orientation or "looking out of the corner of…

Age-associated impairments in contraction-induced rapid-onset vasodilatation within the forearm are independent of mechanical factors.

Science.gov (United States)

Hughes, William E; Kruse, Nicholas T; Casey, Darren P

2018-05-01

What is the central question of this study? We examined whether the mechanical contribution to contraction-induced rapid-onset vasodilatation (ROV) differed with age and whether ROV is associated with peripheral artery stiffness. Furthermore, we examined how manipulation of perfusion pressure modulates ROV in young and older adults. What is the main finding and its importance? The mechanical contribution to ROV is similar in young and older adults. Conversely, peripheral arterial stiffness is not associated with ROV. Enhancing perfusion pressure augments ROV to a similar extent in young and older adults. These results suggest that age-related attenuations in ROV are not attributable to a mechanical component and that ROV responses are independent of peripheral artery stiffness. Contraction-induced rapid-onset vasodilatation (ROV) is modulated by perfusion and transmural pressure in young adults; however, this effect remains unknown in older adults. The present study examined the mechanical contribution to ROV in young versus older adults, the influence of perfusion pressure and whether these responses are associated with arterial stiffness. Forearm vascular conductance (in millilitres per minute per 100 mmHg) was measured in 12 healthy young (24 ± 4 years old) and 12 older (67 ± 3 years old) adults during: (i) single dynamic contractions at 20% of maximal voluntary contraction; and (ii) single external mechanical compression of the forearm (200 mmHg) positioned above, at and below heart level. Carotid-radial pulse-wave velocity characterized upper limb arterial stiffness. Total ROV responses to single muscle contractions and single external mechanical compressions were attenuated in older adults at heart level (P mechanical contribution to contraction-induced peak (46 ± 14 versus 40 ± 18%; P = 0.21) and total (37 ± 21 versus 32 ± 18%; P = 0.27) responses were not different between young and older adults. Reducing or enhancing perfusion

Independent and additive effects of glutamic acid and methionine on yeast longevity.

Science.gov (United States)

Wu, Ziyun; Song, Lixia; Liu, Shao Quan; Huang, Dejian

2013-01-01

It is established that glucose restriction extends yeast chronological and replicative lifespan, but little is known about the influence of amino acids on yeast lifespan, although some amino acids were reported to delay aging in rodents. Here we show that amino acid composition greatly alters yeast chronological lifespan. We found that non-essential amino acids (to yeast) methionine and glutamic acid had the most significant impact on yeast chronological lifespan extension, restriction of methionine and/or increase of glutamic acid led to longevity that was not the result of low acetic acid production and acidification in aging media. Remarkably, low methionine, high glutamic acid and glucose restriction additively and independently extended yeast lifespan, which could not be further extended by buffering the medium (pH 6.0). Our preliminary findings using yeasts with gene deletion demonstrate that glutamic acid addition, methionine and glucose restriction prompt yeast longevity through distinct mechanisms. This study may help to fill a gap in yeast model for the fast developing view that nutrient balance is a critical factor to extend lifespan.

Alternate capping mechanisms for transcription of spring viremia of carp virus: evidence for independent mRNA initiation.

Science.gov (United States)

Gupta, K C; Roy, P

1980-01-01

Two alternate mechanisms of mRNA capping for spring viremia of carp virus have been observed. Under normal reaction conditions, a ppG residue of the capping GTP is transferred to a pA moiety of the 5' termini of mRNA transcripts. However, in reaction conditions where GppNHp is used instead of GTP, an alternate capping mechanism occurs whereby a pG residue of the capping GTP is transferred to a ppA moiety of the transcripts. The first mechanism is identical to that described previously for vesicular stomatitis virus (G. Abraham, D. P. Rhodes, and A. K. Banerjee, Nature [London] 255:37-40, 1975; A. K. Banerjee, S. A. Moyer, and D. P. Rhodes, Virology 61:547-558, 1974), and thus appears to be a conserved function during the evolution of rhabdoviruses. The alternate mechanism of capping indicates not only that capping can take place by two procedures, but also that the substrate termini have di- or triphosphate 5' ends, indicating that they are probably independently initiated. An analog of ATP, AppNHp, has been found to completely inhibit the initiation of transcription by spring viremia of carp virus, suggesting that a cleavage between the beta and gamma phosphates of ATP is essential for the initiation of transcription. However, in the presence of GppNHp, uncapped (ppAp and pppAp), capped (GpppAp), and capped methylated (m7GpppAmpAp and GpppAmpAp) transcripts are detected. Size analyses of oligodeoxythymidylic acid-cellulose-bound transcripts resolved by formamide gel electrophoresis demonstrated that full-size mRNA transcripts are synthesized as well as larger RNA species. The presence of GppNHp and S-adenosylhomocysteine in reaction mixtures did not have any effect on the type of unmethylated transcription products. Our results favor a transcription model postulated previously (D. H. L. Bishop, in H. Fraenkel-Conrat and R. R. Wagner, ed., Comprehensive Virology, vol. 10, Plenum Press, New York, 1977; D. H. L. Bishop and A. Flamand, in D. C. Burke and W. C. Russell

Development of independent walking in toddlers

NARCIS (Netherlands)

Ivanenko, Yuri P; Dominici, Nadia; Lacquaniti, Francesco

Surprisingly, despite millions of years of bipedal walking evolution, the gravity-related pendulum mechanism of walking does not seem to be implemented at the onset of independent walking, requiring each toddler to develop it. We discuss the precursor of the mature locomotor pattern in infants as an

The use of a path independent integral in non-linear fracture mechanics

International Nuclear Information System (INIS)

Hellen, T.K.

1977-01-01

The use of the Rice J-intergral to assess conditions at a crack tip in an elastic or non-linear elastic body is well known. The integral equals the energy release rate and is path independent for any contour surrounding the crack tip provided no other singularities are encompassed. The path independence propertiy breaks down, however, in more general situations such as in three dimensional stress systems, plasticity unloading, thermal or creep states. Hence the required crack tip characteristics represented by the value of the integral round a contour whose radius about the tip tends to zero, is not reproduced along contours away from the tip. Consequently, an alternative integral, designated J*, has been proposed which equals J for elastic cases and in the other cases cited above remains path independent. A computer program for calculating the J and J* integrals has been developed as an extension to the BERSAFE finite element system. A full analysis of the cracked structure including plasticity, creep and thermal strains is conducted and the results are stored on a permanent data set. The integral values may then be calculated using the post-processor program for any number of contours and load or time steps, without recourse to further expensive computations. (Auth. )

Interactive learning environments to support independent learning: the impact of discernability of embedded support devices

NARCIS (Netherlands)

Martens, Rob; Valcke, Martin; Portier, Stanley

2017-01-01

In this article the effectivity of prototypes of interactive learning environments (ILE) is investigated. These computer-based environments are used for independent learning. In the learning materials, represented in the prototypes, a clear distinction is made between the basic content and embedded

Dimension-independent likelihood-informed MCMC

KAUST Repository

Cui, Tiangang

2015-10-08

Many Bayesian inference problems require exploring the posterior distribution of high-dimensional parameters that represent the discretization of an underlying function. This work introduces a family of Markov chain Monte Carlo (MCMC) samplers that can adapt to the particular structure of a posterior distribution over functions. Two distinct lines of research intersect in the methods developed here. First, we introduce a general class of operator-weighted proposal distributions that are well defined on function space, such that the performance of the resulting MCMC samplers is independent of the discretization of the function. Second, by exploiting local Hessian information and any associated low-dimensional structure in the change from prior to posterior distributions, we develop an inhomogeneous discretization scheme for the Langevin stochastic differential equation that yields operator-weighted proposals adapted to the non-Gaussian structure of the posterior. The resulting dimension-independent and likelihood-informed (DILI) MCMC samplers may be useful for a large class of high-dimensional problems where the target probability measure has a density with respect to a Gaussian reference measure. Two nonlinear inverse problems are used to demonstrate the efficiency of these DILI samplers: an elliptic PDE coefficient inverse problem and path reconstruction in a conditioned diffusion.

Dimension-independent likelihood-informed MCMC

KAUST Repository

Cui, Tiangang; Law, Kody; Marzouk, Youssef M.

2015-01-01

Many Bayesian inference problems require exploring the posterior distribution of high-dimensional parameters that represent the discretization of an underlying function. This work introduces a family of Markov chain Monte Carlo (MCMC) samplers that can adapt to the particular structure of a posterior distribution over functions. Two distinct lines of research intersect in the methods developed here. First, we introduce a general class of operator-weighted proposal distributions that are well defined on function space, such that the performance of the resulting MCMC samplers is independent of the discretization of the function. Second, by exploiting local Hessian information and any associated low-dimensional structure in the change from prior to posterior distributions, we develop an inhomogeneous discretization scheme for the Langevin stochastic differential equation that yields operator-weighted proposals adapted to the non-Gaussian structure of the posterior. The resulting dimension-independent and likelihood-informed (DILI) MCMC samplers may be useful for a large class of high-dimensional problems where the target probability measure has a density with respect to a Gaussian reference measure. Two nonlinear inverse problems are used to demonstrate the efficiency of these DILI samplers: an elliptic PDE coefficient inverse problem and path reconstruction in a conditioned diffusion.

Rolie-Poly fluid flowing through constrictions: Two distinct instabilities

KAUST Repository

Reis, T.; Wilson, H.J.

2013-01-01

Elastic instabilities of entangled polymer melts are common in industrial processes but the physics responsible is not well understood. We present a numerical linear stability study of a molecular based constitutive model which grants us physical insight into the underlying mechanics involved. Two constriction flows are considered - one shear dominated, the other extension dominated - and two distinct instabilities are found. The influence of the molecular structure and the behaviour of the polymer dynamics are investigated and in both cases chain relaxation and orientation play a crucial role. This suggests a molecular-based physical interpretation of the underlying mechanisms responsible for flow instabilities. © 2013 Elsevier B.V.

Rolie-Poly fluid flowing through constrictions: Two distinct instabilities

KAUST Repository

Reis, T.

2013-05-01

Elastic instabilities of entangled polymer melts are common in industrial processes but the physics responsible is not well understood. We present a numerical linear stability study of a molecular based constitutive model which grants us physical insight into the underlying mechanics involved. Two constriction flows are considered - one shear dominated, the other extension dominated - and two distinct instabilities are found. The influence of the molecular structure and the behaviour of the polymer dynamics are investigated and in both cases chain relaxation and orientation play a crucial role. This suggests a molecular-based physical interpretation of the underlying mechanisms responsible for flow instabilities. © 2013 Elsevier B.V.

Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies.

Science.gov (United States)

Arnedo, Javier; Svrakic, Dragan M; Del Val, Coral; Romero-Zaliz, Rocío; Hernández-Cuervo, Helena; Fanous, Ayman H; Pato, Michele T; Pato, Carlos N; de Erausquin, Gabriel A; Cloninger, C Robert; Zwir, Igor

2015-02-01

The authors sought to demonstrate that schizophrenia is a heterogeneous group of heritable disorders caused by different genotypic networks that cause distinct clinical syndromes. In a large genome-wide association study of cases with schizophrenia and controls, the authors first identified sets of interacting single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (SNP sets) regardless of clinical status. Second, they examined the risk of schizophrenia for each SNP set and tested replicability in two independent samples. Third, they identified genotypic networks composed of SNP sets sharing SNPs or subjects. Fourth, they identified sets of distinct clinical features that cluster in particular cases (phenotypic sets or clinical syndromes) without regard for their genetic background. Fifth, they tested whether SNP sets were associated with distinct phenotypic sets in a replicable manner across the three studies. The authors identified 42 SNP sets associated with a 70% or greater risk of schizophrenia, and confirmed 34 (81%) or more with similar high risk of schizophrenia in two independent samples. Seventeen networks of SNP sets did not share any SNP or subject. These disjoint genotypic networks were associated with distinct gene products and clinical syndromes (i.e., the schizophrenias) varying in symptoms and severity. Associations between genotypic networks and clinical syndromes were complex, showing multifinality and equifinality. The interactive networks explained the risk of schizophrenia more than the average effects of all SNPs (24%). Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.

House dust mite major allergens Der p 1 and Der p 5 activate human airway-derived epithelial cells by protease-dependent and protease-independent mechanisms

Directory of Open Access Journals (Sweden)

Timmerman J André B

2006-03-01

Full Text Available Abstract House dust mite allergens (HDM cause bronchoconstriction in asthma patients and induce an inflammatory response in the lungs due to the release of cytokines, chemokines and additional mediators. The mechanism how HDM components achieve this is largely unknown. The objective of this study was to assess whether HDM components of Dermatophagoides pteronissinus with protease activity (Der p 1 and unknown enzymatic activity (Der p 2, Der p 5 induce biological responses in a human airway-derived epithelial cell line (A549, and if so, to elucidate the underlying mechanism(s of action. A549 cells were incubated with HDM extract, Der p 1, recombinant Der p 2 and recombinant Der p 5. Cell desquamation was assessed by microscopy. The proinflammatory cytokines, IL-6 and IL-8, were measured by ELISA. Intracellular Ca2+ levels were assessed in A549 cells and in mouse fibroblasts expressing the human protease activated receptor (PAR1, PAR2 or PAR4. HDM extract, Der p 1 and Der p 5 dose-dependently increased the production of IL-6 and IL-8. Added simultaneously, Der p 1 and Der p 5 further increased the production of IL-6 and IL-8. The action of Der p 1 was blocked by cysteine-protease inhibitors, while that of Der p 5 couldn't be blocked by either serine- or cysteine protease inhibitors. Der p 5 only induced cell shrinking, whereas HDM extract and Der p1 also induced cell desquamation. Der p 2 had no effect on A549 cells. Der p 1's protease activity causes desquamation and induced the release of IL6 and IL-8 by a mechanism independent of Ca2+ mobilisation and PAR activation. Der p 5 exerts a protease-independent activation of A549 that involves Ca2+ mobilisation and also leads to the production of these cytokines. Together, our data indicate that allergens present in HDM extracts can trigger protease-dependent and protease-independent signalling pathways in A549 cells.

Strength and Aerobic Exercises Improve Spatial Memory in Aging Rats Through Stimulating Distinct Neuroplasticity Mechanisms.

Science.gov (United States)

Vilela, Thais Ceresér; Muller, Alexandre Pastoris; Damiani, Adriani Paganini; Macan, Tamires Pavei; da Silva, Sabrina; Canteiro, Paula Bortoluzzi; de Sena Casagrande, Alisson; Pedroso, Giulia Dos Santos; Nesi, Renata Tiscoski; de Andrade, Vanessa Moraes; de Pinho, Ricardo Aurino

2017-12-01

Aging is associated with impaired cognition and memory and increased susceptibility to neurodegenerative disorders. Physical exercise is neuroprotective; however, the major evidence of this effect involves studies of only aerobic training in young animals. The benefits of other exercise protocols such as strength training in aged animals remains unknown. Here, we investigated the effect of aerobic and strength training on spatial memory and hippocampal plasticity in aging rats. Aging Wistar rats performed aerobic or strength training for 50 min 3 to 4 days/week for 8 weeks. Spatial memory and neurotrophic and glutamatergic signaling in the hippocampus of aged rats were evaluated after aerobic or strength training. Both aerobic and strength training improved cognition during the performance of a spatial memory task. Remarkably, the improvement in spatial memory was accompanied by an increase in synaptic plasticity proteins within the hippocampus after exercise training, with some differences in the intracellular functions of those proteins between the two exercise protocols. Moreover, neurotrophic signaling (CREB, BDNF, and the P75 NTR receptor) increased after training for both exercise protocols, and aerobic exercise specifically increased glutamatergic proteins (NMDA receptor and PSD-95). We also observed a decrease in DNA damage after aerobic training. In contrast, strength training increased levels of PKCα and the proinflammatory factors TNF-α and IL-1β. Overall, our results show that both aerobic and strength training improved spatial memory in aging rats through inducing distinct molecular mechanisms of neuroplasticity. Our findings extend the idea that exercise protocols can be used to improve cognition during aging.

Existence of a dictatorial subgroup in social choice with independent subgroup utility scales, an alternative proof

NARCIS (Netherlands)

Khmelnitskaya, Anna Borisovna; van Deemen, Adrian; Rusinowska, Agnieszka

2010-01-01

Social welfare orderings for different scales of individual utility measurement in distinct population subgroups are studied. In Khmelnitskaya (2000), employing the continuous version of Arrow’s impossibility theorem, it was shown that for combinations of independent subgroups scales every

S 47445 Produces Antidepressant- and Anxiolytic-Like Effects through Neurogenesis Dependent and Independent Mechanisms

Directory of Open Access Journals (Sweden)

Indira Mendez-David

2017-07-01

rat model, S 47445 (from 1 mg/kg demonstrated a rapid onset of effect on anhedonia compared to venlafaxine and imipramine. In the CORT model, S 47445 demonstrated significant neurogenic effects on proliferation, survival and maturation of hippocampal newborn neurons at doses inducing an antidepressant-like effect. It also corrected CORT-induced deficits of growth and arborization of dendrites. Finally, the antidepressant/anxiolytic-like activities of S 47445 required adult hippocampal neurogenesis in the novelty suppressed feeding test contrary to OF, EPM and ST. The observed increase in hippocampal BDNF levels could be one of the mechanisms of S 47445 responsible for the adult hippocampal neurogenesis increase. Altogether, S 47445 displays robust antidepressant-anxiolytic-like properties after chronic administration through neurogenesis dependent/independent mechanisms and neuroplastic activities. The AMPA-PAM S 47445 could have promising therapeutic potential for the treatment of major depressive disorders or generalized anxiety disorders.

Extension of Drosophila lifespan by Rhodiola rosea through a mechanism independent from dietary restriction.

Directory of Open Access Journals (Sweden)

Samuel E Schriner

Full Text Available Rhodiola rosea has been extensively used to improve physical and mental performance and to protect against stress. We, and others, have reported that R. rosea can extend lifespan in flies, worms, and yeast. However, its molecular mechanism is currently unknown. Here, we tested whether R. rosea might act through a pathway related to dietary restriction (DR that can extend lifespan in a range of model organisms. While the mechanism of DR itself is also unknown, three molecular pathways have been associated with it: the silent information regulator 2 (SIR2 proteins, insulin and insulin-like growth factor signaling (IIS, and the target of rapamycin (TOR. In flies, DR is implemented through a reduction in dietary yeast content. We found that R. rosea extract extended lifespan in both sexes independent of the yeast content in the diet. We also found that the extract extended lifespan when the SIR2, IIS, or TOR pathways were genetically perturbed. Upon examination of water and fat content, we found that R. rosea decreased water content and elevated fat content in both sexes, but did not sensitize flies to desiccation or protect them against starvation. There were some sex-specific differences in response to R. rosea. In female flies, the expression levels of glycolytic genes and dSir2 were down-regulated, and NADH levels were decreased. In males however, R. rosea provided no protection against heat stress and had no effect on the major heat shock protein HSP70 and actually down-regulated the mitochondrial HSP22. Our findings largely rule out an elevated general resistance to stress and DR-related pathways as mechanistic candidates. The latter conclusion is especially relevant given the limited potential for DR to improve human health and lifespan, and presents R. rosea as a potential viable candidate to treat aging and age-related diseases in humans.

Distinct genetic architectures for phenotype means and plasticities in Zea mays.

Science.gov (United States)

Kusmec, Aaron; Srinivasan, Srikant; Nettleton, Dan; Schnable, Patrick S

2017-09-01

Phenotypic plasticity describes the phenotypic variation of a trait when a genotype is exposed to different environments. Understanding the genetic control of phenotypic plasticity in crops such as maize is of paramount importance for maintaining and increasing yields in a world experiencing climate change. Here, we report the results of genome-wide association analyses of multiple phenotypes and two measures of phenotypic plasticity in a maize nested association mapping (US-NAM) population grown in multiple environments and genotyped with ~2.5 million single-nucleotide polymorphisms. We show that across all traits the candidate genes for mean phenotype values and plasticity measures form structurally and functionally distinct groups. Such independent genetic control suggests that breeders will be able to select semi-independently for mean phenotype values and plasticity, thereby generating varieties with both high mean phenotype values and levels of plasticity that are appropriate for the target performance environments.

Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins

Directory of Open Access Journals (Sweden)

Takeru Hayashi

2017-09-01

Full Text Available Helicobacter pylori East Asian CagA is more closely associated with gastric cancer than Western CagA. Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C. This high-affinity binding is achieved via cryptic interaction between Phe at the +5 position from phosphotyrosine in EPIYA-D and a hollow on the N-SH2 phosphopeptide-binding floor. Also, duplication of EPIYA-C in Western CagA, which increases gastric cancer risk, enables divalent high-affinity binding with SHP2 via N-SH2 and C-SH2. These strong CagA bindings enforce enzymatic activation of SHP2, which endows cells with neoplastic traits. Mechanistically, N-SH2 in SHP2 is in an equilibrium between stimulatory “relaxed” and inhibitory “squeezed” states, which is fixed upon high-affinity CagA binding to the “relaxed” state that stimulates SHP2. Accordingly, East Asian CagA and Western CagA exploit distinct mechanisms for SHP2 deregulation.

Different selection pressures give rise to distinct ethnic phenomena : a functionalist framework with illustrations from the Peruvian Altiplano.

Science.gov (United States)

Moya, Cristina; Boyd, Robert

2015-03-01

Many accounts of ethnic phenomena imply that processes such as stereotyping, essentialism, ethnocentrism, and intergroup hostility stem from a unitary adaptation for reasoning about groups. This is partly justified by the phenomena's co-occurrence in correlational studies. Here we argue that these behaviors are better modeled as functionally independent adaptations that arose in response to different selection pressures throughout human evolution. As such, different mechanisms may be triggered by different group boundaries within a single society. We illustrate this functionalist framework using ethnographic work from the Quechua-Aymara language boundary in the Peruvian Altiplano. We show that different group boundaries motivate different ethnic phenomena. For example, people have strong stereotypes about socioeconomic categories, which are not cooperative units, whereas they hold fewer stereotypes about communities, which are the primary focus of cooperative activity. We also show that, despite the cross-cultural importance of ethnolinguistic boundaries, the Quechua-Aymara linguistic distinction does not strongly motivate any of these intergroup processes.

Autoshaping with common and distinctive stimulus elements, compact and dispersed arrays.

Science.gov (United States)

Sperling, S E; Perkins, M E

1979-05-01

Four groups of pigeons were trained with a standard autoshaping procedure in which a brief fixed-duration interval always followed by a grain delivery alternated with a longer variable-duration interval never associated with grain delivery. One of two stimuli was always presented during each interval. One of them contained three black dots and a black star on a green background; the other contained four black dots on a green background. The four elements of each stimulus were arranged in a more compact array for two groups and in a more dispersed array for the other two groups. Which of the two stimuli preceded grain delivery was counterbalanced within each pair of groups. The speed of occurrence of the first autoshaped peck was not affected by whether the stimulus containing the distinctive star element preceded grain delivery, but autoshaping was faster when the stimulus arrays were compact than when they were dispersed. During 560 response-independent training trials that followed the first autoshaped peck, this pattern reversed; both discriminative control over responding and the relative frequency of pecking the stimulus that preceded grain delivery were greater for the two groups where this stimulus contained the discriminative element than for the two groups where it contained only common elements. During subsequent testing with stimuli containing only a single element each, the distinctive feature was responded to proportionately more often by the two groups for which it had been an element of the stimulus preceding grain delivery than by the two groups for which it had been an element of the stimulus complex that never was associated with grain delivery. These data add further support to the hypothesis that the initial occurrence of autoshaped responding and its subsequent maintenance are not affected by the same variables. They also suggest that automaintenance is as sensitive as response-dependent training to the presence or absence of a distinctive

Load and distinctness interact in working memory for lexical manual gestures

Directory of Open Access Journals (Sweden)

Mary eRudner

2015-08-01

Full Text Available The Ease of Language Understanding model (ELU, Rönnberg et al., 2013 predicts that decreasing the distinctness of language stimuli increases working memory load; in the speech domain this notion is supported by empirical evidence. Our aim was to determine whether such an over-additive interaction can be generalized to sign processing in sign-naïve individuals and whether it is modulated by experience of computer gaming. Twenty young adults with no knowledge of sign language performed an n-back working memory task based on manual gestures lexicalized in sign language; the visual resolution of the signs and working memory load were manipulated. Performance was poorer when load was high and resolution was low. These two effects interacted over-additively, demonstrating that reducing the resolution of signed stimuli increases working memory load when there is no pre-existing semantic representation. This suggests that load and distinctness are handled by a shared amodal mechanism which can be revealed empirically when stimuli are degraded and load is high, even without pre-existing semantic representation. There was some evidence that the mechanism is influenced by computer gaming experience. Future work should explore how the shared mechanism is influenced by pre-existing semantic representation and sensory factors together with computer gaming experience.

Load and distinctness interact in working memory for lexical manual gestures.

Science.gov (United States)

Rudner, Mary; Toscano, Elena; Holmer, Emil

2015-01-01

The Ease of Language Understanding model (Rönnberg et al., 2013) predicts that decreasing the distinctness of language stimuli increases working memory load; in the speech domain this notion is supported by empirical evidence. Our aim was to determine whether such an over-additive interaction can be generalized to sign processing in sign-naïve individuals and whether it is modulated by experience of computer gaming. Twenty young adults with no knowledge of sign language performed an n-back working memory task based on manual gestures lexicalized in sign language; the visual resolution of the signs and working memory load were manipulated. Performance was poorer when load was high and resolution was low. These two effects interacted over-additively, demonstrating that reducing the resolution of signed stimuli increases working memory load when there is no pre-existing semantic representation. This suggests that load and distinctness are handled by a shared amodal mechanism which can be revealed empirically when stimuli are degraded and load is high, even without pre-existing semantic representation. There was some evidence that the mechanism is influenced by computer gaming experience. Future work should explore how the shared mechanism is influenced by pre-existing semantic representation and sensory factors together with computer gaming experience.

Distinct neural control of intrinsic and extrinsic muscles of the hand during single finger pressing.

Science.gov (United States)

Dupan, Sigrid S G; Stegeman, Dick F; Maas, Huub

2018-06-01

Single finger force tasks lead to unintended activation of the non-instructed fingers, commonly referred to as enslaving. Both neural and mechanical factors have been associated with this absence of finger individuality. This study investigates the amplitude modulation of both intrinsic and extrinsic finger muscles during single finger isometric force tasks. Twelve participants performed single finger flexion presses at 20% of maximum voluntary contraction, while simultaneously the electromyographic activity of several intrinsic and extrinsic muscles associated with all four fingers was recorded using 8 electrode pairs in the hand and two 30-electrode grids on the lower arm. The forces exerted by each of the fingers, in both flexion and extension direction, were recorded with individual force sensors. This study shows distinct activation patterns in intrinsic and extrinsic hand muscles. Intrinsic muscles exhibited individuation, where the agonistic and antagonistic muscles associated with the instructed fingers showed the highest activation. This activation in both agonistic and antagonistic muscles appears to facilitate finger stabilisation during the isometric force task. Extrinsic muscles show an activation independent from instructed finger in both agonistic and antagonistic muscles, which appears to be associated with stabilisation of the wrist, with an additional finger-dependent modulation only present in the agonistic extrinsic muscles. These results indicate distinct muscle patterns in intrinsic and extrinsic hand muscles during single finger isometric force pressing. We conclude that the finger specific activation of intrinsic muscles is not sufficient to fully counteract enslaving caused by the broad activation of the extrinsic muscles. Copyright © 2018 Elsevier B.V. All rights reserved.

Distinct Neural Mechanisms Mediate Olfactory Memory Formation at Different Timescales

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McNamara, Ann Marie; Magidson, Phillip D.; Linster, Christiane; Wilson, Donald A.; Cleland, Thomas A.

2008-01-01

Habituation is one of the oldest forms of learning, broadly expressed across sensory systems and taxa. Here, we demonstrate that olfactory habituation induced at different timescales (comprising different odor exposure and intertrial interval durations) is mediated by different neural mechanisms. First, the persistence of habituation memory is…

The Gaseous State. Independent Learning Project for Advanced Chemistry (ILPAC). Unit P1.

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Inner London Education Authority (England).

This unit on the gaseous state is one of 10 first year units produced by the Independent Learning Project for Advanced Chemistry (ILPAC). The unit consists of two levels. Level one deals with the distinctive characteristics of gases, then considers the gas laws, in particular the ideal gas equation and its applications. Level two concentrates on…

Distinct mechanisms are responsible for osteopenia and growth retardation in OASIS-deficient mice.

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Murakami, Tomohiko; Hino, Shin-Ichiro; Nishimura, Riko; Yoneda, Toshiyuki; Wanaka, Akio; Imaizumi, Kazunori

2011-03-01

Old astrocyte specifically induced substance (OASIS), which is a new type of endoplasmic reticulum (ER) stress transducer, is a basic leucine zipper transcription factor of the CREB/ATF family that contains a transmembrane domain and is processed by regulated intramembrane proteolysis in response to ER stress. OASIS is selectively expressed in certain types of cells such as astrocytes and osteoblasts. We have previously demonstrated that OASIS activates transcription of the type I collagen gene Col1a1 and contributes to the secretion of bone matrix proteins in osteoblasts, and that OASIS-/- mice exhibit osteopenia and growth retardation. In the present study, we examined whether osteopenia in OASIS-/- mice is rescued by OASIS introduction into osteoblasts. We generated OASIS-/- mice that specifically expressed OASIS in osteoblasts using a 2.3-kb osteoblast-specific type I collagen promoter (OASIS-/-;Tg mice). Histological analysis of OASIS-/-;Tg mice revealed that osteopenia in OASIS-/- mice was rescued by osteoblast-specific expression of the OASIS transgene. The decreased expression levels of type I collagen mRNAs in the bone tissues of OASIS-/- mice were recovered by the OASIS transgene accompanied by the rescue of an abnormal expansion of the rough ER in OASIS-/- osteoblasts. In contrast, growth retardation in OASIS-/- mice did not improve in OASIS-/-;Tg mice. Interestingly, the serum levels of growth hormone (GH) and insulin-like growth factor (IGF)-1 were downregulated in OASIS-/- mice compared with those in wild-type mice. These decreased GH and IGF-1 levels in OASIS-/- mice did not change when OASIS was introduced into osteoblasts. Taken together, these results indicate that OASIS regulates skeletal development by osteoblast-dependent and -independent mechanisms. Copyright © 2010 Elsevier Inc. All rights reserved.

Distinct neural mechanisms for body form and body motion discriminations

NARCIS (Netherlands)

Vangeneugden, Joris; Peelen, Marius V; Tadin, Duje; Battelli, Lorella

2014-01-01

Actions can be understood based on form cues (e.g., static body posture) as well as motion cues (e.g., gait patterns). A fundamental debate centers on the question of whether the functional and neural mechanisms processing these two types of cues are dissociable. Here, using fMRI, psychophysics, and

Time-independent compaction behavior of quartz sands

NARCIS (Netherlands)

Brzesowsky, R. H.; Spiers, C. J.|info:eu-repo/dai/nl/304829323; Peach, C. J.|info:eu-repo/dai/nl/082101906; Hangx, Suzanne|info:eu-repo/dai/nl/30483579X

Mechanisms such as grain rearrangement, coupled with elastic deformation and grain breakage, are believed to play an important role in the time-independent compaction of sands, controlling porosity and permeability reduction during burial of clastic sediments and during depletion of highly porous

Source independence and the EPR paradox

International Nuclear Information System (INIS)

Mould, R.A.

1989-01-01

It is shown that the lines of action between the photon pairs resulting from a positronium decay are not necessarily in line with the original positronium atom. It is also shown why this 'source-independent' effect is not normally observed, although it is observable in principle. Moreover our initial concerns and some conclusions as they bear on the theory of measurement in quantum mechanics are discussed. Source-independence is shown to give a satisfactory response to a special form of the Einstein-Podolsky-Rosen paradox involving pairs of position measurements. It also leads to a nonlocal relationship between position measurements that depends on the width of the position detectors

Looseness and Independence Number of Triangulations on Closed Surfaces

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Nakamoto Atsuhiro

2016-08-01

Full Text Available The looseness of a triangulation G on a closed surface F2, denoted by ξ (G, is defined as the minimum number k such that for any surjection c : V (G → {1, 2, . . . , k + 3}, there is a face uvw of G with c(u, c(v and c(w all distinct. We shall bound ξ (G for triangulations G on closed surfaces by the independence number of G denoted by α(G. In particular, for a triangulation G on the sphere, we have

Translational analysis of mouse and human placental protein and mRNA reveals distinct molecular pathologies in human preeclampsia.

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Cox, Brian; Sharma, Parveen; Evangelou, Andreas I; Whiteley, Kathie; Ignatchenko, Vladimir; Ignatchenko, Alex; Baczyk, Dora; Czikk, Marie; Kingdom, John; Rossant, Janet; Gramolini, Anthony O; Adamson, S Lee; Kislinger, Thomas

2011-12-01

Preeclampsia (PE) adversely impacts ~5% of pregnancies. Despite extensive research, no consistent biomarkers or cures have emerged, suggesting that different molecular mechanisms may cause clinically similar disease. To address this, we undertook a proteomics study with three main goals: (1) to identify a panel of cell surface markers that distinguish the trophoblast and endothelial cells of the placenta in the mouse; (2) to translate this marker set to human via the Human Protein Atlas database; and (3) to utilize the validated human trophoblast markers to identify subgroups of human preeclampsia. To achieve these goals, plasma membrane proteins at the blood tissue interfaces were extracted from placentas using intravascular silica-bead perfusion, and then identified using shotgun proteomics. We identified 1181 plasma membrane proteins, of which 171 were enriched at the maternal blood-trophoblast interface and 192 at the fetal endothelial interface with a 70% conservation of expression in humans. Three distinct molecular subgroups of human preeclampsia were identified in existing human microarray data by using expression patterns of trophoblast-enriched proteins. Analysis of all misexpressed genes revealed divergent dysfunctions including angiogenesis (subgroup 1), MAPK signaling (subgroup 2), and hormone biosynthesis and metabolism (subgroup 3). Subgroup 2 lacked expected changes in known preeclampsia markers (sFLT1, sENG) and uniquely overexpressed GNA12. In an independent set of 40 banked placental specimens, GNA12 was overexpressed during preeclampsia when co-incident with chronic hypertension. In the current study we used a novel translational analysis to integrate mouse and human trophoblast protein expression with human microarray data. This strategy identified distinct molecular pathologies in human preeclampsia. We conclude that clinically similar preeclampsia patients exhibit divergent placental gene expression profiles thus implicating divergent

Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information.

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Nahman-Averbuch, Hadas; Martucci, Katherine T; Granovsky, Yelena; Weissman-Fogel, Irit; Yarnitsky, David; Coghill, Robert C

2014-12-01

The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intraparietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM-related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Conceptualizing Parental Autonomy Support: Adolescent Perceptions of Promotion of Independence versus Promotion of Volitional Functioning

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Soenens, Bart; Vansteenkiste, Maarten; Lens, Willy; Luyckx, Koen; Goossens, Luc; Beyers, Wim; Ryan, Richard M.

2007-01-01

In current research on parenting, 2 ways of conceptualizing perceived parental autonomy support can be distinguished. Parental autonomy support can be defined in terms of promotion of independence (PI) or in terms of promotion of volitional functioning (PVF). This study aimed to establish the empirical distinctiveness of both conceptualizations…

Keeping conceptual boundaries distinct between decision making and learning is necessary to understand social influence.

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Le Mens, Gaël

2014-02-01

Bentley et al. make the deliberate choice to blur the distinction between learning and decision making. This obscures the social influence mechanisms that operate in the various empirical settings that their map aims to categorize. Useful policy prescriptions, however, require an accurate understanding of the social influence mechanisms that underlie the dynamics of popularity.

Spinal Cord Independence Measure, version III: applicability to the UK spinal cord injured population.

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Glass, Clive A; Tesio, Luigi; Itzkovich, Malka; Soni, Bakul M; Silva, Pedro; Mecci, Munawar; Chadwick, Raymond; el Masry, Waghi; Osman, Aheed; Savic, Gordana; Gardner, Brian; Bergström, Ebba; Catz, Amiram

2009-09-01

To examine the validity, reliability and usefulness of the Spinal Cord Independence Measure for the UK spinal cord injury population. Multi-centre cohort study. Four UK regional spinal cord injury centres. Eighty-six people with spinal cord injury. Spinal Cord Independence Measure and Functional Independence Measure on admission analysed using inferential statistics, and Rasch analysis of Spinal Cord Independence Measure. Internal consistency, inter-rater reliability, discriminant validity; Spinal Cord Independence Measure subscale match between distribution of item difficulty and patient ability measurements; reliability of patient ability measures; fit of data to Rasch model; unidimensionality of subscales; hierarchical ordering of categories within items; differential item functioning across patient groups. Scale reliability (kappa coefficients range 0.491-0.835; (p Spinal Cord Independence Measure subscales compatible with stringent Rasch requirements; mean infit indices high; distinct strata of abilities identified; most thresholds ordered; item hierarchy stable across clinical groups and centres. Misfit and differences in item hierarchy identified. Difficulties assessing central cord injuries highlighted. Conventional statistical and Rasch analyses justify the use of the Spinal Cord Independence Measure in clinical practice and research in the UK. Cross-cultural validity may be further improved.

Distinct structural alterations independently contributing to working memory deficits and symptomatology in paranoid schizophrenia.

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Zierhut, Kathrin C; Schulte-Kemna, Anna; Kaufmann, Jörn; Steiner, Johann; Bogerts, Bernhard; Schiltz, Kolja

2013-04-01

Schizophrenia is considered a brain disease with a quite heterogeneous clinical presentation. Studies in schizophrenia have yielded a wide array of correlations between structural and functional brain changes and clinical and cognitive symptoms. Reductions of grey matter volume (GMV) in the prefrontal and temporal cortex have been described which are crucial for the development of positive and negative symptoms and impaired working memory (WM). Associations between GMV reduction and positive and negative symptoms as well as WM impairment were assessed in schizophrenia patients (symptomatology in 34, WM in 26) and compared to healthy controls (36 total, WM in 26). GMV was determined by voxel-based morphometry and its relation to positive and negative symptoms as well as WM performance was assessed. In schizophrenia patients, reductions of GMV were evident in anterior cingulate cortex, ventrolateral prefrontal cortex (VLPFC), superior temporal cortex, and insula. GMV reductions in the superior temporal gyrus (STG) were associated with positive symptom severity as well as WM impairment. Furthermore, the absolute GMV of VLPFC was strongly related to negative symptoms. These predicted WM performance as well as processing speed. The present results support the assumption of two distinct pathomechanisms responsible for impaired WM in schizophrenia: (1) GMV reductions in the VLPFC predict the severity of negative symptoms. Increased negative symptoms in turn are associated with a slowing down of processing speed and predict an impaired WM. (2) GMV reductions in the temporal and mediofrontal cortex are involved in the development of positive symptoms and impair WM performance, too. Copyright © 2012 Elsevier Ltd. All rights reserved.

Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

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Elena Gammella

2015-01-01

Full Text Available The high incidence of cardiomyopathy in patients with hemosiderosis, particularly in transfusional iron overload, strongly indicates that iron accumulation in the heart plays a major role in the process leading to heart failure. In this context, iron-mediated generation of noxious reactive oxygen species is believed to be the most important pathogenetic mechanism determining cardiomyocyte damage, the initiating event of a pathologic progression involving apoptosis, fibrosis, and ultimately cardiac dysfunction. However, recent findings suggest that additional mechanisms involving subcellular organelles and inflammatory mediators are important factors in the development of this disease. Moreover, excess iron can amplify the cardiotoxic effect of other agents or events. Finally, subcellular misdistribution of iron within cardiomyocytes may represent an additional pathway leading to cardiac injury. Recent advances in imaging techniques and chelators development remarkably improved cardiac iron overload detection and treatment, respectively. However, increased understanding of the pathogenic mechanisms of iron overload cardiomyopathy is needed to pave the way for the development of improved therapeutic strategies.

Menzerath-Altmann law for distinct word distribution analysis in a large text

Science.gov (United States)

Eroglu, Sertac

2013-06-01

The empirical law uncovered by Menzerath and formulated by Altmann, known as the Menzerath-Altmann law (henceforth the MA law), reveals the statistical distribution behavior of human language in various organizational levels. Building on previous studies relating organizational regularities in a language, we propose that the distribution of distinct (or different) words in a large text can effectively be described by the MA law. The validity of the proposition is demonstrated by examining two text corpora written in different languages not belonging to the same language family (English and Turkish). The results show not only that distinct word distribution behavior can accurately be predicted by the MA law, but that this result appears to be language-independent. This result is important not only for quantitative linguistic studies, but also may have significance for other naturally occurring organizations that display analogous organizational behavior. We also deliberately demonstrate that the MA law is a special case of the probability function of the generalized gamma distribution.

Chronic central administration of Ghrelin increases bone mass through a mechanism independent of appetite regulation.

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Hyung Jin Choi

Full Text Available Leptin plays a critical role in the central regulation of bone mass. Ghrelin counteracts leptin. In this study, we investigated the effect of chronic intracerebroventricular administration of ghrelin on bone mass in Sprague-Dawley rats (1.5 μg/day for 21 days. Rats were divided into control, ghrelin ad libitum-fed (ghrelin ad lib-fed, and ghrelin pair-fed groups. Ghrelin intracerebroventricular infusion significantly increased body weight in ghrelin ad lib-fed rats but not in ghrelin pair-fed rats, as compared with control rats. Chronic intracerebroventricular ghrelin infusion significantly increased bone mass in the ghrelin pair-fed group compared with control as indicated by increased bone volume percentage, trabecular thickness, trabecular number and volumetric bone mineral density in tibia trabecular bone. There was no significant difference in trabecular bone mass between the control group and the ghrelin ad-lib fed group. Chronic intracerebroventricular ghrelin infusion significantly increased the mineral apposition rate in the ghrelin pair-fed group as compared with control. In conclusion, chronic central administration of ghrelin increases bone mass through a mechanism that is independent of body weight, suggesting that ghrelin may have a bone anabolic effect through the central nervous system.

On the neural mechanisms subserving consciousness and attention

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Catherine eTallon-Baudry

2012-01-01

Full Text Available Consciousness, as described in the experimental literature, is a multi-faceted phenomenon, that impinges on other well-studied concepts such as attention and control. Do consciousness and attention refer to different aspects of the same core phenomenon, or do they correspond to distinct functions? One possibility to address this question is to examine the neural mechanisms underlying consciousness and attention. If consciousness and attention pertain to the same concept, they should rely on shared neural mechanisms. Conversely, if their underlying mechanisms are distinct, then consciousness and attention should be considered as distinct entities. This paper therefore reviews neurophysiological facts arguing in favor or against a tight relationship between consciousness and attention. Three neural mechanisms that have been associated with both attention and consciousness are examined (neural amplification, involvement of the fronto-parietal network, and oscillatory synchrony, to conclude that the commonalities between attention and consciousness at the neural level may have been overestimated. Last but not least, experiments in which both attention and consciousness were probed at the neural level point toward a dissociation between the two concepts. It therefore appears from this review that consciousness and attention rely on distinct neural properties, although they can interact at the behavioral level. It is proposed that a "cumulative influence model", in which attention and consciousness correspond to distinct neural mechanisms feeding a single decisional process leading to behavior, fits best with available neural and behavioral data. In this view, consciousness should not be considered as a top-level executive function but should rather be defined by its experiential properties.

Rapid and reversible impairments of short- and long-term social recognition memory are caused by acute isolation of adult rats via distinct mechanisms.

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Shahar-Gold, Hadar; Gur, Rotem; Wagner, Shlomo

2013-01-01

Mammalian social organizations require the ability to recognize and remember individual conspecifics. This social recognition memory (SRM) can be examined in rodents using their innate tendency to investigate novel conspecifics more persistently than familiar ones. Here we used the SRM paradigm to examine the influence of housing conditions on the social memory of adult rats. We found that acute social isolation caused within few days a significant impairment in acquisition of short-term SRM of male and female rats. Moreover, SRM consolidation into long-term memory was blocked following only one day of social isolation. Both impairments were reversible, but with different time courses. Furthermore, only the impairment in SRM consolidation was reversed by systemic administration of arginine-vasopressin (AVP). In contrast to SRM, object recognition memory was not affected by social isolation. We conclude that acute social isolation rapidly induces reversible changes in the brain neuronal and molecular mechanisms underlying SRM, which hamper its acquisition and completely block its consolidation. These changes occur via distinct, AVP sensitive and insensitive mechanisms. Thus, acute social isolation of rats swiftly causes changes in their brain and interferes with their normal social behavior.

Rapid and reversible impairments of short- and long-term social recognition memory are caused by acute isolation of adult rats via distinct mechanisms.

Directory of Open Access Journals (Sweden)

Hadar Shahar-Gold

Full Text Available Mammalian social organizations require the ability to recognize and remember individual conspecifics. This social recognition memory (SRM can be examined in rodents using their innate tendency to investigate novel conspecifics more persistently than familiar ones. Here we used the SRM paradigm to examine the influence of housing conditions on the social memory of adult rats. We found that acute social isolation caused within few days a significant impairment in acquisition of short-term SRM of male and female rats. Moreover, SRM consolidation into long-term memory was blocked following only one day of social isolation. Both impairments were reversible, but with different time courses. Furthermore, only the impairment in SRM consolidation was reversed by systemic administration of arginine-vasopressin (AVP. In contrast to SRM, object recognition memory was not affected by social isolation. We conclude that acute social isolation rapidly induces reversible changes in the brain neuronal and molecular mechanisms underlying SRM, which hamper its acquisition and completely block its consolidation. These changes occur via distinct, AVP sensitive and insensitive mechanisms. Thus, acute social isolation of rats swiftly causes changes in their brain and interferes with their normal social behavior.

Vaunting the independent amateur: Scientific American and the representation of lay scientists.

Science.gov (United States)

Johnston, Sean F

2018-04-01

This paper traces how media representations encouraged enthusiasts, youth and skilled volunteers to participate actively in science and technology during the twentieth century. It assesses how distinctive discourses about scientific amateurs positioned them with respect to professionals in shifting political and cultural environments. In particular, the account assesses the seminal role of a periodical, Scientific American magazine, in shaping and championing an enduring vision of autonomous scientific enthusiasms. Between the 1920s and 1970s, editors Albert G. Ingalls and Clair L. Stong shepherded generations of adult 'amateur scientists'. Their columns and books popularized a vision of independent non-professional research that celebrated the frugal ingenuity and skills of inveterate tinkerers. Some of these attributes have found more recent expression in present-day 'maker culture'. The topic consequently is relevant to the historiography of scientific practice, science popularization and science education. Its focus on independent non-professionals highlights political dimensions of agency and autonomy that have often been implicit for such historical (and contemporary) actors. The paper argues that the Scientific American template of adult scientific amateurism contrasted with other representations: those promoted by earlier periodicals and by a science education organization, Science Service, and by the national demands for recruiting scientific labour during and after the Second World War. The evidence indicates that advocates of the alternative models had distinctive goals and adapted their narrative tactics to reach their intended audiences, which typically were conceived as young persons requiring instruction or mentoring. By contrast, the monthly Scientific American columns established a long-lived and stable image of the independent lay scientist.

Interleukin-4- and NACHT, LRR and PYD domains-containing protein 3-independent mechanisms of alum enhanced T helper type 2 responses on basophils.

Science.gov (United States)

Huang, Feng-Juan; Ma, Yi-Lei; Tang, Ruo-Yu; Gong, Wen-Ci; Li, Jun; Chen, Chun-Xia; Yin, Lan; Chen, Xiao-Ping

2016-10-01

Aluminium hydroxide (alum), the most widely used adjuvant in human and animal vaccines, has long been known to promote T helper type 2 (Th2) responses and Th2-associated humoral responses, but the mechanisms have remained poorly understood. In this study, we explored whether alum is able to directly modulate antigen-presenting cells to enhance their potency for Th2 polarization. We found that alum treatment of dendritic cells failed to show any Th2-promoting activities. In contrast, alum was able to enhance the capacity of basophils to induce Th2 cells. When basophils from interleukin-4 (IL-4) knockout mice were examined, the intrinsic Th2-promoting activities by basophils were largely abrogated, but the alum-enhanced Th2-promoting activities on basophils were still detectable. More importantly, Th2-promoting adjuvant activities by alum found in IL-4 knockout mice were also largely reduced when basophils were depleted by antibody administration. Therefore, basophils can mediate Th2-promoting activities by alum both in vitro and in vivo through IL-4-independent mechanisms. Further studies revealed that secreted soluble molecules from alum-treated basophils were able to confer the Th2-promoting activities, and neutralization of thymic stromal lymphopoietin or IL-25 attenuated the IL-4-independent development of Th2 cells elicited by alum-treated basophils. Finally, alum was able to activate NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in murine basophils in the same way as alum in professional antigen-presenting cells, but NLRP3 was not required for Th2-promoting activities on basophils by alum in vitro. These results demonstrated that alum can enhance the capacities of basophils to polarize Th2 cells via IL-4- and NLRP3-independent pathways. © 2016 John Wiley & Sons Ltd.

Determinism, independence, and objectivity are incompatible.

Science.gov (United States)

Ionicioiu, Radu; Mann, Robert B; Terno, Daniel R

2015-02-13

Hidden-variable models aim to reproduce the results of quantum theory and to satisfy our classical intuition. Their refutation is usually based on deriving predictions that are different from those of quantum mechanics. Here instead we study the mutual compatibility of apparently reasonable classical assumptions. We analyze a version of the delayed-choice experiment which ostensibly combines determinism, independence of hidden variables on the conducted experiments, and wave-particle objectivity (the assertion that quantum systems are, at any moment, either particles or waves, but not both). These three ideas are incompatible with any theory, not only with quantum mechanics.

Worker flag. Independent Electrical Policy

International Nuclear Information System (INIS)

Bahen, D.

2000-01-01

This work analyses the initiative of privatization of the Mexican Electric Industry and also it is showed the incoherence of this mistaken proposal. Along the same line is analysed tthe situation of the National Electric Sector and the working process for the distinct types of electric generation just as the syndical and labor situations. In consequence it is proposed an Independent Electrical Policy, which includes the integration of the Nationalized Electric Industry, the syndical union and the Unique Collective Contract. The purpose of this work is to contribute to the success of the electrical and nuclear struggle always maintaining in rising position the red flag of the proletariat. The author considers that the privatization means mercantilization of the human necessities. The privatization is not inevitable at condition of to exercise consequently the political actions necessary through alternatives includes: the worker control of production, research, and the National Electric strike. (Author)

Endocytosis of HERG is clathrin-independent and involves arf6.

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Rucha Karnik

Full Text Available The hERG potassium channel is critical for repolarisation of the cardiac action potential. Reduced expression of hERG at the plasma membrane, whether caused by hereditary mutations or drugs, results in long QT syndrome and increases the risk of ventricular arrhythmias. Thus, it is of fundamental importance to understand how the density of this channel at the plasma membrane is regulated. We used antibodies to an extracellular native or engineered epitope, in conjunction with immunofluorescence and ELISA, to investigate the mechanism of hERG endocytosis in recombinant cells and validated the findings in rat neonatal cardiac myocytes. The data reveal that this channel undergoes rapid internalisation, which is inhibited by neither dynasore, an inhibitor of dynamin, nor a dominant negative construct of Rab5a, into endosomes that are largely devoid of the transferrin receptor. These results support a clathrin-independent mechanism of endocytosis and exclude involvement of dynamin-dependent caveolin and RhoA mechanisms. In agreement, internalised hERG displayed marked overlap with glycosylphosphatidylinositol-anchored GFP, a clathrin-independent cargo. Endocytosis was significantly affected by cholesterol extraction with methyl-β-cyclodextrin and inhibition of Arf6 function with dominant negative Arf6-T27N-eGFP. Taken together, we conclude that hERG undergoes clathrin-independent endocytosis via a mechanism involving Arf6.

Are Independent Fiscal Institutions Really Independent?

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Slawomir Franek

2015-08-01

Full Text Available In the last decade the number of independent fiscal institutions (known also as fiscal councils has tripled. They play an important oversight role over fiscal policy-making in democratic societies, especially as they seek to restore public finance stability in the wake of the recent financial crisis. Although common functions of such institutions include a role in analysis of fiscal policy, forecasting, monitoring compliance with fiscal rules or costing of spending proposals, their roles, resources and structures vary considerably across countries. The aim of the article is to determine the degree of independence of such institutions based on the analysis of the independence index of independent fiscal institutions. The analysis of this index values may be useful to determine the relations between the degree of independence of fiscal councils and fiscal performance of particular countries. The data used to calculate the index values will be derived from European Commission and IMF, which collect sets of information about characteristics of activity of fiscal councils.

Autoshaping with common and distinctive stimulus elements, compact and dispersed arrays1

Science.gov (United States)

Sperling, Sally E.; Perkins, Mark E.

1979-01-01

Four groups of pigeons were trained with a standard autoshaping procedure in which a brief fixed-duration interval always followed by a grain delivery alternated with a longer variable-duration interval never associated with grain delivery. One of two stimuli was always presented during each interval. One of them contained three black dots and a black star on a green background; the other contained four black dots on a green background. The four elements of each stimulus were arranged in a more compact array for two groups and in a more dispersed array for the other two groups. Which of the two stimuli preceded grain delivery was counterbalanced within each pair of groups. The speed of occurrence of the first autoshaped peck was not affected by whether the stimulus containing the distinctive star element preceded grain delivery, but autoshaping was faster when the stimulus arrays were compact than when they were dispersed. During 560 response-independent training trials that followed the first autoshaped peck, this pattern reversed; both discriminative control over responding and the relative frequency of pecking the stimulus that preceded grain delivery were greater for the two groups where this stimulus contained the discriminative element than for the two groups where it contained only common elements. During subsequent testing with stimuli containing only a single element each, the distinctive feature was responded to proportionately more often by the two groups for which it had been an element of the stimulus preceding grain delivery than by the two groups for which it had been an element of the stimulus complex that never was associated with grain delivery. These data add further support to the hypothesis that the initial occurrence of autoshaped responding and its subsequent maintenance are not affected by the same variables. They also suggest that automaintenance is as sensitive as response-dependent training to the presence or absence of a distinctive

TOPOISOMERASE1α Acts through Two Distinct Mechanisms to Regulate Stele and Columella Stem Cell Maintenance.

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Zhang, Yonghong; Zheng, Lanlan; Hong, Jing Han; Gong, Ximing; Zhou, Chun; Pérez-Pérez, José Manuel; Xu, Jian

2016-05-01

TOPOISOMERASE1 (TOP1), which releases DNA torsional stress generated during replication through its DNA relaxation activity, plays vital roles in animal and plant development. In Arabidopsis (Arabidopsis thaliana), TOP1 is encoded by two paralogous genes (TOP1α and TOP1β), of which TOP1α displays specific developmental functions that are critical for the maintenance of shoot and floral stem cells. Here, we show that maintenance of two different populations of root stem cells is also dependent on TOP1α-specific developmental functions, which are exerted through two distinct novel mechanisms. In the proximal root meristem, the DNA relaxation activity of TOP1α is critical to ensure genome integrity and survival of stele stem cells (SSCs). Loss of TOP1α function triggers DNA double-strand breaks in S-phase SSCs and results in their death, which can be partially reversed by the replenishment of SSCs mediated by ETHYLENE RESPONSE FACTOR115 In the quiescent center and root cap meristem, TOP1α is epistatic to RETINOBLASTOMA-RELATED (RBR) in the maintenance of undifferentiated state and the number of columella stem cells (CSCs). Loss of TOP1α function in either wild-type or RBR RNAi plants leads to differentiation of CSCs, whereas overexpression of TOP1α mimics and further enhances the effect of RBR reduction that increases the number of CSCs Taken together, these findings provide important mechanistic insights into understanding stem cell maintenance in plants. © 2016 American Society of Plant Biologists. All Rights Reserved.

Mycobacterial secretion systems ESX-1 and ESX-5 play distinct roles in host cell death and inflammasome activation

KAUST Repository

Abdallah, Abdallah

2011-09-28

During infection of humans and animals, pathogenic mycobacteria manipulate the host cell causing severe diseases such as tuberculosis and leprosy. To understand the basis of mycobacterial pathogenicity, it is crucial to identify the molecular virulence mechanisms. In this study, we address the contribution of ESX-1 and ESX-5 - two homologous type VII secretion systems of mycobacteria that secrete distinct sets of immune modulators - during the macrophage infection cycle. Using wild-type, ESX-1- and ESX-5-deficient mycobacterial strains, we demonstrate that these secretion systems differentially affect subcellular localization and macrophage cell responses. We show that in contrast to ESX-1, the effector proteins secreted by ESX-5 are not required for the translocation of Mycobacterium tuberculosis or Mycobacterium marinum to the cytosol of host cells. However, the M. marinum ESX-5 mutant does not induce inflammasome activation and IL-1b activation. The ESX-5 system also induces a caspase-independent cell death after translocation has taken place. Importantly, by means of inhibitory agents and small interfering RNA experiments, we reveal that cathepsin B is involved in both the induction of cell death and inflammasome activation upon infection with wild-type mycobacteria. These results reveal distinct roles for two different type VII secretion systems during infection and shed light on how virulent mycobacteria manipulate the host cell in various ways to replicate and spread. Copyright © 2011 by The American Association of Immunologists, Inc.

NF-κB dependent and independent mechanisms of quartz-induced proinflammatory activation of lung epithelial cells

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Schins Roel PF

2010-05-01

Full Text Available Abstract In the initiation and progression of pulmonary inflammation, macrophages have classically been considered as a crucial cell type. However, evidence for the role of epithelial type II cells in pulmonary inflammation has been accumulating. In the current study, a combined in vivo and in vitro approach has been employed to investigate the mechanisms of quartz-induced proinflammatory activation of lung epithelial cells. In vivo, enhanced expression of the inflammation- and oxidative stress-related genes HO-1 and iNOS was found on the mRNA level in rat lungs after instillation with DQ12 respirable quartz. Activation of the classical NF-κB pathway in macrophages and type II pneumocytes was indicated by enhanced immunostaining of phospho-IκBα in these specific lung cell types. In vitro, the direct, particle-mediated effect on proinflammatory signalling in a rat lung epithelial (RLE cell line was compared to the indirect, macrophage product-mediated effect. Treatment with quartz particles induced HO-1 and COX-2 mRNA expression in RLE cells in an NF-κB independent manner. Supernatant from quartz-treated macrophages rapidly activated the NF-κB signalling pathway in RLE cells and markedly induced iNOS mRNA expression up to 2000-fold compared to non-treated control cells. Neutralisation of TNFα and IL-1β in macrophage supernatant did not reduce its ability to elicit NF-κB activation of RLE cells. In addition the effect was not modified by depletion or supplementation of intracellular glutathione. The results from the current work suggest that although both oxidative stress and NF-κB are likely involved in the inflammatory effects of toxic respirable particles, these phenomena can operate independently on the cellular level. This might have consequences for in vitro particle hazard testing, since by focusing on NF-κB signalling one might neglect alternative inflammatory pathways.

Partitioning diversity into independent alpha and beta components.

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Jost, Lou

2007-10-01

Existing general definitions of beta diversity often produce a beta with a hidden dependence on alpha. Such a beta cannot be used to compare regions that differ in alpha diversity. To avoid misinterpretation, existing definitions of alpha and beta must be replaced by a definition that partitions diversity into independent alpha and beta components. Such a unique definition is derived here. When these new alpha and beta components are transformed into their numbers equivalents (effective numbers of elements), Whittaker's multiplicative law (alpha x beta = gamma) is necessarily true for all indices. The new beta gives the effective number of distinct communities. The most popular similarity and overlap measures of ecology (Jaccard, Sorensen, Horn, and Morisita-Horn indices) are monotonic transformations of the new beta diversity. Shannon measures follow deductively from this formalism and do not need to be borrowed from information theory; they are shown to be the only standard diversity measures which can be decomposed into meaningful independent alpha and beta components when community weights are unequal.

[Independent ethics committees for clinical research in Argentina. An evaluation and a system to guarantee their independence].

Science.gov (United States)

Gonorazky, Sergio E

2008-01-01

The Administración Nacional de Medicamentos, Alimentos y Tecnología Médica de la República Argentina (ANMAT) requires that an independent ethics committee of sponsors and/or researchers must previously evaluate and approve all the new pharmacological research protocols carried out on human beings. However, due to the lucrative nature of the evaluation, and because the selection of the Independent Ethics Committee is carried out by the sponsors and/or researchers, the assumed autonomy of the former can be reduced to merely a relationship of "service provider-customer". The Institutional Review Board of the Mar del Plata s Community Hospital has evaluated, between 2005 and 2006, thirty three research protocols (with their corresponding information sheets for patients and informed consent forms) previously approved by a non-institutional Independent Ethics Committee. The median number of objections made by the Institutional Review Board, which prompted the previously mentioned protocols to be modified in order to be approved, was of three per protocol. In other words, the accreditation of an Independent Ethics Committee requires a system that guarantees actual independence from the sponsors and/or researchers, as well as management control mechanisms that may lead them into an eventual loss of accreditation. Several measures are proposed in order to correct the deficiencies of the present system.

Distinct parietal sites mediate the influences of mood, arousal, and their interaction on human recognition memory.

Science.gov (United States)

Greene, Ciara M; Flannery, Oliver; Soto, David

2014-12-01

The two dimensions of emotion, mood valence and arousal, have independent effects on recognition memory. At present, however, it is not clear how those effects are reflected in the human brain. Previous research in this area has generally dealt with memory for emotionally valenced or arousing stimuli, but the manner in which interacting mood and arousal states modulate responses in memory substrates remains poorly understood. We investigated memory for emotionally neutral items while independently manipulating mood valence and arousal state by means of music exposure. Four emotional conditions were created: positive mood/high arousal, positive mood/low arousal, negative mood/high arousal, and negative mood/low arousal. We observed distinct effects of mood valence and arousal in parietal substrates of recognition memory. Positive mood increased activity in ventral posterior parietal cortex (PPC) and orbitofrontal cortex, whereas arousal condition modulated activity in dorsal PPC and the posterior cingulate. An interaction between valence and arousal was observed in left ventral PPC, notably in a parietal area distinct from the those identified for the main effects, with a stronger effect of mood on recognition memory responses here under conditions of relative high versus low arousal. We interpreted the PPC activations in terms of the attention-to-memory hypothesis: Increased arousal may lead to increased top-down control of memory, and hence dorsal PPC activation, whereas positive mood valence may result in increased activity in ventral PPC regions associated with bottom-up attention to memory. These findings indicate that distinct parietal sites mediate the influences of mood, arousal, and their interplay during recognition memory.

Unified thalamic model generates multiple distinct oscillations with state-dependent entrainment by stimulation.

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Guoshi Li

2017-10-01

Full Text Available The thalamus plays a critical role in the genesis of thalamocortical oscillations, yet the underlying mechanisms remain elusive. To understand whether the isolated thalamus can generate multiple distinct oscillations, we developed a biophysical thalamic model to test the hypothesis that generation of and transition between distinct thalamic oscillations can be explained as a function of neuromodulation by acetylcholine (ACh and norepinephrine (NE and afferent synaptic excitation. Indeed, the model exhibited four distinct thalamic rhythms (delta, sleep spindle, alpha and gamma oscillations that span the physiological states corresponding to different arousal levels from deep sleep to focused attention. Our simulation results indicate that generation of these distinct thalamic oscillations is a result of both intrinsic oscillatory cellular properties and specific network connectivity patterns. We then systematically varied the ACh/NE and input levels to generate a complete map of the different oscillatory states and their transitions. Lastly, we applied periodic stimulation to the thalamic network and found that entrainment of thalamic oscillations is highly state-dependent. Our results support the hypothesis that ACh/NE modulation and afferent excitation define thalamic oscillatory states and their response to brain stimulation. Our model proposes a broader and more central role of the thalamus in the genesis of multiple distinct thalamo-cortical rhythms than previously assumed.

A Distinct Population of Microglia Supports Adult Neurogenesis in the Subventricular Zone

DEFF Research Database (Denmark)

Ribeiro Xavier, Anna L.; Kress, Benjamin T.; Goldman, Steven A.

2015-01-01

found that microglia residing in the SVZ and adjacent rostral migratory stream (RMS) comprise a morphologically and antigenically distinct phenotype of immune effectors. Whereas exhibiting characteristics of alternatively activated microglia, the SVZ/RMS microglia were clearly distinguished by their low...... STATEMENT: Microglial cells are a specialized population of macrophages in the CNS, playing key roles as immune mediators. As integral components in the CNS, the microglia stand out for using the same mechanisms, phagocytosis and cytochemokine release, to promote homeostasis, synaptic pruning, and neural...... toward olfactory bulb layers. In addition to other unique populations residing in the SVZ niche, microglia display distinct morphofunctional properties that boost neuronal progenitor survival and migration in the mammalian brain....

The pleasures and pains of distinct self-construals: the role of interdependence in regulatory focus.

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Lee, A Y; Aaker, J L; Gardner, W L

2000-06-01

Regulatory focus theory distinguishes between self-regulatory processes that focus on promotion and prevention strategies for goal pursuit. Five studies provide support for the hypothesis that these strategies differ for individuals with distinct self-construals. Specifically, individuals with a dominant independent self-construal were predicted to place more emphasis on promotion-focused information, and those with a dominant interdependent self-construal on prevention-focused information. Support for this hypothesis was obtained for participants who scored high versus low on the Self-Construal Scale, participants who were presented with an independent versus interdependent situation, and participants from a Western versus Eastern culture. The influence of interdependence on regulatory focus was observed in both importance ratings of information and affective responses consistent with promotion or prevention focus.

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

International Nuclear Information System (INIS)

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

2013-01-01

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 h 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. - Highlights: • Defined global mRNA expression

Independent Origin and Global Distribution of Distinct Plasmodium vivax Duffy Binding Protein Gene Duplications.

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Jessica B Hostetler

2016-10-01

Full Text Available Plasmodium vivax causes the majority of malaria episodes outside Africa, but remains a relatively understudied pathogen. The pathology of P. vivax infection depends critically on the parasite's ability to recognize and invade human erythrocytes. This invasion process involves an interaction between P. vivax Duffy Binding Protein (PvDBP in merozoites and the Duffy antigen receptor for chemokines (DARC on the erythrocyte surface. Whole-genome sequencing of clinical isolates recently established that some P. vivax genomes contain two copies of the PvDBP gene. The frequency of this duplication is particularly high in Madagascar, where there is also evidence for P. vivax infection in DARC-negative individuals. The functional significance and global prevalence of this duplication, and whether there are other copy number variations at the PvDBP locus, is unknown.Using whole-genome sequencing and PCR to study the PvDBP locus in P. vivax clinical isolates, we found that PvDBP duplication is widespread in Cambodia. The boundaries of the Cambodian PvDBP duplication differ from those previously identified in Madagascar, meaning that current molecular assays were unable to detect it. The Cambodian PvDBP duplication did not associate with parasite density or DARC genotype, and ranged in prevalence from 20% to 38% over four annual transmission seasons in Cambodia. This duplication was also present in P. vivax isolates from Brazil and Ethiopia, but not India.PvDBP duplications are much more widespread and complex than previously thought, and at least two distinct duplications are circulating globally. The same duplication boundaries were identified in parasites from three continents, and were found at high prevalence in human populations where DARC-negativity is essentially absent. It is therefore unlikely that PvDBP duplication is associated with infection of DARC-negative individuals, but functional tests will be required to confirm this hypothesis.

Cap-independent translation mechanism of red clover necrotic mosaic virus RNA2 differs from that of RNA1 and is linked to RNA replication.

Science.gov (United States)

Mizumoto, Hiroyuki; Iwakawa, Hiro-Oki; Kaido, Masanori; Mise, Kazuyuki; Okuno, Tetsuro

2006-04-01

The genome of Red clover necrotic mosaic virus (RCNMV) in the genus Dianthovirus is divided into two RNA molecules of RNA1 and RNA2, which have no cap structure at the 5' end and no poly(A) tail at the 3' end. The 3' untranslated region (3' UTR) of RCNMV RNA1 contains an essential RNA element (3'TE-DR1), which is required for cap-independent translation. In this study, we investigated a cap-independent translational mechanism of RNA2 using a firefly luciferase (Luc) gene expression assay system in cowpea protoplasts and a cell-free lysate (BYL) prepared from evacuolated tobacco BY2 protoplasts. We were unable to detect cis-acting RNA sequences in RNA2 that can replace the function of a cap structure, such as the 3'TE-DR1 of RNA1. However, the uncapped reporter RNA2, RNA2-Luc, in which the Luc open reading frame (ORF) was inserted between the 5' UTR and the movement protein ORF, was effectively translated in the presence of p27 and p88 in protoplasts in which RNA2-Luc was replicated. Time course experiments in protoplasts showed that the translational activity of RNA2-Luc did not reflect the amount of RNA2. Mutations in cis-acting RNA replication elements of RNA2 abolished the cap-independent translational activity of RNA2-Luc, suggesting that the translational activity of RNA2-Luc is coupled to RNA replication. Our results show that the translational mechanism differs between two segmented genomic RNAs of RCNMV. We present a model in which only RNA2 that is generated de novo through the viral RNA replication machinery functions as mRNA for translation.

Corticosteroid receptors adopt distinct cyclical transcriptional signatures.

Science.gov (United States)

Le Billan, Florian; Amazit, Larbi; Bleakley, Kevin; Xue, Qiong-Yao; Pussard, Eric; Lhadj, Christophe; Kolkhof, Peter; Viengchareun, Say; Fagart, Jérôme; Lombès, Marc

2018-05-07

Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are two closely related hormone-activated transcription factors that regulate major pathophysiologic functions. High homology between these receptors accounts for the crossbinding of their corresponding ligands, MR being activated by both aldosterone and cortisol and GR essentially activated by cortisol. Their coexpression and ability to bind similar DNA motifs highlight the need to investigate their respective contributions to overall corticosteroid signaling. Here, we decipher the transcriptional regulatory mechanisms that underlie selective effects of MRs and GRs on shared genomic targets in a human renal cellular model. Kinetic, serial, and sequential chromatin immunoprecipitation approaches were performed on the period circadian protein 1 ( PER1) target gene, providing evidence that both receptors dynamically and cyclically interact at the same target promoter in a specific and distinct transcriptional signature. During this process, both receptors regulate PER1 gene by binding as homo- or heterodimers to the same promoter region. Our results suggest a novel level of MR-GR target gene regulation, which should be considered for a better and integrated understanding of corticosteroid-related pathophysiology.-Le Billan, F., Amazit, L., Bleakley, K., Xue, Q.-Y., Pussard, E., Lhadj, C., Kolkhof, P., Viengchareun, S., Fagart, J., Lombès, M. Corticosteroid receptors adopt distinct cyclical transcriptional signatures.

Distinct lipid a moieties contribute to pathogen-induced site-specific vascular inflammation.

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Connie Slocum

2014-07-01

Full Text Available Several successful pathogens have evolved mechanisms to evade host defense, resulting in the establishment of persistent and chronic infections. One such pathogen, Porphyromonas gingivalis, induces chronic low-grade inflammation associated with local inflammatory bone loss and systemic inflammation manifested as atherosclerosis. P. gingivalis expresses an atypical lipopolysaccharide (LPS structure containing heterogeneous lipid A species, that exhibit Toll-like receptor-4 (TLR4 agonist or antagonist activity, or are non-activating at TLR4. In this study, we utilized a series of P. gingivalis lipid A mutants to demonstrate that antagonistic lipid A structures enable the pathogen to evade TLR4-mediated bactericidal activity in macrophages resulting in systemic inflammation. Production of antagonistic lipid A was associated with the induction of low levels of TLR4-dependent proinflammatory mediators, failed activation of the inflammasome and increased bacterial survival in macrophages. Oral infection of ApoE(-/- mice with the P. gingivalis strain expressing antagonistic lipid A resulted in vascular inflammation, macrophage accumulation and atherosclerosis progression. In contrast, a P. gingivalis strain producing exclusively agonistic lipid A augmented levels of proinflammatory mediators and activated the inflammasome in a caspase-11-dependent manner, resulting in host cell lysis and decreased bacterial survival. ApoE(-/- mice infected with this strain exhibited diminished vascular inflammation, macrophage accumulation, and atherosclerosis progression. Notably, the ability of P. gingivalis to induce local inflammatory bone loss was independent of lipid A expression, indicative of distinct mechanisms for induction of local versus systemic inflammation by this pathogen. Collectively, our results point to a pivotal role for activation of the non-canonical inflammasome in P. gingivalis infection and demonstrate that P. gingivalis evades immune

Convergent evolution of marine mammals is associated with distinct substitutions in common genes

Science.gov (United States)

Zhou, Xuming; Seim, Inge; Gladyshev, Vadim N.

2015-01-01

Phenotypic convergence is thought to be driven by parallel substitutions coupled with natural selection at the sequence level. Multiple independent evolutionary transitions of mammals to an aquatic environment offer an opportunity to test this thesis. Here, whole genome alignment of coding sequences identified widespread parallel amino acid substitutions in marine mammals; however, the majority of these changes were not unique to these animals. Conversely, we report that candidate aquatic adaptation genes, identified by signatures of likelihood convergence and/or elevated ratio of nonsynonymous to synonymous nucleotide substitution rate, are characterized by very few parallel substitutions and exhibit distinct sequence changes in each group. Moreover, no significant positive correlation was found between likelihood convergence and positive selection in all three marine lineages. These results suggest that convergence in protein coding genes associated with aquatic lifestyle is mainly characterized by independent substitutions and relaxed negative selection. PMID:26549748

Timely activation of budding yeast APCCdh1 involves degradation of its inhibitor, Acm1, by an unconventional proteolytic mechanism.

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Michael Melesse

Full Text Available Regulated proteolysis mediated by the ubiquitin proteasome system is a fundamental and essential feature of the eukaryotic cell division cycle. Most proteins with cell cycle-regulated stability are targeted for degradation by one of two related ubiquitin ligases, the Skp1-cullin-F box protein (SCF complex or the anaphase-promoting complex (APC. Here we describe an unconventional cell cycle-regulated proteolytic mechanism that acts on the Acm1 protein, an inhibitor of the APC activator Cdh1 in budding yeast. Although Acm1 can be recognized as a substrate by the Cdc20-activated APC (APCCdc20 in anaphase, APCCdc20 is neither necessary nor sufficient for complete Acm1 degradation at the end of mitosis. An APC-independent, but 26S proteasome-dependent, mechanism is sufficient for complete Acm1 clearance from late mitotic and G1 cells. Surprisingly, this mechanism appears distinct from the canonical ubiquitin targeting pathway, exhibiting several features of ubiquitin-independent proteasomal degradation. For example, Acm1 degradation in G1 requires neither lysine residues in Acm1 nor assembly of polyubiquitin chains. Acm1 was stabilized though by conditional inactivation of the ubiquitin activating enzyme Uba1, implying some requirement for the ubiquitin pathway, either direct or indirect. We identified an amino terminal predicted disordered region in Acm1 that contributes to its proteolysis in G1. Although ubiquitin-independent proteasome substrates have been described, Acm1 appears unique in that its sensitivity to this mechanism is strictly cell cycle-regulated via cyclin-dependent kinase (Cdk phosphorylation. As a result, Acm1 expression is limited to the cell cycle window in which Cdk is active. We provide evidence that failure to eliminate Acm1 impairs activation of APCCdh1 at mitotic exit, justifying its strict regulation by cell cycle-dependent transcription and proteolytic mechanisms. Importantly, our results reveal that strict cell

Timely Activation of Budding Yeast APCCdh1 Involves Degradation of Its Inhibitor, Acm1, by an Unconventional Proteolytic Mechanism

Science.gov (United States)

Melesse, Michael; Choi, Eunyoung; Hall, Hana; Walsh, Michael J.; Geer, M. Ariel; Hall, Mark C.

2014-01-01

Regulated proteolysis mediated by the ubiquitin proteasome system is a fundamental and essential feature of the eukaryotic cell division cycle. Most proteins with cell cycle-regulated stability are targeted for degradation by one of two related ubiquitin ligases, the Skp1-cullin-F box protein (SCF) complex or the anaphase-promoting complex (APC). Here we describe an unconventional cell cycle-regulated proteolytic mechanism that acts on the Acm1 protein, an inhibitor of the APC activator Cdh1 in budding yeast. Although Acm1 can be recognized as a substrate by the Cdc20-activated APC (APCCdc20) in anaphase, APCCdc20 is neither necessary nor sufficient for complete Acm1 degradation at the end of mitosis. An APC-independent, but 26S proteasome-dependent, mechanism is sufficient for complete Acm1 clearance from late mitotic and G1 cells. Surprisingly, this mechanism appears distinct from the canonical ubiquitin targeting pathway, exhibiting several features of ubiquitin-independent proteasomal degradation. For example, Acm1 degradation in G1 requires neither lysine residues in Acm1 nor assembly of polyubiquitin chains. Acm1 was stabilized though by conditional inactivation of the ubiquitin activating enzyme Uba1, implying some requirement for the ubiquitin pathway, either direct or indirect. We identified an amino terminal predicted disordered region in Acm1 that contributes to its proteolysis in G1. Although ubiquitin-independent proteasome substrates have been described, Acm1 appears unique in that its sensitivity to this mechanism is strictly cell cycle-regulated via cyclin-dependent kinase (Cdk) phosphorylation. As a result, Acm1 expression is limited to the cell cycle window in which Cdk is active. We provide evidence that failure to eliminate Acm1 impairs activation of APCCdh1 at mitotic exit, justifying its strict regulation by cell cycle-dependent transcription and proteolytic mechanisms. Importantly, our results reveal that strict cell-cycle expression profiles

Mechanisms of thermally induced threshold voltage instability in GaN-based heterojunction transistors

International Nuclear Information System (INIS)

Yang, Shu; Liu, Shenghou; Liu, Cheng; Lu, Yunyou; Chen, Kevin J.

2014-01-01

In this work, we attempt to reveal the underlying mechanisms of divergent V TH -thermal-stabilities in III-nitride metal-insulator-semiconductor high-electron-mobility transistor (MIS-HEMT) and MOS-Channel-HEMT (MOSC-HEMT). In marked contrast to MOSC-HEMT featuring temperature-independent V TH , MIS-HEMT with the same high-quality gate-dielectric/III-nitride interface and similar interface trap distribution exhibits manifest thermally induced V TH shift. The temperature-dependent V TH of MIS-HEMT is attributed to the polarized III-nitride barrier layer, which spatially separates the critical gate-dielectric/III-nitride interface from the channel and allows “deeper” interface trap levels emerging above the Fermi level at pinch-off. This model is further experimentally validated by distinct V G -driven Fermi level movements at the critical interfaces in MIS-HEMT and MOSC-HEMT. The mechanisms of polarized III-nitride barrier layer in influencing V TH -thermal-stability provide guidelines for the optimization of insulated-gate III-nitride power switching devices

Hepatocellular carcinoma displays distinct DNA methylation signatures with potential as clinical predictors.

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Hector Hernandez-Vargas

Full Text Available BACKGROUND: Hepatocellular carcinoma (HCC is characterized by late detection and fast progression, and it is believed that epigenetic disruption may be the cause of its molecular and clinicopathological heterogeneity. A better understanding of the global deregulation of methylation states and how they correlate with disease progression will aid in the design of strategies for earlier detection and better therapeutic decisions. METHODS AND FINDINGS: We characterized the changes in promoter methylation in a series of 30 HCC tumors and their respective surrounding tissue and identified methylation signatures associated with major risk factors and clinical correlates. A wide panel of cancer-related gene promoters was analyzed using Illumina bead array technology, and CpG sites were then selected according to their ability to classify clinicopathological parameters. An independent series of HCC tumors and matched surrounding tissue was used for validation of the signatures. We were able to develop and validate a signature of methylation in HCC. This signature distinguished HCC from surrounding tissue and from other tumor types, and was independent of risk factors. However, aberrant methylation of an independent subset of promoters was associated with tumor progression and etiological risk factors (HBV or HCV infection and alcohol consumption. Interestingly, distinct methylation of an independent panel of gene promoters was strongly correlated with survival after cancer therapy. CONCLUSION: Our study shows that HCC tumors exhibit specific DNA methylation signatures associated with major risk factors and tumor progression stage, with potential clinical applications in diagnosis and prognosis.

Endocytosis of hERG Is Clathrin-Independent and Involves Arf6

Science.gov (United States)

Abuarab, Nada; Smith, Andrew J.; Hardy, Matthew E. L.; Elliott, David J. S.; Sivaprasadarao, Asipu

2013-01-01

The hERG potassium channel is critical for repolarisation of the cardiac action potential. Reduced expression of hERG at the plasma membrane, whether caused by hereditary mutations or drugs, results in long QT syndrome and increases the risk of ventricular arrhythmias. Thus, it is of fundamental importance to understand how the density of this channel at the plasma membrane is regulated. We used antibodies to an extracellular native or engineered epitope, in conjunction with immunofluorescence and ELISA, to investigate the mechanism of hERG endocytosis in recombinant cells and validated the findings in rat neonatal cardiac myocytes. The data reveal that this channel undergoes rapid internalisation, which is inhibited by neither dynasore, an inhibitor of dynamin, nor a dominant negative construct of Rab5a, into endosomes that are largely devoid of the transferrin receptor. These results support a clathrin-independent mechanism of endocytosis and exclude involvement of dynamin-dependent caveolin and RhoA mechanisms. In agreement, internalised hERG displayed marked overlap with glycosylphosphatidylinositol-anchored GFP, a clathrin-independent cargo. Endocytosis was significantly affected by cholesterol extraction with methyl-β-cyclodextrin and inhibition of Arf6 function with dominant negative Arf6-T27N-eGFP. Taken together, we conclude that hERG undergoes clathrin-independent endocytosis via a mechanism involving Arf6. PMID:24392021

Brittle Fracture Mechanics of Snow : In Situ Testing and Distinct Element Modeling

Science.gov (United States)

Faillettaz, J.; Daudon, D.; Louchet, F.

A snow slab avalanche release usually results from the rupture of the snow cover at the interface between an upper layer (slab) and an underlying substrate. Amazingly, the models proposed so far to predict this kind of rupture were only based on continuum mechanics, as they did not take into account the existing cracks or cohesion defects at the interface between the two layers, and their possible unstable propagation that eventually triggers the avalanche. This is why the present work, essentially devoted to human triggered avalanches, is based instead on Griffith's fracture approach, widely used in modelling brittle fracture of materials. The possible rupture scenario involves a propagation in a shear mode of a "basal crack" nucleated and gradually grown at the interface by the skier's weight, followed by a mode I opening and propagation of a "crown crack" at the top of the sheared zone. Different avalanche sizes are predicted according whether the basal crack propagation reaches or not the Griffith's instabil- ity size before crown crack opening (Louchet 2000). Accurate predictions therefore require a precise knowledge of snow toughness values in both modes. A theoretical estimation of toughness considering snow as an ice foam was proposed by Kirchner and Michot (2000), but the question of whether these results may be extended to an assembly of sintered grains is still open. A mode I toughness measurement of snow was also published for the first time by Kirchner and Michot on samples gathered in the Vosges range. In the present work, we developed an experimental set similar to Michot's, in order to measure mode I toughness: a vertical crack of increasing size is gradually machined from the top surface in an horizontal snow beam until failure takes place under its own weight. The toughness value is computed from the snow weight and the crack length at the onset of rapid crack propagation. A similar device was designed for mode II testing, but is still under

Distinct Signaling Roles of cIMP, cCMP, and cUMP.

Science.gov (United States)

Seifert, Roland

2016-10-04

The cyclic purine nucleotide cIMP and the cyclic pyrimidine nucleotides cCMP and cUMP are emerging second messengers. These cNMPs show different biological effects, but the molecular mechanisms remain elusive. In this issue of Structure, Ng et al. (2016) provide structural evidence for distinct interactions of cIMP, cCMP, and cUMP with ion channels. Copyright © 2016 Elsevier Ltd. All rights reserved.

Distinctive Citizenship

DEFF Research Database (Denmark)

Kaur, Ravinder

2009-01-01

The refugee, in India's Partition history, appears as an enigmatic construct - part pitiful, part heroic, though mostly shorn of agency - representing the surface of the human tragedy of Partition. Yet this archetype masks the undercurrent of social distinctions that produced hierarchies of post...

The 2015 Nobel Prize in Chemistry The Discovery of Essential Mechanisms that Repair DNA Damage.

Science.gov (United States)

Lindahl, Tomas; Modrich, Paul; Sancar, Aziz

2016-01-01

The Royal Swedish Academy awarded the Nobel Prize in Chemistry for 2015 to Tomas Lindahl, Paul Modrich and Aziz Sancar for their discoveries in fundamental mechanisms of DNA repair. This pioneering research described three different essential pathways that correct DNA damage, safeguard the integrity of the genetic code to ensure its accurate replication through generations, and allow proper cell division. Working independently of each other, Tomas Lindahl, Paul Modrich and Aziz Sancar delineated the mechanisms of base excision repair, mismatch repair and nucleotide excision repair, respectively. These breakthroughs challenged and dismissed the early view that the DNA molecule was very stable, paving the way for the discovery of human hereditary diseases associated with distinct DNA repair deficiencies and a susceptibility to cancer. It also brought a deeper understanding of cancer as well as neurodegenerative or neurological diseases, and let to novel strategies to treat cancer.

Distinct patterns of autophagy evoked by two benzoxazine derivatives in vascular endothelial cells.

Science.gov (United States)

Wang, Li; Dong, ZhiWu; Huang, Bin; Zhao, BaoXiang; Wang, Hua; Zhao, Jing; Kung, HsiangFu; Zhang, ShangLi; Miao, JunYing

2010-11-01

Macroautophagy (referred to as autophagy) is an evolutionarily conserved, bulk-destruction process in eukaryotes. During this process, the cytoplasm containing long-lived proteins and organelles is engulfed into double-membrane autophagosomes, and ultimately undergoes enzymatic degradation within lysosomes. Autophagy serves as a prosurvival machinery, or it may contribute to cell death. Accumulating evidence indicates that autophagy is involved in the pathogenesis and intervention of various human diseases. Pharmacological autophagy modulators are arousing interest from biologists and clinical physicians in light of their potential for disease therapy and increasing our understanding of the mechanism of autophagy. In this study, we identified two autophagy enhancers, 6-amino-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine (ABO) and 6,8-dichloro-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine (DBO), in human umbilical vein endothelial cells (HUVEC s) by autophagy assays, and demonstrate that ABO and DBO could stimulate autophagy in an mtor-independent and mtor-dependent manner, respectively; ABO-stimulated autophagy was attributed to the elevation of the Ca2+ channel annexin A7 (ANXA7), whereas DBO's effect was due to the level of intracellular reactive oxygen species (ROS). Importantly, we found that ANXA7 was essential for autophagy induction via modulating the intracellular calcium concentration ([Ca2+]i) in HUVEC s. In summary, our work introduced two distinct autophagy enhancers and highlighted the critical role of ANXA7 in endothelial autophagy.

Redox-Regulated Pathway of Tyrosine Phosphorylation Underlies NF-κB Induction by an Atypical Pathway Independent of the 26S Proteasome

Science.gov (United States)

Cullen, Sarah; Ponnappan, Subramaniam; Ponnappan, Usha

2015-01-01

Alternative redox stimuli such as pervanadate or hypoxia/reoxygenation, induce transcription factor NF-κB by phospho-tyrosine-dependent and proteasome-independent mechanisms. While considerable attention has been paid to the absence of proteasomal regulation of tyrosine phosphorylated IκBα, there is a paucity of information regarding proteasomal regulation of signaling events distinct from tyrosine phosphorylation of IκBα. To delineate roles for the ubiquitin-proteasome pathway in the phospho-tyrosine dependent mechanism of NF-κB induction, we employed the proteasome inhibitor, Aclacinomycin, and the phosphotyrosine phosphatase inhibitor, pervanadate (PV). Results from these studies demonstrate that phospho-IκBα (Tyr-42) is not subject to proteasomal degradation in a murine stromal epithelial cell line, confirming results previously reported. Correspondingly, proteasome inhibition had no discernable effect on the key signaling intermediaries, Src and ERK1/2, involved in the phospho-tyrosine mechanisms regulating PV-mediated activation of NF-κB. Consistent with previous reports, a significant redox imbalance leading to the activation of tyrosine kinases, as occurs with pervanadate, is required for the induction of NF-κB. Strikingly, our studies demonstrate that proteasome inhibition can potentiate oxidative stress associated with PV-stimulation without impacting kinase activation, however, other cellular implications for this increase in intracellular oxidation remain to be fully delineated. PMID:25671697

Distribution of Disease-Associated Copy Number Variants across Distinct Disorders of Cognitive Development

Science.gov (United States)

Pescosolido, Matthew F.; Gamsiz, Ece D.; Nagpal, Shailender; Morrow, Eric M.

2013-01-01

Objective: The purpose of the present study was to discover the extent to which distinct "DSM" disorders share large, highly recurrent copy number variants (CNVs) as susceptibility factors. We also sought to identify gene mechanisms common to groups of diagnoses and/or specific to a given diagnosis based on associations with CNVs. Method:…

Retention in the Golgi apparatus and expression on the cell surface of Cfr/Esl-1/Glg-1/MG-160 are regulated by two distinct mechanisms.

Science.gov (United States)

Miyaoka, Yuichiro; Kato, Hidenori; Ebato, Kazuki; Saito, Shigeru; Miyata, Naoko; Imamura, Toru; Miyajima, Atsushi

2011-11-15

Cfr (cysteine-rich fibroblast growth factor receptor) is an Fgf (fibroblast growth factor)-binding protein without a tyrosine kinase. We have shown previously that Cfr is involved in Fgf18 signalling via Fgf receptor 3c. However, as Cfr is also known as Glg (Golgi apparatus protein)-1 or MG-160 and occurs in the Golgi apparatus, it remains unknown how the distribution of Cfr is regulated. In the present study, we performed a mutagenic analysis of Cfr to show that two distinct regions contribute to its distribution and stability. First, the C-terminal region retains Cfr in the Golgi apparatus. Secondly, the Cfr repeats in the extracellular juxtamembrane region destabilizes Cfr passed through the Golgi apparatus. This destabilization does not depend on the cleavage and secretion of the extracellular domain of Cfr. Furthermore, we found that Cfr with a GPI (glycosylphosphatidylinositol) anchor was predominantly expressed on the cell surface in Ba/F3 cells and affected Fgf18 signalling in a similar manner to the full-length Cfr, indicating that the interaction of Cfr with Fgfs on the cell surface is important for its function in Fgf signalling. These results suggest that the expression of Cfr in the Golgi apparatus and on the plasma membrane is finely tuned through two distinct mechanisms for exhibiting different functions.

Ego mechanisms of defense are associated with patients’ preference of treatment modality independent of psychological distress in end-stage renal disease

Directory of Open Access Journals (Sweden)

Thomas Hyphantis

2010-02-01

Full Text Available Thomas Hyphantis1, Spiros Katsoudas2, Sonia Voudiclari31Associate Professor of Psychiatry, Department of Psychiatry, Medical School, University of Ioannina, Ioannina, Greece; 2Nephrologist, Renal Clinic, Hippocration General Hospital, Athens, Greece; 3Department of Nephrology, University of Athens, GreeceAbstract: Several parameters mediate the selection of treatment modality in end-stage renal disease (ESRD. The nephrology community suggests that patient preference should be the prime determinant of modality choice. We aimed to test whether ego mechanisms of defense are associated with patients’ treatment modality preferences, independent of psychological distress. In 58 eligible ESRD patients who had themselves chosen their treatment modality, we administered the Symptom Distress Checklist-90-R and the Defense Style Questionnaire. Thirtyseven patients (53.4% had chosen hemodialysis and 21 (46.6% peritoneal dialysis. Patients who preferred peritoneal dialysis were younger (odds ratio [OR], 0.89; 95% confidence interval [CI]: 0.804–0.988, had received more education (OR, 8.84; 95% CI: 1.301–60.161, and were twice as likely to adopt an adaptive defense style as compared to patients who preferred hemodialysis (57.1% vs 27.0%, respectively; P < 0.033. On the contrary, the latter were more likely to adopt an image-distorting defense style (35.1% vs 14.3%; P = 0.038 and passive–aggressive defenses (OR, 0.73: 95% CI: 0.504–1.006. These results were independent of psychological distress. Our findings indicate that the patient’s personality should be taken into account, if we are to better define which modalities are best suited to which patients. Also, physicians should bear in mind passive–aggressive behaviors that warrant attention and intervention in patients who preferred hemodialysis.Keywords: end-stage renal disease, hemodialysis, peritoneal dialysis, ego mechanisms of defense, DSQ, psychopathology

Molecular polymorphism of a cell surface proteoglycan: distinct structures on simple and stratified epithelia.

Science.gov (United States)

Sanderson, R D; Bernfield, M

1988-12-01

Epithelial cells are organized into either a single layer (simple epithelia) or multiple layers (stratified epithelia). Maintenance of these cellular organizations requires distinct adhesive mechanisms involving many cell surface molecules. One such molecule is a cell surface proteoglycan, named syndecan, that contains both heparan sulfate and chondroitin sulfate chains. This proteoglycan binds cells to fibrillar collagens and fibronectin and thus acts as a receptor for interstitial matrix. The proteoglycan is restricted to the basolateral surface of simple epithelial cells, but is located over the entire surface of stratified epithelial cells, even those surfaces not contacting matrix. We now show that the distinct localization in simple and stratified epithelia correlates with a distinct proteoglycan structure. The proteoglycan from simple epithelia (modal molecular size, 160 kDa) is larger than that from stratified epithelia (modal molecular size, 92 kDa), but their core proteins are identical in size and immunoreactivity. The proteoglycan from simple epithelia has more and larger heparan sulfate and chondroitin sulfate chains than the proteoglycan from stratified epithelia. Thus, the cell surface proteoglycan shows a tissue-specific structural polymorphism due to distinct posttranslational modifications. This polymorphism likely reflects distinct proteoglycan functions in simple and stratified epithelia, potentially meeting the different adhesive requirements of the cells in these different organizations.

Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism

NARCIS (Netherlands)

Mandriota, Stefano J.; Valentijn, Linda J.; Lesne, Laurence; Betts, David R.; Marino, Denis; Boudal-Khoshbeen, Mary; London, Wendy B.; Rougemont, Anne-Laure; Attiyeh, Edward F.; Maris, John M.; Hogarty, Michael D.; Koster, Jan; Molenaar, Jan J.; Versteeg, Rogier; Ansari, Marc; Gumy-Pause, Fabienne

2015-01-01

Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most

The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by a PARP independent mechanism

International Nuclear Information System (INIS)

Lakatos, Petra; Hegedűs, Csaba; Salazar Ayestarán, Nerea; Juarranz, Ángeles; Kövér, Katalin E.; Szabó, Éva; Virág, László

2016-01-01

Highlights: • PARP-1 is not a key regulator of photochemotherapy. • The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by a PARP independent mechanism. • Photosensitization by PJ-34 is associated with increased ROS production and DNA damage. • Cells sensitized by PJ-34 undergo caspase-mediated apoptosis. - Abstract: A combination of a photosensitizer with light of matching wavelength is a common treatment modality in various diseases including psoriasis, atopic dermatitis and tumors. DNA damage and production of reactive oxygen intermediates may impact pathological cellular functions and viability. Here we set out to investigate the role of the nuclear DNA nick sensor enzyme poly(ADP-ribose) polymerase 1 in photochemical treatment (PCT)-induced tumor cell killing. We found that silencing PARP-1 or inhibition of its enzymatic activity with Veliparib had no significant effect on the viability of A431 cells exposed to 8-methoxypsoralen (8-MOP) and UVA (2.5 J/cm"2) indicating that PARP-1 is not likely to be a key player in either cell survival or cell death of PCT-exposed cells. Interestingly, however, another commonly used PARP inhibitor PJ-34 proved to be a photosensitizer with potency equal to 8-MOP. Irradiation of PJ-34 with UVA caused changes both in the UV absorption and in the 1H NMR spectra of the compound with the latter suggesting UVA-induced formation of tautomeric forms of the compound. Characterization of the photosensitizing effect revealed that PJ–34 + UVA triggers overproduction of reactive oxygen species, induces DNA damage, activation of caspase 3 and caspase 8 and internucleosomal DNA fragmentation. Cell death in this model could not be prevented by antioxidants (ascorbic acid, trolox, glutathione, gallotannin or cell permeable superoxide dismutase or catalase) but could be suppressed by inhibitors of caspase-3 and −8. In conclusion, PJ-34 is a photosensitizer and PJ–34 + UVA causes DNA damage and caspase

The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by a PARP independent mechanism

Energy Technology Data Exchange (ETDEWEB)

Lakatos, Petra; Hegedűs, Csaba [Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen (Hungary); Salazar Ayestarán, Nerea; Juarranz, Ángeles [Department of Biology, Faculty of Sciences, Universidad Autónoma of Madrid, 28049-Madrid (Spain); Kövér, Katalin E. [Department of Inorganic and Analytical Chemistry, Faculty of Sciences, University of Debrecen, Debrecen (Hungary); Szabó, Éva [Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen (Hungary); Virág, László, E-mail: lvirag@med.unideb.hu [Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen (Hungary); MTA-DE Cell Biology and Signaling Research Group, Debrecen (Hungary)

2016-08-15

Highlights: • PARP-1 is not a key regulator of photochemotherapy. • The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by a PARP independent mechanism. • Photosensitization by PJ-34 is associated with increased ROS production and DNA damage. • Cells sensitized by PJ-34 undergo caspase-mediated apoptosis. - Abstract: A combination of a photosensitizer with light of matching wavelength is a common treatment modality in various diseases including psoriasis, atopic dermatitis and tumors. DNA damage and production of reactive oxygen intermediates may impact pathological cellular functions and viability. Here we set out to investigate the role of the nuclear DNA nick sensor enzyme poly(ADP-ribose) polymerase 1 in photochemical treatment (PCT)-induced tumor cell killing. We found that silencing PARP-1 or inhibition of its enzymatic activity with Veliparib had no significant effect on the viability of A431 cells exposed to 8-methoxypsoralen (8-MOP) and UVA (2.5 J/cm{sup 2}) indicating that PARP-1 is not likely to be a key player in either cell survival or cell death of PCT-exposed cells. Interestingly, however, another commonly used PARP inhibitor PJ-34 proved to be a photosensitizer with potency equal to 8-MOP. Irradiation of PJ-34 with UVA caused changes both in the UV absorption and in the 1H NMR spectra of the compound with the latter suggesting UVA-induced formation of tautomeric forms of the compound. Characterization of the photosensitizing effect revealed that PJ–34 + UVA triggers overproduction of reactive oxygen species, induces DNA damage, activation of caspase 3 and caspase 8 and internucleosomal DNA fragmentation. Cell death in this model could not be prevented by antioxidants (ascorbic acid, trolox, glutathione, gallotannin or cell permeable superoxide dismutase or catalase) but could be suppressed by inhibitors of caspase-3 and −8. In conclusion, PJ-34 is a photosensitizer and PJ–34 + UVA causes DNA damage and caspase

Handedness of a motor program in C. elegans is independent of left-right body asymmetry.

Directory of Open Access Journals (Sweden)

Joanna C Downes

Full Text Available Complex animals display bilaterally asymmetric motor behavior, or "motor handedness," often revealed by preferential use of limbs on one side. For example, use of right limbs is dominant in a strong majority of humans. While the mechanisms that establish bilateral asymmetry in motor function are unknown in humans, they appear to be distinct from those for other handedness asymmetries, including bilateral visceral organ asymmetry, brain laterality, and ocular dominance. We report here that a simple, genetically homogeneous animal comprised of only ~1000 somatic cells, the nematode C. elegans, also shows a distinct motor handedness preference: on a population basis, males show a pronounced right-hand turning bias during mating. The handedness bias persists through much of adult lifespan, suggesting that, as in more complex animals, it is an intrinsic trait of each individual, which can differ from the population mean. Our observations imply that the laterality of motor handedness preference in C. elegans is driven by epigenetic factors rather than by genetic variation. The preference for right-hand turns is also seen in animals with mirror-reversed anatomical handedness and is not attributable to stochastic asymmetric loss of male sensory rays that occurs by programmed cell death. As with C. elegans, we also observed a substantial handedness bias, though not necessarily the same preference in direction, in several gonochoristic Caenorhabditis species. These findings indicate that the independence of bilaterally asymmetric motor dominance from overall anatomical asymmetry, and a population-level tendency away from ambidexterity, occur even in simple invertebrates, suggesting that these may be common features of bilaterian metazoans.

Mechanisms of Interaction in Speech Production

Science.gov (United States)

Baese-Berk, Melissa; Goldrick, Matthew

2009-01-01

Many theories predict the presence of interactive effects involving information represented by distinct cognitive processes in speech production. There is considerably less agreement regarding the precise cognitive mechanisms that underlie these interactive effects. For example, are they driven by purely production-internal mechanisms (e.g., Dell,…

Hypoxia independent drivers of melanoma angiogenesis

Directory of Open Access Journals (Sweden)

Svenja eMeierjohann

2015-05-01

Full Text Available Tumor angiogenesis is a process which is traditionally regarded as the tumor`s response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a prerequisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia independent mechanisms of tumor angiogenesis in melanoma.

Quercetin enhances adiponectin secretion by a PPAR-gamma independent mechanism

DEFF Research Database (Denmark)

Wein, Silvia; Behm, Norma; Petersen, Rasmus Koefoed

2010-01-01

To study possible insulin sensitizing, anti-inflammatory and anti-oxidative effects of the flavonol quercetin, rats were fed a high-fat diet (19%, w/w) with (HFQ) or without (HF) 0.03% quercetin or a flavonoid-poor low-fat (5%, w/w) maintenance diet (LF) over 4 weeks. Body weight was measured...... and WAT mRNA levels of adiponectin were elevated compared with the HF group, however, PPAR-gamma mRNA concentration in WAT was decreased (HFQ vs. HF). Compared to both other groups quercetin feeding significantly reduced oxidative stress, measured by plasma 8-iso-PGF(2alpha), while body weight gain, body...... composition and plasma leptin levels were not affected. Neither quercetin nor its metabolites induced PPAR-gamma-mediated transactivation in vitro. Adiponectin stimulating effects of quercetin are PPAR-gamma-independent and prevent impairment of insulin sensitivity without affecting body weight...

The Role of Cognitive Content and Cognitive Processes in Chronic Pain: An Important Distinction?

Science.gov (United States)

Jensen, Mark P; Thorn, Beverly E; Carmody, James; Keefe, Francis J; Burns, John W

2018-05-01

Pain-related cognitive content (what people think about pain) and cognitive processes (how people think about pain; what they do with their pain-related thoughts) and their interaction are hypothesized to play distinct roles in patient function. However, questions have been raised regarding whether it is possible or practical to assess cognitive content and cognitive process as distinct domains. The aim of this study was to determine the extent to which measures that seem to assess mostly pain-related cognitive content, cognitive processes, and content and process, are relatively independent from each other and contribute unique variance to the prediction of patient function. Individuals with chronic low back pain (N=165) participating in an ongoing RCT were administered measures of cognitions, pain, and function (depressive symptoms and pain interference) pretreatment. Analyses provided support for the hypothesis that cognitive content and cognitive process, while related, can be assessed as distinct components. However, the measure assessing a cognitive process-mindfulness-evidenced relatively weak associations with function, especially compared with the stronger and more consistent findings for the measures of content (catastrophizing and self-efficacy). The results provide preliminary evidence for the possibility that mindfulness could have both benefits and costs. Research to evaluate this possibility is warranted.

The use of a path independent integral in non-linear fracture mechanics

International Nuclear Information System (INIS)

Hellen, T.K.

1977-01-01

A computer program for calculating the J and J* integrals has been developed as an extension to the BERSAFE finite element system. A full analysis of the cracked structure including plasticity, creep and thermal strains is conducted and the results are stored on a permanent data set. The integral values may then be calculated using the post-processor program for any number of contours and load or time steps, without recourse to further expensive computations. Numerical examples are presented comparing the J and J* integrals for a number of cracked plates under thermal, plastic and creep environments. To demonstrate the accuracy for a simple thermo-elastic case, a centre cracked plate subject to a symmetric quadratic gradient is included. Here, the J integral is shown to be path dependent whereas good independence is seen for the J* integral. The case of an elastic-plastic plate is invetigated to demonstrate path independence for both integrals in non-linear elasticity, and the effects of unloading are discussed. An alternative method for obtaining the change of potential energy over a small crack extension is briefly mentioned and compared to the J and J* results in this case. An axisymmetric bar with an internal penny-shaped crack subjected to tension is discussed under elastic-plastic materials behavior

Distinct activities of Bartonella henselae type IV secretion effector proteins modulate capillary-like sprout formation.

Science.gov (United States)

Scheidegger, F; Ellner, Y; Guye, P; Rhomberg, T A; Weber, H; Augustin, H G; Dehio, C

2009-07-01

The zoonotic pathogen Bartonella henselae (Bh) can lead to vasoproliferative tumour lesions in the skin and inner organs known as bacillary angiomatosis and bacillary peliosis. The knowledge on the molecular and cellular mechanisms involved in this pathogen-triggered angiogenic process is confined by the lack of a suitable animal model and a physiologically relevant cell culture model of angiogenesis. Here we employed a three-dimensional in vitro angiogenesis assay of collagen gel-embedded endothelial cell (EC) spheroids to study the angiogenic properties of Bh. Spheroids generated from Bh-infected ECs displayed a high capacity to form sprouts, which represent capillary-like projections into the collagen gel. The VirB/VirD4 type IV secretion system and a subset of its translocated Bartonella effector proteins (Beps) were found to profoundly modulate this Bh-induced sprouting activity. BepA, known to protect ECs from apoptosis, strongly promoted sprout formation. In contrast, BepG, triggering cytoskeletal rearrangements, potently inhibited sprouting. Hence, the here established in vitro model of Bartonella- induced angiogenesis revealed distinct and opposing activities of type IV secretion system effector proteins, which together with a VirB/VirD4-independent effect may control the angiogenic activity of Bh during chronic infection of the vasculature.

Agricultural mechanization policy and strategy : the case of Thailand

NARCIS (Netherlands)

Rijk, A.G.

1989-01-01

The role of agricultural mechanization in a developing economy is examined in order to enhance the formulation of mechanization policy and strategy. As a result of the review and assessment of the mechanization process, seven distinct stages in the mechanization process are specified and

Mild MPP+ exposure impairs autophagic degradation through a novel lysosomal acidity-independent mechanism.

Science.gov (United States)

Miyara, Masatsugu; Kotake, Yaichiro; Tokunaga, Wataru; Sanoh, Seigo; Ohta, Shigeru

2016-10-01

Parkinson's disease (PD) is the second most common neurodegenerative disorder, but its underlying cause remains unknown. Although recent studies using PD-related neurotoxin MPP + suggest autophagy involvement in the pathogenesis of PD, the effect of MPP + on autophagic processes under mild exposure, which mimics the slow progressive nature of PD, remains largely unclear. We examined the effect of mild MPP + exposure (10 and 200 μM for 48 h), which induces a more slowly developing cell death, on autophagic processes and the mechanistic differences with acute MPP + toxicity (2.5 and 5 mM for 24 h). In SH-SY5Y cells, mild MPP + exposure predominantly inhibited autophagosome degradation, whereas acute MPP + exposure inhibited both autophagosome degradation and basal autophagy. Mild MPP + exposure reduced lysosomal hydrolase cathepsin D activity without changing lysosomal acidity, whereas acute exposure decreased lysosomal density. Lysosome biogenesis enhancers trehalose and rapamycin partially alleviated mild MPP + exposure induced impaired autophagosome degradation and cell death, but did not prevent the pathogenic response to acute MPP + exposure, suggesting irreversible lysosomal damage. We demonstrated impaired autophagic degradation by MPP + exposure and mechanistic differences between mild and acute MPP + toxicities. Mild MPP + toxicity impaired autophagosome degradation through novel lysosomal acidity-independent mechanisms. Sustained mild lysosomal damage may contribute to PD. We examined the effects of MPP + on autophagic processes under mild exposure, which mimics the slow progressive nature of Parkinson's disease, in SH-SY5Y cells. This study demonstrated impaired autophagic degradation through a reduction in lysosomal cathepsin D activity without altering lysosomal acidity by mild MPP + exposure. Mechanistic differences between acute and mild MPP + toxicity were also observed. Sustained mild damage of lysosome may be an underlying cause of Parkinson

Counselor Identity: Conformity or Distinction?

Science.gov (United States)

McLaughlin, Jerry E.; Boettcher, Kathryn

2009-01-01

The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

Cyclin D1 represses p300 transactivation through a cyclin-dependent kinase-independent mechanism.

Science.gov (United States)

Fu, Maofu; Wang, Chenguang; Rao, Mahadev; Wu, Xiaofang; Bouras, Toula; Zhang, Xueping; Li, Zhiping; Jiao, Xuanmao; Yang, Jianguo; Li, Anping; Perkins, Neil D; Thimmapaya, Bayar; Kung, Andrew L; Munoz, Alberto; Giordano, Antonio; Lisanti, Michael P; Pestell, Richard G

2005-08-19

Cyclin D1 encodes a regulatory subunit, which with its cyclin-dependent kinase (Cdk)-binding partner forms a holoenzyme that phosphorylates and inactivates the retinoblastoma protein. In addition to its Cdk binding-dependent functions, cyclin D1 regulates cellular differentiation in part by modifying several transcription factors and nuclear receptors. The molecular mechanism through which cyclin D1 regulates the function of transcription factors involved in cellular differentiation remains to be clarified. The histone acetyltransferase protein p300 is a co-integrator required for regulation of multiple transcription factors. Here we show that cyclin D1 physically interacts with p300 and represses p300 transactivation. We demonstrated further that the interaction of the two proteins occurs at the peroxisome proliferator-activated receptor gamma-responsive element of the lipoprotein lipase promoter in the context of the local chromatin structure. We have mapped the domains in p300 and cyclin D1 involved in this interaction. The bromo domain and cysteine- and histidine-rich domains of p300 were required for repression by cyclin D1. Cyclin D1 repression of p300 was independent of the Cdk- and retinoblastoma protein-binding domains of cyclin D1. Cyclin D1 inhibits histone acetyltransferase activity of p300 in vitro. Microarray analysis identified a signature of genes repressed by cyclin D1 and induced by p300 that promotes cellular differentiation and induces cell cycle arrest. Together, our results suggest that cyclin D1 plays an important role in cellular proliferation and differentiation through regulation of p300.

Fine particles from Independence Day fireworks events: chemical characterization and source apportionment

Science.gov (United States)

Zhang, J.; Lance, S.; Freedman, J. M.; Yele, S.; Crandall, B.; Wei, X.; Schwab, J. J.

2017-12-01

To study the impact of fireworks (FW) events on air quality, aerosol particles from FW displays were measured using a High-Resolution Time-of-Flight Aerosol Mass Spectrometer (HR-ToF-AMS) and collocated instruments during the Independence Day holiday 2017 in Albany, NY. Three FW events were identified through potassium ion (K+) signals in the mass spectra. The largest FW event signal measured at two different locations was the Independence Day celebration in Albany, with maximum aerosol concentrations of about 55 ug/m3 at the downtown site and 35 ug/m3 at the uptown site. The aerosol concentration peaked at the uptown site about 2 hours later than at the downtown site. FW events resulted in significant increases in both organic and inorganic (K+, sulfate, chloride) compounds. Among the organics, Positive Matrix Factorization (PMF) identified one special FW organic aerosol factor (FW-OA), which was highly oxidized. The intense emission of FW particles from the Independence Day celebration contributed 76% of total PM1 at the uptown site. The aerosol and wind LiDAR measurements showed two distinct pollution sources, one from the Independence Day FW event in Albany, and another aerosol source transported from other areas, potentially associated with other town's FW events.

Specialization of the left supramarginal gyrus for hand-independent praxis representation is not related to hand dominance

Science.gov (United States)

Króliczak, Gregory; Piper, Brian J.; Frey, Scott H.

2016-01-01

Data from focal brain injury and functional neuroimaging studies implicate a distributed network of parieto-fronto-temporal areas in the human left cerebral hemisphere as playing distinct roles in the representation of meaningful actions (praxis). Because these data come primarily from right-handed individuals, the relationship between left cerebral specialization for praxis representation and hand dominance remains unclear. We used functional magnetic resonance imaging (fMRI) to evaluate the hypothesis that strongly left-handed (right hemisphere motor dominant) adults also exhibit this left cerebral specialization. Participants planned familiar actions for subsequent performance with the left or right hand in response to transitive (e.g., “pounding”) or intransitive (e.g. “waving”) action words. In linguistic control trials, cues denoted non-physical actions (e.g., “believing”). Action planning was associated with significant, exclusively left-lateralized and extensive increases of activity in the supramarginal gyrus (SMg), and more focal modulations in the left caudal middle temporal gyrus (cMTg). This activity was hand- and gesture-independent, i.e., unaffected by the hand involved in subsequent action performance, and the type of gesture (i.e., transitive or intransitive). Compared directly with right-handers, left-handers exhibited greater involvement of the right angular gyrus (ANg) and dorsal premotor cortex (dPMC), which is indicative of a less asymmetric functional architecture for praxis representation. We therefore conclude that the organization of mechanisms involved in planning familiar actions is influenced by one’s motor dominance. However, independent of hand dominance, the left SMg and cMTg are specialized for ideomotor transformations—the integration of conceptual knowledge and motor representations into meaningful actions. These findings support the view that higher-order praxis representation and lower-level motor dominance rely

Fluid mechanics as a driver of tissue-scale mechanical signaling in organogenesis.

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Gilbert, Rachel M; Morgan, Joshua T; Marcin, Elizabeth S; Gleghorn, Jason P

2016-12-01

Organogenesis is the process during development by which cells self-assemble into complex, multi-scale tissues. Whereas significant focus and research effort has demonstrated the importance of solid mechanics in organogenesis, less attention has been given to the fluid forces that provide mechanical cues over tissue length scales. Fluid motion and pressure is capable of creating spatial gradients of forces acting on cells, thus eliciting distinct and localized signaling patterns essential for proper organ formation. Understanding the multi-scale nature of the mechanics is critically important to decipher how mechanical signals sculpt developing organs. This review outlines various mechanisms by which tissues generate, regulate, and sense fluid forces and highlights the impact of these forces and mechanisms in case studies of normal and pathological development.

LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

International Nuclear Information System (INIS)

Sun Haipeng; Xu Beibei; Sheveleva, Elena; Chen, Qin M.

2008-01-01

Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT)-induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a structural analogue and a negative control for PI3K inhibitory activity of LY29, also suppressed COX-2 induction. These data suggest PI3K-independent mechanisms in regulating CT-induced COX-2 expression. LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), and DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca 2+ concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT-induced COX-2 expression in cardiomyocytes

The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB2 receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy

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Deng Liting

2012-09-01

Full Text Available Abstract Background Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB2 agonist, produces antinociception without producing central nervous system (CNS-associated side effects. The present study was conducted to examine the antinociceptive effect of AM1710 in rodent models of neuropathic pain evoked by diverse chemotherapeutic agents (cisplatin and paclitaxel. A secondary objective was to investigate the potential contribution of alpha-chemokine receptor (CXCR4 signaling to both chemotherapy-induced neuropathy and CB2 agonist efficacy. Results AM1710 (0.1, 1 or 5 mg/kg i.p. suppressed the maintenance of mechanical and cold allodynia in the cisplatin and paclitaxel models. Anti-allodynic effects of AM1710 were blocked by the CB2 antagonist AM630 (3 mg/kg i.p., but not the CB1 antagonist AM251 (3 mg/kg i.p., consistent with a CB2-mediated effect. By contrast, blockade of CXCR4 signaling with its receptor antagonist AMD3100 (10 mg/kg i.p. failed to attenuate mechanical or cold hypersensitivity induced by either cisplatin or paclitaxel. Moreover, blockade of CXCR4 signaling failed to alter the anti-allodynic effects of AM1710 in the paclitaxel model, further suggesting distinct mechanisms of action. Conclusions Our results indicate that activation of cannabinoid CB2 receptors by AM1710 suppresses both mechanical and cold allodynia in two distinct models of chemotherapy-induced neuropathic pain. By contrast, CXCR4 signaling does not contribute to the maintenance of chemotherapy-induced established neuropathy or efficacy of AM1710. Our studies suggest that CB2 receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents.

Modeling of short-term mechanism of arterial pressure control in the cardiovascular system: object-oriented and acausal approach.

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Kulhánek, Tomáš; Kofránek, Jiří; Mateják, Marek

2014-11-01

This letter introduces an alternative approach to modeling the cardiovascular system with a short-term control mechanism published in Computers in Biology and Medicine, Vol. 47 (2014), pp. 104-112. We recommend using abstract components on a distinct physical level, separating the model into hydraulic components, subsystems of the cardiovascular system and individual subsystems of the control mechanism and scenario. We recommend utilizing an acausal modeling feature of Modelica language, which allows model variables to be expressed declaratively. Furthermore, the Modelica tool identifies which are the dependent and independent variables upon compilation. An example of our approach is introduced on several elementary components representing the hydraulic resistance to fluid flow and the elastic response of the vessel, among others. The introduced model implementation can be more reusable and understandable for the general scientific community. Copyright © 2014 Elsevier Ltd. All rights reserved.

Independence of Movement Preparation and Movement Initiation.

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Haith, Adrian M; Pakpoor, Jina; Krakauer, John W

2016-03-09

Initiating a movement in response to a visual stimulus takes significantly longer than might be expected on the basis of neural transmission delays, but it is unclear why. In a visually guided reaching task, we forced human participants to move at lower-than-normal reaction times to test whether normal reaction times are strictly necessary for accurate movement. We found that participants were, in fact, capable of moving accurately ∼80 ms earlier than their reaction times would suggest. Reaction times thus include a seemingly unnecessary delay that accounts for approximately one-third of their duration. Close examination of participants' behavior in conventional reaction-time conditions revealed that they generated occasional, spontaneous errors in trials in which their reaction time was unusually short. The pattern of these errors could be well accounted for by a simple model in which the timing of movement initiation is independent of the timing of movement preparation. This independence provides an explanation for why reaction times are usually so sluggish: delaying the mean time of movement initiation relative to preparation reduces the risk that a movement will be initiated before it has been appropriately prepared. Our results suggest that preparation and initiation of movement are mechanistically independent and may have a distinct neural basis. The results also demonstrate that, even in strongly stimulus-driven tasks, presentation of a stimulus does not directly trigger a movement. Rather, the stimulus appears to trigger an internal decision whether to make a movement, reflecting a volitional rather than reactive mode of control. Copyright © 2016 the authors 0270-6474/16/363007-10$15.00/0.

The value of independent specialty designation for interventional cardiology.

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Blankenship, James C; Powell, Wayne A; Gray, Dawn R; Duffy, Peter L

2017-01-01

Interventional cardiology has finally completed, after 26 years of advocacy, a professional hat trick: independent board certification, membership as a unique specialty in the American Medical Association House of Delegates (AMA HOD), and recognition by the Centers for Medicaid and Medicare Services (CMS) as a separate medical specialty. This article points out how these distinctions for interventional cardiology and its professional society, the Society for Cardiovascular Angiography and Interventions (SCAI), have led to clear and definite benefits for interventional cardiologists and their patients. We focus on the least understood of these three-recognition by CMS and its implications for reimbursement and quality assessment for interventional cardiologists. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Observational attachment theory-based parenting measures predict children's attachment narratives independently from social learning theory-based measures.

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Matias, Carla; O'Connor, Thomas G; Futh, Annabel; Scott, Stephen

2014-01-01

Conceptually and methodologically distinct models exist for assessing quality of parent-child relationships, but few studies contrast competing models or assess their overlap in predicting developmental outcomes. Using observational methodology, the current study examined the distinctiveness of attachment theory-based and social learning theory-based measures of parenting in predicting two key measures of child adjustment: security of attachment narratives and social acceptance in peer nominations. A total of 113 5-6-year-old children from ethnically diverse families participated. Parent-child relationships were rated using standard paradigms. Measures derived from attachment theory included sensitive responding and mutuality; measures derived from social learning theory included positive attending, directives, and criticism. Child outcomes were independently-rated attachment narrative representations and peer nominations. Results indicated that Attachment theory-based and Social Learning theory-based measures were modestly correlated; nonetheless, parent-child mutuality predicted secure child attachment narratives independently of social learning theory-based measures; in contrast, criticism predicted peer-nominated fighting independently of attachment theory-based measures. In young children, there is some evidence that attachment theory-based measures may be particularly predictive of attachment narratives; however, no single model of measuring parent-child relationships is likely to best predict multiple developmental outcomes. Assessment in research and applied settings may benefit from integration of different theoretical and methodological paradigms.

Telomere dysfunction and cell survival: roles for distinctTIN2-containing complexes

Energy Technology Data Exchange (ETDEWEB)

Kim, Sahn-Ho; Davalos, Albert R.; Heo, Seok-Jin; Rodier, Francis; Beausejour, Christian; Kaminker, Patrick; Campisi, Judith

2006-11-07

Telomeres are maintained by three DNA binding proteins, TRF1, TRF2 and POT1, and several associated factors. One factor, TIN2, binds TRF1 and TRF2 directly and POT1 indirectly. These and two other proteins form a soluble complex that may be the core telomere-maintenance complex. It is not clear whether subcomplexes exist or function in vivo. Here, we provide evidence for two TIN2 subcomplexes with distinct functions in human cells. TIN2 ablation by RNA interference caused telomere uncapping and p53-independent cell death in all cells tested. However, we isolated two TIN2 complexes from cell lysates, each selectively sensitive to a TIN2 mutant (TIN2-13, TIN2-15C). In cells with wild-type p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere uncapping and eventual growth arrest. In cells lacking p53 function, TIN215C more than TIN2-13 caused genomic instability and cell death. Thus, TIN2 subcomplexes likely have distinct functions in telomere maintenance, and may provide selective targets for eliminating cells with mutant p53.

Production, Characterization, and Flocculation Mechanism of Cation Independent, pH Tolerant, and Thermally Stable Bioflocculant from Enterobacter sp. ETH-2

Science.gov (United States)

Tang, Wei; Song, Liyan; Li, Dou; Qiao, Jing; Zhao, Tiantao; Zhao, Heping

2014-01-01

Synthetic high polymer flocculants, frequently utilized for flocculating efficiency and low cost, recently have been discovered as producing increased risk to human health and the environment. Development of a more efficient and environmentally sound alternative flocculant agent is investigated in this paper. Bioflocculants are produced by microorganisms and may exhibit a high rate of flocculation activity. The bioflocculant ETH-2, with high flocculating activity (2849 mg Kaolin particle/mg ETH-2), produced by strain Enterobacter sp. isolated from activated sludge, was systematically investigated with regard to its production, characterization, and flocculation mechanism. Analyses of microscopic observation, zeta potential and ETH-2 structure demonstrates the bridging mechanism, as opposed to charge neutralization, was responsible for flocculation of the ETH-2. ETH-2 retains high molecular weight (603 to 1820 kDa) and multi-functional groups (hydroxyl, amide and carboxyl) that contributed to flocculation. Polysaccharides mainly composed of mannose, glucose, and galactose, with a molar ratio of 1∶2.9∶9.8 were identified as the active constituents in bioflocculant. The structure of the long backbone with active sites of polysaccharides was determined as a primary basis for the high flocculation activity. Bioflocculant ETH-2 is cation independent, pH tolerant, and thermally stable, suggesting a potential fit for industrial application. PMID:25485629

Production, characterization, and flocculation mechanism of cation independent, pH tolerant, and thermally stable bioflocculant from Enterobacter sp. ETH-2.

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Wei Tang

Full Text Available Synthetic high polymer flocculants, frequently utilized for flocculating efficiency and low cost, recently have been discovered as producing increased risk to human health and the environment. Development of a more efficient and environmentally sound alternative flocculant agent is investigated in this paper. Bioflocculants are produced by microorganisms and may exhibit a high rate of flocculation activity. The bioflocculant ETH-2, with high flocculating activity (2849 mg Kaolin particle/mg ETH-2, produced by strain Enterobacter sp. isolated from activated sludge, was systematically investigated with regard to its production, characterization, and flocculation mechanism. Analyses of microscopic observation, zeta potential and ETH-2 structure demonstrates the bridging mechanism, as opposed to charge neutralization, was responsible for flocculation of the ETH-2. ETH-2 retains high molecular weight (603 to 1820 kDa and multi-functional groups (hydroxyl, amide and carboxyl that contributed to flocculation. Polysaccharides mainly composed of mannose, glucose, and galactose, with a molar ratio of 1:2.9:9.8 were identified as the active constituents in bioflocculant. The structure of the long backbone with active sites of polysaccharides was determined as a primary basis for the high flocculation activity. Bioflocculant ETH-2 is cation independent, pH tolerant, and thermally stable, suggesting a potential fit for industrial application.

Endocytic crosstalk: cavins, caveolins, and caveolae regulate clathrin-independent endocytosis.

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Natasha Chaudhary

2014-04-01

Full Text Available Several studies have suggested crosstalk between different clathrin-independent endocytic pathways. However, the molecular mechanisms and functional relevance of these interactions are unclear. Caveolins and cavins are crucial components of caveolae, specialized microdomains that also constitute an endocytic route. Here we show that specific caveolar proteins are independently acting negative regulators of clathrin-independent endocytosis. Cavin-1 and Cavin-3, but not Cavin-2 or Cavin-4, are potent inhibitors of the clathrin-independent carriers/GPI-AP enriched early endosomal compartment (CLIC/GEEC endocytic pathway, in a process independent of caveola formation. Caveolin-1 (CAV1 and CAV3 also inhibit the CLIC/GEEC pathway upon over-expression. Expression of caveolar protein leads to reduction in formation of early CLIC/GEEC carriers, as detected by quantitative electron microscopy analysis. Furthermore, the CLIC/GEEC pathway is upregulated in cells lacking CAV1/Cavin-1 or with reduced expression of Cavin-1 and Cavin-3. Inhibition by caveolins can be mimicked by the isolated caveolin scaffolding domain and is associated with perturbed diffusion of lipid microdomain components, as revealed by fluorescence recovery after photobleaching (FRAP studies. In the absence of cavins (and caveolae CAV1 is itself endocytosed preferentially through the CLIC/GEEC pathway, but the pathway loses polarization and sorting attributes with consequences for membrane dynamics and endocytic polarization in migrating cells and adult muscle tissue. We also found that noncaveolar Cavin-1 can act as a modulator for the activity of the key regulator of the CLIC/GEEC pathway, Cdc42. This work provides new insights into the regulation of noncaveolar clathrin-independent endocytosis by specific caveolar proteins, illustrating multiple levels of crosstalk between these pathways. We show for the first time a role for specific cavins in regulating the CLIC/GEEC pathway, provide

Cluster Analysis of an International Pressure Pain Threshold Database Identifies 4 Meaningful Subgroups of Adults With Mechanical Neck Pain

DEFF Research Database (Denmark)

Walton, David M; Kwok, Timothy S H; Mehta, Swati

2017-01-01

OBJECTIVE: To determine pressure pain detection threshold (PPDT) related phenotypes of individuals with mechanical neck pain that may be identifiable in clinical practice. METHODS: This report describes a secondary analysis of 5 independent, international mechanical neck pain databases of PPDT...... values taken at both a local and distal region (total N=1176). Minor systematic differences in mean PPDT values across cohorts necessitated z-transformation before analysis, and each cohort was split into male and female sexes. Latent profile analysis (LPA) using the k-means approach was undertaken...... to identify the most parsimonious set of PPDT-based phenotypes that were both statistically and clinically meaningful. RESULTS: LPA revealed 4 distinct clusters named according to PPDT levels at the local and distal zones: low-low PPDT (67%), mod-mod (25%), mod-high (4%), and high-high (4%). Secondary...

Distinct trajectories of positive and negative affect after colorectal cancer diagnosis.

Science.gov (United States)

Ciere, Yvette; Janse, Moniek; Almansa, Josué; Visser, Annemieke; Sanderman, Robbert; Sprangers, Mirjam A G; Ranchor, Adelita V; Fleer, Joke

2017-06-01

Insight into trajectories of positive affect (PA) and negative affect (NA) across the cancer continuum may improve understanding of the nature of adjustment problems. The primary aim of this study was to identify subgroups of patients with distinct trajectories of PA and NA following diagnosis of colorectal cancer (CRC). Secondary to this aim, the co-occurrence between trajectories and their association with goal-related processes was explored. CRC patients (n = 186) completed questionnaires within 1 month, 7 months, and 18 months after diagnosis. Multilevel models were used to study the trajectory of PA and NA, as measured with the Positive and Negative Affect Schedule (PANAS). Four classes with distinct PA trajectories were identified: low (18.8%), increasing (6.7%), moderate (68.2%), and high (6.3%); 2 trajectories of NA emerged: low (36.3%) and moderate (63.7%). There was no significant association between PA and NA trajectory class probabilities. The average trajectory of PA covaried with levels of goal disturbance and goal reengagement over time, while the average NA trajectory covaried with goal disturbance and goal disengagement. Compared with the general population, our sample of cancer patients suffered from a lack of positive emotions, but not a high presence of negative emotions. About one fifth of patients reported low PA up to 18 months after diagnosis and may benefit from supportive care. Furthermore, the trajectory of PA was independent of that of NA and related with a distinct goal adjustment process (i.e., goal disengagement vs. goal reengagement). This finding indicates the need to tailor psychological care to the nature of the adjustment problem. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Ddc2 mediates Mec1 activation through a Ddc1- or Dpb11-independent mechanism.

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Amitava Bandhu

2014-02-01

Full Text Available The protein kinase Mec1 (ATR ortholog and its partner Ddc2 (ATRIP ortholog play a key role in DNA damage checkpoint responses in budding yeast. Previous studies have established the model in which Ddc1, a subunit of the checkpoint clamp, and Dpb11, related to TopBP1, activate Mec1 directly and control DNA damage checkpoint responses at G1 and G2/M. In this study, we show that Ddc2 contributes to Mec1 activation through a Ddc1- or Dpb11-independent mechanism. The catalytic activity of Mec1 increases after DNA damage in a Ddc2-dependent manner. In contrast, Mec1 activation occurs even in the absence of Ddc1 and Dpb11 function at G2/M. Ddc2 recruits Mec1 to sites of DNA damage. To dissect the role of Ddc2 in Mec1 activation, we isolated and characterized a separation-of-function mutation in DDC2, called ddc2-S4. The ddc2-S4 mutation does not affect Mec1 recruitment but diminishes Mec1 activation. Mec1 phosphorylates histone H2A in response to DNA damage. The ddc2-S4 mutation decreases phosphorylation of histone H2A more significantly than the absence of Ddc1 and Dpb11 function does. Our results suggest that Ddc2 plays a critical role in Mec1 activation as well as Mec1 localization at sites of DNA damage.

Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair.

Science.gov (United States)

Haradhvala, N J; Kim, J; Maruvka, Y E; Polak, P; Rosebrock, D; Livitz, D; Hess, J M; Leshchiner, I; Kamburov, A; Mouw, K W; Lawrence, M S; Getz, G

2018-05-01

Fidelity of DNA replication is maintained using polymerase proofreading and the mismatch repair pathway. Tumors with loss of function of either mechanism have elevated mutation rates with characteristic mutational signatures. Here we report that tumors with concurrent loss of both polymerase proofreading and mismatch repair function have mutational patterns that are not a simple sum of the signatures of the individual alterations, but correspond to distinct, previously unexplained signatures: COSMIC database signatures 14 and 20. We then demonstrate that in all five cases in which the chronological order of events could be determined, polymerase epsilon proofreading alterations precede the defect in mismatch repair. Overall, we illustrate that multiple distinct mutational signatures can result from different combinations of a smaller number of mutational processes (of either damage or repair), which can influence the interpretation and discovery of mutational signatures.

Red wine polyphenol compounds favor neovascularisation through estrogen receptor α-independent mechanism in mice.

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Matthieu Chalopin

Full Text Available Red wine polyphenol compounds (RWPC exert paradoxical effects depending on the dose on post-ischemic neovascularisation. Low dose RWPC (0.2 mg/kg/day is pro-angiogenic, whereas high dose (20 mg/kg/day is anti-angiogenic. We recently reported that the endothelial effect of RWPC is mediated through the activation of a redox-sensitive pathway, mitochondrial biogenesis and the activation of α isoform of the estrogen receptor (ERα. Here, we investigated the implication of ERα on angiogenic properties of RWPC. Using ovariectomized mice lacking ERα treated with high dose of RWPC after hindlimb ischemia, we examined blood flow reperfusion, vascular density, nitric oxide (NO production, expression and activation of proteins involved in angiogenic process and muscle energy sensing network. As expected, high dose of RWPC treatment reduced both blood flow and vascular density in muscles of mice expressing ERα. These effects were associated with reduced NO production resulting from diminished activity of eNOS. In the absence of RWPC, ERα deficient mice showed a reduced neo-vascularisation associated with a decreased NO production. Surprisingly in mice lacking ERα, high dose of RWPC increased blood flow and capillary density in conjunction with increased NO pathway and production as well as VEGF expression. Of particular interest is the activation of Sirt-1, AMPKα and PGC-1α/β axis in ischemic hindlimb from both strains. Altogether, the results highlight a pro-angiogenic property of RWPC via an ERα-independent mechanism that is associated with an up-regulation of energy sensing network. This study brings a corner stone of a novel pathway for RWPC to correct cardiovascular diseases associated with failed neovascularisation.

Shutter mechanism for spacecraft spectrophotometer

Science.gov (United States)

Weilbach, A.

1972-01-01

A shutter mechanism is described for the backscatter ultraviolet spectrophotometer experiment on the Nimbus D satellite. The purpose of the experiment is to determine spatial distribution of atmospheric ozone from measurements of ultraviolet radiation backscattered by the earth's atmosphere. The system consists of two independent, rotary cylinder shutters, controlled by a dual star Geneva mechanism, and driven by a single stepper motor. A single driver controls a combination of two independently driven Geneva stars. Design considerations involved the use of low friction, nonmetallic materials.

Unified treatment of the classical and quantum mechanics

International Nuclear Information System (INIS)

Shirokov, Yu.M.

1979-01-01

Classical and Quantum Mechanics are unified in the sense that almost all axioms of both mechanics are identical. The only distinction is the explicit form of one algebraic identity. The unified theory is applied to scattering problem. (Z.M.)

The pursuit of optimal distinctiveness and consumer preferences.

Science.gov (United States)

He, Lingnan; Cong, Feng; Liu, Yanping; Zhou, Xinyue

2010-10-01

This article investigates the effect of optimal distinctiveness on consumer product consumption. The authors argue that consumers acquire and display material possessions to restore their optimal levels of distinctiveness. Results showed that placing consumers in a state of low distinctiveness increased desire to acquire distinctive products, whereas perceptions of high distinctiveness reduced desire to acquire such products. Consumers' desire for distinctiveness-related products held true for various consumer choices, including willingness to pay more for limited-edition products and preference for unpopular gifts. This finding has implications for understanding consumer choice in expressing identity. © 2010 The Authors. Scandinavian Journal of Psychology © 2010 The Scandinavian Psychological Associations.

Distinct pathways mediate the sorting of tail-anchored proteins to the plastid outer envelope.

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Preetinder K Dhanoa

Full Text Available BACKGROUND: Tail-anchored (TA proteins are a distinct class of membrane proteins that are sorted post-translationally to various organelles and function in a number of important cellular processes, including redox reactions, vesicular trafficking and protein translocation. While the molecular targeting signals and pathways responsible for sorting TA proteins to their correct intracellular destinations in yeasts and mammals have begun to be characterized, relatively little is known about TA protein biogenesis in plant cells, especially for those sorted to the plastid outer envelope. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated the biogenesis of three plastid TA proteins, including the 33-kDa and 34-kDa GTPases of the translocon at the outer envelope of chloroplasts (Toc33 and Toc34 and a novel 9-kDa protein of unknown function that we define here as an outer envelope TA protein (OEP9. Using a combination of in vivo and in vitro assays we show that OEP9 utilizes a different sorting pathway than that used by Toc33 and Toc34. For instance, while all three TA proteins interact with the cytosolic OEP chaperone/receptor, AKR2A, the plastid targeting information within OEP9 is distinct from that within Toc33 and Toc34. Toc33 and Toc34 also appear to differ from OEP9 in that their insertion is dependent on themselves and the unique lipid composition of the plastid outer envelope. By contrast, the insertion of OEP9 into the plastid outer envelope occurs in a proteinaceous-dependent, but Toc33/34-independent manner and membrane lipids appear to serve primarily to facilitate normal thermodynamic integration of this TA protein. CONCLUSIONS/SIGNIFICANCE: Collectively, the results provide evidence in support of at least two sorting pathways for plastid TA outer envelope proteins and shed light on not only the complex diversity of pathways involved in the targeting and insertion of proteins into plastids, but also the molecular mechanisms that underlie

Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

NARCIS (Netherlands)

Landor, S.; Mutvei, A.P.; Mamaeva, V.; Jin, S.; Busk, M.; Borra, R.; Grönroos, T.J.; Kronqvist, P.; Lendahl, U.; Sahlgren, C.M.

2011-01-01

A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular

Stretch-induced Ca2+ independent ATP release in hippocampal astrocytes.

Science.gov (United States)

Xiong, Yingfei; Teng, Sasa; Zheng, Lianghong; Sun, Suhua; Li, Jie; Guo, Ning; Li, Mingli; Wang, Li; Zhu, Feipeng; Wang, Changhe; Rao, Zhiren; Zhou, Zhuan

2018-02-28

Similar to neurons, astrocytes actively participate in synaptic transmission via releasing gliotransmitters. The Ca 2+ -dependent release of gliotransmitters includes glutamate and ATP. Following an 'on-cell-like' mechanical stimulus to a single astrocyte, Ca 2+ independent single, large, non-quantal, ATP release occurs. Astrocytic ATP release is inhibited by either selective antagonist treatment or genetic knockdown of P2X7 receptor channels. Our work suggests that ATP can be released from astrocytes via two independent pathways in hippocampal astrocytes; in addition to the known Ca 2+ -dependent vesicular release, larger non-quantal ATP release depends on P2X7 channels following mechanical stretch. Astrocytic ATP release is essential for brain functions such as synaptic long-term potentiation for learning and memory. However, whether and how ATP is released via exocytosis remains hotly debated. All previous studies of non-vesicular ATP release have used indirect assays. By contrast, two recent studies report vesicular ATP release using more direct assays. In the present study, using patch clamped 'ATP-sniffer cells', we re-investigated astrocytic ATP release at single-vesicle resolution in hippocampal astrocytes. Following an 'on-cell-like' mechanical stimulus of a single astrocyte, a Ca 2+ independent single large non-quantal ATP release occurred, in contrast to the Ca 2+ -dependent multiple small quantal ATP release in a chromaffin cell. The mechanical stimulation-induced ATP release from an astrocyte was inhibited by either exposure to a selective antagonist or genetic knockdown of P2X7 receptor channels. Functional P2X7 channels were expressed in astrocytes in hippocampal brain slices. Thus, in addition to small quantal ATP release, larger non-quantal ATP release depends on P2X7 channels in astrocytes. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Pulmonary Mechanics and Mortality in Mechanically Ventilated Patients Without Acute Respiratory Distress Syndrome: A Cohort Study.

Science.gov (United States)

Fuller, Brian M; Page, David; Stephens, Robert J; Roberts, Brian W; Drewry, Anne M; Ablordeppey, Enyo; Mohr, Nicholas M; Kollef, Marin H

2018-03-01

Driving pressure has been proposed as a major determinant of outcome in patients with acute respiratory distress syndrome (ARDS), but there is little data examining the association between pulmonary mechanics, including driving pressure, and outcomes in mechanically ventilated patients without ARDS. Secondary analysis from 1,705 mechanically ventilated patients enrolled in a clinical study that examined outcomes associated with the use of early lung-protective mechanical ventilation. The primary outcome was mortality and the secondary outcome was the incidence of ARDS. Multivariable models were constructed to: define the association between pulmonary mechanics (driving pressure, plateau pressure, and compliance) and mortality; and evaluate if driving pressure contributed information beyond that provided by other pulmonary mechanics. The mortality rate for the entire cohort was 26.0%. Compared with survivors, non-survivors had significantly higher driving pressure [15.9 (5.4) vs. 14.9 (4.4), P = 0.005] and plateau pressure [21.4 (5.7) vs. 20.4 (4.6), P = 0.001]. Driving pressure was independently associated with mortality [adjusted OR, 1.04 (1.01-1.07)]. Models related to plateau pressure also revealed an independent association with mortality, with similar effect size and interval estimates as driving pressure. There were 152 patients who progressed to ARDS (8.9%). Along with driving pressure and plateau pressure, mechanical power [adjusted OR, 1.03 (1.00-1.06)] was also independently associated with ARDS development. In mechanically ventilated patients, driving pressure and plateau pressure are risk factors for mortality and ARDS, and provide similar information. Mechanical power is also a risk factor for ARDS.

Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation.

Science.gov (United States)

Koziel, Lydia; Wuelling, Manuela; Schneider, Sabine; Vortkamp, Andrea

2005-12-01

During endochondral ossification, the secreted growth factor Indian hedgehog (Ihh) regulates several differentiation steps. It interacts with a second secreted factor, parathyroid hormone-related protein (PTHrP), to regulate the onset of hypertrophic differentiation, and it regulates chondrocyte proliferation and ossification of the perichondrium independently of PTHrP. To investigate how the Ihh signal is translated in the different target tissues, we analyzed the role of the zinc-finger transcription factor Gli3, which acts downstream of hedgehog signals in other organs. Loss of Gli3 in Ihh mutants restores chondrocyte proliferation and delays the accelerated onset of hypertrophic differentiation observed in Ihh-/- mutants. Furthermore the expression of the Ihh target genes patched (Ptch) and PTHrP is reactivated in Ihh-/-;Gli3-/- mutants. Gli3 seems thus to act as a strong repressor of Ihh signals in regulating chondrocyte differentiation. In addition, loss of Gli3 in mice that overexpress Ihh in chondrocytes accelerates the onset of hypertrophic differentiation by reducing the domain and possibly the level of PTHrP expression. Careful analysis of chondrocyte differentiation in Gli3-/- mutants revealed that Gli3 negatively regulates the differentiation of distal, low proliferating chondrocytes into columnar, high proliferating cells. Our results suggest a model in which the Ihh/Gli3 system regulates two distinct steps of chondrocyte differentiation: (1) the switch from distal into columnar chondrocytes is repressed by Gli3 in a PTHrP-independent mechanism; (2) the transition from proliferating into hypertrophic chondrocytes is regulated by Gli3-dependent expression of PTHrP. Furthermore, by regulating distal chondrocyte differentiation, Gli3 seems to position the domain of PTHrP expression.

Suppressor of Cytokine Signaling (SOCS 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1.

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Edmond M Linossi

Full Text Available Suppressor of Cytokine Signaling (SOCS5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR. Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2 autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling.

Mechanisms of thermally induced threshold voltage instability in GaN-based heterojunction transistors

Energy Technology Data Exchange (ETDEWEB)

Yang, Shu; Liu, Shenghou; Liu, Cheng; Lu, Yunyou; Chen, Kevin J., E-mail: eekjchen@ust.hk [Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon (Hong Kong)

2014-12-01

In this work, we attempt to reveal the underlying mechanisms of divergent V{sub TH}-thermal-stabilities in III-nitride metal-insulator-semiconductor high-electron-mobility transistor (MIS-HEMT) and MOS-Channel-HEMT (MOSC-HEMT). In marked contrast to MOSC-HEMT featuring temperature-independent V{sub TH}, MIS-HEMT with the same high-quality gate-dielectric/III-nitride interface and similar interface trap distribution exhibits manifest thermally induced V{sub TH} shift. The temperature-dependent V{sub TH} of MIS-HEMT is attributed to the polarized III-nitride barrier layer, which spatially separates the critical gate-dielectric/III-nitride interface from the channel and allows “deeper” interface trap levels emerging above the Fermi level at pinch-off. This model is further experimentally validated by distinct V{sub G}-driven Fermi level movements at the critical interfaces in MIS-HEMT and MOSC-HEMT. The mechanisms of polarized III-nitride barrier layer in influencing V{sub TH}-thermal-stability provide guidelines for the optimization of insulated-gate III-nitride power switching devices.

On the mechanics of thin films and growing surfaces

KAUST Repository

Holland, M. A.

2013-05-24

Many living structures are coated by thin films, which have distinct mechanical properties from the bulk. In particular, these thin layers may grow faster or slower than the inner core. Differential growth creates a balanced interplay between tension and compression and plays a critical role in enhancing structural rigidity. Typical examples with a compressive outer surface and a tensile inner core are the petioles of celery, caladium, or rhubarb. While plant physiologists have studied the impact of tissue tension on plant rigidity for more than a century, the fundamental theory of growing surfaces remains poorly understood. Here, we establish a theoretical and computational framework for continua with growing surfaces and demonstrate its application to classical phenomena in plant growth. To allow the surface to grow independently of the bulk, we equip it with its own potential energy and its own surface stress. We derive the governing equations for growing surfaces of zero thickness and obtain their spatial discretization using the finite-element method. To illustrate the features of our new surface growth model we simulate the effects of growth-induced longitudinal tissue tension in a stalk of rhubarb. Our results demonstrate that different growth rates create a mechanical environment of axial tissue tension and residual stress, which can be released by peeling off the outer layer. Our novel framework for continua with growing surfaces has immediate biomedical applications beyond these classical model problems in botany: it can be easily extended to model and predict surface growth in asthma, gastritis, obstructive sleep apnoea, brain development, and tumor invasion. Beyond biology and medicine, surface growth models are valuable tools for material scientists when designing functionalized surfaces with distinct user-defined properties. © The Author(s) 2013.

Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors.

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Mirjam E Belderbos

Full Text Available Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP or soluble CD14 (sCD14. The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection.

Neonatal Plasma Polarizes TLR4-Mediated Cytokine Responses towards Low IL-12p70 and High IL-10 Production via Distinct Factors

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Belderbos, Mirjam E.; Levy, Ofer; Stalpers, Femke; Kimpen, Jan L.; Meyaard, Linde; Bont, Louis

2012-01-01

Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR) responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs) produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP) or soluble CD14 (sCD14). The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection. PMID:22442690

The rock mechanical stability of the VLJ repository

International Nuclear Information System (INIS)

Kuula, H.; Johansson, E.

1991-03-01

The aim of the study was to determine the rock mechanical stability around the VLJ repository based on the rock mechanical monitoring and rock mechanical modeling. Rock mechanical calculations were made in order to calculate the rock mass displacements and to analyze the stability around the VLJ repository The calculations were performed with three diiferent methods: continuum finite difference code FLAC, distinct element code UDEC and three dimensional distinct element code 3DEC. The first analyses were based on preliminary site investigations. The final modeling was based on investigations and rock mechanical monitoring done during the excavation. Some sensitive analyses were also performed. The modelled rock mass behaviour and the measured behaviour are generally close to each other. Both results show that the VLJ repository is rock mechanically stable. The modelled displacements and stresses were small enough to cause no instability around the rock caverns. The measured values do not indicate any discontinuous deformations like block movements or joint slip. The measured displacements in the extensometers during excavation indicates that the rock mass is even stiffer than anticipated

Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms.

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DePina, Ana S; Iser, Wendy B; Park, Sung-Soo; Maudsley, Stuart; Wilson, Mark A; Wolkow, Catherine A

2011-07-12

Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues. In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS). We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+) sperm. However, yolk protein (YP) levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms. C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.

Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms

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Wilson Mark A

2011-07-01

Full Text Available Abstract Background Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues. Results In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS. We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+ sperm. However, yolk protein (YP levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms. Conclusions C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.

The upstream regulatory sequence of the light harvesting complex Lhcf2 gene of the marine diatom Phaeodactylum tricornutum enhances transcription in an orientation- and distance-independent fashion.

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Russo, Monia Teresa; Annunziata, Rossella; Sanges, Remo; Ferrante, Maria Immacolata; Falciatore, Angela

2015-12-01

Diatoms are a key phytoplankton group in the contemporary ocean, showing extraordinary adaptation capacities to rapidly changing environments. The recent availability of whole genome sequences from representative species has revealed distinct features in their genomes, like novel combinations of genes encoding distinct metabolisms and a significant number of diatom-specific genes. However, the regulatory mechanisms driving diatom gene expression are still largely uncharacterized. Considering the wide variety of fields of study orbiting diatoms, ranging from ecology, evolutionary biology to biotechnology, it is thus essential to increase our understanding of fundamental gene regulatory processes such as transcriptional regulation. To this aim, we explored the functional properties of the 5'-flanking region of the Phaeodatylum tricornutum Lhcf2 gene, encoding a member of the Light Harvesting Complex superfamily and we showed that this region enhances transcription of a GUS reporter gene in an orientation- and distance-independent fashion. This represents the first example of a cis-regulatory sequence with enhancer-like features discovered in diatoms and it is instrumental for the generation of novel genetic tools and diatom exploitation in different areas of study. Copyright © 2015 Elsevier B.V. All rights reserved.

Change detection for synthetic aperture radar images based on pattern and intensity distinctiveness analysis

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Wang, Xiao; Gao, Feng; Dong, Junyu; Qi, Qiang

2018-04-01

Synthetic aperture radar (SAR) image is independent on atmospheric conditions, and it is the ideal image source for change detection. Existing methods directly analysis all the regions in the speckle noise contaminated difference image. The performance of these methods is easily affected by small noisy regions. In this paper, we proposed a novel change detection framework for saliency-guided change detection based on pattern and intensity distinctiveness analysis. The saliency analysis step can remove small noisy regions, and therefore makes the proposed method more robust to the speckle noise. In the proposed method, the log-ratio operator is first utilized to obtain a difference image (DI). Then, the saliency detection method based on pattern and intensity distinctiveness analysis is utilized to obtain the changed region candidates. Finally, principal component analysis and k-means clustering are employed to analysis pixels in the changed region candidates. Thus, the final change map can be obtained by classifying these pixels into changed or unchanged class. The experiment results on two real SAR images datasets have demonstrated the effectiveness of the proposed method.

Vitamin A Transport Mechanism of the Multitransmembrane Cell-Surface Receptor STRA6

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Riki Kawaguchi

2015-08-01

Full Text Available Vitamin A has biological functions as diverse as sensing light for vision, regulating stem cell differentiation, maintaining epithelial integrity, promoting immune competency, regulating learning and memory, and acting as a key developmental morphogen. Vitamin A derivatives have also been used in treating human diseases. If vitamin A is considered a drug that everyone needs to take to survive, evolution has come up with a natural drug delivery system that combines sustained release with precise and controlled delivery to the cells or tissues that depend on it. This “drug delivery system” is mediated by plasma retinol binding protein (RBP, the principle and specific vitamin A carrier protein in the blood, and STRA6, the cell-surface receptor for RBP that mediates cellular vitamin A uptake. The mechanism by which the RBP receptor absorbs vitamin A from the blood is distinct from other known cellular uptake mechanisms. This review summarizes recent progress in elucidating the fundamental molecular mechanism mediated by the RBP receptor and multiple newly discovered catalytic activities of this receptor, and compares this transport system with retinoid transport independent of RBP/STRA6. How to target this new type of transmembrane receptor using small molecules in treating diseases is also discussed.

Characterization of Trichome-Expressed BAHD Acyltransferases in Petunia axillaris Reveals Distinct Acylsugar Assembly Mechanisms within the Solanaceae.

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Nadakuduti, Satya Swathi; Uebler, Joseph B; Liu, Xiaoxiao; Jones, A Daniel; Barry, Cornelius S

2017-09-01

Acylsugars are synthesized in the glandular trichomes of the Solanaceae family and are implicated in protection against abiotic and biotic stress. Acylsugars are composed of either sucrose or glucose esterified with varying numbers of acyl chains of differing length. In tomato ( Solanum lycopersicum ), acylsugar assembly requires four acylsugar acyltransferases (ASATs) of the BAHD superfamily. Tomato ASATs catalyze the sequential esterification of acyl-coenzyme A thioesters to the R4, R3, R3', and R2 positions of sucrose, yielding a tetra-acylsucrose. Petunia spp. synthesize acylsugars that are structurally distinct from those of tomato. To explore the mechanisms underlying this chemical diversity, a Petunia axillaris transcriptome was mined for trichome preferentially expressed BAHDs. A combination of phylogenetic analyses, gene silencing, and biochemical analyses coupled with structural elucidation of metabolites revealed that acylsugar assembly is not conserved between tomato and petunia. In P. axillaris , tetra-acylsucrose assembly occurs through the action of four ASATs, which catalyze sequential addition of acyl groups to the R2, R4, R3, and R6 positions. Notably, in P. axillaris , PaxASAT1 and PaxASAT4 catalyze the acylation of the R2 and R6 positions of sucrose, respectively, and no clear orthologs exist in tomato. Similarly, petunia acylsugars lack an acyl group at the R3' position, and congruently, an ortholog of SlASAT3, which catalyzes acylation at the R3' position in tomato, is absent in P. axillaris Furthermore, where putative orthologous relationships of ASATs are predicted between tomato and petunia, these are not supported by biochemical assays. Overall, these data demonstrate the considerable evolutionary plasticity of acylsugar biosynthesis. © 2017 American Society of Plant Biologists. All Rights Reserved.

Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum

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Katharine L. Dobson

2015-01-01

Full Text Available In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic “ectopic” sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16 Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia.

Distinct effects of rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on cellular bioenergetics and cell death.

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Samantha Giordano

Full Text Available Parkinson's disease is characterized by dopaminergic neurodegeneration and is associated with mitochondrial dysfunction. The bioenergetic susceptibility of dopaminergic neurons to toxins which induce Parkinson's like syndromes in animal models is then of particular interest. For example, rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and its active metabolite 1-methyl-4-phenylpyridinium (MPP(+, and 6-hydroxydopamine (6-OHDA, have been shown to induce dopaminergic cell death in vivo and in vitro. Exposure of animals to these compounds induce a range of responses characteristics of Parkinson's disease, including dopaminergic cell death, and Reactive Oxygen Species (ROS production. Here we test the hypothesis that cellular bioenergetic dysfunction caused by these compounds correlates with induction of cell death in differentiated dopaminergic neuroblastoma SH-SY5Y cells. At increasing doses, rotenone induced significant cell death accompanied with caspase 3 activation. At these concentrations, rotenone had an immediate inhibition of mitochondrial basal oxygen consumption rate (OCR concomitant with a decrease of ATP-linked OCR and reserve capacity, as well as a stimulation of glycolysis. MPP(+ exhibited a different behavior with less pronounced cell death at doses that nearly eliminated basal and ATP-linked OCR. Interestingly, MPP(+, unlike rotenone, stimulated bioenergetic reserve capacity. The effects of 6-OHDA on bioenergetic function was markedly less than the effects of rotenone or MPP(+ at cytotoxic doses, suggesting a mechanism largely independent of bioenergetic dysfunction. These studies suggest that these dopaminergic neurotoxins induce cell death through distinct mechanisms and differential effects on cellular bioenergetics.

Taxonomic distinctness and richness of helminth parasite assemblages of freshwater fishes in Mexican hydrological basins.

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Quiroz-Martínez, Benjamín; Salgado-Maldonado, Guillermo

2013-01-01

In this paper, we analyse the distributional patterns of adult helminth parasites of freshwater fishes with respect to the main hydrological basins of Mexico. We use the taxonomic distinctness and the variation in taxonomic distinctness to explore patterns of parasite diversity and how these patterns change between zoogeographical regions. We address questions about the factors that determine the variation of observed diversity of helminths between basins. We also investigate patterns of richness, taxonomic distinctness and distance decay of similarity amongst basins. Our analyses suggest that the evolution of the fauna of helminth parasites in Mexico is mostly dominated by independent host colonization events and that intra--host speciation could be a minor factor explaining the origin of this diversity. This paper points out a clear separation between the helminth faunas of northern--nearctic and southern--neotropical components in Mexican continental waters, suggesting the availability of two distinct taxonomic pools of parasites in Mexican drainage basins. Data identifies Mexican drainage basins as unities inhabited by freshwater fishes, hosting a mixture of neotropical and nearctic species, in addition, data confirms neotropical and neartic basins/helminth faunas. The neotropical basins of Mexico are host to a richest and more diversified helminth fauna, including more families, genera and species, compared to the less rich and less diverse helminth fauna in the nearctic basins. The present analysis confirms distance--decay as one of the important factors contributing to the patterns of diversity observed. The hypothesis that helminth diversity could be explained by the ichthyological diversity of the basin received no support from present analysis.

Taxonomic distinctness and richness of helminth parasite assemblages of freshwater fishes in Mexican hydrological basins.

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Benjamín Quiroz-Martínez

Full Text Available In this paper, we analyse the distributional patterns of adult helminth parasites of freshwater fishes with respect to the main hydrological basins of Mexico. We use the taxonomic distinctness and the variation in taxonomic distinctness to explore patterns of parasite diversity and how these patterns change between zoogeographical regions. We address questions about the factors that determine the variation of observed diversity of helminths between basins. We also investigate patterns of richness, taxonomic distinctness and distance decay of similarity amongst basins. Our analyses suggest that the evolution of the fauna of helminth parasites in Mexico is mostly dominated by independent host colonization events and that intra--host speciation could be a minor factor explaining the origin of this diversity. This paper points out a clear separation between the helminth faunas of northern--nearctic and southern--neotropical components in Mexican continental waters, suggesting the availability of two distinct taxonomic pools of parasites in Mexican drainage basins. Data identifies Mexican drainage basins as unities inhabited by freshwater fishes, hosting a mixture of neotropical and nearctic species, in addition, data confirms neotropical and neartic basins/helminth faunas. The neotropical basins of Mexico are host to a richest and more diversified helminth fauna, including more families, genera and species, compared to the less rich and less diverse helminth fauna in the nearctic basins. The present analysis confirms distance--decay as one of the important factors contributing to the patterns of diversity observed. The hypothesis that helminth diversity could be explained by the ichthyological diversity of the basin received no support from present analysis.

Novel co-culture plate enables growth dynamic-based assessment of contact-independent microbial interactions.

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Thomas J Moutinho

Full Text Available Interactions between microbes are central to the dynamics of microbial communities. Understanding these interactions is essential for the characterization of communities, yet challenging to accomplish in practice. There are limited available tools for characterizing diffusion-mediated, contact-independent microbial interactions. A practical and widely implemented technique in such characterization involves the simultaneous co-culture of distinct bacterial species and subsequent analysis of relative abundance in the total population. However, distinguishing between species can be logistically challenging. In this paper, we present a low-cost, vertical membrane, co-culture plate to quantify contact-independent interactions between distinct bacterial populations in co-culture via real-time optical density measurements. These measurements can be used to facilitate the analysis of the interaction between microbes that are physically separated by a semipermeable membrane yet able to exchange diffusible molecules. We show that diffusion across the membrane occurs at a sufficient rate to enable effective interaction between physically separate cultures. Two bacterial species commonly found in the cystic fibrotic lung, Pseudomonas aeruginosa and Burkholderia cenocepacia, were co-cultured to demonstrate how this plate may be implemented to study microbial interactions. We have demonstrated that this novel co-culture device is able to reliably generate real-time measurements of optical density data that can be used to characterize interactions between microbial species.

Distinct Motivational Effects of Contingent and Noncontingent Rewards.

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Manohar, Sanjay G; Finzi, Rebecca Dawn; Drew, Daniel; Husain, Masud

2017-07-01

When rewards are available, people expend more energy, increasing their motivational vigor. In theory, incentives might drive behavior for two distinct reasons: First, they increase expected reward; second, they increase the difference in subjective value between successful and unsuccessful performance, which increases contingency-the degree to which action determines outcome. Previous studies of motivational vigor have never compared these directly. Here, we indexed motivational vigor by measuring the speed of eye movements toward a target after participants heard a cue indicating how outcomes would be determined. Eye movements were faster when the cue indicated that monetary rewards would be contingent on performance than when the cue indicated that rewards would be random. But even when the cue indicated that a reward was guaranteed regardless of speed, movement was still faster than when no reward was available. Motivation by contingent and certain rewards was uncorrelated across individuals, which suggests that there are two separable, independent components of motivation. Contingent motivation generated autonomic arousal, and unlike noncontingent motivation, was effective with penalties as well as rewards.

α-Synuclein-induced dopaminergic neurodegeneration in a rat model of Parkinson's disease occurs independent of ATP13A2 (PARK9).

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Daniel, Guillaume; Musso, Alessandra; Tsika, Elpida; Fiser, Aris; Glauser, Liliane; Pletnikova, Olga; Schneider, Bernard L; Moore, Darren J

2015-01-01

Mutations in the ATP13A2 (PARK9) gene cause early-onset, autosomal recessive Parkinson's disease (PD) and Kufor-Rakeb syndrome. ATP13A2 mRNA is spliced into three distinct isoforms encoding a P5-type ATPase involved in regulating heavy metal transport across vesicular membranes. Here, we demonstrate that three ATP13A2 mRNA isoforms are expressed in the normal human brain and are modestly increased in the cingulate cortex of PD cases. ATP13A2 can mediate protection toward a number of stressors in mammalian cells and can protect against α-synuclein-induced toxicity in cellular and invertebrate models of PD. Using a primary cortical neuronal model combined with lentiviral-mediated gene transfer, we demonstrate that human ATP13A2 isoforms 1 and 2 display selective neuroprotective effects toward toxicity induced by manganese and hydrogen peroxide exposure through an ATPase-independent mechanism. The familial PD mutations, F182L and G504R, abolish the neuroprotective effects of ATP13A2 consistent with a loss-of-function mechanism. We further demonstrate that the AAV-mediated overexpression of human ATP13A2 is not sufficient to attenuate dopaminergic neurodegeneration, neuropathology, and striatal dopamine and motoric deficits induced by human α-synuclein expression in a rat model of PD. Intriguingly, the delivery of an ATPase-deficient form of ATP13A2 (D513N) to the substantia nigra is sufficient to induce dopaminergic neuronal degeneration and motor deficits in rats, potentially suggesting a dominant-negative mechanism of action. Collectively, our data demonstrate a distinct lack of ATP13A2-mediated protection against α-synuclein-induced neurotoxicity in the rat nigrostriatal dopaminergic pathway, and limited neuroprotective capacity overall, and raise doubts about the potential of ATP13A2 as a therapeutic target for PD. Copyright © 2015 Elsevier Inc. All rights reserved.

Protection of cortical cells by equine estrogens against glutamate-induced excitotoxicity is mediated through a calcium independent mechanism

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Perrella Joel

2005-05-01

Full Text Available Abstract Background High concentrations of glutamate can accumulate in the brain and may be involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. This form of neurotoxicity involves changes in the regulation of cellular calcium (Ca2+ and generation of free radicals such as peroxynitrite (ONOO-. Estrogen may protect against glutamate-induced cell death by reducing the excitotoxic Ca2+ influx associated with glutamate excitotoxicity. In this study, the inhibition of N-methyl-D-aspartate (NMDA receptor and nitric oxide synthase (NOS along with the effect of 17β-estradiol (17β-E2 and a more potent antioxidant Δ8, 17β-estradiol (Δ8, 17β-E2 on cell viability and intracellular Ca2+ ([Ca2+]i, following treatment of rat cortical cells with glutamate, was investigated. Results Primary rat cortical cells were cultured for 7–12 days in Neurobasal medium containing B27 supplements. Addition of glutamate (200 μM decreased cell viability to 51.3 ± 0.7% compared to control. Treatment with the noncompetitive NMDAR antagonist, MK-801, and the NOS inhibitor, L-NAME, completely prevented cell death. Pretreatment (24 hrs with 17β-E2 and Δ8, 17β-E2 (0.01 to 10 μM significantly reduced cell death. 17β-E2 was more potent than Δ8, 17β-E2. Glutamate caused a rapid 2.5 fold increase in [Ca2+]i. Treatment with 0.001 to 10 μM MK-801 reduced the initial Ca2+ influx by 14–41% and increased cell viability significantly. Pretreatment with 17β-E2 and Δ8, 17β-E2 had no effect on Ca2+ influx but protected the cortical cells against glutamate-induced cell death. Conclusion Glutamate-induced cell death in cortical cultures can occur through NMDAR and NOS-linked mechanisms by increasing nitric oxide and ONOO-. Equine estrogens: 17β-E2 and Δ8, 17β-E2, significantly protected cortical cells against glutamate-induced excitotoxicity by a mechanism that appears to be independent of Ca2+ influx. To our knowledge, this is a first

Rapid generation of mitochondrial superoxide induces mitochondrion-dependent but caspase-independent cell death in hippocampal neuronal cells that morphologically resembles necroptosis☆

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Fukui, Masayuki; Choi, Hye Joung; Zhu, Bao Ting

2013-01-01

Studies in recent years have revealed that excess mitochondrial superoxide production is an important etiological factor in neurodegenerative diseases, resulting from oxidative modifications of cellular lipids, proteins, and nucleic acids. Hence, it is important to understand the mechanism by which mitochondrial oxidative stress causes neuronal death. In this study, the immortalized mouse hippocampal neuronal cells (HT22) in culture were used as a model and they were exposed to menadione (also known as vitamin K3) to increase intracellular superoxide production. We found that menadione causes preferential accumulation of superoxide in the mitochondria of these cells, along with the rapid development of mitochondrial dysfunction and cellular ATP depletion. Neuronal death induced by menadione is independent of the activation of the MAPK signaling pathways and caspases. The lack of caspase activation is due to the rapid depletion of cellular ATP. It was observed that two ATP-independent mitochondrial nucleases, namely, AIF and Endo G, are released following menadione exposure. Silencing of their expression using specific siRNAs results in transient suppression (for ~12 h) of mitochondrial superoxide-induced neuronal death. While suppression of the mitochondrial superoxide dismutase expression markedly sensitizes neuronal cells to mitochondrial superoxide-induced cytotoxicity, its over-expression confers strong protection. Collectively, these findings showed that many of the observed features associated with mitochondrial superoxide-induced cell death, including caspase independency, rapid depletion of ATP level, mitochondrial release of AIF and Endo G, and mitochondrial swelling, are distinctly different from those of apoptosis; instead they resemble some of the known features of necroptosis. PMID:22575170

A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism.

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Marie Courbebaisse

Full Text Available BACKGROUND: The sodium-hydrogen exchanger regulatory factor 1 (NHERF1 binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH receptor. We have recently identified mutations in NHERF1 that decrease renal phosphate reabsorption by increasing PTH-induced cAMP production in the renal proximal tubule. METHODS: We compared relevant parameters of phosphate homeostasis in a patient with a previously undescribed mutation in NHERF1 and in control subjects. We expressed the mutant NHERF1 protein in Xenopus Oocytes and in cultured cells to study its effects on phosphate transport and PTH-induced cAMP production. RESULTS: We identified in a patient with inappropriate renal phosphate reabsorption a previously unidentified mutation (E68A located in the PDZ1 domain of NHERF1.We report the consequences of this mutation on NHERF1 function. E68A mutation did not modify cAMP production in the patient. PTH-induced cAMP synthesis and PKC activity were not altered by E68A mutation in renal cells in culture. In contrast to wild-type NHERF1, expression of the E68A mutant in Xenopus oocytes and in human cells failed to increase phosphate transport. Pull down experiments showed that E68A mutant did not interact with NPT2a, which robustly interacted with wild type NHERF1 and previously identified mutants. Biotinylation studies revealed that E68A mutant was unable to increase cell surface expression of NPT2a. CONCLUSIONS: Our results indicate that the PDZ1 domain is critical for NHERF1-NPT2a interaction in humans and for the control of NPT2a expression at the plasma membrane. Thus we have identified a new mechanism of renal phosphate loss and shown that different mutations in NHERF1 can alter renal phosphate reabsorption via distinct mechanisms.

Distinctiveness of Saudi Arabian EFL Learners

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Manssour Habbash

2016-04-01

Full Text Available In view of the increasing concern among English language teachers dealing with students from Saudi Arabia, as it manifests in TESOL community discussions, about the uniqueness of Saudi Arabian EFL learners, this paper attempts to document the outcome of a study of their distinctiveness from the perspective of expatriate teachers working for PYPs (Preparatory Year Programs in Saudi Arabia. This study examines the distinctiveness with regard to the learning attitudes of Saudi students that are often cultivated by the culture and academic environment in their homeland. Employing an emic approach for collecting the required data an analysis was carried out in light of the other studies on ‘education’ in Saudi Arabia that have particular reference to the factors that can positively influence student motivation, student success and the academic environment. The findings were used in constructing the rationale behind such distinctiveness. Assuming that the outcome of the discussion on the findings of this exploration can be helpful for teachers in adapting their teaching methodology and improving their teacher efficacy in dealing with students both from the kingdom and in the kingdom, some recommendations are made. Keywords: China Distinctiveness, Saudi Arabian University context, Expatriate teachers’ perspective, Distinctiveness Theory

Central Bank independence

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Vasile DEDU

2012-08-01

Full Text Available In this paper we present the key aspects regarding central bank’s independence. Most economists consider that the factor which positively influences the efficiency of monetary policy measures is the high independence of the central bank. We determined that the National Bank of Romania (NBR has a high degree of independence. NBR has both goal and instrument independence. We also consider that the hike of NBR’s independence played an important role in the significant disinflation process, as headline inflation dropped inside the targeted band of 3% ± 1 percentage point recently.

Abstract and Effector-Selective Decision Signals Exhibit Qualitatively Distinct Dynamics before Delayed Perceptual Reports.

Science.gov (United States)

Twomey, Deirdre M; Kelly, Simon P; O'Connell, Redmond G

2016-07-13

isolated abstract neural signatures of decision formation that are independent of specific sensory and motor requirements. Here, we examine the functional distinctions between the two distinct classes of decision variable signal during decisions with deferred actions with and without foreknowledge of stimulus-effector mapping. We find salient distinctions in the dynamics of abstract versus effector-selective decision signals in the human brain, in terms of sustainment through response delays and contingency on foreknowledge of stimulus-response mapping. Copyright © 2016 Twomey et al.

Experimental acidification of two biogeochemically-distinct neotropical streams: Buffering mechanisms and macroinvertebrate drift

International Nuclear Information System (INIS)

Ardón, Marcelo; Duff, John H.; Ramírez, Alonso; Small, Gaston E.; Jackman, Alan P.; Triska, Frank J.; Pringle, Catherine M.

2013-01-01

Research into the buffering mechanisms and ecological consequences of acidification in tropical streams is lacking. We have documented seasonal and episodic acidification events in streams draining La Selva Biological Station, Costa Rica. Across this forested landscape, the severity in seasonal and episodic acidification events varies due to interbasin groundwater flow (IGF). Streams that receive IGF have higher concentrations of solutes and more stable pH (∼ 6) than streams that do not receive IGF (pH ∼ 5). To examine the buffering capacity and vulnerability of macroinvertebrates to short-term acidification events, we added hydrochloric acid to acidify a low-solute, poorly buffered (without IGF) and a high-solute, well buffered stream (with IGF). We hypothesized that: 1) protonation of bicarbonate (HCO 3 − ) would neutralize most of the acid added in the high-solute stream, while base cation release from the sediments would be the most important buffering mechanism in the low-solute stream; 2) pH declines would mobilize inorganic aluminum (Ali) from sediments in both streams; and 3) pH declines would increase macroinvertebrate drift in both streams. We found that the high-solute stream neutralized 745 μeq/L (96% of the acid added), while the solute poor stream only neutralized 27.4 μeq/L (40%). Protonation of HCO 3 − was an important buffering mechanism in both streams. Base cation, Fe 2+ , and Ali release from sediments and protonation of organic acids also provided buffering in the low-solute stream. We measured low concentrations of Ali release in both streams (2-9 μeq/L) in response to acidification, but the low-solute stream released double the amount Ali per 100 μeq of acid added than the high solute stream. Macroinvertebrate drift increased in both streams in response to acidification and was dominated by Ephemeroptera and Chironomidae. Our results elucidate the different buffering mechanisms in tropical streams and suggest that low

Rapid generation of mitochondrial superoxide induces mitochondrion-dependent but caspase-independent cell death in hippocampal neuronal cells that morphologically resembles necroptosis

International Nuclear Information System (INIS)

Fukui, Masayuki; Choi, Hye Joung; Zhu, Bao Ting

2012-01-01

Studies in recent years have revealed that excess mitochondrial superoxide production is an important etiological factor in neurodegenerative diseases, resulting from oxidative modifications of cellular lipids, proteins, and nucleic acids. Hence, it is important to understand the mechanism by which mitochondrial oxidative stress causes neuronal death. In this study, the immortalized mouse hippocampal neuronal cells (HT22) in culture were used as a model and they were exposed to menadione (also known as vitamin K 3 ) to increase intracellular superoxide production. We found that menadione causes preferential accumulation of superoxide in the mitochondria of these cells, along with the rapid development of mitochondrial dysfunction and cellular ATP depletion. Neuronal death induced by menadione is independent of the activation of the MAPK signaling pathways and caspases. The lack of caspase activation is due to the rapid depletion of cellular ATP. It was observed that two ATP-independent mitochondrial nucleases, namely, AIF and Endo G, are released following menadione exposure. Silencing of their expression using specific siRNAs results in transient suppression (for ∼ 12 h) of mitochondrial superoxide-induced neuronal death. While suppression of the mitochondrial superoxide dismutase expression markedly sensitizes neuronal cells to mitochondrial superoxide-induced cytotoxicity, its over-expression confers strong protection. Collectively, these findings showed that many of the observed features associated with mitochondrial superoxide-induced cell death, including caspase independency, rapid depletion of ATP level, mitochondrial release of AIF and Endo G, and mitochondrial swelling, are distinctly different from those of apoptosis; instead they resemble some of the known features of necroptosis. -- Highlights: ► Menadione causes mitochondrial superoxide accumulation and injury. ► Menadione-induced cell death is caspase-independent, due to rapid depletion of ATP

Rapid generation of mitochondrial superoxide induces mitochondrion-dependent but caspase-independent cell death in hippocampal neuronal cells that morphologically resembles necroptosis

Energy Technology Data Exchange (ETDEWEB)

Fukui, Masayuki; Choi, Hye Joung; Zhu, Bao Ting, E-mail: BTZhu@kumc.edu

2012-07-15

Studies in recent years have revealed that excess mitochondrial superoxide production is an important etiological factor in neurodegenerative diseases, resulting from oxidative modifications of cellular lipids, proteins, and nucleic acids. Hence, it is important to understand the mechanism by which mitochondrial oxidative stress causes neuronal death. In this study, the immortalized mouse hippocampal neuronal cells (HT22) in culture were used as a model and they were exposed to menadione (also known as vitamin K{sub 3}) to increase intracellular superoxide production. We found that menadione causes preferential accumulation of superoxide in the mitochondria of these cells, along with the rapid development of mitochondrial dysfunction and cellular ATP depletion. Neuronal death induced by menadione is independent of the activation of the MAPK signaling pathways and caspases. The lack of caspase activation is due to the rapid depletion of cellular ATP. It was observed that two ATP-independent mitochondrial nucleases, namely, AIF and Endo G, are released following menadione exposure. Silencing of their expression using specific siRNAs results in transient suppression (for ∼ 12 h) of mitochondrial superoxide-induced neuronal death. While suppression of the mitochondrial superoxide dismutase expression markedly sensitizes neuronal cells to mitochondrial superoxide-induced cytotoxicity, its over-expression confers strong protection. Collectively, these findings showed that many of the observed features associated with mitochondrial superoxide-induced cell death, including caspase independency, rapid depletion of ATP level, mitochondrial release of AIF and Endo G, and mitochondrial swelling, are distinctly different from those of apoptosis; instead they resemble some of the known features of necroptosis. -- Highlights: ► Menadione causes mitochondrial superoxide accumulation and injury. ► Menadione-induced cell death is caspase-independent, due to rapid depletion of

Single-hit mechanism of tumour cell killing by radiation.

Science.gov (United States)

Chapman, J D

2003-02-01

To review the relative importance of the single-hit mechanism of radiation killing for tumour response to 1.8-2.0 Gy day(-1) fractions and to low dose-rate brachytherapy. Tumour cell killing by ionizing radiation is well described by the linear-quadratic equation that contains two independent components distinguished by dose kinetics. Analyses of tumour cell survival curves that contain six or more dose points usually provide good estimates of the alpha- and beta-inactivation coefficients. Superior estimates of tumour cell intrinsic radiosensitivity are obtained when synchronized populations are employed. The characteristics of single-hit inactivation of tumour cells are reviewed and compared with the characteristics of beta-inactivation. Potential molecular targets associated with single-hit inactivation are discussed along with strategies for potentiating cell killing by this mechanism. The single-hit mechanism of tumour cell killing shows no dependence on dose-rate and, consequently, no evidence of sublethal damage repair. It is uniquely potentiated by high linear-energy-transfer radiation, exhibits a smaller oxygen enhancement ratio and exhibits a larger indirect effect by hydroxyl radicals than the beta-mechanism. alpha-inactivation coefficients vary slightly throughout interphase but mitotic cells exhibit extremely high alpha-coefficients in the range of those observed for lymphocytes and some repair-deficient cells. Evidence is accumulating to suggest that chromatin in compacted form could be a radiation-hypersensitive target associated with single-hit radiation killing. Analyses of tumour cell survival curves demonstrate that it is the single-hit mechanism (alpha) that determines the majority of cell killing after doses of 2Gy and that this mechanism is highly variable between tumour cell lines. The characteristics of single-hit inactivation are qualitatively and quantitatively distinct from those of beta-inactivation. Compacted chromatin in tumour cells

Visual distinctiveness can enhance recency effects.

Science.gov (United States)

Bornstein, B H; Neely, C B; LeCompte, D C

1995-05-01

Experimental efforts to meliorate the modality effect have included attempts to make the visual stimulus more distinctive. McDowd and Madigan (1991) failed to find an enhanced recency effect in serial recall when the last item was made more distinct in terms of its color. In an attempt to extend this finding, three experiments were conducted in which visual distinctiveness was manipulated in a different manner, by combining the dimensions of physical size and coloration (i.e., whether the stimuli were solid or outlined in relief). Contrary to previous findings, recency was enhanced when the size and coloration of the last item differed from the other items in the list, regardless of whether the "distinctive" item was larger or smaller than the remaining items. The findings are considered in light of other research that has failed to obtain a similar enhanced recency effect, and their implications for current theories of the modality effect are discussed.

Oct-1 potentiates CREB-driven cyclin D1 promoter activation via a phospho-CREB- and CREB binding protein-independent mechanism.

Science.gov (United States)

Boulon, Séverine; Dantonel, Jean-Christophe; Binet, Virginie; Vié, Annick; Blanchard, Jean-Marie; Hipskind, Robert A; Philips, Alexandre

2002-11-01

Cyclin D1, the regulatory subunit for mid-G(1) cyclin-dependent kinases, controls the expression of numerous cell cycle genes. A cyclic AMP-responsive element (CRE), located upstream of the cyclin D1 mRNA start site, integrates mitogenic signals that target the CRE-binding factor CREB, which can recruit the transcriptional coactivator CREB-binding protein (CBP). We describe an alternative mechanism for CREB-driven cyclin D1 induction that involves the ubiquitous POU domain protein Oct-1. In the breast cancer cell line MCF-7, overexpression of Oct-1 or its POU domain strongly increases transcriptional activation of cyclin D1 and GAL4 reporter genes that is specifically dependent upon CREB but independent of Oct-1 DNA binding. Gel retardation and chromatin immunoprecipitation assays confirm that POU forms a complex with CREB bound to the cyclin D1 CRE. In solution, CREB interaction with POU requires the CREB Q2 domain and, notably, occurs with CREB that is not phosphorylated on Ser 133. Accordingly, Oct-1 also potently enhances transcriptional activation mediated by a Ser133Ala CREB mutant. Oct-1/CREB synergy is not diminished by the adenovirus E1A 12S protein, a repressor of CBP coactivator function. In contrast, E1A strongly represses CBP-enhanced transactivation by CREB phosphorylated on Ser 133. Our observation that Oct-1 potentiates CREB-dependent cyclin D1 transcriptional activity independently of Ser 133 phosphorylation and E1A-sensitive coactivator function offers a new paradigm for the regulation of cyclin D1 induction by proliferative signals.

On the Status of Cue Independence as a Criterion for Memory Inhibition: Evidence against the Covert Blocking Hypothesis

Science.gov (United States)

Weller, Peter D.; Anderson, Michael C.; Gómez-Ariza, Carlos J.; Bajo, M. Teresa

2013-01-01

Retrieving memories can impair recall of other related traces. Items affected by this retrieval-induced forgetting (RIF) are often less accessible when tested with independent probes, a characteristic known as cue independence. Cue independence has been interpreted as evidence for inhibitory mechanisms that suppress competing items during…

Probing the two-scale-factor universality hypothesis by exact rotation symmetry-breaking mechanism

Energy Technology Data Exchange (ETDEWEB)

Neto, J.F.S.; Lima, K.A.L.; Carvalho, P.R.S. [Universidade Federal do Piaui, Departamento de Fisica, Teresina, PI (Brazil); Sena-Junior, M.I. [Universidade de Pernambuco, Escola Politecnica de Pernambuco, Recife, PE (Brazil); Universidade Federal de Alagoas, Instituto de Fisica, Maceio, AL (Brazil)

2017-12-15

We probe the two-scale-factor universality hypothesis by evaluating, firstly explicitly and analytically at the one-loop order, the loop quantum corrections to the amplitude ratios for O(N)λφ{sup 4} scalar field theories with rotation symmetry breaking in three distinct and independent methods in which the rotation symmetry-breaking mechanism is treated exactly. We show that the rotation symmetry-breaking amplitude ratios turn out to be identical in the three methods and equal to their respective rotation symmetry-breaking ones, although the amplitudes themselves, in general, depend on the method employed and on the rotation symmetry-breaking parameter. At the end, we show that all these results can be generalized, through an inductive process based on a general theorem emerging from the exact calculation, to any loop level and physically interpreted based on symmetry ideas. (orig.)

Evolution of shutdown mechanism for PHWRs

International Nuclear Information System (INIS)

Singh, Manjit; Govindarajan, G.

1997-01-01

In 500 MWe PHWR, there are two independent fast acting shutdown systems namely (1) mechanical shut-off rod system and (2) liquid poison injection system. Both systems are independently capable of keeping the reactor in sub-critical condition during long shutdown. Mechanical shut-off rod system being primary shutdown system calls for a very high reliability of operation as well as effectiveness, which are mainly governed by its ability to operate within a very short time and the magnitude of negative reactivity worth it can provide. Mechanical shut-off rods are normally parked above the core by shut-off rod drive mechanism. On receiving a scram signal, shut-off rods are released from the holding electromagnetic clutch and fall under gravity into the core. This paper discusses the salient features of mechanical shut-off rod system. A brief account of detailed design and development of sub-assemblies of shut-off rod drive mechanism is also presented. (author)

On Hobbes’s distinction of accidents

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Lupoli Agostino

2012-06-01

Full Text Available An interpolation introduced by K. Schuhmann in his critical edition of "De corpore" (chap. VI, § 13 diametrically overturns the meaning of Hobbes’s doctrine of distinction of accidents in comparison with all previous editions. The article focuses on the complexity of this crucial juncture in "De corpore" argument on which depends the interpretation of Hobbes’s whole conception of science. It discusses the reasons pro and contra Schuhmann’s interpolation and concludes against it, because it is not compatible with the rationale underlying the complex architecture of "De corpore", which involves a symmetry between the ‘logical’ distinction of accidents and the ‘metaphysical’ distinction of phantasms.

EGL-13/SoxD Specifies Distinct O2 and CO2 Sensory Neuron Fates in Caenorhabditis elegans

DEFF Research Database (Denmark)

Gramstrup Petersen, Jakob; Rojo Romanos, Teresa; Juozaityte, Vaida

2013-01-01

that EGL-13 is sufficient to induce O2- and CO2-sensing cell fates in some cellular contexts. Thus, the same core regulatory factor, egl-13, is required and sufficient to specify the distinct fates of O2- and CO2-sensing neurons in C. elegans. These findings extend our understanding of mechanisms......Animals harbor specialized neuronal systems that are used for sensing and coordinating responses to changes in oxygen (O2) and carbon dioxide (CO2). In Caenorhabditis elegans, the O2/CO2 sensory system comprises functionally and morphologically distinct sensory neurons that mediate rapid behavioral...

Management Technology of Students’ Independent Work

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Melis K. Asanaliev

2012-09-01

Full Text Available The researchers are convinced that for an intensification of educational process in higher education institution it is necessary development of essentially new approaches, forms and the methods of social and pedagogical interaction adequate to new requirements, new pedagogical thinking. Among them we can choose the methods of social and psychological training (SPT which received their development in experimental psychology by synthesis of wide practical experience educational, creative, administrative, and other types of interrelation between people. These methods conditionally divide on: debatable (group discussion, analysis of a situation of a moral choice, game methods (didactic, creative, role-playing games, sensitive training (training of interpersonal sensitivity which are formations of independent informative activity of students on the basis of modern technologies, as the mechanism of improvement of independent work. Researches are expressed in search and finding enough effective forms and means of activation of educational and informative process of preparation of young teachers of vocational training, theoretically and practically prepared in the field of the independent informative activity, use the modern technology of training and its further realization in work with students of technical secondary. It is offered the model of the organization and application in educational process of the complex of these methods in contents complex of training programs of systems of tasks as one of ways of formation of social and psychological culture of future teacher.

Quantum and classical mechanics in the phase space representation

International Nuclear Information System (INIS)

Shirokov, Yu.M.

1979-01-01

The theory of the hamiltonian mechanical systems has been formulated in terms of only such physical and mathematical concepts which are meaningful in both mechanics. For instance the observables in both mechanics are represented as c-number functions of coordinates and momenta. The operations of the usual multiplication of observables as well as Poisson bracket (also treated as a sort of multiplication) are singled out as separate objects which can possess their own structure including h-dependence. This leads to the conclusion that the only primary distinction between classical and quantum mechanics is reduced to the distinction in the form of the algebraic identity for the multiplication operations. All other distinctions are proved to be of the secondary origin. The formalism developed in the paper is especially useful for quantizations and for the transitions (including partial ones) to the classical limits. The transitions in both directions are transparent and accessible for analysis for any quantity at any step of calculations. The unified quantum-classical scattering theory is constructed. The integral quantum Lippman-Schwinder type equation is derived where the free solution term is replaced by the solution of the corresponding classical problem. The iteration of this equation gives the quantum corrections to the classical solution

Neural dissociations in attitude strength: Distinct regions of cingulate cortex track ambivalence and certainty.

Science.gov (United States)

Luttrell, Andrew; Stillman, Paul E; Hasinski, Adam E; Cunningham, William A

2016-04-01

People's behaviors are often guided by valenced responses to objects in the environment. Beyond positive and negative evaluations, attitudes research has documented the importance of attitude strength--qualities of an attitude that enhance or attenuate its impact and durability. Although neuroscience research has extensively investigated valence, little work exists on other related variables like metacognitive judgments about one's attitudes. It remains unclear, then, whether the various indicators of attitude strength represent a single underlying neural process or whether they reflect independent processes. To examine this, we used functional MRI (fMRI) to identify the neural correlates of attitude strength. Specifically, we focus on ambivalence and certainty, which represent metacognitive judgments that people can make about their evaluations. Although often correlated, prior neuroscience research suggests that these 2 attributes may have distinct neural underpinnings. We investigate this by having participants make evaluative judgments of visually presented words while undergoing fMRI. After scanning, participants rated the degree of ambivalence and certainty they felt regarding their attitudes toward each word. We found that these 2 judgments corresponded to distinct brain regions' activity during the process of evaluation. Ambivalence corresponded to activation in anterior cingulate cortex, dorsomedial prefrontal cortex, and posterior cingulate cortex. Certainty, however, corresponded to activation in unique areas of the precuneus/posterior cingulate cortex. These results support a model treating ambivalence and certainty as distinct, though related, attitude strength variables, and we discuss implications for both attitudes and neuroscience research. (c) 2016 APA, all rights reserved).

Amygdalar auditory neurons contribute to self-other distinction during ultrasonic social vocalization in rats

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Jumpei Matsumoto

2016-09-01

Full Text Available Although clinical studies reported hyperactivation of the auditory system and amygdala in patients with auditory hallucinations (hearing others’ but not one’s own voice, independent of any external stimulus, neural mechanisms of self/other attribution is not well understood. We recorded neuronal responses in the dorsal amygdala including the lateral amygdaloid nucleus to ultrasonic vocalization (USVs emitted by subjects and conspecifics during free social interaction in 16 adult male rats. The animals emitting the USVs were identified by EMG recordings. One-quarter of the amygdalar neurons (15/60 responded to 50 kHz calls by the subject and/or conspecifics. Among the responsive neurons, most neurons (Type-Other neurons (73%, 11/15 responded only to calls by conspecifics but not subjects. Two Type-Self neurons (13%, 2/15 responded to calls by the subject but not those by conspecifics, although their response selectivity to subjects vs. conspecifics was lower than that of Type-Other neurons. The remaining two neurons (13% responded to calls by both the subject and conspecifics. Furthermore, population coding of the amygdalar neurons represented distinction of subject vs. conspecific calls. The present results provide the first neurophysiological evidence that the amygdala discriminately represents affective social calls by subject and conspecifics. These findings suggest that the amygdala is an important brain region for self/other attribution. Furthermore, pathological activation of the amygdala, where Type-Other neurons predominate, could induce external misattribution of percepts of vocalization.

Experimental acidification of two biogeochemically-distinct neotropical streams: Buffering mechanisms and macroinvertebrate drift

Energy Technology Data Exchange (ETDEWEB)

Ardón, Marcelo, E-mail: ardonsayaom@ecu.edu [Department of Biology and North Carolina Center for Biodiversity, East Carolina University, Greenville, NC 27858 (United States); Duff, John H. [U.S. Geological Survey, Menlo Park, CA 94025 (United States); Ramírez, Alonso [Department of Environmental Sciences, University of Puerto Rico, San Juan, PR 00931 (Puerto Rico); Small, Gaston E. [Department of Ecology, Evolution, and Behavior, University of Minnesota, St. Paul, MN 55108 (United States); Jackman, Alan P. [University of California, Davis, CA 95616 (United States); Triska, Frank J. [U.S. Geological Survey, Menlo Park, CA 94025 (United States); Pringle, Catherine M. [Odum School of Ecology, University of Georgia, Athens, GA 30602 (United States)

2013-01-15

Research into the buffering mechanisms and ecological consequences of acidification in tropical streams is lacking. We have documented seasonal and episodic acidification events in streams draining La Selva Biological Station, Costa Rica. Across this forested landscape, the severity in seasonal and episodic acidification events varies due to interbasin groundwater flow (IGF). Streams that receive IGF have higher concentrations of solutes and more stable pH (∼ 6) than streams that do not receive IGF (pH ∼ 5). To examine the buffering capacity and vulnerability of macroinvertebrates to short-term acidification events, we added hydrochloric acid to acidify a low-solute, poorly buffered (without IGF) and a high-solute, well buffered stream (with IGF). We hypothesized that: 1) protonation of bicarbonate (HCO{sub 3}{sup −}) would neutralize most of the acid added in the high-solute stream, while base cation release from the sediments would be the most important buffering mechanism in the low-solute stream; 2) pH declines would mobilize inorganic aluminum (Ali) from sediments in both streams; and 3) pH declines would increase macroinvertebrate drift in both streams. We found that the high-solute stream neutralized 745 μeq/L (96% of the acid added), while the solute poor stream only neutralized 27.4 μeq/L (40%). Protonation of HCO{sub 3}{sup −} was an important buffering mechanism in both streams. Base cation, Fe{sup 2+}, and Ali release from sediments and protonation of organic acids also provided buffering in the low-solute stream. We measured low concentrations of Ali release in both streams (2-9 μeq/L) in response to acidification, but the low-solute stream released double the amount Ali per 100 μeq of acid added than the high solute stream. Macroinvertebrate drift increased in both streams in response to acidification and was dominated by Ephemeroptera and Chironomidae. Our results elucidate the different buffering mechanisms in tropical streams and

Tax management in strengthening financial independence of local government

Directory of Open Access Journals (Sweden)

Badida M.P.

2017-05-01

Full Text Available The article analyses the directions of tax management in the context of budgetary decentralization. The paper aims to research tax management in the system of forming local budgets in the conditions of financial resources decentralization and analyze the current tools of tax management on the local level. In spite of a great number of researches, the issue of tax management in strengthening financial independence of local budgets is not enough studied; therefore, to reach financial independence of local communities it is necessary to adopt new normative and legal acts concerning decentralization of financial resources taking into account tax potential of each territorial community. The lack of financial resources causes the problem of optimal redistribution of power among central and local authorities. The author proposes the new mechanisms of solving the current problems on the example of local budget of the city of Uzgorod to contribute budgetary decentralization. The principal idea while conducting the reform of the budgetary process must be the adoption of certain changes in budgetary legislation which have to shift the mechanisms of budgetary financing and equating local budgets. The author concludes that the progressive vector of well-being increasing completely depends on the developed concept of regional economic policy. The article pays attention to the importance of taking into account the tax potential of a territory and characterizes the directions of strengthening financial independence of local government.

Furanodiene Induces Extrinsic and Intrinsic Apoptosis in Doxorubicin-Resistant MCF-7 Breast Cancer Cells via NF-κB-Independent Mechanism.

Science.gov (United States)

Zhong, Zhang-Feng; Yu, Hai-Bing; Wang, Chun-Ming; Qiang, Wen-An; Wang, Sheng-Peng; Zhang, Jin-Ming; Yu, Hua; Cui, Liao; Wu, Tie; Li, De-Qiang; Wang, Yi-Tao

2017-01-01

Chemotherapy is used as a primary approach in cancer treatment after routine surgery. However, chemo-resistance tends to occur when chemotherapy is used clinically, resulting in poor prognosis and recurrence. Currently, Chinese medicine may provide insight into the design of new therapies to overcome chemo-resistance. Furanodiene, as a heat-sensitive sesquiterpene, is isolated from the essential oil of Rhizoma Curcumae . Even though mounting evidence claiming that furanodiene possesses anti-cancer activities in various types of cancers, the underlying mechanisms against chemo-resistant cancer are not fully clear. Our study found that furanodiene could display anti-cancer effects by inhibiting cell viability, inducing cell cytotoxicity, and suppressing cell proliferation in doxorubicin-resistant MCF-7 breast cancer cells. Furthermore, furanodiene preferentially causes apoptosis by interfering with intrinsic/extrinsic-dependent and NF-κB-independent pathways in doxorubicin-resistant MCF-7 cells. These observations also prompt that furanodiene may be developed as a promising natural product for multidrug-resistant cancer therapy in the future.

Annonaceous acetogenin mimic AA005 induces cancer cell death via apoptosis inducing factor through a caspase-3-independent mechanism.

Science.gov (United States)

Han, Bing; Wang, Tong-Dan; Shen, Shao-Ming; Yu, Yun; Mao, Chan; Yao, Zhu-Jun; Wang, Li-Shun

2015-03-18

Annonaceous acetogenins are a family of natural products with antitumor activities. Annonaceous acetogenin mimic AA005 reportedly inhibits mammalian mitochondrial NADH-ubiquinone reductase (Complex I) and induces gastric cancer cell death. However, the mechanisms underlying its cell-death-inducing activity are unclear. We used SW620 colorectal adenocarcinoma cells to study AA005 cytotoxic activity. Cell deaths were determined by Trypan blue assay and flow cytometry, and related proteins were characterized by western blot. Immunofluorescence and subcellular fractionation were used to evaluate AIF nuclear translocation. Reactive oxygen species were assessed by using redox-sensitive dye DCFDA. AA005 induces a unique type of cell death in colorectal adenocarcinoma cells, characterized by lack of caspase-3 activation or apoptotic body formation, sensitivity to poly (ADP-ribose) polymerase inhibitor Olaparib (AZD2281) but not pan-caspase inhibitor Z-VAD.fmk, and dependence on apoptosis-inducing factor (AIF). AA005 treatment also reduced expression of mitochondrial Complex I components, and leads to accumulation of intracellular reactive oxygen species (ROS) at the early stage. Blocking ROS formation significantly suppresses AA005-induced cell death in SW620 cells. Moreover, blocking activation of RIP-1 by necroptosis inhibitor necrotatin-1 inhibits AIF translocation and partially suppresses AA005-induced cell death in SW620 cells demonstrating that RIP-1 protein may be essential for cell death. AA005 may trigger the cell death via mediated by AIF through caspase-3 independent pathway. Our work provided new mechanisms for AA005-induced cancer cell death and novel clues for cancer treatment via AIF dependent cell death.

Intra-Gene DNA Methylation Variability Is a Clinically Independent Prognostic Marker in Women's Cancers.

Science.gov (United States)

Bartlett, Thomas E; Jones, Allison; Goode, Ellen L; Fridley, Brooke L; Cunningham, Julie M; Berns, Els M J J; Wik, Elisabeth; Salvesen, Helga B; Davidson, Ben; Trope, Claes G; Lambrechts, Sandrina; Vergote, Ignace; Widschwendter, Martin

2015-01-01

We introduce a novel per-gene measure of intra-gene DNA methylation variability (IGV) based on the Illumina Infinium HumanMethylation450 platform, which is prognostic independently of well-known predictors of clinical outcome. Using IGV, we derive a robust gene-panel prognostic signature for ovarian cancer (OC, n = 221), which validates in two independent data sets from Mayo Clinic (n = 198) and TCGA (n = 358), with significance of p = 0.004 in both sets. The OC prognostic signature gene-panel is comprised of four gene groups, which represent distinct biological processes. We show the IGV measurements of these gene groups are most likely a reflection of a mixture of intra-tumour heterogeneity and transcription factor (TF) binding/activity. IGV can be used to predict clinical outcome in patients individually, providing a surrogate read-out of hard-to-measure disease processes.

Long-term future risk of severe exacerbations: Distinct 5-year trajectories of problematic asthma.

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Yii, A C A; Tan, J H Y; Lapperre, T S; Chan, A K W; Low, S Y; Ong, T H; Tan, K L; Chotirmall, S H; Sterk, P J; Koh, M S

2017-09-01

Assessing future risk of exacerbations is an important component of asthma management. Existing studies have investigated short- but not long-term risk. Problematic asthma patients with unfavorable long-term disease trajectory and persistently frequent severe exacerbations need to be identified early to guide treatment. To identify distinct trajectories of severe exacerbation rates among "problematic asthma" patients and develop a risk score to predict the most unfavorable trajectory. Severe exacerbation rates over five years for 177 "problematic asthma" patients presenting to a specialist asthma clinic were tracked. Distinct trajectories of severe exacerbation rates were identified using group-based trajectory modeling. Baseline predictors of trajectory were identified and used to develop a clinical risk score for predicting the most unfavorable trajectory. Three distinct trajectories were found: 58.5% had rare intermittent severe exacerbations ("infrequent"), 32.0% had frequent severe exacerbations at baseline but improved subsequently ("nonpersistently frequent"), and 9.5% exhibited persistently frequent severe exacerbations, with the highest incidence of near-fatal asthma ("persistently frequent"). A clinical risk score composed of ≥2 severe exacerbations in the past year (+2 points), history of near-fatal asthma (+1 point), body mass index ≥25kg/m 2 (+1 point), obstructive sleep apnea (+1 point), gastroesophageal reflux (+1 point), and depression (+1 point) was predictive of the "persistently frequent" trajectory (area under the receiver operating characteristic curve: 0.84, sensitivity 72.2%, specificity 81.1% using cutoff ≥3 points). The trajectories and clinical risk score had excellent performance in an independent validation cohort. Patients with problematic asthma follow distinct illness trajectories over a period of five years. We have derived and validated a clinical risk score that accurately identifies patients who will have persistently

Parathyroid Hormone Activates Phospholipase C (PLC)-Independent Protein Kinase C Signaling Pathway via Protein Kinase A (PKA)-Dependent Mechanism: A New Defined Signaling Route Would Induce Alternative Consideration to Previous Conceptions.

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Tong, Guojun; Meng, Yue; Hao, Song; Hu, Shaoyu; He, Youhua; Yan, Wenjuan; Yang, Dehong

2017-04-20

BACKGROUND Parathyroid hormone (PTH) is an effective anti-osteoporosis agent, after binding to its receptor PTHR1, several signaling pathways, including cAMP/protein kinase A (PKA) and phospholipase C (PLC)/protein kinase C (PKC), are initiated through G proteins; with the cAMP/PKA pathway as the major pathway. Earlier studies have reported that PTHR1 might also activate PKC via a PLC-independent mechanism, but this pathway remains unclear. MATERIAL AND METHODS In HEK293 cells, cAMP accumulation was measured with ELISA and PKC was measured with fluorescence resonance energy transfer (FRET) analysis using CKAR plasmid. In MC3T3-E1 cells, real-time PCR was performed to examine gene expressions. Then assays for cell apoptosis, cell differentiation, alkaline phosphatase activity, and mineralization were performed. RESULTS The FRET analysis found that PTH(1-34), [G1,R19]PTH(1-34) (GR(1-34), and [G1,R19]PTH(1-28) (GR(1-28) were all activated by PKC. The PKC activation ability of GR(1-28) was blocked by cAMP inhibitor (Rp-cAMP) and rescued with the addition of active PKA-α and PKA-β. The PKC activation ability of GR(1-34) was partially inhibited by Rp-cAMP. In MC3T3-E1 cells, gene expressions of ALP, CITED1, NR4a2, and OSX that was regulated by GR(1-28) were significantly changed by the pan-PKC inhibitor Go6983. After pretreatment with Rp-cAMP, the gene expressions of ALP, CITED1, and OPG were differentially regulated by GR(1-28) or GR(1-34), and the difference was blunted by Go6983. PTH(1-34), GR(1-28), and GR(1-34) significantly decreased early apoptosis and augmented osteoblastic differentiation in accordance with the activities of PKA and PKC. CONCLUSIONS PLC-independent PKC activation induced by PTH could be divided into two potential mechanisms: one was PKA-dependent and associated with PTH(1-28); the other was PKA-independent and associated with PTH(29-34). We also found that PTH could activate PLC-independent PKC via PKA-dependent mechanisms.

Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

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Lequerré, Thierry; Bansard, Carine; Vittecoq, Olivier; Derambure, Céline; Hiron, Martine; Daveau, Maryvonne; Tron, François; Ayral, Xavier; Biga, Norman; Auquit-Auckbur, Isabelle; Chiocchia, Gilles; Le Loët, Xavier; Salier, Jean-Philippe

2009-01-01

Introduction Rheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia. Methods Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and healthy synovia were linked to the biological processes involved in each situation. Results Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from healthy synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA. Conclusions Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment. PMID:19563633

Speed invariance of independent control of finger movements in pianists.

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Furuya, Shinichi; Soechting, John F

2012-10-01

Independent control of finger movements characterizes skilled motor behaviors such as tool use and musical performance. The purpose of the present study was to identify the effect of movement frequency (tempo) on individuated finger movements in piano playing. Joint motion at the digits was recorded while 5 expert pianists were playing 30 excerpts from musical pieces with different fingering and key locations either at a predetermined normal tempo or as fast as possible. Principal component analysis and cluster analysis using an expectation-maximization algorithm determined three distinct patterns of finger movement coordination for a keypress with each of the index, middle, ring, and little fingers at each of the two tempi. The finger kinematics of each coordination pattern was overall similar across the tempi. Tone sequences assigned into each cluster were also similar for both tempi. A linear regression analysis determined no apparent difference in the amount of movement covariation between the striking and nonstriking fingers at both metacarpo-phalangeal and proximal-interphalangeal joints across the two tempi, which indicated no effect of tempo on independent finger movements in piano playing. In addition, the standard deviation of interkeystroke interval across strokes did not differ between the two tempi, indicating maintenance of rhythmic accuracy of keystrokes. Strong temporal constraints on finger movements during piano playing may underlie the maintained independent control of fingers over a wider range of tempi, a feature being likely to be specific to skilled pianists.

Creep-recovery constitutive equation and its time-independent limit

International Nuclear Information System (INIS)

Chang, S.J.

1978-01-01

The effect of strain recovery is taken into consideration in establishing a constitutive equation for metals at elevated temperatures. Internal state variables and Rice's flow potential are used in the representation. Growth law for the state variables is discussed and interpreted to be a more general form of the kinematic hardening condition. Yield condition is obtained from the flow law. Accordingly, the flow rule is established with the effect of the recovery mechanism, as a slightly general version of the time-independent theory with the kinematic hardening rule. In the discussion of the time-independent limit, the duration of time required for the inelastic strain to reach its saturated value is defined

The Dirac equation in classical statistical mechanics

International Nuclear Information System (INIS)

Ord, G.N.

2002-01-01

The Dirac equation, usually obtained by 'quantizing' a classical stochastic model is here obtained directly within classical statistical mechanics. The special underlying space-time geometry of the random walk replaces the missing analytic continuation, making the model 'self-quantizing'. This provides a new context for the Dirac equation, distinct from its usual context in relativistic quantum mechanics

Pou1f1, the key transcription factor related to somatic growth in tilapia (Orechromis niloticus), is regulated by two independent post-transcriptional regulation mechanisms.

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Wang, Dongfang; Qin, Jingkai; Jia, Jirong; Yan, Peipei; Li, Wensheng

2017-01-29

This study aims to determine the post-transcriptional regulation mechanism of the transcription factor pou1f1 (pou class 1 homeobox 1), which is the key gene for pituitary development, somatic growth in vertebrates, and transcription of several hormone genes in teleost fish. MicroRNA miR-223-3p was identified as a bona fide target of pou1f; overexpression of miR-223-3p in primary pituitary cells led to the down-regulation of pou1f1 and downstream genes, and inhibition of miR-223-3p led to the up-regulation of pou1f1 in Nile tilapia dispersed primary pituitary cells. An adenylate-uridylate-rich element (AU-Rich element) was found in the 3'UTR of pou1f1 mRNA, and deletion of the AU-Rich element led to slower mRNA decay and therefore more protein output. A potential mutual relationship between miR-223-3p and the AU-rich element was also investigated, and the results demonstrated that with or without the AU-Rich element, miR-223-3p induced the up-regulation of a reporter system under serum starvation conditions, indicating that miR-223-3p and the AU-Rich element function independent of each other. This study is the first to investigate the post-transcriptional mechanism of pou1f1, which revealed that miR-223-3p down-regulated pou1f1 and downstream gene expressions, and the AU-Rich element led to rapid decay of pou1f1 mRNA. MicroRNA miR-223-3p and the AU-Rich element co-regulated the post-transcriptional expression of pou1f1 independently in Nile tilapia, demonstrating that pou1f1 is under the control of a dual post-transcription regulation mechanism. Copyright © 2016 Elsevier Inc. All rights reserved.

Facets of contextual realism in quantum mechanics

International Nuclear Information System (INIS)

Pan, Alok Kumar; Home, Dipankar

2011-01-01

In recent times, there is an upsurge of interest in demonstrating the quantum contextuality. In this proceedings, we explore the two different forms of arguments that have been used for showing the contextual character of quantum mechanics. First line of study concerns the violations of the noncontextual realist models by quantum mechanics, where second line of study that is qualitatively distinct from the earlier one, demonstrates the contextuality within the formalism of quantum mechanics.

Recurrent Rearrangements of Human Amylase Genes Create Multiple Independent CNV Series.

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Shwan, Nzar A A; Louzada, Sandra; Yang, Fengtang; Armour, John A L

2017-05-01

The human amylase gene cluster includes the human salivary (AMY1) and pancreatic amylase genes (AMY2A and AMY2B), and is a highly variable and dynamic region of the genome. Copy number variation (CNV) of AMY1 has been implicated in human dietary adaptation, and in population association with obesity, but neither of these findings has been independently replicated. Despite these functional implications, the structural genomic basis of CNV has only been defined in detail very recently. In this work, we use high-resolution analysis of copy number, and analysis of segregation in trios, to define new, independent allelic series of amylase CNVs in sub-Saharan Africans, including a series of higher-order expansions of a unit consisting of one copy each of AMY1, AMY2A, and AMY2B. We use fiber-FISH (fluorescence in situ hybridization) to define unexpected complexity in the accompanying rearrangements. These findings demonstrate recurrent involvement of the amylase gene region in genomic instability, involving at least five independent rearrangements of the pancreatic amylase genes (AMY2A and AMY2B). Structural features shared by fundamentally distinct lineages strongly suggest that the common ancestral state for the human amylase cluster contained more than one, and probably three, copies of AMY1. © 2017 WILEY PERIODICALS, INC.

Independence of automorphism group, center, and state space of quantum logics

International Nuclear Information System (INIS)

Navara, M.

1992-01-01

We prove that quantum logics (-orthomodular posets) admit full independence of the attributes important within the foundations of quantum mechanics. Namely, we present the construction of quantum logics with given sublogics (=physical subsystems), automorphism groups, centers (=open-quotes classical partsclose quotes of the systems), and state spaces. Thus, all these open-quotes parametersclose quotes are independent. Our result is rooted in the line of investigation carried out by Greechie; Kallus and Trnkova; Kalmbach; and Navara and Ptak; and considerably enriches the known algebraic methods in orthomodular posets. 19 refs., 1 fig

Structural plasticity mediates distinct GAP-dependent GTP hydrolysis mechanisms in Rab33 and Rab5.

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Majumdar, Soneya; Acharya, Abhishek; Prakash, Balaji

2017-12-01

The classical GTP hydrolysis mechanism, as seen in Ras, employs a catalytic glutamine provided in cis by the GTPase and an arginine supplied in trans by a GTPase activating protein (GAP). The key idea emergent from a large body of research on small GTPases is that GTPases employ a variety of different hydrolysis mechanisms; evidently, these variations permit diverse rates of GTPase inactivation, crucial for temporal regulation of different biological processes. Recently, we unified these variations and argued that a steric clash between active site residues (corresponding to positions 12 and 61 of Ras) governs whether a GTPase utilizes the cis-Gln or the trans-Gln (from the GAP) for catalysis. As the cis-Gln encounters a steric clash, the Rab GTPases employ the so-called dual finger mechanism where the interacting GAP supplies a trans-Gln for catalysis. Using experimental and computational methods, we demonstrate how the cis-Gln of Rab33 overcomes the steric clash when it is stabilized by a residue in the vicinity. In effect, this demonstrates how both cis-Gln- and trans-Gln-mediated mechanisms could operate in the same GTPase in different contexts, i.e. depending on the GAP that regulates its action. Interestingly, in the case of Rab5, which possesses a higher intrinsic GTP hydrolysis rate, a similar stabilization of the cis-Gln appears to overcome the steric clash. Taken together with the mechanisms seen for Rab1, it is evident that the observed variations in Rab and their GAP partners allow structural plasticity, or in other words, the choice of different catalytic mechanisms. © 2017 Federation of European Biochemical Societies.

Fully Device-Independent Quantum Key Distribution

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Vazirani, Umesh; Vidick, Thomas

2014-10-01

Quantum cryptography promises levels of security that are impossible to replicate in a classical world. Can this security be guaranteed even when the quantum devices on which the protocol relies are untrusted? This central question dates back to the early 1990s when the challenge of achieving device-independent quantum key distribution was first formulated. We answer this challenge by rigorously proving the device-independent security of a slight variant of Ekert's original entanglement-based protocol against the most general (coherent) attacks. The resulting protocol is robust: While assuming only that the devices can be modeled by the laws of quantum mechanics and are spatially isolated from each other and from any adversary's laboratory, it achieves a linear key rate and tolerates a constant noise rate in the devices. In particular, the devices may have quantum memory and share arbitrary quantum correlations with the eavesdropper. The proof of security is based on a new quantitative understanding of the monogamous nature of quantum correlations in the context of a multiparty protocol.

Distinct signaling roles of ceramide species in yeast revealed through systematic perturbation and systems biology analyses.

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Montefusco, David J; Chen, Lujia; Matmati, Nabil; Lu, Songjian; Newcomb, Benjamin; Cooper, Gregory F; Hannun, Yusuf A; Lu, Xinghua

2013-10-29

Ceramide, the central molecule of sphingolipid metabolism, is an important bioactive molecule that participates in various cellular regulatory events and that has been implicated in disease. Deciphering ceramide signaling is challenging because multiple ceramide species exist, and many of them may have distinct functions. We applied systems biology and molecular approaches to perturb ceramide metabolism in the yeast Saccharomyces cerevisiae and inferred causal relationships between ceramide species and their potential targets by combining lipidomic, genomic, and transcriptomic analyses. We found that during heat stress, distinct metabolic mechanisms controlled the abundance of different groups of ceramide species and provided experimental support for the importance of the dihydroceramidase Ydc1 in mediating the decrease in dihydroceramides during heat stress. Additionally, distinct groups of ceramide species, with different N-acyl chains and hydroxylations, regulated different sets of functionally related genes, indicating that the structural complexity of these lipids produces functional diversity. The transcriptional modules that we identified provide a resource to begin to dissect the specific functions of ceramides.

HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms

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White, Christy L.; Whittington, Amy; Barnes, Maria J.; Wang, Zhong; Bray, George A.; Morrison, Christopher D.

2009-01-01

Protein tyrosine phosphatase 1B (PTP1B) contributes to leptin resistance by inhibiting intracellular leptin receptor signaling. Mice with whole body or neuron-specific deletion of PTP1B are hypersensitive to leptin and resistant to diet-induced obesity. Here we report a significant increase in PTP1B protein levels in the mediobasal hypothalamus (P = 0.003) and a concomitant reduction in leptin sensitivity following 28 days of high-fat (HF) feeding in rats. A significant increase in PTP1B mRNA levels was also observed in rats chronically infused with leptin (3 μg/day icv) for 14 days (P = 0.01) and in leptin-deficient ob/ob mice infused with leptin (5 μg/day sc for 14 days; P = 0.003). When saline-infused ob/ob mice were placed on a HF diet for 14 days, an increase in hypothalamic PTP1B mRNA expression was detected (P = 0.001) despite the absence of circulating leptin. In addition, although ob/ob mice were much more sensitive to leptin on a low-fat (LF) diet, a reduction in this sensitivity was still observed following exposure to a HF diet. Taken together, these data indicate that hypothalamic PTP1B is specifically increased during HF diet-induced leptin resistance. This increase in PTP1B is due in part to chronic hyperleptinemia, suggesting that hyperleptinemia is one mechanism contributing to the development of leptin resistance. However, these data also indicate that leptin is not required for the increase in hypothalamic PTP1B or the development of leptin resistance. Therefore, additional, leptin-independent mechanisms must exist that increase hypothalamic PTP1B and contribute to leptin resistance. PMID:19017730

Identification of a Sgo2-Dependent but Mad2-Independent Pathway Controlling Anaphase Onset in Fission Yeast

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John C. Meadows

2017-02-01

Full Text Available The onset of anaphase is triggered by activation of the anaphase-promoting complex/cyclosome (APC/C following silencing of the spindle assembly checkpoint (SAC. APC/C triggers ubiquitination of Securin and Cyclin B, which leads to loss of sister chromatid cohesion and inactivation of Cyclin B/Cdk1, respectively. This promotes relocalization of Aurora B kinase and other components of the chromosome passenger complex (CPC from centromeres to the spindle midzone. In fission yeast, this is mediated by Clp1 phosphatase-dependent interaction of CPC with Klp9/MKLP2 (kinesin-6. When this interaction is disrupted, kinetochores bi-orient normally, but APC/C activation is delayed via a mechanism that requires Sgo2 and some (Bub1, Mph1/Mps1, and Mad3, but not all (Mad1 and Mad2, components of the SAC and the first, but not second, lysine, glutamic acid, glutamine (KEN box in Mad3. These data indicate that interaction of CPC with Klp9 terminates a Sgo2-dependent, but Mad2-independent, APC/C-inhibitory pathway that is distinct from the canonical SAC.

Dynamic mechanical oscillations during metamorphosis of the monarch butterfly

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Pelling, Andrew E; Wilkinson, Paul R; Stringer, Richard; Gimzewski, James K

2008-01-01

The mechanical oscillation of the heart is fundamental during insect metamorphosis, but it is unclear how morphological changes affect its mechanical dynamics. Here, the micromechanical heartbeat with the monarch chrysalis (Danaus plexippus) during metamorphosis is compared with the structural changes observed through in vivo magnetic resonance imaging (MRI). We employ a novel ultra-sensitive detection approach, optical beam deflection, in order to measure the microscale motions of the pupae during the course of metamorphosis. We observed very distinct mechanical contractions occurring at regular intervals, which we ascribe to the mechanical function of the heart organ. Motion was observed to occur in approximately 15 min bursts of activity with frequencies in the 0.4–1.0 Hz range separated by periods of quiescence during the first 83 per cent of development. In the final stages, the beating was found to be uninterrupted until the adult monarch butterfly emerged. Distinct stages of development were characterized by changes in frequency, amplitude, mechanical quality factor and de/repolarization times of the mechanical pulsing. The MRI revealed that the heart organ remains functionally intact throughout metamorphosis but undergoes morphological changes that are reflected in the mechanical oscillation. PMID:18682363

Anatomical coupling between distinct metacognitive systems for memory and visual perception.

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McCurdy, Li Yan; Maniscalco, Brian; Metcalfe, Janet; Liu, Ka Yuet; de Lange, Floris P; Lau, Hakwan

2013-01-30

A recent study found that, across individuals, gray matter volume in the frontal polar region was correlated with visual metacognition capacity (i.e., how well one's confidence ratings distinguish between correct and incorrect judgments). A question arises as to whether the putative metacognitive mechanisms in this region are also used in other metacognitive tasks involving, for example, memory. A novel psychophysical measure allowed us to assess metacognitive efficiency separately in a visual and a memory task, while taking variations in basic task performance capacity into account. We found that, across individuals, metacognitive efficiencies positively correlated between the two tasks. However, voxel-based morphometry analysis revealed distinct brain structures for the two kinds of metacognition. Replicating a previous finding, variation in visual metacognitive efficiency was correlated with volume of frontal polar regions. However, variation in memory metacognitive efficiency was correlated with volume of the precuneus. There was also a weak correlation between visual metacognitive efficiency and precuneus volume, which may account for the behavioral correlation between visual and memory metacognition (i.e., the precuneus may contain common mechanisms for both types of metacognition). However, we also found that gray matter volumes of the frontal polar and precuneus regions themselves correlated across individuals, and a formal model comparison analysis suggested that this structural covariation was sufficient to account for the behavioral correlation of metacognition in the two tasks. These results highlight the importance of the precuneus in higher-order memory processing and suggest that there may be functionally distinct metacognitive systems in the human brain.

Human brain basis of musical rhythm perception: common and distinct neural substrates for meter, tempo, and pattern.

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Thaut, Michael H; Trimarchi, Pietro Davide; Parsons, Lawrence M

2014-06-17

Rhythm as the time structure of music is composed of distinct temporal components such as pattern, meter, and tempo. Each feature requires different computational processes: meter involves representing repeating cycles of strong and weak beats; pattern involves representing intervals at each local time point which vary in length across segments and are linked hierarchically; and tempo requires representing frequency rates of underlying pulse structures. We explored whether distinct rhythmic elements engage different neural mechanisms by recording brain activity of adult musicians and non-musicians with positron emission tomography (PET) as they made covert same-different discriminations of (a) pairs of rhythmic, monotonic tone sequences representing changes in pattern, tempo, and meter, and (b) pairs of isochronous melodies. Common to pattern, meter, and tempo tasks were focal activities in right, or bilateral, areas of frontal, cingulate, parietal, prefrontal, temporal, and cerebellar cortices. Meter processing alone activated areas in right prefrontal and inferior frontal cortex associated with more cognitive and abstract representations. Pattern processing alone recruited right cortical areas involved in different kinds of auditory processing. Tempo processing alone engaged mechanisms subserving somatosensory and premotor information (e.g., posterior insula, postcentral gyrus). Melody produced activity different from the rhythm conditions (e.g., right anterior insula and various cerebellar areas). These exploratory findings suggest the outlines of some distinct neural components underlying the components of rhythmic structure.

What makes health promotion research distinct?

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Woodall, James; Warwick-Booth, Louise; South, Jane; Cross, Ruth

2018-02-01

There have been concerns about the decline of health promotion as a practice and discipline and, alongside this, calls for a clearer articulation of health promotion research and what, if anything, makes it distinct. This discussion paper, based on a review of the literature, the authors' own experiences in the field, and a workshop delivered by two of the authors at the 8th Nordic Health Promotion Conference, seeks to state the reasons why health promotion research is distinctive. While by no means exhaustive, the paper suggests four distinctive features. The paper hopes to be a catalyst to enable health promotion researchers to be explicit in their practice and to begin the process of developing an agreed set of research principles.

Rate-independent dissipation and loading direction effects in compressed carbon nanotube arrays

International Nuclear Information System (INIS)

Raney, J R; Fraternali, F; Daraio, C

2013-01-01

Arrays of nominally-aligned carbon nanotubes (CNTs) under compression deform locally via buckling, exhibit a foam-like, dissipative response, and can often recover most of their original height. We synthesize millimeter-scale CNT arrays and report the results of compression experiments at different strain rates, from 10 −4 to 10 −1 s −1 , and for multiple compressive cycles to different strains. We observe that the stress–strain response proceeds independently of the strain rate for all tests, but that it is highly dependent on loading history. Additionally, we examine the effect of loading direction on the mechanical response of the system. The mechanical behavior is modeled using a multiscale series of bistable springs. This model captures the rate independence of the constitutive response, the local deformation, and the history-dependent effects. We develop here a macroscopic formulation of the model to represent a continuum limit of the mesoscale elements developed previously. Utilizing the model and our experimental observations we discuss various possible physical mechanisms contributing to the system’s dissipative response. (paper)

Genomic and phenotypic characterization of myxoma virus from Great Britain reveals multiple evolutionary pathways distinct from those in Australia.

Directory of Open Access Journals (Sweden)

Peter J Kerr

2017-03-01

Full Text Available The co-evolution of myxoma virus (MYXV and the European rabbit occurred independently in Australia and Europe from different progenitor viruses. Although this is the canonical study of the evolution of virulence, whether the genomic and phenotypic outcomes of MYXV evolution in Europe mirror those observed in Australia is unknown. We addressed this question using viruses isolated in the United Kingdom early in the MYXV epizootic (1954-1955 and between 2008-2013. The later UK viruses fell into three distinct lineages indicative of a long period of separation and independent evolution. Although rates of evolutionary change were almost identical to those previously described for MYXV in Australia and strongly clock-like, genome evolution in the UK and Australia showed little convergence. The phenotypes of eight UK viruses from three lineages were characterized in laboratory rabbits and compared to the progenitor (release Lausanne strain. Inferred virulence ranged from highly virulent (grade 1 to highly attenuated (grade 5. Two broad disease types were seen: cutaneous nodular myxomatosis characterized by multiple raised secondary cutaneous lesions, or an amyxomatous phenotype with few or no secondary lesions. A novel clinical outcome was acute death with pulmonary oedema and haemorrhage, often associated with bacteria in many tissues but an absence of inflammatory cells. Notably, reading frame disruptions in genes defined as essential for virulence in the progenitor Lausanne strain were compatible with the acquisition of high virulence. Combined, these data support a model of ongoing host-pathogen co-evolution in which multiple genetic pathways can produce successful outcomes in the field that involve both different virulence grades and disease phenotypes, with alterations in tissue tropism and disease mechanisms.

Genomic and phenotypic characterization of myxoma virus from Great Britain reveals multiple evolutionary pathways distinct from those in Australia.

Science.gov (United States)

Kerr, Peter J; Cattadori, Isabella M; Rogers, Matthew B; Fitch, Adam; Geber, Adam; Liu, June; Sim, Derek G; Boag, Brian; Eden, John-Sebastian; Ghedin, Elodie; Read, Andrew F; Holmes, Edward C

2017-03-01

The co-evolution of myxoma virus (MYXV) and the European rabbit occurred independently in Australia and Europe from different progenitor viruses. Although this is the canonical study of the evolution of virulence, whether the genomic and phenotypic outcomes of MYXV evolution in Europe mirror those observed in Australia is unknown. We addressed this question using viruses isolated in the United Kingdom early in the MYXV epizootic (1954-1955) and between 2008-2013. The later UK viruses fell into three distinct lineages indicative of a long period of separation and independent evolution. Although rates of evolutionary change were almost identical to those previously described for MYXV in Australia and strongly clock-like, genome evolution in the UK and Australia showed little convergence. The phenotypes of eight UK viruses from three lineages were characterized in laboratory rabbits and compared to the progenitor (release) Lausanne strain. Inferred virulence ranged from highly virulent (grade 1) to highly attenuated (grade 5). Two broad disease types were seen: cutaneous nodular myxomatosis characterized by multiple raised secondary cutaneous lesions, or an amyxomatous phenotype with few or no secondary lesions. A novel clinical outcome was acute death with pulmonary oedema and haemorrhage, often associated with bacteria in many tissues but an absence of inflammatory cells. Notably, reading frame disruptions in genes defined as essential for virulence in the progenitor Lausanne strain were compatible with the acquisition of high virulence. Combined, these data support a model of ongoing host-pathogen co-evolution in which multiple genetic pathways can produce successful outcomes in the field that involve both different virulence grades and disease phenotypes, with alterations in tissue tropism and disease mechanisms.

Genomic and phenotypic characterization of myxoma virus from Great Britain reveals multiple evolutionary pathways distinct from those in Australia

Science.gov (United States)

Kerr, Peter J.; Cattadori, Isabella M.; Fitch, Adam; Geber, Adam; Liu, June; Sim, Derek G.; Boag, Brian; Ghedin, Elodie

2017-01-01

The co-evolution of myxoma virus (MYXV) and the European rabbit occurred independently in Australia and Europe from different progenitor viruses. Although this is the canonical study of the evolution of virulence, whether the genomic and phenotypic outcomes of MYXV evolution in Europe mirror those observed in Australia is unknown. We addressed this question using viruses isolated in the United Kingdom early in the MYXV epizootic (1954–1955) and between 2008–2013. The later UK viruses fell into three distinct lineages indicative of a long period of separation and independent evolution. Although rates of evolutionary change were almost identical to those previously described for MYXV in Australia and strongly clock-like, genome evolution in the UK and Australia showed little convergence. The phenotypes of eight UK viruses from three lineages were characterized in laboratory rabbits and compared to the progenitor (release) Lausanne strain. Inferred virulence ranged from highly virulent (grade 1) to highly attenuated (grade 5). Two broad disease types were seen: cutaneous nodular myxomatosis characterized by multiple raised secondary cutaneous lesions, or an amyxomatous phenotype with few or no secondary lesions. A novel clinical outcome was acute death with pulmonary oedema and haemorrhage, often associated with bacteria in many tissues but an absence of inflammatory cells. Notably, reading frame disruptions in genes defined as essential for virulence in the progenitor Lausanne strain were compatible with the acquisition of high virulence. Combined, these data support a model of ongoing host-pathogen co-evolution in which multiple genetic pathways can produce successful outcomes in the field that involve both different virulence grades and disease phenotypes, with alterations in tissue tropism and disease mechanisms. PMID:28253375

The cross-bridge dynamics is determined by two length-independent kinetics: Implications on muscle economy and Frank-Starling Law.

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Amiad Pavlov, Daria; Landesberg, Amir

2016-01-01

The cellular mechanisms underlying the Frank-Starling Law of the heart and the skeletal muscle force-length relationship are not clear. This study tested the effects of sarcomere length (SL) on the average force per cross-bridge and on the rate of cross-bridge cycling in intact rat cardiac trabeculae (n=9). SL was measured by laser diffraction and controlled with a fast servomotor to produce varying initial SLs. Tetanic contractions were induced by addition of cyclopiazonic acid, to maintain a constant activation. Stress decline and redevelopment in response to identical ramp shortenings, starting at various initial SLs, was analyzed. Both stress decline and redevelopment responses revealed two distinct kinetics: a fast and a slower phase. The duration of the rapid phases (4.2 ± 0.1 msec) was SL-independent. The second slower phase depicted a linear dependence of the rate of stress change on the instantaneous stress level. Identical slopes (70.5 ± 1.6 [1/s], p=0.33) were obtained during ramp shortening at all initial SLs, indicating that the force per cross-bridge and cross-bridge cycling kinetics are length-independent. A decrease in the slope at longer SLs was obtained during stress redevelopment, due to internal shortening. The first phase is attributed to rapid changes in the average force per cross-bridge. The second phase is ascribed to both cross-bridge cycling between its strong and weak conformations and to changes in the number of strong cross-bridges. Cross-bridge cycling kinetics and muscle economy are length-independent and the Frank-Starling Law cannot be attributed to changes in the force per cross-bridge or in the single cross-bridge cycling rates. Copyright © 2015 Elsevier Ltd. All rights reserved.

Bifactor Models of Religious and Spiritual Struggles: Distinct from Religiousness and Distress

Directory of Open Access Journals (Sweden)

Nick Stauner

2016-06-01

Full Text Available The Religious and Spiritual Struggles Scale (RSS measures important psychological constructs in an underemphasized section of the overlap between religion and well-being. Are religious/spiritual struggles distinct from religiousness, distress, and each other? To test the RSS’ internal discriminant validity, we replicated the original six-factor measurement model across five large samples (N = 5705 and tested the fit of a restricted bifactor model, which supported the mutual viability of multidimensional and unidimensional scoring systems for the RSS. Additionally, we explored a bifactor model with correlated group factors that exhibited optimal fit statistics. This model maintained the correlations among the original factors while extracting a general factor from the RSS. This general factor’s strong correlations with religious participation and belief salience suggested that this factor resembles religiousness itself. Estimating this general factor seemed to improve Demonic and Moral struggles’ independence from religiousness, but did not change any factor’s correlations with neuroticism, depression, anxiety, and stress. These distress factors correlated with most of the independent group factors corresponding to the original dimensions of the RSS, especially Ultimate Meaning and Divine struggles. These analyses demonstrate the discriminant validity of religious/spiritual struggles and the complexity of their relationships with religiousness and distress.

Distinct Reward Properties are Encoded via Corticostriatal Interactions.

Science.gov (United States)

Smith, David V; Rigney, Anastasia E; Delgado, Mauricio R

2016-02-02

The striatum serves as a critical brain region for reward processing. Yet, understanding the link between striatum and reward presents a challenge because rewards are composed of multiple properties. Notably, affective properties modulate emotion while informative properties help obtain future rewards. We approached this problem by emphasizing affective and informative reward properties within two independent guessing games. We found that both reward properties evoked activation within the nucleus accumbens, a subregion of the striatum. Striatal responses to informative, but not affective, reward properties predicted subsequent utilization of information for obtaining monetary reward. We hypothesized that activation of the striatum may be necessary but not sufficient to encode distinct reward properties. To investigate this possibility, we examined whether affective and informative reward properties were differentially encoded in corticostriatal interactions. Strikingly, we found that the striatum exhibited dissociable connectivity patterns with the ventrolateral prefrontal cortex, with increasing connectivity for affective reward properties and decreasing connectivity for informative reward properties. Our results demonstrate that affective and informative reward properties are encoded via corticostriatal interactions. These findings highlight how corticostriatal systems contribute to reward processing, potentially advancing models linking striatal activation to behavior.

Consumer perspectives on nurse practitioners and independent practice.

Science.gov (United States)

Brown, Deonne J

2007-10-01

The purposes of this study were to report the results of a survey for determining the feasibility and sustainability of independently managed nurse practitioner (NP) practices, to identify the characteristics of consumers who would likely choose an independent NP practice, to assess consumer needs, and to define a target market for competitively positioning NPs. An anonymous electronic survey of 1000 employees (response rate = 21%) at a large nonprofit organization in King County, Washington. This organization employs persons in a wide range of socioeconomic and vocational situations. Descriptive statistics and chi-square analyses were applied to determine associations between demographic characteristics and having used an NP or having the intent to use an independent NP practice. Most respondents knew about NPs, and the majority had seen an NP for their care. Most were satisfied or very satisfied with NP care. A much larger percentage (90%) than previous studies knew about NPs; 58% had seen an NP for their care, making NPs the most used practitioner alternative to physicians. Evidence suggests that NP users are more likely to be female and younger. Eighty-two percent of NP users were satisfied or very satisfied with the care they had received compared to a 70% satisfaction rate for current providers. Women, relatively younger respondents, those who had seen a physician assistant or NP, and those who considered NPs to provide quality and more personalized care were significantly more likely to indicate that they would choose an independent NP practice in their community. Based on a standard marketing formula, 30% of the sample in this study would be expected to change their health care to such a practice. This is the first descriptive study to suggest widespread acceptance of NPs as independent practitioners. Compared to a 1985 study of Seattle residents, consumers are far more likely to know about NPs. Consumer studies such as this one identify the characteristics

Independent Emergence of Yersinia ruckeri Biotype 2 in the United States and Europe

DEFF Research Database (Denmark)

Welch, Timothy J.; Verner-Jeffreys, David W.; Dalsgaard, Inger

2011-01-01

with an increased frequency of enteric redmouth disease (ERM) outbreaks in previously vaccinated salmonid fish. In this study, four independent specific natural mutations that cause the loss of both motility and secreted lipase activity were identified in BT2 strains from the United States, United Kingdom...... emerged separately at least four times. In addition, BT2 strains from the United Kingdom were shown to have the same mutant allele found in U.S. BT2 strains, suggesting a common origin of this BT2 lineage. This differentiation of distinct BT2 lineages is of critical importance for the development...

A comparative study of small RNAs in Toxoplasma gondii of distinct genotypes

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Wang Jielin

2012-09-01

Full Text Available Abstract Background Toxoplasma gondii is an intracellular parasite with a significant impact on human health. Inside the mammalian and avian hosts, the parasite can undergo rapid development or remain inactive in the cysts. The mechanism that regulates parasite proliferation has not been fully understood. Small noncoding RNAs (sncRNA such as microRNAs (miRNAs are endogenous regulatory factors that can modulate cell differentiation and development. It is anticipated that hundreds of miRNAs regulate the expression of thousands of genes in a single organism. SncRNAs have been identified in T. gondii, however the profiles of sncRNAs expression and their potential regulatory function in parasites of distinct genotypes has largely been unknown. Methods The transcription profiles of miRNAs in the two genetically distinct strains, RH and ME49, of T. gondii were investigated and compared by a high-through-put RNA sequencing technique and systematic bioinformatics analysis. The expression of some of the miRNAs was confirmed by Northern blot analysis. Results 1,083,320 unique sequences were obtained. Of which, 17 conserved miRNAs related to 2 metazoan miRNA families and 339 novel miRNAs were identified. A total of 175 miRNAs showed strain-specific expression, of which 155 miRNAs were up-regulated in RH strain and 20 miRNAs were up-regulated in ME49 strain. Strain-specific expression of miRNAs in T. gondii could be due to activation of specific genes at different genomic loci or due to arm-switching of the same pre-miRNA duplex. Conclusions Evidence for the differential expression of miRNAs in the two genetically distinct strains of T. gondii has been identified and defined. MiRNAs of T. gondii are more species-specific as compared to other organisms, which can be developed as diagnostic biomarkers for toxoplasmosis. The data also provide a framework for future studies on RNAi-dependent regulatory mechanisms in the zoonotic parasite.

Distinct Functions of Endophilin Isoforms in Synaptic Vesicle Endocytosis

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Jifeng Zhang

2015-01-01

Full Text Available Endophilin isoforms perform distinct characteristics in their interactions with N-type Ca2+ channels and dynamin. However, precise functional differences for the endophilin isoforms on synaptic vesicle (SV endocytosis remain unknown. By coupling RNA interference and electrophysiological recording techniques in cultured rat hippocampal neurons, we investigated the functional differences of three isoforms of endophilin in SV endocytosis. The results showed that the amplitude of normalized evoked excitatory postsynaptic currents in endophilin1 knockdown neurons decreased significantly for both single train and multiple train stimulations. Similar results were found using endophilin2 knockdown neurons, whereas endophilin3 siRNA exhibited no change compared with control neurons. Endophilin1 and endophilin2 affected SV endocytosis, but the effect of endophilin1 and endophilin2 double knockdown was not different from that of either knockdown alone. This result suggested that endophilin1 and endophilin2 functioned together but not independently during SV endocytosis. Taken together, our results indicate that SV endocytosis is sustained by endophilin1 and endophilin2 isoforms, but not by endophilin3, in primary cultured hippocampal neurons.

Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis.

Science.gov (United States)

Zeng, Chong; Xing, Rui; Liu, Jing; Xing, Feiyue

2016-01-01

Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

Intra-Gene DNA Methylation Variability Is a Clinically Independent Prognostic Marker in Women's Cancers.

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Thomas E Bartlett

Full Text Available We introduce a novel per-gene measure of intra-gene DNA methylation variability (IGV based on the Illumina Infinium HumanMethylation450 platform, which is prognostic independently of well-known predictors of clinical outcome. Using IGV, we derive a robust gene-panel prognostic signature for ovarian cancer (OC, n = 221, which validates in two independent data sets from Mayo Clinic (n = 198 and TCGA (n = 358, with significance of p = 0.004 in both sets. The OC prognostic signature gene-panel is comprised of four gene groups, which represent distinct biological processes. We show the IGV measurements of these gene groups are most likely a reflection of a mixture of intra-tumour heterogeneity and transcription factor (TF binding/activity. IGV can be used to predict clinical outcome in patients individually, providing a surrogate read-out of hard-to-measure disease processes.

RIPK1 and PGAM5 Control Leishmania Replication through Distinct Mechanisms.

Science.gov (United States)

Farias Luz, Nivea; Balaji, Sakthi; Okuda, Kendi; Barreto, Aline Silva; Bertin, John; Gough, Peter J; Gazzinelli, Ricardo; Almeida, Roque P; Bozza, Marcelo T; Borges, Valeria M; Chan, Francis Ka-Ming

2016-06-15

Leishmaniasis is an important parasitic disease found in the tropics and subtropics. Cutaneous and visceral leishmaniasis affect an estimated 1.5 million people worldwide. Despite its human health relevance, relatively little is known about the cell death pathways that control Leishmania replication in the host. Necroptosis is a recently identified form of cell death with potent antiviral effects. Receptor interacting protein kinase 1 (RIPK1) is a critical kinase that mediates necroptosis downstream of death receptors and TLRs. Heme, a product of hemoglobin catabolism during certain intracellular pathogen infections, is also a potent inducer of macrophage necroptosis. We found that human visceral leishmaniasis patients exhibit elevated serum levels of heme. Therefore, we examined the impact of heme and necroptosis on Leishmania replication. Indeed, heme potently inhibited Leishmania replication in bone marrow-derived macrophages. Moreover, we found that inhibition of RIPK1 kinase activity also enhanced parasite replication in the absence of heme. We further found that the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5), a putative downstream effector of RIPK1, was also required for inhibition of Leishmania replication. In mouse infection, both PGAM5 and RIPK1 kinase activity are required for IL-1β expression in response to Leishmania However, PGAM5, but not RIPK1 kinase activity, was directly responsible for Leishmania-induced IL-1β secretion and NO production in bone marrow-derived macrophages. Collectively, these results revealed that RIPK1 and PGAM5 function independently to exert optimal control of Leishmania replication in the host. Copyright © 2016 by The American Association of Immunologists, Inc.

Intra-Gene DNA Methylation Variability Is a Clinically Independent Prognostic Marker in Women’s Cancers

Science.gov (United States)

Bartlett, Thomas E.; Jones, Allison; Goode, Ellen L.; Fridley, Brooke L.; Cunningham, Julie M.; Berns, Els M. J. J.; Wik, Elisabeth; Salvesen, Helga B.; Davidson, Ben; Trope, Claes G.; Lambrechts, Sandrina; Vergote, Ignace; Widschwendter, Martin

2015-01-01

We introduce a novel per-gene measure of intra-gene DNA methylation variability (IGV) based on the Illumina Infinium HumanMethylation450 platform, which is prognostic independently of well-known predictors of clinical outcome. Using IGV, we derive a robust gene-panel prognostic signature for ovarian cancer (OC, n = 221), which validates in two independent data sets from Mayo Clinic (n = 198) and TCGA (n = 358), with significance of p = 0.004 in both sets. The OC prognostic signature gene-panel is comprised of four gene groups, which represent distinct biological processes. We show the IGV measurements of these gene groups are most likely a reflection of a mixture of intra-tumour heterogeneity and transcription factor (TF) binding/activity. IGV can be used to predict clinical outcome in patients individually, providing a surrogate read-out of hard-to-measure disease processes. PMID:26629914

Independence and interdependence predict health and wellbeing: divergent patterns in the United States and Japan

Directory of Open Access Journals (Sweden)

Shinobu Kitayama

2010-12-01

Full Text Available A cross-cultural survey was used to examine two hypotheses designed to link culture to well-being and health. The first hypothesis states that people are motivated toward prevalent cultural mandates of either independence (personal control in the United States or interdependence (relational harmony in Japan. As predicted, Americans with compromised personal control and Japanese with strained relationships reported high perceived constraint. The second hypothesis holds that people achieve well-being and health through actualizing the respective cultural mandates in their modes of being. As predicted, the strongest predictor of well-being and health was personal control in the United States, but the absence of relational strain in Japan. All analyses controlled for age, gender, and personality traits. The overall pattern of findings underscores culturally distinct pathways (independent versus interdependent in achieving these positive life outcomes.

Independence and Product Systems

OpenAIRE

Skeide, Michael

2003-01-01

Starting from elementary considerations about independence and Markov processes in classical probability we arrive at the new concept of conditional monotone independence (or operator-valued monotone independence). With the help of product systems of Hilbert modules we show that monotone conditional independence arises naturally in dilation theory.

Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms

Science.gov (United States)

dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

2015-01-01

The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs. PMID:26209364

Characterization of Trichome-Expressed BAHD Acyltransferases in Petunia axillaris Reveals Distinct Acylsugar Assembly Mechanisms within the Solanaceae1[OPEN

Science.gov (United States)

Uebler, Joseph B.; Liu, Xiaoxiao

2017-01-01

Acylsugars are synthesized in the glandular trichomes of the Solanaceae family and are implicated in protection against abiotic and biotic stress. Acylsugars are composed of either sucrose or glucose esterified with varying numbers of acyl chains of differing length. In tomato (Solanum lycopersicum), acylsugar assembly requires four acylsugar acyltransferases (ASATs) of the BAHD superfamily. Tomato ASATs catalyze the sequential esterification of acyl-coenzyme A thioesters to the R4, R3, R3ʹ, and R2 positions of sucrose, yielding a tetra-acylsucrose. Petunia spp. synthesize acylsugars that are structurally distinct from those of tomato. To explore the mechanisms underlying this chemical diversity, a Petunia axillaris transcriptome was mined for trichome preferentially expressed BAHDs. A combination of phylogenetic analyses, gene silencing, and biochemical analyses coupled with structural elucidation of metabolites revealed that acylsugar assembly is not conserved between tomato and petunia. In P. axillaris, tetra-acylsucrose assembly occurs through the action of four ASATs, which catalyze sequential addition of acyl groups to the R2, R4, R3, and R6 positions. Notably, in P. axillaris, PaxASAT1 and PaxASAT4 catalyze the acylation of the R2 and R6 positions of sucrose, respectively, and no clear orthologs exist in tomato. Similarly, petunia acylsugars lack an acyl group at the R3ʹ position, and congruently, an ortholog of SlASAT3, which catalyzes acylation at the R3ʹ position in tomato, is absent in P. axillaris. Furthermore, where putative orthologous relationships of ASATs are predicted between tomato and petunia, these are not supported by biochemical assays. Overall, these data demonstrate the considerable evolutionary plasticity of acylsugar biosynthesis. PMID:28701351

Testing the distinctiveness of visual imagery and motor imagery in a reach paradigm.

Science.gov (United States)

Gabbard, Carl; Ammar, Diala; Cordova, Alberto

2009-01-01

We examined the distinctiveness of motor imagery (MI) and visual imagery (VI) in the context of perceived reachability. The aim was to explore the notion that the two visual modes have distinctive processing properties tied to the two-visual-system hypothesis. The experiment included an interference tactic whereby participants completed two tasks at the same time: a visual or motor-interference task combined with a MI or VI-reaching task. We expected increased error would occur when the imaged task and the interference task were matched (e.g., MI with the motor task), suggesting an association based on the assumption that the two tasks were in competition for space on the same processing pathway. Alternatively, if there were no differences, dissociation could be inferred. Significant increases in the number of errors were found when the modalities for the imaged (both MI and VI) task and the interference task were matched. Therefore, it appears that MI and VI in the context of perceived reachability recruit different processing mechanisms.

Organizing Independent Student Work

Directory of Open Access Journals (Sweden)

Zhadyra T. Zhumasheva

2015-03-01

Full Text Available This article addresses issues in organizing independent student work. The author defines the term “independence”, discusses the concepts of independent learner work and independent learner work under the guidance of an instructor, proposes a classification of assignments to be done independently, and provides methodological recommendations as to the organization of independent student work. The article discusses the need for turning the student from a passive consumer of knowledge into an active creator of it, capable of formulating a problem, analyzing the ways of solving it, coming up with an optimum outcome, and proving its correctness. The preparation of highly qualified human resources is the primary condition for boosting Kazakhstan’s competitiveness. Independent student work is a means of fostering the professional competence of future specialists. The primary form of self-education is independent work.

New therapeutic activity of metabolic enhancer piracetam in treatment of neurodegenerative disease: Participation of caspase independent death factors, oxidative stress, inflammatory responses and apoptosis.

Science.gov (United States)

Verma, Dinesh Kumar; Gupta, Sonam; Biswas, Joyshree; Joshi, Neeraj; Singh, Abhishek; Gupta, Parul; Tiwari, Shubhangini; Sivarama Raju, K; Chaturvedi, Swati; Wahajuddin, M; Singh, Sarika

2018-03-16

Piracetam, a nootropic drug that has been clinically used for decades but remains enigmatic due to no distinct understanding of its mechanism of action. The present study aimed to investigate the role of caspase independent pathway in piracetam mediated neuroprotection. LPS administration caused significant alterations in oxidative stress related parameters like glutathione, glutathione reductase and increased lipid peroxidation. LPS administration also caused augmented expression of inflammatory cytokines and astrocytes activation. Piracetam treatment offered significant protection against LPS induced oxidative and inflammatory parameters and inhibited astrocytes activation. LPS administration caused augmented level of reactive oxygen species and depleted mitochondrial membrane potential which were attenuated with piracetam treatment. This study for the first time demonstrates the role of caspase independent death factors in piracetam induced neuroprotective effects in rat brain. Translocation of mitochondrial resident apoptosis inducing factor and endonuclease G to nucleus through cytosol after LPS administration was significantly blocked with piracetam treatment. Further, LPS induced DNA fragmentation along with up regulated Poly [ADP-ribose] polymerase 1 (PARP1) levels were also inhibited with piracetam treatment. Apoptotic death was confirmed by the cleavage of caspase 3 as well as histological alteration in rat brain regions. LPS administration caused significantly increased level of cleaved caspase 3, altered neuronal morphology and decreased neuronal density which were restored with piracetam treatment. Collectively our findings indicate that piracetam offered protection against LPS induced inflammatory responses and cellular death including its antioxidative antiapoptotic activity with its attenuation against mitochondria mediated caspase independent pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

Variable mechanical ventilation.

Science.gov (United States)

Fontela, Paula Caitano; Prestes, Renata Bernardy; Forgiarini, Luiz Alberto; Friedman, Gilberto

2017-01-01

To review the literature on the use of variable mechanical ventilation and the main outcomes of this technique. Search, selection, and analysis of all original articles on variable ventilation, without restriction on the period of publication and language, available in the electronic databases LILACS, MEDLINE®, and PubMed, by searching the terms "variable ventilation" OR "noisy ventilation" OR "biologically variable ventilation". A total of 36 studies were selected. Of these, 24 were original studies, including 21 experimental studies and three clinical studies. Several experimental studies reported the beneficial effects of distinct variable ventilation strategies on lung function using different models of lung injury and healthy lungs. Variable ventilation seems to be a viable strategy for improving gas exchange and respiratory mechanics and preventing lung injury associated with mechanical ventilation. However, further clinical studies are necessary to assess the potential of variable ventilation strategies for the clinical improvement of patients undergoing mechanical ventilation.

Distinct Contributions of Autophagy Receptors in Measles Virus Replication.

Science.gov (United States)

Petkova, Denitsa S; Verlhac, Pauline; Rozières, Aurore; Baguet, Joël; Claviere, Mathieu; Kretz-Remy, Carole; Mahieux, Renaud; Viret, Christophe; Faure, Mathias

2017-05-22

Autophagy is a potent cell autonomous defense mechanism that engages the lysosomal pathway to fight intracellular pathogens. Several autophagy receptors can recognize invading pathogens in order to target them towards autophagy for their degradation after the fusion of pathogen-containing autophagosomes with lysosomes. However, numerous intracellular pathogens can avoid or exploit autophagy, among which is measles virus (MeV). This virus induces a complete autophagy flux, which is required to improve viral replication. We therefore asked how measles virus interferes with autophagy receptors during the course of infection. We report that in addition to NDP52/CALCOCO₂ and OPTINEURIN/OPTN, another autophagy receptor, namely T6BP/TAXIBP1, also regulates the maturation of autophagosomes by promoting their fusion with lysosomes, independently of any infection. Surprisingly, only two of these receptors, NDP52 and T6BP, impacted measles virus replication, although independently, and possibly through physical interaction with MeV proteins. Thus, our results suggest that a restricted set of autophagosomes is selectively exploited by measles virus to replicate in the course of infection.

Tagging like Humans: Diverse and Distinct Image Annotation

KAUST Repository

Wu, Baoyuan

2018-03-31

In this work we propose a new automatic image annotation model, dubbed {\\\\bf diverse and distinct image annotation} (D2IA). The generative model D2IA is inspired by the ensemble of human annotations, which create semantically relevant, yet distinct and diverse tags. In D2IA, we generate a relevant and distinct tag subset, in which the tags are relevant to the image contents and semantically distinct to each other, using sequential sampling from a determinantal point process (DPP) model. Multiple such tag subsets that cover diverse semantic aspects or diverse semantic levels of the image contents are generated by randomly perturbing the DPP sampling process. We leverage a generative adversarial network (GAN) model to train D2IA. Extensive experiments including quantitative and qualitative comparisons, as well as human subject studies, on two benchmark datasets demonstrate that the proposed model can produce more diverse and distinct tags than the state-of-the-arts.

Creating fair lineups for suspects with distinctive features

OpenAIRE

Zarkadi, Theodora; Wade, Kimberley A.; Stewart, Neil

2009-01-01

In their descriptions, eyewitnesses often refer to a culprit's distinctive facial features. However, in a police lineup, selecting the only member with the described distinctive feature is unfair to the suspect and provides the police with little further information. For fair and informative lineups, the distinctive feature should be either replicated across foils or concealed on the target. In the present experiments, replication produced more correct identifications in target-present lineup...

The evolution of compositionally and functionally distinct actin filaments.

Science.gov (United States)

Gunning, Peter W; Ghoshdastider, Umesh; Whitaker, Shane; Popp, David; Robinson, Robert C

2015-06-01

The actin filament is astonishingly well conserved across a diverse set of eukaryotic species. It has essentially remained unchanged in the billion years that separate yeast, Arabidopsis and man. In contrast, bacterial actin-like proteins have diverged to the extreme, and many of them are not readily identified from sequence-based homology searches. Here, we present phylogenetic analyses that point to an evolutionary drive to diversify actin filament composition across kingdoms. Bacteria use a one-filament-one-function system to create distinct filament systems within a single cell. In contrast, eukaryotic actin is a universal force provider in a wide range of processes. In plants, there has been an expansion of the number of closely related actin genes, whereas in fungi and metazoa diversification in tropomyosins has increased the compositional variety in actin filament systems. Both mechanisms dictate the subset of actin-binding proteins that interact with each filament type, leading to specialization in function. In this Hypothesis, we thus propose that different mechanisms were selected in bacteria, plants and metazoa, which achieved actin filament compositional variation leading to the expansion of their functional diversity. © 2015. Published by The Company of Biologists Ltd.

The effects of a driving mechanism on Oslo models

International Nuclear Information System (INIS)

Pan, Gui-Jun; Pan, Yong-Cai

2010-01-01

Isotropic and anisotropic Oslo models (IOM and AOM) under a bulk driving mechanism have been investigated. We apply the moment analysis to evaluate critical exponents and the finite size scaling method to consistently test the obtained results. We find that both types of Oslo model have different critical behaviour. However, the critical exponents are the same for deterministic and random IOMs, and are independent of the strength of the anisotropy for the AOM. In contrast to a boundary driving mechanism, we find that the critical exponents depend crucially on the driving mechanism for the IOM, and are independent of the driving mechanism for the AOM.

Distinct molecular subtypes of uterine leiomyosarcoma respond differently to chemotherapy treatment.

Science.gov (United States)

An, Yang; Wang, Shuzhen; Li, Songlin; Zhang, Lulu; Wang, Dayong; Wang, Haojie; Zhu, Shibai; Zhu, Wan; Li, Yongqiang; Chen, Wenwu; Ji, Shaoping; Guo, Xiangqian

2017-09-11

Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood. Expression profiling data were used to determine the possibility and optimal number of ULMS molecular subtypes. Next, clinicopathological characters and molecular pathways were analyzed in each subtype to prospect the clinical applications and progression mechanisms of ULMS. Two distinct molecular subtypes of ULMS were defined based on different gene expression signatures. Subtype I ULMS recapitulated low-grade ULMS, the gene expression pattern of which resembled normal smooth muscle cells, characterized by overexpression of smooth muscle function genes such as LMOD1, SLMAP, MYLK, MYH11. In contrast, subtype II ULMS recapitulated high-grade ULMS with higher tumor weight and invasion rate, and was characterized by overexpression of genes involved in the pathway of epithelial to mesenchymal transition and tumorigenesis, such as CDK6, MAPK13 and HOXA1. We identified two distinct molecular subtypes of ULMS responding differently to chemotherapy treatment. Our findings provide a better understanding of ULMS intrinsic molecular subtypes, and will potentially facilitate the development of subtype-specific diagnosis biomarkers and therapy strategies for these tumors.

Novel Sensor Technology To Assess Independence and Limb-Use Laterality in Cervical Spinal Cord Injury.

Science.gov (United States)

Brogioli, Michael; Popp, Werner L; Albisser, Urs; Brust, Anne K; Frotzler, Angela; Gassert, Roger; Curt, Armin; Starkey, Michelle L

2016-11-01

After spinal cord injury (SCI), levels of independence are commonly assessed with standardized clinical assessments. However, such tests do not provide information about the actual extent of upper limb activities or the impact on independence of bi- versus unilateral usage throughout daily life following cervical SCI. The objective of this study was to correlate activity intensity and laterality of upper extremity activity measured by body-fixed inertial measurement units (IMUs) with clinical assessment scores of independence. Limb-use intensity and laterality of activities performed by the upper extremities was measured in 12 subjects with cervical SCI using four IMUs (positioned on both wrists, on the chest, and on one wheel of the wheelchair). Algorithms capable of reliably detecting self-propulsion and arm activity in a clinical environment were applied to rate functional outcome levels, and were related to clinical independence measures during inpatient rehabilitation. Measures of intensity of upper extremity activity during self-propulsion positively correlated (p laterality were positively correlated (p laterality as measured by IMUs during "daily life," and increased laterality was negatively correlated (p laterality in human cervical SCI. Continuous and objective movement data of distinct daily activities (i.e., mobility and day-to-day activities) can be related to levels of independence. Therefore, IMU sensor technology is suitable not only for monitoring activity levels during rehabilitation (including during clinical trials) but could also be used to assess levels of participation after discharge.

Excellent polarization-independent reflector based on guided mode resonance effect

International Nuclear Information System (INIS)

Xu Cheng; Xu Lin-Min; Qiang Ying-Huai; Zhu Ya-Bo; Liu Jiong-Tian; Ma Jian-Yong

2011-01-01

A broad band polarization-independent reflector working in the telecommunication C+L band is proposed using the guided mode resonance effect of a periodic surface relief element deposited by a layer of silicon medium. It is shown that this structure can provide high reflection (R > 99.5%) and wide angular bandwidth (θ ≈ 20°, R > 98%) for both TE and TM polarizations over a wide spectrum band 1.5 μm∼1.6 μm. Furthermore, it is found by rigorous coupled wave analysis that the polarization-independent reflector proposed here is tolerant of a deviation of grating thickness, which makes it very easy to fabricate in experiments. (electromagnetism, optics, acoustics, heat transfer, classical mechanics, and fluid dynamics)

Proteomic Characterization of Armillaria mellea Reveals Oxidative Stress Response Mechanisms and Altered Secondary Metabolism Profiles

Directory of Open Access Journals (Sweden)

Cassandra Collins

2017-09-01

Full Text Available Armillaria mellea is a major plant pathogen. Yet, the strategies the organism uses to infect susceptible species, degrade lignocellulose and other plant material and protect itself against plant defences and its own glycodegradative arsenal are largely unknown. Here, we use a combination of gel and MS-based proteomics to profile A. mellea under conditions of oxidative stress and changes in growth matrix. 2-DE and LC-MS/MS were used to investigate the response of A. mellea to H2O2 and menadione/FeCl3 exposure, respectively. Several proteins were detected with altered abundance in response to H2O2, but not menadione/FeCl3 (i.e., valosin-containing protein, indicating distinct responses to these different forms of oxidative stress. One protein, cobalamin-independent methionine synthase, demonstrated a common response in both conditions, which may be a marker for a more general stress response mechanism. Further changes to the A. mellea proteome were investigated using MS-based proteomics, which identified changes to putative secondary metabolism (SM enzymes upon growth in agar compared to liquid cultures. Metabolomic analyses revealed distinct profiles, highlighting the effect of growth matrix on SM production. This establishes robust methods by which to utilize comparative proteomics to characterize this important phytopathogen.

Toxin-independent virulence of Bacillus anthracis in rabbits.

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Haim Levy

Full Text Available The accepted paradigm states that anthrax is both an invasive and toxinogenic disease and that the toxins play a major role in pathogenicity. In the guinea pig (GP model we have previously shown that deletion of all three toxin components results in a relatively moderate attenuation in virulence, indicating that B. anthracis possesses an additional toxin-independent virulence mechanism. To characterize this toxin-independent mechanism in anthrax disease, we developed a new rabbit model by intravenous injection (IV of B. anthracis encapsulated vegetative cells, artificially creating bacteremia. Using this model we were able to demonstrate that also in rabbits, B. anthracis mutants lacking the toxins are capable of killing the host within 24 hours. This virulent trait depends on the activity of AtxA in the presence of pXO2, as, in the absence of the toxin genes, deletion of either component abolishes virulence. Furthermore, this IV virulence depends mainly on AtxA rather than the whole pXO1. A similar pattern was shown in the GP model using subcutaneous (SC administration of spores of the mutant strains, demonstrating the generality of the phenomenon. The virulent strains showed higher bacteremia levels and more efficient tissue dissemination; however our interpretation is that tissue dissemination per se is not the main determinant of virulence whose exact nature requires further elucidation.

Qualitative insights on fundamental mechanics

OpenAIRE

Mardari, G. N.

2002-01-01

The gap between classical mechanics and quantum mechanics has an important interpretive implication: the Universe must have an irreducible fundamental level, which determines the properties of matter at higher levels of organization. We show that the main parameters of any fundamental model must be theory-independent. They cannot be predicted, because they cannot have internal causes. However, it is possible to describe them in the language of classical mechanics. We invoke philosophical reas...

Reperfusion of specific cortical areas is associated with improvement in distinct forms of hemispatial neglect.

Science.gov (United States)

Khurshid, Shaan; Trupe, Lydia A; Newhart, Melissa; Davis, Cameron; Molitoris, John J; Medina, Jared; Leigh, Richard; Hillis, Argye E

2012-05-01

To test the hypothesis that restoring blood flow to specific right cortical regions in acute stroke results in improvement in distinct forms of hemispatial neglect distinguished by reference frame: viewer-centered versus stimulus-centered neglect. Twenty five patients with acute right stroke were evaluated at Day 1 and Day 3-5 with a battery of neglect tests and Diffusion- and Perfusion-Weighted MR Imaging. Multivariate linear regression analysis revealed Brodmann areas (BAs) where reperfusion predicted degree of improvement in scores on each type of neglect, independently of reperfusion of other areas, total change in the volume of infarct or hypoperfusion, and age. Reperfusion of dorsal frontoparietal cortex (including BAs 40, 46, and 4) independently predicted improvement in viewer-centered neglect, such as detecting stimuli on left in line cancellation and scene copying (r=.951; p<.0001). Reperfusion of a more ventral temporo-occipital cortex, including right BAs 37, 38, 21 and 18, independently contributed to improvement in stimulus-centered neglect, such as detecting left gaps in circles (r=.926; p<.0001). Reperfusion of right midfusiform gyrus (temporal occipital cortex), change in total volume of ischemia, change in volume of hypoperfusion and age predicted degree of improvement in reading (reduction in "neglect dyslexic" errors; r=.915; p<.0001). Results demonstrate that reperfusing specific cortical regions yields improvement in different types of neglect. Copyright © 2011 Elsevier Srl. All rights reserved.

Distinct moieties underlie biphasic H+ gating of connexin43 channels, producing a pH optimum for intercellular communication

Science.gov (United States)

Garciarena, Carolina D.; Malik, Akif; Swietach, Pawel; Moreno, Alonso P.; Vaughan-Jones, Richard D.

2018-01-01

Most mammalian cells can intercommunicate via connexin-assembled, gap-junctional channels. To regulate signal transmission, connexin (Cx) channel permeability must respond dynamically to physiological and pathophysiological stimuli. One key stimulus is intracellular pH (pHi), which is modulated by a tissue’s metabolic and perfusion status. Our understanding of the molecular mechanism of H+ gating of Cx43 channels—the major isoform in the heart and brain—is incomplete. To interrogate the effects of acidic and alkaline pHi on Cx43 channels, we combined voltage-clamp electrophysiology with pHi imaging and photolytic H+ uncaging, performed over a range of pHi values. We demonstrate that Cx43 channels expressed in HeLa or N2a cell pairs are gated biphasically by pHi via a process that consists of activation by H+ ions at alkaline pHi and inhibition at more acidic pHi. For Cx43 channel–mediated solute/ion transmission, the ensemble of these effects produces a pHi optimum, near resting pHi. By using Cx43 mutants, we demonstrate that alkaline gating involves cysteine residues of the C terminus and is independent of motifs previously implicated in acidic gating. Thus, we present a molecular mechanism by which cytoplasmic acid–base chemistry fine tunes intercellular communication and establishes conditions for the optimal transmission of solutes and signals in tissues, such as the heart and brain.—Garciarena, C. D., Malik, A., Swietach, P., Moreno, A. P., Vaughan-Jones, R. D. Distinct moieties underlie biphasic H+ gating of connexin43 channels, producing a pH optimum for intercellular communication. PMID:29183963

Reassessing Judicial Independence and Impartiality against the Backdrop of Judicial Appointments in South Africa

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Koos Malan

2014-12-01

Full Text Available The South African Judicial Service Commission (JSC, considered to be exemplary for its independence, plays a pivotal part in judicial appointments. Yet the Commission has long been marred by tensions that have lately erupted into a full-blown conflict between those who could here be referred to as the transformationists, on the one hand, and the liberals, on the other. The transformationists, who may generally be regarded as falling within the sphere of influence of the ruling elite under the African National Congress (ANC, are bent on pursuing the policy of transformation. Hence they insist that the composition of the bench must reflect the national population profile and on individual judges' pursuing the ruling party's ideological goals. The liberals reject this as a threat to judicial independence and the professional competence of the judiciary. On close analysis the clash is based on incompatible interpretations of judicial independence and impartiality. This article is a critique of these interpretations against the backdrop of an assessment of what these notions can reasonably be expected to achieve. It is argued that the liberals are harbouring unrealistic views about judiciaries, believing them to wield power which may even extend over matters of political significance, powers on a par with or even outweighing those of the political branches. However, on proper analysis it is clear that the judiciary is in fact, firstly, inherently weak and dependent on the support of the political branches; and, secondly, it is integrated into the ruling elite with whom they share the same ideological assumptions without any inclination to oppose them. Hence, the impartiality of the courts, when it comes to politically sensitive issues, is distinctively politically (regime relative and ideologically conditioned. Ironically the transformationists have bought into the liberals' erroneous belief in the potency of the courts (in the above-mentioned sense

Distinct pigmentary and melanocortin 1 receptor-dependent components of cutaneous defense against ultraviolet radiation.

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Craig S April

2007-01-01

Full Text Available Genetic variation at the melanocortin 1 receptor (MC1R is an important risk factor for developing ultraviolet (UV radiation-induced skin cancer, the most common form of cancer in humans. The underlying mechanisms by which the MC1R defends against UV-induced skin cancer are not known. We used neonatal mouse skin (which, like human skin, contains a mixture of melanocytes and keratinocytes to study how pigment cells and Mc1r genotype affect the genome-level response to UV radiation. Animals without viable melanocytes (Kit(W-v/Kit(W-v or animals lacking a functional Mc1r (Mc1r(e/Mc1r(e were exposed to sunburn-level doses of UVB radiation, and the patterns of large-scale gene expression in the basal epidermis were compared to each other and to nonmutant animals. Our analysis revealed discrete Kit- and Mc1r-dependent UVB transcriptional responses in the basal epidermis. The Kit-dependent UVB response was characterized largely by an enrichment of oxidative and endoplasmic reticulum stress genes, highlighting a distinctive role for pigmented melanocytes in mediating antioxidant defenses against genotoxic stresses within the basal epidermal environment. By contrast, the Mc1r-dependent UVB response contained an abundance of genes associated with regulating the cell cycle and oncogenesis. To test the clinical relevance of these observations, we analyzed publicly available data sets for primary melanoma and melanoma metastases and found that the set of genes specific for the Mc1r-dependent UVB response was able to differentiate between different clinical subtypes. Our analysis also revealed that the classes of genes induced by UVB differ from those repressed by UVB with regard to their biological functions, their overall number, and their size. The findings described here offer new insights into the transcriptional nature of the UV response in the skin and provide a molecular framework for the underlying mechanisms by which melanocytes and the Mc1r

Defining poverty as distinctively human

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H.P.P. Lötter

2007-05-01

Full Text Available While it is relatively easy for most people to identify human beings suffering from poverty, it is rather more difficult to come to a proper understanding of poverty. In this article the author wants to deepen our understanding of poverty by interpreting the conventional definitions of poverty in a new light. The article starts with a defence of a claim that poverty is a concept uniquely applicable to humans. It then present a critical discussion of the distinction between absolute and relative poverty and it is then argued that a revision of this distinction can provide general standards applicable to humans everywhere.

Variable-temperature independently driven four-tip scanning tunneling microscope

International Nuclear Information System (INIS)

Hobara, Rei; Nagamura, Naoka; Hasegawa, Shuji; Matsuda, Iwao; Yamamoto, Yuko; Miyatake, Yutaka; Nagamura, Toshihiko

2007-01-01

The authors have developed an ultrahigh vacuum (UHV) variable-temperature four-tip scanning tunneling microscope (STM), operating from room temperature down to 7 K, combined with a scanning electron microscope (SEM). Four STM tips are mechanically and electrically independent and capable of positioning in arbitrary configurations in nanometer precision. An integrated controller system for both of the multitip STM and SEM with a single computer has also been developed, which enables the four tips to operate either for STM imaging independently and for four-point probe (4PP) conductivity measurements cooperatively. Atomic-resolution STM images of graphite were obtained simultaneously by the four tips. Conductivity measurements by 4PP method were also performed at various temperatures with the four tips in square arrangement with direct contact to the sample surface

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.

Science.gov (United States)

Levy, Bruce D; Lukacs, Nicholas W; Berlin, Aaron A; Schmidt, Birgitta; Guilford, William J; Serhan, Charles N; Parkinson, John F

2007-12-01

Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A4 (LXA4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA4 analog (ATLa) and a 3-oxa-15-epi-LXA4 analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At 50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA4 analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs' therapeutic potential as new agonists for the resolution of inflammation.

Electrogenic Na+-independent Pi transport in canine renal basolateral membrane vesicles

International Nuclear Information System (INIS)

Schwab, S.J.; Hammerman, M.R.

1986-01-01

To define the mechanism by which Pi exists from the renal proximal tubular cell across the basolateral membrane, we measured 32Pi uptake in basolateral membrane vesicles from dog kidney in the absence of Na+. Preloading of basolateral vesicles with 2 mM Pi transstimulated 32Pi uptake, which is consistent with counterflow. We used measurements of transstimulation to quantitate the transport component of 32Pi uptake. Transstimulation of 32Pi uptake was inhibited less than 30% by concentrations of probenecid as high as 50 mM. In contrast, transstimulation of 35SO4(2-) uptake by intravesicular SO4(2-) was inhibited 92% by 5 mM probenecid. Preloading basolateral vesicles with SO4(2-) did not result in transstimulation of 32Pi uptake. Accumulation of 32Pi in basolateral vesicles above steady state was driven by a membrane potential (intravesicular positive), consistent with Na+-independent Pi transport being accompanied by the net transfer of negative charge across the membrane. We conclude that carrier-mediated, electrogenic Na+-independent 32Pi transport can be demonstrated in basolateral vesicles from dog kidney. This process appears to be mediated, at least in part, via a mechanism different from that by which SO4(2-) is transported. Electrogenic Na+-independent Pi transport may reflect one means by which Pi reabsorbed across the luminal membrane exists from the proximal tubular cell down an electrochemical gradient

On the k-independence required by linear probing and minwise independence

DEFF Research Database (Denmark)

Pǎtraşcu, Mihai; Thorup, Mikkel

2016-01-01

We show that linear probing requires 5-independent hash functions for expected constant-time performance, matching an upper bound of Pagh et al. [2009]. More precisely, we construct a random 4-independent hash function yielding expected logarithmic search time for certain keys. For (1 + ε......)-approximate minwise independence, we show that Ω(lg1 ε)-independent hash functions are required, matching an upper bound of Indyk [2001]. We also show that the very fast 2-independent multiply-shift scheme of Dietzfelbinger [1996] fails badly in both applications....

Tumor Necrosis Factor α Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl–Rank Interaction

Science.gov (United States)

Kobayashi, Kanichiro; Takahashi, Naoyuki; Jimi, Eijiro; Udagawa, Nobuyuki; Takami, Masamichi; Kotake, Shigeru; Nakagawa, Nobuaki; Kinosaki, Masahiko; Yamaguchi, Kyoji; Shima, Nobuyuki; Yasuda, Hisataka; Morinaga, Tomonori; Higashio, Kanji; Martin, T. John; Suda, Tatsuo

2000-01-01

Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of osteoclast progenitors of the monocyte/macrophage lineage into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase–positive osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor α (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases. PMID:10637272

Independent Reporting Mechanism (IRM)

DEFF Research Database (Denmark)

Eberholst, Mads Kæmsgaard

2017-01-01

To raise the impact of OGP in Denmark, the government can broaden the inclusivity of the OGP process and deepen in-person engagement with a more diverse group of stakeholders. Future action plans may include commitments regarding political party fnancing, lobbying regulations and access to inform...

Independently evolved upper jaw protrusion mechanisms show convergent hydrodynamic function in teleost fishes.

Science.gov (United States)

Staab, Katie Lynn; Holzman, Roi; Hernandez, L Patricia; Wainwright, Peter C

2012-05-01

A protrusible upper jaw has independently evolved multiple times within teleosts and has been implicated in the success of two groups in particular: Acanthomorpha and Cypriniformes. We use digital particle image velocimetry (DPIV) to compare suction feeding flow dynamics in a representative of each of these clades: goldfish and bluegill. Using DPIV, we contrast the spatial pattern of flow, the temporal relationship between flow and head kinematics, and the contribution of jaw protrusion to the forces exerted on prey. As expected, the spatial patterns of flow were similar in the two species. However, goldfish were slower to reach maximal kinematic excursions, and were more flexible in the relative timing of jaw protrusion, other jaw movements and suction flows. Goldfish were also able to sustain flow speeds for a prolonged period of time as compared with bluegill, in part because goldfish generate lower peak flow speeds. In both species, jaw protrusion increased the force exerted on the prey. However, slower jaw protrusion in goldfish resulted in less augmentation of suction forces. This difference in force exerted on prey corresponds with differences in trophic niches and feeding behavior of the two species. The bluegill uses powerful suction to capture insect larvae whereas the goldfish uses winnowing to sort through detritus and sediment. The kinethmoid of goldfish may permit jaw protrusion that is independent of lower jaw movement, which could explain the ability of goldfish to decouple suction flows (due to buccal expansion) from upper jaw protrusion. Nevertheless, our results show that jaw protrusion allows both species to augment the force exerted on prey, suggesting that this is a fundamental benefit of jaw protrusion to suction feeders.

Mechanisms of spectral and temporal integration in the mustached bat inferior colliculus

Science.gov (United States)

Wenstrup, Jeffrey James; Nataraj, Kiran; Sanchez, Jason Tait

2012-01-01

This review describes mechanisms and circuitry underlying combination-sensitive response properties in the auditory brainstem and midbrain. Combination-sensitive neurons, performing a type of auditory spectro-temporal integration, respond to specific, properly timed combinations of spectral elements in vocal signals and other acoustic stimuli. While these neurons are known to occur in the auditory forebrain of many vertebrate species, the work described here establishes their origin in the auditory brainstem and midbrain. Focusing on the mustached bat, we review several major findings: (1) Combination-sensitive responses involve facilitatory interactions, inhibitory interactions, or both when activated by distinct spectral elements in complex sounds. (2) Combination-sensitive responses are created in distinct stages: inhibition arises mainly in lateral lemniscal nuclei of the auditory brainstem, while facilitation arises in the inferior colliculus (IC) of the midbrain. (3) Spectral integration underlying combination-sensitive responses requires a low-frequency input tuned well below a neuron's characteristic frequency (ChF). Low-ChF neurons in the auditory brainstem project to high-ChF regions in brainstem or IC to create combination sensitivity. (4) At their sites of origin, both facilitatory and inhibitory combination-sensitive interactions depend on glycinergic inputs and are eliminated by glycine receptor blockade. Surprisingly, facilitatory interactions in IC depend almost exclusively on glycinergic inputs and are largely independent of glutamatergic and GABAergic inputs. (5) The medial nucleus of the trapezoid body (MNTB), the lateral lemniscal nuclei, and the IC play critical roles in creating combination-sensitive responses. We propose that these mechanisms, based on work in the mustached bat, apply to a broad range of mammals and other vertebrates that depend on temporally sensitive integration of information across the audible spectrum. PMID:23109917

Reaction mechanism in high energy heavy-ion collisions

International Nuclear Information System (INIS)

Tanihata, Isao.

1982-04-01

The reaction mechanism in high energy heavy-ion collision is discussed. The discussion is mainly based on the experimental data. Empirical equations have been given for the total cross-sections of nucleus-nucleus reactions and the reaction cross-sections. These cross-sections are well described by the geometrical size of the colliding nuclei. The cross-sections are also understood by microscopic calculation. The charged particle multiplicity gives additional information about the geometrical aspect of heavy ion collision. The data suggested that the total energy, independent of projectile size, is most important for determining the multiplicity. The inclusive proton spectrum in a heavy ion collision showed two distinct regions. The one is the fragment region, and the other the participant region. The spectral shapes of inclusive pion spectra are reasonably well explained by the Coulomb interaction of pions with nuclear fragments. The high energy heavy ion reaction occurs in the overlap region of the projectile and target. This has been tested by measuring the number of participants for various reactions. The space and the time structure of the collision are also discussed in this paper as well as the dynamical aspects of the collision. (Kato, T.)

Mechanisms of social buffering of fear in zebrafish.

Science.gov (United States)

Faustino, Ana I; Tacão-Monteiro, André; Oliveira, Rui F

2017-03-31

Some humans thrive whereas others resign when exposed to threatening situations throughout life. Social support has been identified as an important modulator of these discrepancies in human behaviour, and other social animals also exhibit phenomena in which individuals recover better from aversive events when conspecifics are present - aka social buffering. Here we studied social buffering in zebrafish, by exposing focal fish to an aversive stimulus (alarm substance - AS) either in the absence or presence of conspecific cues. When exposed to AS in the presence of both olfactory (shoal water) and visual (sight of shoal) conspecific cues, focal fish exhibited a lower fear response than when tested alone, demonstrating social buffering in zebrafish. When separately testing each cue's effectiveness, we verified that the visual cue was more effective than the olfactory in reducing freezing in a persistent threat scenario. Finally, we verified that social buffering was independent of shoal size and coincided with a distinct pattern of co-activation of brain regions known to be involved in mammalian social buffering. Thus, this study suggests a shared evolutionary origin for social buffering in vertebrates, bringing new evidence on the behavioural, sensory and neural mechanisms underlying this phenomenon.

Assessment of Cultivar Distinctness in Alfalfa: A Comparison of Genotyping-by-Sequencing, Simple-Sequence Repeat Marker, and Morphophysiological Observations

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Paolo Annicchiarico

2016-07-01

Full Text Available Cultivar registration agencies typically require morphophysiological trait-based distinctness of candidate cultivars. This requirement is difficult to achieve for cultivars of major perennial forages because of their genetic structure and ever-increasing number of registered material, leading to possible rejection of agronomically valuable cultivars. This study aimed to explore the value of molecular markers applied to replicated bulked plants (three bulks of 100 independent plants each per cultivar to assess alfalfa ( L. subsp. cultivar distinctness. We compared genotyping-by-sequencing information based on 2902 polymorphic single-nucleotide polymorphism (SNP markers (>30 reads per DNA sample with morphophysiological information based on 11 traits and with simple-sequence repeat (SSR marker information from 41 polymorphic markers for their ability to distinguish 11 alfalfa landraces representative of the germplasm from northern Italy. Three molecular criteria, one based on cultivar differences for individual SSR bands and two based on overall SNP marker variation assessed either by statistically significant cultivar differences on principal component axes or discriminant analysis, distinctly outperformed the morphophysiological criterion. Combining the morphophysiological criterion with either molecular marker method increased discrimination among cultivars, since morphophysiological diversity was unrelated to SSR marker-based diversity ( = 0.04 and poorly related to SNP marker-based diversity ( = 0.23, < 0.15. The criterion based on statistically significant SNP allele frequency differences was less discriminating than morphophysiological variation. Marker-based distinctness, which can be assessed at low cost and without interactions with testing conditions, could validly substitute for (or complement morphophysiological distinctness in alfalfa cultivar registration schemes. It also has interest in sui generis registration systems aimed at

Azospirillum brasilense Chemotaxis Depends on Two Signaling Pathways Regulating Distinct Motility Parameters.

Science.gov (United States)

Mukherjee, Tanmoy; Kumar, Dhivya; Burriss, Nathan; Xie, Zhihong; Alexandre, Gladys

2016-06-15

The genomes of most motile bacteria encode two or more chemotaxis (Che) systems, but their functions have been characterized in only a few model systems. Azospirillum brasilense is a motile soil alphaproteobacterium able to colonize the rhizosphere of cereals. In response to an attractant, motile A. brasilense cells transiently increase swimming speed and suppress reversals. The Che1 chemotaxis pathway was previously shown to regulate changes in the swimming speed, but it has a minor role in chemotaxis and root surface colonization. Here, we show that a second chemotaxis system, named Che4, regulates the probability of swimming reversals and is the major signaling pathway for chemotaxis and wheat root surface colonization. Experimental evidence indicates that Che1 and Che4 are functionally linked to coordinate changes in the swimming motility pattern in response to attractants. The effect of Che1 on swimming speed is shown to enhance the aerotactic response of A. brasilense in gradients, likely providing the cells with a competitive advantage in the rhizosphere. Together, the results illustrate a novel mechanism by which motile bacteria utilize two chemotaxis pathways regulating distinct motility parameters to alter movement in gradients and enhance the chemotactic advantage. Chemotaxis provides motile bacteria with a competitive advantage in the colonization of diverse niches and is a function enriched in rhizosphere bacterial communities, with most species possessing at least two chemotaxis systems. Here, we identify the mechanism by which cells may derive a significant chemotactic advantage using two chemotaxis pathways that ultimately regulate distinct motility parameters. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Which activities threaten independent living of elderly when becoming problematic: inspiration for meaningful service robot functionality.

Science.gov (United States)

Bedaf, Sandra; Gelderblom, Gert Jan; Syrdal, Dag Sverre; Lehmann, Hagen; Michel, Hervé; Hewson, David; Amirabdollahian, Farshid; Dautenhahn, Kerstin; de Witte, Luc

2014-11-01

In light of the increasing elderly population and the growing demand for home care, the potential of robot support is given increasing attention. In this paper, an inventory of activities was made that threaten independent living of elderly when becoming problematic. Results will guide the further development of an existing service robot, the Care-O-bot®. A systematic literature search of PubMed was performed, focused on the risk factors for institutionalization. Additionally, focus group sessions were conducted in the Netherlands, United Kingdom and France. In these focus group sessions, problematic activities threatening the independence of elderly people were discussed. Three separate target groups were included in the focus group sessions: (1) elderly persons (n = 41), (2) formal caregivers (n = 40) and (3) informal caregivers (n = 32). Activities within the International Classification of Functioning domains mobility, self-care, and interpersonal interaction and relationships were found to be the most problematic. A distinct set of daily activities was identified that may threaten independent living, but no single activity could be selected as the main activity causing a loss of independence as it is often a combination of problematic activities that is person-specific. Supporting the problematic activities need not involve a robotic solution.

Parkin suppresses Drp1-independent mitochondrial division

Energy Technology Data Exchange (ETDEWEB)

Roy, Madhuparna, E-mail: mroy17@jhmi.edu; Itoh, Kie, E-mail: kito5@jhmi.edu; Iijima, Miho, E-mail: miijima@jhmi.edu; Sesaki, Hiromi, E-mail: hsesaki@jhmi.edu

2016-07-01

The cycle of mitochondrial division and fusion disconnect and reconnect individual mitochondria in cells to remodel this energy-producing organelle. Although dynamin-related protein 1 (Drp1) plays a major role in mitochondrial division in cells, a reduced level of mitochondrial division still persists even in the absence of Drp1. It is unknown how much Drp1-mediated mitochondrial division accounts for the connectivity of mitochondria. The role of a Parkinson’s disease-associated protein—parkin, which biochemically and genetically interacts with Drp1—in mitochondrial connectivity also remains poorly understood. Here, we quantified the number and connectivity of mitochondria using mitochondria-targeted photoactivatable GFP in cells. We show that the loss of Drp1 increases the connectivity of mitochondria by 15-fold in mouse embryonic fibroblasts (MEFs). While a single loss of parkin does not affect the connectivity of mitochondria, the connectivity of mitochondria significantly decreased compared with a single loss of Drp1 when parkin was lost in the absence of Drp1. Furthermore, the loss of parkin decreased the frequency of depolarization of the mitochondrial inner membrane that is caused by increased mitochondrial connectivity in Drp1-knockout MEFs. Therefore, our data suggest that parkin negatively regulates Drp1-indendent mitochondrial division. -- Highlights: •A Drp1-mediated mechanism accounts for ∼95% of mitochondrial division. •Parkin controls the connectivity of mitochondria via a mechanism that is independent of Drp1. •In the absence of Drp1, connected mitochondria transiently depolarize. •The transient depolarization is independent of calcium signaling and uncoupling protein 2.

Parkin suppresses Drp1-independent mitochondrial division

International Nuclear Information System (INIS)

Roy, Madhuparna; Itoh, Kie; Iijima, Miho; Sesaki, Hiromi

2016-01-01

The cycle of mitochondrial division and fusion disconnect and reconnect individual mitochondria in cells to remodel this energy-producing organelle. Although dynamin-related protein 1 (Drp1) plays a major role in mitochondrial division in cells, a reduced level of mitochondrial division still persists even in the absence of Drp1. It is unknown how much Drp1-mediated mitochondrial division accounts for the connectivity of mitochondria. The role of a Parkinson’s disease-associated protein—parkin, which biochemically and genetically interacts with Drp1—in mitochondrial connectivity also remains poorly understood. Here, we quantified the number and connectivity of mitochondria using mitochondria-targeted photoactivatable GFP in cells. We show that the loss of Drp1 increases the connectivity of mitochondria by 15-fold in mouse embryonic fibroblasts (MEFs). While a single loss of parkin does not affect the connectivity of mitochondria, the connectivity of mitochondria significantly decreased compared with a single loss of Drp1 when parkin was lost in the absence of Drp1. Furthermore, the loss of parkin decreased the frequency of depolarization of the mitochondrial inner membrane that is caused by increased mitochondrial connectivity in Drp1-knockout MEFs. Therefore, our data suggest that parkin negatively regulates Drp1-indendent mitochondrial division. -- Highlights: •A Drp1-mediated mechanism accounts for ∼95% of mitochondrial division. •Parkin controls the connectivity of mitochondria via a mechanism that is independent of Drp1. •In the absence of Drp1, connected mitochondria transiently depolarize. •The transient depolarization is independent of calcium signaling and uncoupling protein 2.

Merging of independent condensates: disentangling the Kibble-Zurek mechanism

Science.gov (United States)

Ville, Jean-Loup; Aidelsburger, Monika; Saint-Jalm, Raphael; Nascimbene, Sylvain; Beugnon, Jerome; Dalibard, Jean

2017-04-01

An important step in the study of out-of-equilibrium physics is the Kibble-Zurek theory which describes a system after a quench through a second-order phase transition. This was studied in our group with a temperature quench across the normal-to-superfluid phase transition in an annular trap geometry, inducing the formation of supercurrents. Their magnitude and direction were detected by measuring spiral patterns resulting from the interference of the ring-shaped condensate with a central reference disk. According to the KZ mechanism domains of phase are created during the quench, with a characteristic size depending of its duration. In our case this results in a stochastic formation of supercurrents depending on the relative phases of the domains. As a next step of this study, we now design ourselves the patches thanks to our tunable trapping potential. We control both the number of condensates to be merged (from one to twelve) and their merging time. We report an increase of the vorticity in the ring for an increased number of patches compatible with a random phase model. We further investigate the time required by the phase to homogenize between two condensates.

Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension.

Science.gov (United States)

El Kasmi, Karim C; Pugliese, Steven C; Riddle, Suzette R; Poth, Jens M; Anderson, Aimee L; Frid, Maria G; Li, Min; Pullamsetti, Soni S; Savai, Rajkumar; Nagel, Maria A; Fini, Mehdi A; Graham, Brian B; Tuder, Rubin M; Friedman, Jacob E; Eltzschig, Holger K; Sokol, Ronald J; Stenmark, Kurt R

2014-07-15

Macrophage accumulation is not only a characteristic hallmark but is also a critical component of pulmonary artery remodeling associated with pulmonary hypertension (PH). However, the cellular and molecular mechanisms that drive vascular macrophage activation and their functional phenotype remain poorly defined. Using multiple levels of in vivo (bovine and rat models of hypoxia-induced PH, together with human tissue samples) and in vitro (primary mouse, rat, and bovine macrophages, human monocytes, and primary human and bovine fibroblasts) approaches, we observed that adventitial fibroblasts derived from hypertensive pulmonary arteries (bovine and human) regulate macrophage activation. These fibroblasts activate macrophages through paracrine IL-6 and STAT3, HIF1, and C/EBPβ signaling to drive expression of genes previously implicated in chronic inflammation, tissue remodeling, and PH. This distinct fibroblast-activated macrophage phenotype was independent of IL-4/IL-13-STAT6 and TLR-MyD88 signaling. We found that genetic STAT3 haplodeficiency in macrophages attenuated macrophage activation, complete STAT3 deficiency increased macrophage activation through compensatory upregulation of STAT1 signaling, and deficiency in C/EBPβ or HIF1 attenuated fibroblast-driven macrophage activation. These findings challenge the current paradigm of IL-4/IL-13-STAT6-mediated alternative macrophage activation as the sole driver of vascular remodeling in PH, and uncover a cross-talk between adventitial fibroblasts and macrophages in which paracrine IL-6-activated STAT3, HIF1α, and C/EBPβ signaling are critical for macrophage activation and polarization. Thus, targeting IL-6 signaling in macrophages by completely inhibiting C/EBPβ or HIF1α or by partially inhibiting STAT3 may hold therapeutic value for treatment of PH and other inflammatory conditions characterized by increased IL-6 and absent IL-4/IL-13 signaling. Copyright © 2014 by The American Association of Immunologists

Peptidomic and transcriptomic profiling of four distinct spider venoms.

Directory of Open Access Journals (Sweden)

Vera Oldrati

Full Text Available Venom based research is exploited to find novel candidates for the development of innovative pharmacological tools, drug candidates and new ingredients for cosmetic and agrochemical industries. Moreover, venomics, as a well-established approach in systems biology, helps to elucidate the genetic mechanisms of the production of such a great molecular biodiversity. Today the advances made in the proteomics, transcriptomics and bioinformatics fields, favor venomics, allowing the in depth study of complex matrices and the elucidation even of minor compounds present in minute biological samples. The present study illustrates a rapid and efficient method developed for the elucidation of venom composition based on NextGen mRNA sequencing of venom glands and LC-MS/MS venom proteome profiling. The analysis of the comprehensive data obtained was focused on cysteine rich peptide toxins from four spider species originating from phylogenetically distant families for comparison purposes. The studied species were Heteropoda davidbowie (Sparassidae, Poecilotheria formosa (Theraphosidae, Viridasius fasciatus (Viridasiidae and Latrodectus mactans (Theridiidae. This led to a high resolution profiling of 284 characterized cysteine rich peptides, 111 of which belong to the Inhibitor Cysteine Knot (ICK structural motif. The analysis of H. davidbowie venom revealed a high richness in term of venom diversity: 95 peptide sequences were identified; out of these, 32 peptides presented the ICK structural motif and could be classified in six distinct families. The profiling of P. formosa venom highlighted the presence of 126 peptide sequences, with 52 ICK toxins belonging to three structural distinct families. V. fasciatus venom was shown to contain 49 peptide sequences, out of which 22 presented the ICK structural motif and were attributed to five families. The venom of L. mactans, until now studied for its large neurotoxins (Latrotoxins, revealed the presence of 14

Learning-performance distinction and memory processes for motor skills: a focused review and perspective.

Science.gov (United States)

Kantak, Shailesh S; Winstein, Carolee J

2012-03-01

Behavioral research in cognitive psychology provides evidence for an important distinction between immediate performance that accompanies practice and long-term performance that reflects the relative permanence in the capability for the practiced skill (i.e. learning). This learning-performance distinction is strikingly evident when challenging practice conditions may impair practice performance, but enhance long-term retention of motor skills. A review of motor learning studies with a specific focus on comparing differences in performance between that at the end of practice and at delayed retention suggests that the delayed retention or transfer performance is a better indicator of motor learning than the performance at (or end of) practice. This provides objective evidence for the learning-performance distinction. This behavioral evidence coupled with an understanding of the motor memory processes of encoding, consolidation and retrieval may provide insight into the putative mechanism that implements the learning-performance distinction. Here, we propose a simplistic empirically-based framework--motor behavior-memory framework--that integrates the temporal evolution of motor memory processes with the time course of practice and delayed retention frequently used in behavioral motor learning paradigms. In the context of the proposed framework, recent research has used noninvasive brain stimulation to decipher the role of each motor memory process, and specific cortical brain regions engaged in motor performance and learning. Such findings provide beginning insights into the relationship between the time course of practice-induced performance changes and motor memory processes. This in turn has promising implications for future research and practical applications. Copyright © 2011 Elsevier B.V. All rights reserved.

Multiple mechanisms for CRISPR-Cas inhibition by anti-CRISPR proteins.

Science.gov (United States)

Bondy-Denomy, Joseph; Garcia, Bianca; Strum, Scott; Du, Mingjian; Rollins, MaryClare F; Hidalgo-Reyes, Yurima; Wiedenheft, Blake; Maxwell, Karen L; Davidson, Alan R

2015-10-01

The battle for survival between bacteria and the viruses that infect them (phages) has led to the evolution of many bacterial defence systems and phage-encoded antagonists of these systems. Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated (cas) genes comprise an adaptive immune system that is one of the most widespread means by which bacteria defend themselves against phages. We identified the first examples of proteins produced by phages that inhibit a CRISPR-Cas system. Here we performed biochemical and in vivo investigations of three of these anti-CRISPR proteins, and show that each inhibits CRISPR-Cas activity through a distinct mechanism. Two block the DNA-binding activity of the CRISPR-Cas complex, yet do this by interacting with different protein subunits, and using steric or non-steric modes of inhibition. The third anti-CRISPR protein operates by binding to the Cas3 helicase-nuclease and preventing its recruitment to the DNA-bound CRISPR-Cas complex. In vivo, this anti-CRISPR can convert the CRISPR-Cas system into a transcriptional repressor, providing the first example-to our knowledge-of modulation of CRISPR-Cas activity by a protein interactor. The diverse sequences and mechanisms of action of these anti-CRISPR proteins imply an independent evolution, and foreshadow the existence of other means by which proteins may alter CRISPR-Cas function.

High-Speed Device-Independent Quantum Random Number Generation without a Detection Loophole

Science.gov (United States)

Liu, Yang; Yuan, Xiao; Li, Ming-Han; Zhang, Weijun; Zhao, Qi; Zhong, Jiaqiang; Cao, Yuan; Li, Yu-Huai; Chen, Luo-Kan; Li, Hao; Peng, Tianyi; Chen, Yu-Ao; Peng, Cheng-Zhi; Shi, Sheng-Cai; Wang, Zhen; You, Lixing; Ma, Xiongfeng; Fan, Jingyun; Zhang, Qiang; Pan, Jian-Wei

2018-01-01

Quantum mechanics provides the means of generating genuine randomness that is impossible with deterministic classical processes. Remarkably, the unpredictability of randomness can be certified in a manner that is independent of implementation devices. Here, we present an experimental study of device-independent quantum random number generation based on a detection-loophole-free Bell test with entangled photons. In the randomness analysis, without the independent identical distribution assumption, we consider the worst case scenario that the adversary launches the most powerful attacks against the quantum adversary. After considering statistical fluctuations and applying an 80 Gb ×45.6 Mb Toeplitz matrix hashing, we achieve a final random bit rate of 114 bits /s , with a failure probability less than 10-5. This marks a critical step towards realistic applications in cryptography and fundamental physics tests.

Medically important differences in snake venom composition are dictated by distinct postgenomic mechanisms.

Science.gov (United States)

Casewell, Nicholas R; Wagstaff, Simon C; Wüster, Wolfgang; Cook, Darren A N; Bolton, Fiona M S; King, Sarah I; Pla, Davinia; Sanz, Libia; Calvete, Juan J; Harrison, Robert A

2014-06-24

Variation in venom composition is a ubiquitous phenomenon in snakes and occurs both interspecifically and intraspecifically. Venom variation can have severe outcomes for snakebite victims by rendering the specific antibodies found in antivenoms ineffective against heterologous toxins found in different venoms. The rapid evolutionary expansion of different toxin-encoding gene families in different snake lineages is widely perceived as the main cause of venom variation. However, this view is simplistic and disregards the understudied influence that processes acting on gene transcription and translation may have on the production of the venom proteome. Here, we assess the venom composition of six related viperid snakes and compare interspecific changes in the number of toxin genes, their transcription in the venom gland, and their translation into proteins secreted in venom. Our results reveal that multiple levels of regulation are responsible for generating variation in venom composition between related snake species. We demonstrate that differential levels of toxin transcription, translation, and their posttranslational modification have a substantial impact upon the resulting venom protein mixture. Notably, these processes act to varying extents on different toxin paralogs found in different snakes and are therefore likely to be as important as ancestral gene duplication events for generating compositionally distinct venom proteomes. Our results suggest that these processes may also contribute to altering the toxicity of snake venoms, and we demonstrate how this variability can undermine the treatment of a neglected tropical disease, snakebite.

Are children conservative, liberal, or metacognitive? Preliminary evidence for the involvement of the distinctiveness heuristic in decision making.

Science.gov (United States)

Geurten, Marie; Willems, Sylvie; Meulemans, Thierry

2015-04-01

The experiment tested whether young children are able to reduce their false recognition rate after distinctive encoding by implementing a strategic metacognitive rule. The participants, 72 children aged 4, 6, and 9 years, studied two lists of unrelated items. One of these lists was visually displayed (picture condition), whereas the other was presented auditorily (word condition). After each study phase, participants completed recognition tests. Finally, they answered questions about their explicit knowledge of the distinctive encoding effect. The results revealed that even the youngest children in our sample showed a smaller proportion of intrusions in the picture condition than in the word condition. Furthermore, the results of the signal detection analyses were consistent with the hypothesis that the lower rate of false recognitions after picture encoding results from the implementation of a conservative response criterion based on metacognitive expectations (distinctiveness heuristic). Moreover, the absence of correlation between children's explicit knowledge of the distinctiveness rule and their effective use of this metacognitive heuristic seems to indicate that its involvement in memory decisions could be mediated by implicit mechanisms. Copyright © 2015 Elsevier Inc. All rights reserved.

Mechanics of couple-stress fluid coatings

Science.gov (United States)

Waxman, A. M.

1982-01-01

The formal development of a theory of viscoelastic surface fluids with bending resistance - their kinematics, dynamics, and rheology are discussed. It is relevant to the mechanics of fluid drops and jets coated by a thin layer of immiscible fluid with rather general rheology. This approach unifies the hydrodynamics of two-dimensional fluids with the mechanics of an elastic shell in the spirit of a Cosserat continuum. There are three distinct facets to the formulation of surface continuum mechanics. Outlined are the important ideas and results associated with each: the kinematics of evolving surface geometries, the conservation laws governing the mechanics of surface continua, and the rheological equations of state governing the surface stress and moment tensors.

Distributed Large Independent Sets in One Round On Bounded-independence Graphs

OpenAIRE

Halldorsson , Magnus M.; Konrad , Christian

2015-01-01

International audience; We present a randomized one-round, single-bit messages, distributed algorithm for the maximum independent set problem in polynomially bounded-independence graphs with poly-logarithmic approximation factor. Bounded-independence graphs capture various models of wireless networks such as the unit disc graphs model and the quasi unit disc graphs model. For instance, on unit disc graphs, our achieved approximation ratio is O((log(n)/log(log(n)))^2).A starting point of our w...

Water as an Independent Taste Modality

Directory of Open Access Journals (Sweden)

Andrew M Rosen

2010-10-01

Full Text Available To qualify as a basic taste quality or modality, defined as a group of chemicals that taste alike, three empirical benchmarks have commonly been used. The first is that a candidate group of tastants must have a dedicated transduction mechanism in the peripheral nervous system. The second is that the tastants evoke physiological responses in dedicated afferent taste nerves innervating the oropharyngeal cavity. Last, the taste stimuli evoke activity in central gustatory neurons, some of which may respond only to that group of tastants. Here we argue that water may also be an independent taste modality. This argument is based on the identification of a water dedicated transduction mechanism in the peripheral nervous system, water responsive fibers of the peripheral taste nerves and the observation of water responsive neurons in all gustatory regions within the central nervous system. We have described electrophysiological responses from single neurons in nucleus of the solitary tract (NTS and parabrachial nucleus of the pons (PbN, respectively the first two central relay nuclei in the rodent brainstem, to water presented as a taste stimulus in anesthetized rats. Responses to water were in some cases as robust as responses to other taste qualities and sometimes occurred in the absence of responses to other tastants. Both excitatory and inhibitory responses were observed. Also, the temporal features of the water response resembled those of other taste responses. We argue that water may constitute an independent taste modality that is processed by dedicated neural channels at all levels of the gustatory neuraxis. Water-dedicated neurons in the brainstem may constitute key elements in the regulatory system for fluid in the body, i.e. thirst, and as part of the swallowing reflex circuitry.

Lifetime risk of distinct upper aerodigestive tract cancers and consumption of alcohol, betel and cigarette.

Science.gov (United States)

Hsu, Wan-Lun; Chien, Yin-Chu; Chiang, Chun-Ju; Yang, Hwai-I; Lou, Pei-Jen; Wang, Cheng-Ping; Yu, Kelly J; You, San-Lin; Wang, Li-Yu; Chen, Shu-Yuan; Yang, Czau-Siung; Chen, Chien-Jen

2014-09-15

The cancer of upper aerodigestive tract (UADT) is a common cancers in the world. However, its lifetime risk by consumption of alcohol, betel and cigarettes remain to be elucidated. This study aimed to estimate lifetime risk of distinct UADT cancers and assess their associations with alcohol, betel and cigarette consumption. Three cohorts of 25,611 men were enrolled in 1982-1992 in Taiwan. The history of alcohol, betel and cigarette consumption was enquired through questionnaire interview. Newly developed UADT cancers were ascertained through computerized linkage with national cancer registry profile. Lifetime (30-80 years old) risk and multivariate-adjusted hazard ratio (HRadj) of distinct UADT cancers by alcohol, betel and cigarette consumption were estimated. A total of 269 pathologically confirmed cases of UADT cancers were newly-diagnosed during 472,096 person-years of follow-up. The lifetime risk of UADT cancer was 9.42 and 1.65% for betel chewers and nonchewers, 3.22 and 1.21% for cigarette smokers and nonsmokers and 4.77 and 1.85% for alcohol drinkers and nondrinkers. The HRadj (95% confidence interval) of developing UADT cancer was 3.36 (2.51-4.49), 2.02 (1.43-2.84), 1.90 (1.46-2.49), respectively, for the consumption of betel, cigarette and alcohol. Alcohol, betel and cigarette had different effect on cancers at various anatomical sites of UADT. The cancer risk from the mouth, pharynx, esophagus to larynx increased for alcohol and cigarette consumption, but decreased for betel consumption. Alcohol, betel and cigarette consumption are independent risk predictors for distinct UADT cancers. © 2014 UICC.

Validation and psychometric properties of the Alcohol Positive and Negative Affect Schedule: Are drinking emotions distinct from general emotions?

Science.gov (United States)

Lac, Andrew; Donaldson, Candice D

2018-02-01

People vary in experiences of positive and negative emotions from consuming alcohol, but no validated measurement instrument exclusively devoted to assessing drinking emotions exists in the literature. The current research validated and evaluated the psychometric properties of an alcohol affect scale based on adjectives from the Positive and Negative Affect Schedule (PANAS) and tested the extent that emotions incurred from drinking were distinct from general trait-based emotions. Three studies tested independent samples of adult alcohol users. In Study 1 (N = 494), exploratory factor analyses of the Alcohol PANAS revealed that both the 20-item model and the 9-parcel model (represented by similar mood content) supported the 2-factor dimensionality of alcohol positive and negative affect. In Study 2 (N = 302), confirmatory factor analyses corroborated the measurement structure of alcohol positive and negative affect, and both constructs evidenced statistical independence from general positive and negative affect. In Study 3 (N = 452), alcohol positive and negative affect exhibited discriminant, convergent, and criterion validity with established alcohol scales. Incremental validity tests demonstrated that alcohol positive and negative affect uniquely contributed (beyond general positive and negative affect) to alcohol expectancies, use, and problems. Findings support that alcohol emotions are conceptually distinct from trait emotions, and underscore the necessity of an assessment instrument tailored to the former to examine associations with alcohol beliefs and behaviors. The Alcohol PANAS confers theoretical and practical applications to understand the emotional consequences of drinking. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types.

Science.gov (United States)

Zhang, Feifan; Bhattacharya, Abhishek; Nelson, Jessica C; Abe, Namiko; Gordon, Patricia; Lloret-Fernandez, Carla; Maicas, Miren; Flames, Nuria; Mann, Richard S; Colón-Ramos, Daniel A; Hobert, Oliver

2014-01-01

Transcription factors that drive neuron type-specific terminal differentiation programs in the developing nervous system are often expressed in several distinct neuronal cell types, but to what extent they have similar or distinct activities in individual neuronal cell types is generally not well explored. We investigate this problem using, as a starting point, the C. elegans LIM homeodomain transcription factor ttx-3, which acts as a terminal selector to drive the terminal differentiation program of the cholinergic AIY interneuron class. Using a panel of different terminal differentiation markers, including neurotransmitter synthesizing enzymes, neurotransmitter receptors and neuropeptides, we show that ttx-3 also controls the terminal differentiation program of two additional, distinct neuron types, namely the cholinergic AIA interneurons and the serotonergic NSM neurons. We show that the type of differentiation program that is controlled by ttx-3 in different neuron types is specified by a distinct set of collaborating transcription factors. One of the collaborating transcription factors is the POU homeobox gene unc-86, which collaborates with ttx-3 to determine the identity of the serotonergic NSM neurons. unc-86 in turn operates independently of ttx-3 in the anterior ganglion where it collaborates with the ARID-type transcription factor cfi-1 to determine the cholinergic identity of the IL2 sensory and URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features.

Reduction of Asymmetric Information through Corporate Governance Mechanisms

DEFF Research Database (Denmark)

Holm, Claus; Schøler, Finn

2010-01-01

Research Question/Issue: The purpose of this study is to examine how differences in "ownership dispersion" and "exposure toward the international capital market" affect the particular use of the corporate governance mechanisms "transparency" and "board independence" in listed companies. Research...... Findings/Insights: Our findings are based on a Danish dataset which includes 100 listed companies. We find that transparency is a more important corporate governance mechanism for companies with an exposure toward the international capital market, while differences in ownership dispersion do not affect...... the use of the transparency mechanism. In contrast, we find that board independence in the context of a two-tier board member system is an important corporate governance mechanism for companies with widely dispersed ownership and not for companies with an exposure toward the international capital market...

Forgetting in immediate serial recall: decay, temporal distinctiveness, or interference?

Science.gov (United States)

Oberauer, Klaus; Lewandowsky, Stephan

2008-07-01

Three hypotheses of forgetting from immediate memory were tested: time-based decay, decreasing temporal distinctiveness, and interference. The hypotheses were represented by 3 models of serial recall: the primacy model, the SIMPLE (scale-independent memory, perception, and learning) model, and the SOB (serial order in a box) model, respectively. The models were fit to 2 experiments investigating the effect of filled delays between items at encoding or at recall. Short delays between items, filled with articulatory suppression, led to massive impairment of memory relative to a no-delay baseline. Extending the delays had little additional effect, suggesting that the passage of time alone does not cause forgetting. Adding a choice reaction task in the delay periods to block attention-based rehearsal did not change these results. The interference-based SOB fit the data best; the primacy model overpredicted the effect of lengthening delays, and SIMPLE was unable to explain the effect of delays at encoding. The authors conclude that purely temporal views of forgetting are inadequate. Copyright (c) 2008 APA, all rights reserved.

Single-molecule spectroscopy of LHCSR1 protein dynamics identifies two distinct states responsible for multi-timescale photosynthetic photoprotection

Science.gov (United States)

Kondo, Toru; Pinnola, Alberta; Chen, Wei Jia; Dall'Osto, Luca; Bassi, Roberto; Schlau-Cohen, Gabriela S.

2017-08-01

In oxygenic photosynthesis, light harvesting is regulated to safely dissipate excess energy and prevent the formation of harmful photoproducts. Regulation is known to be necessary for fitness, but the molecular mechanisms are not understood. One challenge has been that ensemble experiments average over active and dissipative behaviours, preventing identification of distinct states. Here, we use single-molecule spectroscopy to uncover the photoprotective states and dynamics of the light-harvesting complex stress-related 1 (LHCSR1) protein, which is responsible for dissipation in green algae and moss. We discover the existence of two dissipative states. We find that one of these states is activated by pH and the other by carotenoid composition, and that distinct protein dynamics regulate these states. Together, these two states enable the organism to respond to two types of intermittency in solar intensity—step changes (clouds and shadows) and ramp changes (sunrise), respectively. Our findings reveal key control mechanisms underlying photoprotective dissipation, with implications for increasing biomass yields and developing robust solar energy devices.

Distinctive Dynamic Capabilities for New Business Creation

DEFF Research Database (Denmark)

Rosenø, Axel; Enkel, Ellen; Mezger, Florian

2013-01-01

This study examines the distinctive dynamic capabilities for new business creation in established companies. We argue that these are very different from those for managing incremental innovation within a company's core business. We also propose that such capabilities are needed in both slow...... and fast-paced industries, and that similarities exist across industries. Hence, the study contributes to dynamic capabilities literature by: 1) identifying the distinctive dynamic capabilities for new business creation; 2) shifting focus away from dynamic capabilities in environments characterised by high...... clock-speed and uncertainty towards considering dynamic capabilities for the purpose of developing new businesses, which also implies a high degree of uncertainty. Based on interviews with 33 companies, we identify distinctive dynamic capabilities for new business creation, find that dynamic...

Allelic recombination between distinct genomic locations generates copy number diversity in human β-defensins

Science.gov (United States)

Bakar, Suhaili Abu; Hollox, Edward J.; Armour, John A. L.

2009-01-01

β-Defensins are small secreted antimicrobial and signaling peptides involved in the innate immune response of vertebrates. In humans, a cluster of at least 7 of these genes shows extensive copy number variation, with a diploid copy number commonly ranging between 2 and 7. Using a genetic mapping approach, we show that this cluster is at not 1 but 2 distinct genomic loci ≈5 Mb apart on chromosome band 8p23.1, contradicting the most recent genome assembly. We also demonstrate that the predominant mechanism of change in β-defensin copy number is simple allelic recombination occurring in the interval between the 2 distinct genomic loci for these genes. In 416 meiotic transmissions, we observe 3 events creating a haplotype copy number not found in the parent, equivalent to a germ-line rate of copy number change of ≈0.7% per gamete. This places it among the fastest-changing copy number variants currently known. PMID:19131514

State-Independent Proof of Kochen—Specker Theorem with Thirty Rank-Two Projectors

International Nuclear Information System (INIS)

Toh, S. P.

2013-01-01

The Kochen—Specker theorem states that noncontextual hidden variable theories are incompatible with quantum mechanics. We provide a state-independent proof of the Kochen—Specker theorem using the smallest number of projectors, i.e., thirty rank-2 projectors, associated with the Mermin pentagram for a three-qubit system

Brownian motion or Lévy walk? Stepping towards an extended statistical mechanics for animal locomotion.

Science.gov (United States)

Gautestad, Arild O

2012-09-07

Animals moving under the influence of spatio-temporal scaling and long-term memory generate a kind of space-use pattern that has proved difficult to model within a coherent theoretical framework. An extended kind of statistical mechanics is needed, accounting for both the effects of spatial memory and scale-free space use, and put into a context of ecological conditions. Simulations illustrating the distinction between scale-specific and scale-free locomotion are presented. The results show how observational scale (time lag between relocations of an individual) may critically influence the interpretation of the underlying process. In this respect, a novel protocol is proposed as a method to distinguish between some main movement classes. For example, the 'power law in disguise' paradox-from a composite Brownian motion consisting of a superposition of independent movement processes at different scales-may be resolved by shifting the focus from pattern analysis at one particular temporal resolution towards a more process-oriented approach involving several scales of observation. A more explicit consideration of system complexity within a statistical mechanical framework, supplementing the more traditional mechanistic modelling approach, is advocated.

Media independence and dividend policy

DEFF Research Database (Denmark)

Farooq, Omar; Dandoune, Salma

2012-01-01

independence and dividend policies in emerging markets. Using a dataset from twenty three emerging markets, we show a significantly negative relationship between dividend policies (payout ratio and decision to pay dividend) and media independence. We argue that independent media reduces information asymmetries...... for stock market participants. Consequently, stock market participants in emerging markets with more independent media do not demand as high and as much dividends as their counterparts in emerging markets with less independent media. We also show that press independence is more important in defining......Can media pressurize managers to disgorge excess cash to shareholders? Do firms in countries with more independent media follow different dividend policies than firms with less independent media? This paper seeks to answer these questions and aims to document the relationship between media...

Many-Objective Distinct Candidates Optimization using Differential Evolution

DEFF Research Database (Denmark)

Justesen, Peter; Ursem, Rasmus Kjær

2010-01-01

for each objective. The Many-Objective Distinct Candidates Optimization using Differential Evolution (MODCODE) algorithm takes a novel approach by focusing search using a user-defined number of subpopulations each returning a distinct optimal solution within the preferred region of interest. In this paper......, we present the novel MODCODE algorithm incorporating the ROD measure to measure and control candidate distinctiveness. MODCODE is tested against GDE3 on three real world centrifugal pump design problems supplied by Grundfos. Our algorithm outperforms GDE3 on all problems with respect to all...

Independent lung ventilation in a newborn with asymmetric acute lung injury due to respiratory syncytial virus: a case report

Directory of Open Access Journals (Sweden)

Di Nardo Matteo

2008-06-01

Full Text Available Abstract Introduction Independent lung ventilation is a form of protective ventilation strategy used in adult asymmetric acute lung injury, where the application of conventional mechanical ventilation can produce ventilator-induced lung injury and ventilation-perfusion mismatch. Only a few experiences have been published on the use of independent lung ventilation in newborn patients. Case presentation We present a case of independent lung ventilation in a 16-day-old infant of 3.5 kg body weight who had an asymmetric lung injury due to respiratory syncytial virus bronchiolitis. We used independent lung ventilation applying conventional protective pressure controlled ventilation to the less-compromised lung, with a respiratory frequency proportional to the age of the patient, and a pressure controlled high-frequency ventilation to the atelectatic lung. This was done because a single tube conventional ventilation protective strategy would have exposed the less-compromised lung to a high mean airways pressure. The target of independent lung ventilation is to provide adequate gas exchange at a safe mean airways pressure level and to expand the atelectatic lung. Independent lung ventilation was accomplished for 24 hours. Daily chest radiograph and gas exchange were used to evaluate the efficacy of independent lung ventilation. Extubation was performed after 48 hours of conventional single-tube mechanical ventilation following independent lung ventilation. Conclusion This case report demonstrates the feasibility of independent lung ventilation with two separate tubes in neonates as a treatment of an asymmetric acute lung injury.

Short-range phenotypic divergence among genetically distinct parapatric populations of an Australian funnel-web spider.

Science.gov (United States)

Wong, Mark K L; Woodman, James D; Rowell, David M

2017-07-01

Speciation involves divergence at genetic and phenotypic levels. Where substantial genetic differentiation exists among populations, examining variation in multiple phenotypic characters may elucidate the mechanisms by which divergence and speciation unfold. Previous work on the Australian funnel-web spider Atrax sutherlandi Gray (2010; Records of the Australian Museum 62 , 285-392; Mygalomorphae: Hexathelidae: Atracinae) has revealed a marked genetic structure along a 110-kilometer transect, with six genetically distinct, parapatric populations attributable to past glacial cycles. In the present study, we explore variation in three classes of phenotypic characters (metabolic rate, water loss, and morphological traits) within the context of this phylogeographic structuring. Variation in metabolic and water loss rates shows no detectable association with genetic structure; the little variation observed in these rates may be due to the spiders' behavioral adaptations (i.e., burrowing), which buffer the effects of climatic gradients across the landscape. However, of 17 morphological traits measured, 10 show significant variation among genetic populations, in a disjunct manner that is clearly not latitudinal. Moreover, patterns of variation observed for morphological traits serving different organismic functions (e.g., prey capture, burrowing, and locomotion) are dissimilar. In contrast, a previous study of an ecologically similar sympatric spider with little genetic structure indicated a strong latitudinal response in 10 traits over the same range. The congruence of morphological variation with deep phylogeographic structure in Tallaganda's A. sutherlandi populations, as well as the inconsistent patterns of variation across separate functional traits, suggest that the spiders are likely in early stages of speciation, with parapatric populations independently responding to local selective forces.

Einstein's statistical mechanics

Energy Technology Data Exchange (ETDEWEB)

Baracca, A; Rechtman S, R

1985-08-01

The foundation of equilibrium classical statistical mechanics were laid down in 1902 independently by Gibbs and Einstein. The latter's contribution, developed in three papers published between 1902 and 1904, is usually forgotten and when not, rapidly dismissed as equivalent to Gibb's. We review in detail Einstein's ideas on the foundations of statistical mechanics and show that they constitute the beginning of a research program that led Einstein to quantum theory. We also show how these ideas may be used as a starting point for an introductory course on the subject.

Einstein's statistical mechanics

International Nuclear Information System (INIS)

Baracca, A.; Rechtman S, R.

1985-01-01

The foundation of equilibrium classical statistical mechanics were laid down in 1902 independently by Gibbs and Einstein. The latter's contribution, developed in three papers published between 1902 and 1904, is usually forgotten and when not, rapidly dismissed as equivalent to Gibb's. We review in detail Einstein's ideas on the foundations of statistical mechanics and show that they constitute the beginning of a research program that led Einstein to quantum theory. We also show how these ideas may be used as a starting point for an introductory course on the subject. (author)

Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases

Energy Technology Data Exchange (ETDEWEB)

Yu, Hao; Dranchak, Patricia; Li, Zhiru; MacArthur, Ryan; Munson, Matthew S.; Mehzabeen, Nurjahan; Baird, Nathan J.; Battalie, Kevin P.; Ross, David; Lovell, Scott; Carlow, Clotilde K.S.; Suga, Hiroaki; Inglese, James (U of Tokyo); (NEB); (Kansas); (NIH); (NIST); (HHMI)

2017-04-03

Glycolytic interconversion of phosphoglycerate isomers is catalysed in numerous pathogenic microorganisms by a cofactor-independent mutase (iPGM) structurally distinct from the mammalian cofactor-dependent (dPGM) isozyme. The iPGM active site dynamically assembles through substrate-triggered movement of phosphatase and transferase domains creating a solvent inaccessible cavity. Here we identify alternate ligand binding regions using nematode iPGM to select and enrich lariat-like ligands from an mRNA-display macrocyclic peptide library containing >1012 members. Functional analysis of the ligands, named ipglycermides, demonstrates sub-nanomolar inhibition of iPGM with complete selectivity over dPGM. The crystal structure of an iPGM macrocyclic peptide complex illuminated an allosteric, locked-open inhibition mechanism placing the cyclic peptide at the bi-domain interface. This binding mode aligns the pendant lariat cysteine thiolate for coordination with the iPGM transition metal ion cluster. The extended charged, hydrophilic binding surface interaction rationalizes the persistent challenges these enzymes have presented to small-molecule screening efforts highlighting the important roles of macrocyclic peptides in expanding chemical diversity for ligand discovery.

L-rhamnose induction of Aspergillus nidulans α-L-rhamnosidase genes is glucose repressed via a CreA-independent mechanism acting at the level of inducer uptake.

Science.gov (United States)

Tamayo-Ramos, Juan A; Flipphi, Michel; Pardo, Ester; Manzanares, Paloma; Orejas, Margarita

2012-02-21

Little is known about the structure and regulation of fungal α-L-rhamnosidase genes despite increasing interest in the biotechnological potential of the enzymes that they encode. Whilst the paradigmatic filamentous fungus Aspergillus nidulans growing on L-rhamnose produces an α-L-rhamnosidase suitable for oenological applications, at least eight genes encoding putative α-L-rhamnosidases have been found in its genome. In the current work we have identified the gene (rhaE) encoding the former activity, and characterization of its expression has revealed a novel regulatory mechanism. A shared pattern of expression has also been observed for a second α-L-rhamnosidase gene, (AN10277/rhaA). Amino acid sequence data for the oenological α-L-rhamnosidase were determined using MALDI-TOF mass spectrometry and correspond to the amino acid sequence deduced from AN7151 (rhaE). The cDNA of rhaE was expressed in Saccharomyces cerevisiae and yielded pNP-rhamnohydrolase activity. Phylogenetic analysis has revealed this eukaryotic α-L-rhamnosidase to be the first such enzyme found to be more closely related to bacterial rhamnosidases than other α-L-rhamnosidases of fungal origin. Northern analyses of diverse A. nidulans strains cultivated under different growth conditions indicate that rhaA and rhaE are induced by L-rhamnose and repressed by D-glucose as well as other carbon sources, some of which are considered to be non-repressive growth substrates. Interestingly, the transcriptional repression is independent of the wide domain carbon catabolite repressor CreA. Gene induction and glucose repression of these rha genes correlate with the uptake, or lack of it, of the inducing carbon source L-rhamnose, suggesting a prominent role for inducer exclusion in repression. The A. nidulans rhaE gene encodes an α-L-rhamnosidase phylogenetically distant to those described in filamentous fungi, and its expression is regulated by a novel CreA-independent mechanism. The identification of

Compound C inhibits macrophage chemotaxis through an AMPK-independent mechanism

Energy Technology Data Exchange (ETDEWEB)

Lee, Youngyi [College of Pharmacy, Woosuk University, Wanju, Jeonbuk 55338 (Korea, Republic of); Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896 (Korea, Republic of); Park, Byung-Hyun, E-mail: bhpark@jbnu.ac.kr [Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896 (Korea, Republic of); Bae, Eun Ju, E-mail: ejbae@woosuk.ac.kr [College of Pharmacy, Woosuk University, Wanju, Jeonbuk 55338 (Korea, Republic of)

2016-01-15

Macrophage infiltration in adipose tissue is a well-established cause of obesity-linked insulin resistance. AMP-activated protein kinase (AMPK) activation in peripheral tissues such as adipose tissue has beneficial effects on the protection against obesity-induced insulin resistance, which is mainly mediated by prevention of adipose tissue macrophage infiltration and inflammation. In examining the role of AMPK on adipose tissue inflammation, we unexpectedly found that compound C (CC), despite its inhibition of AMPK, robustly inhibited macrophage chemotaxis in RAW 264.7 cells when adipocyte conditioned medium (CM) was used as a chemoattractant. Here, we report that CC inhibition of macrophage migration occurred independently of AMPK. Mechanistically, this inhibitory effect of cell migration by CC was mediated by inhibition of the focal adhesion kinase, AKT, nuclear factor κB pathways. Moreover, the expression of chemokine monocyte chemoattractant protein-1 and pro-inflammatory genes such as tumor necrosis factor α and inducible nitric oxide synthase were prevented by CC treatment in RAW 264.7 cells stimulated with either adipocyte CM or lipopolysaccharide. Lastly, in accord with the findings of the anti-inflammatory effect of CC, we demonstrated that CC functioned as a repressor of macrophage CM-mediated insulin resistance in adipocytes. Taken together, our results suggest that CC serves as a useful inhibitory molecule against macrophage chemotaxis into adipose tissue and thus might have therapeutic potential for the treatment of obesity-linked adipose inflammation. - Highlights: • Compound C (CC) inhibits macrophage chemotaxis regardless of AMPK suppression. • CC enhances insulin sensitivity in adipocytes. • CC inhibits focal adhesion kinase, AKT, and NF-κB signaling in RAW 264.7 cells.

Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease

OpenAIRE

Bouybayoune, I.; Mantovani, S.; Del Gallo, F.; Bertani, I.; Restelli, E.; Comerio, L.; Tapella, L.; Baracchi, F.; Fernández-Borges, N.; Mangieri, M.; Bisighini, C.; Beznoussenko, G..V.; Paladini, A.; Balducci, C.; Micotti, E.

2015-01-01

Author Summary Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD) and fatal familial insomnia (FFI). The reason for this variability is not known, but assembly of the mutant PrPs into distinct aggregates that spread in the brain by promoting PrP aggregation may contribute to the disease phenotype. We previously generated transgenic ...

Tamoxifen-independent recombination in the RIP-CreER mouse.

Directory of Open Access Journals (Sweden)

Yanmei Liu

Full Text Available BACKGROUND: The inducible Cre-lox system is a valuable tool to study gene function in a spatial and time restricted fashion in mouse models. This strategy relies on the limited background activity of the modified Cre recombinase (CreER in the absence of its inducer, the competitive estrogen receptor ligand, tamoxifen. The RIP-CreER mouse (Tg (Ins2-cre/Esr1 1Dam is among the few available β-cell specific CreER mouse lines and thus it has been often used to manipulate gene expression in the insulin-producing cells of the endocrine pancreas. PRINCIPAL FINDINGS: Here, we report the detection of tamoxifen-independent Cre activity as early as 2 months of age in RIP-CreER mice crossed with three distinct reporter strains. SIGNIFICANCE: Evidence of Cre-mediated recombination of floxed alleles even in the absence of tamoxifen administration should warrant cautious use of this mouse for the study of pancreatic β-cells.

The rodent ultrasound production mechanism.

Science.gov (United States)

Roberts, L H

1975-03-01

Rodents produce two types of sounds, audible and ultrasonic, that differ markedly in physical structure. Studies of sound production in light gases show that whereas the audible cries appear to be produced, as in the case of most other mammals, by vibrating structures in the larynx, the ultrasonic cries are produced by a different mechanism, probably a whistle. 'Bird-call' whistles are shown to have all the properties of rodent ultrasonic cries and to mimic them in almost every detail. Thus it is concluded that rodents have two distinct sound production mechanisms, one for audible cries and one for ultrasonic cries.

Differential recruitment of theory of mind brain network across three tasks: An independent component analysis.

Science.gov (United States)

Thye, Melissa D; Ammons, Carla J; Murdaugh, Donna L; Kana, Rajesh K

2018-07-16

Social neuroscience research has focused on an identified network of brain regions primarily associated with processing Theory of Mind (ToM). However, ToM is a broad cognitive process, which encompasses several sub-processes, such as mental state detection and intentional attribution, and the connectivity of brain regions underlying the broader ToM network in response to paradigms assessing these sub-processes requires further characterization. Standard fMRI analyses which focus only on brain activity cannot capture information about ToM processing at a network level. An alternative method, independent component analysis (ICA), is a data-driven technique used to isolate intrinsic connectivity networks, and this approach provides insight into network-level regional recruitment. In this fMRI study, three complementary, but distinct ToM tasks assessing mental state detection (e.g. RMIE: Reading the Mind in the Eyes; RMIV: Reading the Mind in the Voice) and intentional attribution (Causality task) were each analyzed using ICA in order to separately characterize the recruitment and functional connectivity of core nodes in the ToM network in response to the sub-processes of ToM. Based on visual comparison of the derived networks for each task, the spatiotemporal network patterns were similar between the RMIE and RMIV tasks, which elicited mentalizing about the mental states of others, and these networks differed from the network derived for the Causality task, which elicited mentalizing about goal-directed actions. The medial prefrontal cortex, precuneus, and right inferior frontal gyrus were seen in the components with the highest correlation with the task condition for each of the tasks highlighting the role of these regions in general ToM processing. Using a data-driven approach, the current study captured the differences in task-related brain response to ToM in three distinct ToM paradigms. The findings of this study further elucidate the neural mechanisms associated

Tp53 gene mediates distinct dopaminergic neuronal damage in different dopaminergic neurotoxicant models

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Tao Lu

2017-01-01

Full Text Available Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson's disease. However, whether the neuronal Tp53 protein plays a direct role in regulating dopaminergic (DA neuronal cell death or neuronal terminal damage in different neurotoxicant models is unknown. In our recent studies, in contrast to the global inhibition of Tp53 function by pharmacological inhibitors and in traditional Tp53 knock-out mice, we examined the effects of DA-specific Tp53 gene deletion after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine exposure. Our data suggests that the Tp53 gene might be involved in both neuronal apoptosis and neuronal terminal damage caused by different neurotoxicants. Additional results from other studies also suggest that as a master regulator of many pathways that regulate apoptosis and synaptic terminal damage, it is possible that Tp53 may function as a signaling hub to integrate different signaling pathways to mediate distinctive target pathways. Tp53 protein as a signaling hub might be able to evaluate the microenvironment of neurons, assess the forms and severities of injury incurred, and determine whether apoptotic cell death or neuronal terminal degeneration occurs. Identification of the precise mechanisms activated in distinct neuronal damage caused by different forms and severities of injuries might allow for development of specific Tp53 inhibitors or ways to modulate distinct downstream target pathways involved.

The importance of board independence

NARCIS (Netherlands)

Zijl, N.J.M.

2012-01-01

Although the attributed importance of board independence is high, a clear definition of independence does not exist. Furthermore, the aim and consequences of independence are the subject of discussion and empirical evidence about the impact of independence is weak and disputable. Despite this lack

Creating fair lineups for suspects with distinctive features.

Science.gov (United States)

Zarkadi, Theodora; Wade, Kimberley A; Stewart, Neil

2009-12-01

In their descriptions, eyewitnesses often refer to a culprit's distinctive facial features. However, in a police lineup, selecting the only member with the described distinctive feature is unfair to the suspect and provides the police with little further information. For fair and informative lineups, the distinctive feature should be either replicated across foils or concealed on the target. In the present experiments, replication produced more correct identifications in target-present lineups--without increasing the incorrect identification of foils in target-absent lineups--than did concealment. This pattern, and only this pattern, is predicted by the hybrid-similarity model of recognition.

Are skeletal muscles independent actuators? Force transmission from soleus muscle in the cat

NARCIS (Netherlands)

Maas, H.; Sandercock, T.G.

2008-01-01

It is unclear if skeletal muscles act mechanically as independent actuators. The purpose of the present study was to investigate force transmission from soleus (SO) muscle for physiological lengths as well as relative positions in the intact cat hindlimb. We hypothesized that force transmission from

Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms.

Science.gov (United States)

Alexander, Matthew R; Murgai, Meera; Moehle, Christopher W; Owens, Gary K

2012-04-02

Smooth muscle cell (SMC) phenotypic modulation in atherosclerosis and in response to PDGF in vitro involves repression of differentiation marker genes and increases in SMC proliferation, migration, and matrix synthesis. However, SMCs within atherosclerotic plaques can also express a number of proinflammatory genes, and in cultured SMCs the inflammatory cytokine IL-1β represses SMC marker gene expression and induces inflammatory gene expression. Studies herein tested the hypothesis that IL-1β modulates SMC phenotype to a distinct inflammatory state relative to PDGF-DD. Genome-wide gene expression analysis of IL-1β- or PDGF-DD-treated SMCs revealed that although both stimuli repressed SMC differentiation marker gene expression, IL-1β distinctly induced expression of proinflammatory genes, while PDGF-DD primarily induced genes involved in cell proliferation. Promoters of inflammatory genes distinctly induced by IL-1β exhibited over-representation of NF-κB binding sites, and NF-κB inhibition in SMCs reduced IL-1β-induced upregulation of proinflammatory genes as well as repression of SMC differentiation marker genes. Interestingly, PDGF-DD-induced SMC marker gene repression was not NF-κB dependent. Finally, immunofluorescent staining of mouse atherosclerotic lesions revealed the presence of cells positive for the marker of an IL-1β-stimulated inflammatory SMC, chemokine (C-C motif) ligand 20 (CCL20), but not the PDGF-DD-induced gene, regulator of G protein signaling 17 (RGS17). Results demonstrate that IL-1β- but not PDGF-DD-induced phenotypic modulation of SMC is characterized by NF-κB-dependent activation of proinflammatory genes, suggesting the existence of a distinct inflammatory SMC phenotype. In addition, studies provide evidence for the possible utility of CCL20 and RGS17 as markers of inflammatory and proliferative state SMCs within atherosclerotic plaques in vivo.

Wide frequency independently controlled dual-band inkjet-printed antenna

KAUST Repository

AbuTarboush, Hattan F.

2014-01-08

A low-cost inkjet-printed multiband monopole antenna is presented. The unique advantage of the proposed antenna is the freedom to adjust and set the dual-band of the antenna independently over a wide range (148.83%). To demonstrate the independent control feature, the 2.4 and 3.4 GHz bands for the wireless local area network (WLAN) and worldwide interoperability for microwave access (WiMAX) applications are selected as an example. The measured impedance bandwidths for the 2.4 and 3.4 GHz are 15.2 and 23.7%, respectively. These dual-bands have the ability to be controlled independently between 1.1 and 7.5 GHz without affecting the other band. In addition, the proposed antenna can be assigned for different mobile and wireless applications such as GPS, PCS, GSM 1800, 1900, UMTS, and up to 5-GHz WLAN and WiMAX applications. The mechanism of independent control of each radiator through dimensional variation is discussed in detail. The antenna has a compact size of 10 × 37.3 × 0.44 mm3, leaving enough space for the driving electronics on the paper substrate. The measured results from the prototype are in good agreement with the simulated results. Owing to inkjet printing on an ordinary paper, the design is extremely light weight and highly suitable for low cost and large volume manufacturing. © The Institution of Engineering and Technology 2013.

Electrophysiological localization of distinct calcium potentials at selective somatodendritic sites in the substantia nigra

DEFF Research Database (Denmark)

Hounsgaard, J; Nedergaard, S; Greenfield, S A

1992-01-01

of differential polarization through applied electric fields, the cell body and dendrites have been activated in effective isolation during intracellular recordings from pars compacta neurons in the substantia nigra in vitro. In one class of neurons, which discharge in a "phasic" fashion and are located......The dendrites of dopaminergic neurons in the substantia nigra play a pivotal role in the neurochemical homeostasis of the nucleus. It is conceivable therefore that the cell body and dendrites of these nigral neurons possess distinct and independent electro-responsive features. By means......, a high-threshold calcium spike is located principally in the cell body. The differential localization of these calcium conductances in sub-populations of neurons is likely to determine the functions for the calcium responses in each type of neuron, and moreover highlight the dendrites as dynamic...

Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.

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Winyoo Chowanadisai

Full Text Available The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05 (S2 Table. Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.

Ancient, independent evolution and distinct molecular features of the novel human T-lymphotropic virus type 4

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Wolfe Nathan D

2009-02-01

Full Text Available Abstract Background Human T-lymphotropic virus type 4 (HTLV-4 is a new deltaretrovirus recently identified in a primate hunter in Cameroon. Limited sequence analysis previously showed that HTLV-4 may be distinct from HTLV-1, HTLV-2, and HTLV-3, and their simian counterparts, STLV-1, STLV-2, and STLV-3, respectively. Analysis of full-length genomes can provide basic information on the evolutionary history and replication and pathogenic potential of new viruses. Results We report here the first complete HTLV-4 sequence obtained by PCR-based genome walking using uncultured peripheral blood lymphocyte DNA from an HTLV-4-infected person. The HTLV-4(1863LE genome is 8791-bp long and is equidistant from HTLV-1, HTLV-2, and HTLV-3 sharing only 62–71% nucleotide identity. HTLV-4 has a prototypic genomic structure with all enzymatic, regulatory, and structural proteins preserved. Like STLV-2, STLV-3, and HTLV-3, HTLV-4 is missing a third 21-bp transcription element found in the long terminal repeats of HTLV-1 and HTLV-2 but instead contains unique c-Myb and pre B-cell leukemic transcription factor binding sites. Like HTLV-2, the PDZ motif important for cellular signal transduction and transformation in HTLV-1 and HTLV-3 is missing in the C-terminus of the HTLV-4 Tax protein. A basic leucine zipper (b-ZIP region located in the antisense strand of HTLV-1 and believed to play a role in viral replication and oncogenesis, was also found in the complementary strand of HTLV-4. Detailed phylogenetic analysis shows that HTLV-4 is clearly a monophyletic viral group. Dating using a relaxed molecular clock inferred that the most recent common ancestor of HTLV-4 and HTLV-2/STLV-2 occurred 49,800 to 378,000 years ago making this the oldest known PTLV lineage. Interestingly, this period coincides with the emergence of Homo sapiens sapiens during the Middle Pleistocene suggesting that early humans may have been susceptible hosts for the ancestral HTLV-4. Conclusion The

Independent procedure of checking dose calculations using an independent calculus algorithm

International Nuclear Information System (INIS)

Perez Rozos, A.; Jerez Sainz, I.; Carrasco Rodriguez, J. L.

2006-01-01

In radiotherapy it is recommended the use of an independent procedure of checking dose calculations, in order to verify the main treatment planning system and double check every patient dosimetry. In this work we present and automatic spreadsheet that import data from planning system using IMPAC/RTP format and verify monitor unit calculation using an independent calculus algorithm. Additionally, it perform a personalized analysis of dose volume histograms and several radiobiological parameters like TCP and NTCP. Finally, the application automatically generate a clinical dosimetry report for every patient, including treatment fields, fractionation, independent check results, dose volume analysis, and first day forms. (Author)

A proof of the Kochen–Specker theorem can always be converted to a state-independent noncontextuality inequality

International Nuclear Information System (INIS)

Yu, Xiao-Dong; Tong, D M; Guo, Yan-Qing

2015-01-01

Quantum contextuality is one of the fundamental notions in quantum mechanics. Proofs of the Kochen–Specker theorem and noncontextuality inequalities are two means for revealing the contextuality phenomenon in quantum mechanics. It has been found that some proofs of the Kochen-Specker theorem, such as those based on rays, can be converted to a state-independent noncontextuality inequality, but it remains open whether this is true in general, i.e., whether any proof of the Kochen-Specker theorem can always be converted to a noncontextuality inequality. In this paper, we address this issue. We prove that all kinds of proofs of the Kochen-Specker theorem, based on rays or any other observables, can always be converted to state-independent noncontextuality inequalities. Besides, our constructive proof also provides a general approach for deriving a state-independent noncontextuality inequality from a proof of the KS theorem. (paper)

Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.

Science.gov (United States)

Tae, Hyun-Jin; Petrashevskaya, Natalia; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

2016-01-15

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

Independence and deterrence. Britain and atomic energy 1945-1952. References to official papers

International Nuclear Information System (INIS)

Gowing, M.

1979-01-01

This booklet contains a list of references which were not published in Independence and Deterrence because they related to papers still closed under the 1958 and 1967 Public Records Acts. Since 1974, some post-war records have been reviewed by departments and the UKAEA and have been transferred to the Public Record Office; the earliest are already open and more will, of course, be opened in January each year. This list, unfortunately, cannot distinguish between papers open in the Public Record Office and those still closed in departmental archives. Even if it could, the distinction would become progressively out-of-date. We have however given as much information as we can to assist searchers. (author)

Distinct Effects of the Cervicovaginal Microbiota and Herpes Simplex Type 2 Infection on Female Genital Tract Immunology.

Science.gov (United States)

Shannon, B; Gajer, P; Yi, T J; Ma, B; Humphrys, M S; Thomas-Pavanel, J; Chieza, L; Janakiram, P; Saunders, M; Tharao, W; Huibner, S; Shahabi, K; Ravel, J; Kaul, R

2017-05-01

Genital inflammation is a key determinant of human immunodeficiency virus (HIV) transmission, and may increase HIV-susceptible target cells and alter epithelial integrity. Several genital conditions that increase HIV risk are more prevalent in African, Caribbean, and other black (ACB) women, including bacterial vaginosis and herpes simplex virus type-2 (HSV-2) infection. Therefore, we assessed the impact of the genital microbiota on mucosal immunology in ACB women and microbiome-HSV-2 interactions. Cervicovaginal secretions and endocervical cells were collected by cytobrush and Instead Softcup, respectively. T cells and dendritic cells were assessed by flow cytometry, cytokines by multiplex enzyme-linked immunosorbent assay (ELISA), and the microbiota by 16S ribosomal ribonucleic acid gene sequencing. The cervicovaginal microbiota of 51 participants were composed of community state types (CSTs) showing diversity (20/51; 39%) or predominated by Lactobacillus iners (22/51; 42%), L. crispatus (7/51; 14%), or L. gasseri (2/51; 4%). High-diversity CSTs and specific bacterial phyla (Gardnerella vaginalis and Prevotella bivia) were strongly associated with cervicovaginal inflammatory cytokines, but not with altered endocervical immune cells. However, cervical CD4+ T-cell number was associated with HSV-2 infection and a distinct cytokine profile. This suggests that the genital microbiota and HSV-2 infection may influence HIV susceptibility through independent biological mechanisms. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Classifying distinct basal cell carcinoma subtype by means of dermatoscopy and reflectance confocal microscopy.

Science.gov (United States)

Longo, Caterina; Lallas, Aimilios; Kyrgidis, Athanassios; Rabinovitz, Harold; Moscarella, Elvira; Ciardo, Silvana; Zalaudek, Iris; Oliviero, Margaret; Losi, Amanda; Gonzalez, Salvador; Guitera, Pascale; Piana, Simonetta; Argenziano, Giuseppe; Pellacani, Giovanni

2014-10-01

The current guidelines for the management of basal cell carcinoma (BCC) suggest a different therapeutic approach according to histopathologic subtype. Although dermatoscopic and confocal criteria of BCC have been investigated, no specific studies were performed to evaluate the distinct reflectance confocal microscopy (RCM) aspects of BCC subtypes. To define the specific dermatoscopic and confocal criteria for delineating different BCC subtypes. Dermatoscopic and confocal images of histopathologically confirmed BCCs were retrospectively evaluated for the presence of predefined criteria. Frequencies of dermatoscopic and confocal parameters are provided. Univariate and adjusted odds ratios were calculated. Discriminant analyses were performed to define the independent confocal criteria for distinct BCC subtypes. Eighty-eight BCCs were included. Dermatoscopically, superficial BCCs (n=44) were primarily typified by the presence of fine telangiectasia, multiple erosions, leaf-like structures, and revealed cords connected to the epidermis and epidermal streaming upon RCM. Nodular BCCs (n=22) featured the classic dermatoscopic features and well outlined large basaloid islands upon RCM. Infiltrative BCCs (n=22) featured structureless, shiny red areas, fine telangiectasia, and arborizing vessels on dermatoscopy and dark silhouettes upon RCM. The retrospective design. Dermatoscopy and confocal microscopy can reliably classify different BCC subtypes. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Retinal ganglion cells with distinct directional preferences differ in molecular identity, structure, and central projections.

Science.gov (United States)

Kay, Jeremy N; De la Huerta, Irina; Kim, In-Jung; Zhang, Yifeng; Yamagata, Masahito; Chu, Monica W; Meister, Markus; Sanes, Joshua R

2011-05-25

The retina contains ganglion cells (RGCs) that respond selectively to objects moving in particular directions. Individual members of a group of ON-OFF direction-selective RGCs (ooDSGCs) detect stimuli moving in one of four directions: ventral, dorsal, nasal, or temporal. Despite this physiological diversity, little is known about subtype-specific differences in structure, molecular identity, and projections. To seek such differences, we characterized mouse transgenic lines that selectively mark ooDSGCs preferring ventral or nasal motion as well as a line that marks both ventral- and dorsal-preferring subsets. We then used the lines to identify cell surface molecules, including Cadherin 6, CollagenXXVα1, and Matrix metalloprotease 17, that are selectively expressed by distinct subsets of ooDSGCs. We also identify a neuropeptide, CART (cocaine- and amphetamine-regulated transcript), that distinguishes all ooDSGCs from other RGCs. Together, this panel of endogenous and transgenic markers distinguishes the four ooDSGC subsets. Patterns of molecular diversification occur before eye opening and are therefore experience independent. They may help to explain how the four subsets obtain distinct inputs. We also demonstrate differences among subsets in their dendritic patterns within the retina and their axonal projections to the brain. Differences in projections indicate that information about motion in different directions is sent to different destinations.

An overexpression screen of Toxoplasma gondii Rab-GTPases reveals distinct transport routes to the micronemes.

Directory of Open Access Journals (Sweden)

Katrin Kremer

2013-03-01

Full Text Available The basic organisation of the endomembrane system is conserved in all eukaryotes and comparative genome analyses provides compelling evidence that the endomembrane system of the last common eukaryotic ancestor (LCEA is complex with many genes required for regulated traffic being present. Although apicomplexan parasites, causative agents of severe human and animal diseases, appear to have only a basic set of trafficking factors such as Rab-GTPases, they evolved unique secretory organelles (micronemes, rhoptries and dense granules that are sequentially secreted during invasion of the host cell. In order to define the secretory pathway of apicomplexans, we performed an overexpression screen of Rabs in Toxoplasma gondii and identified Rab5A and Rab5C as important regulators of traffic to micronemes and rhoptries. Intriguingly, we found that not all microneme proteins traffic depends on functional Rab5A and Rab5C, indicating the existence of redundant microneme targeting pathways. Using two-colour super-resolution stimulated emission depletion (STED we verified distinct localisations of independent microneme proteins and demonstrate that micronemal organelles are organised in distinct subsets or subcompartments. Our results suggest that apicomplexan parasites modify classical regulators of the endocytic system to carryout essential parasite-specific roles in the biogenesis of their unique secretory organelles.