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Sample records for potential mechanisms underlying

  1. Linking Pesticide Exposure with Pediatric Leukemia: Potential Underlying Mechanisms

    PubMed Central

    Hernández, Antonio F.; Menéndez, Pablo

    2016-01-01

    Leukemia is the most common cancer in children, representing 30% of all childhood cancers. The disease arises from recurrent genetic insults that block differentiation of hematopoietic stem and/or progenitor cells (HSPCs) and drives uncontrolled proliferation and survival of the differentiation-blocked clone. Pediatric leukemia is phenotypically and genetically heterogeneous with an obscure etiology. The interaction between genetic factors and environmental agents represents a potential etiological driver. Although information is limited, the principal toxic mechanisms of potential leukemogenic agents (e.g., etoposide, benzene metabolites, bioflavonoids and some pesticides) include topoisomerase II inhibition and/or excessive generation of free radicals, which may induce DNA single- and double-strand breaks (DNA-DSBs) in early HSPCs. Chromosomal rearrangements (duplications, deletions and translocations) may occur if these lesions are not properly repaired. The initiating hit usually occurs in utero and commonly leads to the expression of oncogenic fusion proteins. Subsequent cooperating hits define the disease latency and occur after birth and may be of a genetic, epigenetic or immune nature (i.e., delayed infection-mediated immune deregulation). Here, we review the available experimental and epidemiological evidence linking pesticide exposure to infant and childhood leukemia and provide a mechanistic basis to support the association, focusing on early initiating molecular events. PMID:27043530

  2. Risk factors for pancreatic cancer: underlying mechanisms and potential targets

    PubMed Central

    Kolodecik, Thomas; Shugrue, Christine; Ashat, Munish; Thrower, Edwin C.

    2014-01-01

    Purpose of the review: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer. Recent findings: Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer. Summary: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions. PMID:24474939

  3. Music and Memory in Alzheimer's Disease and The Potential Underlying Mechanisms.

    PubMed

    Peck, Katlyn J; Girard, Todd A; Russo, Frank A; Fiocco, Alexandra J

    2016-01-01

    With population aging and a projected exponential expansion of persons diagnosed with Alzheimer's disease (AD), the development of treatment and prevention programs has become a fervent area of research and discovery. A growing body of evidence suggests that music exposure can enhance memory and emotional function in persons with AD. However, there is a paucity of research that aims to identify specific underlying neural mechanisms associated with music's beneficial effects in this particular population. As such, this paper reviews existing anecdotal and empirical evidence related to the enhancing effects of music exposure on cognitive function and further provides a discussion on the potential underlying mechanisms that may explain music's beneficial effect. Specifically, this paper will outline the potential role of the dopaminergic system, the autonomic nervous system, and the default network in explaining how music may enhance memory function in persons with AD. PMID:26967216

  4. Simultaneous Measurement of [Ca2+]i and Membrane Potential under Mechanical or Biochemical Stimulation

    NASA Astrophysics Data System (ADS)

    Sano, Minoru; Imura, Katsuaki; Ushida, Takashi; Tateishi, Tetsuya

    In human umbilical endothelial cells (HUVEC), mechanical stress is known to induce transients of [Ca2+]i that lead to the regulation of vascular functions in vivo. The transmembraneous influx of Ca2+ is thought to be mediated by voltage-dependent ion channels or stretch-activated ion channels. In order to elucidate the correlation of [Ca2+]i and membrane potential under mechanical stress, the influences of mechanical or biochemical stimulation on endothelial cells stained with both fura-2 and DiBAC4(3) were studied in vitro, by constructing an imaging system that could capture four kinds of fluorescence images simultaneously at real-time. In the application of thrombin, [Ca2+]i transients were accompanied with preceding depolarization, while mechanical stress that were loaded on a single cell with a micropipette did not evoke dramatic changes of membrane potential. These results indicate that the signaling pathway initiated by mechanical stress could be independent of electrochemical activation, and different from that by biochemical stimulation in HUVEC.

  5. Potential mechanisms underlying ectodermal differentiation of Wharton's jelly mesenchymal stem cells.

    PubMed

    Jadalannagari, Sushma; Berry, Abigale M; Hopkins, Richard A; Bhavsar, Dhaval; Aljitawi, Omar S

    2016-09-16

    Wharton's jelly mesenchymal stem cells (WJMSCs) are being increasingly recognized for their ectodermal differentiation potential. Previously, we demonstrated that when WJMSC were seeded onto an acellular matrix material derived from Wharton's jelly and cultured in osteogenic induction media, generated CK19 positive cells and hair-like structures indicative of ectodermal differentiation of WJMSCs. In this manuscript, we examine the underlying mechanism behind this observation using a variety of microscopy and molecular biology techniques such as western blotting and qPCR. We demonstrate that these hair-like structures are associated with live cells that are positive for epithelial and mesenchymal markers such as cytokeratin-19 and α-smooth muscle actin, respectively. We also show that up-regulation of β-catenin and noggin, along with the expression of TGF-β and SMAD and inhibition of BMP4 could be the mechanism behind this ectodermal differentiation and hair-like structure formation. PMID:27501759

  6. Potential of wind power projects under the Clean Development Mechanism in India

    PubMed Central

    Purohit, Pallav; Michaelowa, Axel

    2007-01-01

    Background So far, the cumulative installed capacity of wind power projects in India is far below their gross potential (≤ 15%) despite very high level of policy support, tax benefits, long term financing schemes etc., for more than 10 years etc. One of the major barriers is the high costs of investments in these systems. The Clean Development Mechanism (CDM) of the Kyoto Protocol provides industrialized countries with an incentive to invest in emission reduction projects in developing countries to achieve a reduction in CO2 emissions at lowest cost that also promotes sustainable development in the host country. Wind power projects could be of interest under the CDM because they directly displace greenhouse gas emissions while contributing to sustainable rural development, if developed correctly. Results Our estimates indicate that there is a vast theoretical potential of CO2 mitigation by the use of wind energy in India. The annual potential Certified Emissions Reductions (CERs) of wind power projects in India could theoretically reach 86 million. Under more realistic assumptions about diffusion of wind power projects based on past experiences with the government-run programmes, annual CER volumes by 2012 could reach 41 to 67 million and 78 to 83 million by 2020. Conclusion The projections based on the past diffusion trend indicate that in India, even with highly favorable assumptions, the dissemination of wind power projects is not likely to reach its maximum estimated potential in another 15 years. CDM could help to achieve the maximum utilization potential more rapidly as compared to the current diffusion trend if supportive policies are introduced. PMID:17663772

  7. An insight into the gastrointestinal component of fibromyalgia: clinical manifestations and potential underlying mechanisms.

    PubMed

    Slim, Mahmoud; Calandre, Elena Pita; Rico-Villademoros, Fernando

    2015-03-01

    Fibromyalgia syndrome is characterized by chronic generalized pain accompanied by a broad symptomatologic spectrum. Besides chronic fatigue, sleep disturbances, headaches and cognitive dysfunction that are extensively described in the literature, a considerable proportion of patients with fibromyalgia experience gastrointestinal symptoms that are commonly overlooked in the studies that are not specifically dedicated to evaluate these manifestations. Nevertheless, various attempts were undertaken to explore the gastrointestinal dimension of fibromyalgia. Several studies have demonstrated an elevated comorbidity of irritable bowel syndrome (IBS) among patients with fibromyalgia. Other studies have investigated the frequency of presentation of gastrointestinal symptoms in fibromyalgia in a nonspecific approach describing several gastrointestinal complaints frequently reported by these patients such as abdominal pain, dyspepsia and bowel changes, among others. Several underlying mechanisms that require further investigation could serve as potential explanatory hypotheses for the appearance of such manifestations. These include sensitivity to dietary constituents such as gluten, lactose or FODMAPs or alterations in the brain-gut axis as a result of small intestinal bacterial overgrowth or subclinical enteric infections such as giardiasis. The gastrointestinal component of fibromyalgia constitutes a relevant element of the multidisciplinary pathophysiologic mechanisms underlying fibromyalgia that need to be unveiled, as this would contribute to the adequate designation of relevant treatment alternatives corresponding to these manifestations. PMID:25119830

  8. Potential underlying mechanisms for greater weight gain in massaged preterm infants.

    PubMed

    Field, Tiffany; Diego, Miguel; Hernandez-Reif, Maria

    2011-06-01

    In this paper, potential underlying mechanisms for massage therapy effects on preterm infant weight gain are reviewed. Path analyses are presented suggesting that: (1) increased vagal activity was associated with (2) increased gastric motility, which, in turn, was related to (3) greater weight gain; and (4) increased IGF-1 was related to greater weight gain. The change in vagal activity during the massage explained 49% of the variance in the change in gastric activity. And, the change in vagal activity during the massage explained 62% of the variance in the change in insulin. That the change in gastric activity was not related to the change in insulin suggests two parallel pathways via which massage therapy leads to increased weight gain: (1) insulin release via the celiac branch of the vagus; and (2) increased gastric activity via the gastric branch of the vagus. PMID:21570125

  9. PRGD/PDLLA conduit potentiates rat sciatic nerve regeneration and the underlying molecular mechanism.

    PubMed

    Li, Binbin; Qiu, Tong; Iyer, K Swaminathan; Yan, Qiongjiao; Yin, Yixia; Xie, Lijuan; Wang, Xinyu; Li, Shipu

    2015-07-01

    Peripheral nerve injury requires optimal conditions in both macro-environment and micro-environment for reestablishment. Though various strategies have been carried out to improve the macro-environment, the underlying molecular mechanism of axon regeneration in the micro-environment provided by nerve conduit remains unclear. In this study, the rat sciatic nerve of 10 mm defect was made and bridged by PRGD/PDLLA nerve conduit. We investigated the process of nerve regeneration using histological, functional and real time PCR analyses after implantation from 7 to 35 days. Our data demonstrated that the ciliary neurotrophic factor highly expressed and up-regulated the downstream signaling pathways, in the case of activated signals, the expressions of axon sprout relative proteins, such as tubulin and growth-associated protein-43, were strongly augmented. Taken together, these data suggest a possible mechanism of axon regeneration promoted by PRGD/PDLLA conduit, which created a micro-environment for enhancement of diffusion of neurotrophic factors secreted by the injured nerve stumps, and activation of molecular signal transduction involved in growth cone, to potentiate the nerve recovery. PMID:25934451

  10. Nanoscale copper in the soil–plant system – toxicity and underlying potential mechanisms

    SciTech Connect

    Anjum, Naser A.; Adam, Vojtech; Iqbal, Muhammad; Lukatkin, Alexander S.; Ahmad, Iqbal

    2015-04-15

    Nanoscale copper particles (nano-Cu) are used in many antimicrobial formulations and products for their antimicrobial activity. They may enter deliberately and/or accidentally into terrestrial environments including soils. Being the major ‘eco-receptors’ of nanoscale particles in the terrestrial ecosystem, soil–microbiota and plants (the soil–plant system) have been used as a model to dissect the potential impact of these particles on the environmental and human health. In the soil–plant system, the plant can be an indirect non-target organism of the soil-associated nano-Cu that may in turn affect plant-based products and their consumers. By all accounts, information pertaining to nano-Cu toxicity and the underlying potential mechanisms in the soil–plant system remains scanty, deficient and little discussed. Therefore, based on some recent reports from (bio)chemical, molecular and genetic studies of nano-Cu versus soil–plant system, this article: (i) overviews the status, chemistry and toxicity of nano-Cu in soil and plants, (ii) discusses critically the poorly understood potential mechanisms of nano-Cu toxicity and tolerance both in soil–microbiota and plants, and (iii) proposes future research directions. It appears from studies hitherto made that the uncontrolled generation and inefficient metabolism of reactive oxygen species through different reactions are the major factors underpinning the overall nano-Cu consequences in both the systems. However, it is not clear whether the nano-Cu or the ion released from it is the cause of the toxicity. We advocate to intensify the multi-approach studies focused at a complete characterization of the nano-Cu, its toxicity (during life cycles of the least-explored soil–microbiota and plants), and behavior in an environmentally relevant terrestrial exposure setting. Such studies may help to obtain a deeper insight into nano-Cu actions and address adequately the nano-Cu-associated safety concerns in the

  11. Shared cognitive and behavioral impairments in epilepsy and Alzheimer’s disease and potential underlying mechanisms

    PubMed Central

    Chin, Jeannie; Scharfman, Helen E.

    2014-01-01

    Seizures in patients with Alzheimer’s disease (AD) have been examined by many investigators over the last several decades, and there are diverse opinions about their potential relevance to AD pathophysiology. Some studies suggest that seizures appear to be a fairly uncommon co-morbidity, whereas other studies report a higher incidence of seizures in patients with AD. It was previously thought that seizures play a minor role in AD pathophysiology because of their low frequency, and also because they may only be noticed during late stages of AD, suggesting that seizures are likely to be a consequence of neurodegeneration rather than a contributing factor. However, clinical reports indicate that seizures can occur early in the emergence of AD symptoms, particularly in familial AD. In this case, seizures may be an integral part of the emerging pathophysiology. This view has been supported by evidence of recurrent spontaneous seizures in transgenic mouse models of AD in which familial AD is simulated. Additional data from transgenic animals suggest that there may be a much closer relationship between seizures and AD than previously considered. There is also evidence that seizures facilitate production of amyloid β (Aβ) and can cause impairments in cognition and behavior in both animals and humans. However, whether seizures play a role in the early stages of AD pathogenesis is still debated. Therefore, it is timely to review the similarities and differences between AD and epilepsy, as well as data suggesting that seizures may contribute to cognitive and behavioral dysfunction in AD. Here we focus on AD and temporal lobe epilepsy (TLE), a particular type of epilepsy that involves the temporal lobe, a region that influences behavior and is critical to memory. We also consider potential neuro-biological mechanisms that support the view that the causes of seizures in TLE may be related to the causes of cognitive dysfunction in AD. We suggest that similar underlying

  12. Potential neural mechanisms underlying the effectiveness of early intervention for children with autism spectrum disorder

    PubMed Central

    Sullivan, Katherine; Stone, Wendy L.; Dawson, Geraldine

    2014-01-01

    Although evidence supports the efficacy of early intervention for improving outcomes for children with autism spectrum disorder (ASD), the mechanisms underlying their effectiveness remain poorly understood. This paper reviews the research literature on the neural bases of the early core deficits in ASD and proposes three key features of early intervention related to the neural mechanisms that may contribute to its effectiveness in improving deficit areas. These features include (1) the early onset of intensive intervention which capitalizes on the experience-expectant plasticity of the immature brain, (2) the use of treatment strategies that address core deficits in social motivation through an emphasis on positive social engagement and arousal modulation, and (3) promotion of complex neural networks and connectivity through thematic, multi-sensory and multi-domain teaching approaches. Understanding the mechanisms of effective early intervention will enable us to identify common or foundational active ingredients for promoting optimal outcomes in children with ASD. PMID:25108609

  13. Spinal mechanisms underlying potentiation of hindpaw responses observed after transient hindpaw ischemia in mice

    PubMed Central

    Watanabe, Tatsunori; Sasaki, Mika; Komagata, Seiji; Tsukano, Hiroaki; Hishida, Ryuichi; Kohno, Tatsuro; Baba, Hiroshi; Shibuki, Katsuei

    2015-01-01

    Transient ischemia produces postischemic tingling sensation. Ischemia also produces nerve conduction block that may modulate spinal neural circuits. In the present study, reduced mechanical thresholds for hindpaw-withdrawal reflex were found in mice after transient hindpaw ischemia, which was produced by a high pressure applied around the hindpaw for 30 min. The reduction in the threshold was blocked by spinal application of LY354740, a specific agonist of group II metabotropic glutamate receptors. Neural activities in the spinal cord and the primary somatosensory cortex (S1) were investigated using activity-dependent changes in endogenous fluorescence derived from mitochondrial flavoproteins. Ischemic treatment induced potentiation of the ipsilateral spinal and contralateral S1 responses to hindpaw stimulation. Both types of potentiation were blocked by spinal application of LY354740. The contralateral S1 responses, abolished by lesioning the ipsilateral dorsal column, reappeared after ischemic treatment, indicating that postischemic tingling sensation reflects a sensory modality shift from tactile sensation to nociception in the spinal cord. Changes in neural responses were investigated during ischemic treatment in the contralateral spinal cord and the ipsilateral S1. Potentiation already appeared during ischemic treatment for 30 min. The present findings suggest that the postischemic potentiation shares spinal mechanisms, at least in part, with neuropathic pain. PMID:26165560

  14. Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on

    PubMed Central

    Granger, Adam J.; Nicoll, Roger A.

    2014-01-01

    This review focuses on the research that has occurred over the past decade which has solidified a postsynaptic expression mechanism for long-term potentiation (LTP). However, experiments that have suggested a presynaptic component are also summarized. It is argued that the pairing of glutamate uncaging onto single spines with postsynaptic depolarization provides the final and most elegant demonstration of a postsynaptic expression mechanism for NMDA receptor-dependent LTP. The fact that the magnitude of this LTP is similar to that evoked by pairing synaptic stimulation and depolarization leaves little room for a substantial presynaptic component. Finally, recent data also require a revision in our thinking about the way AMPA receptors (AMPARs) are recruited to the postsynaptic density during LTP. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors. PMID:24298139

  15. Repeated ischaemic preconditioning: a novel therapeutic intervention and potential underlying mechanisms.

    PubMed

    Thijssen, Dick H J; Maxwell, Joseph; Green, Daniel J; Cable, N Timothy; Jones, Helen

    2016-06-01

    What is the topic of this review? This review discusses the effects of repeated exposure of tissue to ischaemic preconditioning on cardiovascular function, the attendant adaptations and their potential clinical relevance. What advances does it highlight? We discuss the effects of episodic exposure to ischaemic preconditioning to prevent and/or attenuate ischaemic injury and summarize evidence pertaining to improvements in cardiovascular function and structure. Discussion is provided regarding the potential mechanisms that contribute to both local and systemic adaptation. Findings suggest that clinical benefits result from both the prevention of ischaemic events and the attenuation of their consequences. Ischaemic preconditioning (IPC) refers to the phenomenon whereby short periods of cyclical tissue ischaemia confer subsequent protection against ischaemia-induced injury. As a consequence, IPC can ameliorate the myocardial damage following infarction and can reduce infarct size. The ability of IPC to confer remote protection makes IPC a potentially feasible cardioprotective strategy. In this review, we discuss the concept that repeated exposure of tissue to IPC may increase the 'dose' of protection and subsequently lead to enhanced protection against ischaemia-induced myocardial injury. This may be relevant for clinical populations, who demonstrate attenuated efficacy of IPC to prevent or attenuate ischaemic injury (and therefore myocardial infarct size). Furthermore, episodic IPC facilitates repeated exposure to local (e.g. shear stress) and systemic stimuli (e.g. hormones, cytokines, blood-borne substances), which may induce improvement in vascular function and health. Such adaptation may contribute to prevention of cardio- and cerebrovascular events. The clinical benefits of repeated IPC may, therefore, result from both the prevention of ischaemic events and the attenuation of their consequences. We provide an overview of the literature pertaining to the impact

  16. Potential mechanisms underlying the Runx2 induced osteogenesis of bone marrow mesenchymal stem cells

    PubMed Central

    Xu, Jiahai; Li, Zhanghua; Hou, Yudong; Fang, Weijun

    2015-01-01

    Bone marrow derived mesenchymal stem cells (BM-MSCs) belong a type of pluripotent stem cells and can be induced to differentiate into osteoblasts (OB). Runt-related transcription factor 2 (Runx2) is an osteogenesis specific transcription factor and plays an important role in osteogenesis of BM-MSCs. It can promote the expression of osteogenesis related genes, regulate cell cycle progression, improve bone microenvironment and affect functions of chondrocytes and osteoclasts, which have involvement of a large amount of signal molecules including TGF-β, BMP, Notch, Wnt, Hedgehog, FGF and microRNA. In this paper, we summarize the mechanisms underlying the Runx2 induced osteogenesis of BM-MSCs. PMID:26885254

  17. Silver nanoparticles: their potential toxic effects after oral exposure and underlying mechanisms--a review.

    PubMed

    Gaillet, Sylvie; Rouanet, Jean-Max

    2015-03-01

    Because of their antimicrobial properties, the use of silver nanoparticles (AgNPs) is increasing fast in industry, food, and medicine. In the food industry, nanoparticles are used in packaging to enable better conservation products such as sensors to track their lifetime, and as food additives, such as anti-caking agents and clarifying agents for fruit juices. Nanoemulsions, used to encapsulate, protect and deliver additives are also actively developed. Nanomaterials in foods will be ingested and passed through the digestive tract. Those incorporated in food packaging may also be released unintentionally into food, ending up in the gastrointestinal tract. It is therefore important to make a risk assessment of nanomaterials to the consumer. Thus, exposure to AgNPs is increasing in quantity and it is imperative to know their adverse effects in man. However, controversies still remain with respect to their toxic effects and their mechanisms. Understanding the toxic effects and the interactions of AgNPs with biological systems is necessary to handle these nanoparticles and their use. They usually generate reactive oxygen species resulting in increased pro-inflammatory reactions and oxidative stress via intracellular signalling pathways. Here, we mainly focus on the routes of exposure of AgNPs, toxic effects and the mechanisms underlying the induced toxicity. PMID:25556118

  18. Molecular mechanisms underlying the potential antiobesity-related diseases effect of cocoa polyphenols.

    PubMed

    Ali, Faisal; Ismail, Amin; Kersten, Sander

    2014-01-01

    Obesity and related metabolic diseases (e.g., type 2 diabetes, cardiovascular diseases, and hypertension) are the most prevailing nutrition-related issues in the world. An emerging feature of obesity is their relationship with chronic inflammation that begins in white adipose tissue and eventually becomes systemic. One potential dietary strategy to reduce glucose intolerance and inflammation is consumption of polyphenol-rich cocoa-like cocoa or their by-products. In vitro as well as in vivo data indicate that cocoa polyphenols (CPs) may exhibit antioxidant and anti-inflammatory properties. Polyphenols commonly found in cocoa have been reported to regulate lipid metabolism via inducing metabolic gene expression or activating transcription factors that regulate the expression of numerous genes, many of which play an important role in energy metabolism. Currently, several molecular targets (e.g., nuclear factor Kappa B, activated protein-1, peroxisome proliferator-activated receptors, liver X receptors, and adiponectin gene) have been identified, which may explain potential beneficial obesity-associated diseases effects of CPs. Further studies have been performed regarding the protective effects of CPs against metabolic diseases by suppressing transcription factors that antagonize lipid accumulation. Thus, polyphenols-rich cocoa products may diminish obesity-mediated metabolic diseases by multiple mechanisms, thereby attenuating chronic inflammation. PMID:24259381

  19. Potential molecular mechanisms underlying muscle fatigue mediated by reactive oxygen and nitrogen species

    PubMed Central

    Debold, Edward P.

    2015-01-01

    Intense contractile activity causes a dramatic decline in the force and velocity generating capacity of skeletal muscle within a few minutes, a phenomenon that characterizes fatigue. Much of the research effort has focused on how elevated levels of the metabolites of ATP hydrolysis might inhibit the function of the contractile proteins. However, there is now growing evidence that elevated levels of reactive oxygen and nitrogen species (ROS/RNS), which also accumulate in the myoplasm during fatigue, also play a causative role in this type of fatigue. The most compelling evidence comes from observations demonstrating that pre-treatment of intact muscle with a ROS scavenger can significantly attenuate the development of fatigue. A clear advantage of this line of inquiry is that the molecular targets and protein modifications of some of the ROS scavengers are well-characterized enabling researchers to begin to identify potential regions and even specific amino acid residues modified during fatigue. Combining this knowledge with assessments of contractile properties from the whole muscle level down to the dynamic motions within specific contractile proteins enable the linking of the structural modifications to the functional impacts, using advanced chemical and biophysical techniques. Based on this approach at least two areas are beginning emerge as potentially important sites, the regulatory protein troponin and the actin binding region of myosin. This review highlights some of these recent efforts which have the potential to offer uniquely precise information on the underlying molecular basis of fatigue. This work may also have implications beyond muscle fatigue as ROS/RNS mediated protein modifications are also thought to play a role in the loss of muscle function with aging and in some acute pathologies like cardiac arrest and ischemia. PMID:26388779

  20. Potential mechanisms underlying the role of chronic inflammation in age-related muscle wasting.

    PubMed

    Jo, Edward; Lee, Sang-Rok; Park, Bong-Sup; Kim, Jeong-Su

    2012-10-01

    Sarcopenia, an age-related condition characterized by progressive skeletal muscle degeneration, might exist as one of the primary clinical conditions underlying severe functional impairment as well as increased risk of co-morbidities in the elderly. Although the etiology of sarcopenia remains multifaceted, age-related chronic inflammation has been strongly implicated in muscle wasting and related sequelae during advanced age. Recent evidence suggests that aberrant, unresolved alterations in regular inflammatory processes during advanced age might ultimately operate as the link that drives skeletal muscle to become more degenerative and dysfunctional in nature. Such negative atrophic muscular outcomes might result from inflammation-induced disruption of central mechanisms regulating skeletal muscle morphology and remodeling. In addition, recent findings demonstrate an adverse confluence between sarcopenia and excessive adiposity (i.e. sarcopenic obesity), as the co-existence of such adverse alterations in body composition may exacerbate systemic inflammation and muscle wasting in the elderly. The following evidence-based review serves to examine sarcopenia from a mechanistic perspective with emphasis on chronic inflammation. PMID:22717404

  1. A potential biochemical mechanism underlying the influence of sterol deprivation stress on Caenorhabditis elegans longevity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To investigate the biochemical mechanism for sterol-mediated alteration in aging in Caenorhabditis elegans, we established sterol depletion conditions by treating worms with azacoprostane, which reduced mean lifespan of adult C. elegans by 35%. Proteomic analyses of egg proteins from treated and un...

  2. Comparison of acuity tests and pattern evoked potential criteria: two mechanisms underly acuity maturation in man.

    PubMed

    Spekreijse, H

    1983-10-01

    A comparative study of acuity tests and pattern evoked potential (EP) criteria was performed on a total of 307 subjects, 214 of them at an age between 2 months post-term and 12 years. All were examined ophthalmologically prior to testing. It was shown that both psychophysical and EP estimated acuity improve in the same way until puberty. From birth to about 6 months a rapid improvement is found. This fast phase can probably be attributed to retinal morphological maturation. During this period a fair estimate of acuity can be obtained by determining the checksize that yields the largest EP; a conclusion of practical importance for screening. The subsequent slow improvement phase, which ends around puberty, is reflected in the development of the waveform of the pattern onset EP. Since it correlates with the growth of a spatial contrast specific component of extrastriate origin in the EP, the slow improvement phase most likely reflects maturation of central processes. PMID:6639719

  3. Control of appetite and energy intake by SCFA: what are the potential underlying mechanisms?

    PubMed

    Chambers, Edward S; Morrison, Douglas J; Frost, Gary

    2015-08-01

    In recent years, there has been a renewed interest in the role of dietary fibre in obesity management. Much of this interest stems from animal and human studies which suggest that an increased intake of fermentable fibre can suppress appetite and improve weight management. A growing number of reports have demonstrated that the principal products of colonic fermentation of dietary fibre, SCFA, contribute to energy homeostasis via effects on multiple cellular metabolic pathways and receptor-mediated mechanisms. In particular, over the past decade it has been identified that a widespread receptor system exists for SCFA. These G-protein-coupled receptors, free fatty acid receptor (FFAR) 2 and FFAR3 are expressed in numerous tissue sites, including the gut epithelium and adipose tissue. Investigations using FFAR2- or FFAR3-deficient animal models suggest that SCFA-mediated stimulation of these receptors enhances the release of the anorectic hormones peptide tyrosine tyrosine and glucagon-like peptide-1 from colonic L cells and leptin from adipocytes. In addition, the SCFA acetate has recently been shown to have a direct role in central appetite regulation. Furthermore, the SCFA propionate is a known precursor for hepatic glucose production, which has been reported to suppress feeding behaviour in ruminant studies through the stimulation of hepatic vagal afferents. The present review therefore proposes that an elevated colonic production of SCFA could stimulate numerous hormonal and neural signals at different organ and tissue sites that would cumulatively suppress short-term appetite and energy intake. PMID:25497601

  4. Harmaline Tremor: Underlying Mechanisms in a Potential Animal Model of Essential Tremor

    PubMed Central

    Handforth, Adrian

    2012-01-01

    Background Harmaline and harmine are tremorigenic β-carbolines that, on administration to experimental animals, induce an acute postural and kinetic tremor of axial and truncal musculature. This drug-induced action tremor has been proposed as a model of essential tremor. Here we review what is known about harmaline tremor. Methods Using the terms harmaline and harmine on PubMed, we searched for papers describing the effects of these β-carbolines on mammalian tissue, animals, or humans. Results Investigations over four decades have shown that harmaline induces rhythmic burst-firing activity in the medial and dorsal accessory inferior olivary nuclei that is transmitted via climbing fibers to Purkinje cells and to the deep cerebellar nuclei, then to brainstem and spinal cord motoneurons. The critical structures required for tremor expression are the inferior olive, climbing fibers, and the deep cerebellar nuclei; Purkinje cells are not required. Enhanced synaptic norepinephrine or blockade of ionic glutamate receptors suppresses tremor, whereas enhanced synaptic serotonin exacerbates tremor. Benzodiazepines and muscimol suppress tremor. Alcohol suppresses harmaline tremor but exacerbates harmaline-associated neural damage. Recent investigations on the mechanism of harmaline tremor have focused on the T-type calcium channel. Discussion Like essential tremor, harmaline tremor involves the cerebellum, and classic medications for essential tremor have been found to suppress harmaline tremor, leading to utilization of the harmaline model for preclinical testing of antitremor drugs. Limitations are that the model is acute, unlike essential tremor, and only approximately half of the drugs reported to suppress harmaline tremor are subsequently found to suppress tremor in clinical trials. PMID:23440018

  5. Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension

    PubMed Central

    Panzenboeck, Adelheid; Winter, Max P; Schubert, Uwe; Voswinckel, Robert; Frey, Maria K; Jakowitsch, Johannes; Alimohammadi, Arman; Hobohm, Lukas; Mangold, Andreas; Bergmeister, Helga; Sibilia, Maria; Wagner, Erwin F; Mayer, Eckhard; Klepetko, Walter; Hoelzenbein, Thomas J; Preissner, Klaus T; Lang, Irene M

    2015-01-01

    Objective Restoration of patency is a natural target of vascular remodeling following venous thrombosis that involves vascular endothelial cells and smooth muscle cells as well as leukocytes. Acute pulmonary emboli usually resolve within six months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results Mice with an endothelial-cell-specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor (VEGF-R2/Kdr) were utilized in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of non-resolving venous thromboembolism. Endothelial cell-specific deletion of Kdr and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes such as KDR, vascular endothelial cadherin and podoplanin were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by VEGF. Conclusions In the present work, we propose a mechanism of thrombus non-resolution demonstrating that endothelial cell-specific deletion of Kdr abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis. PMID:24526692

  6. Exploring Potential Mechanisms Underlying the Lack of Uncertainty Monitoring in Capuchin Monkeys

    PubMed Central

    Perdue, Bonnie M.; Church, Barbara A; Smith, J. David; Beran, Michael J.

    2015-01-01

    In a widely used animal-metacognition paradigm, monkeys are positively reinforced with food for correct classifications of stimuli as sparse or dense and punished with timeouts for incorrect responses, but they also have access to an “uncertainty” response that moves them to the next trial without either of these forms of feedback. Rhesus monkeys use this uncertainty response most often for trials on which they are at greatest risk for making an error, suggesting that they are monitoring their ability to make these classifications. Capuchin monkeys do not succeed to the same degree on these tasks—conceivably as a result of differential contingencies in place in all existing studies between the sparse/dense responses (food delivery or timeout) and the uncertainty response (avoidance of a timeout but also no chance for food reward). Here, we used a novel variation of this task in which the outcomes of the three response classes (sparse, dense, uncertain) were functionally equivalent. All responses simply determined the delay interval before presentation of a second task (matching-to-sample), and that task yielded potential food rewards. Overall, capuchin monkeys used the dense and sparse responses appropriately, including some animals that had no prior experience in performing this classification task. However, none used the uncertainty response appropriately even when it was placed on the same contingency plane as the dense and sparse responses. This suggests that the failure of capuchin monkeys to use an uncertainty response is not the result of that response producing a qualitatively different outcome compared to the dense and sparse responses. PMID:26985137

  7. Despair-associated memory requires a slow-onset CA1 long-term potentiation with unique underlying mechanisms

    PubMed Central

    Jing, Liang; Duan, Ting-Ting; Tian, Meng; Yuan, Qiang; Tan, Ji-Wei; Zhu, Yong-Yong; Ding, Ze-Yang; Cao, Jun; Yang, Yue-Xiong; Zhang, Xia; Mao, Rong-Rong; Richter-levin, Gal; Zhou, Qi-Xin; Xu, Lin

    2015-01-01

    The emotion of despair that occurs with uncontrollable stressful event is probably retained by memory, termed despair-associated memory, although little is known about the underlying mechanisms. Here, we report that forced swimming (FS) with no hope to escape, but not hopefully escapable swimming (ES), enhances hippocampal α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-dependent GluA1 Ser831 phosphorylation (S831-P), induces a slow-onset CA1 long-term potentiation (LTP) in freely moving rats and leads to increased test immobility 24-h later. Before FS application of the antagonists to block S831-P or N-methyl-D-aspartic acid receptor (NMDAR) or glucocorticoid receptor (GR) disrupts LTP and reduces test immobility, to levels similar to those of the ES group. Because these mechanisms are specifically linked with the hopeless of escape from FS, we suggest that despair-associated memory occurs with an endogenous CA1 LTP that is intriguingly mediated by a unique combination of rapid S831-P with NMDAR and GR activation to shape subsequent behavioral despair. PMID:26449319

  8. Despair-associated memory requires a slow-onset CA1 long-term potentiation with unique underlying mechanisms.

    PubMed

    Jing, Liang; Duan, Ting-Ting; Tian, Meng; Yuan, Qiang; Tan, Ji-Wei; Zhu, Yong-Yong; Ding, Ze-Yang; Cao, Jun; Yang, Yue-Xiong; Zhang, Xia; Mao, Rong-Rong; Richter-Levin, Gal; Zhou, Qi-Xin; Xu, Lin

    2015-01-01

    The emotion of despair that occurs with uncontrollable stressful event is probably retained by memory, termed despair-associated memory, although little is known about the underlying mechanisms. Here, we report that forced swimming (FS) with no hope to escape, but not hopefully escapable swimming (ES), enhances hippocampal α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-dependent GluA1 Ser831 phosphorylation (S831-P), induces a slow-onset CA1 long-term potentiation (LTP) in freely moving rats and leads to increased test immobility 24-h later. Before FS application of the antagonists to block S831-P or N-methyl-D-aspartic acid receptor (NMDAR) or glucocorticoid receptor (GR) disrupts LTP and reduces test immobility, to levels similar to those of the ES group. Because these mechanisms are specifically linked with the hopeless of escape from FS, we suggest that despair-associated memory occurs with an endogenous CA1 LTP that is intriguingly mediated by a unique combination of rapid S831-P with NMDAR and GR activation to shape subsequent behavioral despair. PMID:26449319

  9. Meditation as a Therapeutic Intervention for Adults at Risk for Alzheimer’s Disease – Potential Benefits and Underlying Mechanisms

    PubMed Central

    Innes, Kim E.; Selfe, Terry Kit

    2014-01-01

    Alzheimer’s disease (AD) is a chronic, progressive, brain disorder that affects at least 5.3 million Americans at an estimated cost of $148 billion, figures that are expected to rise steeply in coming years. Despite decades of research, there is still no cure for AD, and effective therapies for preventing or slowing progression of cognitive decline in at-risk populations remain elusive. Although the etiology of AD remains uncertain, chronic stress, sleep deficits, and mood disturbance, conditions common in those with cognitive impairment, have been prospectively linked to the development and progression of both chronic illness and memory loss and are significant predictors of AD. Therapies such as meditation that specifically target these risk factors may thus hold promise for slowing and possibly preventing cognitive decline in those at risk. In this study, we briefly review the existing evidence regarding the potential utility of meditation as a therapeutic intervention for those with and at risk for AD, discuss possible mechanisms underlying the observed benefits of meditation, and outline directions for future research. PMID:24795656

  10. Net mineralization of N at deeper soil depths as a potential mechanism for sustained forest production under elevated [CO2

    SciTech Connect

    Iversen, Colleen M; Hooker, Toby; Classen, Aimee T; Norby, Richard J

    2011-01-01

    Elevated atmospheric [CO2] is projected to increase forest production, which could increase ecosystem carbon (C) storage. However, sustained forest production will depend on the nutrient balance of the forested ecosystem. Our aim was to examine the causes and consequences of increased fine-root production and mortality throughout the soil profile under elevated CO2 with respect to potential gross nitrogen (N) cycling rates. Our study was conducted in a CO2-enriched sweetgum (Liquidambar styraciflua L.) plantation in Oak Ridge, TN, USA. We used isotope pool dilution methodology to measure potential gross N cycling rates in laboratory incubations of soil from four depth increments to 60 cm. Our objectives were two-fold: (1) determine whether N is available for root acquisition in deeper soil, and (2) determine whether increased inputs of labile C from greater fine-root mortality at depth under elevated [CO2] had altered N cycling rates. While gross N fluxes declined with soil depth, we found that N is potentially available for roots to access, especially below 15 cm depth where microbial consumption of mineral N was reduced. Overall, up to 60% of potential gross N mineralization, and 100% of potential net N mineralization, occurred below 15-cm depth at this site. This finding was supported by in situ measurements from ion-exchange resins, where total inorganic N availability at 55 cm depth was equal to or greater than N availability at 15 cm depth. While it is likely that trees grown under elevated [CO2] are accessing a larger pool of inorganic N by mining deeper soil, we found no effect of elevated [CO2] on potential gross or net N cycling rates. Thus, increased root exploration of the soil volume under elevated [CO2] may be more important than changes in potential gross N cycling rates in sustaining forest responses to rising atmospheric CO2.

  11. Alteration of Basaltic Glass to Mg/Fe-Smectite under Acidic Conditions: A Potential Smectite Formation Mechanism on Mars

    NASA Technical Reports Server (NTRS)

    Peretyazhko, Tanya; Sutter, Brad; Ming, Douglas W.

    2014-01-01

    Phyllosilicates of the smectite group including Mg- and Fe-saponite and Fe(III)-rich nontronite have been identified on Mars. Smectites are believed to be formed under neutral to alkaline conditions that prevailed on early Mars. This hypothesis is supported by the observation of smectite and carbonate deposits in Noachian terrain on Mars. However, smectite may have formed under mildly acidic conditions. Abundant smectite formations have been detected as layered deposits hundreds of meters thick in intracrater depositional fans and plains sediments, while no large deposits of carbonates are found. Development of mildly acidic conditions at early Mars might allow formation of smectite but inhibit widespread carbonate precipitation. Little is known regarding the mechanisms of smectite formation from basaltic glass under acidic conditions. The objective of this study was to test a hypothesis that Mars-analogue basaltic glass alters to smectite minerals under acidic conditions (pH 4). The effects of Mg and Fe concentrations and temperature on smectite formation from basaltic glass were evaluated. Phyllosilicate synthesis was performed in batch reactors (Parr acid digestion vessel) under reducing hydrothermal conditions at 200 C and 100 C. Synthetic basaltic glass with a composition similar to that of the Gusev crater rock Adirondack (Ground surface APXS measurement) was used in these experiments. Basaltic glass was prepared by melting and quenching procedures. X-ray diffraction (XRD) analysis indicated that the synthesized glass was composed of olivine, magnetite and X-ray amorphous phase. Samples were prepared by mixing 250 mg Adirondack with 0.1 M acetic acid (final pH 4). In order to study influence of Mg concentration on smectite formation, experiments were performed with addition of 0, 1 and 10 mM MgCl2. After 1, 7 and 14 day incubations the solution composition was analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and the altered glass and formed

  12. Phytochemicals in regulating fatty acid β-oxidation: Potential underlying mechanisms and their involvement in obesity and weight loss.

    PubMed

    Rupasinghe, H P Vasantha; Sekhon-Loodu, Satvir; Mantso, Theodora; Panayiotidis, Mihalis I

    2016-09-01

    Excessive accumulation of fat as the result of more energy intake and less energy expenditure is known as obesity. Lipids are essential components in the human body and are vital for maintaining homeostasis and physiological as well as cellular metabolism. Fatty acid synthesis and catabolism (by fatty acid oxidation) are normal part of basic fuel metabolism in animals. Fatty acids are degraded in the mitochondria by a biochemical process called β-oxidation in which two-carbon fragments are produced in each cycle. The increase in fatty acid β-oxidation is negatively correlated with body mass index. Although healthy life style, avoiding Western diet, dieting and strenuous exercise are the commonly used methods to lose weight, they are not considered a permanent solution in addition to risk attenuation of basal metabolic rate (BMR). Pharmacotherapy offers benefits of weight loss by altering the satiety and lowering absorption of fat from the food; however, its side effects may outweigh the benefits of weight loss. Alternatively, dietary phytochemicals and natural health products offer great potential as an efficient weight loss strategy by modulating lipid metabolism and/or increasing BMR and thermogenesis. Specifically, polyphenols such as citrus flavonoids, green tea epigallocatechin gallate, resveratrol, capsaicin and curcumin, have been reported to increase lipolysis and induce fatty acid β-oxidation through modulation of hormone sensitive lipase, acetyl-coA carboxylase, carnitine acyl transferase and peroxisome proliferator-activated receptor gamma coactivator-1. In this review article, we discuss selected phytochemicals in relation to their integrated functionalities and specific mechanisms for weight loss. PMID:27288729

  13. Measurement of conduction band deformation potential constants using gate direct tunneling current in n-type metal oxide semiconductor field effect transistors under mechanical stress

    NASA Astrophysics Data System (ADS)

    Lim, Ji-Song; Yang, Xiaodong; Nishida, Toshikazu; Thompson, Scott E.

    2006-08-01

    An experimental method to determine both the hydrostatic and shear deformation potential constants is introduced. The technique is based on the change in the gate tunneling currents of Si-metal oxide semiconductor field effect transistors (MOSFETs) under externally applied mechanical stress and has been applied to industrial n-type MOSFETs. The conduction band hydrostatic and shear deformation potential constants (Ξd and Ξu) are extracted to be 1.0±0.1 and 9.6±1.0eV, respectively, which is consistent with recent theoretical works.

  14. Comparison of brain mechanisms underlying the processing of Chinese characters and pseudo-characters: an event-related potential study.

    PubMed

    Wang, Ting; Li, Hong; Zhang, Qinglin; Tu, Shen; Yu, Caiyun; Qiu, Jiang

    2010-04-01

    Most Chinese characters are composed of a semantic radical on the left and a phonetic radical on the right. The semantic radical provides the semantic information; the phonetic radical provides information concerning the pronunciation of the whole character. The pseudo-characters in the study consisted of different sub-lexical parts of real Chinese characters and consequently they also had the semantic radical and the phonetic radical. But they were not readable and had no actual meaning. In order to investigate the spatiotemporal cortical activation patterns underlying the orthographic, phonological and semantic processing of Chinese characters, we used event-related brain potentials (ERPs) to explore the processing of Chinese characters and pseudo-characters when 14 healthy Chinese college students viewed the characters passively. Results showed that both Chinese characters and pseudo-characters elicited an evident negative potential peaking around 120 ms (N120), which appeared to reflect initial orthographic distinction and evaluation. Then, Chinese pseudo-characters elicited a more positive ERP deflection (P220) than did Chinese characters 200-250 ms after onset of the stimuli. It was similar to the recognition potential (RP) and might reflect the integration processes of phonological and semantic processing on the basis of early orthographic information. Dipole source analysis of the difference wave (pseudo-characters minus characters) indicated that a generator localized in the left temporal-occipital junction contributed to this effect, which was possibly related to phonological and perceptual-semantic information integration. Between 350-450 ms, a greater negativity (N360) in pseudo-characters as compared to characters was found over midline fronto-central scalp regions. Dipole analysis localized the generator of N360 in the right parahippocampal cortex. Therefore, the N360 might be an N400 component and reflect the higher-level semantic activation on the

  15. A brief update on potential molecular mechanisms underlying antimicrobial and wound-healing potency of snake venom molecules.

    PubMed

    Samy, Ramar Perumal; Sethi, Gautam; Lim, Lina H K

    2016-09-01

    Infectious diseases remain a significant cause of morbidity and mortality worldwide. A wide range of diverse, novel classes of natural antibiotics have been isolated from different snake species in the recent past. Snake venoms contain diverse groups of proteins with potent antibacterial activity against a wide range of human pathogens. Some snake venom molecules are pharmacologically attractive, as they possess promising broad-spectrum antibacterial activities. Furthermore, snake venom proteins (SVPs)/peptides also bind to integrins with high affinity, thereby inhibiting cell adhesion and accelerating wound healing in animal models. Thus, SVPs are a potential alternative to chemical antibiotics. The mode of action for many antibacterial peptides involves pore formation and disruption of the plasma membrane. This activity often includes modulation of nuclear factor kappa B (NF-κB) activation during skin wound healing. The NF-κB pathway negatively regulates the transforming growth factor (TGF)-β1/Smad pathway by inducing the expression of Smad7 and eventually reducing in vivo collagen production at the wound sites. In this context, SVPs that regulate the NF-κB signaling pathway may serve as potential targets for drug development. PMID:26975619

  16. Examination of the cytotoxic and embryotoxic potential and underlying mechanisms of next-generation synthetic trioxolane and tetraoxane antimalarials.

    PubMed

    Copple, Ian M; Mercer, Amy E; Firman, James; Donegan, Gail; Herpers, Bram; Wong, Michael Hl; Chadwick, James; Bringela, Andreia D; Cristiano, Maria L S; van de Water, Bob; Ward, Stephen A; O'Neill, Paul M; Park, B Kevin

    2012-01-01

    Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria. PMID:22669474

  17. Snapping mechanical metamaterials under tension.

    PubMed

    Rafsanjani, Ahmad; Akbarzadeh, Abdolhamid; Pasini, Damiano

    2015-10-21

    A snapping mechanical metamaterial is designed, which exhibits a sequential snap-through behavior under tension. The tensile response of this mechanical metamaterial can be altered by tuning the architecture of the snapping segments to achieve a range of nonlinear mechanical responses, including monotonic, S-shaped, plateau, and non-monotonic snap-through behavior. PMID:26314680

  18. Quantum mechanics without potential function

    SciTech Connect

    Alhaidari, A. D.; Ismail, M. E. H.

    2015-07-15

    In the standard formulation of quantum mechanics, one starts by proposing a potential function that models the physical system. The potential is then inserted into the Schrödinger equation, which is solved for the wavefunction, bound states energy spectrum, and/or scattering phase shift. In this work, however, we propose an alternative formulation in which the potential function does not appear. The aim is to obtain a set of analytically realizable systems, which is larger than in the standard formulation and may or may not be associated with any given or previously known potential functions. We start with the wavefunction, which is written as a bounded infinite sum of elements of a complete basis with polynomial coefficients that are orthogonal on an appropriate domain in the energy space. Using the asymptotic properties of these polynomials, we obtain the scattering phase shift, bound states, and resonances. This formulation enables one to handle not only the well-known quantum systems but also previously untreated ones. Illustrative examples are given for two- and three-parameter systems.

  19. Neural Dynamics Underlying Event-Related Potentials

    NASA Technical Reports Server (NTRS)

    Shah, Ankoor S.; Bressler, Steven L.; Knuth, Kevin H.; Ding, Ming-Zhou; Mehta, Ashesh D.; Ulbert, Istvan; Schroeder, Charles E.

    2003-01-01

    There are two opposing hypotheses about the brain mechanisms underlying sensory event-related potentials (ERPs). One holds that sensory ERPs are generated by phase resetting of ongoing electroencephalographic (EEG) activity, and the other that they result from signal averaging of stimulus-evoked neural responses. We tested several contrasting predictions of these hypotheses by direct intracortical analysis of neural activity in monkeys. Our findings clearly demonstrate evoked response contributions to the sensory ERP in the monkey, and they suggest the likelihood that a mixed (Evoked/Phase Resetting) model may account for the generation of scalp ERPs in humans.

  20. Neural Mechanisms Underlying Breathing Complexity

    PubMed Central

    Hess, Agathe; Yu, Lianchun; Klein, Isabelle; De Mazancourt, Marine; Jebrak, Gilles; Mal, Hervé; Brugière, Olivier; Fournier, Michel; Courbage, Maurice; Dauriat, Gaelle; Schouman-Clayes, Elisabeth; Clerici, Christine; Mangin, Laurence

    2013-01-01

    Breathing is maintained and controlled by a network of automatic neurons in the brainstem that generate respiratory rhythm and receive regulatory inputs. Breathing complexity therefore arises from respiratory central pattern generators modulated by peripheral and supra-spinal inputs. Very little is known on the brainstem neural substrates underlying breathing complexity in humans. We used both experimental and theoretical approaches to decipher these mechanisms in healthy humans and patients with chronic obstructive pulmonary disease (COPD). COPD is the most frequent chronic lung disease in the general population mainly due to tobacco smoke. In patients, airflow obstruction associated with hyperinflation and respiratory muscles weakness are key factors contributing to load-capacity imbalance and hence increased respiratory drive. Unexpectedly, we found that the patients breathed with a higher level of complexity during inspiration and expiration than controls. Using functional magnetic resonance imaging (fMRI), we scanned the brain of the participants to analyze the activity of two small regions involved in respiratory rhythmogenesis, the rostral ventro-lateral (VL) medulla (pre-Bötzinger complex) and the caudal VL pons (parafacial group). fMRI revealed in controls higher activity of the VL medulla suggesting active inspiration, while in patients higher activity of the VL pons suggesting active expiration. COPD patients reactivate the parafacial to sustain ventilation. These findings may be involved in the onset of respiratory failure when the neural network becomes overwhelmed by respiratory overload We show that central neural activity correlates with airflow complexity in healthy subjects and COPD patients, at rest and during inspiratory loading. We finally used a theoretical approach of respiratory rhythmogenesis that reproduces the kernel activity of neurons involved in the automatic breathing. The model reveals how a chaotic activity in neurons can

  1. In search of underlying mechanisms and potential drugs of melphalan-induced vascular toxicity through retinal endothelial cells using bioinformatics approach.

    PubMed

    Yang, Yang; Xing, Yiqiao; Liang, Chaoqun; Hu, Liya; Xu, Fei; Mei, Qi

    2016-05-01

    We aimed to explore molecular mechanism and drug candidates of vascular toxicities associated with melphalan after treating human retinal endothelial cells (RECs). GSE34381 microarray data was firstly downloaded and used to identify the differentially expressed genes (DEGs) in human REC treated with melphalan vs. untreated cells by limma package in R language. The transcription network was constructed based on TRANSFAC database and the top five transcription factors (TFs) were select with a measure of regulatory impact factor, followed by the construction of function modules. Gene ontology enrichment analyses were performed to explore the enriched functions. Connectivity Map analysis was conducted to predict the potential drugs overcoming the melphalan's actions on REC. Totally, 75 DEGs were identified, including 70 up-regulated and five down-regulated genes. Transcription network with 1311 nodes and 1875 edges was constructed and the top five TFs were CREM, MYC, FLI1, NF-κB1, and JUN. Functional modules indicated that NF-κB1 and MYC were the important nodes. The upregulated genes as well as the genes involved in the modules mainly participated in biological process of immune response, cell proliferation, and cell motion. Five small molecules were predicted to be potential drug candidates, including doxorubicin, fipexide, daunorubicin, tiabendazole, and GW-8510. Based on these results, we speculate that NF-κB1 and MYC might involve in the molecular mechanism of vascular toxicity induced by melphalan through regulating their target genes. Five small molecules might be drug candidates to overcome the melphalan-induced vascular toxicity via targeting to MYC and JUN. PMID:26662105

  2. Scleral Mechanisms Underlying Ocular Growth and Myopia

    PubMed Central

    Metlapally, Ravi; Wildsoet, Christine F.

    2015-01-01

    In the regulation of ocular growth, scleral events critically determine eye size and thus the refractive status of the eye. Increased scleral matrix remodeling can lead to exaggerated eye growth causing myopia and additionally increased risk of ocular pathological complications. Thus, therapies targeting these changes in sclera hold potential to limit such complications since sclera represents a relatively safe and accessible drug target. Understanding the scleral molecular mechanisms underlying ocular growth is essential to identifying plausible therapeutic targets in the sclera. This section provides a brief update on molecular studies that pertain to the sclera in the context of ocular growth regulation and myopia. PMID:26310158

  3. Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells

    PubMed Central

    Yaniv, Yael; Lyashkov, Alexey E.; Sirenko, Syevda; Okamoto, Yosuke; Guiriba, Toni-Rose; Ziman, Bruce D.; Morrell, Christopher H.; Lakatta, Edward G.

    2014-01-01

    Recent evidence indicates that the spontaneous action potential (AP) of isolated sinoatrial node cells (SANC) is regulated by a system of stochastic mechanisms embodied within two clocks: ryanodine receptors of the “Ca2+ clock” within the sarcoplasmic reticulum, spontaneously activate during diastole and discharge local Ca2+ releases (LCRs) beneath the cell surface membrane; clock crosstalk occurs as LCRs activate an inward Na+/Ca2+ exchanger current (INCX), which together with If and decay of K+ channels prompts the “M clock,” the ensemble of sarcolemmal-electrogenic molecules, to generate APs. Prolongation of the average LCR period accompanies prolongation of the average AP beating interval (BI). Moreover, prolongation of the average AP BI accompanies increased AP BI variability. We hypothesized that both the average AP BI and AP BI variability are dependent upon stochasticity of clock mechanisms reported by the variability of LCR period. We perturbed the coupled-clock system by directly inhibiting the M clock by ivabradine (IVA) or the Ca2+ clock by cyclopiazonic acid (CPA). When either clock is perturbed by IVA (3, 10 and 30μM), which has no direct effect on Ca2+ cycling, or CPA ( 0.5 and 5μM), which has no direct effect on the M clock ion channels, the clock system failed to achieve the basal AP BI and both AP BI and AP BI variability increased. The changes in average LCR period and its variability in response to perturbations of the coupled-clock system were correlated with changes in AP beating interval and AP beating interval variability. We conclude that the stochasticity within the coupled-clock system affects and is affected by the AP BI firing rate and rhythm via modulation of the effectiveness of clock coupling. PMID:25257916

  4. Molecular Mechanisms Underlying Pituitary Pathogenesis.

    PubMed

    Sapochnik, Melanie; Nieto, Leandro Eduardo; Fuertes, Mariana; Arzt, Eduardo

    2016-04-01

    During the last years, progress has been made on the identification of mechanisms involved in anterior pituitary cell transformation and tumorigenesis. Oncogene activation, tumor suppressor gene inactivation, epigenetic changes, and microRNAs deregulation contribute to the initiation of pituitary tumors. Despite the high prevalence of pituitary adenomas, they are mostly benign, indicating that intrinsic mechanisms may regulate pituitary cell expansion. Senescence is characterized by an irreversible cell cycle arrest and represents an important protective mechanism against malignancy. Pituitary tumor transforming gene (PTTG) is an oncogene involved in early stages of pituitary tumor development, and also triggers a senescence response by activating DNA-damage signaling pathway. Cytokines, as well as many other factors, play an important role in pituitary physiology, affecting not only cell proliferation but also hormone secretion. Special interest is focused on interleukin-6 (IL-6) because its dual function of stimulating pituitary tumor cell growth but inhibiting normal pituitary cells proliferation. It has been demonstrated that IL-6 has a key role in promoting and maintenance of the senescence program in tumors. Senescence, triggered by PTTG activation and mediated by IL-6, may be a mechanism for explaining the benign nature of pituitary tumors. PMID:26718581

  5. Neuroendocrine immunomodulation network dysfunction in SAMP8 mice and PrP-hAβPPswe/PS1ΔE9 mice: potential mechanism underlying cognitive impairment.

    PubMed

    Wang, Jian-Hui; Cheng, Xiao-Rui; Zhang, Xiao-Rui; Wang, Tong-Xing; Xu, Wen-Jian; Li, Fei; Liu, Feng; Cheng, Jun-Ping; Bo, Xiao-Chen; Wang, Sheng-Qi; Zhou, Wen-Xia; Zhang, Yong-Xiang

    2016-04-26

    Senescence-accelerated mouse prone 8 strain (SAMP8) and PrP-hAβPPswe/PS1ΔE9 (APP/PS1) mice are classic animal models of sporadic Alzheimer's disease and familial AD respectively. Our study showed that object recognition memory, spatial learning and memory, active and passive avoidance were deteriorated and neuroendocrine immunomodulation (NIM) network was imbalance in SAMP8 and APP/PS1 mice. SAMP8 and APP/PS1 mice had their own specific phenotype of cognition, neuroendocrine, immune and NIM molecular network. The endocrine hormone corticosterone, luteinizing hormone and follicle-stimulating hormone, chemotactic factor monocyte chemotactic protein-1, macrophage inflammatory protein-1β, regulated upon activation normal T cell expressed and secreted factor and eotaxin, pro-inflammatory factor interleukin-23, and the Th1 cell acting as cell immunity accounted for cognitive deficiencies in SAMP8 mice, while adrenocorticotropic hormone and gonadotropin-releasing hormone, colony stimulating factor granulocyte colony stimulating factor, and Th2 cell acting as humoral immunity in APP/PS1 mice. On the pathway level, chemokine signaling and T cell receptor signaling pathway played the key role in cognition impairments of two models, while cytokine-cytokine receptor interaction and natural killer cell mediated cytotoxicity were more important in cognitive deterioration of SAMP8 mice than APP/PS1 mice. This mechanisms of NIM network underlying cognitive impairment is significant for further understanding the pathogenesis of AD and can provide useful information for development of AD therapeutic drug. PMID:27049828

  6. Mechanisms Underlying Inflammation in Neurodegeneration

    PubMed Central

    Glass, Christopher K.; Saijo, Kaoru; Winner, Beate; Marchetto, Maria Carolina; Gage, Fred H.

    2010-01-01

    Inflammation is associated with many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In this Review, we discuss inducers, sensors, transducers, and effectors of neuroinflammation that contribute to neuronal dysfunction and death. Although inducers of inflammation may be generated in a disease-specific manner, there is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators. A major unanswered question is whether pharmacological inhibition of inflammation pathways will be able to safely reverse or slow the course of disease. PMID:20303880

  7. Metacognitive mechanisms underlying lucid dreaming.

    PubMed

    Filevich, Elisa; Dresler, Martin; Brick, Timothy R; Kühn, Simone

    2015-01-21

    Lucid dreaming is a state of awareness that one is dreaming, without leaving the sleep state. Dream reports show that self-reflection and volitional control are more pronounced in lucid compared with nonlucid dreams. Mostly on these grounds, lucid dreaming has been associated with metacognition. However, the link to lucid dreaming at the neural level has not yet been explored. We sought for relationships between the neural correlates of lucid dreaming and thought monitoring. Human participants completed a questionnaire assessing lucid dreaming ability, and underwent structural and functional MRI. We split participants based on their reported dream lucidity. Participants in the high-lucidity group showed greater gray matter volume in the frontopolar cortex (BA9/10) compared with those in the low-lucidity group. Further, differences in brain structure were mirrored by differences in brain function. The BA9/10 regions identified through structural analyses showed increases in blood oxygen level-dependent signal during thought monitoring in both groups, and more strongly in the high-lucidity group. Our results reveal shared neural systems between lucid dreaming and metacognitive function, in particular in the domain of thought monitoring. This finding contributes to our understanding of the mechanisms enabling higher-order consciousness in dreams. PMID:25609624

  8. Mechanisms underlying Children's susceptibility to environmental toxicants.

    PubMed Central

    Faustman, E M; Silbernagel, S M; Fenske, R A; Burbacher, T M; Ponce, R A

    2000-01-01

    An important public health challenge has been the need to protect children's health. To accomplish this goal, the scientific community needs scientifically based child-specific risk assessment methods. Critical to their development is the need to understand mechanisms underlying children's sensitivity to environmental toxicants. Risk is defined as the probability of adverse outcome and when applied to environmental risk assessment is usually defined as a function of both toxicity and exposure. To adequately evaluate the potential for enhanced health risks during development, both child-specific factors affecting toxicity and exposure need to be considered. In the first section of this article, example mechanisms of susceptibility relevant for toxicity assessment are identified and discussed. In the second section, examples of exposure factors that help define children's susceptibility are presented. Examples of pesticide research from the newly funded Child Health Center at the University of Washington will be given for illustration. The final section discusses the importance of putting these considerations of children's susceptibility into an overall framework for ascertaining relevancy for human risk assessment. Images Figure 1 Figure 3 Figure 4 Figure 5 Figure 6 PMID:10698720

  9. Deformation Mechanisms of Gum Metals Under Nanoindentation

    NASA Astrophysics Data System (ADS)

    Sankaran, Rohini Priya

    Gum Metal is a set of multi-component beta-Ti alloys designed and developed by Toyota Central R&D Labs in 2003 to have a nearly zero shear modulus in the direction. After significant amounts of cold-work (>90%), these alloys were found to have yield strengths at a significant fraction of the predicted ideal strengths and exhibited very little work hardening. It has been speculated that this mechanical behavior may be realized through an ideal shear mechanism as opposed to conventional plastic deformation mechanisms, such as slip, and that such a mechanism may be realized through a defect structure termed "nanodisturbance". It is furthermore theorized that for near ideal strength to be attained, dislocations need to be pinned at sufficiently high stresses. It is the search for these defects and pinning points that motivates the present study. However, the mechanism of plastic deformation and the true origin of specific defect structures unique to gum metals is still controversial, mainly due to the complexity of the beta-Ti alloy system and the heavily distorted lattice exhibited in cold worked gum metals, rendering interpretation of images difficult. Accordingly, the first aim of this study is to clarify the starting as-received microstructures of gum metal alloys through conventional transmission electron microscopy (TEM) and aberration-corrected high resolution scanning transmission electron microscopy with high-angle annular dark field detector (HAADF-HRSTEM) imaging. To elucidate the effects of beta-stability and starting microstructure on the deformation behavior of gum metals and thus to provide adequate context for potentially novel deformation structures, we investigate three alloy conditions: gum metal that has undergone solution heat treatment (STGM), gum metal that has been heavily cold worked (CWGM), and a solution treated alloy of nominal gum metal composition, but leaner in beta-stabilizing content (ST Ref-1). In order to directly relate observed

  10. Deformation Mechanisms of Gum Metals Under Nanoindentation

    NASA Astrophysics Data System (ADS)

    Sankaran, Rohini Priya

    Gum Metal is a set of multi-component beta-Ti alloys designed and developed by Toyota Central R&D Labs in 2003 to have a nearly zero shear modulus in the direction. After significant amounts of cold-work (>90%), these alloys were found to have yield strengths at a significant fraction of the predicted ideal strengths and exhibited very little work hardening. It has been speculated that this mechanical behavior may be realized through an ideal shear mechanism as opposed to conventional plastic deformation mechanisms, such as slip, and that such a mechanism may be realized through a defect structure termed "nanodisturbance". It is furthermore theorized that for near ideal strength to be attained, dislocations need to be pinned at sufficiently high stresses. It is the search for these defects and pinning points that motivates the present study. However, the mechanism of plastic deformation and the true origin of specific defect structures unique to gum metals is still controversial, mainly due to the complexity of the beta-Ti alloy system and the heavily distorted lattice exhibited in cold worked gum metals, rendering interpretation of images difficult. Accordingly, the first aim of this study is to clarify the starting as-received microstructures of gum metal alloys through conventional transmission electron microscopy (TEM) and aberration-corrected high resolution scanning transmission electron microscopy with high-angle annular dark field detector (HAADF-HRSTEM) imaging. To elucidate the effects of beta-stability and starting microstructure on the deformation behavior of gum metals and thus to provide adequate context for potentially novel deformation structures, we investigate three alloy conditions: gum metal that has undergone solution heat treatment (STGM), gum metal that has been heavily cold worked (CWGM), and a solution treated alloy of nominal gum metal composition, but leaner in beta-stabilizing content (ST Ref-1). In order to directly relate observed

  11. Epigenetic mechanisms underlying cardiac degeneration and regeneration*

    PubMed Central

    Chaturvedi, Pankaj; Tyagi, Suresh C.

    2014-01-01

    Epigenetic modifications which are defined by DNA methylation, histone modifications and microRNA mediated gene regulation, have been found to be associated with cardiac dysfunction and cardiac regeneration but the mechanisms are unclear. MicroRNA therapies have been proposed for cardiac regeneration and proliferation of stem cells into cardiomyocytes. Cardiovascular disorders are represented by abnormal methylation of CpG islands and drugs that inhibit DNA methyl transferases such as 5-methyl Aza cytidine are under trials. Histone modifications which include acetylation, methylation, phosphorylation, ADP ribosylation, sumoylation and biotinylation are represented within abnormal phenotypes of cardiac hypertrophy, cardiac development and contractility. MicroRNAs have been used efficiently to epigenetically reprogram fibroblasts into cardiomyocytes. MicroRNAs represent themselves as potential biomarkers for early detection of cardiac disorders which are difficult to diagnose and are captured at later stages. Because microRNAs regulate circadian genes, for example a nocturnin gene of circadian clockwork is regulated by mir122, they have profound role in regulating biological clock and this may explain the high cardiovascular risk during the morning time. This review highlights the role of epigenetics which can be helpful in disease management strategies. PMID:24636549

  12. Environmentally induced autoimmune diseases: potential mechanisms.

    PubMed Central

    Rao, T; Richardson, B

    1999-01-01

    Environmental and other xenobiotic agents can cause autoimmunity. Examples include drug-induced lupus, toxic oil syndrome, and contaminated l-tryptophan ingestion. Numerous mechanisms, based on (italic)in vitro(/italic) evidence and animal models, have been proposed to explain how xenobiotics induce or accelerate autoimmunity. The majority of these can be divided into three general categories. The first is those inhibiting the processes involved in establishing tolerance by deletion. Inhibiting deletion can result in the release of newly generated autoreactive cells into the periphery. The second mechanism is the modification of gene expression in the cells participating in the immune response, permitting lymphocytes to respond to signals normally insufficient to initiate a response or allowing the antigen-presenting cells to abnormally stimulate a response. Abnormal gene expression can thus disrupt tolerance maintained by suppression or anergy, permitting activation of autoreactive cells. The third is the modification of self-molecules such that they are recognized by the immune system as foreign. Examples illustrating these concepts are presented, and related mechanisms that have the potential to similarly affect the immune system are noted. Some mechanisms appear to be common to a variety of agents, and different mechanisms appear to produce similar diseases. However, evidence that any of these mechanisms are actually responsible for xenobiotic-induced human autoimmune disease is still largely lacking, and the potential for numerous and as yet unidentified mechanisms also exists. PMID:10502539

  13. Cognitive Mechanisms Underlying Second Language Listening Comprehension

    ERIC Educational Resources Information Center

    Hu, Guiling

    2009-01-01

    This dissertation research investigates the cognitive mechanisms underlying second language (L2) listening comprehension. I use three types of sentential contexts, congruent, neutral and incongruent, to look at how L2 learners construct meaning in spoken sentence comprehension. The three types of contexts differ in their context predictability.…

  14. Mechanical surface waves accompany action potential propagation.

    PubMed

    El Hady, Ahmed; Machta, Benjamin B

    2015-01-01

    Many diverse studies have shown that a mechanical displacement of the axonal membrane accompanies the electrical pulse defining the action potential (AP). We present a model for these mechanical displacements as arising from the driving of surface wave modes in which potential energy is stored in elastic properties of the neuronal membrane and cytoskeleton while kinetic energy is carried by the axoplasmic fluid. In our model, these surface waves are driven by the travelling wave of electrical depolarization characterizing the AP, altering compressive electrostatic forces across the membrane. This driving leads to co-propagating mechanical displacements, which we term Action Waves (AWs). Our model allows us to estimate the shape of the AW that accompanies any travelling wave of voltage, making predictions that are in agreement with results from several experimental systems. Our model can serve as a framework for understanding the physical origins and possible functional roles of these AWs. PMID:25819404

  15. Mechanical surface waves accompany action potential propagation

    NASA Astrophysics Data System (ADS)

    El Hady, Ahmed; Machta, Benjamin B.

    2015-03-01

    Many diverse studies have shown that a mechanical displacement of the axonal membrane accompanies the electrical pulse defining the action potential (AP). We present a model for these mechanical displacements as arising from the driving of surface wave modes in which potential energy is stored in elastic properties of the neuronal membrane and cytoskeleton while kinetic energy is carried by the axoplasmic fluid. In our model, these surface waves are driven by the travelling wave of electrical depolarization characterizing the AP, altering compressive electrostatic forces across the membrane. This driving leads to co-propagating mechanical displacements, which we term Action Waves (AWs). Our model allows us to estimate the shape of the AW that accompanies any travelling wave of voltage, making predictions that are in agreement with results from several experimental systems. Our model can serve as a framework for understanding the physical origins and possible functional roles of these AWs.

  16. Quantum mechanical streamlines. I - Square potential barrier

    NASA Technical Reports Server (NTRS)

    Hirschfelder, J. O.; Christoph, A. C.; Palke, W. E.

    1974-01-01

    Exact numerical calculations are made for scattering of quantum mechanical particles hitting a square two-dimensional potential barrier (an exact analog of the Goos-Haenchen optical experiments). Quantum mechanical streamlines are plotted and found to be smooth and continuous, to have continuous first derivatives even through the classical forbidden region, and to form quantized vortices around each of the nodal points. A comparison is made between the present numerical calculations and the stationary wave approximation, and good agreement is found between both the Goos-Haenchen shifts and the reflection coefficients. The time-independent Schroedinger equation for real wavefunctions is reduced to solving a nonlinear first-order partial differential equation, leading to a generalization of the Prager-Hirschfelder perturbation scheme. Implications of the hydrodynamical formulation of quantum mechanics are discussed, and cases are cited where quantum and classical mechanical motions are identical.

  17. Mechanical Surface Waves Accompany Action Potential Propagation

    NASA Astrophysics Data System (ADS)

    Machta, Benjamin; El Hady, Ahmed

    2015-03-01

    The action potential (AP) is the basic mechanism by which information is transmitted along neuronal axons. Although the excitable nature of axons is understood to be primarily electrical, many experimental studies have shown that a mechanical displacement of the axonal membrane co-propagates with the electrical signal. While the experimental evidence for co-propagating mechanical waves is diverse and compelling, there is no consensus for their physical underpinnings. We present a model in which these mechanical displacements arise from the driving of mechanical surface waves, in which potential energy is stored in elastic deformations of the neuronal membrane and cytoskeleton while kinetic energy is stored in the movement of the axoplasmic fluid. In our model these surface waves are driven by the traveling wave of electrical depolarization that characterizes the AP, altering the electrostatic forces across the membrane as it passes. Our model allows us to predict the shape of the displacement that should accompany any traveling wave of voltage, including the well-characterized AP. We expect our model to serve as a framework for understanding the physical origins and possible functional roles of these AWs in neurobiology. See Arxiv/1407.7600

  18. Growth instabilities in mechanical breakdown under mechanical and thermal stresses

    NASA Astrophysics Data System (ADS)

    Zhang, S.-Z.; Louis, E.; Plá, O.; Guinea, F.

    1995-12-01

    A linear stability analysis is used to investigate crack growth in two dimensional elastic media, and under mechanical or thermal stresses. Although in most cases a circular geometry is considered, the instability of a planar crack is also discussed. Several boundary conditions and size effects are considered. The results indicate that the tendency towards instabilities in mechanical breakdown is stronger than in the case of growth in fields governed by the Laplace equation (diffusion or electrostatic fields), in line with the smaller fractal dimensions obtained in the first case. Instabilities under thermal stresses are shown to depend on the actual thermal gradients. Finally, a model previously investigated numerically is used to show that plasticity decreases the strength of the instability. (c) 1995 The American Physical Society

  19. Investigation of defect nucleation in titanium under mechanical loading

    SciTech Connect

    Zolnikov, Konstantin P. Kryzhevich, Dmitrij S.; Korchuganov, Aleksandr V.; Psakhie, Sergey G.

    2014-11-14

    The paper undertakes a study of plastic deformation in a titanium crystallite under mechanical loading (uniaxial tension and indentation) in terms of atomic mechanisms of its generation and development. The molecular dynamics method with many-body interatomic potentials is employed. It is shown that there is a threshold strain, at which a crystal reveals the generation of local structural transformations associated with changes in atomic configurations of the first and second coordination spheres. The onset of plastic deformation in a crystallite is accompanied by a stepwise decrease in potential energy. The effect of free surfaces and grain boundaries on the generation of local structural transformations in a titanium crystallite is investigated.

  20. MECHANICS OF CRACK BRIDGING UNDER DYNAMIC LOADS

    SciTech Connect

    N. SRIDHAR; ET AL

    2001-02-01

    A bridging law for fiber reinforced composites under dynamic crack propagation conditions has been derived. Inertial effects in the mechanism of fiber pullout during dynamic propagation of a bridged crack are critically examined for the first time. By reposing simple shear lag models of pullout as problems of dynamic wave propagation, the effect of the frictional coupling between the fibers and the matrix is accounted for in a fairly straightforward way. The solutions yield the time-dependent relationship between the crack opening displacement and the bridging traction. Engineering criteria and the role of material and geometrical parameters for significant inertial effects are identified.

  1. Cellular and molecular mechanisms underlying muscular dystrophy

    PubMed Central

    2013-01-01

    The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes. PMID:23671309

  2. Protein under tension and mechanical unfolding

    NASA Astrophysics Data System (ADS)

    Shen, Tongye; Canino, Larry; Wolynes, Peter G.; McCammon, J. Andrew

    2003-03-01

    The mechanical properties of proteins are important for a wide variety of functions ranging from stabilizing cellular structures to the transduction of signals across the membrane. We examined changes in protein conformation under external force fields by simple theoretical methods and new simulation techniques. The theoretical model solved a Gaussian chain plus native contact residue-level model under approximations. The simulations used the force ensemble replica exchange method and all-atom stochastic dynamics with a generalized Born plus solvent accessible surface as the solvation model. We applied these methods to study the protein spectrin as well as the domains of titin. Both global properties (such as energy and extension) and local roperties (especially, the specific contacts maintained and the secondary structure) are shown as functions of external force.

  3. Synaptic mechanisms underlying persistent cocaine craving.

    PubMed

    Wolf, Marina E

    2016-06-01

    Although it is challenging for individuals with cocaine addiction to achieve abstinence, the greatest difficulty is avoiding relapse to drug taking, which is often triggered by cues associated with prior cocaine use. This vulnerability to relapse persists for long periods (months to years) after abstinence is achieved. Here, I discuss rodent studies of cue-induced cocaine craving during abstinence, with a focus on neuronal plasticity in the reward circuitry that maintains high levels of craving. Such work has the potential to identify new therapeutic targets and to further our understanding of experience-dependent plasticity in the adult brain under normal circumstances and in the context of addiction. PMID:27150400

  4. Environmental genotoxicity: Probing the underlying mechanisms

    SciTech Connect

    Shugart, L.; Theodorakis, C.

    1993-12-31

    Environmental pollution is a complex issue because of the diversity of anthropogenic agents, both chemical and physical, that have been detected and catalogued. The consequences to biota from exposure to genotoxic agents present an additional problem because of the potential for these agents to produce adverse change at the cellular and organismal levels. Past studies in genetic toxicology at the Oak Ridge National Laboratory have focused on structural damage to the DNA of environmental species that may occur after exposure to genotoxic agents and the use of this information to document exposure and to monitor remediation. In an effort to predict effects at the population, community and ecosystem levels, current studies in genetic ecotoxicology are attempting to characterize the biological mechanisms at the gene level that regulate and limit the response of an individual organism to genotoxic factors in their environment.

  5. Mechanical annealing under low-amplitude cyclic loading in micropillars

    NASA Astrophysics Data System (ADS)

    Cui, Yi-nan; Liu, Zhan-li; Wang, Zhang-jie; Zhuang, Zhuo

    2016-04-01

    Mechanical annealing has been demonstrated to be an effective method for decreasing the overall dislocation density in submicron single crystal. However, simultaneously significant shape change always unexpectedly happens under extremely high monotonic loading to drive the pre-existing dislocations out of the free surfaces. In the present work, through in situ TEM experiments it is found that cyclic loading with low stress amplitude can drive most dislocations out of the submicron sample with virtually little change of the shape. The underlying dislocation mechanism is revealed by carrying out discrete dislocation dynamic (DDD) simulations. The simulation results indicate that the dislocation density decreases within cycles, while the accumulated plastic strain is small. By comparing the evolution of dislocation junction under monotonic, cyclic and relaxation deformation, the cumulative irreversible slip is found to be the key factor of promoting junction destruction and dislocation annihilation at free surface under low-amplitude cyclic loading condition. By introducing this mechanics into dislocation density evolution equations, the critical conditions for mechanical annealing under cyclic and monotonic loadings are discussed. Low-amplitude cyclic loading which strengthens the single crystal without seriously disturbing the structure has the potential applications in the manufacture of defect-free nano-devices.

  6. Mechanical buckling of veins under internal pressure.

    PubMed

    Martinez, Ricky; Fierro, Cesar A; Shireman, Paula K; Han, Hai-Chao

    2010-04-01

    Venous tortuosity is associated with multiple disease states and is often thought to be a consequence of venous hypertension and chronic venous disease. However, the underlying mechanisms of vein tortuosity are unclear. We hypothesized that increased pressure causes vein buckling that leads to a tortuous appearance. The specific aim of this study was to determine the critical buckling pressure of veins. We determined the buckling pressure of porcine jugular veins and measured the mechanical properties of these veins. Our results showed that the veins buckle when the transmural pressure exceeds a critical pressure that is strongly related to the axial stretch ratio in the veins. The critical pressures of the eight veins tested were 14.2 +/- 5.4 and 26.4 +/- 9.0 mmHg at axial stretch ratio 1.5 and 1.7, respectively. In conclusion, veins buckle into a tortuous shape at high lumen pressures or reduced axial stretch ratios. Our results are useful in understanding the development of venous tortuosity associated with varicose veins, venous valvular insufficiency, diabetic retinopathy, and vein grafts. PMID:20094913

  7. Mechanical Buckling of Veins under Internal Pressure

    PubMed Central

    Martinez, Ricky; Fierro, Cesar A.; Shireman, Paula K.; Han, Hai-Chao

    2010-01-01

    Venous tortuosity is associated with multiple disease states and is often thought to be a consequence of venous hypertension and chronic venous disease. However, the underlying mechanisms of vein tortuosity are unclear. We hypothesized that increased pressure causes vein buckling that leads to a tortuous appearance. The specific aim of this study was to determine the critical buckling pressure of veins. We determined the buckling pressure of porcine jugular veins and measured the mechanical properties of these veins. Our results showed that veins buckle when the transmural pressure exceeds a critical pressure that is strongly related to the axial stretch ratio in the veins. The critical pressures of the eight veins tested were 14.2 ± 5.4 mmHg and 26.4 ± 9.0 mmHg at axial stretch ratio 1.5 and 1.7, respectively. In conclusion, veins buckle into a tortuous shape at high lumen pressures or reduced axial stretch ratios. Our results are useful in understanding the development of venous tortuosity associated with varicose veins, venous valvular insufficiency, diabetic retinopathy and vein grafts. PMID:20094913

  8. Two distinct neural mechanisms underlying indirect reciprocity.

    PubMed

    Watanabe, Takamitsu; Takezawa, Masanori; Nakawake, Yo; Kunimatsu, Akira; Yamasue, Hidenori; Nakamura, Mitsuhiro; Miyashita, Yasushi; Masuda, Naoki

    2014-03-18

    Cooperation is a hallmark of human society. Humans often cooperate with strangers even if they will not meet each other again. This so-called indirect reciprocity enables large-scale cooperation among nonkin and can occur based on a reputation mechanism or as a succession of pay-it-forward behavior. Here, we provide the functional and anatomical neural evidence for two distinct mechanisms governing the two types of indirect reciprocity. Cooperation occurring as reputation-based reciprocity specifically recruited the precuneus, a region associated with self-centered cognition. During such cooperative behavior, the precuneus was functionally connected with the caudate, a region linking rewards to behavior. Furthermore, the precuneus of a cooperative subject had a strong resting-state functional connectivity (rsFC) with the caudate and a large gray matter volume. In contrast, pay-it-forward reciprocity recruited the anterior insula (AI), a brain region associated with affective empathy. The AI was functionally connected with the caudate during cooperation occurring as pay-it-forward reciprocity, and its gray matter volume and rsFC with the caudate predicted the tendency of such cooperation. The revealed difference is consistent with the existing results of evolutionary game theory: although reputation-based indirect reciprocity robustly evolves as a self-interested behavior in theory, pay-it-forward indirect reciprocity does not on its own. The present study provides neural mechanisms underlying indirect reciprocity and suggests that pay-it-forward reciprocity may not occur as myopic profit maximization but elicit emotional rewards. PMID:24591599

  9. Two distinct neural mechanisms underlying indirect reciprocity

    PubMed Central

    Watanabe, Takamitsu; Takezawa, Masanori; Nakawake, Yo; Kunimatsu, Akira; Yamasue, Hidenori; Nakamura, Mitsuhiro; Miyashita, Yasushi; Masuda, Naoki

    2014-01-01

    Cooperation is a hallmark of human society. Humans often cooperate with strangers even if they will not meet each other again. This so-called indirect reciprocity enables large-scale cooperation among nonkin and can occur based on a reputation mechanism or as a succession of pay-it-forward behavior. Here, we provide the functional and anatomical neural evidence for two distinct mechanisms governing the two types of indirect reciprocity. Cooperation occurring as reputation-based reciprocity specifically recruited the precuneus, a region associated with self-centered cognition. During such cooperative behavior, the precuneus was functionally connected with the caudate, a region linking rewards to behavior. Furthermore, the precuneus of a cooperative subject had a strong resting-state functional connectivity (rsFC) with the caudate and a large gray matter volume. In contrast, pay-it-forward reciprocity recruited the anterior insula (AI), a brain region associated with affective empathy. The AI was functionally connected with the caudate during cooperation occurring as pay-it-forward reciprocity, and its gray matter volume and rsFC with the caudate predicted the tendency of such cooperation. The revealed difference is consistent with the existing results of evolutionary game theory: although reputation-based indirect reciprocity robustly evolves as a self-interested behavior in theory, pay-it-forward indirect reciprocity does not on its own. The present study provides neural mechanisms underlying indirect reciprocity and suggests that pay-it-forward reciprocity may not occur as myopic profit maximization but elicit emotional rewards. PMID:24591599

  10. Variation potential in higher plants: Mechanisms of generation and propagation

    PubMed Central

    Vodeneev, Vladimir; Akinchits, Elena; Sukhov, Vladimir

    2015-01-01

    Long-distance intercellular electrical signals, including variation potential (VP) in higher plants, are a potential mechanism of coordinate functional responses in different plant cells under action of stressors. VP, which is caused by damaging factors (e.g., heating, crushing), is transient depolarization with an irregular shape. It can include a long-term depolarization and fast impulse depolarization (‘AP-like’ spikes). Mechanisms of VP generation and propagation are still under investigation. It is probable that VP is a local electrical response induced by propagation of hydraulic wave and (or) chemical agent. Both hypotheses are based on numerous experimental results but they predict VP velocities which are not in a good accordance with speed of variation potential propagation. Thus combination of hydraulic and chemical signals is the probable mechanism of VP propagation. VP generation is traditionally connected with transient H+-ATPase inactivation, but AP-like spikes are also connected with passive ions fluxes. Ca2+ influx is a probable mechanism which triggers H+-ATPase inactivation and ions channels activation at VP. PMID:26313506

  11. Complex Classical Mechanics of a QES Potential

    NASA Astrophysics Data System (ADS)

    Bhabani Prasad, Mandal; Sushant, S. Mahajan

    2015-10-01

    We study a combined parity (P) and time reversal (T) invariant non-Hermitian quasi-exactly solvable (QES) potential, which exhibits PT phase transition, in the complex plane classically to demonstrate different quantum effects. The particle with real energy makes closed orbits around one of the periodic wells of the complex potential depending on the initial condition. However interestingly the particle escapes to an open orbits even with real energy if it is placed beyond a certain distance from the center of the well. On the other hand when the particle energy is complex the trajectory is open and the particle tunnels back and forth between two wells which are separated by a classically forbidden path. The tunneling time is calculated for different pair of wells and is shown to vary inversely with the imaginary component of energy. Our study reveals that spontaneous PT symmetry breaking does not affect the qualitative features of the particle trajectories in the analogous complex classical model. Support from Department of Science and Technology (DST), Govt. of India under SERC Project Sanction Grant No. SR/S2/HEP-0009/2012

  12. Modulation of mechanical resonance by chemical potential oscillation in graphene

    NASA Astrophysics Data System (ADS)

    Chen, Changyao; Deshpande, Vikram V.; Koshino, Mikito; Lee, Sunwoo; Gondarenko, Alexander; MacDonald, Allan H.; Kim, Philip; Hone, James

    2016-03-01

    The classical picture of the force on a capacitor assumes a large density of electronic states, such that the electrochemical potential of charges added to the capacitor is given by the external electrostatic potential and the capacitance is determined purely by geometry. Here we consider capacitively driven motion of a nano-mechanical resonator with a low density of states, in which these assumptions can break down. We find three leading-order corrections to the classical picture: the first of which is a modulation in the static force due to variation in the internal chemical potential; the second and third are changes in the static force and dynamic spring constant due to the rate of change of chemical potential, expressed as the quantum (density of states) capacitance. As a demonstration, we study capacitively driven graphene mechanical resonators, where the chemical potential is modulated independently of the gate voltage using an applied magnetic field to manipulate the energy of electrons residing in discrete Landau levels. In these devices, we observe large periodic frequency shifts consistent with the three corrections to the classical picture. In devices with extremely low strain and disorder, the first correction term dominates and the resonant frequency closely follows the chemical potential. The theoretical model fits the data with only one adjustable parameter representing disorder-broadening of the Landau levels. The underlying electromechanical coupling mechanism is not limited by the particular choice of material, geometry, or mechanism for variation in the chemical potential, and can thus be extended to other low-dimensional systems.

  13. On the physical mechanism underlying asymptotic safety

    NASA Astrophysics Data System (ADS)

    Nink, Andreas; Reuter, Martin

    2013-01-01

    We identify a simple physical mechanism which is at the heart of Asymptotic Safety in Quantum Einstein Gravity (QEG) according to all available effective average action-based investigations. Upon linearization the gravitational field equations give rise to an inverse propagator for metric fluctuations comprising two pieces: a covariant Laplacian and a curvature dependent potential term. By analogy with elementary magnetic systems they lead to, respectively, dia- and paramagnetic-type interactions of the metric fluctuations with the background gravitational field. We show that above 3 spacetime dimensions the gravitational antiscreening occurring in QEG is entirely due to a strong dominance of the ultralocal paramagnetic interactions over the diamagnetic ones that favor screening. (Below 3 dimensions both the dia- and paramagnetic effects support antiscreening.) The spacetimes of QEG are interpreted as a polarizable medium with a "paramagnetic" response to external perturbations, and similarities with the vacuum state of Yang-Mills theory are pointed out. As a by-product, we resolve a longstanding puzzle concerning the beta function of Newton's constant in 2 + ɛ dimensional gravity.

  14. Molecular Mechanisms Underlying Peritoneal EMT and Fibrosis

    PubMed Central

    Strippoli, Raffaele; Moreno-Vicente, Roberto; Battistelli, Cecilia; Cicchini, Carla; Noce, Valeria; Amicone, Laura; Marchetti, Alessandra; del Pozo, Miguel Angel; Tripodi, Marco

    2016-01-01

    Peritoneal dialysis is a form of renal replacement alternative to the hemodialysis. During this treatment, the peritoneal membrane acts as a permeable barrier for exchange of solutes and water. Continual exposure to dialysis solutions, as well as episodes of peritonitis and hemoperitoneum, can cause acute/chronic inflammation and injury to the peritoneal membrane, which undergoes progressive fibrosis, angiogenesis, and vasculopathy, eventually leading to discontinuation of the peritoneal dialysis. Among the different events controlling this pathological process, epithelial to mesenchymal transition of mesothelial cells plays a main role in the induction of fibrosis and in subsequent functional deterioration of the peritoneal membrane. Here, the main extracellular inducers and cellular players are described. Moreover, signaling pathways acting during this process are elucidated, with emphasis on signals delivered by TGF-β family members and by Toll-like/IL-1β receptors. The understanding of molecular mechanisms underlying fibrosis of the peritoneal membrane has both a basic and a translational relevance, since it may be useful for setup of therapies aimed at counteracting the deterioration as well as restoring the homeostasis of the peritoneal membrane. PMID:26941801

  15. Molecular Mechanisms Underlying Psychological Stress and Cancer.

    PubMed

    Shin, Kyeong Jin; Lee, Yu Jin; Yang, Yong Ryoul; Park, Seorim; Suh, Pann-Ghill; Follo, Matilde Yung; Cocco, Lucio; Ryu, Sung Ho

    2016-01-01

    Psychological stress is an emotion experienced when people are under mental pressure or encounter unexpected problems. Extreme or repetitive stress increases the risk of developing human disease, including cardiovascular disease (CVD), immune diseases, mental disorders, and cancer. Several studies have shown an association between psychological stress and cancer growth and metastasis in animal models and case studies of cancer patients. Stress induces the secretion of stress-related mediators, such as catecholamine, cortisol, and oxytocin, via the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic nervous system (SNS). These stress-related hormones and neurotransmitters adversely affect stress-induced tumor progression and cancer therapy. Catecholamine is the primary factor that influences tumor progression. It can regulate diverse cellular signaling pathways through adrenergic receptors (ADRs), which are expressed by several types of cancer cells. Activated ADRs enhance the proliferation and invasion abilities of cancer cells, alter cell activity in the tumor microenvironment, and regulate the interaction between cancer and its microenvironment to promote tumor progression. Additionally, other stress mediators, such as glucocorticoids and oxytocin, and their cognate receptors are involved in stress-induced cancer growth and metastasis. Here, we will review how each receptor-mediated signal cascade contributes to tumor initiation and progression and discuss how we can use these molecular mechanisms for cancer therapy. PMID:26916018

  16. [Auditory evoked potentials under attentional lapses].

    PubMed

    Lazarev, I E; Bryzgalov, D V; Osokina, E S; Viazovtseva, A A; Antonenko, A S; Arkhipova, E A; Chernyshev, B V

    2014-01-01

    In order to study spontaneous attentional lapses the experimental task was used that created a moderately high attentional load and involved response choice based on stimulus feature conjunction. The participant's average correct response rate was 85.1%; they made errors in 9.6% trials and response omissions in 5.4% trials. Peak N1 of the evoked potential was consistent across all behavioral outcomes, while peak P2 amplitude was significantly greater before errors and response omissions compared to correct responses. The analysis of polygraphic indexes (ECG, EMG, SGR) did not reveal any arousal level reduction before attentional lapses. The proposed interpretation of the results obtained is based on the assumption that attentional lapses are mediated by the suppression of external stimuli information processing caused by the state of mind-wandering. PMID:25723016

  17. Turbine under Gulf Stream: Potential energy source

    SciTech Connect

    Venezia, W.A.; Holt, J.

    1995-09-01

    Turbine under the Gulf Stream (TUGS) is a project to design, build, and deploy the prototypes necessary to demonstrate the economic and technical feasibility of generating electric power from the Gulf Stream. The project is based in part on new generator designs and emerging materials technologies. Its successful completion would demonstrate the technology and produce prototype turbines that can be mass produced and sold with service support. Past research and experimentation indicates that energy can be generated from the Gulf Stream. Problems exist such as fluctuations in the current`s axis and inconsistency. Above all, the ocean is a difficult environment in which to work. Therefore, the question is not whether or not a generator can be put in the ocean to generate electricity, but rather can it be done in an economically and environmentally sound way and still be practical?

  18. Cellular Mechanisms Underlying Eosinophilic and Neutrophilic Airway Inflammation in Asthma

    PubMed Central

    Vatrella, Alessandro; Busceti, Maria Teresa; Gallelli, Luca; Calabrese, Cecilia; Terracciano, Rosa

    2015-01-01

    Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments. PMID:25878402

  19. Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma.

    PubMed

    Pelaia, Girolamo; Vatrella, Alessandro; Busceti, Maria Teresa; Gallelli, Luca; Calabrese, Cecilia; Terracciano, Rosa; Maselli, Rosario

    2015-01-01

    Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments. PMID:25878402

  20. Neural mechanisms and potential treatment of epilepsy and its complications

    PubMed Central

    Liu, Tao-Tao; He, Zhi-Gang; Tian, Xue-Bi; Xiang, Hong-Bing

    2014-01-01

    The factors underlying epilepsy are multifaceted, but recent research suggests that the brain’s neural circuits, which play a key role in controlling the balance between epileptic and antiepileptic factors, may lie at the heart of epilepsy. This article provides a comprehensive review of the neural mechanisms and potential treatment of intractable epilepsy from neural inflammatory responses, melanocortin circuits in brain and pedunculopontine tegmental nucleus. Further studies should be undertaken to elucidate the nature of neural circuits so that we may more effectively apply these new preventive and symptomatic therapies to the patient suffering from medically refractory seizures and its complications. PMID:25628775

  1. Understanding molecular mechanism of higher plant plasticity under abiotic stress.

    PubMed

    Shao, Hong-Bo; Guo, Qing-Jie; Chu, Li-Ye; Zhao, Xi-Ning; Su, Zhong-Liang; Hu, Ya-Chen; Cheng, Jiang-Feng

    2007-01-15

    Higher plants play the most important role in keeping a stable environment on the earth, which regulate global circumstances in many ways in terms of different levels (molecular, individual, community, and so on), but the nature of the mechanism is gene expression and control temporally and spatially at the molecular level. In persistently changing environment, there are many adverse stress conditions such as cold, drought, salinity and UV-B (280-320 mm), which influence plant growth and crop production greatly. Plants differ from animals in many aspects, but the important may be that plants are more easily influenced by environment than animals. Plants have a series of fine mechanisms for responding to environmental changes, which has been established during their long-period evolution and artificial domestication. These mechanisms are involved in many aspects of anatomy, physiology, biochemistry, genetics, development, evolution and molecular biology, in which the adaptive machinery related to molecular biology is the most important. The elucidation of it will extremely and purposefully promote the sustainable utilization of plant resources and make the best use of its current potential under different scales. This molecular mechanism at least include environmental signal recognition (input), signal transduction (many cascade biochemical reactions are involved in this process), signal output, signal responses and phenotype realization, which is a multi-dimensional network system and contain many levels of gene expression and regulation. We will focus on the molecular adaptive machinery of higher plant plasticity under abiotic stresses. PMID:16914294

  2. Exploration of mechanisms underlying the strain-rate-dependent mechanical property of single chondrocytes

    SciTech Connect

    Nguyen, Trung Dung; Gu, YuanTong

    2014-05-05

    Based on the characterization by Atomic Force Microscopy, we report that the mechanical property of single chondrocytes has dependency on the strain-rates. By comparing the mechanical deformation responses and the Young's moduli of living and fixed chondrocytes at four different strain-rates, we explore the deformation mechanisms underlying this dependency property. We found that the strain-rate-dependent mechanical property of living cells is governed by both of the cellular cytoskeleton and the intracellular fluid when the fixed chondrocytes are mainly governed by their intracellular fluid, which is called the consolidation-dependent deformation behavior. Finally, we report that the porohyperelastic constitutive material model which can capture the consolidation-dependent behavior of both living and fixed chondrocytes is a potential candidature to study living cell biomechanics.

  3. Nanomaterial-modulated autophagy: underlying mechanisms and functional consequences.

    PubMed

    Zheng, Wei; Wei, Min; Li, Song; Le, Weidong

    2016-06-01

    Autophagy is an essential lysosome-dependent process that controls the quality of the cytoplasm and maintains cellular homeostasis, and dysfunction of this protein degradation system is correlated with various disorders. A growing body of evidence suggests that nanomaterials (NMs) have autophagy-modulating effects, thus predicting a valuable and promising application potential of NMs in the diagnosis and treatment of autophagy-related diseases. NMs exhibit unique physical, chemical and biofunctional properties, which may endow NMs with capabilities to modulate autophagy via various mechanisms. The present review highlights the impacts of various NMs on autophagy and their functional consequences. The possible underlying mechanisms for NM-modulated autophagy are also discussed. PMID:27193191

  4. The Mechanism Underlying Inhibition of Saccadic Return

    ERIC Educational Resources Information Center

    Ludwig, Casimir J. H.; Farrell, Simon; Ellis, Lucy A.; Gilchrist, Iain D.

    2009-01-01

    Human observers take longer to re-direct gaze to a previously fixated location. Although there has been some exploration of the characteristics of inhibition of saccadic return (ISR), the exact mechanisms by which ISR operates are currently unknown. In the framework of accumulation models of response times, in which evidence is integrated over…

  5. White speck potential for mechanically harvested cottons

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This paper examines the white speck phenomena as seen in mechanically picked cottons based on HVI, AFIS and white speck fabric data. White specks are dye defects that can be inherent from the variety or can be caused by weather or other field conditions, and the fabric manufacturer is often caught ...

  6. Mechanisms underlying Phalaris aquatica "sudden death" syndrome in sheep.

    PubMed

    Bourke, C A; Carrigan, M J

    1992-07-01

    Twenty outbreaks of Phalaris aquatica "sudden death" syndrome in sheep were investigated between 1981 and 1991. Four were confirmed and one was suspected, to be a cardiac disorder; 5 were confirmed and 3 were suspected, to be a polioencephalomalacic disorder; the aetiology of the remaining 7 outbreaks could not be determined. Potentially toxic levels of hydrocyanic acid (20 to 36 mg/100 g) were measured in the 3 toxic phalaris pastures tested. The measurement of potentially toxic levels of nitrate nitrogen (2920 micrograms/g) in toxic phalaris pastures by others, was noted. It is suggested that phalaris "sudden death" syndrome could have as many as 4 different underlying mechanisms, and that these might reflect the presence in the plant of a cardio-respiratory toxin, a thiaminase and amine co-substate, cyanogenic compounds, and nitrate compounds. PMID:1445081

  7. Probiotics and Alcoholic Liver Disease: Treatment and Potential Mechanisms

    PubMed Central

    Li, Fengyuan; Duan, Kangmin; Wang, Cuiling; McClain, Craig; Feng, Wenke

    2016-01-01

    Despite extensive research, alcohol remains one of the most common causes of liver disease in the United States. Alcoholic liver disease (ALD) encompasses a broad spectrum of disorders, including steatosis, steatohepatitis, and cirrhosis. Although many agents and approaches have been tested in patients with ALD and in animals with experimental ALD in the past, there is still no FDA (Food and Drug Administration) approved therapy for any stage of ALD. With the increasing recognition of the importance of gut microbiota in the onset and development of a variety of diseases, the potential use of probiotics in ALD is receiving increasing investigative and clinical attention. In this review, we summarize recent studies on probiotic intervention in the prevention and treatment of ALD in experimental animal models and patients. Potential mechanisms underlying the probiotic function are also discussed. PMID:26839540

  8. Potential Mechanisms of Cancer Prevention by Weight Control

    NASA Astrophysics Data System (ADS)

    Jiang, Yu; Wang, Weiqun

    Weight control via dietary caloric restriction and/or physical activity has been demonstrated in animal models for cancer prevention. However, the underlying mechanisms are not fully understood. Body weight loss due to negative energy balance significantly reduces some metabolic growth factors and endocrinal hormones such as IGF-1, leptin, and adiponectin, but enhances glucocorticoids, that may be associated with anti-cancer mechanisms. In this review, we summarized the recent studies related to weight control and growth factors. The potential molecular targets focused on those growth factors- and hormones-dependent cellular signaling pathways are further discussed. It appears that multiple factors and multiple signaling cascades, especially for Ras-MAPK-proliferation and PI3K-Akt-anti-apoptosis, could be involved in response to weight change by dietary calorie restriction and/or exercise training. Considering prevalence of obesity or overweight that becomes apparent over the world, understanding the underlying mechanisms among weight control, endocrine change and cancer risk is critically important. Future studies using "-omics" technologies will be warrant for a broader and deeper mechanistic information regarding cancer prevention by weight control.

  9. Developmental mechanisms underlying variation in craniofacial disease and evolution.

    PubMed

    Fish, Jennifer L

    2016-07-15

    Craniofacial disease phenotypes exhibit significant variation in penetrance and severity. Although many genetic contributions to phenotypic variation have been identified, genotype-phenotype correlations remain imprecise. Recent work in evolutionary developmental biology has exposed intriguing developmental mechanisms that potentially explain incongruities in genotype-phenotype relationships. This review focuses on two observations from work in comparative and experimental animal model systems that highlight how development structures variation. First, multiple genetic inputs converge on relatively few developmental processes. Investigation of when and how variation in developmental processes occurs may therefore help predict potential genetic interactions and phenotypic outcomes. Second, genetic mutation is typically associated with an increase in phenotypic variance. Several models outlining developmental mechanisms underlying mutational increases in phenotypic variance are discussed using Satb2-mediated variation in jaw size as an example. These data highlight development as a critical mediator of genotype-phenotype correlations. Future research in evolutionary developmental biology focusing on tissue-level processes may help elucidate the "black box" between genotype and phenotype, potentially leading to novel treatment, earlier diagnoses, and better clinical consultations for individuals affected by craniofacial anomalies. PMID:26724698

  10. Potential of isotope analysis (C, Cl) to identify dechlorination mechanisms

    NASA Astrophysics Data System (ADS)

    Cretnik, Stefan; Thoreson, Kristen; Bernstein, Anat; Ebert, Karin; Buchner, Daniel; Laskov, Christine; Haderlein, Stefan; Shouakar-Stash, Orfan; Kliegman, Sarah; McNeill, Kristopher; Elsner, Martin

    2013-04-01

    Chloroethenes are commonly used in industrial applications, and detected as carcinogenic contaminants in the environment. Their dehalogenation is of environmental importance in remediation processes. However, a detailed understanding frequently accounted problem is the accumulation of toxic degradation products such as cis-dichloroethylene (cis-DCE) at contaminated sites. Several studies have addressed the reductive dehalogenation reactions using biotic and abiotic model systems, but a crucial question in this context has remained open: Do environmental transformations occur by the same mechanism as in their corresponding in vitro model systems? The presented study shows the potential to close this research gap using the latest developments in compound specific chlorine isotope analysis, which make it possible to routinely measure chlorine isotope fractionation of chloroethenes in environmental samples and complex reaction mixtures.1,2 In particular, such chlorine isotope analysis enables the measurement of isotope fractionation for two elements (i.e., C and Cl) in chloroethenes. When isotope values of both elements are plotted against each other, different slopes reflect different underlying mechanisms and are remarkably insensitive towards masking. Our results suggest that different microbial strains (G. lovleyi strain SZ, D. hafniense Y51) and the isolated cofactor cobalamin employ similar mechanisms of reductive dechlorination of TCE. In contrast, evidence for a different mechanism was obtained with cobaloxime cautioning its use as a model for biodegradation. The study shows the potential of the dual isotope approach as a tool to directly compare transformation mechanisms of environmental scenarios, biotic transformations, and their putative chemical lab scale systems. Furthermore, it serves as an essential reference when using the dual isotope approach to assess the fate of chlorinated compounds in the environment.

  11. Platelet Activation: The Mechanisms and Potential Biomarkers

    PubMed Central

    Yun, Seong-Hoon; Sim, Eun-Hye; Goh, Ri-Young; Park, Joo-In

    2016-01-01

    Beyond hemostasis and thrombosis, an increasing number of studies indicate that platelets play an integral role in intercellular communication, mediating inflammatory and immunomodulatory activities. Our knowledge about how platelets modulate inflammatory and immunity has greatly improved in recent years. In this review, we discuss recent advances in the pathways of platelet activation and potential application of platelet activation biomarkers to diagnosis and prediction of disease states. PMID:27403440

  12. Molecular mechanisms underlying alcohol-drinking behaviours.

    PubMed

    Ron, Dorit; Barak, Segev

    2016-09-01

    The main characteristic of alcohol use disorder is the consumption of large quantities of alcohol despite the negative consequences. The transition from the moderate use of alcohol to excessive, uncontrolled alcohol consumption results from neuroadaptations that cause aberrant motivational learning and memory processes. Here, we examine studies that have combined molecular and behavioural approaches in rodents to elucidate the molecular mechanisms that keep the social intake of alcohol in check, which we term 'stop pathways', and the neuroadaptations that underlie the transition from moderate to uncontrolled, excessive alcohol intake, which we term 'go pathways'. We also discuss post-transcriptional, genetic and epigenetic alterations that underlie both types of pathways. PMID:27444358

  13. Cellular and molecular mechanisms underlying presynapse formation

    PubMed Central

    Chia, Poh Hui; Li, Pengpeng

    2013-01-01

    Synapse formation is a highly regulated process that requires the coordination of many cell biological events. Decades of research have identified a long list of molecular components involved in assembling a functioning synapse. Yet how the various steps, from transporting synaptic components to adhering synaptic partners and assembling the synaptic structure, are regulated and precisely executed during development and maintenance is still unclear. With the improvement of imaging and molecular tools, recent work in vertebrate and invertebrate systems has provided important insight into various aspects of presynaptic development, maintenance, and trans-synaptic signals, thereby increasing our understanding of how extrinsic organizers and intracellular mechanisms contribute to presynapse formation. PMID:24127213

  14. Mechanisms Underlying Induction of Tolerance to Foods.

    PubMed

    Berin, M Cecilia; Shreffler, Wayne G

    2016-02-01

    Oral tolerance refers to a systemic immune nonresponsiveness to antigens first encountered by the oral route, and a failure in development of this homeostatic process can result in food allergy. Clinical tolerance induced by allergen immunotherapy is associated with alterations in immune mechanisms relevant to the allergic response, including reduction of basophil reactivity, induction of IgG4, loss of effector Th2 cells, and induction of Tregs. The relative contribution of these immune changes to clinical tolerance to foods, and the duration of these immune changes after termination of immunotherapy, remains to be identified. PMID:26617229

  15. Peripheral Receptor Mechanisms Underlying Orofacial Muscle Pain and Hyperalgesia

    NASA Astrophysics Data System (ADS)

    Saloman, Jami L.

    Musculoskeletal pain conditions, particularly those associated with temporomandibular joint and muscle disorders (TMD) are severely debilitating and affect approximately 12% of the population. Identifying peripheral nociceptive mechanisms underlying mechanical hyperalgesia, a prominent feature of persistent muscle pain, could contribute to the development of new treatment strategies for the management of TMD and other muscle pain conditions. This study provides evidence of functional interactions between ligand-gated channels, P2X3 and TRPV1/TRPA1, in trigeminal sensory neurons, and proposes that these interactions underlie the development of mechanical hyperalgesia. In the masseter muscle, direct P2X3 activation, via the selective agonist αβmeATP, induced a dose- and time-dependent hyperalgesia. Importantly, the αβmeATP-induced hyperalgesia was prevented by pretreatment of the muscle with a TRPV1 antagonist, AMG9810, or the TRPA1 antagonist, AP18. P2X3 was co-expressed with both TRPV1 and TRPA1 in masseter muscle afferents confirming the possibility for intracellular interactions. Moreover, in a subpopulation of P2X3 /TRPV1 positive neurons, capsaicin-induced Ca2+ transients were significantly potentiated following P2X3 activation. Inhibition of Ca2+-dependent kinases, PKC and CaMKII, prevented P2X3-mechanical hyperalgesia whereas blockade of Ca2+-independent PKA did not. Finally, activation of P2X3 induced phosphorylation of serine, but not threonine, residues in TRPV1 in trigeminal sensory neurons. Significant phosphorylation was observed at 15 minutes, the time point at which behavioral hyperalgesia was prominent. Similar data were obtained regarding another nonselective cation channel, the NMDA receptor (NMDAR). Our data propose P2X3 and NMDARs interact with TRPV1 in a facilitatory manner, which could contribute to the peripheral sensitization underlying masseter hyperalgesia. This study offers novel mechanisms by which individual pro-nociceptive ligand

  16. Ionizing radiation and genetic risks. XVII. Formation mechanisms underlying naturally occurring DNA deletions in the human genome and their potential relevance for bridging the gap between induced DNA double-strand breaks and deletions in irradiated germ cells.

    PubMed

    Sankaranarayanan, Krishnaswami; Taleei, Reza; Rahmanian, Shirin; Nikjoo, Hooshang

    2013-01-01

    While much is known about radiation-induced DNA double-strand breaks (DSBs) and their repair, the question of how deletions of different sizes arise as a result of the processing of DSBs by the cell's repair systems has not been fully answered. In order to bridge this gap between DSBs and deletions, we critically reviewed published data on mechanisms pertaining to: (a) repair of DNA DSBs (from basic studies in this area); (b) formation of naturally occurring structural variation (SV) - especially of deletions - in the human genome (from genomic studies) and (c) radiation-induced mutations and structural chromosomal aberrations in mammalian somatic cells (from radiation mutagenesis and radiation cytogenetic studies). The specific aim was to assess the relative importance of the postulated mechanisms in generating deletions in the human genome and examine whether empirical data on radiation-induced deletions in mouse germ cells are consistent with predictions of these mechanisms. The mechanisms include (a) NHEJ, a DSB repair process that does not require any homology and which functions in all stages of the cell cycle (and is of particular relevance in G0/G1); (b) MMEJ, also a DSB repair process but which requires microhomology and which presumably functions in all cell cycle stages; (c) NAHR, a recombination-based DSB repair mechanism which operates in prophase I of meiosis in germ cells; (d) MMBIR, a microhomology-mediated, replication-based mechanism which operates in the S phase of the cell cycle, and (e) strand slippage during replication (involved in the origin of small insertions and deletions (INDELs). Our analysis permits the inference that, between them, these five mechanisms can explain nearly all naturally occurring deletions of different sizes identified in the human genome, NAHR and MMBIR being potentially more versatile in this regard. With respect to radiation-induced deletions, the basic studies suggest that those arising as a result of the operation

  17. Mechanisms Underlying Early Medieval Droughts in Mesoamerica

    NASA Astrophysics Data System (ADS)

    Bhattacharya, T.; Chiang, J. C. H.

    2015-12-01

    Multidecadal drought during the early Medieval Climate Anomaly (MCA, 800-1200 CE) in Mesoamerica has been implicated in the demise of many pre-Columbian societies, including the Maya. The mechanisms behind these droughts, however, are poorly understood. Researchers most often interpret these records as tracking the mean position of the ITCZ, with a southward shifted ITCZ resulting in Mesoamerican drought. This is puzzling, however, because our dynamical understanding of the ITCZ and its role in interhemispheric heat transport would suggest a more northward shifted ITCZ during the MCA. Here, we evaluate two hypotheses to reconcile existing proxies and dynamics. First, we assess whether evidence for dry conditions during the MCA is robust across multiple Mesoamerican proxy records, focusing on the influence of radiometric dating uncertainty on estimates of drought timing. Second, we use control simulations of CCSM4 and HadCM3, as well as a broader synthesis of oceanic and terrestrial proxies, to explore the mechanisms responsible for long-term drought in Mesoamerica. Ultimately, we suggest that a temporary slowdown of the AMOC, either internally or externally forced, combined with local and regional land surface feedbacks can explain these droughts in Mesoamerica.

  18. Potential Mechanisms of Progranulin-deficient FTLD

    PubMed Central

    Ward, Michael Emmerson

    2013-01-01

    Frontotemporal lobar dementia (FTLD) is the most common cause of dementia in patients younger than 60 years of age, and causes progressive neurodegeneration of the frontal and temporal lobes usually accompanied by devastating changes in language or behavior in affected individuals. Mutations in the progranulin (GRN) gene account for a significant fraction of familial FTLD, and in the vast majority of cases, these mutations lead to reduced expression of progranulin via nonsense-mediated mRNA decay. Progranulin is a secreted glycoprotein that regulates a diverse range of cellular functions including cell proliferation, cell migration, and inflammation. Recent fundamental discoveries about progranulin biology, including the findings that sortilin and tumor necrosis factor receptor (TNFR) are high affinity progranulin receptors, are beginning to shed light on the mechanism(s) by which progranulin deficiency causes FTLD. This review will explore how alterations in basic cellular functions due to PGRN deficiency, both intrinsic and extrinsic to neurons, might lead to the development of FTLD. PMID:21892758

  19. Vitamin D and Bone Health; Potential Mechanisms

    PubMed Central

    Laird, Eamon; Ward, Mary; McSorley, Emeir; Strain, J.J.; Wallace, Julie

    2010-01-01

    Osteoporosis is associated with increased morbidity, mortality and significant economic and health costs. Vitamin D is a secosteriod hormone essential for calcium absorption and bone mineralization which is positively associated with bone mineral density [BMD]. It is well-established that prolonged and severe vitamin D deficiency leads to rickets in children and osteomalacia in adults. Sub-optimal vitamin D status has been reported in many populations but it is a particular concern in older people; thus there is clearly a need for effective strategies to optimise bone health. A number of recent studies have suggested that the role of vitamin D in preventing fractures may be via its mediating effects on muscle function (a defect in muscle function is one of the classical signs of rickets) and inflammation. Studies have demonstrated that vitamin D supplementation can improve muscle strength which in turn contributes to a decrease in incidence of falls, one of the largest contributors to fracture incidence. Osteoporosis is often considered to be an inflammatory condition and pro-inflammatory cytokines have been associated with increased bone metabolism. The immunoregulatory mechanisms of vitamin D may thus modulate the effect of these cytokines on bone health and subsequent fracture risk. Vitamin D, therefore, may influence fracture risk via a number of different mechanisms. PMID:22254049

  20. Biophysical mechanisms underlying olfactory receptor neuron dynamics

    PubMed Central

    Nagel, Katherine I.; Wilson, Rachel I.

    2010-01-01

    Odor responses of olfactory receptor neurons (ORNs) exhibit complex dynamics. Using genetics and pharmacology, we show that these dynamics in Drosophila ORNs can be separated into sequential steps, corresponding to transduction and spike generation. Each of these steps contributes distinct dynamics. Transduction dynamics can be largely explained by a simple kinetic model of ligand-receptor interactions, together with an adaptive feedback mechanism that slows transduction onset. Spiking dynamics are well-described by a differentiating linear filter that is stereotyped across odors and cells. Genetic knock-down of sodium channels reshapes this filter, implying that it arises from the regulated balance of intrinsic conductances in ORNs. Complex responses can be understood as a consequence of how the stereotyped spike filter interacts with odor- and receptor-specific transduction dynamics. However, in the presence of rapidly fluctuating natural stimuli, spiking simply increases the speed and sensitivity of encoding. PMID:21217763

  1. Neural mechanisms underlying the evolvability of behaviour

    PubMed Central

    Katz, Paul S.

    2011-01-01

    The complexity of nervous systems alters the evolvability of behaviour. Complex nervous systems are phylogenetically constrained; nevertheless particular species-specific behaviours have repeatedly evolved, suggesting a predisposition towards those behaviours. Independently evolved behaviours in animals that share a common neural architecture are generally produced by homologous neural structures, homologous neural pathways and even in the case of some invertebrates, homologous identified neurons. Such parallel evolution has been documented in the chromatic sensitivity of visual systems, motor behaviours and complex social behaviours such as pair-bonding. The appearance of homoplasious behaviours produced by homologous neural substrates suggests that there might be features of these nervous systems that favoured the repeated evolution of particular behaviours. Neuromodulation may be one such feature because it allows anatomically defined neural circuitry to be re-purposed. The developmental, genetic and physiological mechanisms that contribute to nervous system complexity may also bias the evolution of behaviour, thereby affecting the evolvability of species-specific behaviour. PMID:21690127

  2. Cellular and circuit mechanisms underlying spinocerebellar ataxias.

    PubMed

    Meera, Pratap; Pulst, Stefan M; Otis, Thomas S

    2016-08-15

    Degenerative ataxias are a common form of neurodegenerative disease that affect about 20 individuals per 100,000. The autosomal dominant spinocerebellar ataxias (SCAs) are caused by a variety of protein coding mutations (single nucleotide changes, deletions and expansions) in single genes. Affected genes encode plasma membrane and intracellular ion channels, membrane receptors, protein kinases, protein phosphatases and proteins of unknown function. Although SCA-linked genes are quite diverse they share two key features: first, they are highly, although not exclusively, expressed in cerebellar Purkinje neurons (PNs), and second, when mutated they lead ultimately to the degeneration of PNs. In this review we summarize ataxia-related changes in PN neurophysiology that have been observed in various mouse knockout lines and in transgenic models of human SCA. We also highlight emerging evidence that altered metabotropic glutamate receptor signalling and disrupted calcium homeostasis in PNs form a common, early pathophysiological mechanism in SCAs. Together these findings indicate that aberrant calcium signalling and profound changes in PN neurophysiology precede PN cell loss and are likely to lead to cerebellar circuit dysfunction that explains behavioural signs of ataxia characteristic of the disease. PMID:27198167

  3. Changes of trabecular bone under control of biologically mechanical mechanism

    NASA Astrophysics Data System (ADS)

    Wang, C.; Zhang, C. Q.; Dong, X.; Wu, H.

    2008-10-01

    In this study, a biological process of bone remodeling was considered as a closed loop feedback control system, which enables bone to optimize and renew itself over a lifetime. A novel idea of combining strain-adaptive and damage-induced remodeling algorithms at Basic Multicellular Unit (BMU) level was introduced. In order to make the outcomes get closer to clinical observation, the stochastic occurrence of microdamage was involved and a hypothesis that remodeling activation probability is related to the value of damage rate was assumed. Integrated with Finite Element Analysis (FEA), the changes of trabecular bone in morphology and material properties were simulated in the course of five years. The results suggest that deterioration and anisotropy of trabecluar bone are inevitable with natural aging, and that compression rather than tension can be applied to strengthen the ability of resistance to fracture. This investigation helps to gain more insight the mechanism of bone loss and identify improved treatment and prevention for osteoporosis or stress fracture.

  4. Mechanisms underlying the antidepressant response and treatment resistance

    PubMed Central

    Levinstein, Marjorie R.; Samuels, Benjamin A.

    2014-01-01

    Depression is a complex and heterogeneous disorder affecting millions of Americans. There are several different medications and other treatments that are available and effective for many patients with depression. However, a substantial percentage of patients fail to achieve remission with these currently available interventions, and relapse rates are high. Therefore, it is necessary to determine both the mechanisms underlying the antidepressant response and the differences between responders and non-responders to treatment. Delineation of these mechanisms largely relies on experiments that utilize animal models. Therefore, this review provides an overview of the various mouse models that are currently used to assess the antidepressant response, such as chronic mild stress, social defeat, and chronic corticosterone. We discuss how these mouse models can be used to advance our understanding of the differences between responders and non-responders to antidepressant treatment. We also provide an overview of experimental treatment modalities that are used for treatment-resistant depression, such as deep brain stimulation and ketamine administration. We will then review the various genetic polymorphisms and transgenic mice that display resistance to antidepressant treatment. Finally, we synthesize the published data to describe a potential neural circuit underlying the antidepressant response and treatment resistance. PMID:25018708

  5. RPE and Choroid Mechanisms Underlying Ocular Growth and Myopia

    PubMed Central

    Zhang, Yan; Wildsoet, Christine F.

    2016-01-01

    Myopia is the most common type of refractive errors and one of the world’s leading causes of blindness. Visual manipulations in animal models have provided convincing evidence for the role of environmental factors in myopia development. These models along with in vitro studies have provided important insights into underlying mechanisms. The key locations of the retinal pigment epithelium (RPE) and choroid make them plausible conduits for relaying growth regulatory signals originating in the retina to the sclera, which ultimately determines eye size and shape. Identifying the key signal molecules and their targets may lead to the development of new myopia control treatments. This section summarizes findings implicating the RPE and choroid in myopia development. For RPE and/or choroid, changes in morphology, activity of ion channels/transporters, as well as in gene and protein expression, have been linked to altered eye growth. Both tissues thus represent potential targets for novel therapies for myopia. PMID:26310157

  6. Understanding the Mechanism of Hepatic Fibrosis and Potential Therapeutic Approaches

    PubMed Central

    Ahmad, Areeba; Ahmad, Riaz

    2012-01-01

    Hepatic fibrosis (HF) is a progressive condition with serious clinical complications arising from abnormal proliferation and amassing of tough fibrous scar tissue. This defiance of collagen fibers becomes fatal due to ultimate failure of liver functions. Participation of various cell types, interlinked cellular events, and large number of mediator molecules make the fibrotic process enormously complex and dynamic. However, with better appreciation of underlying cellular and molecular mechanisms of fibrosis, the assumption that HF cannot be cured is gradually changing. Recent findings have underlined the therapeutic potential of a number of synthetic compounds as well as plant derivatives for cessation or even the reversal of the processes that transforms the liver into fibrotic tissue. It is expected that future inputs will provide a conceptual framework to develop more specific strategies that would facilitate the assessment of risk factors, shortlist early diagnosis biomarkers, and eventually guide development of effective therapeutic alternatives. PMID:22626794

  7. Effects of interatomic potentials on mechanical deformation of glasses

    NASA Astrophysics Data System (ADS)

    Chen, Wei-Ren; Iwashita, Takuya; Egami, Takeshi

    2013-03-01

    Apparently glasses behave like an elastic solid, which shows a linear relationship between stress and strain in mechanical deformation. However the understanding of the mechanical response of glasses remains elusive because of structural disorder. Mechanical deformation of monatomic model glasses was studied using athermal quasi-static shear (AQS) simulation and with three different potentials. As the interatomic potentials we employed the 12-6 Lennard-Jones (LJ) potential, modified Johnson (mJ) potential, and Dzugutov (Dz) potential, respectively. For mJ and Dz glasses the shear modulus keeps constant below a critical strain, below which it decreases rapidly or discontinuously with strain. Such changes in shear modulus were mostly related to the change in local topology of atomic connectivity or anelasticity. In contrast LJ glass shows a gradual decrease in shear modulus in a continuous manner. The results indicated that the difference arises from the nature of the potentials if the topology of atomic connectivity can be clearly defined.

  8. Unraveling the Molecular Mechanisms Underlying the Nasopharyngeal Bacterial Community Structure.

    PubMed

    de Steenhuijsen Piters, Wouter A A; Bogaert, Debby

    2016-01-01

    The upper respiratory tract is colonized by a diverse array of commensal bacteria that harbor potential pathogens, such as Streptococcus pneumoniae. As long as the local microbial ecosystem-also called "microbiome"-is in balance, these potentially pathogenic bacterial residents cause no harm to the host. However, similar to macrobiological ecosystems, when the bacterial community structure gets perturbed, potential pathogens can overtake the niche and cause mild to severe infections. Recent studies using next-generation sequencing show that S. pneumoniae, as well as other potential pathogens, might be kept at bay by certain commensal bacteria, including Corynebacterium and Dolosigranulum spp. Bomar and colleagues are the first to explore a specific biological mechanism contributing to the antagonistic interaction between Corynebacterium accolens and S. pneumoniae in vitro [L. Bomar, S. D. Brugger, B. H. Yost, S. S. Davies, K. P. Lemon, mBio 7(1):e01725-15, 2016, doi:10.1128/mBio.01725-15]. The authors comprehensively show that C. accolens is capable of hydrolyzing host triacylglycerols into free fatty acids, which display antipneumococcal properties, suggesting that these bacteria might contribute to the containment of pneumococcus. This work exemplifies how molecular epidemiological findings can lay the foundation for mechanistic studies to elucidate the host-microbe and microbial interspecies interactions underlying the bacterial community structure. Next, translation of these results to an in vivo setting seems necessary to unveil the magnitude and importance of the observed effect in its natural, polymicrobial setting. PMID:26838716

  9. Unraveling the Molecular Mechanisms Underlying the Nasopharyngeal Bacterial Community Structure

    PubMed Central

    de Steenhuijsen Piters, Wouter A. A.

    2016-01-01

    ABSTRACT The upper respiratory tract is colonized by a diverse array of commensal bacteria that harbor potential pathogens, such as Streptococcus pneumoniae. As long as the local microbial ecosystem—also called “microbiome”—is in balance, these potentially pathogenic bacterial residents cause no harm to the host. However, similar to macrobiological ecosystems, when the bacterial community structure gets perturbed, potential pathogens can overtake the niche and cause mild to severe infections. Recent studies using next-generation sequencing show that S. pneumoniae, as well as other potential pathogens, might be kept at bay by certain commensal bacteria, including Corynebacterium and Dolosigranulum spp. Bomar and colleagues are the first to explore a specific biological mechanism contributing to the antagonistic interaction between Corynebacterium accolens and S. pneumoniae in vitro [L. Bomar, S. D. Brugger, B. H. Yost, S. S. Davies, K. P. Lemon, mBio 7(1):e01725-15, 2016, doi:10.1128/mBio.01725-15]. The authors comprehensively show that C. accolens is capable of hydrolyzing host triacylglycerols into free fatty acids, which display antipneumococcal properties, suggesting that these bacteria might contribute to the containment of pneumococcus. This work exemplifies how molecular epidemiological findings can lay the foundation for mechanistic studies to elucidate the host-microbe and microbial interspecies interactions underlying the bacterial community structure. Next, translation of these results to an in vivo setting seems necessary to unveil the magnitude and importance of the observed effect in its natural, polymicrobial setting. PMID:26838716

  10. Mechanisms underlying subunit independence in pyramidal neuron dendrites.

    PubMed

    Behabadi, Bardia F; Mel, Bartlett W

    2014-01-01

    Pyramidal neuron (PN) dendrites compartmentalize voltage signals and can generate local spikes, which has led to the proposal that their dendrites act as independent computational subunits within a multilayered processing scheme. However, when a PN is strongly activated, back-propagating action potentials (bAPs) sweeping outward from the soma synchronize dendritic membrane potentials many times per second. How PN dendrites maintain the independence of their voltage-dependent computations, despite these repeated voltage resets, remains unknown. Using a detailed compartmental model of a layer 5 PN, and an improved method for quantifying subunit independence that incorporates a more accurate model of dendritic integration, we first established that the output of each dendrite can be almost perfectly predicted by the intensity and spatial configuration of its own synaptic inputs, and is nearly invariant to the rate of bAP-mediated "cross-talk" from other dendrites over a 100-fold range. Then, through an analysis of conductance, voltage, and current waveforms within the model cell, we identify three biophysical mechanisms that together help make independent dendritic computation possible in a firing neuron, suggesting that a major subtype of neocortical neuron has been optimized for layered, compartmentalized processing under in-vivo-like spiking conditions. PMID:24357611

  11. Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation

    PubMed Central

    Chervyakov, Alexander V.; Chernyavsky, Andrey Yu.; Sinitsyn, Dmitry O.; Piradov, Michael A.

    2015-01-01

    Transcranial magnetic stimulation (TMS) is an effective method used to diagnose and treat many neurological disorders. Although repetitive TMS (rTMS) has been used to treat a variety of serious pathological conditions including stroke, depression, Parkinson’s disease, epilepsy, pain, and migraines, the pathophysiological mechanisms underlying the effects of long-term TMS remain unclear. In the present review, the effects of rTMS on neurotransmitters and synaptic plasticity are described, including the classic interpretations of TMS effects on synaptic plasticity via long-term potentiation and long-term depression. We also discuss the effects of rTMS on the genetic apparatus of neurons, glial cells, and the prevention of neuronal death. The neurotrophic effects of rTMS on dendritic growth and sprouting and neurotrophic factors are described, including change in brain-derived neurotrophic factor concentration under the influence of rTMS. Also, non-classical effects of TMS related to biophysical effects of magnetic fields are described, including the quantum effects, the magnetic spin effects, genetic magnetoreception, the macromolecular effects of TMS, and the electromagnetic theory of consciousness. Finally, we discuss possible interpretations of TMS effects according to dynamical systems theory. Evidence suggests that a rTMS-induced magnetic field should be considered a separate physical factor that can be impactful at the subatomic level and that rTMS is capable of significantly altering the reactivity of molecules (radicals). It is thought that these factors underlie the therapeutic benefits of therapy with TMS. Future research on these mechanisms will be instrumental to the development of more powerful and reliable TMS treatment protocols. PMID:26136672

  12. Potential therapeutic mechanism of K(+) channel block for MS.

    PubMed

    Baker, Mark D

    2013-10-01

    While the potential use of K(+) channel blockers in MS has been explored over many years, the approval in the US, and more recently in the UK, of fampyra (fampridine, 4-aminopyridine, 4-AP) as a symptomatic treatment for walking disability, has reawakened interest. Recent years have seen a real improvement in the treatment options for relapsing remitting MS, but the disease remains inadequately treated, with the progressive phase (characterised by irreversible functional loss) lacking any effective therapy. Whether the symptomatic relief afforded by 4-AP translates into neuroprotection, remains poorly investigated, although there is no clear reason why this would be expected. Importantly, future clinical studies may shed light on this question. This review includes an overview of axonal K(+) channel expression and pharmacology, and the logic of the use of K(+) channel blockers derived from observations in experimental studies of demyelination and synaptic transmission. It provides an insight into the probable biophysical actions of 4-AP, and how its action may aid in the symptomatic treatment of MS. The key message of this review is that 4-AP is a blocker of neuronal K(+) channels, and its administration is known to be of value in the symptomatic treatment of some patients. The details of the mechanism underlying the beneficial effects remain somewhat vague, and the molecular target has not been properly defined. The useful mechanism is likely to include an action on synaptic function, but whether it is the presynaptic terminal or the presynaptic axon that is the primary target is unknown. It is argued that because of the apparent inability of 4-AP to increase safety factor in experimental demyelination when clinically relevant concentrations are used, it cannot be the ideal pharmacological agent for treating demyelination by the widening of axonal action potentials. That said, it remains a possibility that the useful therapeutic effect of 4-AP may involve subtle

  13. Molecular Mechanics: The Method and Its Underlying Philosophy.

    ERIC Educational Resources Information Center

    Boyd, Donald B.; Lipkowitz, Kenny B.

    1982-01-01

    Molecular mechanics is a nonquantum mechanical method for solving problems concerning molecular geometries and energy. Methodology based on: the principle of combining potential energy functions of all structural features of a particular molecule into a total force field; derivation of basic equations; and use of available computer programs is…

  14. The Challenge of Characterizing Operations in the Mechanisms Underlying Behavior

    ERIC Educational Resources Information Center

    Bechtel, William

    2005-01-01

    Neuroscience and cognitive science seek to explain behavioral regularities in terms of underlying mechanisms. An important element of a mechanistic explanation is a characterization of the operations of the parts of the mechanism. The challenge in characterizing such operations is illustrated by an example from the history of physiological…

  15. Students' Conceptual Difficulties in Quantum Mechanics: Potential Well Problems

    ERIC Educational Resources Information Center

    Ozcan, Ozgur; Didis, Nilufer; Tasar, Mehmet Fatih

    2009-01-01

    In this study, students' conceptual difficulties about some basic concepts in quantum mechanics like one-dimensional potential well problems and probability density of tunneling particles were identified. For this aim, a multiple choice instrument named Quantum Mechanics Conceptual Test has been developed by one of the researchers of this study…

  16. Exactly Solvable Quantum Mechanical Potentials: An Alternative Approach.

    ERIC Educational Resources Information Center

    Pronchik, Jeremy N.; Williams, Brian W.

    2003-01-01

    Describes an alternative approach to finding exactly solvable, one-dimensional quantum mechanical potentials. Differs from the usual approach in that instead of starting with a particular potential and seeking solutions to the related Schrodinger equations, it begins with known solutions to second-order ordinary differential equations and seeks to…

  17. Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions.

    PubMed

    Intini, G; Katsuragi, Y; Kirkwood, K L; Yang, S

    2014-05-01

    This article reviews recent research into mechanisms underlying bone resorption and highlights avenues of investigation that may generate new therapies to combat alveolar bone loss in periodontitis. Several proteins, signaling pathways, stem cells, and dietary supplements are discussed as they relate to periodontal bone loss and regeneration. RGS12 is a crucial protein that mediates osteoclastogenesis and bone destruction, and a potential therapeutic target. RGS12 likely regulates osteoclast differentiation through regulating calcium influx to control the calcium oscillation-NFATc1 pathway. A working model for RGS10 and RGS12 in the regulation of Ca(2+) oscillations during osteoclast differentiation is proposed. Initiation of inflammation depends on host cell-microbe interactions, including the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Oral p38 inhibitors reduced lipopolysaccharide (LPS)-induced bone destruction in a rat periodontitis model but showed unsatisfactory safety profiles. The p38 substrate MK2 is a more specific therapeutic target with potentially superior tolerability. Furthermore, MKP-1 shows anti-inflammatory activity, reducing inflammatory cytokine biosynthesis and bone resorption. Multipotent skeletal stem cell (SSC) populations exist within the bone marrow and periosteum of long bones. These bone-marrow-derived SSCs and periosteum-derived SSCs have shown therapeutic potential in several applications, including bone and periodontal regeneration. The existence of craniofacial bone-specific SSCs is suggested based on existing studies. The effects of calcium, vitamin D, and soy isoflavone supplementation on alveolar and skeletal bone loss in post-menopausal women were investigated. Supplementation resulted in stabilization of forearm bone mass density and a reduced rate of alveolar bone loss over 1 yr, compared with placebo. Periodontal attachment levels were also well-maintained and alveolar bone loss suppressed during 24 wk of

  18. Molecular Mechanisms Regulating Muscle Fiber Composition Under Microgravity

    NASA Technical Reports Server (NTRS)

    Rosenthal, Nadia A.

    1999-01-01

    The overall goal of this project is to reveal the molecular mechanisms underlying the selective and debilitating atrophy of specific skeletal muscle fiber types that accompanies sustained conditions of microgravity. Since little is currently known about the regulation of fiber-specific gene expression programs in mammalian muscle, elucidation of the basic mechanisms of fiber diversification is a necessary prerequisite to the generation of therapeutic strategies for attenuation of muscle atrophy on earth or in space. Vertebrate skeletal muscle development involves the fusion of undifferentiated mononucleated myoblasts to form multinucleated myofibers, with a concomitant activation of muscle-specific genes encoding proteins that form the force-generating contractile apparatus. The regulatory circuitry controlling skeletal muscle gene expression has been well studied in a number of vertebrate animal systems. The goal of this project has been to achieve a similar level of understanding of the mechanisms underlying the further specification of muscles into different fiber types, and the role played by innervation and physical activity in the maintenance and adaptation of different fiber phenotypes into adulthood. Our recent research on the genetic basis of fiber specificity has focused on the emergence of mature fiber types and have implicated a group of transcriptional regulatory proteins, known as E proteins, in the control of fiber specificity. The restriction of E proteins to selected muscle fiber types is an attractive hypothetical mechanism for the generation of muscle fiber-specific patterns of gene expression. To date our results support a model wherein different E proteins are selectively expressed in muscle cells to determine fiber-restricted gene expression. These studies are a first step to define the molecular mechanisms responsible for the shifts in fiber type under conditions of microgravity, and to determine the potential importance of E proteins as

  19. The Intricate Interplay between Mechanisms Underlying Aging and Cancer

    PubMed Central

    Piano, Amanda; Titorenko, Vladimir I.

    2015-01-01

    Age is the major risk factor in the incidence of cancer, a hyperplastic disease associated with aging. Here, we discuss the complex interplay between mechanisms underlying aging and cancer as a reciprocal relationship. This relationship progresses with organismal age, follows the history of cell proliferation and senescence, is driven by common or antagonistic causes underlying aging and cancer in an age-dependent fashion, and is maintained via age-related convergent and divergent mechanisms. We summarize our knowledge of these mechanisms, outline the most important unanswered questions and suggest directions for future research. PMID:25657853

  20. Mechanical Modeling of a WIPP Drum Under Pressure

    SciTech Connect

    Smith, Jeffrey A.

    2014-11-25

    Mechanical modeling was undertaken to support the Waste Isolation Pilot Plant (WIPP) technical assessment team (TAT) investigating the February 14th 2014 event where there was a radiological release at the WIPP. The initial goal of the modeling was to examine if a mechanical model could inform the team about the event. The intention was to have a model that could test scenarios with respect to the rate of pressurization. It was expected that the deformation and failure (inability of the drum to contain any pressure) would vary according to the pressurization rate. As the work progressed there was also interest in using the mechanical analysis of the drum to investigate what would happen if a drum pressurized when it was located under a standard waste package. Specifically, would the deformation be detectable from camera views within the room. A finite element model of a WIPP 55-gallon drum was developed that used all hex elements. Analyses were conducted using the explicit transient dynamics module of Sierra/SM to explore potential pressurization scenarios of the drum. Theses analysis show similar deformation patterns to documented pressurization tests of drums in the literature. The calculated failure pressures from previous tests documented in the literature vary from as little as 16 psi to 320 psi. In addition, previous testing documented in the literature shows drums bulging but not failing at pressures ranging from 69 to 138 psi. The analyses performed for this study found the drums failing at pressures ranging from 35 psi to 75 psi. When the drums are pressurized quickly (in 0.01 seconds) there is significant deformation to the lid. At lower pressurization rates the deformation of the lid is considerably less, yet the lids will still open from the pressure. The analyses demonstrate the influence of pressurization rate on deformation and opening pressure of the drums. Analyses conducted with a substantial mass on top of the closed drum demonstrate that the

  1. Calcium signalling in pancreatic stellate cells: Mechanisms and potential roles.

    PubMed

    Gryshchenko, Oleksiy; Gerasimenko, Julia V; Gerasimenko, Oleg V; Petersen, Ole H

    2016-03-01

    Hepatic and pancreatic stellate cells may or may not be regarded as stem cells, but they are capable of remarkable transformations. There is less information about stellate cells in the pancreas than in the liver, where they were discovered much earlier and therefore have been studied longer and more intensively than in the pancreas. Most of the work on pancreatic stellate cells has been carried out in studies on cell cultures, but in this review we focus attention on Ca(2+) signalling in stellate cells in their real pancreatic environment. We review current knowledge on patho-physiologically relevant Ca(2+) signalling events and their underlying mechanisms. We focus on the effects of bradykinin in the initial stages of acute pancreatitis, an often fatal disease in which the pancreas digests itself and its surroundings. Ca(2+) signals, elicited in the stellate cells by the action of bradykinin, may have a negative effect on the outcome of the acute disease process and promote the development of chronic pancreatitis. The bradykinin-elicited Ca(2+) signals can be inhibited by blockade of type 2 receptors and also by blockade of Ca(2+)-release activated Ca(2+) channels. The potential benefits of such pharmacological inhibition for the treatment of pancreatitis are reviewed. PMID:26960936

  2. Assessing Vulnerability of Electricity Generation Under Potential Future Droughts

    NASA Astrophysics Data System (ADS)

    Yan, E.; Tidwell, V. C.; Wigmosta, M. S.

    2014-12-01

    In the past few decades, the western US experienced increased sever, frequent, and prolonged droughts resulting in significant water availability issues, which raised questions as to how electricity sector might be vulnerable to future droughts. To improve our understanding of potential risks of electricity generation curtailment due to drought, an impact analysis was performed with a series of modeling tools including climate downscaling, competitive water-use calculator, hydrologic model for various hydrologic processes, and power-plant specific models. This presentation will demonstrate the predicted effects of potential droughts on power generation at a local level of the USGS 8-digit watersheds and individual power plants within the context of current and future characteristics of power system and water resource system.The study identified three potential drought scenarios based on historical drought records and projected climate changes from the GFDL and the PCM global climate models, for greenhouse gas emission scenarios A1B, A2, and B1 defined by the IPCC. The potential impacts under these three drought scenarios were evaluated with a hydrologic model constructed for the Pacific Northwest River Basin and California River Basin. The hydrologic model incorporates competitive water uses, climate forcing data corresponding to each of drought scenarios, and all major reservoirs that are currently supporting water withdrawal for various sectors and hydroelectric power generation. The hydrologic responses to drought scenarios predicted for each of the USGS 8-digit watersheds and reservoirs are used as input to power-plant specific models to quantify potential risk of curtailment at each power plant. The key findings from this study will help to improve understanding of spatial distribution of vulnerable power plants and watersheds as well as the scale of potential reduction of electricity generation under various drought scenarios. Beyond impacts to the existing

  3. MRZ-99030 - A novel modulator of Aβ aggregation: I - Mechanism of action (MoA) underlying the potential neuroprotective treatment of Alzheimer's disease, glaucoma and age-related macular degeneration (AMD).

    PubMed

    Parsons, Christopher G; Ruitenberg, Maarten; Freitag, Christine E; Sroka-Saidi, Kamila; Russ, Hermann; Rammes, Gerhard

    2015-05-01

    Therapeutic approaches addressing β-amyloid1-42 (Aβ1-42) aggregation represent a promising neuroprotective strategy for the treatment of Alzheimer's disease, dry age-related macular degeneration (AMD) and glaucoma. MRZ-99030 is a dipeptide containing d-tryptophan and 2-amino-2-methylpropionic acid in clinical development for the topical treatment of glaucoma and AMD. MRZ-99030 is an Aβ aggregation modulator, previously reported to prevent the formation of soluble toxic oligomeric Aβ species. The present study confirmed that MRZ-99030 prevents the formation of oligomeric Aβ species using similar SDS-PAGE experiments. However, additional data from TR-FRET, DLS and AFM experiments revealed that MRZ-99030 does not directly prevent early protein/protein interactions between monomeric Aβ, but rather promotes the formation of large, non-amyloidogenic, amorphous Aβ aggregates and thereby reduces the amount of intermediate toxic soluble oligomeric Aβ species. The affinity of MRZ-99030 to Aβ1-42 determined by SPR was 28.4 nM but the ratio of compound to Aβ is also important: a 10-20 fold excess of MRZ-99030 over Aβ is probably required for effective modulation of protein/protein interactions. For example, in glaucoma, assuming a maximal Aβ concentration of 1-15 nM in the retina, up to 150 nM MRZ-99030 could be required at the protein target. In line with this consideration, MRZ-99030 was able to prevent Aβ-induced toxicity on PC12 cells, retinal ganglion cells and retinal pigment epithelium cells when present at a 10-20 fold stoichiometric excess over Aβ. Moreover, in vivo studies demonstrate the neuroprotective potential of MRZ-99030 after systemic and topical administration in animal models of Alzheimer's disease and glaucoma/AMD respectively. PMID:25634238

  4. Damage mechanisms in PBT-GF30 under thermo-mechanical cyclic loading

    SciTech Connect

    Schaaf, A. De Monte, M. Hoffmann, C.; Vormwald, M.; Quaresimin, M.

    2014-05-15

    The scope of this paper is the investigation of damage mechanisms at microscopic scale on a short glass fiber reinforced polybutylene terephthalate (PBT-GF30) under thermo-mechanical cyclic loading. In addition the principal mechanisms are verified through micro mechanical FE models. In order to investigate the fatigue behavior of the material both isothermal strain controlled fatigue (ISCF) tests at three different temperatures and thermo-mechanical fatigue (TMF) tests were conducted on plain and notched specimens, manufactured by injection molding. The goal of the work is to determine the damage mechanisms occurring under TMF conditions and to compare them with the mechanisms occurring under ISCF. For this reason fracture surfaces of TMF and ISCF samples loaded at different temperature levels were analyzed using scanning electron microscopy. Furthermore, specimens that failed under TMF were examined on microsections revealing insight into both crack initiation and crack propagation. The findings of this investigation give valuable information about the main damage mechanisms of PBT-GF30 under TMF loading and serve as basis for the development of a TMF life estimation methodology.

  5. Mechanical Isolation of Highly Stable Antimonene under Ambient Conditions.

    PubMed

    Ares, Pablo; Aguilar-Galindo, Fernando; Rodríguez-San-Miguel, David; Aldave, Diego A; Díaz-Tendero, Sergio; Alcamí, Manuel; Martín, Fernando; Gómez-Herrero, Julio; Zamora, Félix

    2016-08-01

    Antimonene fabricated by mechanical exfoliation is highly stable under atmospheric conditions over periods of months and even when immersed in water. Density functional theory confirms the experiments and predicts an electronic gap of ≈1 eV. These results highlight the use of antimonene for optoelectronics applications. PMID:27272099

  6. Neural Circuitry and Plasticity Mechanisms Underlying Delay Eyeblink Conditioning

    ERIC Educational Resources Information Center

    Freeman, John H.; Steinmetz, Adam B.

    2011-01-01

    Pavlovian eyeblink conditioning has been used extensively as a model system for examining the neural mechanisms underlying associative learning. Delay eyeblink conditioning depends on the intermediate cerebellum ipsilateral to the conditioned eye. Evidence favors a two-site plasticity model within the cerebellum with long-term depression of…

  7. Mechanisms Underlying Language Acquisition: Benefits from a Comparative Approach

    ERIC Educational Resources Information Center

    Weiss, Daniel J.; Newport, Elissa L.

    2006-01-01

    One of the longstanding issues in language research has been the extent to which the mechanisms underlying language acquisition are uniquely human. The primary goal of this article is to introduce the reader to some of the recent developments in comparative language research that have shed new light on this issue. To appreciate the significance of…

  8. New Potentials for Old: The Darboux Transformation in Quantum Mechanics

    ERIC Educational Resources Information Center

    Williams, Brian Wesley; Celius, Tevye C.

    2008-01-01

    The Darboux transformation in quantum mechanics is reviewed at a basic level. Examples of how this transformation leads to exactly solvable potentials related to the "particle in a box" and the harmonic oscillator are shown in detail. The connection between the Darboux transformation and some modern operator based approaches to quantum mechanics…

  9. Child Care Subsidy Use and Child Development: Potential Causal Mechanisms

    ERIC Educational Resources Information Center

    Hawkinson, Laura E.

    2011-01-01

    Research using an experimental design is needed to provide firm causal evidence on the impacts of child care subsidy use on child development, and on underlying causal mechanisms since subsidies can affect child development only indirectly via changes they cause in children's early experiences. However, before costly experimental research is…

  10. Stabilization of solitons under competing nonlinearities by external potentials

    SciTech Connect

    Zegadlo, Krzysztof B. Karpierz, Miroslaw A.; Wasak, Tomasz; Trippenbach, Marek; Malomed, Boris A.

    2014-12-15

    We report results of the analysis for families of one-dimensional (1D) trapped solitons, created by competing self-focusing (SF) quintic and self-defocusing (SDF) cubic nonlinear terms. Two trapping potentials are considered, the harmonic-oscillator (HO) and delta-functional ones. The models apply to optical solitons in colloidal waveguides and other photonic media, and to matter-wave solitons in Bose-Einstein condensates loaded into a quasi-1D trap. For the HO potential, the results are obtained in an approximate form, using the variational and Thomas-Fermi approximations, and in a full numerical form, including the ground state and the first antisymmetric excited one. For the delta-functional attractive potential, the results are produced in a fully analytical form, and verified by means of numerical methods. Both exponentially localized solitons and weakly localized trapped modes are found for the delta-functional potential. The most essential conclusions concern the applicability of competing Vakhitov-Kolokolov (VK) and anti-VK criteria to the identification of the stability of solitons created under the action of the competing SF and SDF terms.

  11. Stabilization of solitons under competing nonlinearities by external potentials

    NASA Astrophysics Data System (ADS)

    Zegadlo, Krzysztof B.; Wasak, Tomasz; Malomed, Boris A.; Karpierz, Miroslaw A.; Trippenbach, Marek

    2014-12-01

    We report results of the analysis for families of one-dimensional (1D) trapped solitons, created by competing self-focusing (SF) quintic and self-defocusing (SDF) cubic nonlinear terms. Two trapping potentials are considered, the harmonic-oscillator (HO) and delta-functional ones. The models apply to optical solitons in colloidal waveguides and other photonic media, and to matter-wave solitons in Bose-Einstein condensates loaded into a quasi-1D trap. For the HO potential, the results are obtained in an approximate form, using the variational and Thomas-Fermi approximations, and in a full numerical form, including the ground state and the first antisymmetric excited one. For the delta-functional attractive potential, the results are produced in a fully analytical form, and verified by means of numerical methods. Both exponentially localized solitons and weakly localized trapped modes are found for the delta-functional potential. The most essential conclusions concern the applicability of competing Vakhitov-Kolokolov (VK) and anti-VK criteria to the identification of the stability of solitons created under the action of the competing SF and SDF terms.

  12. Formation of the imidazolides of dinucleotides under potentially prebiotic conditions

    NASA Technical Reports Server (NTRS)

    Sleeper, H. L.; Lohrmann, R.; Orgel, L. E.

    1978-01-01

    Imidazolides of dinucleotides such as ImpApA can be formed from the corresponding dinucleotides in a two-stage process, which gives up to 15% yields under potentially prebiotic conditions. First a solution of the dinucleotide and sodium trimetaphosphate is dried out at constant temperature and humidity. This produces polyphosphates such as p(n)ApA in excellent yield (greater than or equal to 80%). The products are dissolved in water, imidazole is added, and the solution is dried out again. This yields the 5'-phosphorimidazolides.

  13. Mechanisms of enhanced taurine release under Ca2+ depletion.

    PubMed

    Molchanova, Svetlana M; Oja, Simo S; Saransaari, Pirjo

    2005-10-01

    The sulfur-containing amino acid taurine is an inhibitory neuromodulator in the brain of mammals, as well as a key substance in the regulation of cell volumes. The effect of Ca(2+) on extracellular taurine concentrations is of special interest in the context of the regulatory mechanisms of taurine release. The aim of this study was to characterize the basal release of taurine in Ca(2+)-free medium using in vivo microdialysis of the striatum of anesthetized rats. Perfusion of Ca(2+)-free medium via a microdialysis probe evoked a sustained release of taurine (up to 180 % compared to the basal levels). The Ca(2+) chelator EGTA (1mM) potentiated Ca(2+) depletion-evoked taurine release. The substitution of CaCl(2) by choline chloride did not alter the observed effect. Ca(2+)-free solution did not significantly evoke release of taurine from tissue loaded with the competitive inhibitor of taurine transporter guanidinoethanesulfonate (1mM), suggesting that in Ca(2+) depletion taurine is released by the transporter operating in the outward direction. The volume-sensitive chloride channel blocker diisothiocyanostilbene-2,2'-disulfonate (1mM) did not attenuate the taurine release evoked by Ca(2+) depletion. The non-specific blocker of voltage-sensitive Ca(2+) channels NiCl(2) (0.65 mM) enhanced taurine release in the presence of Ca(2+). CdCl(2) (0.25 mM) had no effect under these conditions. However, both CdCl(2) and NiCl(2) attenuated the effect of Ca(2+)-free medium on the release of taurine. The data obtained imply the involvement of both decreased influx of Ca(2+) and increased non-specific influx of Na(+) through voltage-sensitive calcium channels in the regulation of transporter-mediated taurine release in Ca(2+) depletion. PMID:15982785

  14. The Potential Neural Mechanisms of Acute Indirect Vibration

    PubMed Central

    2011-01-01

    There is strong evidence to suggest that acute indirect vibration acts on muscle to enhance force, power, flexibility, balance and proprioception suggesting neural enhancement. Nevertheless, the neural mechanism(s) of vibration and its potentiating effect have received little attention. One proposal suggests that spinal reflexes enhance muscle contraction through a reflex activity known as tonic vibration stretch reflex (TVR), which increases muscle activation. However, TVR is based on direct, brief, and high frequency vibration (>100 Hz) which differs to indirect vibration, which is applied to the whole body or body parts at lower vibration frequency (5-45 Hz). Likewise, muscle tuning and neuromuscular aspects are other candidate mechanisms used to explain the vibration phenomenon. But there is much debate in terms of identifying which neural mechanism(s) are responsible for acute vibration; due to a number of studies using various vibration testing protocols. These protocols include: different methods of application, vibration variables, training duration, exercise types and a range of population groups. Therefore, the neural mechanism of acute vibration remain equivocal, but spinal reflexes, muscle tuning and neuromuscular aspects are all viable factors that may contribute in different ways to increasing muscular performance. Additional research is encouraged to determine which neural mechanism(s) and their contributions are responsible for acute vibration. Testing variables and vibration applications need to be standardised before reaching a consensus on which neural mechanism(s) occur during and post-vibration. Key points There is strong evidence to suggest that acute indirect vibration acts on muscle to enhance force, power, flexibility, balance and proprioception, but little attention has been given to the neural mechanism(s) of acute indirect vibration. Current findings suggest that acute vibration exposure may cause a neural response, but there is little

  15. Dynamic performance of dissipative dielectric elastomers under alternating mechanical load

    NASA Astrophysics Data System (ADS)

    Zhang, Junshi; Chen, Hualing; Sheng, Junjie; Liu, Lei; Wang, Yongquan; Jia, Shuhai

    2014-07-01

    This paper presents a theoretical study about the effect of dissipation on the dynamic performance of a dielectric elastomer membrane subject to a combination of mechanical load and voltage. The thermodynamic dissipative model is given and the equation of motion is deduced by a free energy method. It is found that when the applied mechanical load and voltage are static, the membrane may reach a state of equilibrium after the viscoelastic relaxation. When the voltage is static but the mechanical load is sinusoidal, the membrane will resonate at multiple frequencies. The study result indicates that the viscoelasticity can reduce the natural frequency and increase the mean stretch of the dielectric elastomer. After the power source is cut off, the effect of current leakage on dynamic performance under alternating mechanical load is that the natural frequency increases and the mean stretch reduces.

  16. Linkages of plant-soil feedbacks and underlying invasion mechanisms.

    PubMed

    Inderjit; Cahill, James F

    2015-01-01

    Soil microbial communities and processes have repeatedly been shown to impact plant community assembly and population growth. Soil-driven effects may be particularly pronounced with the introduction of plants to non-native ranges, as introduced plants are not typically accompanied by transference of local soil communities. Here we describe how the mechanisms by which soil community processes influence plant growth overlap with several known and well-described mechanisms of plant invasion. Critically, a given soil community process may either facilitate or limit invasion, depending upon local conditions and the specific mechanisms of soil processes involved. Additionally, as soil communities typically consist of species with short generation times, the net consequences of plant-soil feedbacks for invasion trajectories are likely to change over time, as ecological and evolutionary adjustments occur. Here we provide an overview of the ecological linkages of plant-soil feedbacks and underlying mechanisms of invasion. PMID:25784668

  17. Thermal and mechanical response of PBX 9501 under contact excitation

    NASA Astrophysics Data System (ADS)

    Mares, J. O.; Miller, J. K.; Sharp, N. D.; Moore, D. S.; Adams, D. E.; Groven, L. J.; Rhoads, J. F.; Son, S. F.

    2013-02-01

    The thermal and mechanical responses of a cyclotetramethylene-tetranitramine-based explosive (PBX 9501) and two non-energetic mock materials (900-21 and PBS 9501) under high-frequency mechanical excitation are presented. Direct contact ultrasound transducers were used to excite samples through a frequency range of 50 kHz to 40 MHz. The mechanical response of each sample was approximated from a contact receiving transducer and trends were confirmed via laser Doppler vibrometry. The steady-state thermal response of the samples was measured at discrete excitation frequencies via infrared thermography. A maximum temperature rise of approximately 15 K was observed in PBX 9501, and the mock materials exhibited similar thermal characteristics. Temperature gradients were calculated to estimate the total heat generated within the samples due to the mechanical excitation. The active heating mechanisms were found to be highly dependent on the frequency of excitation. Possible mechanisms of heating at frequencies below 1 MHz are likely related to bulk motion. Above this frequency, the active heating mechanisms are likely related to particle-scale processes. The observed phenomena may prove useful in the aid of current trace vapor detection methods for explosives.

  18. A potential mechanism underlying atypical antipsychotics-induced lipid disturbances

    PubMed Central

    Cai, H L; Tan, Q Y; Jiang, P; Dang, R L; Xue, Y; Tang, M M; Xu, P; Deng, Y; Li, H D; Yao, J K

    2015-01-01

    Previous findings suggested that a four-protein complex, including sterol-regulatory element-binding protein (SREBP), SREBP-cleavage-activating protein (SCAP), insulin-induced gene (INSIG) and progesterone receptor membrane component 1 (PGRMC1), within the endoplasmic reticulum appears to be an important regulator responsible for atypical antipsychotic drug (AAPD)-induced lipid disturbances. In the present study, effects of typical antipsychotic drug and AAPDs as well as treatment outcome of steroid antagonist mifepristone (MIF) on the PGRMC1/INSIG/SCAP/SREBP pathway were investigated in rat liver using real-time quantitative polymerase chain reaction (qPCR) and western blot analysis. In addition, serum triacylglycerol, total cholesterol, free fatty acids and various hormones including progesterone, corticosterone and insulin were measured simultaneously. Following treatment with clozapine or risperidone, both lipogenesis and cholesterogenesis were enhanced via inhibition of PGRMC1/INSIG-2 and activation of SCAP/SREBP expressions. Such metabolic disturbances, however, were not demonstrated in rats treated with aripiprazole (ARI) or haloperidol (HAL). Moreover, the add-on treatment of MIF was effective in reversing the AAPD-induced lipid disturbances by upregulating the expression of PGRMC1/INSIG-2 and subsequent downregulation of SCAP/SREBP. Taken together, our findings suggest that disturbances in lipid metabolism can occur at an early stage of AAPD treatment before the presence of weight gain. Such metabolic defects can be modified by an add-on treatment of steroid antagonist MIF enhancing the PGRMC1 pathway. Thus, it is likely that PGRMC1/INSIG-2 signaling may be a therapeutic target for AAPD-induced weight gain. PMID:26485545

  19. Potential Mechanisms Underlying Intercortical Signal Regulation via Cholinergic Neuromodulators

    PubMed Central

    Whittington, Miles A.; Kopell, Nancy J.

    2015-01-01

    The dynamical behavior of the cortex is extremely complex, with different areas and even different layers of a cortical column displaying different temporal patterns. A major open question is how the signals from different layers and different brain regions are coordinated in a flexible manner to support function. Here, we considered interactions between primary auditory cortex and adjacent association cortex. Using a biophysically based model, we show how top-down signals in the beta and gamma regimes can interact with a bottom-up gamma rhythm to provide regulation of signals between the cortical areas and among layers. The flow of signals depends on cholinergic modulation: with only glutamatergic drive, we show that top-down gamma rhythms may block sensory signals. In the presence of cholinergic drive, top-down beta rhythms can lift this blockade and allow signals to flow reciprocally between primary sensory and parietal cortex. SIGNIFICANCE STATEMENT Flexible coordination of multiple cortical areas is critical for complex cognitive functions, but how this is accomplished is not understood. Using computational models, we studied the interactions between primary auditory cortex (A1) and association cortex (Par2). Our model is capable of replicating interaction patterns observed in vitro and the simulations predict that the coordination between top-down gamma and beta rhythms is central to the gating process regulating bottom-up sensory signaling projected from A1 to Par2 and that cholinergic modulation allows this coordination to occur. PMID:26558772

  20. Emotional responses to music: the need to consider underlying mechanisms.

    PubMed

    Juslin, Patrik N; Västfjäll, Daniel

    2008-10-01

    Research indicates that people value music primarily because of the emotions it evokes. Yet, the notion of musical emotions remains controversial, and researchers have so far been unable to offer a satisfactory account of such emotions. We argue that the study of musical emotions has suffered from a neglect of underlying mechanisms. Specifically, researchers have studied musical emotions without regard to how they were evoked, or have assumed that the emotions must be based on the "default" mechanism for emotion induction, a cognitive appraisal. Here, we present a novel theoretical framework featuring six additional mechanisms through which music listening may induce emotions: (1) brain stem reflexes, (2) evaluative conditioning, (3) emotional contagion, (4) visual imagery, (5) episodic memory, and (6) musical expectancy. We propose that these mechanisms differ regarding such characteristics as their information focus, ontogenetic development, key brain regions, cultural impact, induction speed, degree of volitional influence, modularity, and dependence on musical structure. By synthesizing theory and findings from different domains, we are able to provide the first set of hypotheses that can help researchers to distinguish among the mechanisms. We show that failure to control for the underlying mechanism may lead to inconsistent or non-interpretable findings. Thus, we argue that the new framework may guide future research and help to resolve previous disagreements in the field. We conclude that music evokes emotions through mechanisms that are not unique to music, and that the study of musical emotions could benefit the emotion field as a whole by providing novel paradigms for emotion induction. PMID:18826699

  1. Experimental Analysis of the Mechanism of Hearing under Water

    PubMed Central

    Chordekar, Shai; Kishon-Rabin, Liat; Kriksunov, Leonid; Adelman, Cahtia; Sohmer, Haim

    2015-01-01

    The mechanism of human hearing under water is debated. Some suggest it is by air conduction (AC), others by bone conduction (BC), and others by a combination of AC and BC. A clinical bone vibrator applied to soft tissue sites on the head, neck, and thorax also elicits hearing by a mechanism called soft tissue conduction (STC) or nonosseous BC. The present study was designed to test whether underwater hearing at low intensities is by AC or by osseous BC based on bone vibrations or by nonosseous BC (STC). Thresholds of normal hearing participants to bone vibrator stimulation with their forehead in air were recorded and again when forehead and bone vibrator were under water. A vibrometer detected vibrations of a dry human skull in all similar conditions (in air and under water) but not when water was the intermediary between the sound source and the skull forehead. Therefore, the intensities required to induce vibrations of the dry skull in water were significantly higher than the underwater hearing thresholds of the participants, under conditions when hearing by AC and osseous BC is not likely. The results support the hypothesis that hearing under water at low sound intensities may be attributed to nonosseous BC (STC). PMID:26770975

  2. Atypical Gaze Following in Autism: A Comparison of Three Potential Mechanisms

    ERIC Educational Resources Information Center

    Gillespie-Lynch, K.; Elias, R.; Escudero, P.; Hutman, T.; Johnson, S. P.

    2013-01-01

    In order to evaluate the following potential mechanisms underlying atypical gaze following in autism, impaired reflexive gaze following, difficulty integrating gaze and affect, or reduced understanding of the referential significance of gaze, we administered three paradigms to young children with autism (N = 21) and chronological (N = 21) and…

  3. The mismatch negativity: a review of underlying mechanisms.

    PubMed

    Garrido, Marta I; Kilner, James M; Stephan, Klaas E; Friston, Karl J

    2009-03-01

    The mismatch negativity (MMN) is a brain response to violations of a rule, established by a sequence of sensory stimuli (typically in the auditory domain) [Näätänen R. Attention and brain function. Hillsdale, NJ: Lawrence Erlbaum; 1992]. The MMN reflects the brain's ability to perform automatic comparisons between consecutive stimuli and provides an electrophysiological index of sensory learning and perceptual accuracy. Although the MMN has been studied extensively, the neurophysiological mechanisms underlying the MMN are not well understood. Several hypotheses have been put forward to explain the generation of the MMN; amongst these accounts, the "adaptation hypothesis" and the "model adjustment hypothesis" have received the most attention. This paper presents a review of studies that focus on neuronal mechanisms underlying the MMN generation, discusses the two major explanatory hypotheses, and proposes predictive coding as a general framework that attempts to unify both. PMID:19181570

  4. Mechanical properties of graphynes under shearing and bending

    NASA Astrophysics Data System (ADS)

    Yi, Lijun; Zhang, Yingyan; Feng, Xiqiao; Chang, Tienchong; Wang, Ji; Du, Jianke; Zhou, Jianxin

    2016-05-01

    Graphynes are the allotrope of graphene. In this work, extensive molecular dynamics simulations are performed on four different graphynes ( α - , β - , γ - , and 6,6,12-graphynes) to explore their mechanical properties (shear modulus, shear strength, and bending rigidity) under shearing and bending. While the shearing properties are anisotropic, the bending rigidity is almost independent of the chirality of graphynes. We also find that the shear modulus and shear fracture strength of graphynes decrease with increasing temperature. The effect of the percentage of the acetylenic linkages on the shear mechanical properties and bending rigidity is investigated. It is shown that the fracture shear strengths and bending rigidities of the four types of graphynes decrease, while the fracture shear strain increases, with increasing percentages of the acetylenic linkages. Significant wrinkling is observed in graphyne under shear strain. The influence of the temperatures and percentages of the acetylenic linkages on the ratio of amplitude-to-wavelength in the wrinkles are examined.

  5. Cognitive interventions for addiction medicine: Understanding the underlying neurobiological mechanisms.

    PubMed

    Zilverstand, Anna; Parvaz, Muhammad A; Moeller, Scott J; Goldstein, Rita Z

    2016-01-01

    Neuroimaging provides a tool for investigating the neurobiological mechanisms of cognitive interventions in addiction. The aim of this review was to describe the brain circuits that are recruited during cognitive interventions, examining differences between various treatment modalities while highlighting core mechanisms, in drug addicted individuals. Based on a systematic Medline search we reviewed neuroimaging studies on cognitive behavioral therapy, cognitive inhibition of craving, motivational interventions, emotion regulation, mindfulness, and neurofeedback training in addiction. Across intervention modalities, common results included the normalization of aberrant activity in the brain's reward circuitry, and the recruitment and strengthening of the brain's inhibitory control network. Results suggest that different cognitive interventions act, at least partly, through recruitment of a common inhibitory control network as a core mechanism. This implies potential transfer effects between training modalities. Overall, results confirm that chronically hypoactive prefrontal regions implicated in cognitive control in addiction can be normalized through cognitive means. PMID:26822363

  6. Closure mechanisms of ventilated supercavities under steady and unsteady flows

    NASA Astrophysics Data System (ADS)

    Karn, Ashish; De, Rohan; Hong, Jiarong; Arndt, Roger E. A.

    2015-12-01

    The present work reports some interesting experimental results for ventilated supercavitation in steady and unsteady flows. First, a variety of closure modes obtained as a result of systematic variation in Froude number and air entrainment, are reported. The closure mechanisms were found to differ from the standard criterion reported in the literature. Further, the occurrence of a variety of stable and unstable closure mechanisms were discovered that have not been reported in the literature. Next, a hypothesis is presented to explain the cause behind these different closure mechanisms. The proposed hypothesis is then validated by synchronized high-speed imaging and pressure measurements inside and outside of the supercavity. These measurements show that the supercavity closure is a function of instantaneous cavitation number under unsteady flow conditions. (Research sponsored by Office of Naval Research, USA)

  7. Analysis of internal crack healing mechanism under rolling deformation.

    PubMed

    Gao, Haitao; Ai, Zhengrong; Yu, Hailiang; Wu, Hongyan; Liu, Xianghua

    2014-01-01

    A new experimental method, called the 'hole filling method', is proposed to simulate the healing of internal cracks in rolled workpieces. Based on the experimental results, the evolution in the microstructure, in terms of diffusion, nucleation and recrystallisation were used to analyze the crack healing mechanism. We also validated the phenomenon of segmented healing. Internal crack healing involves plastic deformation, heat transfer and an increase in the free energy introduced by the cracks. It is proposed that internal cracks heal better under high plastic deformation followed by slow cooling after rolling. Crack healing is controlled by diffusion of atoms from the matrix to the crack surface, and also by the nucleation and growth of ferrite grain on the crack surface. The diffusion mechanism is used to explain the source of material needed for crack healing. The recrystallisation mechanism is used to explain grain nucleation and growth, accompanied by atomic migration to the crack surface. PMID:25003518

  8. An NMDA receptor-dependent mechanism underlies inhibitory synapse development

    PubMed Central

    Gu, Xinglong; Zhou, Liang; Lu, Wei

    2016-01-01

    Summary In the mammalian brain GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here we report that NMDA-type ionotropic glutamate receptors (NMDARs) in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, while GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABAA receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain. PMID:26774487

  9. Analysis of Internal Crack Healing Mechanism under Rolling Deformation

    PubMed Central

    Gao, Haitao; Ai, Zhengrong; Yu, Hailiang; Wu, Hongyan; Liu, Xianghua

    2014-01-01

    A new experimental method, called the ‘hole filling method’, is proposed to simulate the healing of internal cracks in rolled workpieces. Based on the experimental results, the evolution in the microstructure, in terms of diffusion, nucleation and recrystallisation were used to analyze the crack healing mechanism. We also validated the phenomenon of segmented healing. Internal crack healing involves plastic deformation, heat transfer and an increase in the free energy introduced by the cracks. It is proposed that internal cracks heal better under high plastic deformation followed by slow cooling after rolling. Crack healing is controlled by diffusion of atoms from the matrix to the crack surface, and also by the nucleation and growth of ferrite grain on the crack surface. The diffusion mechanism is used to explain the source of material needed for crack healing. The recrystallisation mechanism is used to explain grain nucleation and growth, accompanied by atomic migration to the crack surface. PMID:25003518

  10. Mitophagy: Basic Mechanism and Potential Role in Kidney Diseases

    PubMed Central

    Tang, Chengyuan; He, Liyu; Liu, Jing; Dong, Zheng

    2015-01-01

    Background Mitochondria play fundamental roles in cellular metabolism, signaling, and viability. Disruption of mitochondria not only leads to dysfunction of the organelles but also activates mechanisms of cell injury and death, contributing to the pathogenesis of various diseases. Summary Removal of damaged mitochondria is therefore crucial for cellular homeostasis and survival. Mitophagy, the selective elimination of mitochondria via autophagy, is an important mechanism of mitochondrial quality control in physiological and pathological conditions. Defects in mitophagy have been implicated in a variety of human disorders, including both acute and chronic kidney diseases. However, the role and regulatory mechanisms of mitophagy in kidney cells and tissues remain largely unknown. Key Message This review provides updated information on mitophagy and suggests a potential role of mitophagy in renal pathophysiology.

  11. Fracture mechanics of hydroxyapatite single crystals under geometric confinement.

    PubMed

    Libonati, Flavia; Nair, Arun K; Vergani, Laura; Buehler, Markus J

    2013-04-01

    Geometric confinement to the nanoscale, a concept that refers to the characteristic dimensions of structural features of materials at this length scale, has been shown to control the mechanical behavior of many biological materials or their building blocks, and such effects have also been suggested to play a crucial role in enhancing the strength and toughness of bone. Here we study the effect of geometric confinement on the fracture mechanism of hydroxyapatite (HAP) crystals that form the mineralized phase in bone. We report a series of molecular simulations of HAP crystals with an edge crack on the (001) plane under tensile loading, and we systematically vary the sample height whilst keeping the sample and the crack length constant. We find that by decreasing the sample height the stress concentration at the tip of the crack disappears for samples with a height smaller than 4.15nm, below which the material shows a different failure mode characterized by a more ductile mechanism with much larger failure strains, and the strength approaching that of a flaw-less crystal. This study directly confirms an earlier suggestion of a flaw-tolerant state that appears under geometric confinement and may explain the mechanical stability of the reinforcing HAP platelets in bone. PMID:23500480

  12. Giant panda׳s tooth enamel: Structure, mechanical behavior and toughening mechanisms under indentation.

    PubMed

    Weng, Z Y; Liu, Z Q; Ritchie, R O; Jiao, D; Li, D S; Wu, H L; Deng, L H; Zhang, Z F

    2016-12-01

    The giant panda׳s teeth possess remarkable load-bearing capacity and damage resistance for masticating bamboos. In this study, the hierarchical structure and mechanical behavior of the giant panda׳s tooth enamel were investigated under indentation. The effects of loading orientation and location on mechanical properties of the enamel were clarified and the evolution of damage in the enamel under increasing load evaluated. The nature of the damage, both at and beneath the indentation surfaces, and the underlying toughening mechanisms were explored. Indentation cracks invariably were seen to propagate along the internal interfaces, specifically the sheaths between enamel rods, and multiple extrinsic toughening mechanisms, e.g., crack deflection/twisting and uncracked-ligament bridging, were active to shield the tips of cracks from the applied stress. The giant panda׳s tooth enamel is analogous to human enamel in its mechanical properties, yet it has superior hardness and Young׳s modulus but inferior toughness as compared to the bamboo that pandas primarily feed on, highlighting the critical roles of the integration of underlying tissues in the entire tooth and the highly hydrated state of bamboo foods. Our objective is that this study can aid the understanding of the structure-mechanical property relations in the tooth enamel of mammals and further provide some insight on the food habits of the giant pandas. PMID:27498423

  13. A mechanical wave system to show waveforms similar to quantum mechanical wavefunctions in a potential

    NASA Astrophysics Data System (ADS)

    Faletič, Sergej

    2015-05-01

    Interviews with students suggest that even though they understand the formalism and the formal nature of quantum theory, they still often desire a mental picture of what the equations describe and some tangible experience with the wavefunctions. Here we discuss a mechanical wave system capable of reproducing correctly a mechanical equivalent of a quantum system in a potential, and the resulting waveforms in principle of any form. We have successfully reproduced the finite potential well, the potential barrier and the parabolic potential. We believe that these mechanical waveforms can provide a valuable experience base for introductory students to start from. We aim to show that mechanical systems that are described with the same mathematics as quantum mechanical, indeed behave in the same way. We believe that even if treated purely as a wave phenomenon, the system provides much insight into wave mechanics. This can be especially useful for physics teachers and others who often need to resort to concepts and experience rather than mathematics when explaining physical phenomena.

  14. Electronic Properties of Low-Dimensional Materials Under Periodic Potential

    NASA Astrophysics Data System (ADS)

    Jamei, Mehdi

    In the quest for the further miniaturization of electronic devices, numerous fabrication techniques have been developed. The semiconductor industry has been able to manifest miniaturization in highly complex and ultra low-power integrated circuits and devices, transforming almost every aspect of our lives. However, we may have come very close to the end of this trend. While advanced machines and techniques may be able to overcome technological barriers, theoretical and fundamental barriers are inherent to the top-down miniaturization approach and cannot be circumvented. As a result, the need for novel and natural alternatives to replace old materials is valued now more than ever. Fortunately, there exists a large group of materials that essentially has low-dimensional (quasi-one- or quasi-two-dimensional) structures. Graphene, a two-dimensional form of carbon, which has attracted a lot of attention in recent years, is a perfect example of a prime material from this group. Niobium tri-selenide (NbSe3), from a family of trichalcogenides, has a highly anisotropic structure and electrical conductivity. At sufficiently low temperatures, NbSe3 also exhibits two independent "sliding charge density waves"-- an exciting phenomenon, which could be altered by changing the overall size of the material. In NbSe3 (and Blue Bronze K0.3MoO3 which has a similar structure and electrical behavior), the effect of a periodic potential could be seen in creating a charge density wave (CDW) that is incommensurate to the underlying lattice. The required periodic potential is provided by the crystal ions when ordered in a particular way. The consequence is a peculiar non-linear conductivity behavior, as well as a unique narrow-band noise spectrum. Theoretical and experimental studies have concluded that the dynamic properties of resulting CDW are directly related to the crystal impurity density, and other pinning potentials. Therefore, reducing the overall size of the crystal could

  15. Comparing Chemical Mechanisms using Tagged Ozone Production Potentials

    NASA Astrophysics Data System (ADS)

    Coates, J.; Butler, T. M.

    2013-12-01

    Tropospheric ozone (O3) is a short-lived climate forcing pollutant that is detrimental to human health and crop growth. It is produced by reactions of volatile organic compounds (VOCs) and nitrogen oxides (NOx) in the presence of sunlight [Atkinson,2000]. The chemistry of intermediate species formed during VOC degradation show a time dependence and impacts the amount of O3 produced by the VOC [Butler et al., 2011]. Representing the intricacies of these reactions is not viable for chemical mechanisms used in global and regional models due to the computational resources available. Thus, chemical mechanisms reduce the amount of reactions either by lumping chemical species together as a model species, reducing the number of reaction pathways or both. As different chemical mechanisms use varying reduction techniques and assumptions especially with respect to the intermediate degradation species, it is important to compare the temporal evolution of ozone production obtained from differing chemical mechanisms. In this study, chemical mechanisms are compared using Tagged Ozone Production Potentials (TOPP) [Butler et al.,2011]. TOPPs measure the effect of a VOC on the odd oxygen family (Ox), which includes O3, nitrogen dioxide (NO2) and other species whose cycling effect O3 and NO2 production. TOPP values are obtained via a boxmodel run lasting seven diurnal cycles and tagging all species produced during VOC degradation; this enables the Ox production to be attributed to the VOC. This technique enables the temporal evolution of a VOCs' Ox production to be compared between the mechanisms. Comparing the TOPP profiles of the VOCs obtained using different mechanisms shows the effect of reduction techniques implemented by the mechanism and also allows a comparison of the tropospheric chemistry represented in the mechanisms. [Atkinson,2000] Atkinson, R. (2000). Atmospheric chemistry of VOCs and NOx. Atmospheric Environment, 34:2063-2101 [Butler et al., 2011] Butler, T. M

  16. Embrittlement of a Duplex Stainless Steel in Acidic Environment Under Applied Cathodic Potentials

    NASA Astrophysics Data System (ADS)

    Roychowdhury, S.; Kain, Vivekanand

    2008-10-01

    Hydrogen-induced degradation of mechanical properties of a duplex stainless steel in 0.1N H2SO4 solution has been studied under in situ cathodic charging conditions. Significant reductions in percentage of elongation, toughness, and time to failure were noticed due to the ingress of hydrogen into the material at various applied cathodic potentials in the range of -200 to -800 mV (SCE). Cleavage fractures were identified mainly in the ferritic phases. Crack growth was observed to be inhibited by the austenite phase. However, depending on the severity of the environment, both the ferrite and austenite phases could be embrittled. At less negative potentials, presence of surface film and low hydrogen fugacity seemed to control hydrogen ingress in the metal. Addition of thiosulfate to the acidic solution further degraded the mechanical properties of the steel at the applied cathodic potential.

  17. A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis

    PubMed Central

    Marcoux, Julien; Mangione, P Patrizia; Porcari, Riccardo; Degiacomi, Matteo T; Verona, Guglielmo; Taylor, Graham W; Giorgetti, Sofia; Raimondi, Sara; Sanglier-Cianférani, Sarah; Benesch, Justin LP; Cecconi, Ciro; Naqvi, Mohsin M; Gillmore, Julian D; Hawkins, Philip N; Stoppini, Monica; Robinson, Carol V; Pepys, Mark B; Bellotti, Vittorio

    2015-01-01

    The mechanisms underlying transthyretin-related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49–127 fragment from the prototypic S52P variant, and we show that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. Crucially, the non-amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano-enzymatic mechanism mediates transthyretin amyloid fibrillogenesis in vivo. This may be particularly important in the heart where shear stress is greatest; indeed, the 49–127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis-mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied. PMID:26286619

  18. Corrosion of breached aluminide fuel under potential repository conditions.

    SciTech Connect

    Kaminski, M. D.; Goldberg, M. M.

    2000-11-06

    Permanent disposal of spent nuclear fuel is proposed in a repository located in the volcanic tuff beds near Yucca Mountain, Nevada, and it is the responsibility of the National Spent Nuclear Fuel Program (NSNFP) to provide the Yucca Mountain Project (YMP) with information related to the release of fission products from the DOE-owned SNF resulting from SNF corrosion. Hydrologically unsaturated spent fuel tests (''drip'' tests) are designed to simulate and monitor the release of radionuclides from the spent fuel under potential exposure conditions in the repository. Of the priority fuels being tested under the NSNFP, the aluminum-based fuels are included because of their high relative volume and uranium enrichment. The Al fuel structure is composed of fissile and aluminum powders pressed and annealed between Al plates to form thin metallic plates. The most widely used fissile powder was the intermetallic compound aluminide UAl{sub x} (where x=2,3,4). As part of this testing program, preliminary corrosion tests using unirradiated UAl{sub x} were initiated to address experimental design, sampling, and analysis issues prior to conducting tests with spent fuels. However, during this program the decision was made by U.S. DOE to convert the aluminum-based fuels to safer enrichment levels by using the melt-dilute process at Savannah River. Nonetheless, the product ingot of the melt-dilute process resembles low enriched UAl{sub x} fuel and corrosion of the fuel is expected to be similar. This paper summarizes the preliminary testing results for the first year of the program and compares them to other corrosion testing results on aluminum fuels as well as other DOE fuel types.

  19. Peer influence: neural mechanisms underlying in-group conformity

    PubMed Central

    Stallen, Mirre; Smidts, Ale; Sanfey, Alan G.

    2012-01-01

    People often conform to the behavior of others with whom they identify. However, it is unclear what fundamental mechanisms underlie this type of conformity. Here, we investigate the processes mediating in-group conformity by using functional magnetic resonance imaging (fMRI). Participants completed a perceptual decision-making task while undergoing fMRI, during which they were exposed to the judgments of both in-group and out-group members. Our data suggest that conformity to the in-group is mediated by both positive affect as well as the cognitive capacity of perspective taking. Examining the processes that drive in-group conformity by utilizing a basic decision-making paradigm combined with neuroimaging methods provides important insights into the potential mechanisms of conformity. These results may provide an integral step in developing more effective campaigns using group conformity as a tool for behavioral change. PMID:23482688

  20. Mechanisms underlying astringency: introduction to an oral tribology approach

    NASA Astrophysics Data System (ADS)

    Upadhyay, Rutuja; Brossard, Natalia; Chen, Jianshe

    2016-03-01

    Astringency is one of the predominant factors in the sensory experience of many foods and beverages ranging from wine to nuts. The scientific community is discussing mechanisms that explain this complex phenomenon, since there are no conclusive results which correlate well with sensory astringency. Therefore, the mechanisms and perceptual characteristics of astringency warrant further discussion and investigation. This paper gives a brief introduction of the fundamentals of oral tribology forming a basis of the astringency mechanism. It discusses the current state of the literature on mechanisms underlying astringency describing the existing astringency models. The review discusses the crucial role of saliva and its physiology which contributes significantly in astringency perception in the mouth. It also provides an overview of research concerned with the physiological and psychophysical factors that mediate the perception of this sensation, establishing the ground for future research. Thus, the overall aim of the review is to establish the critical roles of oral friction (thin-film lubrication) in the sensation of astringency and possibly of some other specific sensory features.

  1. Physical mechanisms underlying the strain-rate-dependent mechanical behavior of kangaroo shoulder cartilage

    NASA Astrophysics Data System (ADS)

    Thibbotuwawa, Namal; Oloyede, Adekunle; Li, Tong; Singh, Sanjleena; Senadeera, Wijitha; Gu, YuanTong

    2015-09-01

    Due to anatomical and biomechanical similarities to human shoulder, kangaroo was chosen as a model to study shoulder cartilage. Comprehensive enzymatic degradation and indentation tests were applied on kangaroo shoulder cartilage to study mechanisms underlying its strain-rate-dependent mechanical behavior. We report that superficial collagen plays a more significant role than proteoglycans in facilitating strain-rate-dependent behavior of the kangaroo shoulder cartilage. By comparing the mechanical properties of degraded and normal cartilages, it was noted that proteoglycan and collagen degradation significantly compromised strain-rate-dependent mechanical behavior of the cartilage. Superficial collagen contributed equally to the tissue behavior at all strain-rates. This is different to the studies reported on knee cartilage and confirms the importance of superficial collagen on shoulder cartilage mechanical behavior. A porohyperelastic numerical model also indicated that collagen disruption would lead to faster damage of the shoulder cartilage than when proteoglycans are depleted.

  2. Ballistocardiogram: Mechanism and Potential for Unobtrusive Cardiovascular Health Monitoring

    PubMed Central

    Kim, Chang-Sei; Ober, Stephanie L.; McMurtry, M. Sean; Finegan, Barry A.; Inan, Omer T.; Mukkamala, Ramakrishna; Hahn, Jin-Oh

    2016-01-01

    For more than a century, it has been known that the body recoils each time the heart ejects blood into the arteries. These subtle cardiogenic body movements have been measured with increasingly convenient ballistocardiography (BCG) instruments over the years. A typical BCG measurement shows several waves, most notably the “I”, “J”, and “K” waves. However, the mechanism for the genesis of these waves has remained elusive. We formulated a simple mathematical model of the BCG waveform. We showed that the model could predict the BCG waves as well as physiologic timings and amplitudes of the major waves. The validated model reveals that the principal mechanism for the genesis of the BCG waves is blood pressure gradients in the ascending and descending aorta. This new mechanistic insight may be exploited to allow BCG to realize its potential for unobtrusive monitoring and diagnosis of cardiovascular health and disease. PMID:27503664

  3. Potential Molecular and Cellular Mechanism of Psychotropic Drugs

    PubMed Central

    Seo, Myoung Suk; Scarr, Elizabeth; Lai, Chi-Yu

    2014-01-01

    Psychiatric disorders are among the most debilitating of all medical illnesses. Whilst there are drugs that can be used to treat these disorders, they give sub-optimal recovery in many people and a significant number of individuals do not respond to any treatments and remain treatment resistant. Surprisingly, the mechanism by which psychotropic drugs cause their therapeutic benefits remain unknown but likely involves the underlying molecular pathways affected by the drugs. Hence, in this review, we have focused on recent findings on the molecular mechanism affected by antipsychotic, mood stabilizing and antidepressant drugs at the levels of epigenetics, intracellular signalling cascades and microRNAs. We posit that understanding these important interactions will result in a better understanding of how these drugs act which in turn may aid in considering how to develop drugs with better efficacy or increased therapeutic reach. PMID:25191500

  4. Mental Imagery in Depression: Phenomenology, Potential Mechanisms, and Treatment Implications.

    PubMed

    Holmes, Emily A; Blackwell, Simon E; Burnett Heyes, Stephanie; Renner, Fritz; Raes, Filip

    2016-03-28

    Mental imagery is an experience like perception in the absence of a percept. It is a ubiquitous feature of human cognition, yet it has been relatively neglected in the etiology, maintenance, and treatment of depression. Imagery abnormalities in depression include an excess of intrusive negative mental imagery; impoverished positive imagery; bias for observer perspective imagery; and overgeneral memory, in which specific imagery is lacking. We consider the contribution of imagery dysfunctions to depressive psychopathology and implications for cognitive behavioral interventions. Treatment advances capitalizing on the representational format of imagery (as opposed to its content) are reviewed, including imagery rescripting, positive imagery generation, and memory specificity training. Consideration of mental imagery can contribute to clinical assessment and imagery-focused psychological therapeutic techniques and promote investigation of underlying mechanisms for treatment innovation. Research into mental imagery in depression is at an early stage. Work that bridges clinical psychology and neuroscience in the investigation of imagery-related mechanisms is recommended. PMID:26772205

  5. Biochemical mechanisms of signaling: perspectives in plants under arsenic stress.

    PubMed

    Islam, Ejazul; Khan, Muhammad Tahir; Irem, Samra

    2015-04-01

    Plants are the ultimate food source for humans, either directly or indirectly. Being sessile in nature, they are exposed to various biotic and abiotic stresses because of changing climate that adversely effects their growth and development. Contamination of heavy metals is one of the major abiotic stresses because of anthropogenic as well as natural factors which lead to increased toxicity and accumulation in plants. Arsenic is a naturally occurring metalloid toxin present in the earth crust. Due to its presence in terrestrial and aquatic environments, it effects the growth of plants. Plants can tolerate arsenic using several mechanisms like phytochelation, vacuole sequestration and activation of antioxidant defense systems. Several signaling mechanisms have evolved in plants that involve the use of proteins, calcium ions, hormones, reactive oxygen species and nitric oxide as signaling molecules to cope with arsenic toxicity. These mechanisms facilitate plants to survive under metal stress by activating their defense systems. The pathways by which these stress signals are perceived and responded is an unexplored area of research and there are lots of gaps still to be filled. A good understanding of these signaling pathways can help in raising the plants which can perform better in arsenic contaminated soil and water. In order to increase the survival of plants in contaminated areas there is a strong need to identify suitable gene targets that can be modified according to needs of the stakeholders using various biotechnological techniques. This review focuses on the signaling mechanisms of plants grown under arsenic stress and will give an insight of the different sensory systems in plants. Furthermore, it provides the knowledge about several pathways that can be exploited to develop plant cultivars which are resistant to arsenic stress or can reduce its uptake to minimize the risk of arsenic toxicity through food chain thus ensuring food security. PMID:25637747

  6. Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity.

    PubMed

    Farber, N B; Kim, S H; Dikranian, K; Jiang, X P; Heinkel, C

    2002-01-01

    NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (e.g. antimuscarinics, non-NMDA glutamate antagonists, and alpha(2) adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an alpha(2) adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m(3)) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated. PMID:11803444

  7. Thermal and mechanical responses of PBX 9501 under contact excitation under various driving intensities

    NASA Astrophysics Data System (ADS)

    Mares, J.; Miller, J.; Moore, D.; Groven, L.; Rhoads, J.; Son, S.

    2013-06-01

    The thermal and mechanical responses of a explosive (PBX 9501) and two non-energetic mock materials (900-21 and PBS 9501) under high-frequency mechanical excitation are presented with various driving intensities. Direct contact ultrasound transducers were used to excite samples through a frequency range of 50 kHz to 40 MHz. The mechanical response of each sample was approximated from a contact receiving transducer and trends were confirmed via laser Doppler vibrometry. The steady-state thermal response of the samples was measured at discrete excitation frequencies via infrared thermography. A maximum temperature rise of approximately 15 K was observed in PBX 9501, and the mock materials exhibited similar thermal characteristics. Temperature gradients were calculated to estimate the total heat generated within the samples due to the mechanical excitation. The active heating mechanisms were found to be highly dependent on the frequency of excitation. Possible mechanisms of heating at frequencies below 1 MHz are likely related to bulk motion. Above this frequency, the active heating mechanisms are likely related to particle-scale processes. The observed phenomena may prove useful in the aid of current trace vapor detection methods for explosives. Basic Research Challenge on ``Chemical decomposition in high energy density materials induced by coupled acoustic electromagnetic energy insult'' (through Grant No. N00014-11- 379 1-0466).

  8. Neural Mechanisms Underlying Anxiety-Chronic Pain Interactions.

    PubMed

    Zhuo, Min

    2016-03-01

    Chronic pain is a major medical problem that is resistant to conventional medical intervention. It also causes emotional changes such as anxiety and fear. Furthermore, anxiety or fear often enhances the suffering of pain. Based on recent studies, I propose chronic anxiety triggered by injury or chronic pain is mediated through presynaptic long-term potentiation (LTP) in the anterior cingulate cortex (ACC), a key cortical region for pain perception. Conversely, NMDA receptor-dependent postsynaptic LTP plays a more important role in behavioral sensitization in chronic pain. Thus, postsynaptic and presynaptic LTP in ACC neurons are likely the key cellular mechanisms for causing chronic pain and its associated anxiety, respectively. This suggests potential targets for treating chronic pain and related anxiety. PMID:26878750

  9. Study of mechanical properties of nanomaterials under high pressure

    NASA Astrophysics Data System (ADS)

    Sharma, Jyoti; Kaur, Namrat; Srivastava, A. K.

    2015-08-01

    In the present work, the study of physical properties and behaviour of nanomaterials i.e. n-γ- Al2O3and n-Si3C4 under high pressure is done. For this purpose Murnaghan equation of state is used. The applicability of Murnaghan equation of state is fully tested by calculating mechanical properties of nano materials i.e. volume compression (V/Vo), bulk modulus (KT) and relative isothermal compression coefficient (α(P)/α0) at different pressures. The present calculated values of compression curve for the cited nanomaterials come out to be in reasonable good agreement with the available experimental data.

  10. Crystal nucleation mechanism in melts of short polymer chains under quiescent conditions and under shear flow

    NASA Astrophysics Data System (ADS)

    Anwar, Muhammad; Berryman, Joshua T.; Schilling, Tanja

    2014-09-01

    We present a molecular dynamics simulation study of crystal nucleation from undercooled melts of n-alkanes, and we identify the molecular mechanism of homogeneous crystal nucleation under quiescent conditions and under shear flow. We compare results for n-eicosane (C20) and n-pentacontahectane (C150), i.e., one system below the entanglement length and one above, at 20%-30% undercooling. Under quiescent conditions, we observe that entanglement does not have an effect on the nucleation mechanism. For both chain lengths, the chains first align and then straighten locally, then the local density increases and finally positional ordering sets in. At low shear rates the nucleation mechanism is the same as under quiescent conditions, while at high shear rates the chains align and straighten at the same time. We report on the effects of shear rate and temperature on the nucleation rates and estimate the critical shear rates, beyond which the nucleation rates increase with the shear rate. In agreement with previous experimental observation and theoretical work, we find that the critical shear rate corresponds to a Weissenberg number of order 1. Finally, we show that the viscosity of the system is not affected by the crystalline nuclei.

  11. Possibility and potential of clean development mechanisms in China

    NASA Astrophysics Data System (ADS)

    Gao, Weijun; Zhou, Nan; Li, Haifeng; Kammen, Daniel M.

    2007-10-01

    China has become the world's second largest greenhouse gas (GHG) emitter behind the United States. It emits approximately three billion tons of CO2 equivalents every year. Its growing economy and large population are making a wealthier, more consumption-oriented country. Energy demand is expected to grow 5 10% per year through 2030. Therefore, a large potential of GHG emission reduction in China can be expected. The clean development mechanism (CDM) put forward in the Kyoto Protocol for reductions of GHGs can support the sustainable development of developing countries and help developed countries to achieve their emission reduction targets at low cost. However, there are still many disagreements to be resolved between developing and developed countries. In this letter, we try to introduce the current development of CDM projects in China and discuss its potential and opportunities in the future decades.

  12. Uncertainty Propagation in Nerve Impulses Through the Action Potential Mechanism.

    PubMed

    Torres Valderrama, Aldemar; Witteveen, Jeroen; Navarro, Maria; Blom, Joke

    2015-12-01

    We investigate the propagation of probabilistic uncertainty through the action potential mechanism in nerve cells. Using the Hodgkin-Huxley (H-H) model and Stochastic Collocation on Sparse Grids, we obtain an accurate probabilistic interpretation of the deterministic dynamics of the transmembrane potential and gating variables. Using Sobol indices, out of the 11 uncertain parameters in the H-H model, we unravel two main uncertainty sources, which account for more than 90 % of the fluctuations in neuronal responses, and have a direct biophysical interpretation. We discuss how this interesting feature of the H-H model allows one to reduce greatly the probabilistic degrees of freedom in uncertainty quantification analyses, saving CPU time in numerical simulations and opening possibilities for probabilistic generalisation of other deterministic models of great importance in physiology and mathematical neuroscience. PMID:26458902

  13. Possibility and potential of clean development mechanisms inChina

    SciTech Connect

    Gao, Weijun; Zhou, Nan; Li, Haifeng; Kammen, Daniel

    2007-10-30

    China has become the world's second largest greenhouse gas(GHG) emitter behind the United States. It emits approximately threebillion tons of CO2 equivalents every year. Its growing economy and largepopulation are making a wealthier, more consumption-oriented country.Energy demand is expected to grow 5?10 percent per year through 2030.Therefore, a large potential of GHG emission reduction in Chinacan beexpected. The clean development mechanism (CDM) put forward in the KyotoProtocol for reductions of GHGs can support the sustainable developmentof developing countries and help developed countries to achieve theiremission reduction targets at low cost. However, there are still manydisagreements to be resolved between developing and developed countries.In this letter, we try to introduce the current development of CDMprojects in China and discuss its potential and opportunities in thefuture decades.

  14. Is forebrain neurogenesis a potential repair mechanism after stroke?

    PubMed

    Inta, Dragos; Gass, Peter

    2015-07-01

    The use of adult subventricular zone (SVZ) neurogenesis as brain repair strategy after stroke represents a hot topic in neurologic research. Recent radiocarbon-14 dating has revealed a lack of poststroke neurogenesis in the adult human neocortex; however, adult neurogenesis has been shown to occur, even under physiologic conditions, in the human striatum. Here, these results are contrasted with experimental poststroke neurogenesis in the murine brain. Both in humans and in rodents, the SVZ generates predominantly calretinin (CR)-expressing GABAergic interneurons, which cannot replace the broad spectrum of neuronal subtypes damaged by stroke. Therefore, SVZ neurogenesis may represent a repair mechanism only after genetic manipulation redirecting its differentiation. PMID:25966955

  15. Coping styles and behavioural flexibility: towards underlying mechanisms

    PubMed Central

    Coppens, Caroline M.; de Boer, Sietse F.; Koolhaas, Jaap M.

    2010-01-01

    A coping style (also termed behavioural syndrome or personality) is defined as a correlated set of individual behavioural and physiological characteristics that is consistent over time and across situations. This relatively stable trait is a fundamental and adaptively significant phenomenon in the biology of a broad range of species, i.e. it confers differential fitness consequences under divergent environmental conditions. Behavioural flexibility appears to be an important underlying attribute or feature of the coping style that might explain consistency across situations. Proactive coping is characterized by low flexibility expressed as rather rigid, routine-like behavioural tendencies and reduced impulse control (behavioural inhibition) in operant conditioning paradigms. This article summarizes some of the evidence that individual differentiation in behavioural flexibility emerges as a function of underlying variability in the activation of a brain circuitry that includes the prefrontal cortex and its key neurochemical signalling pathways (e.g. dopaminergic and serotonergic input). We argue that the multidimensional nature of animal personality and the terminology used for the various dimensions should reflect the differential pattern of activation of the underlying neuronal network and the behavioural control function of its components. Accordingly, unravelling the molecular mechanisms that give rise to individual differences in the coping style will be an important topic in biobehavioural neurosciences, ecology and evolutionary biology. PMID:21078654

  16. Mechanical response of brain tissue under blast loading.

    PubMed

    Laksari, Kaveh; Sadeghipour, Keyanoush; Darvish, Kurosh

    2014-04-01

    In this study, a framework for understanding the propagation of stress waves in brain tissue under blast loading has been developed. It was shown that tissue nonlinearity and rate dependence are the key parameters in predicting the mechanical behavior under such loadings, as they determine whether traveling waves could become steeper and eventually evolve into shock discontinuities. To investigate this phenomenon, in the present study, brain tissue has been characterized as a quasi-linear viscoelastic (QLV) material and a nonlinear constitutive model has been developed for the tissue that spans from medium loading rates up to blast rates. It was shown that development of shock waves is possible inside the head in response to high rate compressive pressure waves. Finally, it was argued that injury to the nervous tissue at the microstructural level could be partly attributed to the high stress gradients with high rates generated at the shock front and this was proposed as a mechanism of injury in brain tissue. PMID:24457112

  17. Continuous damage parameter calculation under thermo-mechanical random loading

    PubMed Central

    Nagode, Marko

    2014-01-01

    The paper presents a method on how the mean stress effect on fatigue damage can be taken into account under an arbitrary low cycle thermo-mechanical loading. From known stress, elastoplastic strain and temperature histories the cycle amplitudes and cycle mean values are extracted and the damage parameter is computed. In contrast to the existing methods the proposed method enables continuous damage parameter computation without the need of waiting for the cycles to close. The limitations of the standardized damage parameters are thus surpassed. The damage parameters derived initially for closed and isothermal cycles assuming that the elastoplastic stress–strain response follows the Masing and memory rules can now be used to take the mean stress effect into account under an arbitrary low cycle thermo-mechanical loading. The method includes:•stress and elastoplastic strain history transformation into the corresponding amplitude and mean values;•stress and elastoplastic strain amplitude and mean value transformation into the damage parameter amplitude history;•damage parameter amplitude history transformation into the damage parameter history. PMID:26150939

  18. Mechanisms underlying skin disorders induced by EGFR inhibitors

    PubMed Central

    Holcmann, Martin; Sibilia, Maria

    2015-01-01

    The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is frequently mutated or overexpressed in a large number of tumors such as carcinomas or glioblastoma. Inhibitors of EGFR activation have been successfully established for the therapy of some cancers and are more and more frequently being used as first or later line therapies. Although the side effects induced by inhibitors of EGFR are less severe than those observed with classic cytotoxic chemotherapy and can usually be handled by out-patient care, they may still be a cause for dose reduction or discontinuation of treatment that can reduce the effectiveness of antitumor therapy. The mechanisms underlying these cutaneous side effects are only partly understood. Important questions, such as the reasons for the correlation between the intensity of the side effects and the efficiency of treatment with EGFR inhibitors, remain to be answered. Optimized adjuvant strategies to accompany anti-EGFR therapy need to be found for optimal therapeutic application and improved quality of life of patients. Here, we summarize current literature on the molecular and cellular mechanisms underlying the cutaneous side effects induced by EGFR inhibitors and provide evidence that keratinocytes are probably the optimal targets for adjuvant therapy aimed at alleviating skin toxicities. PMID:27308503

  19. Cell Mechanisms of Bone Tissue Loss Under Space Flight Conditions

    NASA Astrophysics Data System (ADS)

    Rodionova, Natalia

    Investigations on the space biosatellites has shown that the bone skeleton is one of the most im-portant targets of the effect space flight factors on the organism. Bone tissue cells were studied by electron microscopy in biosamples of rats' long bones flown on the board american station "SLS-2" and in experiments with modelling of microgravity ("tail suspension" method) with using autoradiography. The analysis of data permits to suppose that the processes of remod-eling in bone tissue at microgravity include the following succession of cell-to-cell interactions. Osteocytes as mechanosensory cells are first who respond to a changing "mechanical field". The next stage is intensification of osteolytic processes in osteocytes, leading to a volume en-largement of the osteocytic lacunae and removal of the "excess bone". Then mechanical signals have been transmitted through a system of canals and processes of the osteocytic syncitium to certain superficial bone zones and are perceived by osteoblasts and bone-lining cells (superficial osteocytes), as well as by the bone-marrow stromal cells. The sensitivity of stromal cells, pre-osteoblasts and osteoblasts, under microgravity was shown in a number of works. As a response to microgravity, the system of stromal cells -preosteoblasts -osteoblasts displays retardation of proliferation, differentiation and specific functions of osteogenetic cells. This is supported by the 3H-thymidine studies of the dynamics of differentiation of osteogenetic cells in remodeling zones. But unloading is not adequate and in part of the osteocytes are apoptotic changes as shown by our electron microscopic investigations. An osteocytic apoptosis can play the role in attraction the osteoclasts and in regulation of bone remodeling. The apoptotic bodies with a liquid flow through a system of canals are transferred to the bone surface, where they fulfil the role of haemoattractants for monocytes come here and form osteoclasts. The osteoclasts destroy

  20. Sound source mechanisms in under-expanded impinging jets

    NASA Astrophysics Data System (ADS)

    Sinibaldi, Giorgia; Marino, Luca; Romano, Giovanni Paolo

    2015-05-01

    Experiments on the aeroacoustics of an under-expanded supersonic jet impinging on a flat plate are presented and thoroughly discussed. A wide range of nozzle pressure ratios and of nozzle-to-plate distances has been analyzed with particular attention to the behavior of the discrete component of the noise. The investigation has been carried out by means of acoustic, particle image velocimetry and wall pressure measurements. The analysis of the relationship between the acoustic data and the fluid dynamic fields allows to examine the different source mechanisms of the discrete component of the noise and to evaluate the link between the jet flow structure and the acoustic tone features. Specifically, two ranges of nozzle pressure ratio have been observed showing different acoustic behaviors, characterized by distinct mechanisms of discrete noise generation. These regions are separated by a range of nozzle pressure ratios where impinging tones are not observed. The present experimental data extend previously published results, improving the analysis of the connection between fluid dynamic and acoustic fields and leading to a better comprehension of the impinging tone source mechanisms.

  1. Piezoelectric compliant mechanism energy harvesters under large base excitations

    NASA Astrophysics Data System (ADS)

    Ma, Xiaokun; Trolier-McKinstry, Susan; Rahn, Christopher D.

    2016-09-01

    A piezoelectric compliant mechanism (PCM) energy harvester is designed, modeled, and analyzed that consists of a polyvinylidene diflouoride, PVDF unimorph clamped at its base and attached to a compliant mechanism at its tip. The compliant hinge stiffness is carefully tuned to approach a low frequency first mode with an efficient (nearly quadratic) shape that provides a uniform strain distribution. A nonlinear model of the PCM energy harvester under large base excitation is derived to determine the maximum power that can be generated by the device. Experiments with a fabricated PCM energy harvester prototype show that the compliant mechanism introduces a stiffening effect and a much wider bandwidth than a benchmark proof mass cantilever design. The PCM bridge structure self-limits the displacement and maximum strain at large excitations compared with the proof mass cantilever, improving the device robustness. The PCM outperforms the cantilever in both average power and power-strain sensitivity at high accelerations due to the PCM axial stretching effect and its more uniform strain distribution.

  2. Molecular mechanisms underlying the onset of degenerative aortic valve disease.

    PubMed

    Hakuno, Daihiko; Kimura, Naritaka; Yoshioka, Masatoyo; Fukuda, Keiichi

    2009-01-01

    Morbidity from degenerative aortic valve disease is increasing worldwide, concomitant with the ageing of the general population and the habitual consumption of diets high in calories and cholesterol. Immunohistologic studies have suggested that the molecular mechanism occurring in the degenerate aortic valve resembles that of atherosclerosis, prompting the testing of HMG CoA reductase inhibitors (statins) for the prevention of progression of native and bioprosthetic aortic valve degeneration. However, the effects of these therapies remain controversial. Although the molecular mechanisms underlying the onset of aortic valve degeneration are largely unknown, research in this area is advancing rapidly. The signaling components involved in embryonic valvulogenesis, such as Wnt, TGF-beta(1), BMP, and Notch, are also involved in the onset of aortic valve degeneration. Furthermore, investigations into extracellular matrix remodeling, angiogenesis, and osteogenesis in the aortic valve have been reported. Having noted avascularity of normal cardiac valves, we recently identified chondromodulin-I (chm-I) as a crucial anti-angiogenic factor. The expression of chm-I is restricted to cardiac valves from late embryogenesis to adulthood in the mouse, rat, and human. In human degenerate atherosclerotic valves, the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases and angiogenesis is observed in the area of chm-I downregulation. Gene targeting of chm-I resulted in VEGF expression, angiogenesis, and calcification in the aortic valves of aged mice, and aortic stenosis is detected by echocardiography, indicating that chm-I is a crucial factor for maintaining normal cardiac valvular function by preventing angiogenesis. The present review focuses on the animal models of aortic valve degeneration and recent studies on the molecular mechanisms underlying the onset of degenerative aortic valve disease. PMID:18766323

  3. Microcracking in composite laminates under thermal and mechanical loading. Thesis

    SciTech Connect

    Maddocks, J.R.

    1995-05-01

    Composites used in space structures are exposed to both extremes in temperature and applied mechanical loads. Cracks in the matrix form, changing the laminate thermoelastic properties. The goal of the present investigation is to develop a predictive methodology to quantify microcracking in general composite laminates under both thermal and mechanical loading. This objective is successfully met through a combination of analytical modeling and experimental investigation. In the analysis, the stress and displacement distributions in the vicinity of a crack are determined using a shear lag model. These are incorporated into an energy based cracking criterion to determine the favorability of crack formation. A progressive damage algorithm allows the inclusion of material softening effects and temperature-dependent material properties. The analysis is implemented by a computer code which gives predicted crack density and degraded laminate properties as functions of any thermomechanical load history. Extensive experimentation provides verification of the analysis. AS4/3501-6 graphite/epoxy laminates are manufactured with three different layups to investigate ply thickness and orientation effects. Thermal specimens are cooled to progressively lower temperatures down to {minus}184 C. After conditioning the specimens to each temperature, cracks are counted on their edges using optical microscopy and in their interiors by sanding to incremental depths. Tensile coupons are loaded monotonically to progressively higher loads until failure. Cracks are counted on the coupon edges after each loading. A data fit to all available results provides input parameters for the analysis and shows them to be material properties, independent of geometry and loading. Correlation between experiment and analysis is generally very good under both thermal and mechanical loading, showing the methodology to be a powerful, unified tool.

  4. Mechanisms underlying ICU muscle wasting and effects of passive mechanical loading

    PubMed Central

    2012-01-01

    Introduction Critically ill ICU patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life for survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model show that the mechanical silencing associated with CIM is the primary triggering factor. This study aims to unravel the mechanisms underlying CIM, and to evaluate the effects of a specific intervention aiming at reducing mechanical silencing in sedated and mechanically ventilated ICU patients. Methods Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading for 10 hours per day (2.5 hours, four times) for 9 ± 1 days. Results These patients developed a phenotype considered pathognomonic of CIM; that is, severe muscle wasting and a preferential myosin loss (P < 0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of neuronal nitric oxide synthase. Passive mechanical loading for 9 ± 1 days resulted in a 35% higher specific force (P < 0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. Conclusion Mechanical silencing is suggested to be a primary mechanism underlying CIM; that is

  5. Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity

    PubMed Central

    Tarale, Prashant; Chakrabarti, Tapan; Sivanesan, Saravanadevi; Naoghare, Pravin; Bafana, Amit; Krishnamurthi, Kannan

    2016-01-01

    Manganese is a vital nutrient and is maintained at an optimal level (2.5–5 mg/day) in human body. Chronic exposure to manganese is associated with neurotoxicity and correlated with the development of various neurological disorders such as Parkinson's disease. Oxidative stress mediated apoptotic cell death has been well established mechanism in manganese induced toxicity. Oxidative stress has a potential to alter the epigenetic mechanism of gene regulation. Epigenetic insight of manganese neurotoxicity in context of its correlation with the development of parkinsonism is poorly understood. Parkinson's disease is characterized by the α-synuclein aggregation in the form of Lewy bodies in neuronal cells. Recent findings illustrate that manganese can cause overexpression of α-synuclein. α-Synuclein acts epigenetically via interaction with histone proteins in regulating apoptosis. α-Synuclein also causes global DNA hypomethylation through sequestration of DNA methyltransferase in cytoplasm. An individual genetic difference may also have an influence on epigenetic susceptibility to manganese neurotoxicity and the development of Parkinson's disease. This review presents the current state of findings in relation to role of epigenetic mechanism in manganese induced neurotoxicity, with a special emphasis on the development of Parkinson's disease. PMID:27314012

  6. Transient streaming potentials under varying pore-water ionic strength

    NASA Astrophysics Data System (ADS)

    Malama, B.

    2014-12-01

    Streaming potentials (SP) are generated when polar fluids such as groundwater flow through porous media that have charged mineral surfaces. This is due to the flow-shearing of the diffuse layer of the electric double layer (EDL), which is known to form in the fluid phase at the fluid-rock interface. Previous works have suggested that the EDL vanishes at high pore-fluid ionic strengths resulting in vanishing SP signals. However, recent observations in sea-water intrusion applications by Jackson and coworkers indicate that measurable SP signals are obtainable in flows of fluids with high ionic strengths through silica sand. We demonstrate the repeatability of these observations through a series of laboratory flow experiments performed on 98% silica sand in a falling-head permeameter with brines of concentrations ranging from 0.001M to about 5 M NaCl. The results of the experiments, which clearly show measurable SP signals even at the highest concentration of 5 M NaCl, are reported. They are also used to estimate the hydraulic conductivity and electrokinetic coupling coefficient. The linearity assumption for the relation between pressure and SP differentials is evaluated for high pore-water NaCl concentrations. Additionally, displacement of one brine by another of different NaCl concentration yields dramatic transient SP responses that may be harnessed in the development of early-detection/warning technologies for sea-water intrusion applications. Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000. This research is funded by WIPP programs administered by the Office of Environmental Management (EM) of the U.S Department of Energy.

  7. Mechanisms Underlying Mammalian Hybrid Sterility in Two Feline Interspecies Models.

    PubMed

    Davis, Brian W; Seabury, Christopher M; Brashear, Wesley A; Li, Gang; Roelke-Parker, Melody; Murphy, William J

    2015-10-01

    The phenomenon of male sterility in interspecies hybrids has been observed for over a century, however, few genes influencing this recurrent phenotype have been identified. Genetic investigations have been primarily limited to a small number of model organisms, thus limiting our understanding of the underlying molecular basis of this well-documented "rule of speciation." We utilized two interspecies hybrid cat breeds in a genome-wide association study employing the Illumina 63 K single-nucleotide polymorphism array. Collectively, we identified eight autosomal genes/gene regions underlying associations with hybrid male sterility (HMS) involved in the function of the blood-testis barrier, gamete structural development, and transcriptional regulation. We also identified several candidate hybrid sterility regions on the X chromosome, with most residing in close proximity to complex duplicated regions. Differential gene expression analyses revealed significant chromosome-wide upregulation of X chromosome transcripts in testes of sterile hybrids, which were enriched for genes involved in chromatin regulation of gene expression. Our expression results parallel those reported in Mus hybrids, supporting the "Large X-Effect" in mammalian HMS and the potential epigenetic basis for this phenomenon. These results support the value of the interspecies feline model as a powerful tool for comparison to rodent models of HMS, demonstrating unique aspects and potential commonalities that underpin mammalian reproductive isolation. PMID:26006188

  8. Multicomponent diffusion under general chemical potential gradients. Final report, July 1, 1981-June 30, 1984

    SciTech Connect

    Sato, H.; Kikuchi, R.

    1984-06-01

    Theoretical basis for identifying the origin of deterioration of high temperature materials by diffusion has been sought. The need for an appropriate form of irreversible statistical mechanics, rather than commonly utilized irreversible thermodynamics, to this problem was identified. The Path Probability method of irreversible statistical mechanics was thus adapted to diffusion problems and necessary modifications of the method suitable for transport problems in multicomponent systems were made. Thermal diffusion (diffusion which occurs under temperature gradient) was then formulated by the Path Probability method for the first time, and so far elusive concepts such as the heat of transport were thus microscopically identified. An example of demixing of originally homogeneous solid solutions under general chemical potential gradients was thus worked out.

  9. The effects of different size gold nanoparticles on mechanical properties of vascular smooth muscle cells under mechanical stretching

    NASA Astrophysics Data System (ADS)

    Kieu, Tri Minh

    Nanotechnology is an emerging and promising frontier for medicine and biomedical research due to its potential for applications such as drug delivery, imaging enhancement, and cancer treatment. While these materials may possess significant possibilities, the effects of these particles in the body and how the particles affect the cells is not fully understood. In this study, vascular smooth muscle cells (VSMCs) will be exposed to 5 and 20 nm diameter citrate AuNPs under mechanical conditions. The cytotoxicity properties of these particles will be investigated using LDH and MTT assays. Atomic force microscopy will be used to study how the size of the nanoparticles affect the mechanical properties of the VSMCs. Immunofluorescence staining for alpha actin will also be performed to enhance understanding of the phenotypic shift. The LDH and MTT cytotoxicity assay results demonstrated that neither 5 nor 20 nm diameter nanoparticles are cytotoxic to the cells. However, the mechanical properties and cell morphology of the VSMCs was altered. Under static conditions, both AuNP treatments decreased the mechanical properties of the cells. The size of the nanoparticles had a softening effect on elastic modulus of the cell and sign of a synthetic phenotype was observed. The VSMCs subjected to mechanical stretching exhibited higher elastic modulus compared to the static experimental groups. Again, both AuNPs treatments decreased the mechanical properties of the cells and signs of more synthetic phenotype was seen. However, the size of the nanoparticles did not have any influence on cell's elastic modulus unlike the static treated cells. The mechanical testing condition provided a better look at how these particles would affect the cells in vivo. While the nanoparticles are not cytotoxic to the VSMCs, they are altering the mechanical properties and phenotype of the cell.

  10. Theoretical foundations of the sound analog membrane potential that underlies coincidence detection in the barn owl

    PubMed Central

    Ashida, Go; Funabiki, Kazuo; Carr, Catherine E.

    2013-01-01

    A wide variety of neurons encode temporal information via phase-locked spikes. In the avian auditory brainstem, neurons in the cochlear nucleus magnocellularis (NM) send phase-locked synaptic inputs to coincidence detector neurons in the nucleus laminaris (NL) that mediate sound localization. Previous modeling studies suggested that converging phase-locked synaptic inputs may give rise to a periodic oscillation in the membrane potential of their target neuron. Recent physiological recordings in vivo revealed that owl NL neurons changed their spike rates almost linearly with the amplitude of this oscillatory potential. The oscillatory potential was termed the sound analog potential, because of its resemblance to the waveform of the stimulus tone. The amplitude of the sound analog potential recorded in NL varied systematically with the interaural time difference (ITD), which is one of the most important cues for sound localization. In order to investigate the mechanisms underlying ITD computation in the NM-NL circuit, we provide detailed theoretical descriptions of how phase-locked inputs form oscillating membrane potentials. We derive analytical expressions that relate presynaptic, synaptic, and postsynaptic factors to the signal and noise components of the oscillation in both the synaptic conductance and the membrane potential. Numerical simulations demonstrate the validity of the theoretical formulations for the entire frequency ranges tested (1–8 kHz) and potential effects of higher harmonics on NL neurons with low best frequencies (<2 kHz). PMID:24265616

  11. Theoretical foundations of the sound analog membrane potential that underlies coincidence detection in the barn owl.

    PubMed

    Ashida, Go; Funabiki, Kazuo; Carr, Catherine E

    2013-01-01

    A wide variety of neurons encode temporal information via phase-locked spikes. In the avian auditory brainstem, neurons in the cochlear nucleus magnocellularis (NM) send phase-locked synaptic inputs to coincidence detector neurons in the nucleus laminaris (NL) that mediate sound localization. Previous modeling studies suggested that converging phase-locked synaptic inputs may give rise to a periodic oscillation in the membrane potential of their target neuron. Recent physiological recordings in vivo revealed that owl NL neurons changed their spike rates almost linearly with the amplitude of this oscillatory potential. The oscillatory potential was termed the sound analog potential, because of its resemblance to the waveform of the stimulus tone. The amplitude of the sound analog potential recorded in NL varied systematically with the interaural time difference (ITD), which is one of the most important cues for sound localization. In order to investigate the mechanisms underlying ITD computation in the NM-NL circuit, we provide detailed theoretical descriptions of how phase-locked inputs form oscillating membrane potentials. We derive analytical expressions that relate presynaptic, synaptic, and postsynaptic factors to the signal and noise components of the oscillation in both the synaptic conductance and the membrane potential. Numerical simulations demonstrate the validity of the theoretical formulations for the entire frequency ranges tested (1-8 kHz) and potential effects of higher harmonics on NL neurons with low best frequencies (<2 kHz). PMID:24265616

  12. Cap buckling as a potential mechanism of atherosclerotic plaque vulnerability.

    PubMed

    Abdelali, Maria; Reiter, Steven; Mongrain, Rosaire; Bertrand, Michel; L'Allier, Philippe L; Kritikou, Ekaterini A; Tardif, Jean-Claude

    2014-04-01

    Plaque rupture in atherosclerosis is the primary cause of potentially deadly coronary events, yet about 40% of ruptures occur away from the plaque cap shoulders and cannot be fully explained with the current biomechanical theories. Here, cap buckling is considered as a potential destabilizing factor which increases the propensity of the atherosclerotic plaque to rupture and which may also explain plaque failure away from the cap shoulders. To investigate this phenomenon, quasistatic 2D finite element simulations are performed, considering the salient geometrical and nonlinear material properties of diverse atherosclerotic plaques over the range of physiological loads. The numerical results indicate that buckling may displace the location of the peak von Mises stresses in the deflected caps. Plaque buckling, together with its deleterious effects is further observed experimentally in plaque caps using a physical model of deformable mock coronary arteries with fibroatheroma. Moreover, an analytical approach combining quasistatic equilibrium equations with the Navier-Bresse formulas is used to demonstrate the buckling potential of a simplified arched slender cap under intraluminal pressure and supported by foundations. This analysis shows that plaque caps - calcified, fibrotic or cellular - may buckle in specific undulated shapes once submitted to critical loads. Finally, a preliminary analysis of intravascular ultrasonography recordings of patients with atherosclerotic coronary arteries corroborates the numerical, experimental and theoretical findings and shows that various plaque caps buckle in vivo. By displacing the sites of high stresses in the plaque cap, buckling may explain the atherosclerotic plaque cap rupture at various locations, including cap shoulders. PMID:24491969

  13. Mechanisms underlying allergy vaccination with recombinant hypoallergenic allergen derivatives

    PubMed Central

    Linhart, Birgit; Valenta, Rudolf

    2015-01-01

    Hundred years ago therapeutic vaccination with allergen-containing extracts has been introduced as a clinically effective, disease-modifying, allergen-specific and long-lasting form of therapy for allergy, a hypersensitivity disease affecting more than 25% of the population. Today, the structures of most of the disease-causing allergens have been elucidated and recombinant hypoallergenic allergen derivatives with reduced allergenic activity have been engineered to reduce side effects during allergen-specific immunotherapy (SIT). These recombinant hypoallergens have been characterized in vitro, in experimental animal models and in clinical trials in allergic patients. This review provides a summary of the molecular, immunological and preclinical evaluation criteria applied for this new generation of allergy vaccines. Furthermore, we summarize the mechanisms underlying SIT with recombinant hypoallergens which are thought to be responsible for their therapeutic effect. PMID:22100888

  14. Mechanisms Underlying Development of Visual Maps and Receptive Fields

    PubMed Central

    Huberman, Andrew D.; Feller, Marla B.; Chapman, Barbara

    2008-01-01

    Patterns of synaptic connections in the visual system are remarkably precise. These connections dictate the receptive field properties of individual visual neurons and ultimately determine the quality of visual perception. Spontaneous neural activity is necessary for the development of various receptive field properties and visual feature maps. In recent years, attention has shifted to understanding the mechanisms by which spontaneous activity in the developing retina, lateral geniculate nucleus, and visual cortex instruct the axonal and dendritic refinements that give rise to orderly connections in the visual system. Axon guidance cues and a growing list of other molecules, including immune system factors, have also recently been implicated in visual circuit wiring. A major goal now is to determine how these molecules cooperate with spontaneous and visually evoked activity to give rise to the circuits underlying precise receptive field tuning and orderly visual maps. PMID:18558864

  15. The mechanisms underlying fructose-induced hypertension: a review

    PubMed Central

    Klein, Alice Victoria; Kiat, Hosen

    2015-01-01

    We are currently in the midst of an epidemic of metabolic disorders, which may, in part, be explained by excess fructose intake. This theory is supported by epidemiological observations as well as experimental studies in animals and humans. Rising consumption of fructose has been matched with growing rates of hypertension, leading to concern from public health experts. At this stage, the mechanisms underlying fructose-induced hypertension have not been fully characterized and the bulk of our knowledge is derived from animal models. Animal studies have shown that high-fructose diets up-regulate sodium and chloride transporters, resulting in a state of salt overload that increases blood pressure. Excess fructose has also been found to activate vasoconstrictors, inactivate vasodilators, and over-stimulate the sympathetic nervous system. Further work is required to determine the relevance of these findings to humans and to establish the level at which dietary fructose increases the risk of developing hypertension PMID:25715094

  16. Excess body weight during pregnancy and offspring obesity: potential mechanisms.

    PubMed

    Paliy, Oleg; Piyathilake, Chandrika J; Kozyrskyj, Anita; Celep, Gulcin; Marotta, Francesco; Rastmanesh, Reza

    2014-03-01

    The rates of child and adult obesity have increased in most developed countries over the past several decades. The health consequences of obesity affect both physical and mental health, and the excess body weight can be linked to an elevated risk for developing type 2 diabetes, cardiovascular problems, and depression. Among the factors that can influence the development of obesity are higher infant weights and increased weight gain, which are associated with higher risk for excess body weight later in life. In turn, mother's excess body weight during and after pregnancy can be linked to the risk for offspring overweight and obesity through dietary habits, mode of delivery and feeding, breast milk composition, and through the influence on infant gut microbiota. This review considers current knowledge of these potential mechanisms that threaten to create an intergenerational cycle of obesity. PMID:24103493

  17. Artificial Bee Colony Optimization of Capping Potentials for Hybrid Quantum Mechanical/Molecular Mechanical Calculations.

    PubMed

    Schiffmann, Christoph; Sebastiani, Daniel

    2011-05-10

    We present an algorithmic extension of a numerical optimization scheme for analytic capping potentials for use in mixed quantum-classical (quantum mechanical/molecular mechanical, QM/MM) ab initio calculations. Our goal is to minimize bond-cleavage-induced perturbations in the electronic structure, measured by means of a suitable penalty functional. The optimization algorithm-a variant of the artificial bee colony (ABC) algorithm, which relies on swarm intelligence-couples deterministic (downhill gradient) and stochastic elements to avoid local minimum trapping. The ABC algorithm outperforms the conventional downhill gradient approach, if the penalty hypersurface exhibits wiggles that prevent a straight minimization pathway. We characterize the optimized capping potentials by computing NMR chemical shifts. This approach will increase the accuracy of QM/MM calculations of complex biomolecules. PMID:26610125

  18. Tension moderation and fluctuation spectrum in simulated lipid membranes under an applied electric potential.

    PubMed

    Loubet, Bastien; Lomholt, Michael Andersen; Khandelia, Himanshu

    2013-10-28

    We investigate the effect of an applied electric potential on the mechanics of a coarse grained POPC bilayer under tension. The size and duration of our simulations allow for a detailed and accurate study of the fluctuations. Effects on the fluctuation spectrum, tension, bending rigidity, and bilayer thickness are investigated in detail. In particular, the least square fitting technique is used to calculate the fluctuation spectra. The simulations confirm a recently proposed theory that the effect of an applied electric potential on the membrane will be moderated by the elastic properties of the membrane. In agreement with the theory, we find that the larger the initial tension the larger the effect of the electric potential. Application of the electric potential increases the amplitude of the long wavelength part of the spectrum and the bending rigidity is deduced from the short wavelength fluctuations. The effect of the applied electric potential on the bending rigidity is non-existent within error bars. However, when the membrane is stretched there is a point where the bending rigidity is lowered due to a decrease of the thickness of the membrane. All these effects should prove important for mechanosensitive channels and biomembrane mechanics in general. PMID:24182074

  19. Implicit Misattribution as a Mechanism Underlying Evaluative Conditioning

    PubMed Central

    Jones, Christopher R.; Fazio, Russell H.; Olson, Michael A.

    2009-01-01

    Evaluative conditioning (EC) refers to the formation or change of an attitude towards an object following that object’s pairing with positively or negatively valenced stimuli. We provide evidence that EC can occur through an implicit misattribution mechanism in which an evaluative response evoked by a valenced stimulus is incorrectly and implicitly attributed to another stimulus, forming or changing an attitude towards this other stimulus. Five studies measured or manipulated variables related to the potential for the misattribution of an evaluation, or “source confusability.” Greater EC was observed when participants’ eye gaze shifted frequently between a valenced and neutral stimulus (Studies 1 & 2), when the two stimuli appeared in close spatial proximity (Study 3), and when the neutral stimulus was made more perceptually salient than the valenced stimulus due to its larger size (Study 4). In other words, conditions conducive to source confusability increased EC. Study 5 provided evidence for multiple mechanisms of EC by comparing the effects of mildly evocative valenced stimuli (those evoking responses that might more easily be misattributed to another object) to more strongly evocative stimuli. PMID:19379028

  20. Lifelong bilingualism and neural reserve against Alzheimer's disease: a review of findings and potential mechanisms.

    PubMed

    Gold, Brian T

    2015-03-15

    Alzheimer's disease (AD) is a progressive brain disorder that initially affects medial temporal lobe circuitry and memory functions. Current drug treatments have only modest effects on the symptomatic course of the disease. In contrast, a growing body of evidence suggests that lifelong bilingualism may delay the onset of clinical AD symptoms by several years. The purpose of the present review is to summarize evidence for bilingualism as a reserve variable against AD and discuss potential underlying neurocognitive mechanisms. Evidence is reviewed suggesting that bilingualism may delay clinical AD symptoms by protecting frontostriatal and frontoparietal executive control circuitry rather than medial temporal lobe memory circuitry. Cellular and molecular mechanisms that may contribute to bilingual cognitive reserve effects are discussed, including those that may affect neuronal metabolic functions, dynamic neuronal-glial interactions, vascular factors, myelin structure and neurochemical signaling. Future studies that may test some of these potential mechanisms of bilingual CR effects are proposed. PMID:25496781

  1. Using Drosophila to discover mechanisms underlying type 2 diabetes

    PubMed Central

    Alfa, Ronald W.; Kim, Seung K.

    2016-01-01

    ABSTRACT Mechanisms of glucose homeostasis are remarkably well conserved between the fruit fly Drosophila melanogaster and mammals. From the initial characterization of insulin signaling in the fly came the identification of downstream metabolic pathways for nutrient storage and utilization. Defects in these pathways lead to phenotypes that are analogous to diabetic states in mammals. These discoveries have stimulated interest in leveraging the fly to better understand the genetics of type 2 diabetes mellitus in humans. Type 2 diabetes results from insulin insufficiency in the context of ongoing insulin resistance. Although genetic susceptibility is thought to govern the propensity of individuals to develop type 2 diabetes mellitus under appropriate environmental conditions, many of the human genes associated with the disease in genome-wide association studies have not been functionally studied. Recent advances in the phenotyping of metabolic defects have positioned Drosophila as an excellent model for the functional characterization of large numbers of genes associated with type 2 diabetes mellitus. Here, we examine results from studies modeling metabolic disease in the fruit fly and compare findings to proposed mechanisms for diabetic phenotypes in mammals. We provide a systematic framework for assessing the contribution of gene candidates to insulin-secretion or insulin-resistance pathways relevant to diabetes pathogenesis. PMID:27053133

  2. Neurosubstrates and mechanisms underlying the extinction of associative motor memory.

    PubMed

    Hu, Chen; Zhang, Li-Bin; Chen, Hao; Xiong, Yan; Hu, Bo

    2015-12-01

    Eyeblink conditioning is one of the most commonly used model systems to investigate the neural mechanisms underlying associative motor learning. It is well established that the acquisition and retention of conditioned eyeblink responses (CRs) involve neural plasticity in both the cerebellar cortex and deep cerebellar nuclei (DCN). Nevertheless, how learned CRs are extinguished remains relatively unclear. It has been suggested that extinguished CRs can recur spontaneously, can reappear by exposure to certain stimuli, and can be reacquired in fewer training trials than originally needed, indicating that associative motor memory is not merely erased by extinction training. Instead, the motor memory is preserved to some degree. Herein, we reviewed recent experimental findings demonstrating that the cerebellum subserves the preservation of learned CRs. In addition, several lines of evidence have suggested that forebrain structures (i.e., the medial prefrontal cortex and hippocampus) are involved in the CR extinction. We proposed possible mechanisms related to how preserved motor memory in the cerebellum is inhibited by the forebrain structures via the amygdalar complex. PMID:26209112

  3. Simulation of Electrical Transport in Rocks under Mechanical Action

    NASA Astrophysics Data System (ADS)

    Salgueiro da Silva, M. A.; Seixas, T. M.

    2015-12-01

    Rock's electrical properties can be changed by mechanical action, especially when deformation is accompanied by micro-fracturing processes. Knowing how electrical charge is generated in inelastically deformed rocks, the nature and properties of the generated charge carriers, and their spatial distribution and propagation is crucial to gain insight into the origin of seismo-electromagnetic signals. In this work, we describe briefly a model for the numerical simulation of electrical transport in rocks under mechanical action, assuming that high and low mobility charge carriers of opposite signs can be simultaneously generated by micro-fracturing processes and recombine, diffuse and drift across the sample rock. The electrical behavior can then be described using an adaptation of the formalism applied to semiconductors. We provide simulation results on a one-dimensional lattice using finite-difference discretization. Our results show that a large mobility contrast among charge carriers allows charge separation inside the deformation region, which leads to the formation of charged layers of alternate signs. Inside these layers, rapid electric field variations are observed which can lead to the emission of electromagnetic radiation. With proper positioning of current electrodes inside the deformation region, it is possible to collect electrical current even without any applied voltage. We discuss our results in the light of available experimental results on the generation of electrical and electromagnetic signals in deformed rocks.

  4. The Challenge of Characterizing Operations in the Mechanisms Underlying Behavior

    PubMed Central

    Bechtel, William

    2005-01-01

    Neuroscience and cognitive science seek to explain behavioral regularities in terms of underlying mechanisms. An important element of a mechanistic explanation is a characterization of the operations of the parts of the mechanism. The challenge in characterizing such operations is illustrated by an example from the history of physiological chemistry in which some investigators tried to characterize the internal operations in the same terms as the overall physiological system while others appealed to elemental chemistry. In order for biochemistry to become successful, researchers had to identify a new level of operations involving operations over molecular groups. Existing attempts at mechanistic explanation of behavior are in a situation comparable to earlier approaches to physiological chemistry, drawing their inspiration either from overall psychology activities or from low-level neural processes. Successful mechanistic explanations of behavior require the discovery of the appropriate component operations. Such discovery is a daunting challenge but one on which success will be beneficial to both behavioral scientists and cognitive and neuroscientists. PMID:16596967

  5. Mechanisms underlying the impacts of exotic plant invasions.

    PubMed Central

    Levine, Jonathan M; Vilà, Montserrat; D'Antonio, Carla M; Dukes, Jeffrey S; Grigulis, Karl; Lavorel, Sandra

    2003-01-01

    Although the impacts of exotic plant invasions on community structure and ecosystem processes are well appreciated, the pathways or mechanisms that underlie these impacts are poorly understood. Better exploration of these processes is essential to understanding why exotic plants impact only certain systems, and why only some invaders have large impacts. Here, we review over 150 studies to evaluate the mechanisms underlying the impacts of exotic plant invasions on plant and animal community structure, nutrient cycling, hydrology and fire regimes. We find that, while numerous studies have examined the impacts of invasions on plant diversity and composition, less than 5% test whether these effects arise through competition, allelopathy, alteration of ecosystem variables or other processes. Nonetheless, competition was often hypothesized, and nearly all studies competing native and alien plants against each other found strong competitive effects of exotic species. In contrast to studies of the impacts on plant community structure and higher trophic levels, research examining impacts on nitrogen cycling, hydrology and fire regimes is generally highly mechanistic, often motivated by specific invader traits. We encourage future studies that link impacts on community structure to ecosystem processes, and relate the controls over invasibility to the controls over impact. PMID:12737654

  6. Mechanisms underlying the social enhancement of vocal learning in songbirds.

    PubMed

    Chen, Yining; Matheson, Laura E; Sakata, Jon T

    2016-06-14

    Social processes profoundly influence speech and language acquisition. Despite the importance of social influences, little is known about how social interactions modulate vocal learning. Like humans, songbirds learn their vocalizations during development, and they provide an excellent opportunity to reveal mechanisms of social influences on vocal learning. Using yoked experimental designs, we demonstrate that social interactions with adult tutors for as little as 1 d significantly enhanced vocal learning. Social influences on attention to song seemed central to the social enhancement of learning because socially tutored birds were more attentive to the tutor's songs than passively tutored birds, and because variation in attentiveness and in the social modulation of attention significantly predicted variation in vocal learning. Attention to song was influenced by both the nature and amount of tutor song: Pupils paid more attention to songs that tutors directed at them and to tutors that produced fewer songs. Tutors altered their song structure when directing songs at pupils in a manner that resembled how humans alter their vocalizations when speaking to infants, that was distinct from how tutors changed their songs when singing to females, and that could influence attention and learning. Furthermore, social interactions that rapidly enhanced learning increased the activity of noradrenergic and dopaminergic midbrain neurons. These data highlight striking parallels between humans and songbirds in the social modulation of vocal learning and suggest that social influences on attention and midbrain circuitry could represent shared mechanisms underlying the social modulation of vocal learning. PMID:27247385

  7. Generalized coherent states under deformed quantum mechanics with maximum momentum

    NASA Astrophysics Data System (ADS)

    Ching, Chee Leong; Ng, Wei Khim

    2013-10-01

    Following the Gazeau-Klauder approach, we construct generalized coherent states (GCS) as the quantum simulator to examine the deformed quantum mechanics, which exhibits an intrinsic maximum momentum. We study deformed harmonic oscillators and compute their probability distribution and entropy of states exactly. Also, a particle in an infinite potential box is studied perturbatively. In particular, unlike usual quantum mechanics, the present deformed case increases the entropy of the Planck scale quantum optical system. Furthermore, for simplicity, we obtain the modified uncertainty principle (MUP) with the perturbative treatment up to leading order. MUP turns out to increase generally. However, for certain values of γ (a parameter of GCS), it is possible that the MUP will vanish and hence will exhibit the classical characteristic. This is interpreted as the manifestation of the intrinsic high-momentum cutoff at lower momentum in a perturbative treatment. Although the GCS saturates the minimal uncertainty in a simultaneous measurement of physical position and momentum operators, thus constituting the squeezed states, complete coherency is impossible in quantum gravitational physics. The Mandel Q number is calculated, and it is shown that the statistics can be Poissonian and super-/sub-Poissonian depending on γ. The equation of motion is studied, and both Ehrenfest’s theorem and the correspondence principle are recovered. Fractional revival times are obtained through the autocorrelation, and they indicate that the superposition of a classical-like subwave packet is natural in GCS. We also contrast our results with the string-motivated (Snyder) type of deformed quantum mechanics, which incorporates a minimum position uncertainty rather than a maximum momentum. With the advances of quantum optics technology, it might be possible to realize some of these distinguishing quantum-gravitational features within the domain of future experiments.

  8. Different Neurophysiological Mechanisms Underlying Word and Rule Extraction from Speech

    PubMed Central

    De Diego Balaguer, Ruth; Toro, Juan Manuel; Rodriguez-Fornells, Antoni; Bachoud-Lévi, Anne-Catherine

    2007-01-01

    The initial process of identifying words from spoken language and the detection of more subtle regularities underlying their structure are mandatory processes for language acquisition. Little is known about the cognitive mechanisms that allow us to extract these two types of information and their specific time-course of acquisition following initial contact with a new language. We report time-related electrophysiological changes that occurred while participants learned an artificial language. These changes strongly correlated with the discovery of the structural rules embedded in the words. These changes were clearly different from those related to word learning and occurred during the first minutes of exposition. There is a functional distinction in the nature of the electrophysiological signals during acquisition: an increase in negativity (N400) in the central electrodes is related to word-learning and development of a frontal positivity (P2) is related to rule-learning. In addition, the results of an online implicit and a post-learning test indicate that, once the rules of the language have been acquired, new words following the rule are processed as words of the language. By contrast, new words violating the rule induce syntax-related electrophysiological responses when inserted online in the stream (an early frontal negativity followed by a late posterior positivity) and clear lexical effects when presented in isolation (N400 modulation). The present study provides direct evidence suggesting that the mechanisms to extract words and structural dependencies from continuous speech are functionally segregated. When these mechanisms are engaged, the electrophysiological marker associated with rule-learning appears very quickly, during the earliest phases of exposition to a new language. PMID:18000546

  9. Persistent organic pollutants & obesity: potential mechanisms for breast cancer promotion?

    PubMed Central

    Reaves, Denise K.; Ginsburg, Erika; Bang, John J.; Fleming, Jodie M.

    2015-01-01

    Dietary ingestion of persistent organic pollutants (POPs) correlates with developing obesity. Obesity alters metabolism, induces an inflammatory tissue microenvironment, and is also linked with diabetes and breast cancer risk/promotion of the disease. However, no direct evidence exists exploring the correlation among all three of these factors (POPs, obesity, and breast cancer). Herein, we present current correlative studies suggesting a causal link between POPs exposure through diet and their bioaccumulation in adipose that promotes the development of obesity and ultimately influences breast cancer development and/or progression. Furthermore, as endocrine disruptors, POPs can potentially interfere with hormonally responsive tissue functions causing dysregulation in hormone signaling and cell function. This review highlights the critical need for advanced in vitro and in vivo model systems to understand the complex relationship between obesity, POPs, breast cancer, and, more importantly, to delineate their multifaceted molecular, cellular, and biochemical mechanisms. Comprehensive in vitro and in vivo studies directly testing the observed correlations as well as detailing their molecular mechanisms are vital to cancer research and, ultimately, public health. PMID:25624167

  10. Examining cassava's potential to enhance food security under climate change

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent advances in the biofortification of cassava, a substantial yield gap and cassava's potential for increased productivity and its inherent potential to respond positively to globally increasing CO2 are synergistic and encouraging in an otherwise bleak global view of the future of food security ...

  11. [Mechanisms and potential of the therapeutic stimulation of arteriogenesis].

    PubMed

    Schirmer, S H; van Royen, N; Laufs, U; Böhm, M

    2009-02-01

    The stimulation of collateral artery growth (arteriogenesis) is a promising alternative approach to non-invasively treat arterial obstructive disease, such as coronary, peripheral or cerebral artery disease. Patients unable to undergo conventional revascularization strategies may benefit from adaptive arteriogenesis. Underlying mechanisms are experimentally validated and include an increase in shear stress after obstruction or occlusion of a major artery; monocyte adhesion, transmigration and perivascular accumulation, secretion of growth factors; and smooth muscle and endothelial cell proliferation and growth of pre-existent collateral arteries. Therapeutic stimulation of arteriogenesis with cytokines has been successfully performed in experimental models. Translation into clinical practice, however, has hitherto been problematic. Reasons for this include differences between the healthy laboratory animal and an often severely diseased patient, possible harmful effects of pro-arteriogenic therapies and unsuitable clinical endpoints for the detection of collateral artery growth. Recent investigations of human arteriogenesis demonstrate significant inter-individual differences and point towards the importance of anti-arteriogenic mechanisms in patients with impaired adaptive arteriogenesis and high cardiovascular risk factors. PMID:19197812

  12. Investigating the mechanism(s) underlying switching between states in bipolar disorder

    PubMed Central

    Young, Jared W.; Dulcis, Davide

    2015-01-01

    Bipolar Disorder (BD) is a unique disorder that transcends domains of function since the same patient can exhibit depression or mania, states with polar opposite mood symptoms. During depression, people feel helplessness, reduced energy, and risk aversion, while with mania behaviors include grandiosity, increased energy, less sleep, and risk preference. The neural mechanism(s) underlying each state are gaining clarity, with catecholaminergic disruption seen during mania, and cholinergic dysfunction during depression. The fact that the same patient cycles/switches between these states is the defining characteristic of BD however. Of greater importance therefore, is the mechanism(s) underlying cycling from one state - and its associated neural changes - to another, considered the ‘holy grail’ of BD research. Herein, we review studies investigating triggers that induce switching to these states. By identifying such triggers, researchers can study neural mechanisms underlying each state and importantly how such mechanistic changes can occur in the same subject. Current animal models of this switch are also discussed, from submissive- and dominant-behaviors to kindling effects. Focus however, is placed on how seasonal changes can induce manic and depressive states in BD sufferers. Importantly, changing photoperiod lengths can induce local switches in neurotransmitter expression in normal animals, from increased catecholaminergic expression during periods of high activity, to increased somatostatin and corticotrophin releasing factor during periods of low activity. Identifying susceptibilities to this switch would enable the development of targeted animal models. From animal models, targeted treatments could be developed and tested that would minimize the likelihood of switching. PMID:25814263

  13. Investigating the mechanism(s) underlying switching between states in bipolar disorder.

    PubMed

    Young, Jared W; Dulcis, Davide

    2015-07-15

    Bipolar disorder (BD) is a unique disorder that transcends domains of function since the same patient can exhibit depression or mania, states with polar opposite mood symptoms. During depression, people feel helplessness, reduced energy, and risk aversion, while with mania behaviors include grandiosity, increased energy, less sleep, and risk preference. The neural mechanism(s) underlying each state are gaining clarity, with catecholaminergic disruption seen during mania, and cholinergic dysfunction during depression. The fact that the same patient cycles/switches between these states is the defining characteristic of BD however. Of greater importance therefore, is the mechanism(s) underlying cycling from one state - and its associated neural changes - to another, considered the 'holy grail' of BD research. Herein, we review studies investigating triggers that induce switching to these states. By identifying such triggers, researchers can study neural mechanisms underlying each state and importantly how such mechanistic changes can occur in the same subject. Current animal models of this switch are also discussed, from submissive- and dominant-behaviors to kindling effects. Focus however, is placed on how seasonal changes can induce manic and depressive states in BD sufferers. Importantly, changing photoperiod lengths can induce local switches in neurotransmitter expression in normal animals, from increased catecholaminergic expression during periods of high activity, to increased somatostatin and corticotrophin releasing factor during periods of low activity. Identifying susceptibilities to this switch would enable the development of targeted animal models. From animal models, targeted treatments could be developed and tested that would minimize the likelihood of switching. PMID:25814263

  14. Potential mechanisms for low uric acid in Parkinson disease.

    PubMed

    Sampat, Radhika; Young, Sarah; Rosen, Ami; Bernhard, Douglas; Millington, David; Factor, Stewart; Jinnah, H A

    2016-04-01

    Several epidemiologic studies have described an association between low serum uric acid (UA) and Parkinson disease (PD). Uric acid is a known antioxidant, and one proposed mechanism of neurodegeneration in PD is oxidative damage of dopamine neurons. However, other complex metabolic pathways may contribute. The purpose of this study is to elucidate potential mechanisms of low serum UA in PD. Subjects who met diagnostic criteria for definite or probable PD (n = 20) and controls (n = 20) aged 55-80 years were recruited. Twenty-four hour urine samples were collected from all participants, and both uric acid and allantoin were measured and corrected for body mass index (BMI). Urinary metabolites were compared using a twoway ANOVA with diagnosis and sex as the explanatory variables. There were no significant differences between PD and controls for total UA (p = 0.60), UA corrected for BMI (p = 0.37), or in the interaction of diagnosis and sex on UA (p = 0.24). Similarly, there were no significant differences between PD and controls for allantoin (p = 0.47), allantoin corrected for BMI (p = 0.57), or in the interaction of diagnosis and sex on allantoin (p = 0.78). Allantoin/UA ratios also did not significantly differ by diagnosis (p = 0.99). Our results imply that low serum UA in PD may be due to an intrinsic mechanism that alters the homeostatic set point for serum UA in PD, and may contribute to relatively lower protection against oxidative damage. These findings provide indirect support for neuroprotection trials aimed at raising serum UA. PMID:26747026

  15. Microcracking in composite laminates under thermal and mechanical loading. Thesis

    NASA Technical Reports Server (NTRS)

    Maddocks, Jason R.

    1995-01-01

    Composites used in space structures are exposed to both extremes in temperature and applied mechanical loads. Cracks in the matrix form, changing the laminate thermoelastic properties. The goal of the present investigation is to develop a predictive methodology to quantify microcracking in general composite laminates under both thermal and mechanical loading. This objective is successfully met through a combination of analytical modeling and experimental investigation. In the analysis, the stress and displacement distributions in the vicinity of a crack are determined using a shear lag model. These are incorporated into an energy based cracking criterion to determine the favorability of crack formation. A progressive damage algorithm allows the inclusion of material softening effects and temperature-dependent material properties. The analysis is implemented by a computer code which gives predicted crack density and degraded laminate properties as functions of any thermomechanical load history. Extensive experimentation provides verification of the analysis. AS4/3501-6 graphite/epoxy laminates are manufactured with three different layups to investigate ply thickness and orientation effects. Thermal specimens are cooled to progressively lower temperatures down to -184 C. After conditioning the specimens to each temperature, cracks are counted on their edges using optical microscopy and in their interiors by sanding to incremental depths. Tensile coupons are loaded monotonically to progressively higher loads until failure. Cracks are counted on the coupon edges after each loading. A data fit to all available results provides input parameters for the analysis and shows them to be material properties, independent of geometry and loading. Correlation between experiment and analysis is generally very good under both thermal and mechanical loading, showing the methodology to be a powerful, unified tool. Delayed crack initiation observed in a few cases is attributed to a

  16. Vascular remodeling after ischemic stroke: mechanisms and therapeutic potentials

    PubMed Central

    Liu, Jialing; Wang, Yongting; Akamatsu, Yosuke; Lee, Chih Cheng; Stetler, R Anne; Lawton, Michael T.; Yang, Guo-Yuan

    2014-01-01

    The brain vasculature has been increasingly recognized as a key player that directs brain development, regulates homeostasis, and contributes to pathological processes. Following ischemic stroke, the reduction of blood flow elicits a cascade of changes and leads to vascular remodeling. However, the temporal profile of vascular changes after stroke is not well understood. Growing evidence suggests that the early phase of cerebral blood volume (CBV) increase is likely due to the improvement in collateral flow, also known as arteriogenesis, whereas the late phase of CBV increase is attributed to the surge of angiogenesis. Arteriogenesis is triggered by shear fluid stress followed by activation of endothelium and inflammatory processes, while angiogenesis induces a number of pro-angiogenic factors and circulating endothelial progenitor cells (EPCs). The status of collaterals in acute stroke has been shown to have several prognostic implications, while the causal relationship between angiogenesis and improved functional recovery has yet to be established in patients. A number of interventions aimed at enhancing cerebral blood flow including increasing collateral recruitment are under clinical investigation. Transplantation of EPCs to improve angiogenesis is also underway. Knowledge in the underlying physiological mechanisms for improved arteriogenesis and angiogenesis shall lead to more effective therapies for ischemic stroke. PMID:24291532

  17. Ambient-Potential Composite Ewald Method for ab Initio Quantum Mechanical/Molecular Mechanical Molecular Dynamics Simulation.

    PubMed

    Giese, Timothy J; York, Darrin M

    2016-06-14

    A new approach for performing Particle Mesh Ewald in ab initio quantum mechanical/molecular mechanical (QM/MM) simulations with extended atomic orbital basis sets is presented. The new approach, the Ambient-Potential Composite Ewald (CEw) method, does not perform the QM/MM interaction with Mulliken charges nor electrostatically fit charges. Instead the nuclei and electron density interact directly with the MM environment, but in a manner that avoids the use of dense Fourier transform grids. By performing the electrostatics with the underlying QM density, the CEw method avoids self-consistent field instabilities that have been encountered with simple charge mapping procedures. Potential of mean force (PMF) profiles of the p-nitrophenyl phosphate dissociation reaction in explicit solvent are computed from PBE0/6-31G* QM/MM molecular dynamics simulations with various electrostatic protocols. The CEw profiles are shown to be stable with respect to real-space Ewald cutoff, whereas the PMFs computed from truncated and switched electrostatics produce artifacts. PBE0/6-311G**, AM1/d-PhoT, and DFTB2 QM/MM simulations are performed to generate two-dimensional PMF profiles of the phosphoryl transesterification reactions with ethoxide and phenoxide leaving groups. The semiempirical models incorrectly produce a concerted ethoxide mechanism, whereas PBE0 correctly produces a stepwise mechanism. The ab initio reaction barriers agree more closely to experiment than the semiempirical models. The failure of Mulliken-charge QM/MM-Ewald is analyzed. PMID:27171914

  18. Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma.

    PubMed

    Chen, Jiang; Jin, Renan; Zhao, Jie; Liu, Jinghua; Ying, Hanning; Yan, Han; Zhou, Senjun; Liang, Yuelong; Huang, Diyu; Liang, Xiao; Yu, Hong; Lin, Hui; Cai, Xiujun

    2015-10-10

    Sorafenib, an orally-available kinase inhibitor, is the only standard clinical treatment against advanced hepatocellular carcinoma. However, development of resistance to sorafenib has raised concern in recent years due to the high-level heterogeneity of individual response to sorafenib treatment. The resistance mechanism underlying the impaired sensitivity to sorafenib is still elusive though some researchers have made great efforts. Here, we provide a systemic insight into the potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma depending on abundant previous studies and reports. PMID:26170167

  19. Consumption of Red/Processed Meat and Colorectal Carcinoma: Possible Mechanisms Underlying the Significant Association.

    PubMed

    Hammerling, Ulf; Bergman Laurila, Jonas; Grafström, Roland; Ilbäck, Nils-Gunnar

    2016-03-11

    Epidemiology and experimental studies provide an overwhelming support of the notion that diets high in red or processed meat accompany an elevated risk of developing pre-neoplastic colorectal adenoma and frank colorectal carcinoma (CRC). The underlying mechanisms are disputed; thus several hypotheses have been proposed. A large body of reports converges, however, on haem and nitrosyl haem as major contributors to the CRC development, presumably acting through various mechanisms. Apart from a potentially higher intestinal mutagenic load among consumers on a diet rich in red/processed meat, other mechanisms involving subtle interference with colorectal stem/progenitor cell survival or maturation are likewise at play. From an overarching perspective, suggested candidate mechanisms for red/processed meat-induced CRC appear as three partly overlapping tenets: (i) increased N-nitrosation/oxidative load leading to DNA adducts and lipid peroxidation in the intestinal epithelium, (ii) proliferative stimulation of the epithelium through haem or food-derived metabolites that either act directly or subsequent to conversion, and (iii) higher inflammatory response, which may trigger a wide cascade of pro-malignant processes. In this review, we summarize and discuss major findings of the area in the context of potentially pertinent mechanisms underlying the above-mentioned association between consumption of red/processed meat and increased risk of developing CRC. PMID:25849747

  20. Emplacement mechanisms and trapping potential of gravity-driven allochthons

    SciTech Connect

    Pinney, R.B.

    1985-02-01

    Gravity-slide blocks of Paleozoic carbonate detached from the Snake River Range show evidence of episodic emplacement into the Salt Lake group (Mio-Pliocene) in the Palisades reservoir area near Alpine, Wyoming. The allochthons lie in a large graben system created by the Grand Valley listric normal fault, a reactivated thrust that soles into a ramp in the underlying Absaroka thrust. In the Alpine 7 1/2-min quadrangle, one of the detached blocks is 2 1/2 mi (4 km) by 1 mi (1.6 km) in map view and contains the Ferry Peak thrust as well as other Laramide structures. Structures and formations of the Alpine allochthon may be matched to those in the range to restore approximate predetachment position. Very low-angle westward translation at or near the surface moved the blocks across the Grand Valley fault into the graben. The current location and attitude of these allochthons are due to subsequent movement and rotation on the Grand Valley fault. The allochthons occur at different stratigraphic levels in the Salt Lake group, each level corresponding to the time of a specific emplacement event. Catastrophic emplacement of a fractured allochthon, a potential reservoir, into a lacustrine or other source rock depocenter creates a unique and potentially predictable type of petroleum occurrence. Paleogeographic reconstruction may explain anomalous occurrence of discrete allochthons in structurally low areas where it can be shown that a gravitational potential existed for detachment and sliding. The resulting trap would consist of allochthons encased in autochthonous source rock.

  1. Early life stress interactions with the epigenome: potential mechanisms driving vulnerability towards psychiatric illness

    PubMed Central

    Olive, Michael Foster

    2014-01-01

    Throughout the 20th century a body of literature concerning the long lasting effects of early environment was produced. Adverse experiences in early life, or early life stress (ELS), is associated with a higher risk for developing various psychiatric illnesses. The mechanisms driving the complex interplay between ELS and adult phenotype has baffled many investigators for decades. Over the last decade, the new field of neuroepigenetics has emerged as one possible mechanism by which ELS can have far reaching effects on adult phenotype, behavior, and risk for psychiatric illness. Here we review two commonly investigated epigenetic mechanisms, histone modifications and DNA methylation, and the emerging field of neuroepigenetics as they relate to ELS. We discuss the current animal literature demonstrating ELS induced epigenetic modulation of gene expression that results in altered adult phenotypes. We also briefly discuss other areas in which neuroepigenetics has emerged as a potential mechanism underlying environmental and genetic interactions. PMID:25003947

  2. Wind a potential mechanism of Mars gully formation

    NASA Astrophysics Data System (ADS)

    Yue, Z.; Xie, H.

    2007-12-01

    Since Mars gullies were first revealed with the Mars Global Surveyor (MGS) Mars Orbiter Camera (MOC) in 2000, they rapidly became a hotspot in Mars studying in that some of them are very young features on Mars surface. The previous studies focused on their formation and erosion mechanisms. As a result, several mechanisms have been proposed. But none of them can interpret the formation of all gullies perfectly. High resolution HiRISE images give us a good opportunity to examine it. In this study, we propose that wind could play an important role in some of the gullies formation. Wind is the most important agent acting on Mars surface (Fenton, 2003) and produced many features on Mars surface, including ubiquitous dunes, yardangs, deflation pits, dust storms, and dust deposits. Similarly, wind can also affect the inner edge of craters and valleys, where the gullies have been found mostly. Under the erosion of wind, the small channel will turn to a big gully. Wind could be a major reason to explain (1) why gullies formed in one side of a crater wall, while small wind-blown sand deposits in the opposite side of the same crater, as found in the crater of this HiRISE image (PSP_001697_1390_RED.JP2) and (2) why two craters next to each other, but only the big one has gullies developed. The reason for this is that big crater can form a strong wind circulation. In another HiRISE image (PSP_001330_1395_RED.JP2), we found a rock in the lower end of a gully course in a crater wall, for which we explain this gully is in the process of formation. This rock could be moving down and carving in to form the course due to the wind force. Based on the common characteristics of wind abrasion mechanics (Greeley and Iversen, 1985), we propose the following processes of gully formation by wind: (1) Embryonic stage: one side of a crater wall or valley wall was "softened" by the wind storm and formed some irregular and V-shaped fractured channels. (2) Youthful stage: small impact pits formed

  3. Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity

    PubMed Central

    Parekh, Puja K.; McClung, Colleen A.

    2016-01-01

    Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward

  4. Molecular mechanisms underlying progesterone-enhanced breast cancer cell migration.

    PubMed

    Wang, Hui-Chen; Lee, Wen-Sen

    2016-01-01

    Progesterone (P4) was demonstrated to inhibit migration in vascular smooth muscle cells (VSMCs), but to enhance migration in T47D breast cancer cells. To investigate the mechanism responsible for this switch in P4 action, we examined the signaling pathway responsible for the P4-induced migration enhancement in breast cancer cell lines, T47D and MCF-7. Here, we demonstrated that P4 activated the cSrc/AKT signaling pathway, subsequently inducing RSK1 activation, which in turn increased phosphorylation of p27 at T198 and formation of the p27pT198-RhoA complex in the cytosol, thereby preventing RhoA degradation, and eventually enhanced migration in T47D cells. These findings were confirmed in the P4-treated MCF-7. Comparing the P4-induced molecular events in between breast cancer cells and VSMCs, we found that P4 increased p27 phosphorylation at T198 in breast cancer cells through RSK1 activation, while P4 increased p27 phosphorlation at Ser10 in VSMCs through KIS activation. P27pT198 formed the complex with RhoA and prevented RhoA degradation in T47D cells, whereas p-p27Ser10 formed the complex with RhoA and caused RhoA degradation in VSMCs. The results of this study highlight the molecular mechanism underlying P4-enhanced breast cancer cell migration, and suggest that RSK1 activation is responsible for the P4-induced migration enhancement in breast cancer cells. PMID:27510838

  5. Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity.

    PubMed

    Parekh, Puja K; McClung, Colleen A

    2015-01-01

    Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward

  6. Molecular mechanisms underlying progesterone-enhanced breast cancer cell migration

    PubMed Central

    Wang, Hui-Chen; Lee, Wen-Sen

    2016-01-01

    Progesterone (P4) was demonstrated to inhibit migration in vascular smooth muscle cells (VSMCs), but to enhance migration in T47D breast cancer cells. To investigate the mechanism responsible for this switch in P4 action, we examined the signaling pathway responsible for the P4-induced migration enhancement in breast cancer cell lines, T47D and MCF-7. Here, we demonstrated that P4 activated the cSrc/AKT signaling pathway, subsequently inducing RSK1 activation, which in turn increased phosphorylation of p27 at T198 and formation of the p27pT198-RhoA complex in the cytosol, thereby preventing RhoA degradation, and eventually enhanced migration in T47D cells. These findings were confirmed in the P4-treated MCF-7. Comparing the P4-induced molecular events in between breast cancer cells and VSMCs, we found that P4 increased p27 phosphorylation at T198 in breast cancer cells through RSK1 activation, while P4 increased p27 phosphorlation at Ser10 in VSMCs through KIS activation. P27pT198 formed the complex with RhoA and prevented RhoA degradation in T47D cells, whereas p-p27Ser10 formed the complex with RhoA and caused RhoA degradation in VSMCs. The results of this study highlight the molecular mechanism underlying P4-enhanced breast cancer cell migration, and suggest that RSK1 activation is responsible for the P4-induced migration enhancement in breast cancer cells. PMID:27510838

  7. Mechanism Underlying Levofloxacin Uptake by Human Polymorphonuclear Neutrophils

    PubMed Central

    Vazifeh, Doina; Bryskier, André; Labro, Marie-Thérèse

    1999-01-01

    The mechanism of radiolabeled levofloxacin ([3H]levofloxacin) uptake by human polymorphonuclear neutrophils (PMNs) was investigated by a classical velocity centrifugation technique. PMNs were incubated with levofloxacin for 5 to 180 min under various conditions before centrifugation through an oil cushion. Radioactivity was measured in the cell pellet to determine the amount of cell-associated drug. The uptake of levofloxacin was moderate with a cellular concentration/extracellular concentration ratio of about 4 to 6. Levofloxacin accumulated in PMNs parallel to the extracellular concentration, without saturation, over the range of 2.5 to 200 mg/liter (linear regression analysis: r = 0.92; P < 0.001). The activation energy was low (36 ± 7.2 kJ/mol). Levofloxacin uptake was increased in Ca2+-depleted, EGTA-containing medium by approximately 33% (P = 0.022), while Ni2+, a Ca2+ channel inhibitor, inhibited it in a concentration-dependent manner, with the concentration that inhibited 50% of control uptake being approximately 2.65 mM. Verapamil (an l-type Ca2+ channel inhibitor) and other pharmacologic agents which modify Ca2+ homeostasis did not modify levofloxacin uptake. Interestingly, Ca2+ and Mg2+ inhibited levofloxacin uptake in a concentration-dependent manner. EGTA, Ni2+, and verapamil did not modify levofloxacin efflux; thapsigargin, a Ca2+ pool-releasing agent, modestly increased the intracellular retention of levofloxacin. In addition, contrary to other fluoroquinolones, probenecid at 1 to 10 mM did not modify either levofloxacin uptake or efflux. These data are consistent with a mechanism of passive accumulation of levofloxacin in PMNs. Extracellular Ca2+ and Mg2+ may influence the structural conformation of levofloxacin or the lipophilicity of PMN membranes, thus explaining their effect on levofloxacin uptake. PMID:9925513

  8. Mechanisms underlying reduced fertility in anovular dairy cows.

    PubMed

    Santos, J E P; Bisinotto, R S; Ribeiro, E S

    2016-07-01

    Resumption of ovulation after parturition is a coordinated process that involves recoupling of the GH/insulin-like growth factor 1 axis in the liver, increase in follicular development and steroidogenesis, and removal of negative feedback from estradiol in the hypothalamus. Infectious diseases and metabolic disorders associated with extensive negative energy balance during early lactation disrupt this pathway and delay first ovulation postpartum. Extended periods of anovulation postpartum exert long-lasting effects on fertility in dairy cows including the lack of spontaneous estrus, reduced pregnancy per artificial insemination (P/AI), and increased risk of pregnancy loss. Concentrations of progesterone in anovular cows subjected to synchronized programs for AI are insufficient to optimize follicular maturation, oocyte competence, and subsequent fertility to AI. Ovulation of first wave follicles, which develop under low concentrations of progesterone, reduces embryo quality in the first week after fertilization and P/AI in dairy cows. Although the specific mechanisms by which anovulation and low concentrations of progesterone impair oocyte quality have not been defined, studies with persistent follicles support the involvement of premature resumption of meiosis and degradation of maternal RNA. Suboptimal concentrations of progesterone before ovulation also increase the synthesis of PGF2α in response to oxytocin during the subsequent estrous cycle, which explains the greater incidence of short luteal phases after the first AI postpartum in anovular cows compared with estrous cyclic herd mates. It is suggested that increased spontaneous luteolysis early in the estrous cycle is one of the mechanisms that contributes to early embryonic losses in anovular cows. Anovulation also leads to major shifts in gene expression in elongated conceptuses during preimplantation stages of pregnancy. Transcripts involved with control of energy metabolism and DNA repair were

  9. Mechanical properties and potential commercial applications of agricultural composites

    SciTech Connect

    Asadi, M.; Farokhi, S.; McCabe, S.L.

    1995-11-01

    This paper reveals information on the mechanical properties of the agricultural composites and their commercial potential as a substitute for plastics and woods leading to a lower cost for these products. Chopped and particulate agricultural co-products (hereafter referred to agro-fibers) such as wheat, brome hay, switchgrass, and corn were mixed at a ratio of 66:34 fiber/epoxy by volume to manufacture agricultural composites (hereafter referred to agrocomposites) using the hand lay-up molding technique. The manufactured composite samples were tested for their mechanical properties such as tensile stress, compressive stress, moisture absorption, and thermal expansion. According to results, chopped switchgrass agro-composite samples showed the highest tensile strength, yet less than that of soft woods and slightly higher than that of plastics (high density polyethylene known as HDPE). As a result, a second set of agro-composite samples using only chopped switchgrass was manufactured at 10%, 20%, 30%, 40%, and 50% agro-fiber content to obtain the optimal fiber/epoxy ratio for which agro-composite samples show the maximum tensile stress. The same procedure was followed for comprehensive strength, thermal expansion, and moisture absorption measurements. According to the obtained results, at 50:50, agro-composite samples showed the highest tensile stress at 2,925 psi compared to that of plastic at 2,000 psi and of soft wood at 6,600 psi. At 10:90 agro-fiber/epoxy, compressive strength of the agro-composite samples were 60% higher than that of plastic and 80% higher than that of soft woods. Thermal expansion and moisture absorption of the manufactured agro-composite samples showed better performances than both woods and plastics. Optimized agro-composite samples, due to their cost competitiveness and low weight, could replace woods and plastics in some applications. A small fraction of plastic and wood market wood lead to new source of revenues for farmers.

  10. Investigation of Nucleate Boiling Mechanisms Under Microgravity Conditions

    NASA Technical Reports Server (NTRS)

    Dhir, V. K.; Qiu, D. M.; Ramanujapu, N.; Hasan, M. M.

    1999-01-01

    The present work is aimed at the experimental studies and numerical modeling of the bubble growth mechanisms of a single bubble attached to a heating surface and of a bubble sliding along an inclined heated plate. Single artificial cavity of 10 microns in diameter was made on the polished Silicon wafer which was electrically heated at the back side in order to control the surface nucleation superheat. Experiments with a sliding bubble were conducted at different inclination angles of the downward facing heated surface for the purpose of studying the effect of magnitude of components of gravity acting parallel to and normal to the heat transfer surface. Information on the bubble shape and size, the bubble induced liquid velocities as well as the surface temperature were obtained using the high speed imaging and hydrogen bubble techniques. Analytical/numerical models were developed to describe the heat transfer through the micro-macro layer underneath and around a bubble formed at a nucleation site. In the micro layer model the capillary and disjoining pressures were included. Evolution of the bubble-liquid interface along with induced liquid motion was modeled. As a follow-up to the studies at normal gravity, experiments are being conducted in the KC-135 aircraft to understand the bubble growth/detachment under low gravity conditions. Experiments have been defined to be performed under long duration of microgravity conditions in the space shuttle. The experiment in the space shuttle will provide bubble growth and detachment data at microgravity and will lead to validation of the nucleate boiling heat transfer model developed from the preceding studies conducted at normal and low gravity (KC-135) conditions.

  11. On the mechanical properties of tooth enamel under spherical indentation.

    PubMed

    Chai, Herzl

    2014-11-01

    The mechanical properties of tooth enamel generally exhibit large variations, which reflect its structural and material complexity. Some key properties were evaluated under localized contact, simulating actual functioning conditions. Prominent cusps of extracted human molar teeth were polished down ~0.7 mm below the cusp tip and indented by tungsten carbide balls. The internal damage was assessed after unloading from longitudinal or transverse sections. The ultimate tensile stress (UTS) was determined using a novel bilayer specimen. The damage is characterized by penny-like radial cracks driven by hoop stresses and cylindrical cracks driven along protein-rich interrod materials by shear stresses. Shallow cone cracks typical of homogeneous materials which may cause rapid tooth wear under repeat contact are thus avoided. The mean stress vs. indentation strain curve is highly nonlinear, attributable to plastic shearing of protein between and within enamel rods. This curve is also affected by damage, especially radial cracks, the onset of which depends on ball radius. Several material properties were extracted from the tests, including shear strain at the onset of ring cracks γ(F) (=0.14), UTS (=119 MPa), toughness K(C) (=0.94 MPa m(1/2)), a crack propagation law and a constitutive response determined by trial and error with the aid of a finite-element analysis. These quantities, which are only slightly sensitive to anatomical location within the enamel region tested, facilitate a quantitative assessment of crown failure. Causes for variations in published UTS and K(C) values are discussed. PMID:25034644

  12. Investigation of Mechanisms Associated with Nucleate Boiling Under Microgravity Conditions

    NASA Technical Reports Server (NTRS)

    Dhir, Vijay K.

    1996-01-01

    The focus of the present work is to experimentally study and to analytically/numerically model the mechanisms of growth of bubbles attached to, and sliding along, a heated surface. To control the location of the active cavities, the number, the spacing, and the nucleation superheat, artificial cavities will be formed on silicon wafers. In order to study the effect of magnitude of components of gravitational acceleration acting parallel to, and normal to the surface, experiments will be conducted on surfaces inclined at different angles including a downward facing surface. Information on the temperature field around bubbles, bubble shape and size, and bubble induced liquid velocities will be obtained through the use of holography, video/high speed photography and hydrogen bubble techniques, respectively. Analytical/numerical models will be developed to describe the heat transfer including that through the micro-macro layer underneath and around a bubble. In the micro layer model capillary and disjoining pressures will be included. Evolution of the interface along with induced liquid motion will be modelled. Subsequent to the world at normal gravity, experiments will be conducted in the KC-135 or the Lear jet especially to learn about bubble growth/detachment under low gravity conditions. Finally, an experiment will be defined to be conducted under long duration of microgravity conditions in the space shuttle. The experiment in the space shuttle will provide microgravity data on bubble growth and detachment and will lead to a validation of the nucleate boiling heat transfer model developed from the preceding studies performed at normal and low gravity (KC-135 or Lear jet) conditions.

  13. Global hydropower potential during recent droughts and under changing climate

    NASA Astrophysics Data System (ADS)

    Van Vliet, Michelle T. H.; Sheffield, Justin; Wiberg, David; Wood, Eric F.

    2015-04-01

    There is a strong dependency of world's electricity sector on available water resources for hydropower generation. Recent droughts showed the vulnerability of the electricity sector to surface water constraints with reduced potentials for hydropower generation in different regions worldwide. Using a global modelling framework consisting of the VIC hydrological model and a hydropower model, we assess the impacts of recent droughts and future climate change on hydropower generation potentials worldwide. Our hydrological-electricity modelling framework was optimized and evaluated for 1981-2010, showing a realistic representation of observed streamflow and hydropower generation. We assessed the impacts of recent droughts and future climate change for more than 25,000 hydropower plants worldwide. Our results show that hydropower production potentials were significantly reduced during severe recent streamflow droughts (including e.g. summer of 2003 in Europe and 2007 in the United States). Model simulations with bias-corrected CMIP5 general circulation model output indicate that in several regions considerable reductions in hydropower production potentials are projected due to declines in streamflow during parts of the year. Considering these impacts and the long design life of power plant infrastructure, adaptation options should be included in today's planning and strategies to meet the growing electricity demand in the 21st century.

  14. Understanding the Mechanisms Underlying Gambling Behaviour and Sleep.

    PubMed

    Loft, Marisa H; Loo, Jasmine M Y

    2015-12-01

    Problem gambling and sleep difficulty threaten health. Using the basis of self-regulatory theory, potential mechanisms for these problems were investigated. Fifty-nine treatment-seeking gamblers completed the Pittsburgh Sleep Quality Index (sleep difficulty), the Sleep Hygiene Index (negative sleep habits), the Problem Gambling Severity Index and measures of self-regulatory capacity and arousability with data entered into regression analyses. Results supported the relationship between problem gambling and greater sleep difficulty (β = .18, t = 3.22, p < .01). Self-regulatory capacity mediated the relationship between problem gambling and sleep difficulty (R (2) change = .15, F(2, 57) = 12.14, β = -.45, t = -3.45, p < .001) as well as between problem gambling and negative sleep habits; R (2) change = .17, F(2, 57) = 13.57, β = -.28, t = -3.76, p < .001. Arousability predicted sleep difficulty (β = .15, t = 3.07, p < .01) and negative sleep habits (β = .40, t = 5.40, p < .01) but showed no relationship with problem gambling (r = .09, ns). Self-regulatory capacity represents an important mediator of the relationship between problem gambling and sleep-related behaviour and if targeted could reduce behavioural threats to health. PMID:25381635

  15. Metabolite Recognition Principles and Molecular Mechanisms Underlying Riboswitch Function

    PubMed Central

    Serganov, Alexander; Patel, Dinshaw J.

    2015-01-01

    Riboswitches are mRNA elements capable of modulating gene expression in response to specific binding by cellular metabolites. Riboswitches exert their function through the interplay of alternative ligand-free and ligand-bound conformations of the metabolite-sensing domain, which in turn modulate the formation of adjacent gene expression controlling elements. X-ray crystallography and NMR spectroscopy have determined three-dimensional structures of virtually all the major riboswitch classes in the ligand-bound state and, for several riboswitches, in the ligand-free state. The resulting spatial topologies have demonstrated the wide diversity of riboswitch folds and revealed structural principles for specific recognition by cognate metabolites. The available three-dimensional information, supplemented by structure-guided biophysical and biochemical experimentation, has led to an improved understanding of how riboswitches fold, what RNA conformations are required for ligand recognition, and how ligand binding can be transduced into gene expression modulation. These studies have greatly facilitated the dissection of molecular mechanisms underlying riboswitch action and should in turn guide the anticipated development of tools for manipulating gene regulatory circuits. PMID:22577823

  16. CFRP Mechanical Anchorage for Externally Strengthened RC Beams under Flexure

    NASA Astrophysics Data System (ADS)

    Ali, Alnadher; Abdalla, Jamal; Hawileh, Rami; Galal, Khaled

    De-bonding of carbon fiber reinforced polymers (CFRP) sheets and plates from the concrete substrate is one of the major reasons behind premature failures of beams that are externally strengthened with such CFRP materials. To delay or prevent de-bonding and therefore enhancing the load carrying capacity of strengthened beams, several anchorage systems were developed and used. This paper investigates the use of CFRP mechanical anchorage of CFRP sheets and plates used to externally strengthen reinforced concrete beams under flexure. The pin-and-fan shape CFRP anchor, which is custom-made from typical rolled fiber sheets and bundles of loose fiber is used. Several reinforced concrete beams were casted and tested in standard four-point bending scheme to study the effectiveness of this anchorage system. The beams were externally strengthened in flexure with bonded CFRP sheets and plates and then fastened to the soffit of the beams' using various patterns of CFRP anchors. It is observed that the CFRP plates begins to separate from the beams as soon as de-bonding occurs in specimens without CFRP anchors, while in beams with CFRP anchors de-bonding was delayed leading to increase in the load carrying capacity over the un-anchored strengthened beams.

  17. Mechanism of magnetic moment collapse under pressure in ferropericlase

    NASA Astrophysics Data System (ADS)

    Skorikov, N. A.; Shorikov, A. O.; Skornyakov, S. L.; Korotin, M. A.; Anisimov, V. I.

    2015-07-01

    We propose a new scenario for the magnetic collapse under pressure in ferropericlase (FP) (\\text{F}{{\\text{e}}1/4}\\text{M}{{\\text{g}}3/4} )O without the presence of intermediate spin state, which contradicts the mechanism proposed in (2013 Phys. Rev. B 87 165113). This scenario is supported by results of combined local density approximation + dynamical mean-field theory method calculations for the paramagnetic phase at ambient and high pressures. At ambient pressure, calculation gave (\\text{F}{{\\text{e}}1/4}\\text{M}{{\\text{g}}3/4} )O as an insulator with Fe 3d-shell in high-spin state. Experimentally observed high-spin to low-spin state transition of the \\text{F}{{\\text{e}}2+} ion in the pressure range of 35-75 GPa is successfully reproduced in our calculations. The spin crossover is characterized by coexistence of \\text{F}{{\\text{e}}2+} ions in high and low spin state but intermediate spin state is absent in the whole pressure range. Moreover, the probability of Fe ion {{\\text{d}}7} configuration with S=1 grows with pressure due to shortening of metal-oxygen distance. Also, no metal-insulator transition was obtained up to the pressure 140 GPa in agreement with experiment.

  18. Neural mechanisms underlying respiratory rhythm generation in the lamprey.

    PubMed

    Bongianni, Fulvia; Mutolo, Donatella; Cinelli, Elenia; Pantaleo, Tito

    2016-04-01

    The isolated brainstem of the adult lamprey spontaneously generates respiratory activity. The paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator, has been anatomically and functionally characterized. It is sensitive to opioids, neurokinins and acetylcholine. Excitatory amino acids, but not GABA and glycine, play a crucial role in the respiratory rhythmogenesis. These results are corroborated by immunohistochemical data. While only GABA exerts an important modulatory control on the pTRG, both GABA and glycine markedly influence the respiratory frequency via neurons projecting from the vagal motoneuron region to the pTRG. Noticeably, the removal of GABAergic transmission within the pTRG causes the resumption of rhythmic activity during apnea induced by blockade of glutamatergic transmission. The same result is obtained by microinjections of substance P or nicotine into the pTRG during apnea. The results prompted us to present some considerations on the phylogenesis of respiratory pattern generation. They may also encourage comparative studies on the basic mechanisms underlying respiratory rhythmogenesis of vertebrates. PMID:25220696

  19. [Molecular mechanisms underlying the formation of neuromuscular junction].

    PubMed

    Higuchi, Osamu; Yamanashi, Yuji

    2011-07-01

    The neuromuscular junction (NMJ) is a synapse between a motor neuron and skeletal muscle. The contraction of skeletal muscle is controlled by the neurotransmitter acetylcholine (ACh), which is released from the motor nerve terminal. To achieve efficient neuromuscular transmission, acetylcholine receptors (AChRs) must be densely clustered on the muscle membrane of the NMJ. Failure of AChR clustering is associated with disorders of neuromuscular transmission such as congenital myasthenic syndromes (CMS) and myasthenia gravis (MG). Motoneuronal agrin and muscle-specific receptor tyrosine kinase (MuSK) are known to play essential roles in the formation and maintenance of NMJs in the central region of each muscle. However, it had been unclear how agrin activates MuSK. Recent studies have elucidated the roles of several key molecules, including the cytoplasmic adaptor protein Dok-7 and LDL receptor-related protein 4 (Lrp4), in agrin-induced MuSK activation. Moreover, new evidence indicates that cyclin-dependent kinase 5 (Cdk5) regulates postsynaptic differentiation. In this review, we summarize the latest developments in molecular mechanisms underlying NMJ formation in vertebrates. PMID:21747134

  20. Decompaction mechanism of deep crystalline rocks under stress relief

    NASA Astrophysics Data System (ADS)

    Gorbatsevich, F. F.

    2003-07-01

    Within a geological massif in a stable geodynamical situation contacts on the grain boundaries in polycrystalline rocks at great depths are continuous and firm. The stress release of those rocks during drilling and excavation to the surface is accompanied by their disintegration (decompaction). The reason for the decompaction is generation of microcracks during stress release due to the difference between the elastic moduli of crystalline grains at their contacts. The mechanism of decompaction may occur not only in polymineral but in polycrystalline rocks as well. The method of decompaction evaluation of deep crystalline rocks under stress relief is presented. According to the calculations the initial manifestation of the decompaction effect in biotite gneisses will occur when they are extracted from the deep range of 0.8-1 km. The first microcracks arise on the grain borders between quartz-biotite and oligoclase-biotite. It is shown that the uplift of gneiss-granite varities of the rocks cut by the Kola superdeep borehole from depths exceeding 13-15 km will be possible in a form of separate mineral grains. Practical importance of the presented method is in an opportunity to evaluate the level of excavated decompaction. The method allow estimating the depth, from which the rock will be extracted only in a sludge form.

  1. Mechanical degradation of fuel cell membranes under fatigue fracture tests

    NASA Astrophysics Data System (ADS)

    Khorasany, Ramin M. H.; Sadeghi Alavijeh, Alireza; Kjeang, Erik; Wang, G. G.; Rajapakse, R. K. N. D.

    2015-01-01

    The effects of cyclic stresses on the fatigue and mechanical stability of perfluorosulfonic acid (PFSA) membranes are experimentally investigated under standard fuel cell conditions. The experiments are conducted ex-situ by subjecting membrane specimens to cyclic uniaxial tension at controlled temperature and relative humidity. The fatigue lifetime is measured in terms of the number of cycles until ultimate fracture. The results indicate that the membrane fatigue lifetime is a strong function of the applied stress, temperature, and relative humidity. The fatigue life increases exponentially with reduced stresses in all cases. The effect of temperature is found to be more significant than that of humidity, with reduced fatigue life at high temperatures. The maximum membrane strain at fracture is determined to decrease exponentially with increasing membrane lifetime. At a given fatigue life, a membrane exposed to fuel cell conditions is shown to accommodate more plastic strain before fracture than one exposed to room conditions. Overall, the proposed ex-situ membrane fatigue experiment can be utilized to benchmark the fatigue lifetime of new materials in a fraction of the time and cost associated with conventional in-situ accelerated stress testing methods.

  2. Molecular mechanism underlying promiscuous polyamine recognition by spermidine acetyltransferase.

    PubMed

    Sugiyama, Shigeru; Ishikawa, Sae; Tomitori, Hideyuki; Niiyama, Mayumi; Hirose, Mika; Miyazaki, Yuma; Higashi, Kyohei; Murata, Michio; Adachi, Hiroaki; Takano, Kazufumi; Murakami, Satoshi; Inoue, Tsuyoshi; Mori, Yusuke; Kashiwagi, Keiko; Igarashi, Kazuei; Matsumura, Hiroyoshi

    2016-07-01

    Spermidine acetyltransferase (SAT) from Escherichia coli, which catalyses the transfer of acetyl groups from acetyl-CoA to spermidine, is a key enzyme in controlling polyamine levels in prokaryotic cells. In this study, we determined the crystal structure of SAT in complex with spermidine (SPD) and CoA at 2.5Å resolution. SAT is a dodecamer organized as a hexamer of dimers. The secondary structural element and folding topology of the SAT dimer resemble those of spermidine/spermine N(1)-acetyltransferase (SSAT), suggesting an evolutionary link between SAT and SSAT. However, the polyamine specificity of SAT is distinct from that of SSAT and is promiscuous. The SPD molecule is also located at the inter-dimer interface. The distance between SPD and CoA molecules is 13Å. A deep, highly acidic, water-filled cavity encompasses the SPD and CoA binding sites. Structure-based mutagenesis and in-vitro assays identified SPD-bound residues, and the acidic residues lining the walls of the cavity are mostly essential for enzymatic activities. Based on mutagenesis and structural data, we propose an acetylation mechanism underlying promiscuous polyamine recognition for SAT. PMID:27163532

  3. Psychophysiological mechanisms underlying response selection in multidimensional space

    PubMed Central

    Mückschel, Moritz; Beste, Christian

    2015-01-01

    In the outside world, response selection often requires the processing of information from different spatial dimensions. Yet, most neuroscientific approaches to the topic only employ variations in one dimension, namely the horizontal left-right axis. Hence, virtually nothing is known about the neuronal mechanisms underlying response selection in more than one dimension. We investigated this aspect with the help of a two-dimensional flanker task using EEG and source localization techniques. The data shows that response selection processes are differentially modulated across different dimensions. However, this modulation is restricted to conditions imposing increased demands on response selection. In such situations, a distributed fronto-parietal network mediates intensified conflict monitoring processes as well as response inhibition processes. In case response selection is carried out in the horizontal dimension, those brain areas are more active than during response selection in the vertical dimension. Attentional selection processes were not affected. The study's findings are of relevance to our understanding to everyday functioning where response selection is usually carried out in two or three dimensions and not a single dimension as usually investigated in cognitive neuroscience. PMID:25582443

  4. Molecular mechanisms underlying phosphate sensing, signaling, and adaptation in plants.

    PubMed

    Zhang, Zhaoliang; Liao, Hong; Lucas, William J

    2014-03-01

    As an essential plant macronutrient, the low availability of phosphorus (P) in most soils imposes serious limitation on crop production. Plants have evolved complex responsive and adaptive mechanisms for acquisition, remobilization and recycling of phosphate (Pi) to maintain P homeostasis. Spatio-temporal molecular, physiological, and biochemical Pi deficiency responses developed by plants are the consequence of local and systemic sensing and signaling pathways. Pi deficiency is sensed locally by the root system where hormones serve as important signaling components in terms of developmental reprogramming, leading to changes in root system architecture. Root-to-shoot and shoot-to-root signals, delivered through the xylem and phloem, respectively, involving Pi itself, hormones, miRNAs, mRNAs, and sucrose, serve to coordinate Pi deficiency responses at the whole-plant level. A combination of chromatin remodeling, transcriptional and posttranslational events contribute to globally regulating a wide range of Pi deficiency responses. In this review, recent advances are evaluated in terms of progress toward developing a comprehensive understanding of the molecular events underlying control over P homeostasis. Application of this knowledge, in terms of developing crop plants having enhanced attributes for P use efficiency, is discussed from the perspective of agricultural sustainability in the face of diminishing global P supplies. PMID:24417933

  5. Molecular mechanisms underlying neurodevelopmental disorders, ADHD and autism.

    PubMed

    Bădescu, George Mihai; Fîlfan, Mădălina; Sandu, Raluca Elena; Surugiu, Roxana; Ciobanu, Ovidiu; Popa-Wagner, Aurel

    2016-01-01

    Neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism represent a significant economic burden, which justify vigorous research to uncover its genetics and developmental clinics for a diagnostic workup. The urgency of addressing attention deficit hyperactivity disorder comorbidities is seen in the chilling fact that attention deficit hyperactivity disorder (ADHD), mood disorders, substance use disorders and obesity each increase the risk for mortality. However, data about comorbidity is mainly descriptive, with mechanistic studies limited to genetic epidemiological studies that document shared genetic risk factors among these conditions. Autism and intellectual disability affects 1.5 to 2% of the population in Western countries with many individuals displaying social-emotional agnosia and having difficulty in forming attachments and relationships. Underlying mechanisms include: (i) dysfunctions of neuronal miRNAs; (ii) deletions in the chromosome 21, subtelomeric deletions, duplications and a maternally inherited duplication of the chromosomal region 15q11-q13; (iii) microdeletions in on the long (q) arm of the chromosome in a region designated q21.1 increases the risk of delayed development, intellectual disability, physical abnormalities, and neurological and psychiatric problems associated with autism, schizophrenia, and epilepsy and weak muscle tone (hypotonia); (iv) interstitial duplications encompassing 16p13.11. PMID:27516006

  6. Cellular mechanisms underlying the interaction between cannabinoid and opioid system.

    PubMed

    Parolaro, D; Rubino, T; Viganò, D; Massi, P; Guidali, C; Realini, N

    2010-04-01

    Recently, the presence of functional interaction between the opioid and cannabinoid system has been shown in various pharmacological responses. Although there is an increasing interest for the feasible therapeutic application of a co-administration of cannabinoids and opioids in some disorders (i.e. to manage pain, to modulate immune system and emotions) and the combined use of the two drugs by drug abusers is becoming largely diffuse, only few papers focused on cellular and molecular mechanisms underlying this interaction. This review updates the biochemical and molecular underpinnings of opioid and cannabinoid interaction, both within the central nervous system and periphery. The most convincing theory for the explanation of this reciprocal interaction involves (i) the release of opioid peptides by cannabinoids or endocannabinoids by opioids, (ii) the existence of a direct receptor-receptor interaction when the receptors are co-expressed in the same cells, and (iii) the interaction of their intracellular pathways. Finally, the cannabinoid/opioid interaction might be different in the brain rewarding networks and in those accounting for other pharmacological effects (antinociception, modulation of emotionality and cognitive behavior), as well as between the central nervous system and periphery. Further insights about the cannabinoid/opioid interaction could pave the way for new and promising therapeutic approaches. PMID:20017730

  7. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets

    PubMed Central

    Kim, Jong Youl; Kawabori, Masahito; Yenari, Midori A.

    2014-01-01

    Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke. Introduction Stroke refers to conditions caused by occlusion and/or rupture of blood vessels in the brain, and is a leading cause of death and disability in the industrialized world. PMID:24372209

  8. Potential mechanisms of hepatitis B virus induced liver injury.

    PubMed

    Suhail, Mohd; Abdel-Hafiz, Hany; Ali, Ashraf; Fatima, Kaneez; Damanhouri, Ghazi A; Azhar, Esam; Chaudhary, Adeel Ga; Qadri, Ishtiaq

    2014-09-21

    Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury. PMID:25253946

  9. Potential mechanisms of hepatitis B virus induced liver injury

    PubMed Central

    Suhail, Mohd; Abdel-Hafiz, Hany; Ali, Ashraf; Fatima, Kaneez; Damanhouri, Ghazi A; Azhar, Esam; Chaudhary, Adeel GA; Qadri, Ishtiaq

    2014-01-01

    Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury. PMID:25253946

  10. Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment.

    PubMed

    Feron, V J; Til, H P; de Vrijer, F; Woutersen, R A; Cassee, F R; van Bladeren, P J

    1991-01-01

    Aldehydes constitute a group of relatively reactive organic compounds. They occur as natural (flavoring) constituents in a wide variety of foods and food components, often in relatively small, but occasionally in very large concentrations, and are also widely used as food additives. Evidence of carcinogenic potential in experimental animals is convincing for formaldehyde and acetaldehyde, limited for crotonaldehyde, furfural and glycidaldehyde, doubtful for malondialdehyde, very weak for acrolein and absent for vanillin. Formaldehyde carcinogenesis is a high-dose phenomenon in which the cytotoxicity plays a crucial role. Cytotoxicity may also be of major importance in acetaldehyde carcinogenesis but further studies are needed to prove or disprove this assumption. For a large number of aldehydes (relevant) data on neither carcinogenicity nor genotoxicity are available. From epidemiological studies there is no convincing evidence of aldehyde exposure being related to cancer in humans. Overall assessment of the cancer risk of aldehydes in the diet leads to the conclusion that formaldehyde, acrolein, citral and vanillin are no dietary risk factors, and that the opposite may be true for acetaldehyde, crotonaldehyde and furfural. Malondialdehyde, glycidaldehyde, benzaldehyde, cinnamaldehyde and anisaldehyde cannot be evaluated on the basis of the available data. A series of aldehydes should be subjected to at least mutagenicity, cytogenicity and cytotoxicity tests. Priority setting for testing should be based on expected mechanism of action and degree of human exposure. PMID:2017217

  11. Recent experimental developments concerning the mechanisms underlying dust emission

    NASA Astrophysics Data System (ADS)

    McKenna Neuman, C. L.; Sanderson, R. S.; O'Brien, P.

    2012-12-01

    Field based studies have been invaluable in elucidating the great variability and complexity in natural surfaces that emit dust. Spanning hours to days, and meters to kilometers, measurements of the regional and global characteristics of dust emission and transport are contributing to a clearer understanding of these phenomena. This work has been complimented by the development of increasingly more sophisticated atmospheric dispersion models. Only very recently, however, has much attention been paid to the physics of dust emission from the bed surface that necessarily require precise, high frequency measurements over fractions of millimeters under carefully manipulated conditions. This paper provides an overview of recent advances in our understanding of the mechanisms of dust emission, as derived from experiments carried out in the Trent boundary layer wind tunnel by a variety of workers. Energy transfer to the bed surface through the impacts of saltating particles has long been recognized as crucial for the ejection of silt and clay sized particles from surfaces where interparticle bonding is significant. Using Particle Tracking Velocimetry (PTV) and laser Doppler anemometry (LDA), we are now able to measure the energy transfer to the surface and the consequent deformation/rupture for both loose and consolidated beds of silt. The coefficient of restitution is found to decrease with particle impact speed, although some compaction may also occur with plowing and displacement of loose bed material (Gordon and McKenna Neuman, 2009). Further consideration is given to wind pumping as an alternate mechanism for dust entrainment from surfaces that are armored; that is, where insufficient sand supply is available to the support the development of a saltation cloud. LDA and pressure tap measurements confirm that turbulent structures measured in the atmospheric boundary layer are able to penetrate into the pores of gravel sized material, and specifically, the smelter waste

  12. Shifts in a single muscle's control potential of body dynamics are determined by mechanical feedback

    PubMed Central

    Sponberg, Simon; Libby, Thomas; Mullens, Chris H.; Full, Robert J.

    2011-01-01

    Muscles are multi-functional structures that interface neural and mechanical systems. Muscle work depends on a large multi-dimensional space of stimulus (neural) and strain (mechanical) parameters. In our companion paper, we rewrote activation to individual muscles in intact, behaving cockroaches (Blaberus discoidalis L.), revealing a specific muscle's potential to control body dynamics in different behaviours. Here, we use those results to provide the biologically relevant parameters for in situ work measurements. We test four hypotheses about how muscle function changes to provide mechanisms for the observed control responses. Under isometric conditions, a graded increase in muscle stress underlies its linear actuation during standing behaviours. Despite typically absorbing energy, this muscle can recruit two separate periods of positive work when controlling running. This functional change arises from mechanical feedback filtering a linear increase in neural activation into nonlinear work output. Changing activation phase again led to positive work recruitment, but at different times, consistent with the muscle's ability to also produce a turn. Changes in muscle work required considering the natural sequence of strides and separating swing and stance contributions of work. Both in vivo control potentials and in situ work loops were necessary to discover the neuromechanical coupling enabling control. PMID:21502130

  13. The Effects of Calorie Restriction in Depression and Potential Mechanisms

    PubMed Central

    Zhang, Yifan; Liu, Changhong; Zhao, Yinghao; Zhang, Xingyi; Li, Bingjin; Cui, Ranji

    2015-01-01

    Depression, also called major depressive disorder, is a neuropsychiatric disorder jeopardizing an increasing number of the population worldwide. To date, a large number of studies have devoted great attention to this problematic condition and raised several hypotheses of depression. Based on these theories, many antidepressant drugs were developed for the treatment of depression. Yet, the depressed patients are often refractory to the antidepressant therapies. Recently, increasing experimental evidences demonstrated the effects of calorie restriction in neuroendocrine system and in depression. Both basic and clinical investigations indicated that short-term calorie restriction might induce an antidepressant efficacy in depression, providing a novel avenue for treatment. Molecular basis underlying the antidepressant actions of calorie restriction might involve multiple physiological processes, primarily including orexin signaling activation, increased CREB phosphorylation and neurotrophic effects, release of endorphin and ketone production. However, the effects of chronic calorie restriction were quite controversial, in the cases that it often resulted in the long-term detrimental effects via inhibiting the function of 5-HT system and decreasing leptin levels. Here we review such dual effects of calorie restriction in depression and potential molecular basis behind these effects, especially focusing on antidepressant effects. PMID:26412073

  14. Androgen dependence in hamsters: overdose, tolerance, and potential opioidergic mechanisms.

    PubMed

    Peters, K D; Wood, R I

    2005-01-01

    Anabolic steroids are drugs of abuse. However, the potential for steroid reward and addiction remains largely unexplored. This study used i.c.v. testosterone self-administration and controlled infusions of testosterone or vehicle in hamsters to explore central mechanisms of androgen overdose. Forty-two hamsters used nose-pokes to self-administer 1 microg/microl testosterone i.c.v. 4 h/day in an operant chamber. During 1-56 days of androgen self-administration, 10 (24%) hamsters died. Deaths correlated with peak daily intake of testosterone. Of the hamsters that self-administered a peak intake of <20 microg/day, there was 100% survival (10/10). Survival decreased to 86% (19/22) when daily testosterone intake peaked at 20-60 microg/day. Only 30% (three of 10) survived when daily testosterone intake exceeded 60 microg/day. Deaths are not due to volume or vehicle because i.c.v. infusions of 80 mul vehicle had no effect. Testosterone overdose resembles opiate intoxication. When male hamsters received infusions of 40 microg testosterone, locomotion (25.1+/-18.8 grid-crossings/10 min), respiration (72.7+/-5.4 breaths/min) and body temperature (33.5+/-0.4 degrees C) were significantly reduced, compared with males receiving vehicle infusions (186.1+/-8.1 crossings/10 min, 117.6+/-1.0 breaths/min, 35.9+/-0.1 degrees C, P<0.05). However, males developed tolerance to continued daily testosterone infusion. After 15 days, locomotion (170.2+/-6.3 crossings), respiration (118.4+/-1.3 breaths/min), and body temperature (35.3+/-0.3 degrees C) in testosterone-infused males were equivalent to that in vehicle controls (P>0.05). The depressive effects of testosterone infusion are blocked by the opioid antagonist, naltrexone. With naltrexone pre-treatment (10 mg/kg s.c.), locomotion (183.7+/-1.8 crossings/10 min), respiration (116.9+/-0.3 breaths/min), and body temperature (36.1+/-0.4 degrees C) during testosterone infusion were equivalent to vehicle controls. Likewise, naltrexone

  15. Biochar Mechanisms of Heavy Metal Sorption and Potential Utility

    NASA Astrophysics Data System (ADS)

    Ippolito, J.

    2015-12-01

    Mining-affected lands are a global issue; in the USA alone there are an estimated 500,000 abandoned mines encompassing hundreds of thousands of hectares. Many of these sites generate acidic mine drainage that causes release of heavy metals, and subsequently degradation in environmental quality. Because of its potential liming characteristics, biochar may play a pivotal role as a soil amendment in future mine land reclamation. However, to date, most studies have focused on the use of biochar to sorb metals from solution. Previous studies suggest that metals are complexed by biochar surface function groups (leading to ion exchange, complexation), coordination with Pi electrons (C=C) of carbon, and precipitation of inorganic mineral phases. Several recent studies have focused on the use of biochar for amending mine land soils, showing that biochar can indeed reduce heavy metal lability, yet the mechanism(s) behind labile metal reduction have yet to be established. In a proof-of-concept study, we added lodgepole pine, tamarisk, and switchgrass biochar (0, 5, 10, 15% by weight; 500 oC) to four different western US mine land soils affected by various heavy metals (Cd, Cu, Mn, Pb, Zn). Extraction with 0.01M CaCl2 showed that increasing biochar application rate significantly decreased 'bioaccessible' metals in almost all instances. A concomitant increase in solution pH was observed, suggesting that metals may be rendered bio-inaccessible through precipitation as carbonate or (hydr)oxide phases, or sorbed onto mineral surfaces. However, this was only supposition and required further research. Thus, following the 0.01M CaCl2 extraction, biochar-soil mixtures were air-dried and metals were further extracted using the four-step BCR sequential removal procedure. Results from selective extraction suggest that, as compared to the controls, most metals in the biochar-amended mine land soils were associated with exchange sites, carbonate, and oxide phases. Biochar may play a

  16. Cellular mechanisms underlying the pharmacological induction of phosphenes

    PubMed Central

    Cervetto, L; Demontis, G C; Gargini, C

    2007-01-01

    Visual sensations evoked by stimuli other than luminance changes are called phosphenes. Phosphenes may be an early symptom in a variety of diseases of the retina or of the visual pathways, but healthy individuals may perceive them as well. Phosphene-like phenomena are perhaps the most common side effect reported in clinical pharmacology. Ivabradine, a novel anti-anginal drug that reduces heart-rate by inhibiting the hyperpolarization activated current expressed in cardiac sinoatrial node cells (If) induces phosphenes in some patients. One hypothesis is that ivabradine interacts with the visual system by inhibiting hyperpolarization-activated current in retinal cells (Ih). An Ih current with properties similar to cardiac If has been reported in retinal neurones. Under normal circumstances most of the random fluctuations generated within the retinal circuits do not reach the level of conscious perception because they are filtered out. Presumably, filtering occurs mostly within the retina and one serious candidate for this action is the ability of Ih to act as a negative-feedback mechanism. Ih activation in the membrane of visual cells causes dampening of responses to slow noisy inputs thus tuning the visual system to perceptually more relevant signals of higher frequency. Ih inhibition, by altering at the retinal synapses the filtering of signals generated by thermal breakdown of rhodopsin or other fluctuations, is expected to increase the probability of phosphene occurrence. It is the purpose of the present paper to outline and discuss the features of the visual system and the pharmacological conditions relevant to phosphene perception. PMID:17211458

  17. Sex differences in the mechanisms underlying long QT syndrome.

    PubMed

    Salama, Guy; Bett, Glenna C L

    2014-09-01

    Sexual dimorphism is a well-established phenomenon, but its degree varies tremendously among species. Since the early days of Einthoven's development of the three-lead galvanometer ECG, we have known there are marked differences in QT intervals of men and women. It required over a century to appreciate the profound implications of sex-based electrophysiological differences in QT interval on the panoply of sex differences with respect to arrhythmia risk, drug sensitivity, and treatment modalities. Little is known about the fundamental mechanism responsible for sex differences in electrical substrate of the human heart, in large part due to the lack of tissue availability. Animal models are an important research tool, but species differences in the sexual dimorphism of the QT interval, the ionic currents underlying the cardiac repolarization, and effects of sex steroids make it difficult to interpolate animal to human sex differences. In addition, in some species, different strains of the same animal model yield conflicting data. Each model has its strengths, such as ease of genetic manipulation in mice or size in dogs. However, many animals do not reproduce the sexual dimorphism of QT seen in humans. To match sex linked prolongation of QT interval and arrhythmogenic phenotype, the current data suggest that the rabbit may be best suited to provide insight into sex differences in humans. In the future, emerging technologies such as induced pluripotent stem cell derived cardiac myocyte systems may offer the opportunity to study sex differences in a controlled hormonal situation in the context of a sex specific human model system. PMID:24973386

  18. Neural Mechanisms Underlying Compensatory and Noncompensatory Strategies in Risky Choice.

    PubMed

    Van Duijvenvoorde, Anna C K; Figner, Bernd; Weeda, Wouter D; Van der Molen, Maurits W; Jansen, Brenda R J; Huizenga, Hilde M

    2016-09-01

    Individuals may differ systematically in their applied decision strategies, which has critical implications for decision neuroscience but is yet scarcely studied. Our study's main focus was therefore to investigate the neural mechanisms underlying compensatory versus noncompensatory strategies in risky choice. Here, we compared people using a compensatory expected value maximization with people using a simplified noncompensatory loss-minimizing choice strategy. To this end, we used a two-choice paradigm including a set of "simple" items (e.g., simple condition), in which one option was superior on all attributes, and a set of "conflict" items, in which one option was superior on one attribute but inferior on other attributes. A binomial mixture analysis of the decisions elicited by these items differentiated between decision-makers using either a compensatory or a noncompensatory strategy. Behavioral differences were particularly pronounced in the conflict condition, and these were paralleled by neural results. That is, we expected compensatory decision-makers to use an integrated value comparison during choice in the conflict condition. Accordingly, the compensatory group tracked the difference in expected value between choice options reflected in neural activation in the parietal cortex. Furthermore, we expected noncompensatory, compared with compensatory, decision-makers to experience increased conflict when attributes provided conflicting information. Accordingly, the noncompensatory group showed greater dorsomedial PFC activation only in the conflict condition. These pronounced behavioral and neural differences indicate the need for decision neuroscience to account for individual differences in risky choice strategies and to broaden its scope to noncompensatory risky choice strategies. PMID:27167399

  19. Mechanisms underlying obesity resistance associated with high spontaneous physical activity

    PubMed Central

    Teske, Jennifer A.; Billington, Charles J.; Kotz, Catherine M.

    2013-01-01

    Obesity resistance due to elevated orexin signaling is accompanied by high levels of spontaneous physical activity (SPA). The behavioral and neural mechanisms underlying this observation have not been fully worked out. We determined the contribution of hypothalamic orexin receptors (OXR) to SPA stimulated by orexin A (OXA), whether OXA-stimulated SPA was secondary to arousal and whether voluntary wheel running led to compensations in 24-h SPA. We further tested whether orexin action on dopamine one receptors (DA1R) in the substantia nigra (SN) plays an important role in generation of SPA. To test this, SPA response was determined in lean and obese rats with cannulae targeted towards the rostral lateral hypothalamus (rLH) or SN. Sleep/wake states were also measured in rats with rLH cannula and EEG/EMG radiotelemetry transmitters. SPA in lean rats was more sensitive to antagonism of the orexin 1 receptor (OX1R) and in the early response to the orexin 2 agonist. OXA increased arousal equally in lean and obese rodents, which is discordant from the greater SPA response in lean rats. Obesity resistant rats ran more and wheel running was directly related to 24-h SPA levels. The OX1R antagonist, SB-334867-A, and the DA1R antagonist, SCH3390, in SN more effectively reduced SPA stimulated by OXA in OR rats. These data suggest OXA-stimulated SPA is not secondary to enhanced arousal, propensity for SPA parallels inclination to run and that orexin action on dopaminergic neurons in SN may participate in mediation of SPA and running wheel activity. PMID:24161277

  20. Cognitive mechanisms underlying instructed choice exploration of small city maps

    PubMed Central

    Sakellaridi, Sofia; Christova, Peka; Christopoulos, Vassilios N.; Vialard, Alice; Peponis, John; Georgopoulos, Apostolos P.

    2015-01-01

    We investigated the cognitive mechanisms underlying the exploration and decision-making in realistic and novel environments. Twelve human subjects were shown small circular U.S. city maps with two locations highlighted on the circumference, as possible choices for a post office (“targets”). At the beginning of a trial, subjects fixated a spot at the center of the map and ultimately chose one of the two locations. A space syntax analysis of the map paths (from the center to each target) revealed that the chosen location was associated with the less convoluted path, as if subjects navigated mentally the paths in an “ant's way,” i.e., by staying within street boundaries, and ultimately choosing the target that could be reached from the center in the shortest way, and the fewest turns and intersections. The subjects' strategy for map exploration and decision making was investigated by monitoring eye position during the task. This revealed a restricted exploration of the map delimited by the location of the two alternative options and the center of the map. Specifically, subjects explored the areas around the two target options by repeatedly looking at them before deciding which one to choose, presumably implementing an evaluation and decision-making process. The ultimate selection of a specific target was significantly associated with the time spent exploring the area around that target. Finally, an analysis of the sequence of eye fixations revealed that subjects tended to look systematically toward the target ultimately chosen even from the beginning of the trial. This finding indicates an early cognitive selection bias for the ensuing decision process. PMID:25852452

  1. Kinetic modelling and bifurcation analysis of chemomechanically miniaturized gels under mechanical load.

    PubMed

    Wang, Pengfei; Liu, Shaobao; Zhou, Jinxiong; Xu, Feng; Lu, Tianjian

    2013-09-01

    Chemomechanically responsive gels, with great potential applications in the fields of smart structures and biomedicines, present autonomously oscillatory deformation driven by the Belousov-Zhabotinsky chemical reaction. The dynamic behavior of the responsive gels is obviously affected by the external mechanical load. This approach proposed a kinetic model with an ordinary differential equation to describe the oscillatory deformation of the gels under the mechanical load. Then the periodic solutions and phase diagrams of the oscillation are obtained using the improved Runge-Kutta and shooting methods. The results demonstrated that bifurcations are typically existent in the system and the characters of the oscillatory deformation regularly depend on the mechanical load as well as the concentration of reactants and the stoichiometric coefficient of chemical reaction. This development is supposed to promote the practical applications of the chemomechanically responsive gels. PMID:24072466

  2. Neuronal mechanisms and circuits underlying repetitive behaviors in mouse models of autism spectrum disorder.

    PubMed

    Kim, Hyopil; Lim, Chae-Seok; Kaang, Bong-Kiun

    2016-01-01

    Autism spectrum disorder (ASD) refers to a broad spectrum of neurodevelopmental disorders characterized by three central behavioral symptoms: impaired social interaction, impaired social communication, and restricted and repetitive behaviors. However, the symptoms are heterogeneous among patients and a number of ASD mouse models have been generated containing mutations that mimic the mutations found in human patients with ASD. Each mouse model was found to display a unique set of repetitive behaviors. In this review, we summarize the repetitive behaviors of the ASD mouse models and variations found in their neural mechanisms including molecular and electrophysiological features. We also propose potential neuronal mechanisms underlying these repetitive behaviors, focusing on the role of the cortico-basal ganglia-thalamic circuits and brain regions associated with both social and repetitive behaviors. Further understanding of molecular and circuitry mechanisms of the repetitive behaviors associated with ASD is necessary to aid the development of effective treatments for these disorders. PMID:26790724

  3. Flaw tolerance of nuclear intermediate filament lamina under extreme mechanical deformation.

    PubMed

    Qin, Zhao; Buehler, Markus J

    2011-04-26

    The nuclear lamina, composed of intermediate filaments, is a structural protein meshwork at the nuclear membrane that protects genetic material and regulates gene expression. Here we uncover the physical basis of the material design of nuclear lamina that enables it to withstand extreme mechanical deformation of >100% strain despite the presence of structural defects. Through a simple in silico model we demonstrate that this is due to nanoscale mechanisms including protein unfolding, alpha-to-beta transition, and sliding, resulting in a characteristic nonlinear force-extension curve. At the larger microscale this leads to an extreme delocalization of mechanical energy dissipation, preventing catastrophic crack propagation. Yet, when catastrophic failure occurs under extreme loading, individual protein filaments are sacrificed rather than the entire meshwork. This mechanism is theoretically explained by a characteristic change of the tangent stress-strain hardening exponent under increasing strain. Our results elucidate the large extensibility of the nuclear lamina within muscle or skin tissue and potentially many other protein materials that are exposed to extreme mechanical conditions, and provide a new paradigm toward the de novo design of protein materials by engineering the nonlinear stress-strain response to facilitate flaw-tolerant behavior. PMID:21384869

  4. Effects of Delaying Transplanting on Agronomic Traits and Grain Yield of Rice under Mechanical Transplantation Pattern

    PubMed Central

    Liu, Qihua; Wu, Xiu; Ma, Jiaqing; Chen, Bocong; Xin, Caiyun

    2015-01-01

    A delay in the mechanical transplantation (MT) of rice seedlings frequently occurs in Huanghuai wheat-rice rotation cropping districts of China, due to the late harvest of wheat, the poor weather conditions and the insufficiency of transplanters, missing the optimum transplanting time and causing seedlings to age. To identify how delaying transplanting rice affects the agronomic characteristics including the growth duration, photosynthetic productivity and dry matter remobilization efficiency and the grain yield under mechanical transplanting pattern, an experiment with a split-plot design was conducted over two consecutive years. The main plot includes two types of cultivation: mechanical transplanting and artificial transplanting (AT). The subplot comprises four japonica rice cultivars. The results indicate that the rice jointing, booting, heading and maturity stages were postponed under MT when using AT as a control. The tiller occurrence number, dry matter weight per tiller, accumulative dry matter for the population, leaf area index, crop growth rate, photosynthetic potential, and dry matter remobilization efficiency of the leaf under MT significantly decreased compared to those under AT. In contrast, the reduction rate of the leaf area during the heading-maturity stage was markedly enhanced under MT. The numbers of effective panicles and filled grains per panicle and the grain yield significantly decreased under MT. A significant correlation was observed between the dry matter production, remobilization and distribution characteristics and the grain yield. We infer that, as with rice from old seedlings, the decrease in the tiller occurrence, the photosynthetic productivity and the assimilate remobilization efficiency may be important agronomic traits that are responsible for the reduced grain yield under MT. PMID:25875607

  5. Motivation by potential gains and losses affects control processes via different mechanisms in the attentional network.

    PubMed

    Paschke, Lena M; Walter, Henrik; Steimke, Rosa; Ludwig, Vera U; Gaschler, Robert; Schubert, Torsten; Stelzel, Christine

    2015-05-01

    Attentional control in demanding cognitive tasks can be improved by manipulating the motivational state. Motivation to obtain gains and motivation to avoid losses both usually result in faster reaction times and stronger activation in relevant brain areas such as the prefrontal cortex, but little is known about differences in the underlying neurocognitive mechanisms of these types of motivation in an attentional control context. In the present functional magnetic resonance imaging (fMRI) study, we tested whether potential gain and loss as motivating incentives lead to overlapping or distinct neural effects in the attentional network, and whether one of these conditions is more effective than the other. A Flanker task with word stimuli as targets and distracters was performed by 115 healthy participants. Using a mixed blocked and event-related design allowed us to investigate transient and sustained motivation-related effects. Participants could either gain money (potential gain) or avoid losing money (potential loss) in different task blocks. Participants showed a congruency effect with increased reaction times for incongruent compared to congruent trials. Potential gain led to generally faster responses compared to the neutral condition and to stronger improvements than potential loss. Potential loss also led to shorter response times compared to the neutral condition, but participants improved mainly during incongruent and not during congruent trials. The event-related fMRI data revealed a main effect of congruency with increased activity in the left inferior frontal gyrus (IFG) and inferior frontal junction area (IFJ), the pre-supplementary motor area (pre-SMA), bilateral insula, intraparietal sulcus (IPS) and visual word form area (VWFA). While potential gain led to increased activity in a cluster of the IFJ and the VWFA only during incongruent trials, potential loss was linked to activity increases in these regions during incongruent and congruent trials. The

  6. Potential self-regulatory mechanisms of yoga for psychological health

    PubMed Central

    Gard, Tim; Noggle, Jessica J.; Park, Crystal L.; Vago, David R.; Wilson, Angela

    2014-01-01

    Research suggesting the beneficial effects of yoga on myriad aspects of psychological health has proliferated in recent years, yet there is currently no overarching framework by which to understand yoga’s potential beneficial effects. Here we provide a theoretical framework and systems-based network model of yoga that focuses on integration of top-down and bottom-up forms of self-regulation. We begin by contextualizing yoga in historical and contemporary settings, and then detail how specific components of yoga practice may affect cognitive, emotional, behavioral, and autonomic output under stress through an emphasis on interoception and bottom-up input, resulting in physical and psychological health. The model describes yoga practice as a comprehensive skillset of synergistic process tools that facilitate bidirectional feedback and integration between high- and low-level brain networks, and afferent and re-afferent input from interoceptive processes (somatosensory, viscerosensory, chemosensory). From a predictive coding perspective we propose a shift to perceptual inference for stress modulation and optimal self-regulation. We describe how the processes that sub-serve self-regulation become more automatized and efficient over time and practice, requiring less effort to initiate when necessary and terminate more rapidly when no longer needed. To support our proposed model, we present the available evidence for yoga affecting self-regulatory pathways, integrating existing constructs from behavior theory and cognitive neuroscience with emerging yoga and meditation research. This paper is intended to guide future basic and clinical research, specifically targeting areas of development in the treatment of stress-mediated psychological disorders. PMID:25368562

  7. Under Pressure: Mechanical Stress Management in the Nucleus

    PubMed Central

    Belaadi, Néjma; Aureille, Julien; Guilluy, Christophe

    2016-01-01

    Cells are constantly adjusting to the mechanical properties of their surroundings, operating a complex mechanochemical feedback, which hinges on mechanotransduction mechanisms. Whereas adhesion structures have been shown to play a central role in mechanotransduction, it now emerges that the nucleus may act as a mechanosensitive structure. Here, we review recent advances demonstrating that mechanical stress emanating from the cytoskeleton can activate pathways in the nucleus which eventually impact both its structure and the transcriptional machinery. PMID:27314389

  8. Inelastic deformation mechanisms in a transverse MMC lamina under compression

    NASA Technical Reports Server (NTRS)

    Newaz, Golam M.; Majumdar, Bhaskar S.

    1992-01-01

    An investigation was undertaken to study the inelastic deformation mechanisms in (90)(sub 8) Ti 15-3/SCS-6 lamina subjected to pure compression. Both mechanical behavior and microstructural evaluation were undertaken at room temperature, 538 and 650 C. Results indicate that mechanical response and deformation characteristics are significantly different in monotonic tension and compression. The inelastic deformation mechanisms in compression are controlled by radial fiber fracture, matrix plasticity and fiber-matrix debonding. The radial fiber fracture is a new damage mode observed for metal-matrix composites (MMC).

  9. Quantum mechanics of graphene with a one-dimensional potential

    SciTech Connect

    Miserev, D. S.; Entin, M. V.

    2012-10-15

    Electron states in graphene with a one-dimensional potential have been studied. An approximate solution has been obtained for a small angle between vectors of the incident electron momentum and potential gradient. Exactly solvable problems with a potential of the smoothened step type U(x) Utanh(x/a) and a potential with a singularity U(x) = -U/(|x| + d) are considered. The transmission/reflection coefficients and phases for various potential barriers are determined. A quasi-classical solution is obtained.

  10. Newtonian mechanics of a many-particle assembly coupled to an external body potential

    NASA Technical Reports Server (NTRS)

    Salvino, R. E.

    1990-01-01

    The Newtonian mechanics of a many-particle system evolving in time under the influence of an external body potential, that is, an external potential that couples to the center of mass only, is examined. The lack of any other external fields allows the complete separation of the center-of-mass (or external-field-dependent) equations from the internal (or external-field-independent) dynamics. The complete solution of the center-of-mass motion then allows an analytical evaluation of the external body potential contributions to the thermophysical properties of the system. The phenomena of field-induced heating, Taylor-Aris hydrodynamic form for the diffusion tensor, and an analogous hydrodynamic form for the viscosity tensor are derived from microscopic principles. A brief and model-dependent description of equilibrium phenomena is also presented.

  11. Mechanisms underlying reductions in stroke volume at rest and during exercise at high altitude.

    PubMed

    Stembridge, Mike; Ainslie, Philip N; Shave, Rob

    2016-08-01

    High-altitude exposure challenges the cardiovascular system to maintain oxygen delivery to the mitochondria under conditions of hypoxic stress. Following acclimatisation (3-5 days), stroke volume (SV) falls to below sea-level values but heart rate remains elevated, such that cardiac output is maintained compared to sea level. The decrease in SV has been a topic of research for over 40 years, but the underlying mechanisms are incompletely understood. Impaired systolic contractile function secondary to reduced coronary arterial oxygen tension has been investigated as a potential cause for the decrease in SV. However, despite in vitro evidence of impaired cardiac contractile force in severe hypoxia, the majority of studies to date have reported enhanced in vivo ventricular systolic function at rest and during exercise in humans up to and above 5000 m. However, the elevated function observed at rest has recently been suggested to reduce the functional reserve available during exercise. While in vivo systolic function appears enhanced at high altitude, a decrease in left ventricular end-diastolic volume (EDV) and altered filling patterns of both ventricles has been observed. The reduction in ventricular filling will undoubtedly affect SV, and four potential mechanisms have been proposed to explain the reduction in left ventricular filling. In this article, both historical and recent reports of systolic function at high altitude will be reviewed, and evidence supporting and refuting each of the four mechanisms underpinning reduced left ventricular filling will be discussed. PMID:26325452

  12. Near Surface Seismic Reflection Imaging: Great Potential Under Critical Eye

    NASA Astrophysics Data System (ADS)

    Miller, R. D.; Peterie, S.; Judy, B. E.

    2014-12-01

    Seismic-reflection imaging has long been a mainstay in the oil and gas exploration community with mind boggling advancements in just the last decade, but its application to engineering, environmental, and groundwater problems has not seen the same level of utilization. A great deal of the problem lies in the many assumptions that are valid for deep exploration that are violated in the very complex near surface. Large channel systems with acquisition geometries conducive for both deep and shallow targets are many times assumed to be capable of extending the imaging depth window. In reality, constraints of the source and sensor/recording systems must be considered, where large powerful sources are needed to image exploration depths while low-energy, high-frequency sources are required for the shallow and thin targets in the near surface. Attempts to make one size fit all will result in artifacts that result in bogus images and characterizations in the shallow subsurface.Narrow optimum offsets, highly attenuative materials, extreme velocity variability, wavefield interference, and low signal-to-noise ratios provide an ideal breeding ground for the generation of artifacts on near-surface seismic-reflection data. With the cost of shallow reflection data being so high relative to other geophysical methods and invasive sampling, sometimes a single failure can hinder the growth in the use of the method. The method is extremely powerful and has the potential to provide vast quantities of information critical to understand the distributed hydrogeological and biogeochemical processes that elude borehole investigations. It is imperative that data be acquired in its rawest possible form and be processed with an eye to each operation. Cost savings sometimes result in one-size-fits-all acquisition and automated processing flows. Attention to detail and following signal from origination to characterization is essential.

  13. Epigenetic mechanisms underlying learning and the inheritance of learned behaviors

    PubMed Central

    Klengel, Torsten; Ressler, Kerry J

    2014-01-01

    Gene expression and regulation is an important sculptor of the behavior of organisms. Epigenetic mechanisms regulate gene expression not by altering the genetic alphabet but rather by the addition of chemical modifications to proteins associated with the alphabet or of methyl marks to the alphabet itself. Being dynamic, epigenetic mechanisms of gene regulation serve as an important bridge between environmental stimuli and genotype. In this review, we outline epigenetic mechanisms by which gene expression is regulated in animals and humans. Using fear learning as a framework, we then delineate how such mechanisms underlie learning and stress responsiveness. Finally, we discuss how epigenetic mechanisms might inform us about the transgenerational inheritance of behavioral traits that are being increasingly reported. PMID:25544352

  14. Deciphering the underlying mechanisms of Diesun Miaofang in traumatic injury from a systems pharmacology perspective

    PubMed Central

    ZHENG, CHUN-SONG; FU, CHANG-LONG; PAN, CAI-BIN; BAO, HONG-JUAN; CHEN, XING-QIANG; YE, HONG-ZHI; YE, JIN-XIA; WU, GUANG-WEN; LI, XI-HAI; XU, HUI-FENG; XU, XIAO-JIE; LIU, XIAN-XIANG

    2015-01-01

    Diesun Miaofang (DSMF) is a traditional herbal formula, which has been reported to activate blood, remove stasis, promote qi circulation and relieve pain. DSMF holds a great promise for the treatment of traumatic injury in an integrative and holistic manner. However, its underlying mechanisms remain to be elucidated. In the present study, a systems pharmacology model, which integrated cluster ligands, human intestinal absorption and aqueous solution prediction, chemical space mapping, molecular docking and network pharmacology techniques were used. The compounds from DSMF were diverse in the clusters and chemical space. The majority of the compounds exhibited drug-like properties. A total of 59 compounds were identified to interact with 16 potential targets. In the herb-compound-target network, the majority of compounds acted on only one target; however, a small number of compounds acted on a large number of targets, up to a maximum of 12. The comparison of key topological properties in compound-target networks associated with the above efficacy intuitively demonstrated that potential active compounds possessed diverse functions. These results successfully explained the polypharmcological mechanism underlying the efficiency of DSMF for the treatment of traumatic injury as well as provided insight into potential novel therapeutic strategies for traumatic injury from herbal medicine. PMID:25891262

  15. The third exactly solvable hypergeometric quantum-mechanical potential

    NASA Astrophysics Data System (ADS)

    Ishkhanyan, Artur

    2016-07-01

    We introduce the third independent exactly solvable hypergeometric potential, after the Eckart and the Pöschl-Teller potentials, which is proportional to an energy-independent parameter and has a shape that is independent of this parameter. The general solution of the Schrödinger equation for this potential is written through fundamental solutions each of which presents an irreducible combination of two Gauss hypergeometric functions. The potential is an asymmetric step-barrier with variable height and steepness. Discussing the transmission above such a barrier, we derive a compact formula for the reflection coefficient.

  16. Semiclassical stochastic mechanics for the Coulomb potential with applications to modelling dark matter

    NASA Astrophysics Data System (ADS)

    Neate, Andrew; Truman, Aubrey

    2016-05-01

    Little is known about dark matter particles save that their most important interactions with ordinary matter are gravitational and that, if they exist, they are stable, slow moving and relatively massive. Based on these assumptions, a semiclassical approximation to the Schrödinger equation under the action of a Coulomb potential should be relevant for modelling their behaviour. We investigate the semiclassical limit of the Schrödinger equation for a particle of mass M under a Coulomb potential in the context of Nelson's stochastic mechanics. This is done using a Freidlin-Wentzell asymptotic series expansion in the parameter ɛ = √{ ħ / M } for the Nelson diffusion. It is shown that for wave functions ψ ˜ exp((R + iS)/ɛ2) where R and S are real valued, the ɛ = 0 behaviour is governed by a constrained Hamiltonian system with Hamiltonian Hr and constraint Hi = 0 where the superscripts r and i denote the real and imaginary parts of the Bohr correspondence limit of the quantum mechanical Hamiltonian, independent of Nelson's ideas. Nelson's stochastic mechanics is restored in dealing with the nodal surface singularities and by computing (correct to first order in ɛ) the relevant diffusion process in terms of Jacobi fields thereby revealing Kepler's laws in a new light. The key here is that the constrained Hamiltonian system has just two solutions corresponding to the forward and backward drifts in Nelson's stochastic mechanics. We discuss the application of this theory to modelling dark matter particles under the influence of a large gravitating point mass.

  17. Mechanical response of collagen molecule under hydrostatic compression.

    PubMed

    Saini, Karanvir; Kumar, Navin

    2015-04-01

    Proteins like collagen are the basic building blocks of various body tissues (soft and hard). Collagen molecules find their presence in the skeletal system of the body where they bear mechanical loads from different directions, either individually or along with hydroxy-apatite crystals. Therefore, it is very important to understand the mechanical behavior of the collagen molecule which is subjected to multi-axial state of loading. The estimation of strains of collagen molecule along different directions resulting from the changes in hydrostatic pressure magnitude, can provide us new insights into its mechanical behavior. In the present work, full atomistic simulations have been used to study global (volumetric) as well as local (along different directions) mechanical properties of the hydrated collagen molecule which is subjected to different hydrostatic pressure magnitudes. To estimate the local mechanical properties, the strains of collagen molecule along its longitudinal and transverse directions have been acquired at different hydrostatic pressure magnitudes. In spite of non-homogeneous distribution of atoms within the collagen molecule, the calculated values of local mechanical properties have been found to carry the same order of magnitude along the longitudinal and transverse directions. It has been demonstrated that the values of global mechanical properties like compressibility, bulk modulus, etc. as well as local mechanical properties like linear compressibility, linear elastic modulus, etc. are functions of magnitudes of applied hydrostatic pressures. The mechanical characteristics of collagen molecule based on the atomistic model have also been compared with that of the continuum model in the present work. The comparison showed up orthotropic material behavior for the collagen molecule. The information on collagen molecule provided in the present study can be very helpful in designing the future bio-materials. PMID:25687001

  18. Bolted Double-Lap Composite Joints Under Mechanical and Thermal Loading

    NASA Technical Reports Server (NTRS)

    Kradinov, V.; Barut, A.; Madenci, E.; Walker, Sandra P. (Technical Monitor)

    2000-01-01

    This study concerns the determination of the contact stresses and contact region around bolt holes and the bolt load distribution in single- and double-lap joints of composite laminates with arbitrarily located bolts under general mechanical loading conditions and uniform temperature change. The unknown contact stress distribution and contact region between the bolt and laminates and the interaction among the bolts require the bolt load distribution, as well as the contact stresses, to be as part of the solution. The present method is based on the complex potential theory and the variational formulation in order to account for bolt stiffness, bolt-hole clearance, and finite geometry of the composite laminates.

  19. MECHANISMS UNDERLYING SOMATOSENSORY CORTICAL DYNAMICS: II. IN VITRO STUDIES

    EPA Science Inventory

    The response of the sensorimotor cortical slice to repetitive, single site afferent drive is mapped using both evoked potential and metabolic mapping (2DG) methods. ystematic changes (increases or decreases) in the evoked potential occur during repetitive 3-5 Hz stimulation. hese...

  20. Mechanical fatigue performance of PCL-chondroprogenitor constructs after cell culture under bioreactor mechanical stimulus.

    PubMed

    Panadero, Juan Alberto; Sencadas, Vitor; Silva, Sonia C M; Ribeiro, Clarisse; Correia, Vitor; Gama, Francisco M; Gomez Ribelles, José Luis; Lanceros-Mendez, Senentxu

    2016-02-01

    In tissue engineering of cartilage, polymeric scaffolds are implanted in the damaged tissue and subjected to repeated compression loading cycles. The possibility of failure due to mechanical fatigue has not been properly addressed in these scaffolds. Nevertheless, the macroporous scaffold is susceptible to failure after repeated loading-unloading cycles. This is related to inherent discontinuities in the material due to the micropore structure of the macro-pore walls that act as stress concentration points. In this work, chondrogenic precursor cells have been seeded in poly-ε-caprolactone (PCL) scaffolds with fibrin and some were submitted to free swelling culture and others to cyclic loading in a bioreactor. After cell culture, all the samples were analyzed for fatigue behavior under repeated loading-unloading cycles. Moreover, some components of the extracellular matrix (ECM) were identified. No differences were observed between samples undergoing free swelling or bioreactor loading conditions, neither respect to matrix components nor to mechanical performance to fatigue. The ECM did not achieve the desired preponderance of collagen type II over collagen type I which is considered the main characteristic of hyaline cartilage ECM. However, prediction in PCL with ECM constructs was possible up to 600 cycles, an enhanced performance when compared to previous works. PCL after cell culture presents an improved fatigue resistance, despite the fact that the measured elastic modulus at the first cycle was similar to PCL with poly(vinyl alcohol) samples. This finding suggests that fatigue analysis in tissue engineering constructs can provide additional information missed with traditional mechanical measurements. PMID:25772257

  1. Cadmium transfer and detoxification mechanisms in a soil-mulberry-silkworm system: phytoremediation potential.

    PubMed

    Zhou, Lingyun; Zhao, Ye; Wang, Shuifeng

    2015-11-01

    Phytoremediation has been proven to be an environmentally sound alternative for the recovery of contaminated soils, and the economic profit that comes along with the process might stimulate its field use. This study investigated cadmium (Cd) transfer and detoxification mechanisms in a soil-mulberry-silkworm system to estimate the suitability of the mulberry and silkworm as an alternative method for the remediation of Cd-polluted soil; it also explored the underlying mechanisms regulating the trophic transfer of Cd. The results show that both the mulberry and silkworm have high Cd tolerance. The transfer factor suggests that the mulberry has high potential for Cd extraction from polluted soil. The subcellular distribution and chemical forms of Cd in mulberry leaves show that cell wall deposition and vacuolar compartmentalization play important role in Cd tolerance. In the presence of increasing Cd concentrations in silkworm food, detoxification mechanisms (excretion and homeostasis) were activated so that excess Cd was excreted in fecal balls, and metallothionein levels in the mid-gut, the posterior of the silk gland, and the fat body of silkworms were enhanced. And, the Cd concentrations in silk are at a low level, ranging from 0.02 to 0.21 mg kg(-1). Therefore, these mechanisms of detoxification can regulate Cd trophic transfer, and mulberry planting and silkworm breeding has high phytoremediation potential for Cd-contaminated soil. PMID:26169822

  2. Potential mechanisms mediating improved glycemic control after bariatric/metabolic surgery.

    PubMed

    Yamamoto, Hiroshi; Kaida, Sachiko; Yamaguchi, Tsuyoshi; Murata, Satoshi; Tani, Masaji; Tani, Tohru

    2016-03-01

    Conservative medical treatment for morbid obesity generally fails to sustain weight loss. On the other hand, surgical operations, so-called bariatric surgery, have evolved due to their long-term effects. The global increase in the overweight population and the introduction of laparoscopic surgery have resulted in the use of bariatric surgery spreading quickly worldwide in recent years. Recent clinical evidence suggests that bariatric surgery not only reduces body weight, but also improves secondary serious diseases, including type 2 diabetes mellitus, in so-called metabolic surgery. Moreover, several potential mechanisms mediating the improvement in glycemic control after bariatric/metabolic surgery have been proposed based on the animal and human studies. These mechanisms include changes in the levels of gastrointestinal hormones, bacterial flora, bile acids, intestinal gluconeogenesis and gastrointestinal motility as well as adipose tissue and inflammatory mediators after surgery. The mechanisms underlying improved glycemic control are expected to accelerate the promotion of both metabolic and bariatric surgery. This article describes the current status of bariatric surgery worldwide and in Japan, reviews the accumulated data for weight loss and diabetic improvements after surgery and discusses the potential mechanisms mediating improved glycemic control. PMID:25700844

  3. Poroelastic Mechanical Effects of Hemicelluloses on Cellulosic Hydrogels under Compression

    PubMed Central

    Lopez-Sanchez, Patricia; Cersosimo, Julie; Wang, Dongjie; Flanagan, Bernadine; Stokes, Jason R.; Gidley, Michael J.

    2015-01-01

    Hemicelluloses exhibit a range of interactions with cellulose, the mechanical consequences of which in plant cell walls are incompletely understood. We report the mechanical properties of cell wall analogues based on cellulose hydrogels to elucidate the contribution of xyloglucan or arabinoxylan as examples of two hemicelluloses displaying different interactions with cellulose. We subjected the hydrogels to mechanical pressures to emulate the compressive stresses experienced by cell walls in planta. Our results revealed that the presence of either hemicellulose increased the resistance to compression at fast strain rates. However, at slow strain rates, only xyloglucan increased composite strength. This behaviour could be explained considering the microstructure and the flow of water through the composites confirming their poroelastic nature. In contrast, small deformation oscillatory rheology showed that only xyloglucan decreased the elastic moduli. These results provide evidence for contrasting roles of different hemicelluloses in plant cell wall mechanics and man-made cellulose-based composite materials. PMID:25794048

  4. A model for hierarchical patterns under mechanical stresses

    NASA Astrophysics Data System (ADS)

    Corson, F.; Henry, H.; Adda-Bedia, M.

    2010-01-01

    We present a model for mechanically-induced pattern formation in growing biological tissues and discuss its application to the development of leaf venation networks. Drawing an analogy with phase transitions in solids, we use a phase field method to describe the transition between two states of the tissue, e.g. the differentiation of leaf veins, and consider a layered system where mechanical stresses are generated by differential growth. We present analytical and numerical results for one-dimensional systems, showing that a combination of growth and irreversibility gives rise to hierarchical patterns. Two-dimensional simulations suggest that such a mechanism could account for the hierarchical, reticulate structure of leaf venation networks, yet point to the need for a more detailed treatment of the coupling between growth and mechanical stresses.

  5. Triggering Mechanisms of Thermosensitive Nanoparticles Under Hyperthermia Condition.

    PubMed

    Dabbagh, Ali; Abdullah, Basri Johan Jeet; Abdullah, Hadijah; Hamdi, Mohd; Kasim, Noor Hayaty Abu

    2015-08-01

    Nanoparticle-based hyperthermia is an effective therapeutic approach that allows time- and site-specific treatment with minimized off-site effects. The recent advances in materials science have led to design a diversity of thermosensitive nanostructures that exhibit different mechanisms of thermal response to the external stimuli. This article aims to provide an extensive review of the various triggering mechanisms in the nanostructures used as adjuvants to hyperthermia modalities. Understanding the differences between various mechanisms of thermal response in these nanostructures could help researchers in the selection of appropriate materials for each experimental and clinical condition as well as to address the current shortcomings of these mechanisms with improved material design. PMID:26073304

  6. Behavior of cracked cylinders under combined thermal and mechanical loading

    SciTech Connect

    Ignaccolo, S.

    1996-12-01

    Nuclear pressure vessels and pipings can be submitted in their life to severe mechanical and thermal loadings. Engineering methods easy to apply, but sufficiently accurate, are needed to assess the flaws. In the field of non-linear fracture mechanics a lot of work has been achieved for structures submitted to mechanical loadings. But for thermal loadings, and particularly for thermal gradients, only few contributions are available. The authors propose, here, to present the main results of a complete set of finite element computations, conducted in France by CEA, EDF and FRAMATOME, on cracked cylinders submitted to combined mechanical and thermal loads. The interaction between these two types of loads is analyzed in the cases of austenitic and ferritic structures. Moreover, these results are compared to the predictions obtained by simplified engineering methods (R6 procedure, J{sub SA16}, and J{sub EDF} approaches). Their domain of validity is also discussed.

  7. Reaction mechanism underlying the in vitro transformation of thioarsenicals

    SciTech Connect

    Naranmandura, Hua; Suzuki, Noriyuki; Suzuki, Kazuo T.

    2008-09-15

    Thioarsenicals have been paid much attention due to the toxicity of arsenic, since some of them are highly toxic and commonly found in the urine of mammals. We previously reported that thioarsenicals might be produced in red blood cells (RBCs). Here, we further characterized the mechanism underlying the production and metabolism of thioarsenicals in RBCs using {sup 34}S-labeled dimethylmonothioarsinic acid ({sup 34}S-DMMTA{sup V}) and purified rat hemoglobin (Hb) or a rat RBC lysate. {sup 34}S-DMMTA{sup V} did not bind to Hb on incubation with purified rat Hb, remaining in its original form. However, when {sup 34}S-DMMTA{sup V} was incubated with a rat RBC lysate, only arsenic, i.e., not sulfur ({sup 34}S), was detected in a form bound to Hb (As-Hb). In addition, another arsenic product containing sulfur ({sup 34}S) in the molar ratio of {sup 34}S/As = 2 was detected, which was assigned as dimethyldithioarsinic acid (DMDTA{sup V}), suggesting that arsenic does not bind to Hb in the form of {sup 34}S-DMMTA{sup V} but does so in the form of dimethylarsinous acid (DMA{sup III}). Namely, DMMTA{sup V} appeared to be hydrolyzed into dimethylarsinic acid (DMA{sup V}) and H{sup 34}S{sup -}, and the released H{sup 34}S{sup -} reacted with DMMTA{sup V} to produce DMDTA{sup V}. Thus, DMMTA{sup V} was transformed into DMDTA{sup V} and DMA{sup V} (2DMMTA{sup V} - > DMDTA{sup V} + DMA{sup V}), the latter product being reduced to DMA{sup III} in the presence of GSH and bound to Hb. In a separate experiment, {sup 34}S-DMMTA{sup V} was incubated with sulfide (Na{sub 2}S) and GSH. Although DMMTA{sup V} was not transformed into DMDTA{sup V} in the presence of only Na{sub 2}S or GSH, it was transformed into DMDTA{sup V} in the presence of both Na{sub 2}S and GSH. Our results suggest that DMMTA{sup V} is hydrolyzed enzymatically into DMA{sup V} and sulfide, the former being reduced to DMA{sup III} and bound to Hb, and the latter reacting with DMMTA{sup V} to yield DMDTA{sup V}. Thus

  8. Mechanical Behavior of Tissue Simulants and Soft Tissues Under Extreme Loading Conditions

    NASA Astrophysics Data System (ADS)

    Kalcioglu, Zeynep Ilke

    Recent developments in computer-integrated surgery and in tissue-engineered constructs necessitate advances in experimental and analytical techniques in characterizing properties of mechanically compliant materials such as gels and soft tissues, particularly for small sample volumes. One goal of such developments is to quantitatively predict and mimic tissue deformation due to high rate impact events typical of industrial accidents and ballistic insults. This aim requires advances in mechanical characterization to establish tools and design principles for tissue simulant materials that can recapitulate the mechanical responses of hydrated soft tissues under dynamic contact-loading conditions. Given this motivation, this thesis studies the mechanical properties of compliant synthetic materials developed for tissue scaffold applications and of soft tissues, via modifying an established contact based technique for accurate, small scale characterization under fully hydrated conditions, and addresses some of the challenges in the implementation of this method. Two different engineered material systems composed of physically associating block copolymer gels, and chemically crosslinked networks including a solvent are presented as potential tissue simulants for ballistic applications, and compared directly to soft tissues from murine heart and liver. In addition to conventional quasistatic and dynamic bulk mechanical techniques that study macroscale elastic and viscoelastic properties, new methodologies are developed to study the small scale mechanical response of the aforementioned material systems to concentrated impact loading. The resistance to penetration and the energy dissipative constants are quantified in order to compare the deformation of soft tissues and mechanically optimized simulants, and to identify the underlying mechanisms by which the mechanical response of these tissue simulant candidates are modulated. Finally, given that soft tissues are biphasic in

  9. Numerical investigation of pulmonary drug delivery under mechanical ventilation conditions

    NASA Astrophysics Data System (ADS)

    Banerjee, Arindam; van Rhein, Timothy

    2012-11-01

    The effects of mechanical ventilation waveform on fluid flow and particle deposition were studied in a computer model of the human airways. The frequency with which aerosolized drugs are delivered to mechanically ventilated patients demonstrates the importance of understanding the effects of ventilation parameters. This study focuses specifically on the effects of mechanical ventilation waveforms using a computer model of the airways of patient undergoing mechanical ventilation treatment from the endotracheal tube to generation G7. Waveforms were modeled as those commonly used by commercial mechanical ventilators. Turbulence was modeled with LES. User defined particle force models were used to model the drag force with the Cunningham correction factor, the Saffman lift force, and Brownian motion force. The endotracheal tube (ETT) was found to be an important geometric feature, causing a fluid jet towards the right main bronchus, increased turbulence, and a recirculation zone in the right main bronchus. In addition to the enhanced deposition seen at the carinas of the airway bifurcations, enhanced deposition was also seen in the right main bronchus due to impaction and turbulent dispersion resulting from the fluid structures created by the ETT. Authors acknowledge financial support through University of Missouri Research Board Award.

  10. Significant enhancement of photoreactivity of graphitic carbon nitride catalysts under acidic conditions and the underlying H(+)-mediated mechanism.

    PubMed

    Zhang, Xue-Song; Tian, Ke; Hu, Jian-Yang; Jiang, Hong

    2015-12-01

    Graphitic carbon nitride (g-C3N4) is an emerging photocatalyst for organic pollutants degradation owing to its excellent stability and metal-free property. In this study, the photocatalytic activity of acidified g-C3N4 (ag-C3N4) was systematically investigated using rhodamine B (rhB) as a model organic pollutant. The results showed the photoreactivity of ag-C3N4 is significantly enhanced with the decrease of pH values. The apparent rate constant (kapp) of rhB degradation over ag-C3N4 is 11.59×10(-3)min(-1) at pH7.0 and it increases to 103.50×10(-3)min(-1) at pH3.0 under visible light. A series of analyses demonstrate that the photodegradation mechanism is a combination of a H(+)-promoted generation of OH and elevation of the redox potential of conduct band of C3N4. The change of surface properties of C3N4 caused by pH variation also affects the degradation of some zwitterionic compounds by changing the adsorption orientation of pollutants. The revealed mechanism of visible light-C3N4-rhB system is meaningful to broaden the usage of C3N4 to the photodegradation of other organic pollutants. PMID:26172516

  11. Jointless structure and under-actuation mechanism for compact hand exoskeleton.

    PubMed

    In, HyunKi; Cho, Kyu-Jin; Kim, KyuRi; Lee, BumSuk

    2011-01-01

    It is important for a wearable robot to be compact and sufficiently light for use as an assistive device. Since human fingers are arranged in a row in dense space, the concept of traditional wearable robots using a rigid frame and a pin joint result in size and complexity problems. A structure without a conventional pin joint, called a jointless structure, has the potential to be used as a wearable robotic hand because the human skeleton and joint can replace the robot's conventional structure. Another way to reduce the weight of the system is to use under-actuation. Under-actuation enables adaptive grasping with less number of actuators for robotic hands. Differential mechanisms are widely used for multi-finger under-actuation; however, they require additional working space. We propose a design with a jointless structure and a novel under-actuation mechanism to reduce the size and weight of a hand exoskeleton. Using these concepts, we developed a prototype that weighs only 80 grams. To evaluate the prototype, fingertip force and blocked force are measured. Fingertip force is the force that can be applied by the finger of the hand exoskeleton on the object surface. The fingertip force is about 18 N when actuated by a tension force of 35 N from the motor. 18 N is sufficient for simple pinch motion in daily activities. Another factor related to performance of the under-actuation mechanism is blocked force, which is a force required to stop one finger while the other finger keeps on moving. It is measured to be 0.5 N, which is sufficiently small. With these experiments, the feasibility of the new hand exoskeleton has been shown. PMID:22275598

  12. Common mechanism underlies repeated evolution of extreme pollution tolerance

    PubMed Central

    Whitehead, Andrew; Pilcher, Whitney; Champlin, Denise; Nacci, Diane

    2012-01-01

    Human alterations to the environment can exert strong evolutionary pressures, yet contemporary adaptation to human-mediated stressors is rarely documented in wildlife populations. A common-garden experimental design was coupled with comparative transcriptomics to discover evolved mechanisms enabling three populations of killifish resident in urban estuaries to survive normally lethal pollution exposure during development, and to test whether mechanisms are unique or common across populations. We show that killifish populations from these polluted sites have independently converged on a common adaptive mechanism, despite variation in contaminant profiles among sites. These populations are united by a similarly profound desensitization of aryl-hydrocarbon receptor-mediated transcriptional activation, which is associated with extreme tolerance to the lethal effects of toxic dioxin-like pollutants. The rapid, repeated, heritable and convergent nature of evolved tolerance suggests that ancestral killifish populations harboured genotypes that enabled adaptation to twentieth-century industrial pollutants. PMID:21733895

  13. Mechanisms underlying the inhibition of interferon signaling by viruses

    PubMed Central

    Devasthanam, Anand S

    2014-01-01

    A hallmark of the antiviral response is the induction of interferons. First discovered in 1957 by Issac and Lindeman, interferons are noted for their ability to interfere with viral replication. Interferons act via autocrine and paracrine pathways to induce an antiviral state in infected cells and in neighboring cells containing interferon receptors. Interferons are the frontline defenders against viral infection and their primary function is to locally restrict viral propagation. Viruses have evolved mechanisms to escape the host interferon response, thus gaining a replicative advantage in host cells. This review will discuss recent findings on the mechanisms viruses use to evade the host interferon response. This knowledge is important because the treatment of viral infections is a challenge of global proportions and a better understanding of the mechanisms viruses use to persist in the host may uncover valuable insights applicable to the discovery of novel drug targets. PMID:24504013

  14. The maternal brain under stress: Consequences for adaptive peripartum plasticity and its potential functional implications.

    PubMed

    Slattery, David A; Hillerer, Katharina M

    2016-04-01

    The peripartum period represents a time during which all mammalian species undergo substantial physiological and behavioural changes, which prepare the female for the demands of motherhood. In addition to behavioural and physiological alterations, numerous brain regions, such as the medial prefrontal cortex, olfactory bulb, medial amygdala and hippocampus are subject to substantial peripartum-associated neuronal, dendritic and synaptic plasticity. These changes, which are temporally- and spatially-distinct, are strongly influenced by gonadal and adrenal hormones, such as estrogen and cortisol/corticosterone, which undergo dramatic fluctuations across this period. In this review, we describe our current knowledge regarding these plasticity changes and describe how stress affects such normal adaptations. Finally, we discuss the mechanisms potentially underlying these neuronal, dendritic and synaptic changes and their functional relevance for the mother and her offspring. PMID:26828151

  15. Identifying Potential Mechanisms Enabling Acidophily in the Ammonia-Oxidizing Archaeon “Candidatus Nitrosotalea devanaterra”

    PubMed Central

    Sayavedra-Soto, Luis A.; Gallois, Nicolas; Schouten, Stefan; Stein, Lisa Y.; Prosser, James I.; Nicol, Graeme W.

    2016-01-01

    Ammonia oxidation is the first and rate-limiting step in nitrification and is dominated by two distinct groups of microorganisms in soil: ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB). AOA are often more abundant than AOB and dominate activity in acid soils. The mechanism of ammonia oxidation under acidic conditions has been a long-standing paradox. While high rates of ammonia oxidation are frequently measured in acid soils, cultivated ammonia oxidizers grew only at near-neutral pH when grown in standard laboratory culture. Although a number of mechanisms have been demonstrated to enable neutrophilic AOB growth at low pH in the laboratory, these have not been demonstrated in soil, and the recent cultivation of the obligately acidophilic ammonia oxidizer “Candidatus Nitrosotalea devanaterra” provides a more parsimonious explanation for the observed high rates of activity. Analysis of the sequenced genome, transcriptional activity, and lipid content of “Ca. Nitrosotalea devanaterra” reveals that previously proposed mechanisms used by AOB for growth at low pH are not essential for archaeal ammonia oxidation in acidic environments. Instead, the genome indicates that “Ca. Nitrosotalea devanaterra” contains genes encoding both a predicted high-affinity substrate acquisition system and potential pH homeostasis mechanisms absent in neutrophilic AOA. Analysis of mRNA revealed that candidate genes encoding the proposed homeostasis mechanisms were all expressed during acidophilic growth, and lipid profiling by high-performance liquid chromatography–mass spectrometry (HPLC-MS) demonstrated that the membrane lipids of “Ca. Nitrosotalea devanaterra” were not dominated by crenarchaeol, as found in neutrophilic AOA. This study for the first time describes a genome of an obligately acidophilic ammonia oxidizer and identifies potential mechanisms enabling this unique phenotype for future biochemical characterization. PMID:26896134

  16. Identifying Potential Mechanisms Enabling Acidophily in the Ammonia-Oxidizing Archaeon "Candidatus Nitrosotalea devanaterra".

    PubMed

    Lehtovirta-Morley, Laura E; Sayavedra-Soto, Luis A; Gallois, Nicolas; Schouten, Stefan; Stein, Lisa Y; Prosser, James I; Nicol, Graeme W

    2016-05-01

    Ammonia oxidation is the first and rate-limiting step in nitrification and is dominated by two distinct groups of microorganisms in soil: ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB). AOA are often more abundant than AOB and dominate activity in acid soils. The mechanism of ammonia oxidation under acidic conditions has been a long-standing paradox. While high rates of ammonia oxidation are frequently measured in acid soils, cultivated ammonia oxidizers grew only at near-neutral pH when grown in standard laboratory culture. Although a number of mechanisms have been demonstrated to enable neutrophilic AOB growth at low pH in the laboratory, these have not been demonstrated in soil, and the recent cultivation of the obligately acidophilic ammonia oxidizer "Candidatus Nitrosotalea devanaterra" provides a more parsimonious explanation for the observed high rates of activity. Analysis of the sequenced genome, transcriptional activity, and lipid content of "Ca Nitrosotalea devanaterra" reveals that previously proposed mechanisms used by AOB for growth at low pH are not essential for archaeal ammonia oxidation in acidic environments. Instead, the genome indicates that "Ca Nitrosotalea devanaterra" contains genes encoding both a predicted high-affinity substrate acquisition system and potential pH homeostasis mechanisms absent in neutrophilic AOA. Analysis of mRNA revealed that candidate genes encoding the proposed homeostasis mechanisms were all expressed during acidophilic growth, and lipid profiling by high-performance liquid chromatography-mass spectrometry (HPLC-MS) demonstrated that the membrane lipids of "Ca Nitrosotalea devanaterra" were not dominated by crenarchaeol, as found in neutrophilic AOA. This study for the first time describes a genome of an obligately acidophilic ammonia oxidizer and identifies potential mechanisms enabling this unique phenotype for future biochemical characterization. PMID:26896134

  17. Coalescence kinetics under the action of alternative grain growth mechanisms

    SciTech Connect

    Gubanov, P. Yu. Maksimov, I. L.

    2008-01-15

    The coalescence process is considered for the case where the prevailing grain growth mechanism is block-to-block diffusion, during which the motion of atoms in a solution occurs in the form of diffusion flux along the block boundaries. Numerical and analytical investigation of the coalescence kinetics in a homogeneous supersaturated solution is performed with allowance for the finite maximum grain size, and the time evolution of the size distribution function of new-phase grains is theoretically described. Possible transition regimes arising during coalescence at a change in the dominant grain growth mechanism are considered.

  18. Underlying molecular and cellular mechanisms in childhood irritable bowel syndrome.

    PubMed

    Chumpitazi, Bruno P; Shulman, Robert J

    2016-12-01

    Irritable bowel syndrome (IBS) affects a large number of children throughout the world. The symptom expression of IBS is heterogeneous, and several factors which may be interrelated within the IBS biopsychosocial model play a role. These factors include visceral hyperalgesia, intestinal permeability, gut microbiota, psychosocial distress, gut inflammation, bile acids, food intolerance, colonic bacterial fermentation, and genetics. The molecular and cellular mechanisms of these factors are being actively investigated. In this mini-review, we present updates of these mechanisms and, where possible, relate the findings to childhood IBS. Mechanistic elucidation may lead to the identification of biomarkers as well as personalized childhood IBS therapies. PMID:26883355

  19. Tree growth variability under environmental changes - identifying underlying physiological mechanisms by stable C and O isotopes

    NASA Astrophysics Data System (ADS)

    Weigt, Rosemarie; Saurer, Matthias; Siegwolf, Rolf T. W.

    2014-05-01

    Long-term variability of tree growth is a result of changing environmental factors and physiological response mechanisms. Information about these relationships can be retrieved from tree ring width, but also from tree ring isotopes as proxies of photosynthetic rates (13C), stomatal conductance (13C, 18O), and source water (18O) used by the tree. With the interdisciplinary project iTREE, we aim to identify physiological mechanisms by relating time-series of tree ring isotopes from a network of sites to environmental factors, and compare resulting growth reponses with stand surveys and vegetation models. Linking these different scales - from individual trees to site and landscape - will contribute to reduce uncertainties in modeling large-scale variability of forest biomass production under current climate change. At a high altitude site in Switzerland (Loetschental, 2100m asl), ~400 yrs old larch (Larix dedicua) trees showed enhanced tree growth towards the end of the 20th century along with increasing CO2 concentrations and temperature, but also increasing variability between individual trees. At this temperature limited site, both environmental factors seem to act as growth drivers by increasing photosynthesis and cell growth. Because δ18O and δ13C (after correction for atmospheric CO2 increase and 13C decrease) remained rather unchanged over the past ~100 yrs, the stomatal behavior did not change according to the dual isotope model, indicating relatively constant water supply over time. At other sites throughout Central Europe, physiological responses to environmental changes may result in different carbon assimilation or allocation other than stem growth. First data of different sites and species along a temperature gradient in Central Europe show that year-to-year variability of tree ring δ13C and δ18O are positively correlated at most sites indicating pronounced responsiveness of stomatal conductance. A trend of increasing isotopic values across the past

  20. A Hypothesis Regarding the Molecular Mechanism Underlying Dietary Soy-Induced Effects on Seizure Propensity

    PubMed Central

    Westmark, Cara Jean

    2014-01-01

    Numerous neurological disorders including fragile X syndrome, Down syndrome, autism, and Alzheimer’s disease are co-morbid with epilepsy. We have observed elevated seizure propensity in mouse models of these disorders dependent on diet. Specifically, soy-based diets exacerbate audiogenic-induced seizures in juvenile mice. We have also found potential associations between the consumption of soy-based infant formula and seizure incidence, epilepsy comorbidity, and autism diagnostic scores in autistic children by retrospective analyses of medical record data. In total, these data suggest that consumption of high levels of soy protein during postnatal development may affect neuronal excitability. Herein, we present our theory regarding the molecular mechanism underlying soy-induced effects on seizure propensity. We hypothesize that soy phytoestrogens interfere with metabotropic glutamate receptor signaling through an estrogen receptor-dependent mechanism, which results in elevated production of key synaptic proteins and decreased seizure threshold. PMID:25232349

  1. Diagnosing and treating chronic musculoskeletal pain based on the underlying mechanism(s).

    PubMed

    Clauw, Daniel J

    2015-02-01

    Until recently, most clinicians considered chronic pain to be typically due to ongoing peripheral nociceptive input (i.e., damage or inflammation) in the region of the body where the individual is experiencing pain. Clinicians are generally aware of a few types of pain (e.g., headache and phantom limb pain) where chronic pain is not due to such causes, but most do not realize there is not a single chronic pain state where any radiographic, surgical, or pathological description of peripheral nociceptive damage has been reproducibly shown to be related to the presence or severity of pain. The primary reason for this appears to be that both the peripheral and central nervous systems play a critical role in determining which nociceptive input being detected by sensory nerves in the peripheral tissues will lead to the perception of pain in humans. This manuscript reviews some of the latest findings regarding the neural processing of pain, with a special focus on how clinicians can use information gleaned from the history and physical examination to assess which mechanisms are most likely to be responsible for pain in a given individual, and tailors therapy appropriately. A critical construct is that, within any specific diagnostic category (e.g., fibromyalgia (FM), osteoarthritis (OA), and chronic low back pain (CLBP) are specifically reviewed), individual patients may have markedly different peripheral/nociceptive and neural contributions to their pain. Thus, just as low back pain has long been acknowledged to have multiple potential mechanisms, so also is this true of all chronic pain states, wherein some individuals will have pain primarily due to peripheral nociceptive input, whereas in others peripheral (e.g., peripheral sensitization) or central nervous system factors ("central sensitization" or "centralization" of pain via augmented pain processing in spinal and brain) may be playing an equally or even more prominent role in their pain and other symptoms. PMID

  2. Horizontal and Vertical Simon Effect: Different Underlying Mechanisms?

    ERIC Educational Resources Information Center

    Vallesi, A.; Mapelli, D.; Schiff, S.; Amodio, P.; Umilta, C.

    2005-01-01

    Reaction times are usually faster when stimulus and response occur at the same location than when they do not, even if stimulus location is irrelevant to the task (Simon effect). This effect was found with both horizontal and vertical stimulus-response arrangements. The same mechanisms have been proposed to be involved in either case. Here, we…

  3. Mechanical behavior of carpal tunnel subsynovial connective tissue under compression.

    PubMed

    Goetz, Jessica E; Baer, Thomas E

    2011-01-01

    Subsynovial connective tissue (SSCT) is a fluid-permeated loose connective tissue that occupies the majority of the space in the carpal tunnel not occupied by the digital flexor tendons or the median nerve. It is arranged in layers around these more discrete structures, presumably to assist with tendon gliding. As a result of this arrangement, the compressive behavior and the fluid permeability of this tissue may substantially affect the stresses in the median nerve resulting from contact with its neighboring tendons or with the walls of the tunnel itself. These stresses may contribute to damage of the median nerve and the development of carpal tunnel syndrome. In this study, the fluid permeability and the compressive behavior of the SSCT were investigated to better understand the mechanics of this tissue and how it may mediate mechanical insult to the median nerve. A custom experimental apparatus was built to allow simultaneous measurement of tissue compression and fluid flow. Using Darcy's law, the average SSCT fluid permeability was 8.78×10(15) m(4)/Ns. The compressive behavior of the SSCT demonstrated time dependence, with an initial modulus of 395kPa gradually decreasing to a value of 285kPa. These baseline tissue data may serve as a mechanical norm (toward which pathological tissue might be returned, therapeutically) and may serve as essential properties to include in future mechanical models of the carpal tunnel. PMID:22096431

  4. MECHANICAL BEHAVIOR OF CARPAL TUNNEL SUBSYNOVIAL CONNECTIVE TISSUE UNDER COMPRESSION

    PubMed Central

    Goetz, Jessica E; Baer, Thomas E

    2011-01-01

    Subsynovial connective tissue (SSCT) is a fluid-permeated loose connective tissue that occupies the majority of the space in the carpal tunnel not occupied by the digital flexor tendons or the median nerve. It is arranged in layers around these more discrete structures, presumably to assist with tendon gliding. As a result of this arrangement, the compressive behavior and the fluid permeability of this tissue may substantially affect the stresses in the median nerve resulting from contact with its neighboring tendons or with the walls of the tunnel itself. These stresses may contribute to damage of the median nerve and the development of carpal tunnel syndrome. In this study, the fluid permeability and the compressive behavior of the SSCT were investigated to better understand the mechanics of this tissue and how it may mediate mechanical insult to the median nerve. A custom experimental apparatus was built to allow simultaneous measurement of tissue compression and fluid flow. Using Darcy’s law, the average SSCT fluid permeability was 8.78×1015 m4/Ns. The compressive behavior of the SSCT demonstrated time dependence, with an initial modulus of 395kPa gradually decreasing to a value of 285kPa. These baseline tissue data may serve as a mechanical norm (toward which pathological tissue might be returned, therapeutically) and may serve as essential properties to include in future mechanical models of the carpal tunnel. PMID:22096431

  5. Mechanical Solder Characterisation Under High Strain Rate Conditions

    NASA Astrophysics Data System (ADS)

    Meier, Karsten; Roellig, Mike; Wiese, Steffen; Wolter, Klaus-Juergen

    2010-11-01

    Using a setup for high strain rate tensile experiments the mechanical behavior of two lead-free tin based solders is investigated. The first alloy is SnAg1.3Cu0.5Ni. The second alloy has a higher silver content but no addition of Ni. Solder joints are the main electrical, thermal and mechanical interconnection technology on the first and second interconnection level. With the recent rise of 3D packaging technologies many novel interconnection ideas are proposed with innovative or visionary nature. Copper pillar, stud bump, intermetallic (SLID) and even spring like joints are presented in a number of projects. However, soldering will remain one of the important interconnect technologies. Knowing the mechanical properties of solder joints is important for any reliability assessment, especially when it comes to vibration and mechanical shock associated with mobile applications. Taking the ongoing miniaturization and linked changes in solder joint microstructure and mechanical behavior into account the need for experimental work on that issue is not satisfied. The tests are accomplished utilizing miniature bulk specimens to match the microstructure of real solder joints as close as possible. The dogbone shaped bulk specimens have a crucial diameter of 1 mm, which is close to BGA solder joints. Experiments were done in the strain rate range from 20 s-1 to 600 s-1. Solder strengthening has been observed with increased strain rate for both SAC solder alloys. The yield stress increases by about 100% in the investigated strain rate range. The yield level differs strongly. A high speed camera system was used to assist the evaluation process of the stress and strain data. Besides the stress and strain data extracted from the experiment the ultimate fracture strain is determined and the fracture surfaces are evaluated using SEM technique considering rate dependency.

  6. Underlying mechanisms of transient luminous events: a review

    NASA Astrophysics Data System (ADS)

    Surkov, V. V.; Hayakawa, M.

    2012-08-01

    Transient luminous events (TLEs) occasionally observed above a strong thunderstorm system have been the subject of a great deal of research during recent years. The main goal of this review is to introduce readers to recent theories of electrodynamics processes associated with TLEs. We examine the simplest versions of these theories in order to make their physics as transparent as possible. The study is begun with the conventional mechanism for air breakdown at stratospheric and mesospheric altitudes. An electron impact ionization and dissociative attachment to neutrals are discussed. A streamer size and mobility of electrons as a function of altitude in the atmosphere are estimated on the basis of similarity law. An alternative mechanism of air breakdown, runaway electron mechanism, is discussed. In this section we focus on a runaway breakdown field, characteristic length to increase avalanche of runaway electrons and on the role played by fast seed electrons in generation of the runaway breakdown. An effect of thunderclouds charge distribution on initiation of blue jets and gigantic jets is examined. A model in which the blue jet is treated as upward-propagating positive leader with a streamer zone/corona on the top is discussed. Sprite models based on streamer-like mechanism of air breakdown in the presence of atmospheric conductivity are reviewed. To analyze conditions for sprite generation, thunderstorm electric field arising just after positive cloud-to-ground stroke is compared with the thresholds for propagation of positively/negatively charged streamers and with runway breakdown. Our own estimate of tendril's length at the bottom of sprite is obtained to demonstrate that the runaway breakdown can trigger the streamer formation. In conclusion we discuss physical mechanisms of VLF (very low frequency) and ELF (extremely low frequency) phenomena associated with sprites.

  7. Mechanisms underlying nutrient-induced segmentation in isolated guinea pig small intestine.

    PubMed

    Gwynne, R M; Bornstein, J C

    2007-04-01

    Mechanisms underlying nutrient-induced segmentation within the gut are not well understood. We have shown that decanoic acid and some amino acids induce neurally dependent segmentation in guinea pig small intestine in vitro. This study examined the neural mechanisms underlying segmentation in the circular muscle and whether the timing of segmentation contractions also depends on slow waves. Decanoic acid (1 mM) was infused into the lumen of guinea pig duodenum and jejunum. Video imaging was used to monitor intestinal diameter as a function of both longitudinal position and time. Circular muscle electrical activity was recorded by using suction electrodes. Recordings from sites of segmenting contractions showed they are always associated with excitatory junction potentials leading to action potentials. Recordings from sites oral and anal to segmenting contractions revealed inhibitory junction potentials that were time locked to those contractions. Slow waves were never observed underlying segmenting contractions. In paralyzed preparations, intracellular recording revealed that slow-wave frequency was highly consistent at 19.5 (SD 1.4) cycles per minute (c/min) in duodenum and 16.6 (SD 1.1) c/min in jejunum. By contrast, the frequencies of segmenting contractions varied widely (duodenum: 3.6-28.8 c/min, median 10.8 c/min; jejunum: 3.0-27.0 c/min, median 7.8 c/min) and sometimes exceeded slow-wave frequencies for that region. Thus nutrient-induced segmentation contractions in guinea pig small intestine do not depend on slow-wave activity. Rather they result from a neural circuit producing rhythmic localized activity in excitatory motor neurons, while simultaneously activating surrounding inhibitory motor neurons. PMID:17218474

  8. Structural transformation features in titanium crystallite under mechanical loading

    SciTech Connect

    Kryzhevich, Dmitrij S.

    2015-10-27

    The features of defect structure generation and development in titanium crystallites were studied on the basis of molecular dynamics method. Interatomic interaction was described using many-body potentials calculated in the approximation of the embedded atom method. It is shown that local structural changes begin to occur in the crystallite at the achievement of a threshold strain value, which is accompanied by a dramatic decrease of potential energy. The features of the formation of local structural changes, which are precursors of classical stacking faults, were studied.

  9. Mechanical and thermal buckling analysis of rectangular sandwich panels under different edge conditions

    NASA Technical Reports Server (NTRS)

    Ko, William L.

    1994-01-01

    The combined load (mechanical or thermal load) buckling equations were established for orthotropic rectangular sandwich panels under four different edge conditions by using the Rayleigh-Ritz method of minimizing the total potential energy of a structural system. Two-dimensional buckling interaction curves and three-dimensional buckling interaction surfaces were constructed for high-temperature honeycomb-core sandwich panels supported under four different edge conditions. The interaction surfaces provide overall comparison of the panel buckling strengths and the domains of symmetrical and antisymmetrical buckling associated with the different edge conditions. In addition, thermal buckling curves of these sandwich panels are presented. The thermal buckling conditions for the cases with and without thermal moments were found to be identical for the small deformation theory.

  10. Early Damage Mechanisms in Nuclear Grade Graphite under Irradiation

    SciTech Connect

    Eapen, Dr. Jacob; Krishna, Dr Ram; Burchell, Timothy D; Murty, Prof K.L.

    2014-01-01

    Using Raman and X-ray photoelectron spectroscopy,we delineate the bond and defect structures in nuclear block graphite (NBG-18) under neutron and ion irradiation. The strengthening of the defect (D) peak in the Raman spectra under irradiation is attributed to an increase in the topological, sp2-hybridized defects. Using transmission electron microscopy, we provide evidence for prismatic dislocations as well as a number of basal dislocations dissociating into Shockley partials. The non-vanishing D peak in the Raman spectra, together with a generous number of dislocations, even at low irradiation doses, indicates a dislocation-mediated amorphization process in graphite.

  11. Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms

    PubMed Central

    Alcock, Joe; Maley, Carlo C; Aktipis, C Athena

    2014-01-01

    Microbes in the gastrointestinal tract are under selective pressure to manipulate host eating behavior to increase their fitness, sometimes at the expense of host fitness. Microbes may do this through two potential strategies: (i) generating cravings for foods that they specialize on or foods that suppress their competitors, or (ii) inducing dysphoria until we eat foods that enhance their fitness. We review several potential mechanisms for microbial control over eating behavior including microbial influence on reward and satiety pathways, production of toxins that alter mood, changes to receptors including taste receptors, and hijacking of the vagus nerve, the neural axis between the gut and the brain. We also review the evidence for alternative explanations for cravings and unhealthy eating behavior. Because microbiota are easily manipulatable by prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes, altering our microbiota offers a tractable approach to otherwise intractable problems of obesity and unhealthy eating. PMID:25103109

  12. Plant-Microbial Interactions Define Potential Mechanisms of Organic Matter Priming in the Rhizosphere

    NASA Astrophysics Data System (ADS)

    Zhalnina, K.; Cho, H. J.; Hao, Z.; Mansoori, N.; Karaoz, U.; Jenkins, S.; White, R. A., III; Lipton, M. S.; Deng, K.; Zhou, J.; Pett-Ridge, J.; Northen, T.; Firestone, M. K.; Brodie, E.

    2015-12-01

    In the rhizosphere, metabolic processes of plants and microorganisms are closely coupled, and together with soil minerals, their interactions regulate the turnover of soil organic C (SOC). Plants provide readily assimilable metabolites for microorganisms through exudation, and it has been hypothesized that increasing concentrations of exudate C may either stimulate or suppress rates of SOC mineralization (rhizosphere priming). Both positive and negative rhizosphere priming has been widely observed, however the underlying mechanisms remain poorly understood. To begin to identify the molecular mechanisms underlying rhizosphere priming, we isolated a broad range of soil bacteria from a Mediterranean grassland dominated by annual grass. Thirty-nine heterotrophic bacteria were selected for genome sequencing and both rRNA gene analysis and metagenome coverage suggest that these isolates represent naturally abundant strain variants. We analyzed their genomes for potential metabolic traits related to life in the rhizosphere and the decomposition of polymeric SOC. While the two dominant groups, Alphaproteobacteria and Actinobacteria, were enriched in polymer degrading enzymes, Alphaproteobacterial isolates contained greater gene copies of transporters related to amino acid, organic acid and auxin uptake or export, suggesting an enhanced metabolic potential for life in the root zone. To verify this metabolic potential, we determined the enzymatic activities of these isolates and revealed preferences of strains to degrade certain polymers (xylan, cellulose or lignin). Fourier Transform Infrared spectroscopy is being used to determine which polymeric components of plant roots are targeted by specific strains and how exudates may impact their degradation. To verify the potential of isolates to assimilate root exudates and export key metabolites we are using LC-MS/MS based exometabolomic profiling. The traits hypothesized and verified here (transporters, enzymes, exudate uptake

  13. Molecular Mechanism Underlying Lymphatic Metastasis in Pancreatic Cancer

    PubMed Central

    Luo, Guopei; Liu, Chen; Wu, Chuntao; Liu, Liang; Liu, Zuqiang; Ni, Quanxing; Long, Jiang; Yu, Xianjun

    2014-01-01

    As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs) and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer. PMID:24587996

  14. Grained composite materials prepared by combustion synthesis under mechanical pressure

    DOEpatents

    Dunmead, Stephen D.; Holt, Joseph B.; Kingman, Donald D.; Munir, Zuhair A.

    1990-01-01

    Dense, finely grained composite materials comprising one or more ceramic phase or phase and one or more metallic and/or intermetallic phase or phases are produced by combustion synthesis. Spherical ceramic grains are homogeneously dispersed within the matrix. Methods are provided, which include the step of applying mechanical pressure during or immediately after ignition, by which the microstructures in the resulting composites can be controllably selected.

  15. VDAC electronics: 2. A new, anaerobic mechanism of generation of the membrane potentials in mitochondria.

    PubMed

    Lemeshko, Victor V

    2014-07-01

    Mitochondrial hexokinase (HK) and creatine kinase (CK) known to form complexes with a voltage dependent anion channel (VDAC) have been reported to increase cell death resistance under hypoxia/anoxia. In this work we propose a new, non-Mitchell mechanism of generation of the inner and outer membrane potentials at anaerobic conditions. The driving force is provided by the Gibbs free energy of the HK and CK reactions associated with the VDAC-HK and the ANT (adenine nucleotide translocator)-CK-VDAC complexes, respectively, both functioning as voltage generators. In the absence of oxygen, the cytosolic creatine phosphate can be directly used by the ANT-CK-VDAC contact sites to produce ATP from ADP in the mitochondrial matrix. After that, ATP released through the fraction of unbound ANTs in exchange for ADP is used in the mitochondrial intermembrane space by the outer membrane VDAC-HK electrogenic complexes to convert cytosolic glucose into glucose-6-phosphate. A simple computational model based on the application of Ohm's law to an equivalent electrical circuit showed a possibility of generation of the inner membrane potential up to -160mV, under certain conditions, and of relatively high outer membrane potential without wasting of ATP that normally leads to cell death. The calculated membrane potentials depended on the restriction of ATP/ADP diffusion in narrow cristae and through the cristae junctions. We suggest that high inner membrane potential and calcium extrusion from the mitochondrial intermembrane space by generated positive outer membrane potential prevent mitochondrial permeability transition, thus allowing the maintenance of mitochondrial integrity and cell survival in the absence of oxygen. PMID:24565793

  16. Mechanisms defining the electrotonic potential abnormalities in simulated amyotrophic lateral sclerosis.

    PubMed

    Stephanova, D I; Krustev, S M; Negrev, N

    2012-06-01

    Electrotonic potentials allow the accommodative processes to polarizing stimuli to be assessed. Electrotonic potential transients in response to applied polarizing stimuli are caused by the kinetics of underlying axonal conductances. Here, we study these transients using our multi-layered model of the human motor nerve, in three simulated cases of the motor neuron disease amyotrophic lateral sclerosis (ALS): ALS1, ALS2 and ALS3 are three consecutively greater degrees of uniform axonal dysfunctions along the human motor nerve fibre. The results show that the responses in the ALS1 case are quite similar to the normal case. In contrast, in the ALS2 and ALS3 cases, long-lasting (100 ms) subthreshold depolarizing stimuli activate the classical "transient" Na(+) channels in the nodal and in the internodal axolemma beneath the myelin sheath; this leads to action potential generation during the early parts of the electrotonic responses in all compartments along the fibre length. The results also show that the electrotonic potentials in response to long-lasting (100 ms) subthreshold hyperpolarizing stimuli in the ALS1 and ALS2 cases are quiet similar to those of the normal case. However, the current kinetics in the ALS3 case differs from the normal case after the termination of the long-lasting hyperpolarizing stimuli. In the most abnormal ALS3 case, the activation of the Na(+) channels in the nodal and in the internodal axolemma leads to repetitive action potential generation in the late parts (100-200 ms) of the hyperpolarizing electrotonic responses. The results show that the repetitive firing, due to the progressively increased nodal and internodal ion channel dysfunction, are consistent with the loss of functional potassium channels involving both the fast and the slow potassium channel types. The results confirm that the electrotonic potentials in the three simulated ALS cases are specific indicators for the motor neuron disease ALS. The mechanisms underlying the

  17. Photooxidation of tetrahydrobiopterin under UV irradiation: possible pathways and mechanisms.

    PubMed

    Buglak, Andrey A; Telegina, Taisiya A; Lyudnikova, Tamara A; Vechtomova, Yulia L; Kritsky, Mikhail S

    2014-01-01

    Tetrahydrobiopterin (H4 Bip) is a cofactor for several key enzymes, including NO synthases and aromatic amino acid hydroxylases (AAHs). Normal functioning of the H4 Bip regeneration cycle is extremely important for the work of AAHs. Oxidized pterins may accumulate if the H4 Bip regeneration cycle is disrupted or if H4 Bip autoxidation occurs. These oxidized pterins can photosensitize the production of singlet molecular oxygen (1)O2 and thus cause oxidative stress. In this context, we studied the photooxidation of H4 Bip in phosphate buffer at pH 7.2. We found that UV irradiation of H4 Bip affected its oxidation rate (quantum yield Φ300 = (2.7 ± 0.4) × 10(-3)). The effect of UV irradiation at λ = 350 nm on H4 Bip oxidation was stronger, especially in the presence of biopterin (Bip) (Φ350 = (9.7 ± 1.5) × 10(-3)). We showed that the rate of H4 Bip oxidation linearly depends on Bip concentration. Experiments with KI, a selective quencher of triplet pterins at micromolar concentrations, demonstrated that the oxidation is sensitized by the triplet state biopterin (3) Bip. Apparently, electron transfer sensitization (Type-I mechanism) is dominant. Energy transfer (Type-II mechanism) and singlet oxygen generation play only a secondary role. The mechanisms of H4 Bip photooxidation and their biological meaning are discussed. PMID:24773158

  18. Music and literature: are there shared empathy and predictive mechanisms underlying their affective impact?

    PubMed Central

    Omigie, Diana

    2015-01-01

    It has been suggested that music and language had a shared evolutionary precursor before becoming mainly responsible for the communication of emotive and referential meaning respectively. However, emphasis on potential differences between music and language may discourage a consideration of the commonalities that music and literature share. Indeed, one possibility is that common mechanisms underlie their affective impact, and the current paper carefully reviews relevant neuroscientific findings to examine such a prospect. First and foremost, it will be demonstrated that considerable evidence of a common role of empathy and predictive processes now exists for the two domains. However, it will also be noted that an important open question remains: namely, whether the mechanisms underlying the subjective experience of uncertainty differ between the two domains with respect to recruitment of phylogenetically ancient emotion areas. It will be concluded that a comparative approach may not only help to reveal general mechanisms underlying our responses to music and literature, but may also help us better understand any idiosyncrasies in their capacity for affective impact. PMID:26379583

  19. Anti-tumor effect of β-glucan from Lentinus edodes and the underlying mechanism.

    PubMed

    Xu, Hui; Zou, Siwei; Xu, Xiaojuan; Zhang, Lina

    2016-01-01

    β-Glucans are well known for its various bioactivities, but the underlying mechanism has not been fully understood. This study focuses on the anti-tumor effect and the potential mechanism of a branched β-(1, 3)-glucan (LNT) extracted from Lentinus edodes. The in vivo data indicated that LNT showed a profound inhibition ratio of ~75% against S-180 tumor growth, even significantly higher than the positive control of Cytoxan (~54%). Interestingly, LNT sharply promoted immune cells accumulation into tumors accompanied by cell apoptosis and inhibition of cell proliferation during tumor development. Furthermore, LNT not only up-regulated expressions of the tumor suppressor p53, cell cycle arrestin p21 and pro-apoptotic proteins of Bax and caspase 3/9, but also down-regulated PARP1 and anti-apoptotic protein Bcl-2 expressions in tumor tissues. It was first found that LNT initiated p53-dependent signaling pathway to suppress cell proliferation in vitro, and the caspase-dependent pathway to induce cell apoptosis in vivo. The underlying anti-tumor mechanism was proposed that LNT activated immune responses to induce cell apoptosis through caspase 3-dependent signaling pathway and to inhibit cell proliferation possibly via p53-dependent signaling pathway in vivo. Besides, LNT inhibited angiogenesis by suppressing VEGF expression, leading to slow progression of tumors. PMID:27353254

  20. Anti-tumor effect of β-glucan from Lentinus edodes and the underlying mechanism

    PubMed Central

    Xu, Hui; Zou, Siwei; Xu, Xiaojuan; Zhang, Lina

    2016-01-01

    β-Glucans are well known for its various bioactivities, but the underlying mechanism has not been fully understood. This study focuses on the anti-tumor effect and the potential mechanism of a branched β-(1, 3)-glucan (LNT) extracted from Lentinus edodes. The in vivo data indicated that LNT showed a profound inhibition ratio of ~75% against S-180 tumor growth, even significantly higher than the positive control of Cytoxan (~54%). Interestingly, LNT sharply promoted immune cells accumulation into tumors accompanied by cell apoptosis and inhibition of cell proliferation during tumor development. Furthermore, LNT not only up-regulated expressions of the tumor suppressor p53, cell cycle arrestin p21 and pro-apoptotic proteins of Bax and caspase 3/9, but also down-regulated PARP1 and anti-apoptotic protein Bcl-2 expressions in tumor tissues. It was first found that LNT initiated p53-dependent signaling pathway to suppress cell proliferation in vitro, and the caspase-dependent pathway to induce cell apoptosis in vivo. The underlying anti-tumor mechanism was proposed that LNT activated immune responses to induce cell apoptosis through caspase 3-dependent signaling pathway and to inhibit cell proliferation possibly via p53-dependent signaling pathway in vivo. Besides, LNT inhibited angiogenesis by suppressing VEGF expression, leading to slow progression of tumors. PMID:27353254

  1. Potential Role of Epigenetic Mechanisms in the Regulation of Drug Metabolism and Transport

    PubMed Central

    Ingelman-Sundberg, Magnus; Zhong, Xiao-Bo; Hankinson, Oliver; Beedanagari, Sudheer; Yu, Ai-Ming; Peng, Lai

    2013-01-01

    This is a report of a symposium on the potential role of epigenetic mechanisms in the control of drug disposition sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2013 meeting in Boston, MA, April 21, 2013. Epigenetics is a rapidly evolving area, and recent studies have revealed that expression of drug-metabolizing enzymes and transporters is regulated by epigenetic factors, including histone modification, DNA methylation, and noncoding RNAs. The symposium speakers provided an overview of genetic and epigenetic mechanisms underlying variable drug metabolism and drug response, as well as the implications for personalized medicine. Considerable insight into the epigenetic mechanisms in differential regulation of the dioxin-inducible drug and carcinogen-metabolizing enzymes CYP1A1 and 1B1 was provided. The role of noncoding microRNAs in the control of drug metabolism and disposition through targeting of cytochrome P450 (P450) enzymes and ATP-binding cassette membrane transporters was discussed. In addition, potential effects of xenobiotics on chromatin interactions and epigenomics, as well as the possible role of long noncoding RNAs in regulation of P450s during liver maturation were presented. PMID:23918665

  2. Molecular Mechanisms and Potential Clinical Applications of Campylobacter jejuni Cytolethal Distending Toxin

    PubMed Central

    Lai, Cheng-Kuo; Chen, Yu-An; Lin, Chun-Jung; Lin, Hwai-Jeng; Kao, Min-Chuan; Huang, Mei-Zi; Lin, Yu-Hsin; Chiang-Ni, Chuan; Chen, Chih-Jung; Lo, U-Ging; Lin, Li-Chiung; Lin, Ho; Hsieh, Jer-Tsong; Lai, Chih-Ho

    2016-01-01

    Cytolethal distending toxin (CDT), a genotoxin produced by Campylobacter jejuni, is composed of three subunits: CdtA, CdtB, and CdtC. CdtB is a DNase that causes DNA double-strand breaks (DSB) in the nucleus resulting in cell cycle arrest at the G2/M stage and apoptosis. CdtA and CdtC bind to cholesterol-rich microdomains on the cytoplasmic membrane, a process required for the delivery of CdtB to cells. Although a unique motif associated with cholesterol-binding activity has been identified in other pathogens, the mechanism underlying the interaction between the CdtA and CdtC subunits and membrane cholesterol remains unclear. Also, the processes of cell uptake and delivery of CdtB in host cells and the translocation of CdtB into the nucleus are only partially understood. In this review, we focus on the underlying relationship among CDT, membrane cholesterol, and the intracellular trafficking pathway as a unique mechanism for C. jejuni-induced pathogenesis. Moreover, we discuss the clinical aspects of a possible therapeutic application of CDT in cancer therapy. Understanding the molecular mechanism of CDT-host interactions may provide insights into novel strategies to control C. jejuni infection and the development of potential clinical applications of CDT. PMID:26904508

  3. Investigations of Mechanisms Associated with Nucleate Boiling Under Microgravity Conditions

    NASA Technical Reports Server (NTRS)

    Dhir, Vijay K.; Hasan, M.; Chao, David (Technical Monitor)

    2003-01-01

    In this work a building block type of approach is used so that a basic understanding of the processes that contribute to nucleate boiling heat fluxes under microgravity conditions can be developed. This understanding will lead to development of a mechanistic model for nucleate boiling heat transfer which could eventually be used as a design tool in space applications. Task Description Task 1: Fabrication of the Experimental Setup. Under this task, the test section and liquid holding and viewing chambers will be fabricated. Artificial cylinder cavities will be formed on silicon wafers. A single cavity and two or four cavities, with a prescribed spacing and size, will be formed. The desired nucleation wall superheat will be used to determine the size of the mouth of the cavities. Task 2: Experiments. The basic experiments for flow and temperature field around single and multiple (2 or 4 separated or merged bubbles growing on downward facing or inclined surfaces) will be carried out under normal gravity conditions. The experiments will be conducted at one atmosphere pressure, but liquid subcooling will be varied from 0 to 30C. Water and PF-5050 will be used as test liquids. Task 3: Analytical/Numerical Models. In this task, transient temperature and flow field in vapor and liquid will be determined during growth of a single bubble. Analysis will include the evolution of the vapor-liquid interface and development of microlayer underneath the bubbles. For merged bubbles, detailed calculations of flow and temperature field will be carried out for transient shapes of vapor stems supporting a large bubble and the corresponding evaporation rate. Flow and temperature field for a bubble sliding along a heated wall will also be determined. Microgravity conditions will be simulated and a framework of a numerical tool for prediction of nucleate boiling heat fluxes under microgravity conditions will be developed. Task 4: Experiments in a KC-135. To understand bubble growth and

  4. Optimum design of bolted composite lap joints under mechanical and thermal loading

    NASA Astrophysics Data System (ADS)

    Kradinov, Vladimir Yurievich

    A new approach is developed for the analysis and design of mechanically fastened composite lap joints under mechanical and thermal loading. Based on the combined complex potential and variational formulation, the solution method satisfies the equilibrium equations exactly while the boundary conditions are satisfied by minimizing the total potential. This approach is capable of modeling finite laminate planform dimensions, uniform and variable laminate thickness, laminate lay-up, interaction among bolts, bolt torque, bolt flexibility, bolt size, bolt-hole clearance and interference, insert dimensions and insert material properties. Comparing to the finite element analysis, the robustness of the method does not decrease when modeling the interaction of many bolts; also, the method is more suitable for parametric study and design optimization. The Genetic Algorithm (GA), a powerful optimization technique for multiple extrema functions in multiple dimensions search spaces, is applied in conjunction with the complex potential and variational formulation to achieve optimum designs of bolted composite lap joints. The objective of the optimization is to acquire such a design that ensures the highest strength of the joint. The fitness function for the GA optimization is based on the average stress failure criterion predicting net-section, shear-out, and bearing failure modes in bolted lap joints. The criterion accounts for the stress distribution in the thickness direction at the bolt location by applying an approach utilizing a beam on an elastic foundation formulation.

  5. Salicylic acid-induced abiotic stress tolerance and underlying mechanisms in plants

    PubMed Central

    Khan, M. Iqbal R.; Fatma, Mehar; Per, Tasir S.; Anjum, Naser A.; Khan, Nafees A.

    2015-01-01

    Abiotic stresses (such as metals/metalloids, salinity, ozone, UV-B radiation, extreme temperatures, and drought) are among the most challenging threats to agricultural system and economic yield of crop plants. These stresses (in isolation and/or combination) induce numerous adverse effects in plants, impair biochemical/physiological and molecular processes, and eventually cause severe reductions in plant growth, development and overall productivity. Phytohormones have been recognized as a strong tool for sustainably alleviating adverse effects of abiotic stresses in crop plants. In particular, the significance of salicylic acid (SA) has been increasingly recognized in improved plant abiotic stress-tolerance via SA-mediated control of major plant-metabolic processes. However, the basic biochemical/physiological and molecular mechanisms that potentially underpin SA-induced plant-tolerance to major abiotic stresses remain least discussed. Based on recent reports, this paper: (a) overviews historical background and biosynthesis of SA under both optimal and stressful environments in plants; (b) critically appraises the role of SA in plants exposed to major abiotic stresses; (c) cross-talks potential mechanisms potentially governing SA-induced plant abiotic stress-tolerance; and finally (d) briefly highlights major aspects so far unexplored in the current context. PMID:26175738

  6. Neural mechanisms underlying auditory feedback control of speech

    PubMed Central

    Reilly, Kevin J.; Guenther, Frank H.

    2013-01-01

    The neural substrates underlying auditory feedback control of speech were investigated using a combination of functional magnetic resonance imaging (fMRI) and computational modeling. Neural responses were measured while subjects spoke monosyllabic words under two conditions: (i) normal auditory feedback of their speech, and (ii) auditory feedback in which the first formant frequency of their speech was unexpectedly shifted in real time. Acoustic measurements showed compensation to the shift within approximately 135 ms of onset. Neuroimaging revealed increased activity in bilateral superior temporal cortex during shifted feedback, indicative of neurons coding mismatches between expected and actual auditory signals, as well as right prefrontal and Rolandic cortical activity. Structural equation modeling revealed increased influence of bilateral auditory cortical areas on right frontal areas during shifted speech, indicating that projections from auditory error cells in posterior superior temporal cortex to motor correction cells in right frontal cortex mediate auditory feedback control of speech. PMID:18035557

  7. Mechanical response of unidirectional boron/aluminum under combined loading

    NASA Technical Reports Server (NTRS)

    Becker, Wolfgang; Pindera, Marek-Jerzy; Herakovich, Carl T.

    1987-01-01

    Three test methods were employed to characterize the response of unidirectional Boron/Aluminum metal matrix composite material under monotonic and cyclic loading conditions, namely, losipescu shear, off-axis tension and compression. The characterization of the elastic and plastic response includes the elastic material properties, yielding and subsequent hardening of the unidirectional composite under different stress ratios in the material principal coordinate system. Yield loci generated for different stress ratios are compared for the three different test methods, taking into account residual stresses and specimen geometry. Subsequently, the yield locus for in-plane shear is compared with the prediction of an analytical, micromechanical model. The influence of the scatter in the experimental data on the predicted yield surface is also analyzed. Lastly, the experimental material strengths in tension and compression are correlated with the maximum stress and the Tsai-Wu failure criterion.

  8. Simultaneous mechanical stiffness and electrical potential measurements of living vascular endothelial cells using combined atomic force and epifluorescence microscopy

    NASA Astrophysics Data System (ADS)

    Callies, Chiara; Schön, Peter; Liashkovich, Ivan; Stock, Christian; Kusche-Vihrog, Kristina; Fels, Johannes; Sträter, Alexandra S.; Oberleithner, Hans

    2009-04-01

    The degree of mechanical stiffness of vascular endothelial cells determines the endogenous production of the vasodilating gas nitric oxide (NO). However, the underlying mechanisms are not yet understood. Experiments on vascular endothelial cells suggest that the electrical plasma membrane potential is involved in this regulatory process. To test this hypothesis we developed a technique that simultaneously measures the electrical membrane potential and stiffness of vascular endothelial cells (GM7373 cell line derived from bovine aortic endothelium) under continuous perfusion with physiological electrolyte solution. The cellular stiffness was determined by nano-indentation using an atomic force microscope (AFM) while the electrical membrane potential was measured with bis-oxonol, a voltage-reporting fluorescent dye. These two methods were combined using an AFM attached to an epifluorescence microscope. The electrical membrane potential and mechanical stiffness of the same cell were continuously recorded for a time span of 5 min. Fast fluctuations (in the range of seconds) of both the electrical membrane potential and mechanical stiffness could be observed that were not related to each other. In contrast, slow cell depolarizations (in the range of minutes) were paralleled by significant increases in mechanical stiffness. In conclusion, using the combined AFM-fluorescence technique we monitored for the first time simultaneously the electrical plasma membrane potential and mechanical stiffness in a living cell. Vascular endothelial cells exhibit oscillatory non-synchronized waves of electrical potential and mechanical stiffness. The sustained membrane depolarization, however, is paralleled by a concomitant increase of cell stiffness. The described method is applicable for any fluorophore, which opens new perspectives in biomedical research.

  9. (Metabolic mechanisms of plant growth at low-water potentials)

    SciTech Connect

    Boyer, J.S.

    1989-01-01

    For the year 1989, the progress made on this DOE sponsored research will be described by considering the questions presented in the original proposal and describing the work on each one. We used soybean seedlings grown in vermiculite in a dark, humid environment because they are convenient to grow, undergo most of the physiological changes induced by low water potentials in large plants, and have exposed growing regions on which molecular experiments can be done.

  10. Chemical and Mechanical Alteration of Fractured Caprock Under Reactive Flow

    NASA Astrophysics Data System (ADS)

    Elkhoury, J. E.; Ameli, P.; Detwiler, R. L.

    2013-12-01

    Permeability evolution of fractures depends on chemical and mechanical processes. Stress perturbations lead to mechanical deformation and fracture propagation that can increase formation permeability. Chemical disequilibrium between fluids and resident minerals leads to dissolution and precipitation that further alter fracture porosity and permeability. The ability to predict whether these coupled chemical and mechanical processes will enhance or diminish fracture permeability remains elusive. Here, we present results from reactive-transport experiments in fractured anhydrite cores, with significant alteration of the rock matrix, where only the flow rate differed. For high flow rate, the transformation of anhydrite to gypsum occurred uniformly within the fracture leading to compaction and a two-order-of-magnitude decrease in permeability. For low flow rate, rock-fluid reactions proceeded to near equilibrium within the fracture with preferential flow paths persisting over the 6-month duration of the experiment and a negligible change in permeability. Anticipating such permeability evolution is critical for successful geologic CO2 sequestration and waste injection. Additionally, reactive alteration of the porous matrix bounding fractures will influence the strength of earthquake fault zones. Comparison of the aperture field before (a) and after (b) the reactive flow-through experiment at low flow rate. a) Aperture field from optical profilometry measurements of the fracture surfaces. b) Inferred aperture from x-ray computed tomography scans. Color scale I (blue) denotes mainly unaltered regions of the fracture and/or aperture < 200 μm. Color scale II (green/yellow) denotes reacted regions of the fracture surfaces and the matrix adjacent to the fracture. Persistent flow paths are clearly observed in panel (b) (color scale III corresponds to aperture > 200 μm) leading to negligible change in permeability after a 6-month run.

  11. Electronic, mechanical and dielectric properties of silicane under tensile strain

    SciTech Connect

    Jamdagni, Pooja Sharma, Munish; Ahluwalia, P. K.; Kumar, Ashok; Thakur, Anil

    2015-05-15

    The electronic, mechanical and dielectric properties of fully hydrogenated silicene i.e. silicane in stable configuration are studied by means of density functional theory based calculations. The band gap of silicane monolayer can be flexibly reduced to zero when subjected to bi-axial tensile strain, leading to semi-conducting to metallic transition, whereas the static dielectric constant for in-plane polarization increases monotonically with increasing strain. Also the EEL function show the red shift in resonance peak with tensile strain. Our results offer useful insight for the application of silicane monolayer in nano-optical and electronics devices.

  12. Cellular mechanisms underlying growth asymmetry during stem gravitropism

    NASA Technical Reports Server (NTRS)

    Cosgrove, D. J.

    1997-01-01

    Plant stems respond to gravitropic stimulation with a rapid, local and reversible change in cell growth rate (elongation), generally on both the upper and lower sides of the stem. The cellular and biochemical mechanisms for this differential growth are reviewed. Considerable evidence implicates an asymmetry in wall pH in the growth response. The strengths and weaknesses of the wall "loosening enzyme" concept are reviewed and the possibility of expansin involvement in the bending response of stems is considered. Also discussed is the possibility that wall stiffening processes, e.g. phenolic coupling driven by oxidative bursts or altered orientation of newly deposited cellulose, might mediate the growth responses during gravitropism.

  13. Electronic, mechanical and dielectric properties of silicane under tensile strain

    NASA Astrophysics Data System (ADS)

    Jamdagni, Pooja; Kumar, Ashok; Sharma, Munish; Thakur, Anil; Ahluwalia, P. K.

    2015-05-01

    The electronic, mechanical and dielectric properties of fully hydrogenated silicene i.e. silicane in stable configuration are studied by means of density functional theory based calculations. The band gap of silicane monolayer can be flexibly reduced to zero when subjected to bi-axial tensile strain, leading to semi-conducting to metallic transition, whereas the static dielectric constant for in-plane polarization increases monotonically with increasing strain. Also the EEL function show the red shift in resonance peak with tensile strain. Our results offer useful insight for the application of silicane monolayer in nano-optical and electronics devices.

  14. Molecular mechanisms underlying the exceptional adaptations of batoid fins

    PubMed Central

    Nakamura, Tetsuya; Klomp, Jeff; Pieretti, Joyce; Schneider, Igor; Gehrke, Andrew R.; Shubin, Neil H.

    2015-01-01

    Extreme novelties in the shape and size of paired fins are exemplified by extinct and extant cartilaginous and bony fishes. Pectoral fins of skates and rays, such as the little skate (Batoid, Leucoraja erinacea), show a strikingly unique morphology where the pectoral fin extends anteriorly to ultimately fuse with the head. This results in a morphology that essentially surrounds the body and is associated with the evolution of novel swimming mechanisms in the group. In an approach that extends from RNA sequencing to in situ hybridization to functional assays, we show that anterior and posterior portions of the pectoral fin have different genetic underpinnings: canonical genes of appendage development control posterior fin development via an apical ectodermal ridge (AER), whereas an alternative Homeobox (Hox)–Fibroblast growth factor (Fgf)–Wingless type MMTV integration site family (Wnt) genetic module in the anterior region creates an AER-like structure that drives anterior fin expansion. Finally, we show that GLI family zinc finger 3 (Gli3), which is an anterior repressor of tetrapod digits, is expressed in the posterior half of the pectoral fin of skate, shark, and zebrafish but in the anterior side of the pelvic fin. Taken together, these data point to both highly derived and deeply ancestral patterns of gene expression in skate pectoral fins, shedding light on the molecular mechanisms behind the evolution of novel fin morphologies. PMID:26644578

  15. Molecular mechanisms underlying the exceptional adaptations of batoid fins.

    PubMed

    Nakamura, Tetsuya; Klomp, Jeff; Pieretti, Joyce; Schneider, Igor; Gehrke, Andrew R; Shubin, Neil H

    2015-12-29

    Extreme novelties in the shape and size of paired fins are exemplified by extinct and extant cartilaginous and bony fishes. Pectoral fins of skates and rays, such as the little skate (Batoid, Leucoraja erinacea), show a strikingly unique morphology where the pectoral fin extends anteriorly to ultimately fuse with the head. This results in a morphology that essentially surrounds the body and is associated with the evolution of novel swimming mechanisms in the group. In an approach that extends from RNA sequencing to in situ hybridization to functional assays, we show that anterior and posterior portions of the pectoral fin have different genetic underpinnings: canonical genes of appendage development control posterior fin development via an apical ectodermal ridge (AER), whereas an alternative Homeobox (Hox)-Fibroblast growth factor (Fgf)-Wingless type MMTV integration site family (Wnt) genetic module in the anterior region creates an AER-like structure that drives anterior fin expansion. Finally, we show that GLI family zinc finger 3 (Gli3), which is an anterior repressor of tetrapod digits, is expressed in the posterior half of the pectoral fin of skate, shark, and zebrafish but in the anterior side of the pelvic fin. Taken together, these data point to both highly derived and deeply ancestral patterns of gene expression in skate pectoral fins, shedding light on the molecular mechanisms behind the evolution of novel fin morphologies. PMID:26644578

  16. Analysis of thermal conductivity of polymeric nanocomposites under mechanical loading

    NASA Astrophysics Data System (ADS)

    Yu, Suyoung; Yang, Seunghwa; Cho, Maenghyo

    2013-12-01

    When the plastic deformation is applied to neat polymer, the polymer chains are aligned and the thermal conductivity of neat polymer increases linearly along the loading direction. However, the thermal conductivity change of nanocomposites consisting of polymer matrix and nanofillers during plastic deformation is not simple. The volume fraction and size of nanofillers scarcely affect the structural change of polymer chains during the plastic deformation. In this study, the structural change of polymeric materials according to the mechanical loading and its effect on the thermal transport properties are investigated through a molecular dynamics simulation. To investigate the effects of nanofiller, its volume fraction, and size on the thermal transport properties, the unit cells of neat amorphous nylon 6 and nanocomposites consisting of amorphous nylon 6 matrix and spherical silica particles are prepared. The molecular unit cells are uniaxially stretched by applying constant strain along the loading directions. Then, non-equilibrium molecular dynamics (NEMD) simulations are performed to estimate the thermal conductivities during plastic deformation. The alignment of polymer chains is analyzed by tracing the orientation correlation function of each polymer molecule and the free volume change during the mechanical loading is also analyzed.

  17. Mechanisms Underlying Carotenoid Absorption in Oxygenic Photosynthetic Proteins*

    PubMed Central

    Mendes-Pinto, Maria M.; Galzerano, Denise; Telfer, Alison; Pascal, Andrew A.; Robert, Bruno; Ilioaia, Cristian

    2013-01-01

    The electronic properties of carotenoid molecules underlie their multiple functions throughout biology, and tuning of these properties by their in vivo locus is of vital importance in a number of cases. This is exemplified by photosynthetic carotenoids, which perform both light-harvesting and photoprotective roles essential to the photosynthetic process. However, despite a large number of scientific studies performed in this field, the mechanism(s) used to modulate the electronic properties of carotenoids remain elusive. We have chosen two specific cases, the two β-carotene molecules in photosystem II reaction centers and the two luteins in the major photosystem II light-harvesting complex, to investigate how such a tuning of their electronic structure may occur. Indeed, in each case, identical molecular species in the same protein are seen to exhibit different electronic properties (most notably, shifted absorption peaks). We assess which molecular parameters are responsible for this in vivo tuning process and attempt to assign it to specific molecular events imposed by their binding pockets. PMID:23720734

  18. Mechanisms underlying carotenoid absorption in oxygenic photosynthetic proteins.

    PubMed

    Mendes-Pinto, Maria M; Galzerano, Denise; Telfer, Alison; Pascal, Andrew A; Robert, Bruno; Ilioaia, Cristian

    2013-06-28

    The electronic properties of carotenoid molecules underlie their multiple functions throughout biology, and tuning of these properties by their in vivo locus is of vital importance in a number of cases. This is exemplified by photosynthetic carotenoids, which perform both light-harvesting and photoprotective roles essential to the photosynthetic process. However, despite a large number of scientific studies performed in this field, the mechanism(s) used to modulate the electronic properties of carotenoids remain elusive. We have chosen two specific cases, the two β-carotene molecules in photosystem II reaction centers and the two luteins in the major photosystem II light-harvesting complex, to investigate how such a tuning of their electronic structure may occur. Indeed, in each case, identical molecular species in the same protein are seen to exhibit different electronic properties (most notably, shifted absorption peaks). We assess which molecular parameters are responsible for this in vivo tuning process and attempt to assign it to specific molecular events imposed by their binding pockets. PMID:23720734

  19. Mechanisms underlying vertebrate limb regeneration: lessons from the salamander.

    PubMed

    Brockes, Jeremy P; Gates, Phillip B

    2014-06-01

    Limb regeneration in adult salamanders proceeds by formation of a mound of progenitor cells called the limb blastema. It provides several pointers for regenerative medicine. These include the role of differentiated cells in the origin of the blastema, the role of regenerating axons of peripheral nerves and the importance of cell specification in conferring morphogenetic autonomy on the blastema. One aspect of regeneration that has received less attention is the ability to undergo multiple episodes without detectable change in the outcome, and with minimal effect of aging. We suggest that, although such pointers are valuable, it is important to understand why salamanders are the only adult tetrapod vertebrates able to regenerate their limbs. Although this remains a controversial issue, the existence of salamander-specific genes that play a significant role in the mechanism of regeneration provides evidence for the importance of local evolution, rather than a purely ancestral mechanism. The three-finger protein called Prod1 is discussed in the present article as an exemplar of this approach. PMID:24849229

  20. Neuropharmacological Mechanisms Underlying the Neuroprotective Effects of Methylphenidate

    PubMed Central

    Volz, T.J

    2008-01-01

    Methylphenidate is a psychostimulant that inhibits the neuronal dopamine transporter. In addition, methylphenidate has the intriguing ability to provide neuroprotection from the neurotoxic effects of methamphetamine and perhaps also Parkinson’s disease; both of which may likely involve the abnormal accumulation of cytoplasmic dopamine inside dopaminergic neurons and the resulting formation of dopamine-associated reactive oxygen species. As delineated in this review, the neuroprotective effects of methylphenidate are due, at least in part, to its ability to attenuate or prevent this abnormal cytoplasmic dopamine accumulation through several possible neuropharmacological mechanisms. These may include 1) direct interactions between methylphenidate and the neuronal dopamine transporter which may attenuate or prevent the entry of methamphetamine into dopaminergic neurons and may also decrease the synthesis of cytoplasmic dopamine through a D2 receptor-mediated signal cascade process, and 2) indirect effects upon the functioning of the vesicular monoamine transporter-2 which may increase vesicular dopamine sequestration through both vesicle trafficking and the kinetic upregulation of the vesicular monoamine transporter-2 protein. Understanding these neuropharmacological mechanisms of methylphenidate neuroprotection may provide important insights into the physiologic regulation of dopaminergic systems as well as the pathophysiology of a variety of disorders involving abnormal dopamine disposition ranging from substance abuse to neurodegenerative diseases such as Parkinson’s disease. PMID:19587858

  1. Serotonin Receptor 2B Mediates Mechanical Hyperalgesia by Regulating Transient Receptor Potential Vanilloid 1.

    PubMed

    Su, Yeu-Shiuan; Chiu, Yuan-Yi; Lin, Shih-Yuan; Chen, Chih-Cheng; Sun, Wei-Hsin

    2016-05-01

    Serotonin [5-hydroxytryptamine (5-HT)], an inflammatory mediator, contributes to inflammatory pain. The presence of multiple 5-HT subtype receptors on peripheral and central nociceptors complicates the role of 5-HT in pain. Previously, we found that 5-HT2B/2C antagonist could block 5-HT-induced mechanical hyperalgesia. However, the types of neurons or circuits underlying this effect remained unsolved. Here, we demonstrate that the Gq/11-phospholipase Cβ-protein kinase Cε (PKCε) pathway mediated by 5-HT2B is involved in 5-HT-induced mechanical hyperalgesia in mice. Administration of a transient receptor potential vanilloid 1 (TRPV1) antagonist inhibited the 5-HT-induced mechanical hyperalgesia. 5-HT injection enhanced 5-HT- and capsaicin-evoked calcium signals specifically in isolectin B4 (IB4)-negative neurons; signals were inhibited by a 5-HT2B/2C antagonist and PKCε blocker. Thus, 5-HT2B mediates 5-HT-induced mechanical hyperalgesia by regulating TRPV1 function. PMID:26635025

  2. The Cardioprotective Effects of Hydrogen Sulfide in Heart Diseases: From Molecular Mechanisms to Therapeutic Potential

    PubMed Central

    Shen, Yaqi; Shen, Zhuqing; Luo, Shanshan; Guo, Wei; Zhu, Yi Zhun

    2015-01-01

    Hydrogen sulfide (H2S) is now recognized as a third gaseous mediator along with nitric oxide (NO) and carbon monoxide (CO), though it was originally considered as a malodorous and toxic gas. H2S is produced endogenously from cysteine by three enzymes in mammalian tissues. An increasing body of evidence suggests the involvement of H2S in different physiological and pathological processes. Recent studies have shown that H2S has the potential to protect the heart against myocardial infarction, arrhythmia, hypertrophy, fibrosis, ischemia-reperfusion injury, and heart failure. Some mechanisms, such as antioxidative action, preservation of mitochondrial function, reduction of apoptosis, anti-inflammatory responses, angiogenic actions, regulation of ion channel, and interaction with NO, could be responsible for the cardioprotective effect of H2S. Although several mechanisms have been identified, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases. Therefore, insight into the molecular mechanisms underlying H2S action in the heart may promote the understanding of pathophysiology of cardiac diseases and lead to new therapeutic targets based on modulation of H2S production. PMID:26078822

  3. Mechanisms of cardiac radiation injury and potential preventive approaches.

    PubMed

    Slezak, Jan; Kura, Branislav; Ravingerová, Táňa; Tribulova, Narcisa; Okruhlicova, Ludmila; Barancik, Miroslav

    2015-09-01

    In addition to cytostatic treatment and surgery, the most common cancer treatment is gamma radiation. Despite sophisticated radiological techniques however, in addition to irradiation of the tumor, irradiation of the surrounding healthy tissue also takes place, which results in various side-effects, depending on the absorbed dose of radiation. Radiation either damages the cell DNA directly, or indirectly via the formation of oxygen radicals that in addition to the DNA damage, react with all cell organelles and interfere with their molecular mechanisms. The main features of radiation injury besides DNA damage is inflammation and increased expression of pro-inflammatory genes and cytokines. Endothelial damage and dysfunction of capillaries and small blood vessels plays a particularly important role in radiation injury. This review is focused on summarizing the currently available data concerning the mechanisms of radiation injury, as well as the effectiveness of various antioxidants, anti-inflammatory cytokines, and cytoprotective substances that may be utilized in preventing, mitigating, or treating the toxic effects of ionizing radiation on the heart. PMID:26030720

  4. Misfolded Protein Aggregates: Mechanisms, Structures and Potential for Disease Transmission

    PubMed Central

    Moreno-Gonzalez, Ines; Soto, Claudio

    2011-01-01

    Some of the most prevalent human degenerative diseases appear as a result of the misfolding and aggregation of proteins. Compelling evidence suggest that misfolded protein aggregates play an important role in cell dysfunction and tissue damage, leading to the disease. Prion protein (Prion diseases), amyloid-beta (Alzheimer’s disease), alpha-synuclein (Parkinson’s disease), Huntingtin (Huntington’s disease), serum amyloid A (AA amyloidosis) and islet amyloid polypeptide (Type 2 Diabetes) are some of the proteins that trigger disease when they get misfolded. The recent understanding of the crucial role of misfolded proteins as well as the structural requirements and mechanism of protein misfolding have raised the possibility that these diseases may be transmissible by self-propagation of the protein misfolding process in a similar way as the infamous prions transmit prion diseases. Future research in this field should aim to clarify this possibility and translate the knowledge of the basic disease mechanisms into development of novel strategies for early diagnosis and efficient treatment. PMID:21571086

  5. Challenging Mycobacterium tuberculosis dormancy mechanisms and their immunodiagnostic potential.

    PubMed

    Chaves, Alexandre Silva; Rodrigues, Michele Fernandes; Mattos, Ana Márcia Menezes; Teixeira, Henrique Couto

    2015-01-01

    Mycobacterium tuberculosis is the etiologic agent of tuberculosis, one of the world's greatest cause of morbidity and mortality due to infectious disease. Many evolutionary mechanisms have contributed to its high level of adaptation as a host pathogen. Prior to become dormant, a group of about 50 genes related to metabolic changes are transcribed by the DosR regulon, one of the most complex and important systems of host-pathogen interaction. This genetic mechanism allows the mycobacteria to persist during long time periods, establishing the so-called latent infection. Even in the presence of a competent immune response, the host cannot eliminate the pathogen, only managing to keep it surrounded by an unfavorable microenvironment for its growth. However, conditions such as immunosuppression may reestablish optimal conditions for bacterial growth, culminating in the onset of active disease. The interactions between the pathogen and its host are still not completely elucidated. Nonetheless, many studies are being carried out in order to clarify this complex relationship, thus creating new possibilities for patient approach and laboratory screening. PMID:26358744

  6. Signaling mechanism underlying the histamine-modulated action of hypoglossal motoneurons.

    PubMed

    Liu, Zi-Long; Wu, Xu; Luo, Yan-Jia; Wang, Lu; Qu, Wei-Min; Li, Shan-Qun; Huang, Zhi-Li

    2016-04-01

    Histamine, an important modulator of the arousal states of the central nervous system, has been reported to contribute an excitatory drive at the hypoglossal motor nucleus to the genioglossus (GG) muscle, which is involved in the pathogenesis of obstructive sleep apnea. However, the effect of histamine on hypoglossal motoneurons (HMNs) and the underlying signaling mechanisms have remained elusive. Here, whole-cell patch-clamp recordings were conducted using neonatal rat brain sections, which showed that histamine excited HMNs with an inward current under voltage-clamp and a depolarization membrane potential under current-clamp via histamine H1 receptors (H1 Rs). The phospholipase C inhibitor U-73122 blocked H1 Rs-mediated excitatory effects, but protein kinase A inhibitor and protein kinase C inhibitor did not, indicating that the signal transduction cascades underlying the excitatory action of histamine on HMNs were H1 R/Gq/11 /phospholipase C/inositol-1,4,5-trisphosphate (IP3 ). The effects of histamine were also dependent on extracellular Na(+) and intracellular Ca(2+) , which took place via activation of Na(+) -Ca(2+) exchangers. These results identify the signaling molecules associated with the regulatory effect of histamine on HMNs. The findings of this study may provide new insights into therapeutic approaches in obstructive sleep apnea. We proposed the post-synaptic mechanisms underlying the modulation effect of histamine on hypoglossal motoneuron. Histamine activates the H1 Rs via PLC and IP3 , increases Ca(2+) releases from intracellular stores, promotes Na(+) influx and Ca(2+) efflux via the NCXs, and then produces an inward current and depolarizes the neurons. Histamine modulates the excitability of HMNs with other neuromodulators, such as noradrenaline, serotonin and orexin. We think that these findings should provide an important new direction for drug development for the treatment of obstructive sleep apnea. PMID:26811198

  7. Biosensor regeneration via substrate electric potential: A physical mechanism

    NASA Astrophysics Data System (ADS)

    Jiang, Rui-Bin; Lei, U.

    2010-06-01

    Literatures showed that the immune type biosensors can be regenerated by applying a voltage (ΔΦ) across the combined macromolecules but the underlying physics was not clarified. By incorporating an electric double layer force and a van der Waals force into a weight-ensemble Brownian dynamics simulation, we found that the dissociation rate constant for biotin-streptavidin increases exponentially with ΔΦ, and reaches 418-fold when ΔΦ equals 1 V. Macroscopic diffusion simulations using such enhanced dissociation rate constants agree with the previous experiments, and explain quantitatively the finding that the regeneration using square-wave voltage is superior to that using saw-tooth voltage.

  8. Mechanism and kinetics of parathion degradation under ultrasonic irradiation.

    PubMed

    Yao, Juan-Juan; Gao, Nai-Yun; Li, Cong; Li, Lei; Xu, Bin

    2010-03-15

    The parathion degradation under ultrasonic irradiation in aqueous solution was investigated. The results indicate that at the conditions in question, degradation rate of parathion decreased with increasing initial concentration and decreasing power. The optimal frequency for parathion degradation was 600 kHz. The free radical reactions predominate in the sonochemical degradation of parathion and the reaction zones are predominately at the bubble interface and, to a much lesser extent, in bulk solution. The gas/liquid interfacial regions are the real effective reaction sites for sonochemical degradation of parathion. The reaction can be well described as a gas/liquid heterogeneous reaction which obeys a kinetic model based on Langmuir-Hinshelwood model. The main pathways of parathion degradation by ultrasonic irradiation were also proposed by qualitative and quantitative analysis of organic and inorganic byproducts. It is indicated that the N(2) in air takes part in the parathion degradation through the formation of NO(2) under ultrasonic irradiation. Parathion is decomposed into paraoxon and 4-nitrophenol in the first step via two different pathways, respectively, which is in agreement with the theoretical molecular orbital (MO) calculations. PMID:19854573

  9. Reliability of piezoceramic patch sensors under cyclic mechanical loading

    NASA Astrophysics Data System (ADS)

    Thielicke, Bärbel; Gesang, Thomas; Wierach, Peter

    2003-12-01

    Piezoceramic patch sensors have to withstand the primary stresses and strains of a structure during operation. In the leading project 'Adaptronics' a lifespan of 106 cycles at 0.1% strain was required for sensors applied on components of steel and carbon fibre reinforced plastic (CFRP). In order to test the reliability of the patches themselves and of their adhesion on the substrate, special four-point bending tests were carried out under quasistatic loading and under cyclic loading at different strain levels. The specimens consisted in sheets of steel and CFRP as substrates on which the newly developed patches with embedded piezoelectric foils and fibres were glued. In the quasistatic bending tests the performance of each sensor was characterized by measuring the sensor signal (charge) as a function of strain before and after cycling. Damage of the specimens would result in a decreasing slope of the charge-strain-curve after cycling. However, all the specimens tested survived 107 cycles up to 0.12% strain without marked loss of performance.

  10. Mechanical Behaviour of Reservoir Rock Under Brine Saturation

    NASA Astrophysics Data System (ADS)

    Shukla, Richa; Ranjith, P. G.; Choi, S. K.; Haque, A.; Yellishetty, Mohan; Hong, Li

    2013-01-01

    Acoustic emissions (AE) and stress-strain curve analysis are well accepted ways of analysing crack propagation and monitoring the various failure stages (such as crack closure, crack initiation level during rock failure under compression) of rocks and rock-like materials. This paper presents details and results of experimental investigations conducted for characterizing the brittle failure processes induced in a rock due to monocyclic uniaxial compression on loading of two types of sandstone core samples saturated in NaCl brines of varying concentration (0, 2, 5, 10 and 15 % NaCl by weight). The two types of sandstone samples were saturated under vacuum for more than 45 days with the respective pore fluid to allow them to interact with the rocks. It was observed that the uniaxial compressive strength and stress-strain behaviour of the rock specimens changed with increasing NaCl concentration in the saturating fluid. The acoustic emission patterns also varied considerably for increasing ionic strength of the saturating brines. These observations can be attributed to the deposition of NaCl crystals in the rock's pore spaces as well some minor geo-chemical interactions between the rock minerals and the brine. The AE pattern variations could also be partly related to the higher conductivity of the ionic strength of the high-NaCl concentration brine as it is able to transfer more acoustic energy from the cracks to the AE sensors.

  11. Mechanisms underlying sporadic cerebral small vessel disease: insights from neuroimaging

    PubMed Central

    Wardlaw, JM; Smith, C; Dichgans, M

    2013-01-01

    The term “cerebral small vessel disease” (SVD) describes a range of neuroimaging, pathological and associated clinical features. The latter range from none, to discrete focal neurological symptoms (stroke), to insidious global neurological dysfunction and dementia. The public health burden is considerable. The pathogenesis is largely unknown. Although associated with vascular risk factors, and generally considered to result from an intrinsic cerebral arteriolar occlusive disease, the pathological processes leading to the arteriolar disease, how these result in brain disease, how SVD lesions contribute to neurological or cognitive symptoms and the relationship to risk factors, have been the subject of much speculation. Pathology often reflects end-stage disease making determination of the earliest stages difficult. Neuroimaging provides considerable insights: the small vessels are not easily seen themselves, but the effects of their malfunction on the brain can be tracked on detailed brain imaging. We review the growing evidence for the most likely mechanisms. PMID:23602162

  12. Circuit Mechanisms Underlying Motor Memory Formation in the Cerebellum

    PubMed Central

    Lee, Ka Hung; Mathews, Paul J.; Reeves, Alexander M.B.; Choe, Katrina Y.; Jami, Shekib A.; Serrano, Raul E.; Otis, Thomas S.

    2015-01-01

    SUMMARY The cerebellum stores associative motor memories essential for properly timed movement; however, the mechanisms by which these memories form and are acted upon remain unclear. To determine how cerebellar activity relates to movement and motor learning, we used optogenetics to manipulate spontaneously firing Purkinje neurons (PNs) in mouse simplex lobe. Using high-speed videography and motion tracking, we found that altering PN activity produced rapid forelimb movement. PN inhibition drove movements time-locked to stimulus onset, whereas PN excitation drove delayed movements time-locked to stimulus offset. Pairing either PN inhibition or excitation with sensory stimuli triggered the formation of robust, associative motor memories; however, PN excitation led to learned movements whose timing more closely matched training intervals. These findings implicate inhibition of PNs as a teaching signal, consistent with a model whereby learning leads first to reductions in PN firing that subsequently instruct circuit changes in the cerebellar nucleus. PMID:25843404

  13. Mechanisms underlying the antimotion sickness effects of psychostimulants

    NASA Technical Reports Server (NTRS)

    Kohl, Randall L.; Lewis, Michael R.

    1987-01-01

    Data related to the mechanism responsible for the antimotion sickness effects of psychostimulants such as amphetamine are examined. From the analysis of current literature and new evidence, the following three hypotheses are suggested: (1) selective enhancement of dopaminergic, but not noradrenergic, transmission is sufficient to account for amphetamine-induced resistance and, perhaps, for natural resistance to motion sickness; (2) the site of this enhanced dopaminergic transmission is probably within the basal ganglia; and (3) the neuropharmacology of the basal ganglia, but not of the brain-stem vestibular areas, can account for the therapeutic synergism of scopolamine and amphetamine. The therapeutic action of psychostimulants may be dissociable from some of their side effects, particularly cardiovascular effects related to peripheral norepinephrine release.

  14. The CHAIN program: forging evolutionary links to underlying mechanisms.

    PubMed

    Neuwald, Andrew F

    2007-11-01

    Proteins evolve new functions by modifying and extending the molecular machinery of an ancestral protein. Such changes show up as divergent sequence patterns, which are conserved in descendent proteins that maintain the divergent function. After multiply-aligning a set of input sequences, the CHAIN program partitions the sequences into two functionally divergent groups and then outputs an alignment that is annotated to reveal the selective pressures imposed on divergent residue positions. If atomic coordinates are also provided, hydrogen bonds and other atomic interactions associated with various categories of divergent residues are graphically displayed. Such analyses establish links between protein evolutionary divergence and functionally crucial atomic features and, as a result, can suggest plausible molecular mechanisms for experimental testing. This is illustrated here by its application to bacterial clamp-loader ATPases. PMID:17962021

  15. Aging and emotional memory: cognitive mechanisms underlying the positivity effect.

    PubMed

    Spaniol, Julia; Voss, Andreas; Grady, Cheryl L

    2008-12-01

    Younger adults tend to remember negative information better than positive or neutral information (negativity bias). The negativity bias is reduced in aging, with older adults occasionally exhibiting superior memory for positive, as opposed to negative or neutral, information (positivity bias). Two experiments with younger (N=24 in Experiment 1, N=25 in Experiment 2; age range: 18-35 years) and older adults (N=24 in both experiments; age range: 60-85 years) investigated the cognitive mechanisms responsible for age-related differences in recognition memory for emotional information. Results from diffusion model analyses (R. Ratcliff, 1978) indicated that the effects of valence on response bias were similar in both age groups but that Age x Valence interactions emerged in memory retrieval. Specifically, older adults experienced greater overall familiarity for positive items than younger adults. We interpret this finding in terms of an age-related increase in the accessibility of positive information in long-term memory. PMID:19140656

  16. Common Mechanisms Underlying Epileptogenesis and the Comorbidities of Epilepsy.

    PubMed

    Mazarati, Andrey; Sankar, Raman

    2016-01-01

    The importance of comorbidities in determining the quality of life of individuals with epilepsy and their families has received increasing attention in the past decade. Along with it has come a recognition that in some individuals, certain comorbidities may have preexisted, and may have contributed to their developing epilepsy. Many mechanisms are capable of interconnecting different dysfunctions that manifest as distinct disorders, often diagnosed and managed by different specialists. We review the human data from the perspective of epidemiology as well as insights gathered from neurodiagnostic and endocrine studies. Animal studies are reviewed to refine our mechanistic understanding of the connections, because they permit the narrowing of variables, which is not possible when studying humans. PMID:27371669

  17. Underlying Mechanism of Antimicrobial Activity of Chitosan Microparticles and Implications for the Treatment of Infectious Diseases

    PubMed Central

    Jeon, Soo Jin; Oh, Manhwan; Yeo, Won-Sik; Galvão, Klibs N.; Jeong, Kwang Cheol

    2014-01-01

    The emergence of antibiotic resistant microorganisms is a great public health concern and has triggered an urgent need to develop alternative antibiotics. Chitosan microparticles (CM), derived from chitosan, have been shown to reduce E. coli O157:H7 shedding in a cattle model, indicating potential use as an alternative antimicrobial agent. However, the underlying mechanism of CM on reducing the shedding of this pathogen remains unclear. To understand the mode of action, we studied molecular mechanisms of antimicrobial activity of CM using in vitro and in vivo methods. We report that CM are an effective bactericidal agent with capability to disrupt cell membranes. Binding assays and genetic studies with an ompA mutant strain demonstrated that outer membrane protein OmpA of E. coli O157:H7 is critical for CM binding, and this binding activity is coupled with a bactericidal effect of CM. This activity was also demonstrated in an animal model using cows with uterine diseases. CM treatment effectively reduced shedding of intrauterine pathogenic E. coli (IUPEC) in the uterus compared to antibiotic treatment. Since Shiga-toxins encoded in the genome of bacteriophage is often overexpressed during antibiotic treatment, antibiotic therapy is generally not recommended because of high risk of hemolytic uremic syndrome. However, CM treatment did not induce bacteriophage or Shiga-toxins in E. coli O157:H7; suggesting that CM can be a potential candidate to treat infections caused by this pathogen. This work establishes an underlying mechanism whereby CM exert antimicrobial activity in vitro and in vivo, providing significant insight for the treatment of diseases caused by a broad spectrum of pathogens including antibiotic resistant microorganisms. PMID:24658463

  18. Multiple mechanisms underlying troglitazone-induced mitochondrial permeability transition

    SciTech Connect

    Okuda, Takuya; Norioka, Misaki; Shitara, Yoshihisa; Horie, Toshiharu

    2010-11-01

    Troglitazone, a thiazolidinedione class antidiabetic drug, was withdrawn from the market because of its severe idiosyncratic hepatotoxicity. It causes a mitochondrial permeability transition (MPT), which may in part contribute to its hepatotoxicity. In the present study, the mechanism of troglitazone mitochondrial toxicity was investigated in isolated rat liver mitochondria. Mitochondrial swelling induced by 10 {mu}M troglitazone was attenuated by bromoenol lactone (BEL), an inhibitor of Ca{sup 2+}-independent phospholipase A{sub 2} (iPLA{sub 2}). In contrast, that induced by 50 {mu}M troglitazone was exacerbated by BEL. This exacerbation was diminished by addition of 2 mM glutathione, an antioxidant. Oxygen consumption by state 3 respiration in isolated mitochondria was also decreased by troglitazone, but it was not affected by BEL. Mitochondrial swelling induced by 10 {mu}M troglitazone was completely attenuated in the absence of Ca{sup 2+} while that induced by 50 {mu}M troglitazone was not affected. Addition of 1 {mu}M cyclosporin A (CsA), an inhibitor of MPT pores, completely attenuated swelling induced by 10 {mu}M troglitazone while it only partly diminished that induced by 50 {mu}M troglitazone. Thus, the MPT induced by 10 and 50 {mu}M troglitazone are regulated by different mechanism; the MPT induced by 10 {mu}M troglitazone is regulated by the activation of iPLA{sub 2} and caused by the opening of CsA-regulating MPT pores followed by accumulation of Ca{sup 2+} in mitochondria, while that induced by 50 {mu}M troglitazone is partly regulated by reactive oxygen species and mainly caused by the opening of CsA-insensitive MPT pores.

  19. Breather mechanism of the void ordering in crystals under irradiation

    NASA Astrophysics Data System (ADS)

    Dubinko, Vladimir

    2009-09-01

    The void ordering has been observed in very different radiation environments ranging from metals to ionic crystals. In the present paper the ordering phenomenon is considered as a consequence of the energy transfer along the close packed directions provided by self-focusing discrete breathers. The self-focusing breathers are energetic, mobile and highly localized lattice excitations that propagate great distances in atomic-chain directions in crystals. This points to the possibility of atoms being ejected from the void surface by the breather-induced mechanism, which is similar to the focuson-induced mechanism of vacancy emission from voids proposed in our previous paper. The main difference between focusons and breathers is that the latter are stable against thermal motion. There is evidence that breathers can occur in various crystals, with path lengths ranging from 104 to 107 unit cells. Since the breather propagating range can be larger than the void spacing, the voids can shield each other from breather fluxes along the close packed directions, which provides a driving force for the void ordering. Namely, the vacancy emission rate for "locally ordered" voids (which have more immediate neighbors along the close packed directions) is smaller than that for the "interstitial" ones, and so they have some advantage in growth. If the void number density is sufficiently high, the competition between them makes the "interstitial" voids shrink away resulting in the void lattice formation. The void ordering is intrinsically connected with a saturation of the void swelling, which is shown to be another important consequence of the breather-induced vacancy emission from voids.

  20. Mechanical behavior of enamel rods under micro-compression.

    PubMed

    Yilmaz, Ezgi D; Schneider, Gerold A

    2016-10-01

    Exploring the structural strategies behind the optimized mechanical performance of hierarchical materials has been a focal point of extensive research over the past decades. Dental enamel is one such natural material, comprising a complicated hierarchical structure with a high level of mineral content. Bundles of hydroxyapatite nanofibers (level-1) Ø: 50nm form enamel rods (level-2) Ø: 5µm, which constitute bands (level-3) Ø: 50µm. While a number of studies in the last decade using advanced fracture mechanical methods have revealed an increasing trend in the fracture toughness of enamel with each additional level of hierarchy, there is still no general agreement on how hierarchical structuring affects the stiffness and strength of enamel. In this study, we identified the stiffness and strength values of the isolated rods (level-2) via micro-compression. The rods were tested in three different orientations with respect to the loading direction: parallel, perpendicular and oblique. The highest stress level withstood before catastrophic fracture was observed to be ~1500MPa in perpendicular orientation. In the oblique loading, the specimens failed by shearing and exhibited a damage-tolerant deformation behavior, which was attributed to the conjugation spots identified between the rods and interrod sheets. The elastic modulus was ~60GPa on average and similar in all orientations. The isotropy in stiffness was attributed to the mineral contacts residing between rods. This was verified by an analytical model derived for level-1 and extended over higher hierarchical levels. The experimental results obtained at level-2 were comparable to the compressive strength and stiffness values reported for level-1 and bulk enamel in the literature. In general, our results suggest that hierarchy has only a minor influence on the compressive properties of enamel. PMID:27415405

  1. Rainbow-shift mechanism behind discrete optical-potential ambiguities

    SciTech Connect

    Brandan, M.E. ); McVoy, K.W. )

    1991-03-01

    Some years ago, Drisko {ital et} {ital al}. suggested that the discrete ambiguity often encountered for elastic scattering optical potentials could be understood as being due to the interior or small-{ital l} {ital S}-matrix elements for two equivalent'' potentials differing in phase by 2{pi}, {ital l}-by-{ital l}. We point out that the {ital absence} of this phase change for peripheral partial waves is equally essential, and suggest that a deeper understanding of the ambiguity may be achieved by viewing it as a consequence of a farside interference between interior and peripheral partial waves. It is this interference which produces the broad Airy maxima'' of a nuclear rainbow, and we show that a Drisko-type phase-shift increment {delta}{sub {ital l}}{r arrow}({delta}{sub {ital l}}+{pi}) for low-{ital l} phases relative to the high-{ital l} ones is exactly what is needed to shift a farside rainbow pattern by one Airy maximum, thus providing an equivalent rainbow-shift'' interpretation of the discrete ambiguity. The physical importance of both interpretations lies in the fact that the existence of discrete ambiguities (as well as of nuclear rainbows) is explicit evidence for low-{ital l} transparency in nucleus-nucleus collisions. The essential role played by low partial waves explains why peripheral reactions have generally not proven helpful in resolving this ambiguity.

  2. Comparing potential copper chelation mechanisms in Parkinson's disease protein

    NASA Astrophysics Data System (ADS)

    Rose, Frisco; Hodak, Miroslav; Bernholc, Jerry

    2011-03-01

    We have implemented the nudged elastic band (NEB) as a guided dynamics framework for our real-space multigrid method of DFT-based quantum simulations. This highly parallel approach resolves a minimum energy pathway (MEP) on the energy hypersurface by relaxing intermediates in a chain-of-states. As an initial application we present an investigation of chelating agents acting on copper ion bound to α -synuclein, whose misfolding is implicated in Parkinson's disease (PD). Copper ions are known to act as highly effective misfolding agents in a-synuclein and are thus an important target in understanding PD. Furthermore, chelation therapy has shown promise in the treatment of Alzheimer's and other neuro-degenerative diseases with similar metal-correlated pathologies. At present, our candidate chelating agents include nicotine, curcumin and clioquinol. We examine their MEP activation barriers in the context of a PD onset mechanism to assess the viability of various chelators for PD remediation.

  3. Algorithmic Mechanisms for Reliable Crowdsourcing Computation under Collusion

    PubMed Central

    Fernández Anta, Antonio; Georgiou, Chryssis; Mosteiro, Miguel A.; Pareja, Daniel

    2015-01-01

    We consider a computing system where a master processor assigns a task for execution to worker processors that may collude. We model the workers’ decision of whether to comply (compute the task) or not (return a bogus result to save the computation cost) as a game among workers. That is, we assume that workers are rational in a game-theoretic sense. We identify analytically the parameter conditions for a unique Nash Equilibrium where the master obtains the correct result. We also evaluate experimentally mixed equilibria aiming to attain better reliability-profit trade-offs. For a wide range of parameter values that may be used in practice, our simulations show that, in fact, both master and workers are better off using a pure equilibrium where no worker cheats, even under collusion, and even for colluding behaviors that involve deviating from the game. PMID:25793524

  4. Cellular mechanisms underlying oxidative stress in human exercise.

    PubMed

    Jackson, Malcolm J; Vasilaki, Aphrodite; McArdle, Anne

    2016-09-01

    A relative increase in oxidation of lipids, proteins and DNA has been recognised to occur in the circulation and tissues of exercising humans and animals since the late 1970s and throughout the ensuing 40 years a great deal of work has been undertaken to elucidate the potential source(s) of this exercise-induced "oxidative stress". Specific aspects of physical exercise (e.g. contractile activity, relative hypoxia, hyperaemia) may theoretically induce increased generation of reactive oxygen species in a number of potential tissues, but data strongly indicate that contractile activity of skeletal muscle predominates as the source of oxidants and contributes to local oxidation and that of extracellular biomaterials. Taken together with the relatively large mass of muscle compared with other tissues and cells it appears that muscle fibres are the major contributor to the relative increase in whole body "oxidative stress" during some forms of exercise. The sub-cellular sources of this increased oxidation have also been the subject of considerable research with early studies predominantly indicating that muscle mitochondria were the likely increased source of oxidants, such as hydrogen peroxide, but assessments of the relative concentrations of hydrogen peroxide in skeletal muscle fibres at rest and during contractile activity do not support this possibility. In contrast, several recent studies have identified NADPH oxidase enzymes in skeletal muscle that appear to play a signalling role in physiological responses exercise and together with xanthine oxidase enzymes may contribute to the relative increase in whole body oxidation. A fuller understanding of the relative roles of these sources and the function(s) of the species generated appears increasingly important in attempts to harness the beneficial effects of exercise for maintenance of health in aging and a variety of chronic conditions. PMID:26912036

  5. Potential Mechanism Leading to Impaired Thermoregulation Following Microgravity Exposure

    NASA Technical Reports Server (NTRS)

    Crandall, C. G.; Etzel, R. A.

    1999-01-01

    Prolonged exposure to microgravity or its analogues impairs thermoregulation in humans evidenced by higher internal temperatures following the exposure during a thermal challenge. Although the mechanism leading to this response has not been clearly delineated, we identified that prolonged head-down tilt (HDT) markedly impairs thermoregulatory reflex control of skin blood flow, as demonstrated by an increased internal temperature threshold for cutaneous vasodilation, and by a reduced slope of the relationship between the elevation in skin blood flow relative to the elevation in internal temperature. Recently, Fortney et al. identified similar responses in two individuals following 115 days of microgravity exposure. One possible mechanism leading to altered cutaneous vasodilation during a thermal challenge following actual or simulated microgravity exposure may be associated with baroreflex-mediated attenuation in the elevation of skin blood flow. During a heat stress the elevation in skin blood flow is accomplished through a combination of increased cutaneous vascular conductance and cardiac output, both of which result in central venous pressure (CVP) decreasing 2-6 mmHg. Reductions in CVP of this magnitude in normothermia decrease muscle blood flow and skin blood flow presumably through unloading the cardiopulmonary baroreceptors. It is unclear whether the reduction in CVP, and accompanying cardiopulmonary baroreceptor unloading, during passive heating buffers the elevation in skin blood flow. That is, would the elevation in skin blood flow be greater if CVP did not decrease, or decreased to a lesser extent during the heat stress? Conversely, if CVP decreased to a greater extend during a thermal challenge following a perturbation such as prolonged HDT, would the elevation in skin blood flow be attenuated during that thermal challenge? Given that prolonged HDT decreases plasma volume and central venous pressure, such a finding would provide a plausible hypothesis

  6. Assessing mechanical vulnerability in water distribution networks under multiple failures

    NASA Astrophysics Data System (ADS)

    Berardi, Luigi; Ugarelli, Rita; Røstum, Jon; Giustolisi, Orazio

    2014-03-01

    Understanding mechanical vulnerability of water distribution networks (WDN) is of direct relevance for water utilities since it entails two different purposes. On the one hand, it might support the identification of severe failure scenarios due to external causes (e.g., natural or intentional events) which result into the most critical consequences on WDN supply capacity. On the other hand, it aims at figure out the WDN portions which are more prone to be affected by asset disruptions. The complexity of such analysis stems from the number of possible scenarios with single and multiple simultaneous shutdowns of asset elements leading to modifications of network topology and insufficient water supply to customers. In this work, the search for the most disruptive combinations of multiple asset failure events is formulated and solved as a multiobjective optimization problem. The higher vulnerability failure scenarios are detected as those causing the lower supplied demand due to the lower number of simultaneous failures. The automatic detection of WDN topology, subsequent to the detachments of failed elements, is combined with pressure-driven analysis. The methodology is demonstrated on a real water distribution network. Results show that, besides the failures causing the detachment of reservoirs, tanks, or pumps, there are other different topological modifications which may cause severe WDN service disruptions. Such information is of direct relevance to support planning asset enhancement works and improve the preparedness to extreme events.

  7. Consensus Paper: Pathological Mechanisms Underlying Neurodegeneration in Spinocerebellar Ataxias

    PubMed Central

    Matilla-Dueñas, A.; Ashizawa, T.; Brice, A.; Magri, S.; McFarland, K. N.; Pandolfo, M.; Pulst, S. M.; Riess, O.; Rubinsztein, D. C.; Schmidt, J.; Schmidt, T.; Scoles, D. R.; Stevanin, G.; Taroni, F.; Underwood, B. R.; Sánchez, I.

    2014-01-01

    Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice. PMID:24307138

  8. Coordination of frontline defense mechanisms under severe oxidative stress.

    PubMed

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

    2010-07-01

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

  9. Pathological mechanisms underlying aneurysmal subarachnoid haemorrhage and vasospasm.

    PubMed

    Penn, David L; Witte, Samantha R; Komotar, Ricardo J; Sander Connolly, E

    2015-01-01

    Aneurysmal subarachnoid haemorrhage is a cerebrovascular disease associated with an overall mortality as high as 50%. Delayed ischaemic neurologic deficits are a major contributor to this statistic, as well as the significant morbidity associated with the disease. Studies examining the pathophysiologic events causing these devastating changes in cerebral blood flow have identified several mechanisms which are thought to contribute to the development of delayed ischaemic neurological deficits, perhaps the most damaging of which are increased intracranial pressure and cerebral vasospasm. In addition, the presence of blood in the subarachnoid space can trigger a myriad of reactions resulting in increased capillary permeability, breakdown of the blood-brain barrier, and inflammation in surrounding neural tissue that adds to the devastating effects of haemorrhage. A detailed understanding of the post-haemorrhagic cellular and molecular changes that contribute to the development of cerebral ischaemia and vasospasm is imperative to the formulation of treatment and prevention options for subarachnoid haemorrhage patients. Despite a large body of research within this field, a complete understanding of rupture and vasospasm remains elusive. This study reviews the role of vasoactive substances, such as endothelin-1, as well as the histochemistry and molecular pathology of post-haemorrhage inflammation in the development of vasospasm and cerebral ischaemia. PMID:25113969

  10. Improving beef color stability: practical strategies and underlying mechanisms.

    PubMed

    Suman, Surendranath P; Hunt, Melvin C; Nair, Mahesh N; Rentfrow, Gregg

    2014-11-01

    This paper overviewed the current literature on strategies to improve beef color and attempted to logically explain the fundamental mechanisms involved. Surface color and its stability are critical traits governing the marketability of fresh beef when sold, whereas internal cooked color is utilized as an indicator for doneness at the point of consumption. A multitude of exogenous and endogenous factors interact with the redox biochemistry of myoglobin in post-mortem skeletal muscles. The scientific principles of these biomolecular interactions are applied by the meat industry as interventions for pre-harvest (i.e. diet, animal management) and post-harvest (i.e. packaging, aging, antioxidants) strategies to improve color stability in fresh and cooked beef. Current research suggests that the effects of several of these strategies are specific to type of animal, feeding regimen, packaging system, and muscle source. Meat scientists should explore novel ways to manipulate these factors using a biosystems approach to achieve improved beef color stability, satisfy consumer perception, and increase market profitability. PMID:25041654

  11. Common Neural Mechanisms Underlying Reversal Learning by Reward and Punishment

    PubMed Central

    Xue, Gui; Xue, Feng; Droutman, Vita; Lu, Zhong-Lin; Bechara, Antoine; Read, Stephen

    2013-01-01

    Impairments in flexible goal-directed decisions, often examined by reversal learning, are associated with behavioral abnormalities characterized by impulsiveness and disinhibition. Although the lateral orbital frontal cortex (OFC) has been consistently implicated in reversal learning, it is still unclear whether this region is involved in negative feedback processing, behavioral control, or both, and whether reward and punishment might have different effects on lateral OFC involvement. Using a relatively large sample (N = 47), and a categorical learning task with either monetary reward or moderate electric shock as feedback, we found overlapping activations in the right lateral OFC (and adjacent insula) for reward and punishment reversal learning when comparing correct reversal trials with correct acquisition trials, whereas we found overlapping activations in the right dorsolateral prefrontal cortex (DLPFC) when negative feedback signaled contingency change. The right lateral OFC and DLPFC also showed greater sensitivity to punishment than did their left homologues, indicating an asymmetry in how punishment is processed. We propose that the right lateral OFC and anterior insula are important for transforming affective feedback to behavioral adjustment, whereas the right DLPFC is involved in higher level attention control. These results provide insight into the neural mechanisms of reversal learning and behavioral flexibility, which can be leveraged to understand risky behaviors among vulnerable populations. PMID:24349211

  12. Molecular mechanisms underlying KVS-1-MPS-1 complex assembly.

    PubMed

    Wang, Yi; Sesti, Federico

    2007-11-01

    Formation of heteromeric complexes between voltage-gated K(+) (Kv) channels and accessory (beta) subunits is a widespread means to generate heterogeneity of K(+) current in the nervous system. Here we investigate the principles that determine the interactions of Caenorhabditis elegans MPS-1, a bifunctional beta-subunit that possesses kinase activity, with Kv channels. MPS-1 belongs to the evolutionarily conserved family of KCNE beta-subunits that modulate the functional properties of a variety of Kv channels and that, when defective, can cause congenital and acquired disease in Homo sapiens. In Chinese hamster ovary cells, MPS-1 forms stable complexes with different alpha-subunits. The transmembrane domain of MPS-1 is necessary and sufficient for MPS-1 complex formation. The hydropathicity of the transmembrane domain is an important factor controlling MPS-1 assembly. A highly hydrophobic MPS-1 mutant fails to interact with its endogenous channel partners when transgenically expressed in living worms. The hydropathic mechanism does not require specific points of contact between interacting proteins. This may allow MPS-1 to assemble with various Kv channels, presumably modifying the electrical properties of each. PMID:17604313

  13. Effect of biochar on nitrous oxide emission and its potential mechanisms.

    PubMed

    Liu, Liang; Shen, Guoqing; Sun, Mingxing; Cao, Xinde; Shang, Guofeng; Chen, Ping

    2014-08-01

    Extensive use of biochar to mitigate nitrous oxide (N2O) emission is limited by the lack of understanding on the exact mechanisms altering N2O emission from biochar-amended soil. Biochars produced from rice straw and dairy manure at 350 and 500 degrees C by oxygen-limited pyrolysis were used to investigate their influence on N2O emission. A quadratic effect of biochar levels was observed on the N2O emissions. The potential mechanisms were explored by terminal restriction fragment length polymorphism (T-RFLP) and real-time polymerase chain reaction (qPCR). A lower relative abundance of bacteria, which included ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB), was observed at 4% biochar application rate. Reduced copy numbers of the ammonia monooxygenase gene amoA and the nitrite reductase gene nirS coincided with decreased N2O emissions. Therefore, biochar may potentially alter N2O emission by affecting ammonia-oxidizing and denitrification bacteria, which is determined by the application rate of biochar in soil. Implications: Biochar research has received increased interest in recent years because of the potential beneficial effects of biochar on soil properties. Recent research shows that biochar can alter the rates of nitrogen cycling in soil systems by influencing nitrification and denitrification, which are key sources of the greenhouse gas nitrous oxide (N2O). However, there are still some controversial data. The purpose of this research was to (1) examine how applications of different dose of biochar to soil affect emission of N2O and (2) improve the understanding of the underlying mechanisms. PMID:25185392

  14. Metabolic memory and diabetic nephropathy: potential role for epigenetic mechanisms.

    PubMed

    Tonna, Stephen; El-Osta, Assam; Cooper, Mark E; Tikellis, Chris

    2010-06-01

    Many clinical studies have shown that intensive glycemic control in patients with diabetes can reduce the incidence and progression of diabetic nephropathy and can also reduce the incidence of other complications. These beneficial effects persist after patients return to usual (often worse) glycemic control. The Diabetes Control and Complications Trial was the first to refer to this phenomenon as 'metabolic memory'. Many patients with diabetes, however, still develop diabetic nephropathy despite receiving intensified glycemic control. Preliminary work in endothelial cells has shown that transient episodes of hyperglycemia can induce changes in gene expression that are dependent on modifications to histone tails (for example, methylation), and that these changes persist after return to normoglycemia. The persistence of such modifications cannot yet be fully explained, but certain epigenetic changes, as well as biochemical mechanisms such as advanced glycation, may provide new and interesting clues towards explaining the pathogenesis of this phenomenon. Further elucidation of the molecular events that enable prior glycemic control to result in end-organ protection in diabetes may lead to the development of new approaches for reducing the burden of diabetic nephropathy. PMID:20421885

  15. Sexual intercourse and cerebral aneurysmal rupture: potential mechanisms and precipitants.

    PubMed

    Reynolds, Matthew R; Willie, Jon T; Zipfel, Gregory J; Dacey, Ralph G

    2011-04-01

    Aneurysmal subarachnoid hemorrhage (SAH) is a significant cause of death in young and middle-aged individuals and causes tremendous morbidity in affected patients. Despite the identification of various risk factors, the series of events leading to the formation, growth, and rupture of intracranial aneurysms is poorly understood. Cerebral aneurysm rupture has been associated with sexual intercourse and other forms of physical exercise. In fact, multiple case series reported that coitus was the immediate preceding activity in 3.8-14.5% of patients suffering from aneurysmal SAH. This may be related to the large elevations in mean arterial blood pressure that occur in both males and females during sexual intercourse (130-175 and 125-160 mm Hg, respectively). While coitus and physical exercise share important physiological similarities, each may differentially affect the probability that a preformed aneurysm will rupture. In this literature review and synthesis, the authors analyze the physiological human response to sexual intercourse in an effort to delineate those factors that may precipitate aneurysmal rupture. The authors' analysis is based on the original data collected by Masters and Johnson. To the authors' knowledge, this is the first review to address the link between sexual intercourse and intracranial aneurysmal rupture. While actual measurements of the physiological variables relevant to SAH were not performed in this article, the authors make reasonable assumptions based on the available data to help elucidate the mechanism of sexually induced aneurysmal rupture. PMID:20540599

  16. Mechanisms Underlying Auditory Hallucinations—Understanding Perception without Stimulus

    PubMed Central

    Tracy, Derek K.; Shergill, Sukhwinder S.

    2013-01-01

    Auditory verbal hallucinations (AVH) are a common phenomenon, occurring in the “healthy” population as well as in several mental illnesses, most notably schizophrenia. Current thinking supports a spectrum conceptualisation of AVH: several neurocognitive hypotheses of AVH have been proposed, including the “feed-forward” model of failure to provide appropriate information to somatosensory cortices so that stimuli appear unbidden, and an “aberrant memory model” implicating deficient memory processes. Neuroimaging and connectivity studies are in broad agreement with these with a general dysconnectivity between frontotemporal regions involved in language, memory and salience properties. Disappointingly many AVH remain resistant to standard treatments and persist for many years. There is a need to develop novel therapies to augment existing pharmacological and psychological therapies: transcranial magnetic stimulation has emerged as a potential treatment, though more recent clinical data has been less encouraging. Our understanding of AVH remains incomplete though much progress has been made in recent years. We herein provide a broad overview and review of this. PMID:24961419

  17. PERK-opathies: An Endoplasmic Reticulum Stress Mechanism Underlying Neurodegeneration.

    PubMed

    Bell, Michelle C; Meier, Shelby E; Ingram, Alexandria L; Abisambra, Jose F

    2016-01-01

    The unfolded protein response (UPR) plays a vital role in maintaining cell homeostasis as a consequence of endoplasmic reticulum (ER) stress. However, prolonged UPR activity leads to cell death. This time-dependent dual functionality of the UPR represents the adaptive and cytotoxic pathways that result from ER stress. Chronic UPR activation in systemic and neurodegenerative diseases has been identified as an early sign of cellular dyshomeostasis. The Protein Kinase R-like ER Kinase (PERK) pathway is one of three major branches in the UPR, and it is the only one to modulate protein synthesis as an adaptive response. The specific identification of prolonged PERK activity has been correlated with the progression of disorders such as diabetes, Alzheimer's disease, and cancer, suggesting that PERK plays a role in the pathology of these disorders. For the first time, the term "PERK-opathies" is used to group these diseases in which PERK mediates detriment to the cell culminating in chronic disorders. This article reviews the literature documenting links between systemic disorders with the UPR, but with a specific emphasis on the PERK pathway. Then, articles reporting links between the UPR, and more specifically PERK, and neurodegenerative disorders are presented. Finally, a therapeutic perspective is discussed, where PERK interventions could be potential remedies for cellular dysfunction in chronic neurodegenerative disorders. PMID:26679859

  18. The cellular mechanisms of neuronal swelling underlying cytotoxic edema.

    PubMed

    Rungta, Ravi L; Choi, Hyun B; Tyson, John R; Malik, Aqsa; Dissing-Olesen, Lasse; Lin, Paulo J C; Cain, Stuart M; Cullis, Pieter R; Snutch, Terrance P; MacVicar, Brian A

    2015-04-23

    Cytotoxic brain edema triggered by neuronal swelling is the chief cause of mortality following brain trauma and cerebral infarct. Using fluorescence lifetime imaging to analyze contributions of intracellular ionic changes in brain slices, we find that intense Na(+) entry triggers a secondary increase in intracellular Cl(-) that is required for neuronal swelling and death. Pharmacological and siRNA-mediated knockdown screening identified the ion exchanger SLC26A11 unexpectedly acting as a voltage-gated Cl(-) channel that is activated upon neuronal depolarization to membrane potentials lower than -20 mV. Blockade of SLC26A11 activity attenuates both neuronal swelling and cell death. Therefore cytotoxic neuronal edema occurs when sufficient Na(+) influx and depolarization is followed by Cl(-) entry via SLC26A11. The resultant NaCl accumulation causes subsequent neuronal swelling leading to neuronal death. These findings shed light on unique elements of volume control in excitable cells and lay the ground for the development of specific treatments for brain edema. PMID:25910210

  19. Mechanisms underlying global stereopsis in fovea and periphery.

    PubMed

    Witz, Nirel; Hess, Robert F

    2013-07-19

    To better understand the pooling properties underlying global stereopsis we examined the relationship between carrier luminance spatial frequency and modulator disparity spatial frequency. Thresholds for detecting global sinusoidal disparity corrugations of spatially band-pass noise were measured as a function of modulator disparity spatial frequency for both centrally and peripherally located stimuli using a standard 2-IFC task. We found a characteristic relationship that depended on modulator disparity spatial frequency. At high modulator disparity spatial frequencies (>1c/d), there is an optimal ratio of around 2.6, whereas at low modulator disparity spatial frequencies, there is an optimal absolute carrier luminance spatial frequency (i.e., 3c/d). In the periphery, vision is restricted to modulator disparity spatial frequencies below 1c/d and, as a consequence, following the above rule, there is an optimum absolute carrier luminance spatial frequency that reduces in spatial frequency with increasing eccentricity. This finding is consistent with there being more than one channel processing global stereo that is subsequently confirmed using a 2×2 AFC detection/discrimination paradigm. Furthermore, because of the different carrier/modulator relationships in central and peripheral vision, peripheral global stereo cannot be simply related to central global stereo by a scaling factor and thus cannot be simply due to cortical magnification, as originally thought. PMID:23680486

  20. Mechanical Model for Dynamic Behavior of Concrete Under Impact Loading

    NASA Astrophysics Data System (ADS)

    Sun, Yuanxiang

    Concrete is a geo-material which is used substantively in the civil building and military safeguard. One coupled model of damage and plasticity to describe the complex behavior of concrete subjected to impact loading is proposed in this research work. The concrete is assumed as homogeneous continuum with pre-existing micro-cracks and micro-voids. Damage to concrete is caused due to micro-crack nucleation, growth and coalescence, and defined as the probability of fracture at a given crack density. It induces a decrease of strength and stiffness of concrete. Compaction of concrete is physically a collapse of the material voids. It produces the plastic strain in the concrete and, at the same time, an increase of the bulk modulus. In terms of crack growth model, micro-cracks are activated, and begin to propagate gradually. When crack density reaches a critical value, concrete takes place the smashing destroy. The model parameters for mortar are determined using plate impact experiment with uni-axial strain state. Comparison with the test results shows that the proposed model can give consistent prediction of the impact behavior of concrete. The proposed model may be used to design and analysis of concrete structures under impact and shock loading. This work is supported by State Key Laboratory of Explosion science and Technology, Beijing Institute of Technology (YBKT14-02).

  1. Neural mechanism underlying autobiographical memory modulated by remoteness and emotion

    NASA Astrophysics Data System (ADS)

    Ge, Ruiyang; Fu, Yan; Wang, DaHua; Yao, Li; Long, Zhiying

    2012-03-01

    Autobiographical memory is the ability to recollect past events from one's own life. Both emotional tone and memory remoteness can influence autobiographical memory retrieval along the time axis of one's life. Although numerous studies have been performed to investigate brain regions involved in retrieving processes of autobiographical memory, the effect of emotional tone and memory age on autobiographical memory retrieval remains to be clarified. Moreover, whether the involvement of hippocampus in consolidation of autobiographical events is time dependent or independent has been controversial. In this study, we investigated the effect of memory remoteness (factor1: recent and remote) and emotional valence (factor2: positive and negative) on neural correlates underlying autobiographical memory by using functional magnetic resonance imaging (fMRI) technique. Although all four conditions activated some common regions known as "core" regions in autobiographical memory retrieval, there are some other regions showing significantly different activation for recent versus remote and positive versus negative memories. In particular, we found that bilateral hippocampal regions were activated in the four conditions regardless of memory remoteness and emotional valence. Thus, our study confirmed some findings of previous studies and provided further evidence to support the multi-trace theory which believes that the role of hippocampus involved in autobiographical memory retrieval is time-independent and permanent in memory consolidation.

  2. Neural network mechanisms underlying stimulus driven variability reduction.

    PubMed

    Deco, Gustavo; Hugues, Etienne

    2012-01-01

    It is well established that the variability of the neural activity across trials, as measured by the Fano factor, is elevated. This fact poses limits on information encoding by the neural activity. However, a series of recent neurophysiological experiments have changed this traditional view. Single cell recordings across a variety of species, brain areas, brain states and stimulus conditions demonstrate a remarkable reduction of the neural variability when an external stimulation is applied and when attention is allocated towards a stimulus within a neuron's receptive field, suggesting an enhancement of information encoding. Using an heterogeneously connected neural network model whose dynamics exhibits multiple attractors, we demonstrate here how this variability reduction can arise from a network effect. In the spontaneous state, we show that the high degree of neural variability is mainly due to fluctuation-driven excursions from attractor to attractor. This occurs when, in the parameter space, the network working point is around the bifurcation allowing multistable attractors. The application of an external excitatory drive by stimulation or attention stabilizes one specific attractor, eliminating in this way the transitions between the different attractors and resulting in a net decrease in neural variability over trials. Importantly, non-responsive neurons also exhibit a reduction of variability. Finally, this reduced variability is found to arise from an increased regularity of the neural spike trains. In conclusion, these results suggest that the variability reduction under stimulation and attention is a property of neural circuits. PMID:22479168

  3. Mechanisms underlying angiotensin II-induced calcium oscillations

    PubMed Central

    Edwards, Aurélie; Pallone, Thomas L.

    2008-01-01

    To gain insight into the mechanisms that underlie angiotensin II (ANG II)-induced cytoplasmic Ca2+ concentration ([Ca]cyt) oscillations in medullary pericytes, we expanded a prior model of ion fluxes. ANG II stimulation was simulated by doubling maximal inositol trisphosphate (IP3) production and imposing a 90% blockade of K+ channels. We investigated two configurations, one in which ryanodine receptors (RyR) and IP3 receptors (IP3R) occupy a common store and a second in which they reside on separate stores. Our results suggest that Ca2+ release from stores and import from the extracellular space are key determinants of oscillations because both raise [Ca] in subplasmalemmal spaces near RyR. When the Ca2+-induced Ca2+ release (CICR) threshold of RyR is exceeded, the ensuing Ca2+ release is limited by Ca2+ reuptake into stores and export across the plasmalemma. If sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps do not remain saturated and sarcoplasmic reticulum Ca2+ stores are replenished, that phase is followed by a resumption of leak from internal stores that leads either to [Ca]cyt elevation below the CICR threshold (no oscillations) or to elevation above it (oscillations). Our model predicts that oscillations are more prone to occur when IP3R and RyR stores are separate because, in that case, Ca2+ released by RyR during CICR can enhance filling of adjacent IP3 stores to favor a high subsequent leak that generates further CICR events. Moreover, the existence or absence of oscillations depends on the set points of several parameters, so that biological variation might well explain the presence or absence of oscillations in individual pericytes. PMID:18562632

  4. Molecular Mechanisms Underlying Origin and Diversification of the Angiosperm Flower

    PubMed Central

    Theissen, Guenter; Melzer, Rainer

    2007-01-01

    Background Understanding the mode and mechanisms of the evolution of the angiosperm flower is a long-standing and central problem of evolutionary biology and botany. It has essentially remained unsolved, however. In contrast, considerable progress has recently been made in our understanding of the genetic basis of flower development in some extant model species. The knowledge that accumulated this way has been pulled together in two major hypotheses, termed the ‘ABC model’ and the ‘floral quartet model’. These models explain how the identity of the different types of floral organs is specified during flower development by homeotic selector genes encoding transcription factors. Scope We intend to explain how the ‘ABC model’ and the ‘floral quartet model’ are now guiding investigations that help to understand the origin and diversification of the angiosperm flower. Conclusions Investigation of orthologues of class B and class C floral homeotic genes in gymnosperms suggest that bisexuality was one of the first innovations during the origin of the flower. The transition from dimer to tetramer formation of floral homeotic proteins after establishment of class E proteins may have increased cooperativity of DNA binding of the transcription factors controlling reproductive growth. That way, we hypothesize, better ‘developmental switches’ originated that facilitated the early evolution of the flower. Expression studies of ABC genes in basally diverging angiosperm lineages, monocots and basal eudicots suggest that the ‘classical’ ABC system known from core eudicots originated from a more fuzzy system with fading borders of gene expression and gradual transitions in organ identity, by sharpening of ABC gene expression domains and organ borders. Shifting boundaries of ABC gene expression may have contributed to the diversification of the angiosperm flower many times independently, as may have changes in interactions between ABC genes and their target

  5. Untangling the web: Mechanisms underlying ER network formation

    PubMed Central

    Goyal, Uma; Blackstone, Craig

    2013-01-01

    The ER is a continuous membrane system consisting of the nuclear envelope, flat sheets often studded with ribosomes, and a polygonal network of highly-curved tubules extending throughout the cell. Although protein and lipid biosynthesis, protein modification, vesicular transport, Ca2+dynamics, and protein quality control have been investigated in great detail, mechanisms that generate the distinctive architecture of the ER have been uncovered only recently. Several protein families including the reticulons and REEPs/DP1/Yop1p harbor hydrophobic hairpin domains that shape high-curvature ER tubules and mediate intramembrane protein interactions. Members of the atlastin/RHD3/Sey1p family of dynamin-related GTPases interact with the ER-shaping proteins and mediate the formation of three-way junctions responsible for the polygonal structure of the tubular ER network, with Lunapark proteins acting antagonistically. Additional classes of tubular ER proteins including some REEPs and the M1 spastin ATPase interact with the microtubule cytoskeleton. Flat ER sheets possess a different complement of proteins such as p180, CLIMP-63 and kinectin implicated in shaping, cisternal stacking and cytoskeletal interactions. The ER is also in constant motion, and numerous signaling pathways as well as interactions among cytoskeletal elements, the plasma membrane, and organelles cooperate to position and shape the ER dynamically. Finally, many proteins involved in shaping the ER network are mutated in the most common forms of hereditary spastic paraplegia, indicating a particular importance for proper ER morphology and distribution in large, highly-polarized cells such as neurons. PMID:23602970

  6. Mechanisms underlying optical spectroscopic changes in primate and human cortex

    NASA Astrophysics Data System (ADS)

    Hochman, Daryl

    2003-03-01

    The optical scattering and absorption properties of brain tissue are correlated with changes in the level of neuronal activity. These activity-evoked optical changes are known as 'intrinsic optical signals' (IOS). Such changes are thought to be generated by a combination of least three physiological mechanisms: i) changes in blood volume, ii) changes in blood oxygenation, and iii) blood-independent light scattering changes resulting from ion fluxes associated with neuronal activity. The usefulness of IOS depends upon knowledge of the spatial and temporal relationships between neuronal activity and changes in brain metabolism and cerebral hemodynamics. Our studies focus on better understanding these relationships. The two major hemodynamic changes evoked by increases in neuronal activity are i) increases in blood volume mediated by dilation of microscopic pial arterioles, and ii) increases in blood oxygenation in the veins draining regions of activated cortex. Our experimental strategy has been to acquire high-magnification data sufficient to resolve the dynamics occurring within the distinct microvascular compartments. At specific wavelengths, contributions of blood oxygenation and volume to the IOS can be directly determined by observing the optical changes occurring within the distinct microvascular compartments. In this way, we have directly identified wavelengths that are either highly 'volume-selective' or 'oxygenation-selective'. Blood volume maps correlate closely with the spatial locations of neuronal activity, while blood oxygenation maps are often maximal in the larger draining veins at sites distant to neuronal activity. We have characterized novel spatio-temporal phenomena including propagating circular waves of activity evoked by epileptic activity.

  7. Compression under a mechanical counter pressure space suit glove

    NASA Technical Reports Server (NTRS)

    Waldie, James M A.; Tanaka, Kunihiko; Tourbier, Dietmar; Webb, Paul; Jarvis, Christine W.; Hargens, Alan R.

    2002-01-01

    Background: Current gas-pressurized space suits are bulky stiff shells severely limiting astronaut function and capability. A mechanical counter pressure (MCP) space suit in the form of a tight elastic garment could dramatically improve extravehicular activity (EVA) dexterity, but also be advantageous in safety, cost, mass and volume. The purpose of this study was to verify that a prototype MCP glove exerts the design compression of 200 mmHg, a pressure similar to the current NASA EVA suit. Methods: Seven male subjects donned a pressure measurement array and MCP glove on the right hand, which was placed into a partial vacuum chamber. Average compression was recorded on the palm, the bottom of the middle finger, the top of the middle finger and the dorsum of the hand at pressures of 760 (ambient), 660 and 580 mmHg. The vacuum chamber was used to simulate the pressure difference between the low breathing pressure of the current NASA space suits (approximately 200 mmHg) and an unprotected hand in space. Results: At ambient conditions, the MCP glove compressed the dorsum of the hand at 203.5 +/- 22.7 mmHg, the bottom of the middle finger at 179.4 +/- 16.0 mmHg, and the top of the middle finger at 183.8 +/- 22.6 mmHg. The palm compression was significantly lower (59.6 +/- 18.8 mmHg, p<0.001). There was no significant change in glove compression with the chamber pressure reductions. Conclusions: The MCP glove compressed the dorsum of the hand and middle finger at the design pressure.

  8. Enhancement of sleep slow waves: underlying mechanisms and practical consequences

    PubMed Central

    Bellesi, Michele; Riedner, Brady A.; Garcia-Molina, Gary N.; Cirelli, Chiara; Tononi, Giulio

    2014-01-01

    Even modest sleep restriction, especially the loss of sleep slow wave activity (SWA), is invariably associated with slower electroencephalogram (EEG) activity during wake, the occurrence of local sleep in an otherwise awake brain, and impaired performance due to cognitive and memory deficits. Recent studies not only confirm the beneficial role of sleep in memory consolidation, but also point to a specific role for sleep slow waves. Thus, the implementation of methods to enhance sleep slow waves without unwanted arousals or lightening of sleep could have significant practical implications. Here we first review the evidence that it is possible to enhance sleep slow waves in humans using transcranial direct-current stimulation (tDCS) and transcranial magnetic stimulation. Since these methods are currently impractical and their safety is questionable, especially for chronic long-term exposure, we then discuss novel data suggesting that it is possible to enhance slow waves using sensory stimuli. We consider the physiology of the K-complex (KC), a peripheral evoked slow wave, and show that, among different sensory modalities, acoustic stimulation is the most effective in increasing the magnitude of slow waves, likely through the activation of non-lemniscal ascending pathways to the thalamo-cortical system. In addition, we discuss how intensity and frequency of the acoustic stimuli, as well as exact timing and pattern of stimulation, affect sleep enhancement. Finally, we discuss automated algorithms that read the EEG and, in real-time, adjust the stimulation parameters in a closed-loop manner to obtain an increase in sleep slow waves and avoid undesirable arousals. In conclusion, while discussing the mechanisms that underlie the generation of sleep slow waves, we review the converging evidence showing that acoustic stimulation is safe and represents an ideal tool for slow wave sleep (SWS) enhancement. PMID:25389394

  9. Evaluating Molecular Mechanical Potentials for Helical Peptides and Proteins

    PubMed Central

    Thompson, Erik J.; DePaul, Allison J.; Patel, Sarav S.; Sorin, Eric J.

    2010-01-01

    Multiple variants of the AMBER all-atom force field were quantitatively evaluated with respect to their ability to accurately characterize helix-coil equilibria in explicit solvent simulations. Using a global distributed computing network, absolute conformational convergence was achieved for large ensembles of the capped A21 and Fs helical peptides. Further assessment of these AMBER variants was conducted via simulations of a flexible 164-residue five-helix-bundle protein, apolipophorin-III, on the 100 ns timescale. Of the contemporary potentials that had not been assessed previously, the AMBER-99SB force field showed significant helix-destabilizing tendencies, with beta bridge formation occurring in helical peptides, and unfolding of apolipophorin-III occurring on the tens of nanoseconds timescale. The AMBER-03 force field, while showing adequate helical propensities for both peptides and stabilizing apolipophorin-III, (i) predicts an unexpected decrease in helicity with ALA→ARG+ substitution, (ii) lacks experimentally observed 310 helical content, and (iii) deviates strongly from average apolipophorin-III NMR structural properties. As is observed for AMBER-99SB, AMBER-03 significantly overweighs the contribution of extended and polyproline backbone configurations to the conformational equilibrium. In contrast, the AMBER-99φ force field, which was previously shown to best reproduce experimental measurements of the helix-coil transition in model helical peptides, adequately stabilizes apolipophorin-III and yields both an average gyration radius and polar solvent exposed surface area that are in excellent agreement with the NMR ensemble. PMID:20418937

  10. Barrier formation: potential molecular mechanism of enamel fluorosis.

    PubMed

    Lyaruu, D M; Medina, J F; Sarvide, S; Bervoets, T J M; Everts, V; Denbesten, P; Smith, C E; Bronckers, A L J J

    2014-01-01

    Enamel fluorosis is an irreversible structural enamel defect following exposure to supraoptimal levels of fluoride during amelogenesis. We hypothesized that fluorosis is associated with excess release of protons during formation of hypermineralized lines in the mineralizing enamel matrix. We tested this concept by analyzing fluorotic enamel defects in wild-type mice and mice deficient in anion exchanger-2a,b (Ae2a,b), a transmembrane protein in maturation ameloblasts that exchanges extracellular Cl(-) for bicarbonate. Defects were more pronounced in fluorotic Ae2a,b (-/-) mice than in fluorotic heterozygous or wild-type mice. Phenotypes included a hypermineralized surface, extensive subsurface hypomineralization, and multiple hypermineralized lines in deeper enamel. Mineral content decreased in all fluoride-exposed and Ae2a,b(-/-) mice and was strongly correlated with Cl(-). Exposure of enamel surfaces underlying maturation-stage ameloblasts to pH indicator dyes suggested the presence of diffusion barriers in fluorotic enamel. These results support the concept that fluoride stimulates hypermineralization at the mineralization front. This causes increased release of protons, which ameloblasts respond to by secreting more bicarbonates at the expense of Cl(-) levels in enamel. The fluoride-induced hypermineralized lines may form barriers that impede diffusion of proteins and mineral ions into the subsurface layers, thereby delaying biomineralization and causing retention of enamel matrix proteins. PMID:24170372

  11. Ambient particle inhalation and the cardiovascular system: potential mechanisms.

    PubMed Central

    Donaldson, K; Stone, V; Seaton, A; MacNee, W

    2001-01-01

    Well-documented air pollution episodes throughout recent history have led to deaths among individuals with cardiovascular and respiratory disease. Although the components of air pollution that cause the adverse health effects in these individuals are unknown, a small proportion by mass but a large proportion by number of the ambient air particles are ultrafine, i.e., less than 100 nm in diameter. This ultrafine component of particulate matter with a mass median aerodynamic diameter less than 10 microm (PM(10) may mediate some of the adverse health effects reported in epidemiologic studies and for which there is toxicologic evidence to support this contention. The exact mechanism by which ultrafine particles have adverse effects is unknown, but these particles have recently been shown to enhance calcium influx on contact with macrophages. Oxidative stress is also to be anticipated at the huge particle surface; this can be augmented by oxidants generated by recruited inflammatory leukocytes. Atheromatous plaques form in the coronary arteries and are major causes of morbidity and death associated epidemiologically with particulate air pollution. In populations exposed to air pollution episodes, blood viscosity, fibrinogen, and C-reactive protein (CRP) were higher. More recently, increases in heart rate in response to rising air pollution have been described and are most marked in individuals who have high blood viscosity. In our study of elderly individuals, there were significant rises in CRP, an index of inflammation. In this present review, we consider the likely interactions between the ultrafine particles the acute phase response and cardiovascular disease. PMID:11544157

  12. Escape rate of Brownian particles from a metastable potential well under time derivative Ornstein-Uhlenbeck noise

    NASA Astrophysics Data System (ADS)

    Bai, Zhan-Wu; Wang, Ping

    2016-03-01

    We investigate the escape rate of Brownian particles that move in a cubic metastable potential subjected to an internal time derivative Ornstein-Uhlenbeck noise (DOUN). This noise can induce the ballistic diffusion of force-free Brownian particles. Some new features are found. The escape rate for DOUN shows qualitative different dependence on potential well width compared with OUN which induces normal diffusion. As the potential barrier height decreases, the escape rate of DOUN deviates from Arrhenius law considerably earlier than that of Ornstein-Uhlenbeck noise (OUN). The Brownian particles escape faster under DOUN than that under OUN. A quasi-periodic oscillation occurs in transient state. A solvable case is presented to demonstrate the significant cancellation behavior in the barrier region that governs most of these phenomena. The physical mechanism of the findings can be clarified by the noise features. These characteristics should be common for internal noises that induce superdiffusion, especially the ballistic diffusion.

  13. The neural mechanisms underlying internally and externally guided task selection.

    PubMed

    Orr, Joseph M; Banich, Marie T

    2014-01-01

    While some prior work suggests that medial prefrontal cortex (MFC) regions mediate freely chosen actions, other work suggests that the lateral frontal pole (LFP) is responsible for control of abstract, internal goals. The present study uses fMRI to determine whether the voluntary selection of a task in pursuit of an overall goal relies on MFC regions or the LFP. To do so, we used a modified voluntary task switching (VTS) paradigm, in which participants choose an individual task to perform on each trial (i.e., a subgoal), under instructions to perform the tasks equally often and in a random order (i.e. the overall goal). In conjunction, we examined patterns of activation in the face of irrelevant, but task-related external stimuli that might nonetheless influence task selection. While there was some evidence that the MFC was involved in voluntary task selection, we found that the LFP and anterior insula (AI) were crucial to task selection in the pursuit of an overall goal. In addition, activation of the LFP and AI increased in the face of environmental stimuli that might serve as an interfering or conflicting external bias on voluntary task choice. These findings suggest that the LFP supports task selection according to abstract, internal goals, and leaves open the possibility that MFC may guide action selection in situations lacking in such top-down biases. As such, the current study represents a critical step towards understanding the neural underpinnings of how tasks are selected voluntarily to enable an overarching goal. PMID:23994316

  14. Determining polarizable force fields with electrostatic potentials from quantum mechanical linear response theory.

    PubMed

    Wang, Hao; Yang, Weitao

    2016-06-14

    We developed a new method to calculate the atomic polarizabilities by fitting to the electrostatic potentials (ESPs) obtained from quantum mechanical (QM) calculations within the linear response theory. This parallels the conventional approach of fitting atomic charges based on electrostatic potentials from the electron density. Our ESP fitting is combined with the induced dipole model under the perturbation of uniform external electric fields of all orientations. QM calculations for the linear response to the external electric fields are used as input, fully consistent with the induced dipole model, which itself is a linear response model. The orientation of the uniform external electric fields is integrated in all directions. The integration of orientation and QM linear response calculations together makes the fitting results independent of the orientations and magnitudes of the uniform external electric fields applied. Another advantage of our method is that QM calculation is only needed once, in contrast to the conventional approach, where many QM calculations are needed for many different applied electric fields. The molecular polarizabilities obtained from our method show comparable accuracy with those from fitting directly to the experimental or theoretical molecular polarizabilities. Since ESP is directly fitted, atomic polarizabilities obtained from our method are expected to reproduce the electrostatic interactions better. Our method was used to calculate both transferable atomic polarizabilities for polarizable molecular mechanics' force fields and nontransferable molecule-specific atomic polarizabilities. PMID:27305996

  15. Lifestyle, health and disease prevention: the underlying mechanisms.

    PubMed

    Weisburger, J H

    2002-08-01

    International studies in geographic pathology provide background information that a disease may have a quite different incidence and resulting mortality as a function of area of residence. Investigations in animals can model fairly precisely what is learned through such international research, and provide the basis for examining relevant hypotheses and, more importantly, possible mechanisms of action. These approaches can yield public health recommendations and health promotion activities. Regular intake of foods rich in saturated fats, such as meat and certain dairy products, raises the risk of coronary heart disease, especially in smokers. The total mixed fat intake is associated with a higher incidence of the nutritionally linked cancers (i.e. of the postmenopausal breast, distal colon, prostate, pancreas, ovary and endometrium). Monounsaturated oils, such as olive or canola oil, are low-risk fats, as shown in animal models, and through the finding that the incidence of coronary heart and neoplastic diseases is lower in the Mediterranean region, where such oils are customarily used. Fish and fish oils are protective. The associated genotoxic carcinogens for several of these cancers, and also in heart disease causation, are heterocyclic amines, produced during the broiling and frying of creatinine-containing foods such as meats. Excessive salt intake is associated with high blood pressure and with stomach cancer, especially with inadequate intake of potassium, from fruits and vegetables, and calcium from certain vegetables and low-fat dairy products. Bran cereal fiber intake, especially with adequate calcium, yields an increased stool bulk, eliminating factors involved in colon and breast cancer. Vegetables and fruits, as well as soy products, are rich in antioxidants that are essential to lower disease risk stemming from reactive oxygen species in the body. Green and black tea are excellent sources of such beneficial antioxidants of a polyphenol nature, as are

  16. Corticonic models of brain mechanisms underlying cognition and intelligence

    NASA Astrophysics Data System (ADS)

    Farhat, Nabil H.

    underlying intelligence and other higher level brain functions.

  17. Change of plans: an evaluation of the effectiveness and underlying mechanisms of successful talent transfer.

    PubMed

    Collins, Rosie; Collins, Dave; MacNamara, Aine; Jones, Martin Ian

    2014-01-01

    Talent transfer (TT) is a recently formalised process used to identify and develop talented athletes by selecting individuals who have already succeeded in one sport and transferring them to another. Despite the increasing popularity of TT amongst national organisations and sport governing body professionals, however, there is little empirical evidence as to its efficacy or how it may be most efficiently employed. Accordingly, this investigation was designed to gain a deeper understanding of the effectiveness and underlying mechanisms of TT, achieved through a two-part study. Stage 1 provided a quantitative analysis of the incidence and distribution or, in this respect, epidemiology of TT, finding the most popular transfer to be sprinting to bobsleigh, with an average transfer age of 19 years. Stage 2 scrutinised the TT process and explored the specific cases revealed in stage 1 by examining the perceptions of four sport science support specialists who had worked in TT settings, finding several emergent themes which, they felt, could explain the TT processes. The most prominent theme was the psychosocial mechanism of TT, an aspect currently missing from TT initiatives, suggesting that current TT systems are poorly structured and should redress their approach to develop a more integrated scheme that encompasses all potential mechanisms of transfer. PMID:24814474

  18. Defect induced plasticity and failure mechanism of boron nitride nanotubes under tension

    SciTech Connect

    Anoop Krishnan, N. M. Ghosh, Debraj

    2014-07-28

    The effects of Stone-Wales (SW) and vacancy defects on the failure behavior of boron nitride nanotubes (BNNTs) under tension are investigated using molecular dynamics simulations. The Tersoff-Brenner potential is used to model the atomic interaction and the temperature is maintained close to 300 K. The effect of a SW defect is studied by determining the failure strength and failure mechanism of nanotubes with different radii. In the case of a vacancy defect, the effect of an N-vacancy and a B-vacancy is studied separately. Nanotubes with different chiralities but similar diameter is considered first to evaluate the chirality dependence. The variation of failure strength with the radius is then studied by considering nanotubes of different diameters but same chirality. It is observed that the armchair BNNTs are extremely sensitive to defects, whereas the zigzag configurations are the least sensitive. In the case of pristine BNNTs, both armchair and zigzag nanotubes undergo brittle failure, whereas in the case of defective BNNTs, only the zigzag ones undergo brittle failure. An interesting defect induced plastic behavior is observed in defective armchair BNNTs. For this nanotube, the presence of a defect triggers mechanical relaxation by bond breaking along the closest zigzag helical path, with the defect as the nucleus. This mechanism results in a plastic failure.

  19. In situ investigation of Geobacillus stearothermophilus spore germination and inactivation mechanisms under moderate high pressure.

    PubMed

    Georget, Erika; Kapoor, Shobhna; Winter, Roland; Reineke, Kai; Song, Youye; Callanan, Michael; Ananta, Edwin; Heinz, Volker; Mathys, Alexander

    2014-08-01

    Bacterial spores are a major concern for food safety due to their high resistance to conventional preservation hurdles. Innovative hurdles can trigger bacterial spore germination or inactivate them. In this work, Geobacillus stearothermophilus spore high pressure (HP) germination and inactivation mechanisms were investigated by in situ infrared spectroscopy (FT-IR) and fluorometry. G. stearothermophilus spores' inner membrane (IM) was stained with Laurdan fluorescent dye. Time-dependent FT-IR and fluorescence spectra were recorded in situ under pressure at different temperatures. The Laurdan spectrum is affected by the lipid packing and level of hydration, and provided information on the IM state through the Laurdan generalized polarization. Changes in the -CH2 and -CH3 asymmetric stretching bands, characteristic of lipids, and in the amide I' band region, characteristic of proteins' secondary structure elements, enabled evaluation of the impact of HP on endospores lipid and protein structures. These studies were complemented by ex situ analyses (plate counts and microscopy). The methods applied showed high potential to identify germination mechanisms, particularly associated to the IM. Germination up to 3 log10 was achieved at 200 MPa and 55 °C. A molecular-level understanding of these mechanisms is important for the development and validation of multi-hurdle approaches to achieve commercial sterility. PMID:24750808

  20. Biological mechanisms underlying the role of physical fitness in health and resilience

    PubMed Central

    Silverman, Marni N.; Deuster, Patricia A.

    2014-01-01

    Physical fitness, achieved through regular exercise and/or spontaneous physical activity, confers resilience by inducing positive psychological and physiological benefits, blunting stress reactivity, protecting against potentially adverse behavioural and metabolic consequences of stressful events and preventing many chronic diseases. In this review, we discuss the biological mechanisms underlying the beneficial effects of physical fitness on mental and physical health. Physical fitness appears to buffer against stress-related disease owing to its blunting/optimizing effects on hormonal stress responsive systems, such as the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system. This blunting appears to contribute to reduced emotional, physiological and metabolic reactivity as well as increased positive mood and well-being. Another mechanism whereby regular exercise and/or physical fitness may confer resilience is through minimizing excessive inflammation. Chronic psychological stress, physical inactivity and abdominal adiposity have been associated with persistent, systemic, low-grade inflammation and exert adverse effects on mental and physical health. The anti-inflammatory effects of regular exercise/activity can promote behavioural and metabolic resilience, and protect against various chronic diseases associated with systemic inflammation. Moreover, exercise may benefit the brain by enhancing growth factor expression and neural plasticity, thereby contributing to improved mood and cognition. In summary, the mechanisms whereby physical fitness promotes increased resilience and well-being and positive psychological and physical health are diverse and complex. PMID:25285199

  1. Mechanical behavior of twinned SiC nanowires under combined tension-torsion and compression-torsion strain

    SciTech Connect

    Li, Zhijie; Wang, Shengjie; Wang, Zhiguo; Zu, Xiaotao T.; Gao, Fei; Weber, William J.

    2010-07-01

    The mechanical behavior of twinned silicon carbide (SiC) nanowires under combined tension-torsion and compression-torsion is investigated using molecular dynamics simulations with an empirical potential. The simulation results show that both the tensile failure stress and buckling stress decrease under combined tension-torsional and combined compression-torsional strain, and they decrease with increasing torsional rate under combined loading. The torsion rate has no effect on the elastic properties of the twinned SiC nanowires. The collapse of the twinned nanowires takes place in a twin stacking fault of the nanowires.

  2. Potential corrosion and degradation mechanisms of Zircaloy cladding on spent nuclear fuel in a tuff repository

    SciTech Connect

    Rothman, A.J.

    1984-09-01

    A literature review and analysis were made of corrosion and degradation processes applicable to Zircaloy cladding on spent nuclear fuel in a tuff repository. In particular, lifetime sought for the Zircaloy is 10,000 years. Among the potential failure mechanisms examined were: oxidation by steam, air, and water, including the effects of ions whose presence is anticipated in the water; mechanical overload; stress (creep) rupture; stress-corrosion cracking (SCC); and delayed failure due to hydride cracking. The conclusion is that failure due to oxidation is not credible, although a few experiments are suggested to confirm the effect of aqueous fluoride on the Zircaloy cladding. Mechanical overload is not a problem, and failure from stress-rupture does not appear likely based on a modified Larson-Miller analysis. Analysis shows that delayed hydride cracking is not anticipated for the bulk of spent fuel pins. However, for a minority of pins under high stress, there is some uncertainty in the analysis as a result of: (1) uncertainty about crack depths in spent fuel claddings and (2) the effect of slow cooling on the formation of radially oriented hydride precipitates. Experimental resolution is called for. Finally, insufficient information is currently available on stress-corrosion cracking. While evidence is presented that SCC failure is not likely to occur, it is difficult to demonstrate this conclusively because the process is not clearly understood and data are limited. Further experimental work on SCC susceptibility is especially needed.

  3. Simple solutions of the free-edge effects in composite laminates under thermal and mechanical loads

    SciTech Connect

    Yin, W.

    1993-01-01

    Intense and localized interlaminar stresses generally occur in a narrow boundary region near the free edge of a multilayered anisotropic laminate under mechanical and temperature loads. Quantitative measures of interlaminar action across interfaces may be readily obtained, through purely algebraic operations, even if nonlinear and inelastic material behavior becomes significant in the boundary region due to severe strain concentration. These measures are the limiting values of the Lekhnitskii stress functions F and psi (and of the normal derivative of F) along interfaces and toward the interior region of the laminate. In the present work, they are used as the basis of an exceedingly simple and efficient method of interlaminar stress analysis that is potentially applicable to free-edge problems involving nonlinear thermoelastic constitutive relations. 11 refs.

  4. Understanding Cellular Mechanisms Underlying Airway Epithelial Repair: Selecting the Most Appropriate Animal Models

    PubMed Central

    Yahaya, B.

    2012-01-01

    Understanding the mechanisms underlying the process of regeneration and repair of airway epithelial structures demands close characterization of the associated cellular and molecular events. The choice of an animal model system to study these processes and the role of lung stem cells is debatable since ideally the chosen animal model should offer a valid comparison with the human lung. Species differences may include the complex three-dimensional lung structures, cellular composition of the lung airway as well as transcriptional control of the molecular events in response to airway epithelium regeneration, and repair following injury. In this paper, we discuss issues related to the study of the lung repair and regeneration including the role of putative stem cells in small- and large-animal models. At the end of this paper, the author discuss the potential for using sheep as a model which can help bridge the gap between small-animal model systems and humans. PMID:23049478

  5. Metabolic Memory and Chronic Diabetes Complications: Potential Role for Epigenetic Mechanisms

    PubMed Central

    Intine, Robert V.; Sarras, Michael P.

    2012-01-01

    Recent estimates indicate that diabetes mellitus currently affects more than ten percent of the world’s population. Evidence from both the laboratory and large scale clinical trials has revealed that prolonged hyperglycemia induces chronic complications which persist and progress unimpeded even when glycemic control is pharmaceutically achieved via the phenomenon of metabolic memory. The epigenome is comprised of all chromatin modifications including post translational histone modification, expression control via miRNAs and the methylation of cytosine within DNA. Modifications of these epigenetic marks not only allow cells and organisms to quickly respond to changing environmental stimuli but also confer the ability of the cell to “memorize” these encounters. As such, these processes have gained much attention as potential molecular mechanisms underlying metabolic memory and chronic diabetic complications. Here we present a review of the very recent literature published pertaining to this subject. PMID:22760445

  6. Atypical Gaze Following in Autism: A Comparison of Three Potential Mechanisms

    PubMed Central

    Gillespie-Lynch, K.; Elias, R.; Escudero, P.; Hutman, T.; Johnson, S. P.

    2014-01-01

    In order to evaluate the following potential mechanisms underlying atypical gaze following in autism, impaired reflexive gaze following, difficulty integrating gaze and affect, or reduced understanding of the referential significance of gaze, we administered three paradigms to young children with autism (N = 21) and chronological (N = 21) and nonverbal mental age (N = 21) matched controls. Children with autism exhibited impaired reflexive gaze following. The absence of evidence of integration of gaze and affect, regardless of diagnosis, indicates ineffective measurement of this construct. Reduced gaze following was apparent among children with autism during eye-tracking and in-person assessments. Word learning from gaze cues was better explained by developmental level than autism. Thus, gaze following may traverse an atypical, rather than just delayed, trajectory in autism. PMID:23619947

  7. Coupled mechanical-electrical-thermal modeling for short-circuit prediction in a lithium-ion cell under mechanical abuse

    NASA Astrophysics Data System (ADS)

    Zhang, Chao; Santhanagopalan, Shriram; Sprague, Michael A.; Pesaran, Ahmad A.

    2015-09-01

    In order to better understand the behavior of lithium-ion batteries under mechanical abuse, a coupled modeling methodology encompassing the mechanical, electrical and thermal response is presented for predicting short-circuit under external crush. The combined mechanical-electrical-thermal response is simulated in a commercial finite element software LS-DYNA® using a representative-sandwich finite-element model, where electrical-thermal modeling is conducted after an instantaneous mechanical crush. The model includes an explicit representation of each individual component such as the active material, current collector, separator, etc., and predicts their mechanical deformation under quasi-static indentation. Model predictions show good agreement with experiments: the fracture of the battery structure under an indentation test is accurately predicted. The electrical-thermal simulation predicts the current density and temperature distribution in a reasonable manner. Whereas previously reported models consider the mechanical response exclusively, we use the electrical contact between active materials following the failure of the separator as a criterion for short-circuit. These results are used to build a lumped representative sandwich model that is computationally efficient and captures behavior at the cell level without resolving the individual layers.

  8. Neural mechanisms underlying the integration of situational information into attribution outcomes.

    PubMed

    Brosch, Tobias; Schiller, Daniela; Mojdehbakhsh, Rachel; Uleman, James S; Phelps, Elizabeth A

    2013-08-01

    When forming impressions and trying to figure out why other people behave the way they do, we should take into account not only dispositional factors (i.e., personality traits) but also situational constraints as potential causes for a behavior. However, in their attributions, people often ignore the importance of situational factors. To investigate the neural mechanisms underlying the integration of situational information into attributions, we decomposed the attribution process by separately presenting information about behaviors and about the situational circumstances in which they occur. After reading the information, participants judged whether dispositional or situational causes explained the behavior (attribution), and how much they liked the person described in the scenario (affective evaluation). The dorsolateral prefrontal cortex showed increased blood oxygenation-level-dependent activation during the encoding of situational information when the resulting attribution was situational, relative to when the attribution was dispositional, potentially reflecting a controlled process that integrates situational information into attributions. Interestingly, attributions were strongly linked to subsequent affective evaluations, with the dorsomedial prefrontal cortex emerging as potential substrate of the integration of attributions and affective evaluations. Our findings demonstrate how top-down control processes regulate impression formation when situational information is taken into account to understand others. PMID:23446840

  9. Multiple NSAID-Induced Hits Injure the Small Intestine: Underlying Mechanisms and Novel Strategies

    PubMed Central

    Boelsterli, Urs A.

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal (GI) injury including jejunal/ileal mucosal ulceration, bleeding, and even perforation in susceptible patients. The underlying mechanisms are largely unknown, but they are distinct from those related to gastric injury. Based on recent insights from experimental models, including genetics and pharmacology in rodents typically exposed to diclofenac, indomethacin, or naproxen, we propose a multiple-hit pathogenesis of NSAID enteropathy. The multiple hits start with an initial pharmacokinetic determinant caused by vectorial hepatobiliary excretion and delivery of glucuronidated NSAID or oxidative metabolite conjugates to the distal small intestinal lumen, where bacterial β-glucuronidase produces critical aglycones. The released aglycones are then taken up by enterocytes and further metabolized by intestinal cytochrome P450s to potentially reactive intermediates. The “first hit” is caused by the NSAID and/or oxidative metabolites that induce severe endoplasmic reticulum stress or mitochondrial stress and lead to cell death. The “second hit” is created by the significant subsequent inflammatory response that would follow such a first-hit injury. Based on these putative mechanisms, strategies have been developed to protect the enterocytes from being exposed to the parent NSAID and/or oxidative metabolites. Among these, a novel strategy already demonstrated in a murine model is the selective disruption of bacteria-specific β-glucuronidases with a novel small molecule inhibitor that does not harm the bacteria and that alleviates NSAID-induced enteropathy. Such mechanism-based strategies require further investigation but provide potential avenues for the alleviation of the GI toxicity caused by multiple NSAID hits. PMID:23091168

  10. Cellular and Deafness Mechanisms Underlying Connexin Mutation-Induced Hearing Loss – A Common Hereditary Deafness

    PubMed Central

    Wingard, Jeffrey C.; Zhao, Hong-Bo

    2015-01-01

    Hearing loss due to mutations in the connexin gene family, which encodes gap junctional proteins, is a common form of hereditary deafness. In particular, connexin 26 (Cx26, GJB2) mutations are responsible for ~50% of non-syndromic hearing loss, which is the highest incidence of genetic disease. In the clinic, Cx26 mutations cause various auditory phenotypes ranging from profound congenital deafness at birth to mild, progressive hearing loss in late childhood. Recent experiments demonstrate that congenital deafness mainly results from cochlear developmental disorders rather than hair cell degeneration and endocochlear potential reduction, while late-onset hearing loss results from reduction of active cochlear amplification, even though cochlear hair cells have no connexin expression. However, there is no apparent, demonstrable relationship between specific changes in connexin (channel) functions and the phenotypes of mutation-induced hearing loss. Moreover, new experiments further demonstrate that the hypothesized K+-recycling disruption is not a principal deafness mechanism for connexin deficiency induced hearing loss. Cx30 (GJB6), Cx29 (GJC3), Cx31 (GJB3), and Cx43 (GJA1) mutations can also cause hearing loss with distinct pathological changes in the cochlea. These new studies provide invaluable information about deafness mechanisms underlying connexin mutation-induced hearing loss and also provide important information for developing new protective and therapeutic strategies for this common deafness. However, the detailed cellular mechanisms underlying these pathological changes remain unclear. Also, little is known about specific mutation-induced pathological changes in vivo and little information is available for humans. Such further studies are urgently required. PMID:26074771

  11. Carbon dioxide emissions under different soil tillage systems in mechanically harvested sugarcane

    NASA Astrophysics Data System (ADS)

    Silva-Olaya, A. M.; Cerri, C. E. P.; La Scala, N., Jr.; Dias, C. T. S.; Cerri, C. C.

    2013-03-01

    Soil tillage and other methods of soil management may influence CO2 emissions because they accelerate the mineralization of organic carbon in the soil. This study aimed to quantify the CO2 emissions under conventional tillage (CT), minimum tillage (MT) and reduced tillage (RT) during the renovation of sugarcane fields in southern Brazil. The experiment was performed on an Oxisol in the sugarcane-planting area with mechanical harvesting. An undisturbed or no-till (NT) plot was left as a control treatment. The CO2 emissions results indicated a significant interaction (p < 0.001) between tillage method and time after tillage. By quantifying the accumulated emissions over the 44 days after soil tillage, we observed that tillage-induced emissions were higher after the CT system than the RT and MT systems, reaching 350.09 g m-2 of CO2 in CT, and 51.7 and 5.5 g m-2 of CO2 in RT and MT respectively. The amount of C lost in the form of CO2 due to soil tillage practices was significant and comparable to the estimated value of potential annual C accumulation resulting from changes in the harvesting system in Brazil from burning of plant residues to the adoption of green cane harvesting. The CO2 emissions in the CT system could respond to a loss of 80% of the potential soil C accumulated over one year as result of the adoption of mechanized sugarcane harvesting. Meanwhile, soil tillage during the renewal of the sugar plantation using RT and MT methods would result in low impact, with losses of 12% and 2% of the C that could potentially be accumulated during a one year period.

  12. In vivo toxicity of nano-alumina on mice neurobehavioral profiles and the potential mechanisms.

    PubMed

    Zhang, Q L; Li, M Q; Ji, J W; Gao, F P; Bai, R; Chen, C Y; Wang, Z W; Zhang, C; Niu, Q

    2011-01-01

    The rapid development and expanding applications of nanotechnology have led to enhanced exposure of human body to nanoparticles. It is, therefore, necessary to address the safety issue via rigorous toxicological evaluation and to understand the underlying interaction mechanism. However, only a few studies to date have evaluated the safety of nano-sized materials and their potential adverse effects on biological systems. In this study, we sought to investigate the potential toxicity of aluminum oxide (alumina) nanoparticles in ICR strained mice, focusing on potential neurobehavioral defects and the possible mechanisms. The results demonstrated that nano-alumina impaired neurobehavioral functions, including lengthened escape latency, shorter time spent in the target quadrant and reductions in the number of platform crossing. In addition, it induced cell necrosis and apoptosis, which were likely mediated by the reduction of MMP and ROS, and the induction of the caspase-3 gene. Our results implicated that mitochondrial impairment plays a key role in neurotoxicity of nano-alumina, sequent oxidative damage and neural cell loss, especially necrosis, may be direct causes for the neurobehavioral defects. Collectively, nano-alumina presents a strong pro-cell death effect on ICR mice in vivo, suggesting that nano-alumina may serve as an inducer for neural toxicology. Findings in the present study indicating that surface chemical characteristics and nanoscale sizes of nano-alumina could co-contribute significantly to neurotoxicity. The impaired neurobehavioral patterns indicate that nano-alumina particles are more toxic to the cerebrum than those of nano-carbon with the same nanoparticle size and micro-alumina with the same surface chemical characteristics. PMID:21329562

  13. Managing the underlying cause of cystic fibrosis: a future role for potentiators and correctors.

    PubMed

    Galietta, Luis J V

    2013-10-01

    Cystic fibrosis (CF), a severe genetic disease, is caused by mutations that alter the structure and function of CFTR, a plasma membrane channel permeable to chloride and bicarbonate. Defective anion transport in CF irreversibly damages the lungs, pancreas, liver, and other organs. CF mutations cause loss of CFTR function in multiple ways. In particular, class 3 mutations such as p.Gly551Asp strongly decrease the time spent by CFTR in the open state (gating defect). Instead, class 2 mutations impair the maturation of CFTR protein and its transport from the endoplasmic reticulum to the plasma membrane (trafficking defect). The deletion of phenylalanine 508 (p.Phe508del), the most frequent mutation among CF patients (70-90 %), destabilizes the CFTR protein, thus causing both a trafficking and a gating defect. These two defects can be overcome with drug-like molecules generically called correctors and potentiators, respectively. The potentiator Kalydeco™ (also known as Ivacaftor or VX-770), developed by Vertex Pharmaceuticals, has been recently approved by the US FDA and the European Medicines Agency (EMA) for the treatment of CF patients carrying at least one CFTR allele with the p.Gly551Asp mutation (2-5 % of all patients). In contrast, the corrector VX-809, which significantly improves p.Phe508del-CFTR trafficking in vitro, is still under study in clinical trials. Because of multiple defects caused by the p.Phe508del mutation, it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action. This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect. PMID:23757197

  14. Atomic and global mechanical properties of systems described by the Stillinger-Weber potential.

    PubMed

    Voyiatzis, Evangelos; Böhm, Michael C

    2016-08-17

    Analytical expressions for the stress and elasticity tensors of materials, in which the interactions are described by the Stillinger-Weber potential, are derived in the context of the stress fluctuation formalism. The derived formulas can be used both in Monte Carlo and molecular dynamics simulations. As an example of possible applications, they are employed to calculate the influence of the temperature and system size on the mechanical properties of crystalline cubic boron nitride. The system has been studied by molecular dynamics simulations. The computed mechanical properties are in good agreement with available experimental data and first principle calculations. In the studied crystalline cubic boron nitride system, the employed formalism is of higher accuracy than the 'small-strain' non-equilibrium method. The dominant contributions to the elastic constants stem from the Born and stress fluctuation terms. An increase in the system size reduces the statistical uncertainties in the computation of the mechanical properties. A rise of the temperature leads to a slight increase in the observed uncertainties. The derived expressions for the stress and elasticity tensors are further decomposed into sums of atomic level stress and atomic level elasticity tensors. The developed factorization enables us (i) to quantify the contribution of the various chemical groups, in the case under consideration of the different atoms, to the observed mechanical properties and (ii) to determine the elastic constants with reduced computational uncertainties. The reason is that the exact values of some terms of the proposed factorization can be determined theoretically beforehand. Thus, they can be substituted in the derived formulas leading to an enhanced convergence. PMID:27345739

  15. Atomic and global mechanical properties of systems described by the Stillinger–Weber potential

    NASA Astrophysics Data System (ADS)

    Voyiatzis, Evangelos; Böhm, Michael C.

    2016-08-01

    Analytical expressions for the stress and elasticity tensors of materials, in which the interactions are described by the Stillinger–Weber potential, are derived in the context of the stress fluctuation formalism. The derived formulas can be used both in Monte Carlo and molecular dynamics simulations. As an example of possible applications, they are employed to calculate the influence of the temperature and system size on the mechanical properties of crystalline cubic boron nitride. The system has been studied by molecular dynamics simulations. The computed mechanical properties are in good agreement with available experimental data and first principle calculations. In the studied crystalline cubic boron nitride system, the employed formalism is of higher accuracy than the ‘small-strain’ non-equilibrium method. The dominant contributions to the elastic constants stem from the Born and stress fluctuation terms. An increase in the system size reduces the statistical uncertainties in the computation of the mechanical properties. A rise of the temperature leads to a slight increase in the observed uncertainties. The derived expressions for the stress and elasticity tensors are further decomposed into sums of atomic level stress and atomic level elasticity tensors. The developed factorization enables us (i) to quantify the contribution of the various chemical groups, in the case under consideration of the different atoms, to the observed mechanical properties and (ii) to determine the elastic constants with reduced computational uncertainties. The reason is that the exact values of some terms of the proposed factorization can be determined theoretically beforehand. Thus, they can be substituted in the derived formulas leading to an enhanced convergence.

  16. Quantum mechanical elucidation of reaction mechanisms of heavy-light-heavy systems: Role of potential ridge

    NASA Astrophysics Data System (ADS)

    Nobusada, Katsuyuki; Tolstikhin, Oleg I.; Nakamura, Hiroki

    1998-06-01

    A new idea to elucidate quantum reaction dynamics of heavy-light-heavy (HLH) systems is proposed on the basis of the hyperspherical elliptic coordinate approach. This coordinate system has a big advantage of nicely expressing good vibrational adiabaticity in the HLH systems. Taking this advantage, the concept of potential ridge is introduced, for the first time, in three-dimensional reactions. The potential ridge is proved to be very useful to extract some important avoided crossings which dominate the reaction dynamics. In fact, qualitative features of the reaction dynamics can be interpreted in terms of nonadiabatic transitions at those important avoided crossings near the potential ridge. Examples are: (i) onset of reaction for a specified initial rotational state, and (ii) major reactive transition for a specified initial rotational state. Avoided crossings to the left of the potential ridge are also useful to interpret certain aspects of reactions accompanying vibrational transitions. The new idea mentioned above is applied to a typical HLH reaction O(3P)+HCl→OH+Cl with the use of two types of potential energy surfaces.

  17. Activation of lipid peroxidation as a mechanism of plant cell rearrangements under microgravity

    NASA Astrophysics Data System (ADS)

    Baranenko, V. V.

    Activation of the lipid peroxidation (LP) is a universal process perturbating cell membranes under different unfavourable conditions. It is suggested that the LP can be one of the important mechanisms of plant cell rearrangements under altered gravity as well. The purpose of this investigation is to study the LP intensity in pea leaves and chloroplasts under 7- and 14-day clinorotation. The intensification of the LP under both terms of clinorotation particularly under more prolonged, is detected. The adaptive increase in the unsaturated fatty acid content under 7-day clinorotation and their minor decrease under 14-day clinorotation are revealed. The lowering of electron transport rate in both photosystems, particularly in PSI, is established. The results confirm that the LPmay be one of the mechanisms of plant cell rearrangements under microgravity.

  18. Microbial community responses to temperature increase the potential for soil carbon losses under climate change.

    NASA Astrophysics Data System (ADS)

    Hartley, Iain; Karhu, Kristiina; Auffret, Marc; Hopkins, David; Prosser, Jim; Singh, Brajesh; Subke, Jens-Arne; Wookey, Philip; Ågren, Göran

    2014-05-01

    There are concerns that global warming may stimulate decomposition rates in soils, with the extra CO2 released representing a positive feedback to climate change. However, there is growing recognition that adaptation of soil microbial communities to temperature changes may alter the potential rate of carbon release. Critically, recent studies have produced conflicting results in terms of whether the medium-term soil microbial community response to temperature reduces (compensatory thermal adaptation) or enhances (enhancing thermal adaptation) the instantaneous direct positive effects of temperature on microbial activity. This lack of understanding adds considerably to uncertainty in predictions of the magnitude and direction of carbon-cycle feedbacks to climate change. In this talk, I present results from one of the most extensive investigations ever undertaken into the role that microbial adaptation plays in controlling the temperature sensitivity of decomposition. Soils were collected from a range of ecosystem types, representing a thermal gradient from the Arctic to the Amazon. Our novel soil-cooling approach minimises issues associated with substrate depletion in warming studies, but still tests whether adaptation enhances or reduces the direct impact of temperature changes on microbial activity. We also investigated the mechanisms underlying changes in microbial respiration by quantifying changes in microbial community composition, microbial biomass, mass-specific activity, carbon-use efficiency, and enzyme activities. Our results indicate that enhancing responses are much more common than compensatory thermal acclimation, with the latter being observed in less than 10% of cases. However, identifying the mechanisms underlying enhancing and compensatory adaptation remained elusive. No consistent changes were observed in terms of mass-specific activity, biomass or enzyme activity, indicating that current theory is inadequate in explaining observed patterns

  19. Fundamental study of failure mechanisms of pressure vessels under thermo-mechanical cycling in multiphase environments

    NASA Astrophysics Data System (ADS)

    Penso Mula, Jorge Antonio

    Cracking and bulging in welded and internally lined pressure vessels that work in thermal-mechanical cycling services have been well known problems in the petrochemical, power and nuclear industries. Published literature and industry surveys show that similar problems have been occurring during the last 50 years. Understanding the causes of cracking and bulging would lead to improvements in the reliability of these pressure vessels. This study attempts to add information required for improving the knowledge and fundamental understanding of these problems. Cracking and bulging, most often in the weld areas, commonly experienced in delayed coking units (e.g. coke drums) in oil refineries are typical examples. The coke drum was selected for this study because of the existing field experience and past industrial investigation results that were available to serve as the baseline references for the analytical studies performed for this dissertation. Another reason for selecting the delayed coking units for this study was due to their high economical yields. Shutting down these units would cause a high negative economic impact on the refinery operations. Several failure mechanisms were hypothesized. The finite element method was used to analyze these significant variables and to verify the hypotheses. In conclusion, a fundamental explanation of the occurrence of bulging and cracking in pressure vessels in multiphase environments has been developed. Several important factors have been identified, including the high convection coefficient of the boiling layer during filling and quenching, the mismatch in physical, thermal and mechanical properties in the dissimilar weld of the clad plates and process conditions such as heating and quenching rate and warming time. Material selection for coke drums should consider not only fatigue strength but also corrosion resistance at high temperatures and low temperatures. Cracking occurs due to low cycle fatigue and corrosion. The FEA

  20. A unifying neuro-fasciagenic model of somatic dysfunction - Underlying mechanisms and treatment - Part II.

    PubMed

    Tozzi, Paolo

    2015-07-01

    This paper offers an extensive review of the main fascia-mediated mechanisms underlying various therapeutic processes of clinical relevance for manual therapy. The concept of somatic dysfunction is revisited in light of the several fascial influences that may come into play during and after manual treatment. A change in perspective is thus proposed: from a nociceptive model that for decades has viewed somatic dysfunction as a neurologically-mediated phenomenon, to a unifying neuro-fascial model that integrates neural influences into a multifactorial and multidimensional interpretation of manual therapeutic effects as being partially, if not entirely, mediated by the fascia. By taking into consideration a wide spectrum of fascia-related factors - from cell-based mechanisms to cognitive and behavioural influences - a model emerges suggesting, amongst other results, a multidisciplinary-approach to the intervention of somatic dysfunction. Finally, it is proposed that a sixth osteopathic 'meta-model' - the connective tissue-fascial model - be added to the existing five models in osteopathic philosophy as the main interface between all body systems, thus providing a structural and functional framework for the body's homoeostatic potential and its inherent abilities to heal. PMID:26118526

  1. A connectionist modeling study of the neural mechanisms underlying pain's ability to reorient attention.

    PubMed

    Dowman, Robert; Ritz, Benjamin; Fowler, Kathleen

    2016-08-01

    Connectionist modeling was used to investigate the brain mechanisms responsible for pain's ability to shift attention away from another stimulus modality and toward itself. Different connectionist model architectures were used to simulate the different possible brain mechanisms underlying this attentional bias, where nodes in the model simulated the brain areas thought to mediate the attentional bias, and the connections between the nodes simulated the interactions between the brain areas. Mathematical optimization techniques were used to find the model parameters, such as connection strengths, that produced the best quantitative fits of reaction time and event-related potential data obtained in our previous work. Of the several architectures tested, two produced excellent quantitative fits of the experimental data. One involved an unexpected pain stimulus activating somatic threat detectors in the dorsal posterior insula. This threat detector activity was monitored by the medial prefrontal cortex, which in turn evoked a phasic response in the locus coeruleus. The locus coeruleus phasic response resulted in a facilitation of the cortical areas involved in decision and response processes time-locked to the painful stimulus. The second architecture involved the presence of pain causing an increase in general arousal. The increase in arousal was mediated by locus coeruleus tonic activity, which facilitated responses in the cortical areas mediating the sensory, decision, and response processes involved in the task. These two neural network architectures generated competing predictions that can be tested in future studies. PMID:27112345

  2. Fatigue responses of PZT stacks under semi-bipolar electric cycling with mechanical preload

    SciTech Connect

    Wang, Hong; Cooper, Thomas A; Lin, Hua-Tay; Wereszczak, Andrew A

    2010-01-01

    PZT stacks that had an inter-digital internal electrode configuration were tested to more than 10^8 cycles. A 100-Hz semi-bipolar sine wave with a field range of +4.5/-0.9 kV/mm was used in cycling with a concurrently-applied 20 MPa preload. Significant reductions in piezoelectric and dielectric responses were observed during the cycling depending on the measuring condition. Extensive surface discharges were also observed. These surface events resulted in the erosion of external electrode and the outcrop of internal electrode. Sections prepared by sequential polishing technique revealed a variety of damage mechanisms including delaminations, pores, and etch grooves. The scale of damage was correlated to the degree of fatigue-induced reduction in piezoelectric and dielectric responses. The results from this study demonstrate the feasibility of using a semi-bipolar mode to drive a PZT stack under a mechanical preload and illustrate the potential fatigue and damages of the stack in service.

  3. Characterization of interdigitated electrode piezoelectric fiber composites under high electrical and mechanical loading

    NASA Astrophysics Data System (ADS)

    Rodgers, John P.; Bent, Aaron A.; Hagood, Nesbitt W.

    1996-05-01

    The primary objective of this work is to develop a standard methodology for characterizing structural actuation systems intended for operation in high electrical and mechanical loading environments. The designed set of tests evaluates the performance of the active materials system under realistic operating conditions. The tests are also used to characterize piezoelectric fiber composites which have been developed as an alternative to monolithic piezoceramic wafers for structural actuation applications. The performance of this actuator system has been improved using an interdigitated electrode pattern, which orients the primary component of the electric field into the plane of the structure, enabling the use of the primary piezoelectric effect along the active fibers. One possible application of this technology is in the integral twist actuation of helicopter rotor blades for higher harmonic control. This application requires actuators which can withstand the harsh rotor blade operating environment. This includes large numbers of electrical and mechanical cycles with considerable centripetal and bending loads. The characterization tests include standard active material tests as well as application-driven tests which evaluate the performance of the actuators during simulated operation. Test results for several actuator configurations are provided, including S2 glass- reinforced and E-glass laminated actuators. The study concludes that the interdigitated electrode piezoelectric fiber composite actuator has great potential for high loading applications.

  4. Lifelong Bilingualism and Neural Reserve against Alzheimer’s disease: A Review of Findings and Potential Mechanisms

    PubMed Central

    Gold, Brian T.

    2014-01-01

    Alzheimer’s disease (AD) is a progressive brain disorder that initially affects medial temporal lobe circuitry and memory functions. Current drug treatments have only modest effects on the symptomatic course of the disease. In contrast, a growing body of evidence suggests that lifelong bilingualism may delay the onset of clinical AD symptoms by several years. The purpose of the present review is to summarize evidence for bilingualism as a reserve variable against AD and discuss potential underlying neurocognitive mechanisms. Evidence is reviewed suggesting that bilingualism may delay clinical AD symptoms by protecting frontostriatal and frontoparietal executive control circuitry rather than medial temporal lobe memory circuitry. Cellular and molecular mechanisms that may contribute to bilingual cognitive reserve effects are discussed, including those that may affect neuronal metabolic functions, dynamic neuronal-glial interactions, vascular factors, myelin structure and neurochemical signaling. Future studies that may test some of these potential mechanisms of bilingual CR effects are proposed. PMID:25496781

  5. Unconventional Mechanics of Lipid Membranes: A Potential Role for Mechanotransduction of Hair Cell Stereocilia

    PubMed Central

    Kim, Jichul

    2015-01-01

    A force-conveying role of the lipid membrane across various mechanoreceptors is now an accepted hypothesis. However, such a mechanism is still not fully understood for mechanotransduction in the hair bundle of auditory sensory hair cells. A major goal of this theoretical assessment was to investigate the role of the lipid membrane in auditory mechanotransduction, especially in generating nonlinear bundle force versus displacement measurements, one of the main features of auditory mechanotransduction. To this end, a hair bundle model that generates lipid membrane tented deformation in the stereocilia was developed. A computational analysis of the model not only reproduced nonlinear bundle force measurements but also generated membrane energy that is potentially sufficient to activate the mechanosensitive ion channel of the hair cell. In addition, the model provides biophysical insight into 1) the likelihood that the channel must be linked in some way to the tip link; 2) how the interplay of the bending and stretching of the lipid bilayer may be responsible for the nonlinear force versus displacement response; 3) how measurements of negative stiffness may be a function of the rotational stiffness of the rootlets; and 4) how the standing tension of the tip link is required to interpret migration of the nonlinear force versus displacement and activation curves. These are all features of hair cell mechanotransduction, but the underlying biophysical mechanism has proved elusive for the last three decades. PMID:25650928

  6. Humor as a reward mechanism: event-related potentials in the healthy and diseased brain.

    PubMed

    Mensen, Armand; Poryazova, Rositsa; Schwartz, Sophie; Khatami, Ramin

    2014-01-01

    Humor processing involves distinct processing stages including incongruity detection, emotional response, and engagement of mesolimbic reward regions. Dysfunctional reward processing and clinical symptoms in response to humor have been previously described in both hypocretin deficient narcolepsy-cataplexy (NC) and in idiopathic Parkinson disease (PD). For NC patients, humor is the strongest trigger for cataplexy, a transient loss of muscle tone, whereas dopamine-deficient PD-patients show blunted emotional responses to humor. To better understand the role of reward system and the various contributions of hypocretinergic and dopaminergic mechanisms to different stages of humor processing we examined the electrophysiological response to humorous and neutral pictures when given as reward feedback in PD, NC and healthy controls. Humor compared to neutral feedback demonstrated modulation of early ERP amplitudes likely corresponding to visual processing stages, with no group differences. At 270 ms post-feedback, conditions showed topographical and amplitudinal differences for frontal and left posterior electrodes, in that humor feedback was absent in PD patients but increased in NC patients. We suggest that this effect relates to a relatively early affective response, reminiscent of increased amygdala response reported in NC patients. Later ERP differences, corresponding to the late positive potential, revealed a lack of sustained activation in PD, likely due to altered dopamine regulation in reward structures in these patients. This research provides new insights into the temporal dynamics and underlying mechanisms of humor detection and appreciation in health and disease. PMID:24489683

  7. Progesterone Inhibition of Voltage-Gated Calcium Channels is a Potential Neuroprotective Mechanism against Excitotoxicity

    PubMed Central

    Luoma, Jessie I; Kelley, Brooke G; Mermelstein, Paul G

    2011-01-01

    The therapeutic use of progesterone following traumatic brain injury has recently entered phase III clinical trials as a means of neuroprotection. Although it has been hypothesized that progesterone protects against calcium overload following excitotoxic shock, the exact mechanisms underlying the beneficial effects of progesterone have yet to be determined. We found that therapeutic concentrations of progesterone to be neuroprotective against depolarization-induced excitotoxicity in cultured striatal neurons. Through use of calcium imaging, electrophysiology and the measurement of changes in activity-dependent gene expression, progesterone was found to block calcium entry through voltage-gated calcium channels, leading to alterations in the signaling of the activity-dependent transcription factors NFAT and CREB. The effects of progesterone were highly specific to this steroid hormone, although they did not appear to be receptor mediated. In addition, progesterone did not inhibit AMPA or NMDA receptor signaling. This analysis regarding the effect of progesterone on calcium signaling provides both a putative mechanism by which progesterone acts as a neuroprotectant, as well as affords a greater appreciation for its potential far-reaching effects on cellular function. PMID:21371490

  8. 3,4-Methylenedioxypyrovalerone (MDPV): in vitro mechanisms of hepatotoxicity under normothermic and hyperthermic conditions.

    PubMed

    Valente, Maria João; Araújo, Ana Margarida; Silva, Renata; Bastos, Maria de Lourdes; Carvalho, Félix; Guedes de Pinho, Paula; Carvalho, Márcia

    2016-08-01

    Synthetic cathinones have emerged in recreational drug markets as legal alternatives for classical amphetamines. Though currently banned in several countries, 3,4-methylenedioxypyrovalerone (MDPV) is one of the most commonly abused cathinone derivatives worldwide. We have recently reported the potential of MDPV to induce hepatocellular damage, but the underlying mechanisms responsible for such toxicity remain to be elucidated. Similar to amphetamines, a prominent toxic effect of acute intoxications by MDPV is hyperthermia. Therefore, the present in vitro study aimed to provide insights into cellular mechanisms involved in MDPV-induced hepatotoxicity and also evaluate the contribution of hyperthermia to the observed toxic effects. Primary cultures of rat hepatocytes were exposed to 0.2-1.6 mM MDPV for 48 h, at 37 or 40.5 °C, simulating the rise in body temperature that follows MDPV intake. Cell viability was measured through the MTT reduction and LDH leakage assays. Oxidative stress endpoints and cell death pathways were evaluated, namely the production of reactive oxygen and nitrogen species (ROS and RNS), intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione, adenosine triphosphate (ATP) and free calcium (Ca(2+)), as well as the activities of caspases 3, 8 and 9, and nuclear morphological changes with Hoechst 33342/PI double staining. At 37 °C, MDPV induced a concentration-dependent loss of cell viability that was accompanied by GSH depletion, as one of the first signs of toxicity, observed already at low concentrations of MDPV, with negligible changes on GSSG levels, followed by accumulation of ROS and RNS, depletion of ATP contents and increases in intracellular Ca(2+) concentrations. Additionally, activation of caspases 3, 8, and 9 and apoptotic nuclear morphological changes were found in primary rat hepatocytes exposed to MDPV, indicating that this cathinone derivative activates both intrinsic and extrinsic apoptotic death pathways. The

  9. Coarse-grained molecular dynamics studies of the translocation mechanism of polyarginines across asymmetric membrane under tension

    PubMed Central

    He, XiaoCong; Lin, Min; Sha, BaoYong; Feng, ShangSheng; Shi, XingHua; Qu, ZhiGuo; Xu, Feng

    2015-01-01

    Understanding interactions between cell-penetrating peptides and biomembrane under tension can help improve drug delivery and elucidate mechanisms underlying fundamental cellular events. As far as the effect of membrane tension on translocation, it is generally thought that tension should disorder the membrane structure and weaken its strength, thereby facilitating penetration. However, our coarse-grained molecular dynamics simulation results showed that membrane tension can restrain polyarginine translocation across the asymmetric membrane and that this effect increases with increasing membrane tension. We also analyzed the structural properties and lipid topology of the tensed membrane to explain the phenomena. Simulation results provide important molecular information on the potential translocation mechanism of peptides across the asymmetric membrane under tension as well as new insights in drug and gene delivery. PMID:26235300

  10. The Mechanism Underlying the Antibacterial Activity of Shikonin against Methicillin-Resistant Staphylococcus aureus

    PubMed Central

    Lee, Young-Seob; Lee, Dae-Young; Kim, Yeon Bok; Lee, Sang-Won; Cha, Seon-Woo; Park, Hong-Woo; Kim, Geum-Soog; Kwon, Dong-Yeul; Lee, Min-Ho; Han, Sin-Hee

    2015-01-01

    Shikonin (SKN), a highly liposoluble naphthoquinone pigment isolated from the roots of Lithospermum erythrorhizon, is known to exert antibacterial, wound-healing, anti-inflammatory, antithrombotic, and antitumor effects. The aim of this study was to examine SKN antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The SKN was analyzed in combination with membrane-permeabilizing agents Tris and Triton X-100, ATPase inhibitors sodium azide and N,N′-dicyclohexylcarbodiimide, and S. aureus-derived peptidoglycan; the effects on MRSA viability were evaluated by the broth microdilution method, time-kill test, and transmission electron microscopy. Addition of membrane-permeabilizing agents or ATPase inhibitors together with a low dose of SKN potentiated SKN anti-MRSA activity, as evidenced by the reduction of MRSA cell density by 75% compared to that observed when SKN was used alone; in contrast, addition of peptidoglycan blocked the antibacterial activity of SKN. The results indicate that the anti-MRSA effect of SKN is associated with its affinity to peptidoglycan, the permeability of the cytoplasmic membrane, and the activity of ATP-binding cassette (ABC) transporters. This study revealed the potential of SKN as an effective natural antibiotic and of its possible use to substantially reduce the use of existing antibiotic may also be important for understanding the mechanism underlying the antibacterial activity of natural compounds. PMID:26265924

  11. Mechanical and thermal buckling analysis of sandwich panels under different edge conditions

    NASA Technical Reports Server (NTRS)

    Ko, William L.

    1993-01-01

    By using the Rayleigh-Ritz method of minimizing the total potential energy of a structural system, combined load (mechanical or thermal load) buckling equations are established for orthotropic rectangular sandwich panels supported under four different edge conditions. Two-dimensional buckling interaction curves and three dimensional buckling interaction surfaces are constructed for high-temperature honeycomb-core sandwich panels supported under four different edge conditions. The interaction surfaces provide easy comparison of the panel buckling strengths and the domains of symmetrical and antisymmetrical buckling associated with the different edge conditions. Thermal buckling curves of the sandwich panels also are presented. The thermal buckling conditions for the cases with and without thermal moments were found to be identical for the small deformation theory. In sandwich panels, the effect of transverse shear is quite large, and by neglecting the transverse shear effect, the buckling loads could be overpredicted considerably. Clamping of the edges could greatly increase buckling strength more in compression than in shear.

  12. Simple solutions of the free-edge stresses in composite laminates under thermal and mechanical loads

    SciTech Connect

    Yin, Wan-Lee )

    1994-01-01

    Intense and localized interlaminar stresses generally occur in a narrow boundary region near the free edge of a multilayered anisotropic laminate under mechanical and temperature loads. Quantitative measures of interlaminar action across interfaces may be readily obtained through purely algebraic operations, even if nonlinear and inelastic material behavior becomes significant in the boundary region due to severe strain concentration. These measures are the limiting values of the Lekhnitskii stress functions F and Psi (and of the normal derivative of F) along interfaces and toward the interior region of the laminate. In the present work, they are used as the basis of an exceedingly simple and efficient method of interlaminar stress analysis that is potentially applicable to free-edge problems involving nonlinear thermoelastic constitutive relations. Example solutions are obtained for symmetric, four-layer, cross-ply, and angle-ply laminates under a temperature load and two different types of strain loads, and the results are found to be in reasonable agreement with the existing numerical and analytical solutions based on elaborate analysis methods. 13 refs.

  13. Potential network mechanisms mediating electroencephalographic beta rhythm changes during propofol-induced paradoxical excitation

    PubMed Central

    McCarthy, Michelle M.; Brown, Emery N.; Kopell, Nancy

    2008-01-01

    Propofol, like most general anesthetic drugs, can induce both behavioral and electroencephalographic (EEG) manifestations of excitation, rather than sedation, at low doses. Neuronal excitation is unexpected in the presence of this GABAa-potentiating drug. We construct a series of network models to understand this paradox. Individual neurons have ion channel conductances with Hodgkin-Huxley-type formulations. Propofol increases the maximal conductance and time-constant of decay of the synaptic GABAa current. Networks range in size from 2–230 neurons. Population output is measured as a function of pyramidal cell activity, with the EEG approximated by the sum of population AMPA activity between pyramidal cells. These model networks suggest propofol-induced paradoxical excitation may result from a membrane level interaction between the GABAa-current and an intrinsic membrane slow potassium current (M-current). This membrane level interaction has consequences at the level of multi-cellular networks enabling a switch from baseline interneuron synchrony to propofol-induced interneuron anti-synchrony. Large network models reproduce the clinical EEG changes characteristic of propofol-induced paradoxical excitation. The EEG changes coincide with the emergence of anti-synchronous interneuron clusters in the model networks. Our findings suggest interneuron anti-synchrony as a potential network mechanism underlying the generation of propofol-induced paradoxical excitation. As correlates of behavioral phenomenology, these networks may refine our understanding of the specific behavioral states associated with general anesthesia. PMID:19074022

  14. Radio-resistant mesenchymal stem cells: mechanisms of resistance and potential implications for the clinic

    PubMed Central

    Nicolay, Nils H.; Perez, Ramon Lopez; Saffrich, Rainer; Huber, Peter E.

    2015-01-01

    Mesenchymal stem cells (MSCs) comprise a heterogeneous population of multipotent stromal cells and can be isolated from various tissues and organs. Due to their regenerative potential, they have been subject to intense research efforts, and they may provide an efficient means for treating radiation-induced tissue damage. MSCs are relatively resistant to ionizing radiation and retain their stem cell characteristics even after high radiation doses. The underlying mechanisms for the observed MSC radioresistance have been extensively studied and may involve efficient DNA damage recognition, double strand break repair and evasion of apoptosis. Here, we present a concise review of the published scientific data on the radiobiological features of MSCs. The involvement of different DNA damage recognition and repair pathways in the creation of a radioresistant MSC phenotype is outlined, and the roles of apoptosis, senescence and autophagy regarding the reported radioresistance are summarized. Finally, potential influences of the radioresistant MSCs for the clinic are discussed with respect to the repair and radioprotection of irradiated tissues. PMID:26203772

  15. Imitation in Newborn Infants: Exploring the Range of Gestures Imitated and the Underlying Mechanisms.

    ERIC Educational Resources Information Center

    Meltzoff, Andrew N.; Moore, M. Keith

    1989-01-01

    Evaluated psychological mechanisms underlying imitation of facial actions in 40 newborn infants. Results showed imitation of head movement and a tongue-protrusion gesture. Subjects imitated from memory after displays had stopped. (RJC)

  16. An underlying mechanism for the increased mutagenesis of lagging-strand genes in Bacillus subtilis

    PubMed Central

    Million-Weaver, Samuel; Samadpour, Ariana N.; Moreno-Habel, Daniela A.; Nugent, Patrick; Brittnacher, Mitchell J.; Weiss, Eli; Hayden, Hillary S.; Miller, Samuel I.; Liachko, Ivan; Merrikh, Houra

    2015-01-01

    We previously reported that lagging-strand genes accumulate mutations faster than those encoded on the leading strand in Bacillus subtilis. Although we proposed that orientation-specific encounters between replication and transcription underlie this phenomenon, the mechanism leading to the increased mutagenesis of lagging-strand genes remained unknown. Here, we report that the transcription-dependent and orientation-specific differences in mutation rates of genes require the B. subtilis Y-family polymerase, PolY1 (yqjH). We find that without PolY1, association of the replicative helicase, DnaC, and the recombination protein, RecA, with lagging-strand genes increases in a transcription-dependent manner. These data suggest that PolY1 promotes efficient replisome progression through lagging-strand genes, thereby reducing potentially detrimental breaks and single-stranded DNA at these loci. Y-family polymerases can alleviate potential obstacles to replisome progression by facilitating DNA lesion bypass, extension of D-loops, or excision repair. We find that the nucleotide excision repair (NER) proteins UvrA, UvrB, and UvrC, but not RecA, are required for transcription-dependent asymmetry in mutation rates of genes in the two orientations. Furthermore, we find that the transcription-coupling repair factor Mfd functions in the same pathway as PolY1 and is also required for increased mutagenesis of lagging-strand genes. Experimental and SNP analyses of B. subtilis genomes show mutational footprints consistent with these findings. We propose that the interplay between replication and transcription increases lesion susceptibility of, specifically, lagging-strand genes, activating an Mfd-dependent error-prone NER mechanism. We propose that this process, at least partially, underlies the accelerated evolution of lagging-strand genes. PMID:25713353

  17. Interatomic potentials from rainbow scattering of keV noble gas atoms under axial surface channeling

    NASA Astrophysics Data System (ADS)

    Schüller, A.; Wethekam, S.; Mertens, A.; Maass, K.; Winter, H.; Gärtner, K.

    2005-04-01

    For grazing scattering of keV Ne and Ar atoms from a Ag(1 1 1) and a Cu(1 1 1) surface under axial surface channeling conditions we observe well defined peaks in the angular distributions for scattered projectiles. These peaks can be attributed to "rainbow-scattering" and are closely related to the geometry of potential energy surfaces which can be approximated by the superposition of continuum potentials along strings of atoms in the surface plane. The dependence of rainbow angles on the scattering geometry provides stringent tests on the scattering potentials. From classical trajectory calculations based on universal (ZBL), adjusted Moliere (O'Connor and Biersack), and individual interatomic potentials we obtain corresponding rainbow angles for comparison with the experimental data. We find good overall agreement with the experiments for a description of trajectories based on adjusted Moliere and individual potentials, whereas the agreement is poorer for potentials with ZBL screening.

  18. Involvement of free radicals followed by the activation of phospholipase A2 in the mechanism that underlies the combined effects of methamphetamine and morphine on subacute toxicity or lethality in mice: comparison of the therapeutic potential of fullerene, mepacrine, and cooling.

    PubMed

    Mori, Tomohisa; Ito, Shinobu; Namiki, Mizuho; Suzuki, Tadashi; Kobayashi, Shizuko; Matsubayashi, Kenji; Sawaguchi, Toshiko

    2007-07-17

    An increase in polydrug abuse is a major problem worldwide. The coadministration of methamphetamine and morphine increased subacute toxicity or lethality in rodents. However, the underlying mechanisms by which lethality is increased by the coadministration of methamphetamine and morphine are not yet fully understood. Coadministered methamphetamine and morphine induced lethality by more than 80% in BALB/c mice, accompanied by the rupture of cells in the kidney and liver, and an increase in poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine was significantly attenuated by pretreatment with mepacrine (phospholipase A(2) inhibitor) or fullerene (a radical scavenger), or by cooling from 30 to 90 min after drug administration. Furthermore, based on the results of the electron spin resonance spin-trapping technique, hydroxyl radicals were increased by the administration of methamphetamine and morphine, and these increased hydroxyl radicals were potently attenuated by fullerene and cooling. These results suggest that hydroxyl radicals plays an important role in the increased lethality induced by the coadministration of methamphetamine plus morphine. The potency of cooling or drugs for decreasing the subacute toxicity or lethality induced by the coadministration of methamphetamine and morphine was in the order fullerene=cooling>mepacrine. These results indicate that fullerene and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine. PMID:17553606

  19. Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

    PubMed Central

    SOMASAGARA, RANGANATHA R.; DEEP, GAGAN; SHROTRIYA, SANGEETA; PATEL, MANISHA; AGARWAL, CHAPLA; AGARWAL, RAJESH

    2015-01-01

    Pancreatic cancer (PanC) is one of the most lethal malignancies, and resistance towards gemcitabine, the front-line chemotherapy, is the main cause for dismal rate of survival in PanC patients; overcoming this resistance remains a major challenge to treat this deadly malignancy. Whereas several molecular mechanisms are known for gemcitabine resistance in PanC cells, altered metabolism and bioenergetics are not yet studied. Here, we compared metabolic and bioenergetic functions between gemcitabine-resistant (GR) and gemcitabine-sensitive (GS) PanC cells and underlying molecular mechanisms, together with efficacy of a natural agent bitter melon juice (BMJ). GR PanC cells showed distinct morphological features including spindle-shaped morphology and a decrease in E-cadherin expression. GR cells also showed higher ATP production with an increase in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Molecular studies showed higher expression of glucose transporters (GLUT1 and 4) suggesting an increase in glucose uptake by GR cells. Importantly, GR cells showed a significant increase in Akt and ERK1/2 phosphorylation and their inhibition decreased cell viability, suggesting their role in survival and drug resistance of these cells. Recently, we reported strong efficacy of BMJ against a panel of GS cells in culture and nude mice, which we expanded here and found that BMJ was also effective in decreasing both Akt and ERK1/2 phosphorylation and viability of GR PanC cells. Overall, we have identified novel mechanisms of gemcitabine resistance in PanC cells which are targeted by BMJ. Considering the short survival in PanC patients, our findings could have high translational potential in controlling this deadly malignancy. PMID:25672620

  20. Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells.

    PubMed

    Somasagara, Ranganatha R; Deep, Gagan; Shrotriya, Sangeeta; Patel, Manisha; Agarwal, Chapla; Agarwal, Rajesh

    2015-04-01

    Pancreatic cancer (PanC) is one of the most lethal malignancies, and resistance towards gemcitabine, the front-line chemotherapy, is the main cause for dismal rate of survival in PanC patients; overcoming this resistance remains a major challenge to treat this deadly malignancy. Whereas several molecular mechanisms are known for gemcitabine resistance in PanC cells, altered metabolism and bioenergetics are not yet studied. Here, we compared metabolic and bioenergetic functions between gemcitabine-resistant (GR) and gemcitabine-sensitive (GS) PanC cells and underlying molecular mechanisms, together with efficacy of a natural agent bitter melon juice (BMJ). GR PanC cells showed distinct morphological features including spindle-shaped morphology and a decrease in E-cadherin expression. GR cells also showed higher ATP production with an increase in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Molecular studies showed higher expression of glucose transporters (GLUT1 and 4) suggesting an increase in glucose uptake by GR cells. Importantly, GR cells showed a significant increase in Akt and ERK1/2 phosphorylation and their inhibition decreased cell viability, suggesting their role in survival and drug resistance of these cells. Recently, we reported strong efficacy of BMJ against a panel of GS cells in culture and nude mice, which we expanded here and found that BMJ was also effective in decreasing both Akt and ERK1/2 phosphorylation and viability of GR PanC cells. Overall, we have identified novel mechanisms of gemcitabine resistance in PanC cells which are targeted by BMJ. Considering the short survival in PanC patients, our findings could have high translational potential in controlling this deadly malignancy. PMID:25672620

  1. Mechanisms Underlying Lexical Access in Native and Second Language Processing of Gender and Number Agreement

    ERIC Educational Resources Information Center

    Romanova, Natalia

    2013-01-01

    Despite considerable evidence suggesting that second language (L2) learners experience difficulties when processing morphosyntactic aspects of L2 in online tasks, the mechanisms underlying these difficulties remain unknown. The aim of this dissertation is to explore possible causes for the difficulties by comparing attentional mechanisms engaged…

  2. Recombination mechanism of point defect loss to coherent precipitates in alloys under irradiation

    NASA Astrophysics Data System (ADS)

    Turkin, A. A.; Bakai, A. S.

    A new mechanism of defect loss by enhanced recombination inside coherent precipitates in alloys under irradiation is described. The mechanism is examined quantitatively to find the microstructural parameters responsible for resistance to dimensional instability. The proposed model explains why radiation properties of Zr-Nb alloys depend on density of fine-grained precipitates of β Nb-phase.

  3. A potential mechanism for a singular solution of the Euler Equations

    NASA Astrophysics Data System (ADS)

    Brenner, Michael; Hormoz, Sahand; Pumir, Alain

    We describe a potential mechanism for a singular solution of the Euler equation. The mechanism involves the interaction of vortex filaments, but occurs sufficiently quickly and at small enough scales that it could have plausibly evaded experimental and computational detection. Scaling estimates for the characteristics of this solution will be presented, as well as numerical simulations of the initial stages.

  4. A potential mechanism for a singular solution of the Euler Equations

    NASA Astrophysics Data System (ADS)

    Brenner, Michael; Hormoz, Sahand; Pumir, Alain

    2015-11-01

    We describe a potential mechanism for a singular solution of the Euler equation. The mechanism involves the interaction of vortex filaments, but occurs sufficiently quickly and at small enough scales that it could have plausibly evaded experimental and computational detection. Scaling estimates for the characteristics of this solution will be presented, as well as numerical simulations of the initial stages.

  5. Investigation of the molecular mechanisms underlying metastasis in prostate cancer by gene expression profiling

    PubMed Central

    Zhang, Xinghua; Yao, Xiaoli; Qin, Cong; Luo, Pengcheng; Zhang, Jie

    2016-01-01

    The present study aimed to screen potential genes associated with metastatic prostate cancer (PCa), in order to improve the understanding of the mechanisms underlying PCa metastasis. The GSE3325 microarray dataset, which was downloaded from the Gene Expression Omnibus database, consists of seven clinically localized PCa samples, six hormone-refractory metastatic PCa samples and six benign prostate tissue samples. The Linear Models for Microarray Data package was used to identify differentially-expressed genes (DEGs) and a hierarchical cluster analysis for DEGs was performed with the pheatmap package. Furthermore, potential functions for the DEGs were predicted by a functional enrichment analysis. Subsequently, microRNAs (miRNAs) potentially involved in the regulation of PCa metastasis were identified by WebGestalt software, and the miRNA-DEG regulatory network was visualized using Cytoscape. In addition, a pathway enrichment analysis for DEGs in the regulatory network was performed. A total of 306 and 2,073 genes were differentially expressed in the clinically localized PCa and the metastatic PCa groups, respectively, as compared with the benign prostate group, of which 174 were differentially expressed in both groups. A number of the DEGs, including CAMK2D and SH3BP4, were significantly enriched in the cell cycle, and others, such as MAF, were associated with the regulation of cell proliferation. Furthermore, some DEGs (CAMK2D and PCDH17) were observed to be regulated by miR-30, whereas others (ADCY2, MAF, SH3BP4 and PCDH17) were modulated by miR-182. Additionally, ADCY2 and CAMK2D were distinctly enriched in the calcium signaling pathway. The present study identified novel DEGs, including ADCY2, CAMK2D, MAF, SH3BP4 and PCDH17, that may be involved in the metastasis of PCa. PMID:27446297

  6. The Double-Well Potential in Quantum Mechanics: A Simple, Numerically Exact Formulation

    ERIC Educational Resources Information Center

    Jelic, V.; Marsiglio, F.

    2012-01-01

    The double-well potential is arguably one of the most important potentials in quantum mechanics, because the solution contains the notion of a state as a linear superposition of "classical" states, a concept which has become very important in quantum information theory. It is therefore desirable to have solutions to simple double-well potentials…

  7. Rapid, Opioid-sensitive Mechanisms Involved in Transient Receptor Potential Vanilloid 1 Sensitization*S⃞

    PubMed Central

    Vetter, Irina; Cheng, Wei; Peiris, Madusha; Wyse, Bruce D.; Roberts-Thomson, Sarah J.; Zheng, Jie; Monteith, Gregory R.; Cabot, Peter J.

    2008-01-01

    TRPV1 is a nociceptive, Ca2+-selective ion channel involved in the development of several painful conditions. Sensitization of TRPV1 responses by cAMP-dependent PKA crucially contributes to the development of inflammatory hyperalgesia. However, the pathways involved in potentiation of TRPV1 responses by cAMP-dependent PKA remain largely unknown. Using HEK cells stably expressing TRPV1 and the μ opioid receptor, we demonstrated that treatment with the adenylate cyclase activator forskolin significantly increased the multimeric TRPV1 species. Pretreatment with the μ opioid receptor agonist morphine reversed this increased TRPV1 multimerization. FRET analysis revealed that treatment with forskolin did not cause multimerization of pre-existing TRPV1 monomers on the plasma membrane and that intracellular pools of TRPV1 exist mostly as monomers in this model. This suggests that increased TRPV1 multimerization occurred from an intracellular store of inactive TRPV1 monomers. Treatment with forskolin also caused an increase in TRPV1 expression on the plasma membrane not resulting from increased TRPV1 expression, and this rapid TRPV1 translocation was inhibited by treatment with morphine. Thus, potentiation of TRPV1 responses by cAMP-dependent PKA involves plasma membrane insertion of functional TRPV1 multimers formed from an intracellular store of inactive TRPV1 monomers. This potentiation occurs rapidly and can be dynamically modulated by activation of the μ opioid receptor under conditions where cAMP levels are raised, such as with inflammation. Increased translocation and multimerization of TRPV1 channels provide a cellular mechanism for finetuning of nociceptive responses that allow for rapid modulation of TRPV1 responses independent of transcriptional changes. PMID:18482991

  8. Priming of Short-Term Potentiation and Synaptic Tagging/Capture Mechanisms by Ryanodine Receptor Activation in Rat Hippocampal CA1

    ERIC Educational Resources Information Center

    Sajikumar, Sreedharan; Li, Qin; Abraham, Wickliffe C.; Xiao, Zhi Cheng

    2009-01-01

    Activity-dependent changes in synaptic strength such as long-term potentiation (LTP) and long-term depression (LTD) are considered to be cellular mechanisms underlying learning and memory. Strengthening of a synapse for a few seconds or minutes is termed short-term potentiation (STP) and is normally unable to take part in the processes of synaptic…

  9. Simplified procedure for evaluating liquefaction potential under ocean trench type long period earthquake

    NASA Astrophysics Data System (ADS)

    Yoshida, Nozomu; Ohya, Yousuke; Sawada, Sumio; Nakamura, Susumu

    A simplified method for evaluating liquefaction potential under ocean trench type long period earthquakes. Since there is no experience on damage or liquefaction under this type of earthquake, effective stress analyses are made on more than 200 sites that are used in the past investigation on liquefaction damage. Accuracy or effectiveness of existing simplified methods is investigated, and is found that they are applicable to near field earthquake, but they result in dangerous evaluation under ocean trench type earthquakes such as artificial earthquake for coming Tonankai earthquake and recorded accelerogram during the Tokachi-oki earthquake of 2003. The reason is found to be effective number of loading cycles; it is about 10 times larger than that considered in the existing simplified procedure. Then a correction factor for liquefaction strength is proposed in order to evaluate liquefaction potential under this type of earthquakes. The factor is a half of the factor in the existing method; liquefaction strength is to be half of the conventional value when comparing maximum shear stress to evaluate FL value. This method works so that dangerous ratio (ratio of number of layers where onset of liquefaction is identified under effective stress analysis but is not identified under existing simplified procedure to the total number of layers) becomes small to be the same order under near field earthquake.

  10. [The mechanical chemical attachment of artificial cartilage (PVA-hydrogel) to metal substrate (or underlying bone)].

    PubMed

    Gu, Z; Xiao, J; Lou, S

    2001-06-01

    The biocompatibility and tribological characteristics of PVA-hydrogel are excellent, but it is very difficult to make the artificial cartilage material (PVA-hydrogel) attach to the underlying bone. In this study, PVA-hydrogel is attached to the metal fibre mesh by means of micro-mechanical interlock methods at first, then the surface of metal fibre mesh is bonded to the underlying bone by the bone cement(PMMA). In this way, the artificial cartilage can be firmly attached to the underlying bone(or metal substrate). Microstructure analysis and mechanical tests show that the attachment between artificial cartilage and the metal substrate is firm. PMID:11450530

  11. The limit passage of space curvature in problems of celestial mechanics with the generalized Kepler and Hooke potentials

    NASA Astrophysics Data System (ADS)

    Vozmishcheva, Tatiana

    2016-09-01

    The connection between the problems of celestial mechanics: the Kepler problem, the two-center problem and the two body problem in spaces of constant curvature with the generalized Kepler and Hooke potentials is investigated. The limit passage in the two-center and two body problems in the Lobachevsky space and on a sphere is carried out as λto0 (λ is the curvature of the corresponding space) for the two potentials. The potentials and metrics in spaces under study are written in the gnomonic coordinates. It is shown that as the curvature radius tends to infinity, the generalized gravitational and elastic potentials transform to the Kepler and Hooke forms in the Euclidean space.

  12. Dynamic polarizability and electric multipolar transitions in two electron atoms under exponential cosine screened coulomb potential

    NASA Astrophysics Data System (ADS)

    Chaudhuri, Supriya K.; Modesto-Costa, Lucas; Mukherjee, Prasanta K.

    2016-05-01

    Detailed investigations on the frequency dependent polarizabilities, transition energies, oscillator strengths, and transition probabilities of two electron systems He, B e2 +, C4 + , and O6 + under electric dipolar (E1) and quadrupolar (E2) excitations have been performed using exponential cosine screened coulomb potential with a view to understand the structural behaviour of such systems due to external confinement produced by plasma environment. Time dependent coupled Hartree-Fock theory within a variational framework has been adopted for studying the first three low lying excited states 1 s2:1Se→1 s n p :1Po (n = 2, 3, 4) and 1 s n d :1De (n = 3, 4, 5) under such excitations. Quantitatively, the effect of confinement produced by the external plasma has been taken care of by considering the change in atomic potential through plasma screening, directly related to the coupling strength of the plasma with the atomic charge cloud. With increased plasma screening, a gradual destabilisation of the energy levels with subsequent reduction of the ionization potential and number of excited states has been observed. Behavioral pattern of the frequency dependent polarizabilities, excitation energies, oscillator strengths, and transition probabilities under systematic increase of the screening has been investigated. Results have been compared thoroughly with those available for free systems and under confinement by exponential cosine screened and screened Coulomb potential.

  13. Numerical investigation of aerosolized drug delivery in the human lungs under mechanical ventilator conditions

    NASA Astrophysics Data System (ADS)

    Vanrhein, Timothy; Banerjee, Arindam

    2010-11-01

    Particle deposition for aerosolized drug delivery in the human airways is heavily dependent upon flow conditions. Numerical modeling techniques have proven valuable for determining particle deposition characteristics under steady flow conditions. For the case of patients under mechanical ventilation, however, flow conditions change drastically and there is an increased importance to understand particle deposition characteristics. This study focuses on mechanically ventilated conditions in the upper trachea-bronchial (TB) region of the human airways. Solution of the continuous phase flow is done under ventilator waveform conditions with a suitable turbulence model in conjunction with a realistic model of upper TB airways. A discrete phase Euler-Lagrange approach is applied to solve for particle deposition characteristics with a focus on the effect of the ventilator inlet waveform. The purpose of this study is to accurately model flow conditions in the upper TB airways under mechanically ventilated conditions with a focus on real-time patient specific targeted aerosolized drug delivery.

  14. Selective Automated Perimetry Under Photopic, Mesopic, and Scotopic Conditions: Detection Mechanisms and Testing Strategies

    PubMed Central

    Simunovic, Matthew P.; Moore, Anthony T.; MacLaren, Robert E.

    2016-01-01

    Purpose Automated scotopic, mesopic, and photopic perimetry are likely to be important paradigms in the assessment of emerging treatments of retinal diseases, yet our knowledge of the photoreceptor mechanisms detecting targets under these conditions remains largely dependent on simian data. We therefore aimed to establish the photoreceptor/postreceptoral mechanisms detecting perimetric targets in humans under photopic, mesopic, and scotopic conditions and to make recommendations for suitable clinical testing strategies for selective perimetry. Methods Perimetric sensitivities within 30° of fixation were determined for eight wavelengths (410, 440, 480, 520, 560, 600, 640, and 680 nm) under scotopic, mesopic (1.3 cd.m−2) and photopic (10 cd.m−2) conditions. Data were fitted with vector combinations of rod, S-cone, nonopponent M+L-cone mechanism, and opponent M- versus L-cone mechanism templates. Results Scotopicperimetric sensitivity was determined by rods peripherally and by a combination of rods and cones at, and immediately around, fixation. Mesopic perimetric sensitivity was mediated by M+L-cones and S-cones centrally and by M+L-cones and rods more peripherally. Photopic perimetric sensitivity was determined by an opponent M- versus L-cone, a nonopponent M+L-cone, and an S-cone mechanism centrally and by a combination of an S-cone and an M+L-cone mechanism peripherally. Conclusions Under scotopic conditions, a 480-nm stimulus provides adequate isolation (≥28 dB) of the rod mechanism. Several mechanisms contribute to mesopic sensitivity: this redundancy in detection may cause both insensitivity to broadband white targets and ambiguity in determining which mechanism is being probed with short-wavelength stimuli. M- and L-cone–derived mechanisms are well isolated at 10 cd.m−2: these may be selectively probed by a stimulus at 640 nm (≥ 20 dB isolation). Translation Relevance In human observers, multiple mechanisms contribute to the detection of Goldmann

  15. Research of mechanics of the compact bone microvolume and porous ceramics under uniaxial compression

    SciTech Connect

    Kolmakova, T. V. Buyakova, S. P. Kul’kov, S. N.

    2015-11-17

    The research results of the mechanics are presented and the effective mechanical characteristics under uniaxial compression of the simulative microvolume of the compact bone are defined subject to the direction of the collagen-mineral fibers, porosity and mineral content. The experimental studies of the mechanics are performed and the effective mechanical characteristics of the produced porous zirconium oxide ceramics are defined. The recommendations are developed on the selection of the ceramic samples designed to replace the fragment of the compact bone of a definite structure and mineral content.

  16. An Integrative View of Mechanisms Underlying Generalized Spike-and-Wave Epileptic Seizures and Its Implication on Optimal Therapeutic Treatments

    PubMed Central

    Yan, Boyuan; Li, Peng

    2011-01-01

    Many types of epileptic seizures are characterized by generalized spike-and-wave discharges. In the past, notable effort has been devoted to understanding seizure dynamics and various hypotheses have been proposed to explain the underlying mechanisms. In this paper, by taking an integrative view of the underlying mechanisms, we demonstrate that epileptic seizures can be generated by many different combinations of synaptic strengths and intrinsic membrane properties. This integrative view has important medical implications: the specific state of a patient characterized by a set of biophysical characteristics ultimately determines the optimal therapeutic treatment. Through the same view, we further demonstrate the potentiation effect of rational polypharmacy in the treatment of epilepsy and provide a new angle to resolve the debate on polypharmacy. Our results underscore the need for personalized medicine and demonstrate that computer modeling and simulation may play an important role in assisting the clinicians in selecting the optimal treatment on an individual basis. PMID:21811612

  17. Euphol prevents experimental autoimmune encephalomyelitis in mice: evidence for the underlying mechanisms.

    PubMed

    Dutra, Rafael Cypriano; de Souza, Paula Roberta de Cezaro; Bento, Allisson Freire; Marcon, Rodrigo; Bicca, Maíra Assunção; Pianowski, Luiz Francisco; Calixto, João B

    2012-02-15

    Multiple sclerosis (MS) is a severe chronic T cell-mediated autoimmune inflammatory disease of the central nervous system (CNS), the existing therapy of which is only partially effective and is associated with undesirable side effects. Euphol, an alcohol tetracyclic triterpene, has a wide range of pharmacological properties and is considered to have anti-inflammatory action. However there are no reports about the effects and mechanisms of euphol in experimental autoimmune encephalomyelitis (EAE), an established model of MS. Here we report the effects and the underlying mechanisms of action of euphol in EAE. Euphol (1-10mg/kg) was administered orally at different time-points of EAE. Immunological and inflammatory responses were evaluated by real-time PCR, Western blot and flow cytometry assays. We provide evidence that euphol significantly attenuates neurological signs of EAE. These beneficial effects of euphol seem to be associated with the down-regulation of mRNA and protein expression of some pro-inflammatory mediators such as TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the CNS. Furthermore, in vitro, euphol consistently inhibited the T cell-mediated immune response including the production of T(H)1 and T(H)17 cytokines in spleen cells of untreated EAE animals. Likewise, oral euphol treatment inhibited the infiltration of T(H)17 myelin-specific cells into the CNS through the adhesion molecule, lymphocyte function-associated antigen 1 (LFA-1). Our findings reveal that oral administration of euphol consistently reduces and limits the severity and development of EAE. Therefore, euphol might represent a potential molecule of interest for the treatment of MS and other T(H)17 cell-mediated inflammatory diseases. PMID:22155310

  18. Molecular Mechanisms Underlying the Rapid Arrhythmogenic Action of Bisphenol A in Female Rat Hearts

    PubMed Central

    Gao, Xiaoqian; Liang, Qian; Chen, Yamei

    2013-01-01

    Previously we showed that bisphenol A (BPA), an environmental estrogenic endocrine disruptor, rapidly altered Ca2+ handling and promoted arrhythmias in female rat hearts. The underlying molecular mechanism was not known. Here we examined the cardiac-specific signaling mechanism mediating the rapid impact of low-dose BPA in female rat ventricular myocytes. We showed that protein kinase A (PKA) and Ca2+/CaM-dependent protein kinase II (CAMKII) signaling pathways are the two major pathways activated by BPA. Exposure to 1 nM BPA rapidly increased production of cAMP and rapidly but transiently increased the phosphorylation of the ryanodine receptors by PKA but not by CAMKII. BPA also rapidly increased the phosphorylation of phospholamban (PLN), a key regulator protein of sarcoplasmic reticulum Ca2+ reuptake, by CAMKII but not PKA. The increase in CAMKII phosphorylation of PLN was mediated by phospholipase C and inositol trisphosphate receptor-mediated Ca2+ release, likely from the endoplasmic reticulum Ca2+ storage. These two pathways are likely localized, impacting only their respective target proteins. The rapid impacts of BPA on ryanodine receptors and PLN phosphorylation were mediated by estrogen receptor-β but not estrogen receptor-α. BPA's rapid signaling in cardiac myocytes did not involve activation of ERK1/2. Functional analysis showed that PKA but not CAMKII activation contributed to BPA-induced sarcoplasmic reticulum Ca2+ leak, and both PKA and CAMKII were necessary contributors to the stimulatory effect of BPA on arrhythmogenesis. These results provide mechanistic insight into BPA's rapid proarrhythmic actions in female cardiac myocytes and contribute to the assessment of the consequence and potential cardiac toxicity of BPA exposure. PMID:24140712

  19. When Events Change Their Nature: The Neurocognitive Mechanisms underlying Aspectual Coercion

    PubMed Central

    Paczynski, Martin; Jackendoff, Ray; Kuperberg, Gina

    2014-01-01

    The verb ‘pounce’ describes a single, near-instantaneous event. Yet, we easily understand that, “For several minutes the cat pounced…” describes a situation in which multiple pounces occurred, even though this interpretation is not overtly specified by the sentence’s syntactic structure or by any of its individual words—a phenomenon known as ‘aspectual coercion’. Previous psycholinguistic studies have reported processing costs in association with aspectual coercion, but the neurocognitive mechanisms giving rise to these costs remain contentious. Additionally, there is some controversy about whether readers commit to a full interpretation of the event when the aspectual information becomes available, or whether they leave it temporarily underspecified until later in the sentence. Using event-related potentials (ERPs), we addressed these questions in a design that fully crossed context type (punctive, durative, frequentative) with verb type (punctive, durative). We found a late, sustained negativity to punctive verbs in durative contexts, but not in frequentative (e.g. explicitly iterative) contexts. This effect was distinct from the N400 in both its time course and scalp distribution, suggesting that it reflected a different underlying neurocognitive mechanism. We also found that ERPs to durative verbs were unaffected by context type. Together, our results provide strong evidence that neural activity associated with aspectual coercion is driven by the engagement of a morphosyntactically unrealized semantic operator rather than by violations of real-world knowledge, more general shifts in event representation, or event iterativity itself. More generally, our results add to a growing body of evidence that a set of late-onset sustained negativities reflect elaborative semantic processing that goes beyond simply combining the meaning of individual words with syntactic structure to arrive at a final representation of meaning. PMID:24702457

  20. Mechanisms Underlying Food-Drug Interactions: Inhibition of Intestinal Metabolism and Transport

    PubMed Central

    Won, Christina S.; Oberlies, Nicholas H.; Paine, Mary F.

    2012-01-01

    Food-drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. These interactions often reflect prandial-associated changes in the extent and/or rate of systemic drug exposure. Physiologic and physicochemical mechanisms underlying food effects on drug disposition are well-characterized. However, biochemical mechanisms involving drug metabolizing enzymes and transport proteins remain underexplored. Several plant-derived beverages have been shown to modulate enzymes and transporters in the intestine, leading to altered pharmacokinetic (PK) and potentially negative pharmacodynamic (PD) outcomes. Commonly consumed fruit juices, teas, and alcoholic drinks contain phytochemicals that inhibit intestinal cytochrome P450 and phase II conjugation enzymes, as well as uptake and efflux transport proteins. Whereas myriad phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been deemed insignificant or undetermined. An overlooked prerequisite for elucidating food effects on drug PK is thorough knowledge of causative bioactive ingredients. Substantial variability in bioactive ingredient composition and activity of a given dietary substance poses a challenge in conducting robust food-drug interaction studies. This confounding factor can be addressed by identifying and characterizing specific components, which could be used as marker compounds to improve clinical trial design and quantitatively predict food effects. Interpretation and integration of data from in vitro, in vivo, and in silico studies require collaborative expertise from multiple disciplines, from botany to clinical pharmacology (i.e., plant to patient). Development of more systematic methods and guidelines is needed to address the general lack of information on examining drug-dietary substance interactions prospectively. PMID:22884524

  1. Potential Mechanisms Supporting the Value of Motor Cortex Stimulation to Treat Chronic Pain Syndromes.

    PubMed

    DosSantos, Marcos F; Ferreira, Natália; Toback, Rebecca L; Carvalho, Antônio C; DaSilva, Alexandre F

    2016-01-01

    Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary MCS to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1) modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g., glutamate, GABA, and serotonin) as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of MCS to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g., tDCS and TMS), which are analyzed comparatively. PMID:26903788

  2. Potential Mechanisms Supporting the Value of Motor Cortex Stimulation to Treat Chronic Pain Syndromes

    PubMed Central

    DosSantos, Marcos F.; Ferreira, Natália; Toback, Rebecca L.; Carvalho, Antônio C.; DaSilva, Alexandre F.

    2016-01-01

    Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary MCS to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1) modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g., glutamate, GABA, and serotonin) as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of MCS to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g., tDCS and TMS), which are analyzed comparatively. PMID:26903788

  3. In vitro exploration of potential mechanisms of toxicity of the human hepatotoxic drug fenclozic acid.

    PubMed

    Rodrigues, Alison V M; Rollison, Helen E; Martin, Scott; Sarda, Sunil; Schulz-Utermoehl, Timothy; Stahl, Simone; Gustafsson, Frida; Eakins, Julie; Kenna, J Gerry; Wilson, Ian D

    2013-08-01

    The carboxylic acid NSAID fenclozic acid exhibited an excellent preclinical safety profile and promising clinical efficacy, yet was withdrawn from clinical development in 1971 due to hepatotoxicity observed in clinical trials. A variety of modern in vitro approaches have been used to explore potential underlying mechanisms. Covalent binding studies were undertaken with [(14)C]-fenclozic acid to investigate the possible role of reactive metabolites. Time-dependent covalent binding to protein was observed in NADPH-supplemented liver microsomes, although no metabolites were detected in these incubations or in reactive metabolite trapping experiments. In human hepatocytes, covalent binding was observed at lower levels than in microsomes and a minor uncharacterizable metabolite was also observed. In addition, covalent binding was observed in incubations undertaken with dog and rat hepatocytes, where a taurine conjugate of the drug was detected. Although an acyl glucuronide metabolite was detected when liver microsomes from human, rat and dog were supplemented with UDPGA, there was no detectable UDPGA-dependent covalent binding. No effects were observed when fenclozic acid was assessed for P450-dependent and P450-independent cytotoxicity to THLE cell lines, time-dependent inhibition of five major human cytochrome P450 enzymes, inhibition of the biliary efflux transporters BSEP and MRP2 or mitochondrial toxicity to THLE or HepG2 cells. These data suggest that Phase 1 bioactivation plays a role in the hepatotoxicity of fenclozic acid and highlight the unique insight into mechanisms of human drug toxicity that can be provided by investigations of biotransformation and covalent binding to proteins. PMID:23609606

  4. Mechanism underlying mitochondrial protection of asiatic acid against hepatotoxicity in mice.

    PubMed

    Gao, Jing; Chen, Jin; Tang, Xinhui; Pan, Liya; Fang, Feng; Xu, Lizhi; Zhao, Xiaoning; Xu, Qiang

    2006-02-01

    Asiatic acid (AA) is one of the triterpenoid components of Terminalia catappa L., which has antioxidative, anti-inflammatory and hepatoprotective activity. This research focused on the mitochondrial protection of AA against acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) in mice. It was found that pretreatment with 25, 50 or 100 mg kg(-1) AA significantly blocked the LPS + D-GalN-induced increase in both serum aspartate aminotransferase (sAST) and serum alanine aminotransferase (sALT) levels, which was confirmed by ultrastructural observation under an electron microscope, showing improved nuclear condensation, ameliorated mitochondrion proliferation and less lipid deposition. Meanwhile, different doses of AA could decrease both the transcription and the translation level of voltage-dependent anion channels (VDACs), the most important mitochondrial PTP component protein, and block the translocation of cytochrome c from mitochondria to cytosol. On the other hand, pre-incubation with 25, 50 and 100 microg mL(-1) AA inhibited the Ca(2+)-induced mitochondrial permeability transition (MPT), including mitochondrial swelling, membrane potential dissipation and releasing of matrix Ca(2+) in liver mitochondria separated from normal mice, indicating the direct role of AA on mitochondria. Collectively, the above data suggest that AA could protect liver from damage and the mechanism might be related to up-regulating mitochondrial VDACs and inhibiting the process of MPT. PMID:16451751

  5. Salicylic acid-induced abiotic stress tolerance and underlying mechanisms in plants.

    PubMed

    Khan, M Iqbal R; Fatma, Mehar; Per, Tasir S; Anjum, Naser A; Khan, Nafees A

    2015-01-01

    Abiotic stresses (such as metals/metalloids, salinity, ozone, UV-B radiation, extreme temperatures, and drought) are among the most challenging threats to agricultural system and economic yield of crop plants. These stresses (in isolation and/or combination) induce numerous adverse effects in plants, impair biochemical/physiological and molecular processes, and eventually cause severe reductions in plant growth, development and overall productivity. Phytohormones have been recognized as a strong tool for sustainably alleviating adverse effects of abiotic stresses in crop plants. In particular, the significance of salicylic acid (SA) has been increasingly recognized in improved plant abiotic stress-tolerance via SA-mediated control of major plant-metabolic processes. However, the basic biochemical/physiological and molecular mechanisms that potentially underpin SA-induced plant-tolerance to major abiotic stresses remain least discussed. Based on recent reports, this paper: (a) overviews historical background and biosynthesis of SA under both optimal and stressful environments in plants; (b) critically appraises the role of SA in plants exposed to major abiotic stresses; PMID:26175738

  6. Chemical and Biochemical Mechanisms Underlying the Cardioprotective Roles of Dietary Organopolysulfides

    PubMed Central

    Tocmo, Restituto; Liang, Dong; Lin, Yi; Huang, Dejian

    2015-01-01

    Foods that are rich in organosulfides are highly regarded for their broad range of functions in disease prevention and health promotion since ancient time yet modern scientific study, particularly clinical studies could not agree with traditional wisdom. One of the complexities is due to the labile nature of organosulfides, which are often transformed to different structures depending on the processing conditions. The recent evidence on polysulfides as H2S donors may open up a new avenue for establishing structure and health promotion activity relationship. To put this development into perspective, we carried out a review on the recent progress on the chemistry and biochemistry of organopolysulfides with emphasis on their cardioprotective property. First, we briefly surveyed the foods that are rich in polysulfides and their structural diversity. This is followed by in-depth discussion on the chemical transformations of polysulfides under various processing conditions. We further reviewed the potential action mechanisms of polysulfides in cardioprotection through: (a) hydrogen sulfide releasing activity; (b) radical scavenging activity; and (c) activity in enzyme inhibition and intervention of gene regulation pathways. Based on the literature trend, we can conclude that the emerging concept of organopolysulfides as naturally occurring H2S donors is intriguing and warrants further research to establish the structure and activity relationship of the organopolysulfides as H2S donors. PMID:25988131

  7. Mechanical properties of gold twinned nanocubes under different triaxial tensile rates

    NASA Astrophysics Data System (ADS)

    Yang, Zailin; Zhang, Guowei; Luo, Gang; Sun, Xiaoqing; Zhao, Jianwei

    2016-08-01

    The gold twinned nanocubes under different triaxial tensile rates are explored by molecular dynamics simulation. Hydrostatic stress and Mises stress are defined in order to understand triaxial stresses. Twin boundaries prevent dislocations between twin boundaries from developing and dislocation angles are inconspicuous, which causes little difference between triaxial stresses. The mechanical properties of the nanocubes under low and high tensile rates are different. The curves of nanocubes under high tensile rates are more abrupt than those under low tensile rates. When the tensile rate is extremely big, the loadings are out of the nanocubes and there are not deformation and fracture in the internal nanocubes.

  8. Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action.

    PubMed

    Dutt, Vikas; Gupta, Sanjeev; Dabur, Rajesh; Injeti, Elisha; Mittal, Ashwani

    2015-09-01

    Over the last two decades, new insights into the etiology of skeletal muscle wasting/atrophy under diverse clinical settings including denervation, AIDS, cancer, diabetes, and chronic heart failure have been reported in the literature. However, the treatment of skeletal muscle wasting remains an unresolved challenge to this day. About nineteen potential drugs that can regulate loss of muscle mass have been reported in the literature. This paper reviews the mechanisms of action of all these drugs by broadly classifying them into six different categories. Mechanistic data of these drugs illustrate that they regulate skeletal muscle loss either by down-regulating myostatin, cyclooxygenase2, pro-inflammatory cytokines mediated catabolic wasting or by up-regulating cyclic AMP, peroxisome proliferator-activated receptor gamma coactivator-1α, growth hormone/insulin-like growth factor1, phosphatidylinositide 3-kinases/protein kinase B(Akt) mediated anabolic pathways. So far, five major proteolytic systems that regulate loss of muscle mass have been identified, but the majority of these drugs control only two or three proteolytic systems. In addition to their beneficial effect on restoring the muscle loss, many of these drugs show some level of toxicity and unwanted side effects such as dizziness, hypertension, and constipation. Therefore, further research is needed to understand and develop treatment strategies for muscle wasting. For successful management of skeletal muscle wasting either therapeutic agent which regulates all five known proteolytic systems or new molecular targets/proteolytic systems must be identified. PMID:26048279

  9. Potential mechanisms and environmental controls of TiO2 nanoparticle effects on soil bacterial communities.

    PubMed

    Ge, Yuan; Priester, John H; Van De Werfhorst, Laurie C; Schimel, Joshua P; Holden, Patricia A

    2013-12-17

    It has been reported that engineered nanoparticles (ENPs) alter soil bacterial communities, but the underlying mechanisms and environmental controls of such effects remain unknown. Besides direct toxicity, ENPs may indirectly affect soil bacteria by changing soil water availability or other properties. Alternatively, soil water or other environmental factors may mediate ENP effects on soil bacterial communities. To test, we incubated nano-TiO2-amended soils across a range of water potentials for 288 days. Following incubation, the soil water characteristics, organic matter, total carbon, total nitrogen, and respiration upon rewetting (an indicator of bioavailable organic carbon) were measured. Bacterial community shifts were characterized by terminal restriction fragment length polymorphism (T-RFLP). The endpoint soil water holding had been reported previously as not changing with this nano-TiO2 amendment; herein, we also found that some selected soil properties were unaffected by the treatments. However, we found that nano-TiO2 altered the bacterial community composition and reduced diversity. Nano-TiO2-induced community dissimilarities increased but tended to approach a plateau when soils became drier. Taken together, nano-TiO2 effects on soil bacteria appear to be a result of direct toxicity rather than indirectly through nano-TiO2 affecting soil water and organic matter pools. However, such directs effects of nano-TiO2 on soil bacterial communities are mediated by soil water. PMID:24256577

  10. Molecular Characterization of HIV-1 Subtype C gp-120 Regions Potentially Involved in Virus Adaptive Mechanisms

    PubMed Central

    Cenci, Alessandra; D'Avenio, Giuseppe; Tavoschi, Lara; Chiappi, Michele; Becattini, Simone; Narino, Maria del Pilar; Picconi, Orietta; Bernasconi, Daniela; Fanales-Belasio, Emanuele; Vardas, Eftyhia; Sukati, Hosea; Presti, Alessandra Lo; Ciccozzi, Massimo; Monini, Paolo; Ensoli, Barbara; Grigioni, Mauro; Buttò, Stefano

    2014-01-01

    The role of variable regions of HIV-1 gp120 in immune escape of HIV has been investigated. However, there is scant information on how conserved gp120 regions contribute to virus escaping. Here we have studied how molecular sequence characteristics of conserved C3, C4 and V3 regions of clade C HIV-1 gp120 that are involved in HIV entry and are target of the immune response, are modulated during the disease course. We found an increase of “shifting” putative N-glycosylation sites (PNGSs) in the α2 helix (in C3) and in C4 and an increase of sites under positive selection pressure in the α2 helix during the chronic stage of disease. These sites are close to CD4 and to co-receptor binding sites. We also found a negative correlation between electric charges of C3 and V4 during the late stage of disease counteracted by a positive correlation of electric charges of α2 helix and V5 during the same stage. These data allow us to hypothesize possible mechanisms of virus escape involving constant and variable regions of gp120. In particular, new mutations, including new PNGSs occurring near the CD4 and CCR5 binding sites could potentially affect receptor binding affinity and shield the virus from the immune response. PMID:24788065

  11. Potential Mechanisms for Racial and Ethnic Differences in Antimüllerian Hormone and Ovarian Reserve

    PubMed Central

    Seifer, David B.

    2013-01-01

    Accumulating evidence suggests that reproductive potential and function may be different across racial and ethnic groups. Racial differences have been demonstrated in pubertal timing, infertility, outcomes after assisted reproductive technology (ART) treatment, and reproductive aging. Recently, racial differences have also been described in serum antimüllerian hormone (AMH), a sensitive biomarker of ovarian reserve, supporting the notion that ovarian reserve differs between racial/ethnic groups. The existence of such racial/ethnic differences in ovarian reserve, as reflected by AMH, may have important clinical implications for reproductive endocrinologists. However, the mechanisms which may underlie such racial differences in ovarian reserve are unclear. Various genetic factors and environmental factors such as obesity, smoking, and vitamin D deficiency which have been shown to correlate with serum AMH levels and also display significant racial/ethnic variations are discussed in this review. Improving our understanding of racial differences in ovarian reserve and their underlying causes may be essential for infertility treatment in minority women and lead to better reproductive planning, improved treatment outcomes, and timely interventions which may prolong reproductive lifespan in these women. PMID:24348557

  12. A potential mechanism of dural ossification in ossification of ligamentum flavum.

    PubMed

    Li, Bo; Guo, Shigong; Qiu, Guixing; Li, Wenjing; Liu, Yongsheng; Zhao, Yu

    2016-07-01

    Ossification of the ligamentum flavum (OLF) mostly occurs in the thoracic spine, leading to thoracic spinal stenosis. Surgical treatment is considered as the best option for OLF patients. When the dura mater ossifies, the difficulty of surgery and the risk of complications significantly increase. The cause of dural ossification (DO) is still unknown. Based on the existing research and clinical studies, we propose a potential mechanism of DO in OLF. Firstly, with the progression of OLF, it will compress the dura mater and even the spinal cord. Then, with flexion and extension of spine, relative movement (friction) between the ossified ligamentum flavum and compressed dura mater will lead to local inflammation, subsequently causing dural adhesion. Finally, the adhesion tissue can serve as a pathway for the transportation of osteogenic cytokines (BMP for example) from the ossified ligamentum flavum to the compressed dura mater. Dura will ossify under exposure of these osteogenic cytokines. If this hypothesis is confirmed, it will contribute to the prevention and management of DO. For progressive OLF patients, early surgical treatment before DO should be recommended. PMID:27241243

  13. Neurocognitive mechanisms of statistical-sequential learning: what do event-related potentials tell us?

    PubMed

    Daltrozzo, Jerome; Conway, Christopher M

    2014-01-01

    Statistical-sequential learning (SL) is the ability to process patterns of environmental stimuli, such as spoken language, music, or one's motor actions, that unfold in time. The underlying neurocognitive mechanisms of SL and the associated cognitive representations are still not well understood as reflected by the heterogeneity of the reviewed cognitive models. The purpose of this review is: (1) to provide a general overview of the primary models and theories of SL, (2) to describe the empirical research - with a focus on the event-related potential (ERP) literature - in support of these models while also highlighting the current limitations of this research, and (3) to present a set of new lines of ERP research to overcome these limitations. The review is articulated around three descriptive dimensions in relation to SL: the level of abstractness of the representations learned through SL, the effect of the level of attention and consciousness on SL, and the developmental trajectory of SL across the life-span. We conclude with a new tentative model that takes into account these three dimensions and also point to several promising new lines of SL research. PMID:24994975

  14. Age-Related Neurodegeneration Prevention Through mTOR Inhibition: Potential Mechanisms and Remaining Questions

    PubMed Central

    Jahrling, Jordan B.; Laberge, Remi-Martin

    2016-01-01

    With the global aging population, Alzheimer's disease, Parkinson's disease and mild cognition impairment are increasing in prevalence. The success of rapamycin as an agent to extend lifespan in various organisms, including mice, brings hope that chronic mTOR inhibition could also refrain age-related neurodegeneration. Here we review the evidence suggesting that mTOR inhibition - mainly with rapamycin - is a valid intervention to delay age-related neurodegeneration. We discuss the potential mechanisms by which rapamycin may facilitate neurodegeneration prevention or restoration of cognitive function. We also discuss the known side effects of rapamycin and provide evidence to alleviate exaggerated concerns regarding its wider clinical use. We explore the small molecule alternatives to rapamycin and propose future directions for their development, mainly by exploring the possibility of targeting the downstream effectors of mTOR: S6K1 and especially S6K2. Finally, we discuss the strengths and weaknesses of the models used to determine intervention efficacy for neurodegeneration. We address the difficulties of interpreting data using the common way of investigating the efficacy of interventions to delay/prevent neurodegeneration by observing animal behavior while these animals are under treatment. We propose an experimental design that should isolate the variable of aging in the experimental design and resolve the ambiguity present in recent literature. PMID:26059360

  15. Different routes, same pathways: Molecular mechanisms under silver ion and nanoparticle exposures in the soil sentinel Eisenia fetida.

    PubMed

    Novo, Marta; Lahive, Elma; Díez-Ortiz, María; Matzke, Marianne; Morgan, Andrew J; Spurgeon, David J; Svendsen, Claus; Kille, Peter

    2015-10-01

    Use of nanotechnology products is increasing; with silver (Ag) nanoparticles particularly widely used. A key uncertainty surrounding the risk assessment of AgNPs is whether their effects are driven through the same mechanism of action that underlies the toxic effects of Ag ions. We present the first full transcriptome study of the effects of Ag ions and NPs in an ecotoxicological model soil invertebrate, the earthworm Eisenia fetida. Gene expression analyses indicated similar mechanisms for both silver forms with toxicity being exerted through pathways related to ribosome function, sugar and protein metabolism, molecular stress, disruption of energy production and histones. The main difference seen between Ag ions and NPs was associated with potential toxicokinetic effects related to cellular internalisation and communication, with pathways related to endocytosis and cilia being significantly enriched. These results point to a common final toxicodynamic response, but initial internalisation driven by different exposure routes and toxicokinetic mechanisms. PMID:26204059

  16. Underlying Mechanisms of Gene-Environment Interactions in Externalizing Behavior: A Systematic Review and Search for Theoretical Mechanisms.

    PubMed

    Weeland, Joyce; Overbeek, Geertjan; de Castro, Bram Orobio; Matthys, Walter

    2015-12-01

    Over the last decade, several candidate genes (i.e., MAOA, DRD4, DRD2, DAT1, 5-HTTLPR, and COMT) have been extensively studied as potential moderators of the detrimental effects of postnatal family adversity on child externalizing behaviors, such as aggression and conduct disorder. Many studies on such candidate gene by environment interactions (i.e., cG × E) have been published, and the first part of this paper offers a systematic review and integration of their findings (n = 53). The overview shows a set of heterogeneous findings. However, because of large differences between studies in terms of sample composition, conceptualizations, and power, it is difficult to determine if different findings indeed illustrate inconsistent cG × E findings or if findings are simply incomparable. In the second part of the paper, therefore, we argue that one way to help resolve this problem is the development of theory-driven a priori hypotheses on which biopsychosocial mechanisms might underlie cG × E. Such a theoretically based approach can help us specify our research strategies, create more comparable findings, and help us interpret different findings between studies. In accordance, we describe three possible explanatory mechanisms, based on extant literature on the concepts of (1) emotional reactivity, (2) reward sensitivity, and (3) punishment sensitivity. For each mechanism, we discuss the link between the putative mechanism and externalizing behaviors, the genetic polymorphism, and family adversity. Possible research strategies to test these mechanisms, and implications for interventions, are discussed. PMID:26537239

  17. Evaluation of explosive sublimation as the mechanism of nanosecond laser ablation of tungsten under vacuum conditions

    NASA Astrophysics Data System (ADS)

    Oderji, Hassan Yousefi; Farid, Nazar; Sun, Liying; Fu, Cailong; Ding, Hongbin

    2016-08-01

    A non-equilibrium mechanism for nanosecond laser ablation is suggested herein, and its predictions are compared to the results of W experiments performed under vacuum conditions. A mechanism of particle formation is explained via this model, with partial sublimation of the superheated irradiated zone of the target considered to be the mechanism of laser ablation. In this study, a mixture of vapor and particles was explosively generated and subsequently prevented the rest of a laser pulse from reaching its intended target. This mechanism was found to play an essential role in the ablation of W under vacuum conditions, and it provides a theoretical justification for particle formation. Moreover, special considerations were taken into account for the expansion of plasma into a vacuum. The model was evaluated by measuring the mass of ablated particles using a quartz crystal deposition monitor and time-resolved optical emission spectroscopy. The results of this model were found to be in good agreement with experimental values.

  18. A Potential Role for Mechanical Forces in the Detachment of Podocytes and the Progression of CKD

    PubMed Central

    Lemley, Kevin V.

    2015-01-01

    Loss of podocytes underlies progression of CKD. Detachment of podocytes from the glomerular basement membrane (GBM) rather than apoptosis or necrosis seems to be the major mechanism of podocyte loss. Such detachment of viable podocytes may be caused by increased mechanical distending and shear forces and/or impaired adhesion to the GBM. This review considers the mechanical challenges that may lead to podocyte loss by detachment from the GBM under physiologic and pathophysiologic conditions, including glomerular hypertension, hyperfiltration, hypertrophy, and outflow of filtrate from subpodocyte spaces. Furthermore, we detail the cellular mechanisms by which podocytes respond to these challenges, discuss the protective effects of angiotensin blockade, and note the questions that must be addressed to better understand the relationship between podocyte detachment and progression of CKD. PMID:25060060

  19. The costly filtering of potential distraction: evidence for a supramodal mechanism.

    PubMed

    Marini, Francesco; Chelazzi, Leonardo; Maravita, Angelo

    2013-08-01

    When dealing with significant sensory stimuli, performance can be hampered by distracting events. Attention mechanisms lessen such negative effects, enabling selection of relevant information while blocking potential distraction. Recent work shows that preparatory brain activity, occurring before a critical stimulus, may reflect mechanisms of attentional control aimed to filter upcoming distracters. However, it is unknown whether the engagement of these filtering mechanisms to counteract distraction in itself taxes cognitive-brain systems, leading to performance costs. Here we address this question and, specifically, seek the behavioral signature of a mechanism for the filtering of potential distraction within and between sensory modalities. We show that, in potentially distracting contexts, a filtering mechanism is engaged to cope with forthcoming distraction, causing a dramatic behavioral cost in no-distracter trials during a speeded tactile discrimination task. We thus demonstrate an impaired processing caused by a potential, yet absent, distracter. This effect generalizes across different sensory modalities, such as vision and audition, and across different manipulations of the context, such as the distracter's sensory modality and pertinence to the task. Moreover, activation of the filtering mechanism relies on both strategic and reactive processes, as shown by its dynamic dependence on probabilistic and cross-trial contingencies. Crucially, across participants, the observed strategic cost is inversely related to the interference exerted by a distracter on distracter-present trials. These results attest to a mechanism for the monitoring and filtering of potential distraction in the human brain. Although its activation is indisputably beneficial when distraction occurs, it leads to robust costs when distraction is actually expected but currently absent. PMID:22984954

  20. Correlation of fragility with mechanical moduli in double-well potential for glass-forming liquid

    NASA Astrophysics Data System (ADS)

    Cao, Wan Qiang

    2012-02-01

    The shoving model and the Vogel-Fulcher relation are employed to derive correlation of the fragility with the mechanical moduli for glass-forming simple liquids. The result shows that a liquid with smaller fragility will have larger ratio of K∞/G∞ in dilute liquid system. Based on radial distribution function with the Lennard-Jones potential modified by the Gaussian potential with a second minimum, fragility of the supercooled simple liquid is derived from the correlation between viscosity and shear modulus via configurational entropy. The results demonstrate that the fragility is determined by two parts: thermodynamic components and mechanical moduli. For a weak Gaussian potential liquid, the fragility is proportional to the Tg, while for a strong one, the fragility is inversely proportional to the Tg, and the Gaussian potential will increase fragility.

  1. The role of shape invariance potentials in the relativistic quantum mechanics

    NASA Astrophysics Data System (ADS)

    Bakhshi, Z.; Panahi, H.

    2016-05-01

    The point canonical transformation in non-relativistic quantum mechanics is applied as an algebraic method to obtain the solutions of the Dirac equation with spherical symmetry electromagnetic potentials. We want to show that some of the non-relativistic solvable potentials with shape-invariant symmetry can be related to the radial Dirac equation. Using this method, the idea of supersymmetry and shape invariance can be expanded to the relativistic quantum mechanics. The spinor wave functions for some of the obtained four-component electromagnetic potential are given in terms of special functions such as Jacobi, generalized Laguerre and Hermite polynomials. The relativistic bound-states spectrum for each case is also calculated in terms of the bound-states spectrum of the solvable potentials.

  2. Experimental investigation on mechanical damage characteristics of sandstone under triaxial cyclic loading

    NASA Astrophysics Data System (ADS)

    Yang, Sheng-Qi; Ranjith, P. G.; Huang, Yan-Hua; Yin, Peng-Fei; Jing, Hong-Wen; Gui, Yi-Lin; Yu, Qing-Lei

    2015-05-01

    The mechanical damage characteristics of sandstone subjected to cyclic loading is very significant to evaluate the stability and safety of deep excavation damage zones. However to date, there are very few triaxial experimental studies of sandstone under cyclic loading. Moreover, few X-ray micro-computed tomography (micro-CT) observations have been adopted to reveal the damage mechanism of sandstone under triaxial cyclic loading. Therefore, in this research, a series of triaxial cyclic loading tests and X-ray micro-CT observations were conducted to analyse the mechanical damage characteristics of sandstone with respect to different confining pressures. The results indicated that at lower confining pressures, the triaxial strength of sandstone specimens under cyclic loading is higher than that under monotonic loading; whereas at confining pressures above 20 MPa, the triaxial strength of sandstone under cyclic loading is approximately equal to that under monotonic loading. With the increase of cycle number, the crack damage threshold of sandstone first increases, and then significantly decreases and finally remains constant. Based on the damage evolution of irreversible deformation, it appears that the axial damage value of sandstone is all higher than the radial damage value before the peak strength; whereas the radial damage value is higher than the axial damage value after the peak strength. The evolution of Young's modulus and Poisson's ratio of sandstone can be characterized as having four stages: (i) Stage I: material strengthening; (ii) Stage II: material degradation; (iii) Stage III: material failure and (iv) Stage IV: structure slippage. X-ray micro-CT observations demonstrated that the CT scanning surface images of sandstone specimens are consistent with actual surface crack photographs. The analysis of the cross-sections of sandstone supports that the system of crack planes under triaxial cyclic loading is much more complicated than that under triaxial

  3. Mechanical analysis of wood-fiber cement sheets under constant and repeated loading

    NASA Astrophysics Data System (ADS)

    Teixeira, Divino Eterno

    Douglas fir fiber presented superior mechanical and physical properties as compared to the commercial sheets. Sheets made with recycled OCC fiber presented properties comparable to the commercial product, except for modulus of rupture. However, defects detected after the autoclave process make OCC fibers unsuitable as fiber reinforcement for the sheets are to be cured in autoclave. Finally, results from Manuscript 3 showed that WFC sheets were sensitive to high moisture environment but not to high temperature. Creep deflection was higher under high humidity conditions. Even though moisture played a major role on the creep behavior of the products tested, values of deformation and relative creep were much lower when compared to resin-bonded wood composites. Furthermore, a 5-element model developed to predict creep deflection of the material studied produced coefficient of determination (Rsp2) over 0.977. Results obtained in the current study showed that WFC flat sheets tested are potential candidates for use in structural applications.

  4. Postsynaptic mechanisms underlying the excitatory action of histamine on medial vestibular nucleus neurons in rats

    PubMed Central

    Zhang, Xiao-Yang; Yu, Lei; Zhuang, Qian-Xing; Peng, Shi-Yu; Zhu, Jing-Ning; Wang, Jian-Jun

    2013-01-01

    Background and Purpose Anti-histaminergic drugs have been widely used in the clinical treatment of vestibular disorders and most studies concentrate on their presynaptic actions. The present study investigated the postsynaptic effect of histamine on medial vestibular nucleus (MVN) neurons and the underlying mechanisms. Experimental Approach Histamine-induced postsynaptic actions on MVN neurons and the corresponding receptor and ionic mechanisms were detected by whole-cell patch-clamp recordings on rat brain slices. The distribution of postsynaptic histamine H1, H2 and H4 receptors was mapped by double and single immunostaining. Furthermore, the expression of mRNAs for H1, H2 and H4 receptors and for subtypes of Na+–Ca2+ exchangers (NCXs) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels was assessed by quantitative real-time RT-PCR. Key Results A marked postsynaptic excitatory effect, co-mediated by histamine H1 and H2 receptors, was involved in the histamine-induced depolarization of MVN neurons. Postsynaptic H1 and H2 rather than H4 receptors were co-localized in the same MVN neurons. NCXs contributed to the inward current mediated by H1 receptors, whereas HCN channels were responsible for excitation induced by activation of H2 receptors. Moreover, NCX1 and NCX3 rather than NCX2, and HCN1 rather than HCN2-4 mRNAs, were abundantly expressed in MVN. Conclusion and Implications NCXs coupled to H1 receptors and HCN channels linked to H2 receptors co-mediate the strong postsynaptic excitatory action of histamine on MVN neurons. These results highlight an active role of postsynaptic mechanisms in the modulation by central histaminergic systems of vestibular functions and suggest potential targets for clinical treatment of vestibular disorders. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 PMID:23713466