WorldWideScience

Sample records for cellular mechanisms underlying

  1. Cellular and molecular mechanisms underlying radiation carcinogenesis

    International Nuclear Information System (INIS)

    When considering and analyzing experimental material concerning cellular aspects of the problem of radiation carcinogenesis, the following conclusions can be made: neoplastic transformation of cells in a culture is caused already by small radiation doses, under the effect of which the level of DNA injury is quite insignificant; the frequency of cell transformation depends on the type of radiation, it is particularly pronounced under the effect of radiations with a high linear energy transfer; a correlation between the processes of postradiation recovery and radiogenic transformation of cells is detected, nonrepairable injures of DNA playing the most important role in radiation carcinogenesis; tumour promoters and anticarcinogenic agens produce a modifying effect on the transformation of irradiated cells. Molecular mechanisms of oncogene activation are thoroughly studied using the model of virus carcinogenesis, the problem of the nature of chemical and, in particular, radiation cell transformation remains scantily investigated

  2. Cellular and molecular mechanisms underlying muscular dystrophy

    OpenAIRE

    Rahimov, Fedik; Kunkel, Louis M

    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 ...

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Girolamo Pelaia

    2015-01-01

    Full Text Available 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 (Th2 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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  7. Genomic interrogation of mechanism(s) underlying cellular responses to toxicants

    International Nuclear Information System (INIS)

    Assessment of the impact of xenobiotic exposure on human health and disease progression is complex. Knowledge of mode(s) of action, including mechanism(s) contributing to toxicity and disease progression, is valuable for evaluating compounds. Toxicogenomics, the subdiscipline which merges genomics with toxicology, holds the promise to contributing significantly toward the goal of elucidating mechanism(s) by studying genome-wide effects of xenobiotics. Global gene expression profiling, revolutionized by microarray technology and a crucial aspect of a toxicogenomic study, allows measuring transcriptional modulation of thousands of genes following exposure to a xenobiotic. We use our results from previous studies on compounds representing two different classes of xenobiotics (barbiturate and peroxisome proliferator) to discuss the application of computational approaches for analyzing microarray data to elucidate mechanism(s) underlying cellular responses to toxicants. In particular, our laboratory demonstrated that chemical-specific patterns of gene expression can be revealed using cDNA microarrays. Transcript profiling provides discrimination between classes of toxicants, as well as, genome-wide insight into mechanism(s) of toxicity and disease progression. Ultimately, the expectation is that novel approaches for predicting xenobiotic toxicity in humans will emerge from such information

  8. Diesel exhaust: current knowledge of adverse effects and underlying cellular mechanisms

    OpenAIRE

    Steiner, Sandro; Bisig, Christoph; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

    2016-01-01

    Diesel engine emissions are among the most prevalent anthropogenic pollutants worldwide, and with the growing popularity of diesel-fueled engines in the private transportation sector, they are becoming increasingly widespread in densely populated urban regions. However, a large number of toxicological studies clearly show that diesel engine emissions profoundly affect human health. Thus the interest in the molecular and cellular mechanisms underlying these effects is large, especially c...

  9. Diesel exhaust: current knowledge of adverse effects and underlying cellular mechanisms.

    Science.gov (United States)

    Steiner, Sandro; Bisig, Christoph; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

    2016-07-01

    Diesel engine emissions are among the most prevalent anthropogenic pollutants worldwide, and with the growing popularity of diesel-fueled engines in the private transportation sector, they are becoming increasingly widespread in densely populated urban regions. However, a large number of toxicological studies clearly show that diesel engine emissions profoundly affect human health. Thus the interest in the molecular and cellular mechanisms underlying these effects is large, especially concerning the nature of the components of diesel exhaust responsible for the effects and how they could be eliminated from the exhaust. This review describes the fundamental properties of diesel exhaust as well as the human respiratory tract and concludes that adverse health effects of diesel exhaust not only emerge from its chemical composition, but also from the interplay between its physical properties, the physiological and cellular properties, and function of the human respiratory tract. Furthermore, the primary molecular and cellular mechanisms triggered by diesel exhaust exposure, as well as the fundamentals of the methods for toxicological testing of diesel exhaust toxicity, are described. The key aspects of adverse effects induced by diesel exhaust exposure described herein will be important for regulators to support or ban certain technologies or to legitimate incentives for the development of promising new technologies such as catalytic diesel particle filters. PMID:27165416

  10. Cellular and deafness mechanisms underlying connexin mutation induced hearing loss – A common hereditary deafness

    Directory of Open Access Journals (Sweden)

    Hong-Bo Zhao

    2015-05-01

    Full Text Available 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 nonsyndromic 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 (EP reduction, while late-onset hearing loss results from reduction of active cochlear amplification, even though cochlear hair cells have no connexin expression. Moreover, new experiments further demonstrate that the hypothesized K+-recycling disruption is not a principal deafness mechanism for connexin deficiency induced hearing loss. Additionally, there is no clear relationship between specific changes in connexin (channel functions and the phenotypes of mutation-induced hearing loss. Cx30, Cx29, Cx31, and Cx43 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 and pathogeneses of specific-mutation induced hearing loss remain unclear. Finally, little information is available for humans. Further studies to address these deficiencies are urgently required.

  11. A mathematical model of cortical bone remodeling at cellular level under mechanical stimulus

    Institute of Scientific and Technical Information of China (English)

    Qing-Hua Qin; Ya-Nan Wang

    2012-01-01

    A bone cell population dynamics model for cortical bone remodeling under mechanical stimulus is developed in this paper.The external experiments extracted from the literature which have not been used in the creation of the model are used to test the validity of the model.Not only can the model compare reasonably well with these experimental results such as the increase percentage of final values of bone mineral content (BMC) and bone fracture energy (BFE) among different loading schemes (which proves the validity of the model),but also predict the realtime development pattern of BMC and BFE,as well as the dynamics of osteoblasts (OBA),osteoclasts (OCA),nitric oxide (NO) and prostaglandin E2 (PGE2) for each loading scheme,which can hardly be monitored through experiment.In conclusion,the model is the first of its kind that is able to provide an insight into the quantitative mechanism of bone remodeling at cellular level by which bone cells are activated by mechanical stimulus in order to start resorption/formation of bone mass.More importantly,this model has laid a solid foundation based on which future work such as systemic control theory analysis of bone remodeling under mechanical stimulus can be investigated.The to-be identified control mechanism will help to develop effective drugs and combined nonpharmacological therapies to combat bone loss pathologies.Also this deeper understanding of how mechanical forces quantitatively interact with skeletal tissue is essential for the generation of bone tissue for tissue replacement purposes in tissue engineering.

  12. Axial level-dependent molecular and cellular mechanisms underlying the genesis of the embryonic neural plate.

    Science.gov (United States)

    Kondoh, Hisato; Takada, Shinji; Takemoto, Tatsuya

    2016-06-01

    The transcription factor gene Sox2, centrally involved in neural primordial regulation, is activated by many enhancers. During the early stages of embryonic development, Sox2 is regulated by the enhancers N2 and N1 in the anterior neural plate (ANP) and posterior neural plate (PNP), respectively. This differential use of the enhancers reflects distinct regulatory mechanisms underlying the genesis of ANP and PNP. The ANP develops directly from the epiblast, triggered by nodal signal inhibition, and via the combined action of TFs SOX2, OTX2, POU3F1, and ZIC2, which promotes the the ANP development and inhibits other cell lineages. In contrast, the PNP is derived from neuromesodermal bipotential axial stem cells that develop into the neural plate when Sox2 is activated by the N1 enhancer, whereas they develop into the paraxial mesoderm when the N1 enhancer is repressed by the action of TBX6. The axial stem cells are maintained by the activity of WNT3a and T (Brachyury). However, at axial levels more anterior to the 8th somites (cervical levels), the development of both the neural plate and somite proceeds in the absence of WNT3a, T, or TBX6. These observations indicate that distinct molecular and cellular mechanisms determine neural plate genesis based on the axial level, and contradict the classical concept of the term "neural induction," which assumes a pan-neural plate mechanism. PMID:27279156

  13. Numerical study of mechanical behavior of ceramic composites under compression loading in the framework of movable cellular automaton method

    Energy Technology Data Exchange (ETDEWEB)

    Konovalenko, Igor S., E-mail: igkon@ispms.tsc.ru; Smolin, Alexey Yu., E-mail: igkon@ispms.tsc.ru; Konovalenko, Ivan S., E-mail: igkon@ispms.tsc.ru [Institute of Strength Physics and Materials Science SB RAS, Tomsk, 634055 (Russian Federation); Promakhov, Vladimir V. [Institute of Strength Physics and Materials Science SB RAS, Tomsk, 634055, Russia and National Research Tomsk State University, Tomsk, 634050 (Russian Federation); Psakhie, Sergey G. [Institute of Strength Physics and Materials Science SB RAS, Tomsk, 634055 (Russian Federation); National Research Tomsk State University, Tomsk, 634050 (Russian Federation); National Research Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation)

    2014-11-14

    Movable cellular automaton method was used for investigating the mechanical behavior of ceramic composites under uniaxial compression. A 2D numerical model of ceramic composites based on oxides of zirconium and aluminum with different structural parameters was developed using the SEM images of micro-sections of a real composite. The influence of such structural parameters as the geometrical dimensions of layers, inclusions, and their spatial distribution in the sample, the volume content of the composite components and their mechanical properties (as well as the amount of zirconium dioxide that underwent the phase transformation) on the fracture, strength, deformation and dissipative properties was investigated.

  14. Life under Climate Change Scenarios: Sea Urchins’ Cellular Mechanisms for Reproductive Success

    Directory of Open Access Journals (Sweden)

    Desislava Bögner

    2016-03-01

    Full Text Available Ocean Acidification (OA represents a major field of research and increased efforts are being made to elucidate its repercussions on biota. Species survival is ensured by successful reproduction, which may be threatened under detrimental environmental conditions, such as OA acting in synergy with other climate change related stressors. Achieving successful gametogenesis, fertilization, and the development of larvae into healthy juveniles and adults is crucial for the perpetuation of species and, thus, ecosystems’ functionality. The considerable vulnerability of the abovementioned developmental stages to the adverse conditions that future OA may impose has been shown in many species, including sea urchins which are commonly used due to the feasibility of their maintenance in captivity and the great amount of gametes that a mature adult is able to produce. In the present review, the latest knowledge about the impact of OA on various stages of the life cycle of sea urchins is summarized with remarks on the possible impact of other stressors. The cellular physiology of the gametes before, at fertilization and, at early development, is extensively described with a focus on the complex enzymatic machinery and the intracellular pH (pHi and Ca2+ homeostasis for their vulnerability when facing adverse conditions such as acidification, temperature variations, or hypoxia.

  15. Cellular mechanics and motility

    Science.gov (United States)

    Hénon, Sylvie; Sykes, Cécile

    2015-10-01

    The term motility defines the movement of a living organism. One widely known example is the motility of sperm cells, or the one of flagellar bacteria. The propulsive element of such organisms is a cilium(or flagellum) that beats. Although cells in our tissues do not have a flagellum in general, they are still able to move, as we will discover in this chapter. In fact, in both cases of movement, with or without a flagellum, cell motility is due to a dynamic re-arrangement of polymers inside the cell. Let us first have a closer look at the propulsion mechanism in the case of a flagellum or a cilium, which is the best known, but also the simplest, and which will help us to define the hydrodynamic general conditions of cell movement. A flagellum is sustained by cellular polymers arranged in semi-flexible bundles and flagellar beating generates cell displacement. These polymers or filaments are part of the cellular skeleton, or "cytoskeleton", which is, in this case, external to the cellular main body of the organism. In fact, bacteria move in a hydrodynamic regime in which viscosity dominates over inertia. The system is thus in a hydrodynamic regime of low Reynolds number (Box 5.1), which is nearly exclusively the case in all cell movements. Bacteria and their propulsion mode by flagella beating are our unicellular ancestors 3.5 billion years ago. Since then, we have evolved to form pluricellular organisms. However, to keep the ability of displacement, to heal our wounds for example, our cells lost their flagellum, since it was not optimal in a dense cell environment: cells are too close to each other to leave enough space for the flagella to accomplish propulsion. The cytoskeleton thus developed inside the cell body to ensure cell shape changes and movement, and also mechanical strength within a tissue. The cytoskeleton of our cells, like the polymers or filaments that sustain the flagellum, is also composed of semi-flexible filaments arranged in bundles, and also in

  16. Olfactory stem cells, a new cellular model for studying molecular mechanisms underlying familial dysautonomia.

    Directory of Open Access Journals (Sweden)

    Nathalie Boone

    Full Text Available BACKGROUND: Familial dysautonomia (FD is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells. METHODOLOGY/PRINCIPAL FINDINGS: We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in FD hOE-MSCs. Furthermore, we were able to modify the IKBKAP splicing ratio in FD hOE-MSCs, increasing or reducing the WT (exon 20 inclusion:MU (exon 20 skipping ratio respectively, either by producing free-floating spheres, or by inducing cells into neural differentiation. CONCLUSIONS/SIGNIFICANCE: hOE-MSCs isolated from FD patients represent a new approach for modeling FD to better

  17. Mechanisms underlying cellular responses of cells from haemopoietic tissue to low

    Energy Technology Data Exchange (ETDEWEB)

    Kadhim, Munira A

    2012-08-22

    The above studies will provide fundamental mechanistic information relating genetic predisposition to important low dose phenomena, and will aid in the development of Department of Energy policy, as well as radiation risk policy for the public and the workplace. We believe the proposed studies accurately reflect the goals of the DOE low dose program. To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e. less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these "non-targeted responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate non-targeted effects of ionizing radiation with a focus on the induction of genomic instability (GI) in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/CaH and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition in these models on genomic instability. We will specifically focus on the effects of low doses of low LET radiation, down to the dose of 10mGy (0.01Gy) X-rays. Using conventional X-ray and we will be able to assess the role of genetic variation under various conditions at a range of doses down to the very low dose of 0.01Gy. Irradiations will be carried out using facilities in routine operation for such studies. Mechanistic studies of instability in different cell

  18. Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

    Energy Technology Data Exchange (ETDEWEB)

    Munira A Kadhim

    2010-03-05

    To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim

  19. Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.

    Science.gov (United States)

    Lindqvist, Daniel; Epel, Elissa S; Mellon, Synthia H; Penninx, Brenda W; Révész, Dóra; Verhoeven, Josine E; Reus, Victor I; Lin, Jue; Mahan, Laura; Hough, Christina M; Rosser, Rebecca; Bersani, F Saverio; Blackburn, Elizabeth H; Wolkowitz, Owen M

    2015-08-01

    Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell's mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets. PMID:25999120

  20. Helicobacter pylori eradication to prevent gastric cancer:underlying molecular and cellular mechanisms

    Institute of Scientific and Technical Information of China (English)

    Shingo Tsuji; Norio Hayashi; Masahiko Tsujii; Hiroaki Murata; Tsutomu Nishida; Masato Komori; Masakazu Yasumaru; Shuji Ishii; Yoshiaki Sasayama; Sunao Kawano

    2006-01-01

    Numerous cellular and molecular events have been described in development of gastric cancer. In this article,we overviewed roles of Helicobacter pylori(H pylori) infection on some of the important events in gastric carcinogenesis and discussed whether these cellular and molecular events are reversible after cure of the infection. There are several bacterial components affecting gastric epithelial kinetics and promotion of gastric carcinogenesis. The bacterium also increases risks of genetic instability and mutations due to NO and other reactive oxygen species. Epigenetic silencing of tumor suppressor genes such as RUNX3 may alter the frequency of phenotype change of gastric glands to those with intestinal metaplasia. Host factors such as increased expression of growth factors, cytokines and COX-2 have been also reported in non-cancerous tissue in H pylori-positive subjects. It is noteworthy that most of the above phenomena are reversed after the cure of the infection. However,some of them including overexpression of COX-2 continue to exist and may increase risks for carcinogenesis in metaplastic or dysplastic mucosa even after successful H pylori eradication. Thus, H pylori eradication may not completely abolish the risk for gastric carcinogenesis. Efficiency of the cure of the infection in suppressing gastric cancer depends on the timing and the target population,and warrant further investigation.

  1. Cellular mechanisms during vascular development

    OpenAIRE

    Blum, Yannick

    2012-01-01

    The vascular system is an essential organ in vertebrate animals and provides the organism with enough oxygen and nutrients. It is composed of an interconnected network of blood vessels, which form using a number of different morphogenetic mechanisms. Angiogenesis describes the formation of new blood vessels from preexisting vessels. A number of molecular pathways have been shown to be essential during angiogenesis. However, cellular architecture of blood vessels as well as cellular mechanisms...

  2. Molecular and cellular mechanisms of cadmium carcinogenesis

    International Nuclear Information System (INIS)

    Cadmium is a heavy metal, which is widely used in industry, affecting human health through occupational and environmental exposure. In mammals, it exerts multiple toxic effects and has been classified as a human carcinogen by the International Agency for Research on Cancer. Cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Cd2+ does not catalyze Fenton-type reactions because it does not accept or donate electrons under physiological conditions, and it is only weakly genotoxic. Hence, indirect mechanisms are implicated in the carcinogenicity of cadmium. In this review multiple mechanisms are discussed, such as modulation of gene expression and signal transduction, interference with enzymes of the cellular antioxidant system and generation of reactive oxygen species (ROS), inhibition of DNA repair and DNA methylation, role in apoptosis and disruption of E-cadherin-mediated cell-cell adhesion. Cadmium affects both gene transcription and translation. The major mechanisms of gene induction by cadmium known so far are modulation of cellular signal transduction pathways by enhancement of protein phosphorylation and activation of transcription and translation factors. Cadmium interferes with antioxidant defense mechanisms and stimulates the production of reactive oxygen species, which may act as signaling molecules in the induction of gene expression and apoptosis. The inhibition of DNA repair processes by cadmium represents a mechanism by which cadmium enhances the genotoxicity of other agents and may contribute to the tumor initiation by this metal. The disruption of E-cadherin-mediated cell-cell adhesion by cadmium probably further stimulates the development of tumors. It becomes clear that there exist multiple mechanisms which contribute to the carcinogenicity of cadmium, although the relative weights of these contributions are difficult to estimate

  3. Mechanisms of cellular transformation by carcinogenic agents

    International Nuclear Information System (INIS)

    This book contains 14 chapters. Some of the chapter titles are: DNA Modification by Chemical Carcinogens; Role of DNA Lesions and Repair in the Transformation of Human Cells; The Induction and Regulation of Radiogenic Transformation In Vitro: Cellular and Molecular Mechanisms; Cellular Transformation by Adenoviruses; and The fos Gene

  4. Mechanisms of cellular transformation by carcinogenic agents

    Energy Technology Data Exchange (ETDEWEB)

    Grunberger, D.; Goff, S.P.

    1987-01-01

    This book contains 14 chapters. Some of the chapter titles are: DNA Modification by Chemical Carcinogens; Role of DNA Lesions and Repair in the Transformation of Human Cells; The Induction and Regulation of Radiogenic Transformation In Vitro: Cellular and Molecular Mechanisms; Cellular Transformation by Adenoviruses; and The fos Gene.

  5. Cellular and molecular mechanisms in kidney fibrosis

    Science.gov (United States)

    Duffield, Jeremy S.

    2014-01-01

    Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progression. This review focuses on new findings that enhance understanding of cellular and molecular mechanisms of fibrosis, the characteristics of myofibroblasts, their progenitors, and molecular pathways regulating both fibrogenesis and its resolution. PMID:24892703

  6. Cellular mechanisms that control mistranslation

    DEFF Research Database (Denmark)

    Reynolds, Noah M; Lazazzera, Beth A; Ibba, Michael

    2010-01-01

    Mistranslation broadly encompasses the introduction of errors during any step of protein synthesis, leading to the incorporation of an amino acid that is different from the one encoded by the gene. Recent research has vastly enhanced our understanding of the mechanisms that control mistranslation...

  7. Mechanism of cellular phospholipid efflux.

    Science.gov (United States)

    Kozar, R A; McKeone, B J; Pownall, H J

    1993-11-01

    Plasma phospholipid binding to cell-derived cholesterol is important in reverse cholesterol transport, a key step in the regression of atherosclerosis. However, the mechanism by which phospholipids are transferred from cells to plasma remains unclear. [3H]Choline-labeled phospholipid efflux from fibroblasts has been studied using plasma and its components as acceptors. The kinetics were resolved into a fast component (k1 = 0.119 +/- 0.23 min-1) that corresponded to high-affinity binding of high-density lipoproteins (HDL) to the cell surface and a slow component (k2 = 0.0047 +/- 0.0009 min-1) due to protein-mediated desorption (n = 3). Altering the donor charge with heparinase or the acceptor charge by acetylation abolished the fast component, while the slow phase was unchanged. Only HDL displayed biexponential kinetics, comparable to whole plasma. Half-lives for low-density lipoprotein and very-low-density lipoprotein were t1/2 = 278 +/- 22 min and t1/2 = 1003 +/- 147 min, respectively. In the absence of transfer factor, HDL alone significantly reduced phospholipid efflux (t1/2 = 663 min). Phospholipid transfer protein restored biexponential kinetics. We conclude that cell membranes are a potentially important source of plasma phospholipids and that protein-mediated transfer to HDL is the major route for cell-to-plasma transfer. This step represents a locus for anti-atherosclerotic intervention. PMID:8231174

  8. Cellular and molecular mechanisms in kidney fibrosis

    OpenAIRE

    Duffield, Jeremy S.

    2014-01-01

    Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progressi...

  9. Cellular mechanisms of nociception in the frog

    Czech Academy of Sciences Publication Activity Database

    Kuffler, D. P.; Lyfenko, Alla; Vyklický st., Ladislav; Vlachová, Viktorie

    2002-01-01

    Roč. 88, č. 4 (2002), s. 1843-1850. ISSN 0022-3077 R&D Projects: GA ČR GA305/00/1639; GA MŠk LN00B122 Grant ostatní: NATO(XX) Grant 977062 Institutional research plan: CEZ:AV0Z5011922 Keywords : cellular mechanisms of nociception * frog Subject RIV: FH - Neurology Impact factor: 3.743, year: 2002

  10. Cellular pressure and volume regulation and implications for cell mechanics.

    Science.gov (United States)

    Jiang, Hongyuan; Sun, Sean X

    2013-08-01

    In eukaryotic cells, small changes in cell volume can serve as important signals for cell proliferation, death, and migration. Volume and shape regulation also directly impacts the mechanics of cells and tissues. Here, we develop a mathematical model of cellular volume and pressure regulation, incorporating essential elements such as water permeation, mechanosensitive channels, active ion pumps, and active stresses in the cortex. The model can fully explain recent experimental data, and it predicts cellular volume and pressure for several models of cell cortical mechanics. Moreover, we show that when cells are subjected to an externally applied load, such as in an atomic force microscopy indentation experiment, active regulation of volume and pressure leads to a complex cellular response. Instead of the passive mechanics of the cortex, the observed cell stiffness depends on several factors working together. This provides a mathematical explanation of rate-dependent response of cells under force. PMID:23931309

  11. Molecular and cellular mechanisms of adipogenesis

    Directory of Open Access Journals (Sweden)

    Aleksander Dmitrievich Egorov

    2015-03-01

    Full Text Available The main components of metabolic syndrome include insulin resistance, hypertriglyceridemia and arterial hypertension. Obesity is the cause of metabolic syndrome, mainly as a consequence of the endocrine function of adipose tissue. The volume of adipose tissue depends on the size of individual adipocytes and on their number. The number of adipocytes increases as a result of enhanced adipocyte differentiation. The transcriptional cascade that regulates this differentiation has been well studied. The major adipogenic transcription factor peroxisome proliferator-activated receptor gamma is a ligand-activated nuclear receptor with essential roles in adipogenesis. Its ligands are used to treat metabolic syndrome and type 2 diabetes mellitus. The present article describes the basic molecular and cellular mechanisms of adipogenesis and discusses the impact of insulin, glucocorticoids, cyclic adenosine monophosphate-activating agents, nuclear receptors and transcription factors on the process of adipogenesis. New regulatory regions of the genome that are capable of binding multiple transcription factors are described, and the most promising drug targets for the treatment of metabolic syndrome and obesity, including the homeodomain proteins Pbx1 and Prep1, are discussed.

  12. Mechanisms involved in cellular ceramide homeostasis

    Directory of Open Access Journals (Sweden)

    Hussain M

    2012-07-01

    Full Text Available Abstract Sphingolipids are ubiquitous and critical components of biological membranes. Their biosynthesis starts with soluble precursors in the endoplasmic reticulum and culminates in the Golgi complex and plasma membrane. Ceramides are important intermediates in the biosynthesis of sphingolipids, such as sphingomyelin, and their overload in the membranes is injurious to cells. The major product of ceramide metabolism is sphingomyelin. We observed that sphingomyelin synthase (SMS 1 or SMS2 deficiencies significantly decreased plasma and liver sphingomyelin levels. However, SMS2 but not SMS1 deficiency increased plasma ceramides. Surprisingly, SMS1 deficiency significantly increased glucosylceramide and ganglioside GM3, but SMS2 deficiency did not. To explain these unexpected findings about modest to no significant changes in ceramides and increases in other sphingolipids after the ablation of SMS1, we hypothesize that cells have evolved several organelle specific mechanisms to maintain ceramide homeostasis. First, ceramides in the endoplasmic reticulum membranes are controlled by its export to Golgi by protein mediated transfer. Second, in the Golgi, ceramide levels are modulated by their enzymatic conversion to different sphingolipids such as sphingomyelin, and glucosylceramides. Additionally, these sphingolipids can become part of triglyceride-rich apolipoprotein B-containing lipoproteins and be secreted. Third, in the plasma membrane ceramide levels are maintained by ceramide/sphingomyelin cycle, delivery to lysosomes, and efflux to extracellular plasma acceptors. All these pathways might have evolved to ensure steady cellular ceramide levels.

  13. Cellular and molecular mechanisms in liver fibrogenesis.

    Science.gov (United States)

    Novo, Erica; Cannito, Stefania; Paternostro, Claudia; Bocca, Claudia; Miglietta, Antonella; Parola, Maurizio

    2014-04-15

    Liver fibrogenesis is a dynamic and highly integrated molecular, tissue and cellular process, potentially reversible, that drives the progression of chronic liver diseases (CLD) towards liver cirrhosis and hepatic failure. Hepatic myofibroblasts (MFs), the pro-fibrogenic effector cells, originate mainly from activation of hepatic stellate cells and portal fibroblasts being characterized by a proliferative and survival attitude. MFs also contract in response to vasoactive agents, sustain angiogenesis and recruit and modulate activity of cells of innate or adaptive immunity. Chronic activation of wound healing and oxidative stress as well as derangement of epithelial-mesenchymal interactions are "major" pro-fibrogenic mechanisms, whatever the etiology. However, literature has outlined a complex network of pro-fibrogenic factors and mediators proposed to modulate CLD progression, with some of them being at present highly debated in the field, including the role of epithelial to mesenchymal transition and Hedgehog signaling pathways. Hypoxia and angiogenesis as well as inflammasomes are recently emerged as ubiquitous pro-inflammatory and pro-fibrogenic determinants whereas adipokines are mostly involved in CLD related to metabolic disturbances (metabolic syndrome and/or obesity and type 2 diabetes). Finally, autophagy as well as natural killer and natural killer-T cells have been recently proposed to significantly affect fibrogenic CLD progression. PMID:24631571

  14. Neural and cellular mechanisms of fear and extinction memory formation.

    Science.gov (United States)

    Orsini, Caitlin A; Maren, Stephen

    2012-08-01

    Over the course of natural history, countless animal species have evolved adaptive behavioral systems to cope with dangerous situations and promote survival. Emotional memories are central to these defense systems because they are rapidly acquired and prepare organisms for future threat. Unfortunately, the persistence and intrusion of memories of fearful experiences are quite common and can lead to pathogenic conditions, such as anxiety and phobias. Over the course of the last 30 years, neuroscientists and psychologists alike have attempted to understand the mechanisms by which the brain encodes and maintains these aversive memories. Of equal interest, though, is the neurobiology of extinction memory formation as this may shape current therapeutic techniques. Here we review the extant literature on the neurobiology of fear and extinction memory formation, with a strong focus on the cellular and molecular mechanisms underlying these processes. PMID:22230704

  15. Propagation Mechanism of Cylindrical Cellular Detonation

    Science.gov (United States)

    Han, Wen-Hu; Wang, Cheng; Ning, Jian-Guo

    2012-10-01

    We investigate the evolution of cylindrical cellular detonation with different instabilities. The numerical results show that with decreasing initial temperature, detonation becomes more unstable and the cells of the cylindrical detonation tend to be irregular. For stable detonation, a divergence of cylindrical detonation cells is formed eventually due to detonation instability resulting from a curved detonation front. For mildly unstable detonation, local overdriven detonation occurs. The detonation cell diverges and its size decreases. For highly unstable detonation, locally driven detonation is more obvious and the front is highly wrinkled. As a result, the diverging cylindrical detonation cell becomes highly irregular.

  16. Computer Studies on the Mechanisms Controlling Cellular Proliferation

    International Nuclear Information System (INIS)

    A model of the autoregulation of mitotic and functional activity of the cells is used (R. Tsanev and B. Sendov, J. theoret. Biol. 12 (1966) 327) to study by means of a digital computer the reaction of different cellular systems (a synchronous cellular population, liver and epidermis) to injuring agents disturbing the steady state of the system. The reaction of the cellular models to different kinds of injury was found to imitate adequately some particular features of the real regenerative processes. The model may also be useful to check different hypotheses concerning the mechanisms by which irradiation affects cellular proliferation. (author)

  17. Symposium on molecular and cellular mechanisms of mutagenesis

    International Nuclear Information System (INIS)

    These proceedings contain abstracts only of the 21 papers presented at the Sympsoium. The papers dealt with molecular mechanisms of mutagenesis and cellular responses to chemical and physical mutagenic agents

  18. Cardiovascular effects of cocaine: cellular, ionic and molecular mechanisms.

    Science.gov (United States)

    Turillazzi, E; Bello, S; Neri, M; Pomara, C; Riezzo, I; Fineschi, V

    2012-01-01

    Cocaine is a widely abused drug responsible for the majority of deaths ascribed to drug overdose. Many mechanisms have been proposed in order to explain the various cocaine associated cardiovascular complications. Conventionally, cocaine cardiotoxicity has been thought to be mediated indirectly through its sympathomimetic effect, i.e., by inhibiting the reuptake and thus increasing the levels of neuronal catecholamines at work on adrenoceptors. Increased oxidative stress, reactive oxygen species, and cocaine-induced apoptosis in the heart muscle have suggested a new way to understand the cardiotoxic effects of cocaine. More recent studies have led the attention to the interaction of cocaine and some metabolites with cardiac sodium, calcium and potassium channels. The current paper is aimed to investigate the molecular mechanisms of cocaine cardiotoxicity which have a specific clinical and forensic interest. From a clinical point of view the full knowledge of the exact mechanisms by which cocaine exerts cardio - vascular damage is essential to identify potential therapeutic targets and improve novel strategies for cocaine related cardiovascular diseases. From a forensic point of view, it is to be underlined that cocaine use is often associated to sudden death in young, otherwise healthy individuals. While such events are widely reported, the relationship between cardiac morphological alterations and molecular/cellular mechanisms is still controversial. In conclusion, the study of cocaine cardiovascular toxicity needs a strict collaboration between clinicians and pathologists which may be very effective in further dissecting the mechanisms underlying cocaine cardiotoxicity and understanding the cardiac cocaine connection. PMID:22856657

  19. Mechanical oscillations at the cellular scale

    CERN Document Server

    Jülicher, F

    2001-01-01

    Active phenomena which involve force generation and motion play a key role in a number of phenomena in living cells such as cell motility, muscle contraction and the active transport of material and organelles. Here we discuss mechanical oscillations generated by active systems in cells. Examples are oscillatory regimes in muscles, the periodic beating of axonemal cilia and flagella and spontaneous oscillations of auditory hair cells which play a role in active amplification of weak sounds in hearing. As a prototype system for oscillation generation by proteins, we discuss a general mechanism by which many coupled active elements such as motor molecules can generate oscillations.

  20. Material and mechanical factors:new strategy in cellular neurogenesis

    Institute of Scientific and Technical Information of China (English)

    Hillary Stoll; Il Keun Kwon; Jung Yul Lim

    2014-01-01

    Since damaged neural circuits are not generally self-recovered, developing methods to stimulate neurogenesis is critically required. Most studies have examined the effects of soluble pharma-cological factors on the cellular neurogenesis. On the other hand, it is now recognized that the other extracellular factors, including material and mechanical cues, also have a strong potential to induce cellular neurogenesis. This article will review recent data on the material (chemical patterning, micro/nano-topography, carbon nanotube, graphene) and mechanical (static cue from substrate stiffness, dynamic cue from stretch and lfow shear) stimulations of cellular neuro-genesis. These approaches may provide new neural regenerative medicine protocols. Scaffolding material templates capable of triggering cellular neurogenesis can be explored in the presence of neurogenesis-stimulatory mechanical environments, and also with conventional soluble factors, to enhance axonal growth and neural network formation in neural tissue engineering.

  1. Cellular and molecular mechanisms of muscle atrophy

    Directory of Open Access Journals (Sweden)

    Paolo Bonaldo

    2013-01-01

    Full Text Available Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

  2. Plant regeneration: cellular origins and molecular mechanisms.

    Science.gov (United States)

    Ikeuchi, Momoko; Ogawa, Yoichi; Iwase, Akira; Sugimoto, Keiko

    2016-05-01

    Compared with animals, plants generally possess a high degree of developmental plasticity and display various types of tissue or organ regeneration. This regenerative capacity can be enhanced by exogenously supplied plant hormones in vitro, wherein the balance between auxin and cytokinin determines the developmental fate of regenerating organs. Accumulating evidence suggests that some forms of plant regeneration involve reprogramming of differentiated somatic cells, whereas others are induced through the activation of relatively undifferentiated cells in somatic tissues. We summarize the current understanding of how plants control various types of regeneration and discuss how developmental and environmental constraints influence these regulatory mechanisms. PMID:27143753

  3. Cellular Mechanisms of Ciliary Length Control

    Directory of Open Access Journals (Sweden)

    Jacob Keeling

    2016-01-01

    Full Text Available Cilia and flagella are evolutionarily conserved, membrane-bound, microtubule-based organelles on the surface of most eukaryotic cells. They play important roles in coordinating a variety of signaling pathways during growth, development, cell mobility, and tissue homeostasis. Defects in ciliary structure or function are associated with multiple human disorders called ciliopathies. These diseases affect diverse tissues, including, but not limited to the eyes, kidneys, brain, and lungs. Many processes must be coordinated simultaneously in order to initiate ciliogenesis. These include cell cycle, vesicular trafficking, and axonemal extension. Centrioles play a central role in both cell cycle progression and ciliogenesis, making the transition between basal bodies and mitotic spindle organizers integral to both processes. The maturation of centrioles involves a functional shift from cell division toward cilium nucleation which takes place concurrently with its migration and fusion to the plasma membrane. Several proteinaceous structures of the distal appendages in mother centrioles are required for this docking process. Ciliary assembly and maintenance requires a precise balance between two indispensable processes; so called assembly and disassembly. The interplay between them determines the length of the resulting cilia. These processes require a highly conserved transport system to provide the necessary substances at the tips of the cilia and to recycle ciliary turnover products to the base using a based microtubule intraflagellar transport (IFT system. In this review; we discuss the stages of ciliogenesis as well as mechanisms controlling the lengths of assembled cilia.

  4. Biochemical mechanisms underlying atherogenesis

    Directory of Open Access Journals (Sweden)

    Dr.P.V.L.N. Srinivasa Rao

    2012-02-01

    Full Text Available Atherosclerosis remains one of the major causes of death and premature disability in developed countries. Though atherosclerosis was formerly considered a bland lipid storage disease, substantial advances in basic and experimental sciences have illuminated the role of endothelium, inflammation and immune mechanisms in its pathogenesis. Current concept of atherosclerosis is that of a dynamic and progressive disease arising from in- jury to endothelium, also known as endothelial dysfunction and an inflammatory response to that injury. The lesions of atherosclerosis occur principally in large and medium sized arteries. Atherosclerosis affects various regions of the circulation preferentially and can lead to ischemia of heart, brain or extremities resulting in in- farction.This produces distinct clinical manifestations depending on the vessel involved. Several predisposing factors to cardiovascular diseases such as diabetes mellitus, hypertension, obesity, infections act as triggers to the devel- opment of atherosclerosis by causing endothelial dysfunction and/or promoting inflammatory response. The evolution of pathogenetic mechanisms has passed through various directions such as oxidative stress, inflam- mation and immune responses. It is now known that all these are not acting independently but are interrelated and getting unified in the current concept of atherogenesis. The following discussion aims at providing an in- sight into these developments which can help in a better comprehension of the disease and management of its clinical complications

  5. Mitochondrial and cellular mechanisms for managing lipid excess

    Directory of Open Access Journals (Sweden)

    Miguel A Aon

    2014-07-01

    Full Text Available Current scientific debates center on the impact of lipids and mitochondrial function on diverse aspects of human health, nutrition and disease, among them the association of lipotoxicity with the onset of insulin resistance in skeletal muscle, and with heart dysfunction in obesity and diabetes. Mitochondria play a fundamental role in aging and in prevalent acute or chronic diseases. Lipids are main mitochondrial fuels however these molecules can also behave as uncouplers and inhibitors of oxidative phosphorylation. Knowledge about the functional composition of these contradictory effects and their impact on mitochondrial-cellular energetics/redox status is incomplete.Cells store fatty acids (FAs as triacylglycerol and package them into cytoplasmic lipid droplets (LDs. New emerging data shows the LD as a highly dynamic storage pool of FAs that can be used for energy reserve. Lipid excess packaging into LDs can be seen as an adaptive response to fulfilling energy supply without hindering mitochondrial or cellular redox status and keeping low concentration of lipotoxic intermediates.Herein we review the mechanisms of action and utilization of lipids by mitochondria reported in liver, heart and skeletal muscle under relevant physiological situations, e.g. exercise. We report on perilipins, a family of proteins that associate with LDs in response to loading of cells with lipids. Evidence showing that in addition to physical contact, mitochondria and LDs exhibit metabolic interactions is presented and discussed. A hypothetical model of channeled lipid utilization by mitochondria is proposed. Direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to maintain ROS within levels compatible with signaling while ensuring robust and reliable energy supply.

  6. Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs

    DEFF Research Database (Denmark)

    Francavilla, Chiara; Rigbolt, Kristoffer T.G.; Emdal, Kristina B;

    2013-01-01

    The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferati...

  7. Cellular Mechanisms of L-arginine Induced Experimental Acute Pancreatitis

    OpenAIRE

    Masood, Omar

    2013-01-01

    AbstractThe University Of ManchesterOmar MasoodMD Thesis 2013Cellular Mechanisms of L-arginine Induced Experimental Acute Pancreatitis. IntroductionImpairment of cytosolic calcium ([Ca2+]i) signaling and in particular calcium overload has emerged as a possible unifying mechanism for precipitating acute pancreatitis (AP.)In the L-arginine (L-arg) experimental model of AP, nitric oxide (NO) has been implicated however the disease progression is largely unaffected by nitric oxide synthase (NOS) ...

  8. Unraveling the cellular and molecular mechanisms of repetitive magnetic stimulation

    Directory of Open Access Journals (Sweden)

    Florian Müller-Dahlhaus

    2013-12-01

    Full Text Available Despite numerous clinical studies, which have investigated the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS in various brain diseases, our knowledge of the cellular and molecular mechanisms underlying rTMS-based therapies remains limited. Thus, a deeper understanding of rTMS-induced neural plasticity is required to optimize current treatment protocols. Studies in small animals or appropriate in vitro preparations (including models of brain diseases provide highly useful experimental approaches in this context. State-of-the-art electrophysiological and live-cell imaging techniques that are well established in basic neuroscience can help answering some of the major questions in the field, such as (i which neural structures are activated during TMS, (ii how does rTMS induce Hebbian plasticity, and (iii are other forms of plasticity (e.g., metaplasticity, structural plasticity induced by rTMS? We argue that data gained from these studies will support the development of more effective and specific applications of rTMS in clinical practice.

  9. Porosity and Mechanical Strength of an Autoclaved Clayey Cellular Concrete

    Directory of Open Access Journals (Sweden)

    P. O. Guglielmi

    2010-01-01

    Full Text Available This paper investigates the porosity and the mechanical strength of an Autoclaved Clayey Cellular Concrete (ACCC with the binder produced with 75 wt% kaolinite clay and 25 wt% Portland cement. Aluminum powder was used as foaming agent, from 0.2 wt% to 0.8 wt%, producing specimens with different porosities. The results show that the specimens with higher content of aluminum presented pore coalescence, which can explain the lower porosity of these samples. The porosities obtained with the aluminum contents used in the study were high (approximately 80%, what accounts for the low mechanical strength of the investigated cellular concretes (maximum of 0.62 MPa. Nevertheless, comparing the results obtained in this study to the ones for low temperature clayey aerated concrete with similar compositions, it can be observed that autoclaving is effective for increasing the material mechanical strength.

  10. Composite alginate gels for tunable cellular microenvironment mechanics

    Science.gov (United States)

    Khavari, Adele; Nydén, Magnus; Weitz, David A.; Ehrlicher, Allen J.

    2016-01-01

    The mechanics of the cellular microenvironment can be as critical as biochemistry in directing cell behavior. Many commonly utilized materials derived from extra-cellular-matrix create excellent scaffolds for cell growth, however, evaluating the relative mechanical and biochemical effects independently in 3D environments has been difficult in frequently used biopolymer matrices. Here we present 3D sodium alginate hydrogel microenvironments over a physiological range of stiffness (E = 1.85 to 5.29 kPa), with and without RGD binding sites or collagen fibers. We use confocal microscopy to measure the growth of multi-cellular aggregates (MCAs), of increasing metastatic potential in different elastic moduli of hydrogels, with and without binding factors. We find that the hydrogel stiffness regulates the growth and morphology of these cell clusters; MCAs grow larger and faster in the more rigid environments similar to cancerous breast tissue (E = 4–12 kPa) as compared to healthy tissue (E = 0.4–2 kpa). Adding binding factors from collagen and RGD peptides increases growth rates, and change maximum MCA sizes. These findings demonstrate the utility of these independently tunable mechanical/biochemistry gels, and that mechanical confinement in stiffer microenvironments may increase cell proliferation. PMID:27484403

  11. Composite alginate gels for tunable cellular microenvironment mechanics

    Science.gov (United States)

    Khavari, Adele; Nydén, Magnus; Weitz, David A.; Ehrlicher, Allen J.

    2016-08-01

    The mechanics of the cellular microenvironment can be as critical as biochemistry in directing cell behavior. Many commonly utilized materials derived from extra-cellular-matrix create excellent scaffolds for cell growth, however, evaluating the relative mechanical and biochemical effects independently in 3D environments has been difficult in frequently used biopolymer matrices. Here we present 3D sodium alginate hydrogel microenvironments over a physiological range of stiffness (E = 1.85 to 5.29 kPa), with and without RGD binding sites or collagen fibers. We use confocal microscopy to measure the growth of multi-cellular aggregates (MCAs), of increasing metastatic potential in different elastic moduli of hydrogels, with and without binding factors. We find that the hydrogel stiffness regulates the growth and morphology of these cell clusters; MCAs grow larger and faster in the more rigid environments similar to cancerous breast tissue (E = 4–12 kPa) as compared to healthy tissue (E = 0.4–2 kpa). Adding binding factors from collagen and RGD peptides increases growth rates, and change maximum MCA sizes. These findings demonstrate the utility of these independently tunable mechanical/biochemistry gels, and that mechanical confinement in stiffer microenvironments may increase cell proliferation.

  12. Cellular Pressure and Volume Regulation and Implications for Cell Mechanics

    OpenAIRE

    Jiang, Hongyuan; Sun, Sean X.

    2013-01-01

    In eukaryotic cells, small changes in cell volume can serve as important signals for cell proliferation, death, and migration. Volume and shape regulation also directly impacts the mechanics of cells and tissues. Here, we develop a mathematical model of cellular volume and pressure regulation, incorporating essential elements such as water permeation, mechanosensitive channels, active ion pumps, and active stresses in the cortex. The model can fully explain recent experimental data, and it pr...

  13. Cellular Mechanisms of Tissue Fibrosis. 7. New insights into the cellular mechanisms of pulmonary fibrosis

    OpenAIRE

    Barkauskas, Christina E.; Paul W. Noble

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by severe and progressive scar formation in the gas-exchange regions of the lung. Despite years of research, therapeutic treatments remain elusive and there is a pressing need for deeper mechanistic insights into the pathogenesis of the disease. In this article, we review our current knowledge of the triggers and/or perpetuators of pulmonary fibrosis with special emphasis on the alveolar epithelium and the underlying m...

  14. Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin

    Directory of Open Access Journals (Sweden)

    Sarah Spreckelmeyer

    2014-09-01

    Full Text Available The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir. Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.

  15. Composition, structure and mechanical properties of several natural cellular materials

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The stem piths of sunflower, kaoliang and corn are natural cellular materials. In this paper, the contents of the compositions of these piths are determined and their cell shapes and structures are examined through scanning electron microscope (SEM) and optical microscope. Further research is conducted in the effects of the compositions and structures of the piths on the mechanical properties after testing the partial mechanical properties. The results show that the total cellulose, hemicelluloses and lignin content of each sample approaches 75% of the dry mass of its primary cell walls. With the fall of R value, a parameter relative to the contents of the main compositions, the flexibilities of the cellular piths descend while their stresses and rigidities increase. The basic cell shape making up the sunflower pith is approximately a tetrakaidehedron. The stem piths of kaoliang and corn are made up of cells close to hexangular prisms and a few tubular ones which can observably reinforce their mechanical properties in the axial directions.

  16. Protein Kinase C Deficiency-induced Alcohol Insensitivity and Underlying Cellular Targets in Drosophila

    OpenAIRE

    Chen, Jiang; Zhang, Yan; Shen, Ping

    2009-01-01

    Multiple subtypes of protein kinase C (PKC) isozymes are implicated in various neurological disorders including alcohol insensitivity, a trait strongly associated with alcoholism in humans, but molecular and cellular mechanisms underlying the PKC activities remain poorly understood. Here we show that functional knockdown of conventional, novel or atypical PKC in the fly nervous system each resulted in alcohol insensitivity. Neuroanatomical mapping of conventional Ca2+-sensitive PKC53E activit...

  17. Cellular mechanisms of cadmium-induced toxicity: a review.

    Science.gov (United States)

    Rani, Anju; Kumar, Anuj; Lal, Ankita; Pant, Manu

    2014-08-01

    Cadmium is a widespread toxic pollutant of occupational and environmental concern because of its diverse toxic effects: extremely protracted biological half-life (approximately 20-30 years in humans), low rate of excretion from the body and storage predominantly in soft tissues (primarily, liver and kidneys). It is an extremely toxic element of continuing concern because environmental levels have risen steadily due to continued worldwide anthropogenic mobilization. Cadmium is absorbed in significant quantities from cigarette smoke, food, water and air contamination and is known to have numerous undesirable effects in both humans and animals. Cadmium has a diversity of toxic effects including nephrotoxicity, carcinogenicity, teratogenicity and endocrine and reproductive toxicities. At the cellular level, cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Current evidence suggests that exposure to cadmium induces genomic instability through complex and multifactorial mechanisms. Most important seems to be cadmium interaction with DNA repair mechanism, generation of reactive oxygen species and induction of apoptosis. In this article, we have reviewed recent developments and findings on cadmium toxicology. PMID:24117228

  18. Mechanism of cellular uptake of genotoxic silica nanoparticles

    Directory of Open Access Journals (Sweden)

    Mu Qingshan

    2012-07-01

    Full Text Available Abstract Mechanisms for cellular uptake of nanoparticles have important implications for nanoparticulate drug delivery and toxicity. We have explored the mechanism of uptake of amorphous silica nanoparticles of 14 nm diameter, which agglomerate in culture medium to hydrodynamic diameters around 500 nm. In HT29, HaCat and A549 cells, cytotoxicity was observed at nanoparticle concentrations ≥ 1 μg/ml, but DNA damage was evident at 0.1 μg/ml and above. Transmission electron microscopy (TEM combined with energy-dispersive X-ray spectroscopy confirmed entry of the silica particles into A549 cells exposed to 10 μg/ml of nanoparticles. The particles were observed in the cytoplasm but not within membrane bound vesicles or in the nucleus. TEM of cells exposed to nanoparticles at 4°C for 30 minutes showed particles enter cells when activity is low, suggesting a passive mode of entry. Plasma lipid membrane models identified physical interactions between the membrane and the silica NPs. Quartz crystal microbalance experiments on tethered bilayer lipid membrane systems show that the nanoparticles strongly bind to lipid membranes, forming an adherent monolayer on the membrane. Leakage assays on large unilamellar vesicles (400 nm diameter indicate that binding of the silica NPs transiently disrupts the vesicles which rapidly self-seal. We suggest that an adhesive interaction between silica nanoparticles and lipid membranes could cause passive cellular uptake of the particles.

  19. Relationship between cellular response models and biochemical mechanisms

    International Nuclear Information System (INIS)

    In most cellular response experiments, survival reflects the kinetics of a variety of damage and repair processes. Unfortunately, biochemical studies of molecular repair deal with mechanisms which cannot be readily correlated with these kinetic observations. The difference in these approaches sometimes leads to confusion over terms such as potentially-lethal and sublethal damage. These terms were introduced with operation definitions, derived from kinetic studies of cell survival, but some researchers have since attempted to associate them with specific biochemical mechanisms. Consequently, the terms are often used in totally different ways be different investigators. The use of carefully constructed models originating either out of assumptions based on mechanisms, or on kinetics, can be used to design experiments to eliminate some alternative kinetic schemes. In turn, some mechanisms may also be eliminated, resulting in a reduction in the number of mechanisms which must be investigated biochemically. One must take advantage of a wide range of specialized radiation procedures in order to accomplish this. Examples of the use of such specialized experimental designs, which have led to a more detailed understanding of the kinetics of both algal and mammalian cell responses, are discussed

  20. Molecular Mechanisms Underlying Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Christian Trepo

    2009-11-01

    Full Text Available Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem cell-like properties. The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21Cip1 and p16INK4a/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage. Still obscure mechanisms, but maybe involving the Wnt signaling and Twist proteins, would allow pre-senescent hepatocytes to bypass senescence, acquire immortality by telomerase reactivation and get the last genetic/epigenetic hits necessary for cancerous transformation. Among some of the oncogenic pathways that might play key driving roles in hepatocarcinogenesis, c-myc and the Wnt/β-catenin signaling seem of particular interest. Finally, antiproliferative and apoptosis deficiencies involving TGF-β, Akt/PTEN, IGF2 pathways for instance are prerequisite for cancerous transformation. Of evidence, not only the transformed liver cell per se but the facilitating microenvironment is of fundamental importance for tumor bulk growth and metastasis.

  1. Molecular and cellular mechanisms of vomeronasal signaling in mammals

    OpenAIRE

    Cichy, Annika

    2013-01-01

    The mouse vomeronasal organ plays a critical role in chemosensory communication and regulates diverse social and sexual behaviors. However, many physiological mechanisms underlying vomeronasal chemosensory signaling remain elusive. Therefore, the overall aim of my thesis was to gain a deeper understanding of the basic mechanisms that control VNO physiology. Specifically, my research focused on HCN channel-mediated vomeronasal proton-sensing and its potential role in sensory gain control of so...

  2. Investigation of the Cellular and Molecular Mechanisms of Radiation-induced Bystander Effects

    OpenAIRE

    Furlong, Hayley

    2014-01-01

    The overall aim of this study was to investigate the cellular and molecular mechanisms involved in radiation-induced bystander effects in HaCaT cells, predominantly at low-doses of irradiation. They do not follow the original dose-response theory and exhibit a unique cascade of signalling events, which are under intense investigation for radiation risk purposes. An in vitro system was first used to observe the bystander effect, comparing two cell viability assays while measuring apoptotic cel...

  3. Tensegrity, cellular biophysics, and the mechanics of living systems

    Science.gov (United States)

    Ingber, Donald E.; Wang, Ning; Stamenović, Dimitrije

    2014-01-01

    The recent convergence between physics and biology has led many physicists to enter the fields of cell and developmental biology. One of the most exciting areas of interest has been the emerging field of mechanobiology that centers on how cells control their mechanical properties, and how physical forces regulate cellular biochemical responses, a process that is known as mechanotransduction. In this article, we review the central role that tensegrity (tensional integrity) architecture, which depends on tensile prestress for its mechanical stability, plays in biology. We describe how tensional prestress is a critical governor of cell mechanics and function, and how use of tensegrity by cells contributes to mechanotransduction. Theoretical tensegrity models are also described that predict both quantitative and qualitative behaviors of living cells, and these theoretical descriptions are placed in context of other physical models of the cell. In addition, we describe how tensegrity is used at multiple size scales in the hierarchy of life — from individual molecules to whole living organisms — to both stabilize three-dimensional form and to channel forces from the macroscale to the nanoscale, thereby facilitating mechanochemical conversion at the molecular level. PMID:24695087

  4. Tensegrity, cellular biophysics, and the mechanics of living systems

    Science.gov (United States)

    Ingber, Donald E.; Wang, Ning; Stamenović, Dimitrije

    2014-04-01

    The recent convergence between physics and biology has led many physicists to enter the fields of cell and developmental biology. One of the most exciting areas of interest has been the emerging field of mechanobiology that centers on how cells control their mechanical properties, and how physical forces regulate cellular biochemical responses, a process that is known as mechanotransduction. In this article, we review the central role that tensegrity (tensional integrity) architecture, which depends on tensile prestress for its mechanical stability, plays in biology. We describe how tensional prestress is a critical governor of cell mechanics and function, and how use of tensegrity by cells contributes to mechanotransduction. Theoretical tensegrity models are also described that predict both quantitative and qualitative behaviors of living cells, and these theoretical descriptions are placed in context of other physical models of the cell. In addition, we describe how tensegrity is used at multiple size scales in the hierarchy of life—from individual molecules to whole living organisms—to both stabilize three-dimensional form and to channel forces from the macroscale to the nanoscale, thereby facilitating mechanochemical conversion at the molecular level.

  5. Tensegrity, cellular biophysics, and the mechanics of living systems

    International Nuclear Information System (INIS)

    The recent convergence between physics and biology has led many physicists to enter the fields of cell and developmental biology. One of the most exciting areas of interest has been the emerging field of mechanobiology that centers on how cells control their mechanical properties, and how physical forces regulate cellular biochemical responses, a process that is known as mechanotransduction. In this article, we review the central role that tensegrity (tensional integrity) architecture, which depends on tensile prestress for its mechanical stability, plays in biology. We describe how tensional prestress is a critical governor of cell mechanics and function, and how use of tensegrity by cells contributes to mechanotransduction. Theoretical tensegrity models are also described that predict both quantitative and qualitative behaviors of living cells, and these theoretical descriptions are placed in context of other physical models of the cell. In addition, we describe how tensegrity is used at multiple size scales in the hierarchy of life—from individual molecules to whole living organisms—to both stabilize three-dimensional form and to channel forces from the macroscale to the nanoscale, thereby facilitating mechanochemical conversion at the molecular level. (review article)

  6. Kinesin's backsteps under mechanical load

    CERN Document Server

    Hyeon, Changbong; Onuchic, Jose' N

    2009-01-01

    Kinesins move processively toward the plus end of microtubules by hydrolyzing ATP for each step. From an enzymatic perspective, the mechanism of mechanical motion coupled to the nucleotide chemistry is often well explained using a single-loop cyclic reaction. However, several difficulties arise in interpreting kinesin's backstepping within this framework, especially when external forces oppose the motion of kinesin. We review evidence, such as an ATP-independent stall force and a slower cycle time for backsteps, that has emerged to challenge the idea that kinesin backstepping is due to ATP synthesis, i.e., the reverse cycle of kinesin's forward-stepping chemomechanics. Supplementing the conventional single-loop chemomechanics with routes for ATP-hydrolyzing backward steps and nucleotide-free steps, especially under load, gives a better physical interpretation of the experimental data on backsteps.

  7. Molecular Mechanisms Underlying Bacterial Persisters

    DEFF Research Database (Denmark)

    Maisonneuve, Etienne; Gerdes, Kenn

    2014-01-01

    All bacteria form persisters, cells that are multidrug tolerant and therefore able to survive antibiotic treatment. Due to the low frequencies of persisters in growing bacterial cultures and the complex underlying molecular mechanisms, the phenomenon has been challenging to study. However, recent...... technological advances in microfluidics and reporter genes have improved this scenario. Here, we summarize recent progress in the field, revealing the ubiquitous bacterial stress alarmone ppGpp as an emerging central regulator of multidrug tolerance and persistence, both in stochastically and environmentally...

  8. Interference cancellation technique under imperfect synchronization in cellular systems

    Institute of Scientific and Technical Information of China (English)

    WANG; Xin; WU; Zhuo

    2009-01-01

    In this paper, an asynchronous cooperative cellular system applied with space-time block coding(STBC)is investigated. A signal detector is proposed based on parallel interference cancellation(PIC), to cancel the inter-symbol interference(ISI)caused by the imperfect synchronization. Simulation results show that the proposed PIC detector can effectively suppress the ISI, but there is still a comparatively high error floor, due to the co-channel interference(CCI)of the cellular system.

  9. Cellular and Humoral Mechanisms Involved in the Control of Tuberculosis

    Directory of Open Access Journals (Sweden)

    Joaquin Zuñiga

    2012-01-01

    Full Text Available Mycobacterium tuberculosis (Mtb infection is a major international public health problem. One-third of the world's population is thought to have latent tuberculosis, a condition where individuals are infected by the intracellular bacteria without active disease but are at risk for reactivation, if their immune system fails. Here, we discuss the role of nonspecific inflammatory responses mediated by cytokines and chemokines induced by interaction of innate receptors expressed in macrophages and dendritic cells (DCs. We also review current information regarding the importance of several cytokines including IL-17/IL-23 in the development of protective cellular and antibody-mediated protective responses against Mtb and their influence in containment of the infection. Finally, in this paper, emphasis is placed on the mechanisms of failure of Mtb control, including the immune dysregulation induced by the treatment with biological drugs in different autoimmune diseases. Further functional studies, focused on the mechanisms involved in the early host-Mtb interactions and the interplay between host innate and acquired immunity against Mtb, may be helpful to improve the understanding of protective responses in the lung and in the development of novel therapeutic and prophylactic tools in TB.

  10. Cellular and molecular mechanisms of chemical synaptic transmission.

    Science.gov (United States)

    Millhorn, D E; Bayliss, D A; Erickson, J T; Gallman, E A; Szymeczek, C L; Czyzyk-Krzeska, M; Dean, J B

    1989-12-01

    During the last decade much progress has been made in understanding the cellular and molecular mechanisms by which nerve cells communicate with each other and nonneural (e.g., muscle) target tissue. This review is intended to provide the reader with an account of this work. We begin with an historical overview of research on cell-to-cell communication and then discuss recent developments that, in some instances, have led to dramatic changes in the concept of synaptic transmission. For instance, the finding that single neurons often contain multiple messengers (i.e., neurotransmitters) invalidated the long-held theory (i.e., Dale's Law) that individual neurons contain and release one and only one type of neurotransmitter. Moreover, the last decade witnessed the inclusion of an entire group of compounds, the neuropeptides, as messenger molecules. Enormous progress has also been made in elucidating postsynaptic receptor complexes and biochemical intermediaries involved in synaptic transmission. Here the development of recombinant DNA technology has made it possible to clone and determine the molecular structure for a number of receptors. This information has been used to gain insight into how these receptors function either as a ligand-gated channel or as a G protein-linked ligand recognition molecule. Perhaps the most progress made during this era was in understanding the molecular linkage of G protein-linked receptors to intramembranous and cytoplasmic macromolecules involved in signal amplification and transduction. We conclude with a brief discussion of how synaptic transmission leads to immediate alterations in the electrical activity and, in some cases, to a change in phenotype by altering gene expression. These alterations in cellular behavior are believed to be mediated by phosphoproteins, the final biochemical product of signal transduction. PMID:2575357

  11. Molecular and cellular mechanisms of aldosterone producing adenoma development

    Directory of Open Access Journals (Sweden)

    Sheerazed eBoulkroun

    2015-06-01

    Full Text Available Primary aldosteronism (PA is the most common form of secondary hypertension with an estimated prevalence of ~10% in referred patients. PA occurs as a result of a dysregulation of the normal mechanisms controlling adrenal aldosterone production. It is characterized by hypertension with low plasma renin and elevated aldosterone and often associated with hypokalemia. The two major causes of PA are unilateral aldosterone producing adenoma (APA and bilateral adrenal hyperplasia, accounting together for ~95% of cases. In addition to the well-characterized effect of excess mineralocorticoids on blood pressure, high levels of aldosterone also have cardiovascular, renal and metabolic consequences. Hence, long-term consequences of PA include increased risk of coronary artery disease, myocardial infarction, heart failure and atrial fibrillation. Despite recent progress in the management of patients with PA, critical issues related to diagnosis, subtype differentiation and treatment of non-surgically correctable forms still persist. A better understanding of the pathogenic mechanisms of the disease should lead to the identification of more reliable diagnostic and prognostic biomarkers for a more sensitive and specific screening and new therapeutic options. In this review we will summarize our current knowledge on the molecular and cellular mechanisms of APA development. On one hand, we will discuss how various animal models have improved our understanding of the pathophysiology of excess aldosterone production. On the other hand, we will summarize the major advances made during the last few years in the genetics of APA due to transcriptomic studies and whole exome sequencing. The identification of recurrent and somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D and ATPases (ATP1A1 and ATP2B3 allowed highlighting the central role of calcium signaling in autonomous aldosterone production by the adrenal.

  12. Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system.

    Science.gov (United States)

    Forger, Nancy G; Strahan, J Alex; Castillo-Ruiz, Alexandra

    2016-01-01

    Neuroscientists are likely to discover new sex differences in the coming years, spurred by the National Institutes of Health initiative to include both sexes in preclinical studies. This review summarizes the current state of knowledge of the cellular and molecular mechanisms underlying sex differences in the mammalian nervous system, based primarily on work in rodents. Cellular mechanisms examined include neurogenesis, migration, the differentiation of neurochemical and morphological cell phenotype, and cell death. At the molecular level we discuss evolving roles for epigenetics, sex chromosome complement, the immune system, and newly identified cell signaling pathways. We review recent findings on the role of the environment, as well as genome-wide studies with some surprising results, causing us to re-think often-used models of sexual differentiation. We end by pointing to future directions, including an increased awareness of the important contributions of tissues outside of the nervous system to sexual differentiation of the brain. PMID:26790970

  13. Mechanical models of the cellular cytoskeletal network for the analysis of intracellular mechanical properties and force distributions: a review.

    Science.gov (United States)

    Chen, Ting-Jung; Wu, Chia-Ching; Su, Fong-Chin

    2012-12-01

    The cytoskeleton, which is the major mechanical component of cells, supports the cell body and regulates the cellular motility to assist the cell in performing its biological functions. Several cytoskeletal network models have been proposed to investigate the mechanical properties of cells. This review paper summarizes these models with a focus on the prestressed cable network, the semi-flexible chain network, the open-cell foam, the tensegrity, and the granular models. The components, material parameters, types of connection joints, tension conditions, and the advantages and disadvantages of each model are evaluated from a structural and biological point of view. The underlying mechanisms that are associated with the morphological changes of spreading cells are expected to be simulated using a cytoskeletal model; however, it is still paid less attention most likely due to the lack of a suitable cytoskeletal model that can accurately model the spreading process. In this review article, the established cytoskeletal models are hoped to provide useful information for the development of future cytoskeletal models with different degrees of cell attachment for the study of the mechanical mechanisms underlying the cellular behaviors in response to external stimulations. PMID:23062682

  14. Antidiarrheal efficacy and cellular mechanisms of a Thai herbal remedy.

    Science.gov (United States)

    Tradtrantip, Lukmanee; Ko, Eun-A; Verkman, Alan S

    2014-02-01

    Screening of herbal remedies for Cl(-) channel inhibition identified Krisanaklan, a herbal extract used in Thailand for treatment of diarrhea, as an effective antidiarrheal in mouse models of secretory diarrheas with inhibition activity against three Cl(-) channel targets. Krisanaklan fully inhibited cholera toxin-induced intestinal fluid secretion in a closed-loop mouse model with ∼50% inhibition at a 1 ∶ 50 dilution of the extract. Orally administered Krisanaklan (5 µL/g) prevented rotavirus-induced diarrhea in neonatal mice. Short-circuit current measurements showed full inhibition of cAMP and Ca(2+) agonist-induced Cl(-) conductance in human colonic epithelial T84 cells, with ∼ 50% inhibition at a 1 ∶ 5,000 dilution of the extract. Krisanaklan also strongly inhibited intestinal smooth muscle contraction in an ex vivo preparation. Together with measurements using specific inhibitors, we conclude that the antidiarrheal actions of Krisanaklan include inhibition of luminal CFTR and Ca(2+)-activated Cl(-) channels in enterocytes. HPLC fractionation indicated that the three Cl(-) inhibition actions of Krisanaklan are produced by different components in the herbal extract. Testing of individual herbs comprising Krisanaklan indicated that agarwood and clove extracts as primarily responsible for Cl(-) channel inhibition. The low cost, broad antidiarrheal efficacy, and defined cellular mechanisms of Krisanaklan suggests its potential application for antisecretory therapy of cholera and other enterotoxin-mediated secretory diarrheas in developing countries. PMID:24551253

  15. Antidiarrheal efficacy and cellular mechanisms of a Thai herbal remedy.

    Directory of Open Access Journals (Sweden)

    Lukmanee Tradtrantip

    2014-02-01

    Full Text Available Screening of herbal remedies for Cl(- channel inhibition identified Krisanaklan, a herbal extract used in Thailand for treatment of diarrhea, as an effective antidiarrheal in mouse models of secretory diarrheas with inhibition activity against three Cl(- channel targets. Krisanaklan fully inhibited cholera toxin-induced intestinal fluid secretion in a closed-loop mouse model with ∼50% inhibition at a 1 ∶ 50 dilution of the extract. Orally administered Krisanaklan (5 µL/g prevented rotavirus-induced diarrhea in neonatal mice. Short-circuit current measurements showed full inhibition of cAMP and Ca(2+ agonist-induced Cl(- conductance in human colonic epithelial T84 cells, with ∼ 50% inhibition at a 1 ∶ 5,000 dilution of the extract. Krisanaklan also strongly inhibited intestinal smooth muscle contraction in an ex vivo preparation. Together with measurements using specific inhibitors, we conclude that the antidiarrheal actions of Krisanaklan include inhibition of luminal CFTR and Ca(2+-activated Cl(- channels in enterocytes. HPLC fractionation indicated that the three Cl(- inhibition actions of Krisanaklan are produced by different components in the herbal extract. Testing of individual herbs comprising Krisanaklan indicated that agarwood and clove extracts as primarily responsible for Cl(- channel inhibition. The low cost, broad antidiarrheal efficacy, and defined cellular mechanisms of Krisanaklan suggests its potential application for antisecretory therapy of cholera and other enterotoxin-mediated secretory diarrheas in developing countries.

  16. Cellular mechanisms of skin repair in humans and other mammals.

    Science.gov (United States)

    Rittié, Laure

    2016-06-01

    The increased incidence of non-healing skin wounds in developed societies has prompted tremendous research efforts on the complex process known as "wound healing". Unfortunately, the weak relevance of modern wound healing research to human health continues to be a matter of concern. This review summarizes the current knowledge of the cellular mechanisms that mediate wound closure in the skin of humans and laboratory animals. The author highlights the anatomical singularities of human skin vs. the skin of other mammals commonly used for wound healing research (i.e. as mice, rats, rabbits, and pigs), and discusses the roles of stem cells, myofibroblasts, and the matrix environment in the repair process. The majority of this review focuses on reepithelialization and wound closure. Other aspects of wound healing (e.g. inflammation, fibrous healing) are referred to when relevant to the main topic. This review aims at providing the reader with a clear understanding of the similarities and differences that have been reported over the past 100 years between the healing of human wounds and that of other mammals. PMID:27170326

  17. Relative Contributions of Various Cellular Mechanisms to Loss of Algae during Cnidarian Bleaching

    Science.gov (United States)

    Bieri, Tamaki; Onishi, Masayuki; Xiang, Tingting; Grossman, Arthur R.; Pringle, John R

    2016-01-01

    When exposed to stress such as high seawater temperature, corals and other cnidarians can bleach due to loss of symbiotic algae from the host tissue and/or loss of pigments from the algae. Although the environmental conditions that trigger bleaching are reasonably well known, its cellular and molecular mechanisms are not well understood. Previous studies have reported the occurrence of at least four different cellular mechanisms for the loss of symbiotic algae from the host tissue: in situ degradation of algae, exocytic release of algae from the host, detachment of host cells containing algae, and death of host cells containing algae. The relative contributions of these several mechanisms to bleaching remain unclear, and it is also not known whether these relative contributions change in animals subjected to different types and/or durations of stresses. In this study, we used a clonal population of the small sea anemone Aiptasia, exposed individuals to various precisely controlled stress conditions, and quantitatively assessed the several possible bleaching mechanisms in parallel. Under all stress conditions tested, except for acute cold shock at 4°C, expulsion of intact algae from the host cells appeared to be by far the predominant mechanism of bleaching. During acute cold shock, in situ degradation of algae and host-cell detachment also became quantitatively significant, and the algae released under these conditions appeared to be severely damaged. PMID:27119147

  18. Cellular electron transfer and radical mechanisms for drug metabolism

    International Nuclear Information System (INIS)

    Aerobic and anaerobic reductions of various nitroaromatic compounds by mammalian cells result in the production of reactive intermediates. Drug reduction is dependent upon glucose, nonprotein thiols, endogenous enzyme levels, and drug electron affinity. Drugs with electron affinities approaching that of oxygen are reduced, in the presence of oxygen, beyond a one-electron radical anion. Nitroaromatic radical anion inactivation occurs by reaction with cellular ferricytochrome c, endogenous thiols, and with oxygen. In the latter case the reaction results in the production of peroxide. Drugs that are substrates for the enzyme glutathione-S-transferase remove endogeneous thiols and demonstrate peroxide production without prior thiol removal. Less electron affinic drugs such as misonidazole require thiol removal as well as the presence of cyanide or azide for maximal peroxide production. Under anaerobic conditions radical anion and nitroso intermediates are reactive with glutathione. Removal of endogenous thiols by hypoxic preincubation with misonidazole may be related to the enhanced radiation response and cytotoxicity of this drug. Reduction of nitro compounds in the presence of DNA and chemicals such as dithionite, zinc dust, or polarographic techniques causes binding to macromolecules and DNA breaks. Chemical-reduction of nitro compounds by ascorbate in the presence of cells enhances drug cytotoxic effects

  19. [Glycotoxins and cellular dysfunction. A new mechanism for understanding the preventive effects of lifestyle modifications].

    Science.gov (United States)

    Michalsen, A; Bierhaus, A; Nawroth, P P; Dobos, G J

    2006-08-01

    Recently the AGE-RAGE interaction was identified as a potential mechanism underlying chronic and inflammatory diseases like atherosclerosis, diabetes mellitus and kidney disease. Advanced glycation end products (AGEs) are the derivatives of glucose-protein or glucose-lipid reactions and are mainly generated from the diet (depending on intensity of heating, cooking time and oxygenation). Binding of AGEs or other ligands to the AGE receptor (RAGE) results in cellular activation, i.e. increased expression of inflammatory mediators and oxidative stress. Diet-derived AGEs thus induce deleterious effects on tissues and the cardiovascular system. Recent research also found that other lifestyle factors are associated with pronounced inflammatory activation, e.g. psychosocial stress and smoking. In addition, each intake of meals is associated with proinflammatory cellular changes. The AGE-RAGE model and investigations of the underlying cellular mechanisms thus may lead to a better understanding of the health benefits of diets (Mediterranean diet, uncooked vegetarian diets), caloric restriction and intermittent fasting. The clinical impact of low-AGE diets and fasting and the interaction between stress and food intake should be further investigated in controlled trials. PMID:16897151

  20. The Nucleolus Takes Control of Protein Trafficking Under Cellular Stress

    OpenAIRE

    Nalabothula, Narasimharao; Indig, Fred E.; Carrier, France

    2010-01-01

    The nucleolus is a highly dynamic nuclear substructure that was originally described as the site of ribosome biogenesis. The advent of proteomic analysis has now allowed the identification of over 4500 nucleolus associated proteins with only about 30% of them associated with ribogenesis (1). The great number of nucleolar proteins not associated with traditionally accepted nucleolar functions indicates a role for the nucleolus in other cellular functions such as mitosis, cell-cycle progression...

  1. Molecular Mechanisms Underlying Psychological Stress and Cancer.

    Science.gov (United States)

    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

  2. A sub-cellular viscoelastic model for cell population mechanics.

    Directory of Open Access Journals (Sweden)

    Yousef Jamali

    Full Text Available Understanding the biomechanical properties and the effect of biomechanical force on epithelial cells is key to understanding how epithelial cells form uniquely shaped structures in two or three-dimensional space. Nevertheless, with the limitations and challenges posed by biological experiments at this scale, it becomes advantageous to use mathematical and 'in silico' (computational models as an alternate solution. This paper introduces a single-cell-based model representing the cross section of a typical tissue. Each cell in this model is an individual unit containing several sub-cellular elements, such as the elastic plasma membrane, enclosed viscoelastic elements that play the role of cytoskeleton, and the viscoelastic elements of the cell nucleus. The cell membrane is divided into segments where each segment (or point incorporates the cell's interaction and communication with other cells and its environment. The model is capable of simulating how cells cooperate and contribute to the overall structure and function of a particular tissue; it mimics many aspects of cellular behavior such as cell growth, division, apoptosis and polarization. The model allows for investigation of the biomechanical properties of cells, cell-cell interactions, effect of environment on cellular clusters, and how individual cells work together and contribute to the structure and function of a particular tissue. To evaluate the current approach in modeling different topologies of growing tissues in distinct biochemical conditions of the surrounding media, we model several key cellular phenomena, namely monolayer cell culture, effects of adhesion intensity, growth of epithelial cell through interaction with extra-cellular matrix (ECM, effects of a gap in the ECM, tensegrity and tissue morphogenesis and formation of hollow epithelial acini. The proposed computational model enables one to isolate the effects of biomechanical properties of individual cells and the

  3. Numerical Studies of Homogenization under a Fast Cellular Flow

    KAUST Repository

    Iyer, Gautam

    2012-09-13

    We consider a two dimensional particle diffusing in the presence of a fast cellular flow confined to a finite domain. If the flow amplitude A is held fixed and the number of cells L 2 →∞, then the problem homogenizes; this has been well studied. Also well studied is the limit when L is fixed and A→∞. In this case the solution averages along stream lines. The double limit as both the flow amplitude A→∞and the number of cells L 2 →∞was recently studied [G. Iyer et al., preprint, arXiv:1108.0074]; one observes a sharp transition between the homogenization and averaging regimes occurring at A = L 2. This paper numerically studies a few theoretically unresolved aspects of this problem when both A and L are large that were left open in [G. Iyer et al., preprint, arXiv:1108.0074] using the numerical method devised in [G. A. Pavliotis, A. M. Stewart, and K. C. Zygalakis, J. Comput. Phys., 228 (2009), pp. 1030-1055]. Our treatment of the numerical method uses recent developments in the theory of modified equations for numerical integrators of stochastic differential equations [K. C. Zygalakis, SIAM J. Sci. Comput., 33 (2001), pp. 102-130]. © 2012 Society for Industrial and Applied Mathematics.

  4. Molecular Mechanisms Underlying Pituitary Pathogenesis.

    Science.gov (United States)

    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. Mediated coalescence: a possible mechanism for tumor cellular heterogeneity

    Science.gov (United States)

    Ambrose, Joseph; Livitz, Michelle; Wessels, Deborah; Kuhl, Spencer; Lusche, Daniel F; Scherer, Amanda; Voss, Edward; Soll, David R

    2015-01-01

    Recently, we demonstrated that tumorigenic cell lines and fresh tumor cells seeded in a 3D Matrigel model, first grow as clonal islands (primary aggregates), then coalesce through the formation and contraction of cellular cables. Non-tumorigenic cell lines and cells from normal tissue form clonal islands, but do not form cables or coalesce. Here we show that as little as 5% tumorigenic cells will actively mediate coalescence between primary aggregates of majority non-tumorigenic or non-cancerous cells, by forming cellular cables between them. We suggest that this newly discovered, specialized characteristic of tumorigenic cells may explain, at least in part, why tumors contain primarily non-tumorigenic cells. PMID:26807328

  6. Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

    OpenAIRE

    Adams, Drew J.; Dai, Mingji; Pellegrino, Giovanni; Wagner, Bridget K.; Stern, Andrew M.; Shamji, Alykhan F.; Schreiber, Stuart L.

    2012-01-01

    Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively to cancer cells in vitro and in vivo. This compound was found to elevate cellular levels of reactive oxygen species (ROS) selectively in cancer cell lines. The synthesis of 80 piperlongumine analogs has revealed structural modifications that retain, enhance, and ablate key piperlongumine-associated effects on cells, including elevation of ROS, cancer cell death, and selectivity for cancer cells ...

  7. Cellular solid behaviour of liquid crystal colloids. 2. Mechanical properties

    OpenAIRE

    Anderson, V.J.; Terentjev, E. M.

    2000-01-01

    This paper presents the results of a rheological study of thermotropic nematic colloids aggregated into cellular structures. Small sterically stabilised PMMA particles dispersed in a liquid crystal matrix densely pack on cell interfaces, but reversibly mix with the matrix when the system is heated above Tni. We obtain a remarkably high elastic modulus, G'~10^5 Pa, which is a nearly linear function of particle concentration. A characteristic yield stress is required to disrupt the continuity o...

  8. Mood disorders in Huntington’s disease: from behavior to cellular and molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Patrick Pla

    2014-04-01

    Full Text Available Huntington’s disease (HD is a neurodegenerative disorder that is best known for its effect on motor control. Mood disturbances such as depression, anxiety, and irritability also have a high prevalence in patients with HD, and often start before the onset of motor symptoms. Various rodent models of HD recapitulate the anxiety/depressive behavior seen in patients. HD is caused by an expanded polyglutamine stretch in the N-terminal part of a 350 kDa protein called huntingtin (HTT. HTT is ubiquitously expressed and is implicated in several cellular functions including control of transcription, vesicular trafficking, ciliogenesis, and mitosis. This review summarizes progress in efforts to understand the cellular and molecular mechanisms underlying behavioral disorders in patients with HD. Dysfunctional HTT affects cellular pathways that are involved in mood disorders or in the response to antidepressants, including BDNF/TrkB and serotonergic signaling. Moreover, HTT affects adult hippocampal neurogenesis, a physiological phenomenon that is implicated in some of the behavioral effects of antidepressants and is linked to the control of anxiety. These findings are consistent with the emerging role of wild-type HTT as a crucial component of neuronal development and physiology. Thus, the pathogenic polyQ expansion in HTT could lead to mood disorders not only by the gain of a new toxic function but also by the perturbation of its normal function.

  9. Cellular Mechanisms of Calcium-Mediated Triggered Activity

    Science.gov (United States)

    Song, Zhen

    Life-threatening cardiac arrhythmias continue to pose a major health problem. Ventricular fibrillation, which is a complex form of electrical wave turbulence in the lower chambers of the heart, stops the heart from pumping and is the largest cause of natural death in the United States. Atrial fibrillation, a related form of wave turbulence in the upper heart chambers, is in turn the most common arrhythmia diagnosed in clinical practice. Despite extensive research to date, mechanisms of cardiac arrhythmias remain poorly understood. It is well established that both spatial disorder of the refractory period of heart cells and triggered activity (TA) jointly contribute to the initiation and maintenance of arrhythmias. TA broadly refers to the abnormal generation of a single or a sequence of abnormal excitation waves from a small submillimeter region of the heart in the interval of time between two normal waves generated by the heart's natural pacemaker (the sinoatrial node). TA has been widely investigated experimentally and occurs in several pathological conditions where the intracellular concentration of free Ca2+ ions in heart cells becomes elevated. Under such conditions, Ca2+ can be spontaneously released from intracellular stores, thereby driving an electrogenic current that exchanges 3Na+ ions for one Ca2+ ion across the cell membrane. This current in turn depolarizes the membrane of heart cells after a normal excitation. If this calcium-mediated "delayed after depolarization'' (DAD) is sufficiently large, it can generate an action potential. While the arrhythmogenic importance of spontaneous Ca2+ release and DADs is well appreciated, the conditions under which they occur in heart pathologies remain poorly understood. Calcium overload is only one factor among several other factors that can promote DADs, including sympathetic nerve stimulation, different expression levels of membrane ion channels and calcium handling proteins, and different mutations of those

  10. Metacognitive mechanisms underlying lucid dreaming.

    Science.gov (United States)

    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

  11. Molecular and Cellular Evidence for the Alternative Lengthening of Telomeres (ALT) Mechanism in Chicken

    OpenAIRE

    O'Hare, T.H.; Delany, M. E.

    2011-01-01

    Telomere maintenance is an important genetic mechanism controlling cellular proliferation. Normally, telomeres are maintained by telomerase which is downregulated upon cellular differentiation in most somatic cell lineages. Telomerase activity is upregulated in immortalized cells and cancers to support an infinite lifespan and uncontrolled cell growth; however, some immortalized and transformed cells lack telomerase activity. Telomerase-negative tumors and immortalized cells utilize an altern...

  12. Cellular Mechanisms Underlying Hippocampal CA1 Place Cell Activity

    OpenAIRE

    Fallahnezhad, Mehdi

    2015-01-01

    Norsk Sammendrag: Nerveceller er de grunnleggende byggesteinene i hjernen hos pattedyr og deres aktivitet fører til hjernefunksjoner. Aktivitetsmønsteret til en nervecelle, slik som det romlige fyringsmønsteret laget av en stedcelle i hippocampus, oppstår gjennom samspillet mellom inngangsaktiviteten fra presynaptiske nerveceller og de molekylære mekanismene i nervecellen (cellulær mekanisme). Til tross for omfattende karakterisering av stedcelleaktivitet er ikke de underligge...

  13. Genetic, Molecular and Cellular Mechanisms Underlying the J Wave Syndromes

    OpenAIRE

    Antzelevitch, Charles

    2012-01-01

    An early repolarization (ER) pattern in the ECG, distinguished by J-point elevation, slurring of the terminal part of the QRS and ST-segment elevation has long been recognized and considered to be a benign electrocardiographic manifestation. Experimental studies conducted over a decade ago suggested that some cases of ER may be associated with malignant arrhythmias. Validation of this hypothesis was provided by recent studies demonstrating that an ER pattern in the inferior or inferolateral l...

  14. The Molecular Genetics and Cellular Mechanisms Underlying Pulmonary Arterial Hypertension

    Directory of Open Access Journals (Sweden)

    Rajiv D. Machado

    2012-01-01

    Full Text Available Pulmonary arterial hypertension (PAH is an incurable disorder clinically characterised by a sustained elevation of mean arterial pressure in the absence of systemic involvement. As the adult circulation is a low pressure, low resistance system, PAH represents a reversal to a foetal state. The small pulmonary arteries of patients exhibit luminal occlusion resultant from the uncontrolled growth of endothelial and smooth muscle cells. This vascular remodelling is comprised of hallmark defects, most notably the plexiform lesion. PAH may be familial in nature but the majority of patients present with spontaneous disease or PAH associated with other complications. In this paper, the molecular genetic basis of the disorder is discussed in detail ranging from the original identification of the major genetic contributant to PAH and moving on to current next-generation technologies that have led to the rapid identification of additional genetic risk factors. The impact of identified mutations on the cell is examined, particularly, the determination of pathways disrupted in disease and critical to pulmonary vascular maintenance. Finally, the application of research in this area to the design and development of novel treatment options for patients is addressed along with the future directions PAH research is progressing towards.

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

    OpenAIRE

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

    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 un...

  16. Mechanobiology and the microcirculation: cellular, nuclear and fluid mechanics

    OpenAIRE

    Dahl, Kris Noel; Kalinowski, Agnieszka; Pekkan, Kerem

    2010-01-01

    Endothelial cells are stimulated by shear stress throughout the vasculature and respond with changes in gene expression and by morphological reorganization. Mechanical sensors of the cell are varied and include cell surface sensors that activate intracellular chemical signaling pathways. Here, possible mechanical sensors of the cell including reorganization of the cytoskeleton and the nucleus are discussed in relation to shear flow. A mutation in the nuclear structural protein lamin A, relate...

  17. Predicting bulk mechanical properties of cellularized collagen gels using multiphoton microscopy

    OpenAIRE

    Raub, CB; Putnam, AJ; Tromberg, BJ; George, SC

    2010-01-01

    Cellularized collagen gels are a common model in tissue engineering, but the relationship between the microstructure and bulk mechanical properties is only partially understood. Multiphoton microscopy (MPM) is an ideal non-invasive tool to examine collagen microstructure, cellularity and crosslink content in these gels. In order to identify robust image parameters that characterize microstructural determinants of the bulk elastic modulus, we performed serial MPM and mechanical tests on acellu...

  18. Linking Cellular and Mechanical Processes in Articular Cartilage Lesion Formation: A Mathematical Model

    OpenAIRE

    Kapitanov, Georgi I.; Wang, Xiayi; Ayati, Bruce P; Brouillette, Marc J.; Martin, James A.

    2016-01-01

    A severe application of stress on articular cartilage can initiate a cascade of biochemical reactions that can lead to the development of osteoarthritis. We constructed a multiscale mathematical model of the process with three components: cellular, chemical, and mechanical. The cellular component describes the different chondrocyte states according to the chemicals these cells release. The chemical component models the change in concentrations of those chemicals. The mechanical component cont...

  19. Transglutaminase type 2-dependent selective recruitment of proteins into exosomes under stressful cellular conditions.

    Science.gov (United States)

    Diaz-Hidalgo, Laura; Altuntas, Sara; Rossin, Federica; D'Eletto, Manuela; Marsella, Claudia; Farrace, Maria Grazia; Falasca, Laura; Antonioli, Manuela; Fimia, Gian Maria; Piacentini, Mauro

    2016-08-01

    Numerous studies are revealing a role of exosomes in intercellular communication, and growing evidence indicates an important function for these vesicles in the progression and pathogenesis of cancer and neurodegenerative diseases. However, the biogenesis process of exosomes is still unclear. Tissue transglutaminase (TG2) is a multifunctional enzyme with different subcellular localizations. Particularly, under stressful conditions, the enzyme has been also detected in the extracellular matrix, but the mechanism(s) by which TG2 is released outside the cells requires further investigation. Therefore, the goal of the present study was to determine whether exosomes might be a vehicle for TG2 to reach the extracellular space, and whether TG2 could be involved in exosomes biogenesis. To address this issue, we isolated and characterized exosomes derived from cells either expressing or not TG2, under stressful conditions (i.e. proteasome impairment or expressing a mutated form of huntingtin (mHtt) containing 84 polyglutamine repeats). Our results show that TG2 is present in the exosomes only upon proteasome blockade, a condition in which TG2 interacts with TSG101 and ALIX, two key proteins involved in exosome biogenesis. Interestingly, we found that TG2 favours the assembly of a protein complex including mHtt, ALIX, TSG101 and BAG3, a co-chaperone involved in the clearance of mHtt. The formation of this complex is paralleled by the selective recruitment of mHtt and BAG3 in the exosomes derived from TG2 proficient cells only. Overall, our data indicate that TG2 is an important player in the biogenesis of exosomes controlling the selectivity of their cargo under stressful cellular conditions. In addition, these vesicles represent the way by which cells can release TG2 into the extracellular space under proteostasis impairment. PMID:27169926

  20. Cellular Magnesium Matrix Foam Composites for Mechanical Damping Applications

    Science.gov (United States)

    Shunmugasamy, Vasanth Chakravarthy; Mansoor, Bilal; Gupta, Nikhil

    2016-01-01

    The damping characteristics of metal alloys and metal matrix composites are relevant to the automotive, aerospace, and marine structures. Use of lightweight materials can help in increasing payload capacity and in decreasing fuel consumption. Lightweight composite materials possessing high damping capabilities that can be designed as structural members can greatly benefit in addressing these needs. In this context, the damping properties of lightweight metals such as aluminum and magnesium and their respective composites have been studied in the existing literature. This review focuses on analyzing the damping properties of aluminum and magnesium alloys and their cellular composites. The damping properties of various lightweight alloys and composites are compared on the basis of their density to understand the potential for weight saving in structural applications. Magnesium alloys are observed to possess better damping properties in comparison to aluminum. However, aluminum matrix syntactic foams reinforced with silicon carbide hollow particles possess a damping capacity and density comparable to magnesium alloy. By using the data presented in the study, composites with specific compositions and properties can be selected for a given application. In addition, the comparison of the results helps in identifying the areas where attention needs to be focused to address the future needs.

  1. Lipoprotein(a: Cellular Effects and Molecular Mechanisms

    Directory of Open Access Journals (Sweden)

    Kirsten Riches

    2012-01-01

    Full Text Available Lipoprotein(a (Lp(a is an independent risk factor for the development of cardiovascular disease (CVD. Indeed, individuals with plasma concentrations >20 mg/dL carry a 2-fold increased risk of developing CVD, accounting for ~25% of the population. Circulating levels of Lp(a are remarkably resistant to common lipid lowering therapies, and there are currently no robust treatments available for reduction of Lp(a apart from plasma apheresis, which is costly and labour intensive. The Lp(a molecule is composed of two parts, an LDL/apoB-100 core and a unique glycoprotein, apolipoprotein(a (apo(a, both of which can interact with components of the coagulation cascade, inflammatory pathways, and cells of the blood vessel wall (smooth muscle cells (SMC and endothelial cells (EC. Therefore, it is of key importance to determine the molecular pathways by which Lp(a exerts its influence on the vascular system in order to design therapeutics to target its cellular effects. This paper will summarise the role of Lp(a in modulating cell behaviour in all aspects of the vascular system including platelets, monocytes, SMC, and EC.

  2. Understanding the mechanisms of ATPase beta family genes for cellular thermotolerance in crossbred bulls

    Science.gov (United States)

    Deb, Rajib; Sajjanar, Basavaraj; Singh, Umesh; Alex, Rani; Raja, T. V.; Alyethodi, Rafeeque R.; Kumar, Sushil; Sengar, Gyanendra; Sharma, Sheetal; Singh, Rani; Prakash, B.

    2015-12-01

    Na+/K+-ATPase is an integral membrane protein composed of a large catalytic subunit (alpha), a smaller glycoprotein subunit (beta), and gamma subunit. The beta subunit is essential for ion recognition as well as maintenance of the membrane integrity. Present study was aimed to analyze the expression pattern of ATPase beta subunit genes (ATPase B1, ATPase B2, and ATPase B3) among the crossbred bulls under different ambient temperatures (20-44 °C). The present study was also aimed to look into the relationship of HSP70 with the ATPase beta family genes. Our results demonstrated that among beta family genes, transcript abundance of ATPase B1 and ATPase B2 is significantly ( P P mechanisms of ATPase beta family genes for cellular thermotolerance in cattle.

  3. Mechanics of Cellular Adhesion to Artificial Artery Templates

    OpenAIRE

    Knöner, Gregor; Rolfe, Barbara E.; Campbell, Julie H.; Parkin, Simon J.; Heckenberg, Norman R.; Rubinsztein-Dunlop, Halina

    2006-01-01

    We are using polymer templates to grow artificial artery grafts in vivo for the replacement of diseased blood vessels. We have previously shown that adhesion of macrophages to the template starts the graft formation. We present a study of the mechanics of macrophage adhesion to these templates on a single cell and single bond level with optical tweezers. For whole cells, in vitro cell adhesion densities decreased significantly from polymer templates polyethylene to silicone to Tygon (167, 135...

  4. Antidiabetic properties of dietary flavonoids: a cellular mechanism review

    OpenAIRE

    Vinayagam, Ramachandran; Xu, Baojun

    2015-01-01

    Background Natural food products have been used for combating human diseases for thousands of years. Naturally occurring flavonoids including flavones, flavonols, flavanones, flavonols, isoflavones and anthocyanidins have been proposed as effective supplements for management and prevention of diabetes and its long-term complications based on in vitro and animal models. Aim To summarize the roles of dietary flavonoids in diabetes management and their molecular mechanisms. Findings Tremendous s...

  5. Cellular and molecular mechanisms of HGF/Met in the cardiovascular system.

    Science.gov (United States)

    Gallo, Simona; Sala, Valentina; Gatti, Stefano; Crepaldi, Tiziana

    2015-12-01

    Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the

  6. Coupling of Cellular Processes and Their Coordinated Oscillations under Continuous Light in Cyanothece sp. ATCC 51142, a Diazotrophic Unicellular Cyanobacterium.

    Directory of Open Access Journals (Sweden)

    S Krishnakumar

    Full Text Available Unicellular diazotrophic cyanobacteria such as Cyanothece sp. ATCC 51142 (henceforth Cyanothece, temporally separate the oxygen sensitive nitrogen fixation from oxygen evolving photosynthesis not only under diurnal cycles (LD but also in continuous light (LL. However, recent reports demonstrate that the oscillations in LL occur with a shorter cycle time of ~11 h. We find that indeed, majority of the genes oscillate in LL with this cycle time. Genes that are upregulated at a particular time of day under diurnal cycle also get upregulated at an equivalent metabolic phase under LL suggesting tight coupling of various cellular events with each other and with the cell's metabolic status. A number of metabolic processes get upregulated in a coordinated fashion during the respiratory phase under LL including glycogen degradation, glycolysis, oxidative pentose phosphate pathway, and tricarboxylic acid cycle. These precede nitrogen fixation apparently to ensure sufficient energy and anoxic environment needed for the nitrogenase enzyme. Photosynthetic phase sees upregulation of photosystem II, carbonate transport, carbon concentrating mechanism, RuBisCO, glycogen synthesis and light harvesting antenna pigment biosynthesis. In Synechococcus elongates PCC 7942, a non-nitrogen fixing cyanobacteria, expression of a relatively smaller fraction of genes oscillates under LL condition with the major periodicity being 24 h. In contrast, the entire cellular machinery of Cyanothece orchestrates coordinated oscillation in anticipation of the ensuing metabolic phase in both LD and LL. These results may have important implications in understanding the timing of various cellular events and in engineering cyanobacteria for biofuel production.

  7. Heterogeneity of cellular circadian clocks in intact plants and its correction under light-dark cycles.

    Science.gov (United States)

    Muranaka, Tomoaki; Oyama, Tokitaka

    2016-07-01

    Recent advances in single-cell analysis have revealed the stochasticity and nongenetic heterogeneity inherent to cellular processes. However, our knowledge of the actual cellular behaviors in a living multicellular organism is still limited. By using a single-cell bioluminescence imaging technique on duckweed, Lemna gibba, we demonstrate that, under constant conditions, cells in the intact plant work as individual circadian clocks that oscillate with their own frequencies and respond independently to external stimuli. Quantitative analysis uncovered the heterogeneity and instability of cellular clocks and partial synchronization between neighboring cells. Furthermore, we found that cellular clocks in the plant body under light-dark cycles showed a centrifugal phase pattern in which the effect of cell-to-cell heterogeneity in period lengths was almost masked. The inherent heterogeneity in the properties of cellular clocks observed under constant conditions is corrected under light-dark cycles to coordinate the daily rhythms of the plant body. These findings provide a novel perspective of spatiotemporal architectures in the plant circadian system. PMID:27453946

  8. Heterogeneity of cellular circadian clocks in intact plants and its correction under light-dark cycles

    Science.gov (United States)

    Muranaka, Tomoaki; Oyama, Tokitaka

    2016-01-01

    Recent advances in single-cell analysis have revealed the stochasticity and nongenetic heterogeneity inherent to cellular processes. However, our knowledge of the actual cellular behaviors in a living multicellular organism is still limited. By using a single-cell bioluminescence imaging technique on duckweed, Lemna gibba, we demonstrate that, under constant conditions, cells in the intact plant work as individual circadian clocks that oscillate with their own frequencies and respond independently to external stimuli. Quantitative analysis uncovered the heterogeneity and instability of cellular clocks and partial synchronization between neighboring cells. Furthermore, we found that cellular clocks in the plant body under light-dark cycles showed a centrifugal phase pattern in which the effect of cell-to-cell heterogeneity in period lengths was almost masked. The inherent heterogeneity in the properties of cellular clocks observed under constant conditions is corrected under light-dark cycles to coordinate the daily rhythms of the plant body. These findings provide a novel perspective of spatiotemporal architectures in the plant circadian system. PMID:27453946

  9. Active Cellular Mechanics and Information Processing in the Living Cell

    Science.gov (United States)

    Rao, M.

    2014-07-01

    I will present our recent work on the organization of signaling molecules on the surface of living cells. Using novel experimental and theoretical approaches we have found that many cell surface receptors are organized as dynamic clusters driven by active currents and stresses generated by the cortical cytoskeleton adjoining the cell surface. We have shown that this organization is optimal for both information processing and computation. In connecting active mechanics in the cell with information processing and computation, we bring together two of the seminal works of Alan Turing.

  10. Peeling mechanism of tomato under infrared heating

    Science.gov (United States)

    Critical behaviors of peeling tomatoes using infrared heat are thermally induced peel loosening and subsequent cracking. However, the mechanism of peel loosening and cracking due to infrared heating remains unclear. This study aimed at investigating the mechanism of peeling tomatoes under infrared h...

  11. Nonlinear dose-response relationships and inducible cellular defence mechanisms

    International Nuclear Information System (INIS)

    With the inclusion of inducible radioprotective mechanisms in a radiobiological state-vector model it was possible to explain plateaus in dose-response relationships for neoplastic transformation produced by in vitro irradiation of different cell lines with low-LET irradiation at high dose rates. The current study repeated the simulation of one data set that contains a plateau at mid doses. In contrast to earlier studies, the new one did not model the repair of double-strand breaks (DSBs) located in bulk DNA (likely via non-homologous end joining) as being inducible. Repair of specific DSBs located in actively transcribed genes was assumed to occur via homologous recombination and was considered to be inducible. This reduced the number of parameters that have to be determined by fitting the model to data. In addition, all types of radical scavengers were formerly considered to be inducible by radiation. This was redefined in the current work and the effectiveness of scavengers was implemented in a refined way. The current work investigated whether these and other model adjustments lead to an improved fit of the data set. (author)

  12. Action principle for cellular automata and the linearity of quantum mechanics

    CERN Document Server

    Elze, Hans-Thomas

    2014-01-01

    We introduce an action principle for a class of integer valued cellular automata and obtain Hamiltonian equations of motion. Employing sampling theory, these discrete deterministic equations are invertibly mapped on continuum equations for a set of bandwidth limited harmonic oscillators, which encode the Schr\\"odinger equation. Thus, the linearity of quantum mechanics is related to the action principle of such cellular automata and its conservation laws to discrete ones.

  13. Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes.

    Science.gov (United States)

    Shah, Manasi S; Brownlee, Michael

    2016-05-27

    The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1α, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca

  14. A material optimization model to approximate energy bounds for cellular materials under multiload conditions

    DEFF Research Database (Denmark)

    Guedes, J.M.; Rodrigues, H.C.; Bendsøe, Martin P.

    2003-01-01

    This paper describes a computational model, based on inverse homogenization and topology design, for approximating energy bounds for two-phase composites under multiple load cases. The approach allows for the identification of possible single-scale cellular materials that give rise to the optimal...

  15. Tuning of the electro-mechanical behavior of the cellular carbon nanotube structures with nanoparticle dispersions

    International Nuclear Information System (INIS)

    The mechanical and electrical characteristics of cellular network of the carbon nanotubes (CNT) impregnated with metallic and nonmetallic nanoparticles were examined simultaneously by employing the nanoindentation technique. Experimental results show that the nanoparticle dispersion not only enhances the mechanical strength of the cellular CNT by two orders of magnitude but also imparts variable nonlinear electrical characteristics; the latter depends on the contact resistance between nanoparticles and CNT, which is shown to depend on the applied load while indentation. Impregnation with silver nanoparticles enhances the electrical conductance, the dispersion with copper oxide and zinc oxide nanoparticles reduces the conductance of CNT network. In all cases, a power law behavior with suppression in the differential conductivity at zero bias was noted, indicating electron tunneling through the channels formed at the CNT-nanoparticle interfaces. These results open avenues for designing cellular CNT foams with desired electro-mechanical properties and coupling

  16. Mechanical Buckling of Veins under Internal Pressure

    OpenAIRE

    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 p...

  17. Use of Computational Modeling to Evaluate Hypotheses About the Molecular and Cellular Mechanisms of Bystander Effects

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yuchao; Conolly, Rory B; Andersen, Melvin E.

    2006-11-21

    This report describes the development of a computational systems biology approach to evaluate the hypotheses of molecular and cellular mechanisms of adaptive response to low dose ionizing radiation. Our concept is that computational models of signaling pathways can be developed and linked to biologically based dose response models to evaluate the underlying molecular mechanisms which lead to adaptive response. For development of quantitatively accurate, predictive models, it will be necessary to describe tissues consisting of multiple cell types where the different types each contribute in their own way to the overall function of the tissue. Such a model will probably need to incorporate not only cell type-specific data but also spatial information on the architecture of the tissue and on intercellular signaling. The scope of the current model was more limited. Data obtained in a number of different biological systems were synthesized to describe a chimeric, “average” population cell. Biochemical signaling pathways involved in sensing of DNA damage and in the activation of cell cycle checkpoint controls and the apoptotic path were also included. As with any computational modeling effort, it was necessary to develop these simplified initial descriptions (models) that can be iteratively refined. This preliminary model is a starting point which, with time, can evolve to a level of refinement where large amounts of detailed biological information are synthesized and a capability for robust predictions of dose- and time-response behaviors is obtained.

  18. Structural-mechanical model of wax crystal networks—a mesoscale cellular solid approach

    International Nuclear Information System (INIS)

    Mineral waxes are widely used materials in industrial applications; however, the relationship between structure and mechanical properties is poorly understood. In this work, mineral wax-oil networks were characterized as closed-cell cellular solids, and differences in their mechanical response predicted from structural data. The systems studied included straight-chain paraffin wax (SW)-oil mixtures and polyethylene wax (PW)-oil mixtures. Analysis of cryogenic-SEM images of wax-oil networks allowed for the determination of the length (l) and thickness (t) of the wax cell walls as a function of wax mass fraction (Φ). A linear relationship between t/l and Φ (t/l ∼ Φ 0.89) suggested that wax-oil networks were cellular solids of the closed-cell type. However, the scaling behavior of the elastic modulus with the volume fraction of solids did not agree with theoretical predictions, yielding the same scaling exponent, μ = 0.84, for both waxes. This scaling exponent obtained from mechanical measurements could be predicted from the scaling behavior of the effective wax cell size as a function of wax mass fraction in oil obtained by cryogenic scanning electron microscopy. Microscopy studies allowed us to propose that wax-oil networks are structured as an ensemble of close-packed spherical cells filled with oil, and that it is the links between cells that yield under simple uniaxial compression. Thus, the Young’s moduli for the links between cells in SW and PW wax systems could be estimated as E L(SW) = 2.76 × 109 Pa and E L(PW) = 1.64 × 109 Pa, respectively. The structural parameter responsible for the observed differences in the mechanical strength between the two wax-oil systems is the size of the cells. Polyethylene wax has much smaller cell sizes than the straight chain wax and thus displays a higher Young’s modulus and yield stress. (papers)

  19. Computational up-scaling of anisotropic swelling and mechanical behavior of hierarchical cellular material

    CERN Document Server

    Rafsanjani, Ahmad; Wittel, Falk K; Carmeliet, Jan

    2015-01-01

    The hygro-mechanical behavior of a hierarchical cellular material, i.e. growth rings of softwood is investigated using a two-scale micro-mechanics model based on a computational homogenization technique. The lower scale considers the individual wood cells of varying geometry and dimensions. Honeycomb unit cells with periodic boundary conditions are utilized to calculate the mechanical properties and swelling coefficients of wood cells. Using the cellular scale results, the anisotropy in mechanical and swelling behavior of a growth ring in transverse directions is investigated. Predicted results are found to be comparable to experimental data. It is found that the orthotropic swelling properties of the cell wall in thin-walled earlywood cells produce anisotropic swelling behavior while, in thick latewood cells, this anisotropy vanishes. The proposed approach provides the ability to consider the complex microstructure when predicting the effective mechanical and swelling properties of softwood.

  20. The linearity of quantum mechanics from the perspective of Hamiltonian cellular automata

    CERN Document Server

    Elze, Hans-Thomas

    2014-01-01

    We discuss the action principle and resulting Hamiltonian equations of motion for a class of integer-valued cellular automata introduced recently [1]. Employing sampling theory, these deterministic finite-difference equations are mapped reversibly on continuum equations describing a set of bandwidth limited harmonic oscillators. They represent the Schroedinger equation. However, modifications reflecting the bandwidth limit are incorporated, i.e., the presence of a time (or length) scale. When this discreteness scale is taken to zero, the usual results are obtained. Thus, the linearity of quantum mechanics can be traced to the postulated action principle of such cellular automata and its conservation laws to discrete ones. The cellular automaton conservation laws are in one-to-one correspondence with those of the related quantum mechanical model, while admissible symmetries are not.

  1. The linearity of quantum mechanics from the perspective of Hamiltonian cellular automata

    International Nuclear Information System (INIS)

    We discuss the action principle and resulting Hamiltonian equations of motion for a class of integer-valued cellular automata introduced recently [1]. Employing sampling theory, these deterministic finite-difference equations are mapped reversibly on continuum equations describing a set of bandwidth limited harmonic oscillators. They represent the Schrödinger equation. However, modifications reflecting the bandwidth limit are incorporated, i.e., the presence of a time (or length) scale. When this discreteness scale is taken to zero, the usual results are obtained. Thus, the linearity of quantum mechanics can be traced to the postulated action principle of such cellular automata and its conservation laws to discrete ones. The cellular automaton conservation laws are in one-to-one correspondence with those of the related quantum mechanical model, while admissible symmetries are not.

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

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Trung Dung; Gu, YuanTong, E-mail: yuantong.gu@qut.edu.au [School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology, Brisbane, Queensland (Australia)

    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. Cellular and molecular mechanisms of repair in acute and chronic wound healing

    OpenAIRE

    Martin, P.; Nunan, R

    2015-01-01

    Summary A considerable understanding of the fundamental cellular and molecular mechanisms underpinning healthy acute wound healing has been gleaned from studying various animal models, and we are now unravelling the mechanisms that lead to chronic wounds and pathological healing including fibrosis. A small cut will normally heal in days through tight orchestration of cell migration and appropriate levels of inflammation, innervation and angiogenesis. Major surgeries may take several weeks to ...

  4. Cellular and molecular mechanisms of osteoporosis: current concepts and future direction treatment

    OpenAIRE

    A. T. Dolzhenko; S. Sagalovsky

    2016-01-01

    The article presents review of literature dedicated to the contemporary view on the cellular-molecular mechanisms of the bone remodeling and pathogenesis of the osteoporosis. The discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in process bone remodeling has made progress in understanding the mechanisms development disease and possible to development drugs of the new generation – denosumab, a fully human RANKL monoclonal antibody and inhibitor cathepsin ...

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

    Science.gov (United States)

    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

  6. The role of focal adhesion kinase in the regulation of cellular mechanical properties

    Science.gov (United States)

    Mierke, Claudia Tanja

    2013-12-01

    The regulation of mechanical properties is necessary for cell invasion into connective tissue or intra- and extravasation through the endothelium of blood or lymph vessels. Cell invasion is important for the regulation of many healthy processes such as immune response reactions and wound healing. In addition, cell invasion plays a role in disease-related processes such as tumor metastasis and autoimmune responses. Until now the role of focal adhesion kinase (FAK) in regulating mechanical properties of cells and its impact on cell invasion efficiency is still not well known. Thus, this review focuses on mechanical properties regulated by FAK in comparison to the mechano-regulating protein vinculin. Moreover, it points out the connection between cancer cell invasion and metastasis and FAK by showing that FAK regulates cellular mechanical properties required for cellular motility. Furthermore, it sheds light on the indirect interaction of FAK with vinculin by binding to paxillin, which then impairs the binding of paxillin to vinculin. In addition, this review emphasizes whether FAK fulfills regulatory functions similar to vinculin. In particular, it discusses the differences and the similarities between FAK and vinculin in regulating the biomechanical properties of cells. Finally, this paper highlights that both focal adhesion proteins, vinculin and FAK, synergize their functions to regulate the mechanical properties of cells such as stiffness and contractile forces. Subsequently, these mechanical properties determine cellular invasiveness into tissues and provide a source sink for future drug developments to inhibit excessive cell invasion and hence, metastases formation.

  7. The role of focal adhesion kinase in the regulation of cellular mechanical properties

    International Nuclear Information System (INIS)

    The regulation of mechanical properties is necessary for cell invasion into connective tissue or intra- and extravasation through the endothelium of blood or lymph vessels. Cell invasion is important for the regulation of many healthy processes such as immune response reactions and wound healing. In addition, cell invasion plays a role in disease-related processes such as tumor metastasis and autoimmune responses. Until now the role of focal adhesion kinase (FAK) in regulating mechanical properties of cells and its impact on cell invasion efficiency is still not well known. Thus, this review focuses on mechanical properties regulated by FAK in comparison to the mechano-regulating protein vinculin. Moreover, it points out the connection between cancer cell invasion and metastasis and FAK by showing that FAK regulates cellular mechanical properties required for cellular motility. Furthermore, it sheds light on the indirect interaction of FAK with vinculin by binding to paxillin, which then impairs the binding of paxillin to vinculin. In addition, this review emphasizes whether FAK fulfills regulatory functions similar to vinculin. In particular, it discusses the differences and the similarities between FAK and vinculin in regulating the biomechanical properties of cells. Finally, this paper highlights that both focal adhesion proteins, vinculin and FAK, synergize their functions to regulate the mechanical properties of cells such as stiffness and contractile forces. Subsequently, these mechanical properties determine cellular invasiveness into tissues and provide a source sink for future drug developments to inhibit excessive cell invasion and hence, metastases formation. (paper)

  8. Mechanism resulting in chemical imbalance due to cellular damage associated with mechanoporation: A molecular dynamics study

    Science.gov (United States)

    Sliozberg, Yelena R.; Chantawansri, Tanya L.

    2016-05-01

    To elucidate the mechanism of ion transport through a transmembrane pore, all-atom molecular dynamics simulations were employed. A model membrane where a pore connects the intra- and extra-cellular compartment was considered. Pores with radii of 1.5 nm or less exhibited resealing over the course of 135 ns simulations, and ionic disturbance is minimal. Ion transport through a larger pore (2 nm radius) leads to a substantial change in the intra- and extra-cellular ionic concentrations. The influx of Na+ and Cl- ions down their concentration gradients is greater than the efflux of K+ leading to an osmotic influx of water.

  9. The Physical Mechanism for Retinal Discrete Dark Noise: Thermal Activation or Cellular Ultraweak Photon Emission?

    Science.gov (United States)

    Salari, Vahid; Scholkmann, Felix; Bokkon, Istvan; Shahbazi, Farhad; Tuszynski, Jack

    2016-01-01

    For several decades the physical mechanism underlying discrete dark noise of photoreceptors in the eye has remained highly controversial and poorly understood. It is known that the Arrhenius equation, which is based on the Boltzmann distribution for thermal activation, can model only a part (e.g. half of the activation energy) of the retinal dark noise experimentally observed for vertebrate rod and cone pigments. Using the Hinshelwood distribution instead of the Boltzmann distribution in the Arrhenius equation has been proposed as a solution to the problem. Here, we show that the using the Hinshelwood distribution does not solve the problem completely. As the discrete components of noise are indistinguishable in shape and duration from those produced by real photon induced photo-isomerization, the retinal discrete dark noise is most likely due to ‘internal photons’ inside cells and not due to thermal activation of visual pigments. Indeed, all living cells exhibit spontaneous ultraweak photon emission (UPE), mainly in the optical wavelength range, i.e., 350–700 nm. We show here that the retinal discrete dark noise has a similar rate as UPE and therefore dark noise is most likely due to spontaneous cellular UPE and not due to thermal activation. PMID:26950936

  10. Multiple Molecular and Cellular Mechanisms of Action of Lycopene in Cancer Inhibition

    Directory of Open Access Journals (Sweden)

    Cristina Trejo-Solís

    2013-01-01

    Full Text Available Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.

  11. An evaluation of the mechanism of ABCA7 on cellular lipid release in ABCA7-HEC293 cell

    Institute of Scientific and Technical Information of China (English)

    WU Cheng-ai; WANG Na; ZHAO Dan-hui

    2013-01-01

    Background ABCA7 is a member of the ABCA subfamily that shows a high degree of homology to ABCA1 and,like ABCA1,mediates cellular cholesterol and phospholipid release by apolipoproteins when transfected in vitro.However,expression of ABCA7 has been shown to be downregulated by increased cellular cholesterol while ABCA1 was upregulated.Methods The underlying mechanism for this effect was examined in ABCA1 or ABCA7-transfected HEC293.Lipid content in the medium and cells was determined by enzymatic assays.Gene expression was quantitated by real time PCR,and protein content was determined by Western blotting.Results While ABCA7 mRNA was decreased by 25-hydroxycholesterol treatment,ABCA1 was apparently increased.Treatment with the synthetic LXR agonist T0901317 (T09) upregulated ABCA1 expression and apoAI-mediated cellular lipid release in ABCA1-transfected HEC293 cells,but ABCA7 expression and cellular lipid release in ABCA7-transfected HEC293 cells showed no obvious changes.Conclusion The ABCA7 gene is regulated by sterol in a direction opposite to that of ABCA1.

  12. Determination of the mechanical properties of solid and cellular polymeric dosage forms by diametral compression.

    Science.gov (United States)

    Blaesi, Aron H; Saka, Nannaji

    2016-07-25

    At present, the immediate-release solid dosage forms, such as the oral tablets and capsules, are granular solids. They release drug rapidly and have adequate mechanical properties, but their manufacture is fraught with difficulties inherent in processing particulate matter. Such difficulties, however, could be overcome by liquid-based processing. Therefore, we have recently introduced polymeric cellular (i.e., highly porous) dosage forms prepared from a melt process. Experiments have shown that upon immersion in a dissolution medium, the cellular dosage forms with polyethylene glycol (PEG) as excipient and with predominantly open-cell topology disintegrate by exfoliation, thus enabling rapid drug release. If the volume fraction of voids of the open-cell structures is too large, however, their mechanical strength is adversely affected. At present, the common method for determining the tensile strength of brittle, solid dosage forms (such as select granular forms) is the diametral compression test. In this study, the theory of diametral compression is first refined to demonstrate that the relevant mechanical properties of ductile and cellular solids (i.e., the elastic modulus and the yield strength) can also be extracted from this test. Diametral compression experiments are then conducted on PEG-based solid and cellular dosage forms. It is found that the elastic modulus and yield strength of the open-cell structures are about an order of magnitude smaller than those of the non-porous solids, but still are substantially greater than the stiffness and strength requirements for handling the dosage forms manually. This work thus demonstrates that melt-processed polymeric cellular dosage forms that release drug rapidly can be designed and manufactured to have adequate mechanical properties. PMID:27178343

  13. Mechanical characteristics and microcosmic mechanisms of granite under temperature loads

    Institute of Scientific and Technical Information of China (English)

    XU Xiao-li; GAO Feng; SHEN Xiao-ming; XIE He-ping

    2008-01-01

    The relationships between mechanical characteristics of rock and microcosmic mechanism at high temperatures were investigated by MTS815, as well as the stress-strain behavior of granite under the action of temperatures ranging from room tem-perature to 1200 ℃. Based on a micropore structure analyzer and SEM, the changes in rock porosity and micro'structural mor-phology of sample fractures and brittle-plastic characteristics under high temperatures were analyzed. The results are as follows: 1) Mechanical characteristics do not show obvious variations before 800 ℃; strength decreases suddenly after 800 ℃ and bearing capacity is almost lost at 1200 ℃. 2) Rock porosity increases with rising temperatures; the threshold temperature is about 800 ℃;at this temperature its effect is basically uniform with strength decreasing rapidly. 3) The failure type of granite is a brittle tensile fracture at temperatures below 800 ℃ which transforms into plasticity at temperatures higher than 800 ℃ and crystal formation takes place at this time. Chemical reactions take place at 1200 ℃. Failure of granite under high temperature is a common result of thermal stress as indicated by an increase in the thermal expansion coefficient, transformation to crystal formation of minerals and structural chemical reactions.

  14. Damage of cellular material under simultaneous application of pressure and pulsed electric field

    CERN Document Server

    Bazhal, M I; Vorobev, E I

    2000-01-01

    Influence of pulsed electric field (PEF) simultaneous to pressure treatment on moisture expression from fine-cut cellular raw material has been investigated. Dependencies of specific conductivity $\\sigma$, liquid yield $Y$, instantaneous flow rate $v$ and qualitative juice characteristics at different modes of PEF treatment are discussed. Three main consolidation phases were observed in a case of mechanical expression. A unified approach is proposed for liquid yield data analysis allowing to reduce the data scattering caused by differences in the quality of samples. Simultaneous application of pressure and PEF treatment allows to reveal a passive form of electrical damage. Pressure provokes the damage of defected cells, enhances diffusion migration of moisture in porous cellular material and depresses the cell resealing processes. PEF application at a moment when a sample specific electrical conductivity reaches minimum and pressure achieves its constant value seemed to be the most optimal.

  15. DNA under Force: Mechanics, Electrostatics, and Hydration

    Directory of Open Access Journals (Sweden)

    Jingqiang Li

    2015-02-01

    Full Text Available Quantifying the basic intra- and inter-molecular forces of DNA has helped us to better understand and further predict the behavior of DNA. Single molecule technique elucidates the mechanics of DNA under applied external forces, sometimes under extreme forces. On the other hand, ensemble studies of DNA molecular force allow us to extend our understanding of DNA molecules under other forces such as electrostatic and hydration forces. Using a variety of techniques, we can have a comprehensive understanding of DNA molecular forces, which is crucial in unraveling the complex DNA functions in living cells as well as in designing a system that utilizes the unique properties of DNA in nanotechnology.

  16. Phytoplankton calcification as an effective mechanism to alleviate cellular calcium poisoning

    Science.gov (United States)

    Müller, M. N.; Ramos, J. Barcelos e.; Schulz, K. G.; Riebesell, U.; Kaźmierczak, J.; Gallo, F.; Mackinder, L.; Li, Y.; Nesterenko, P. N.; Trull, T. W.; Hallegraeff, G. M.

    2015-11-01

    Marine phytoplankton have developed the remarkable ability to tightly regulate the concentration of free calcium ions in the intracellular cytosol at a level of ~ 0.1 μmol L-1 in the presence of seawater Ca2+ concentrations of 10 mmol L-1. The low cytosolic calcium ion concentration is of utmost importance for proper cell signalling function. While the regulatory mechanisms responsible for the tight control of intracellular Ca2+ concentration are not completely understood, phytoplankton taxonomic groups appear to have evolved different strategies, which may affect their ability to cope with changes in seawater Ca2+ concentrations in their environment on geological timescales. For example, the Cretaceous (145 to 66 Ma), an era known for the high abundance of coccolithophores and the production of enormous calcium carbonate deposits, exhibited seawater calcium concentrations up to 4 times present-day levels. We show that calcifying coccolithophore species (Emiliania huxleyi, Gephyrocapsa oceanica and Coccolithus braarudii) are able to maintain their relative fitness (in terms of growth rate and photosynthesis) at simulated Cretaceous seawater calcium concentrations, whereas these rates are severely reduced under these conditions in some non-calcareous phytoplankton species (Chaetoceros sp., Ceratoneis closterium and Heterosigma akashiwo). Most notably, this also applies to a non-calcifying strain of E. huxleyi which displays a calcium sensitivity similar to the non-calcareous species. We hypothesize that the process of calcification in coccolithophores provides an efficient mechanism to alleviate cellular calcium poisoning and thereby offered a potential key evolutionary advantage, responsible for the proliferation of coccolithophores during times of high seawater calcium concentrations. The exact function of calcification and the reason behind the highly ornate physical structures of coccoliths remain elusive.

  17. Adaptation of the black yeast Wangiella dermatitidis to ionizing radiation: molecular and cellular mechanisms.

    Directory of Open Access Journals (Sweden)

    Kelly L Robertson

    Full Text Available Observations of enhanced growth of melanized fungi under low-dose ionizing radiation in the laboratory and in the damaged Chernobyl nuclear reactor suggest they have adapted the ability to survive or even benefit from exposure to ionizing radiation. However, the cellular and molecular mechanism of fungal responses to such radiation remains poorly understood. Using the black yeast Wangiella dermatitidis as a model, we confirmed that ionizing radiation enhanced cell growth by increasing cell division and cell size. Using RNA-seq technology, we compared the transcriptomic profiles of the wild type and the melanin-deficient wdpks1 mutant under irradiation and non-irradiation conditions. It was found that more than 3000 genes were differentially expressed when these two strains were constantly exposed to a low dose of ionizing radiation and that half were regulated at least two fold in either direction. Functional analysis indicated that many genes for amino acid and carbohydrate metabolism and cell cycle progression were down-regulated and that a number of antioxidant genes and genes affecting membrane fluidity were up-regulated in both irradiated strains. However, the expression of ribosomal biogenesis genes was significantly up-regulated in the irradiated wild-type strain but not in the irradiated wdpks1 mutant, implying that melanin might help to contribute radiation energy for protein translation. Furthermore, we demonstrated that long-term exposure to low doses of radiation significantly increased survivability of both the wild-type and the wdpks1 mutant, which was correlated with reduced levels of reactive oxygen species (ROS, increased production of carotenoid and induced expression of genes encoding translesion DNA synthesis. Our results represent the first functional genomic study of how melanized fungal cells respond to low dose ionizing radiation and provide clues for the identification of biological processes, molecular pathways and

  18. Cellular graphene aerogel combines ultralow weight and high mechanical strength: A highly efficient reactor for catalytic hydrogenation

    Science.gov (United States)

    Zhang, Bingxing; Zhang, Jianling; Sang, Xinxin; Liu, Chengcheng; Luo, Tian; Peng, Li; Han, Buxing; Tan, Xiuniang; Ma, Xue; Wang, Dong; Zhao, Ning

    2016-01-01

    The construction of three-dimensional graphene aerogels (GAs) is of great importance owing to their outstanding properties for various applications. Up to now, the combination of ultralow weight and super mechanical strength for GA remains a great challenge. Here we demonstrate the fabrication of cellular GAs by a facile, easily controlled and versatile route, i.e. the chemical reduction of graphene oxide assemblies at oil-water interface under a mild condition (70 °C). The GA is ultralight (with density <3 mg cm−3) yet mechanically resilient because the walls of the cell closely pack in a highly ordered manner to maximize mechanical strength. The GA has been utilized as an appealing reactor for catalytic hydrogenation, which exhibited great advantages such as large oil absorption capability, exceptional catalytic activity, ease of product separation and high stability. PMID:27174450

  19. Cellular graphene aerogel combines ultralow weight and high mechanical strength: A highly efficient reactor for catalytic hydrogenation.

    Science.gov (United States)

    Zhang, Bingxing; Zhang, Jianling; Sang, Xinxin; Liu, Chengcheng; Luo, Tian; Peng, Li; Han, Buxing; Tan, Xiuniang; Ma, Xue; Wang, Dong; Zhao, Ning

    2016-01-01

    The construction of three-dimensional graphene aerogels (GAs) is of great importance owing to their outstanding properties for various applications. Up to now, the combination of ultralow weight and super mechanical strength for GA remains a great challenge. Here we demonstrate the fabrication of cellular GAs by a facile, easily controlled and versatile route, i.e. the chemical reduction of graphene oxide assemblies at oil-water interface under a mild condition (70 °C). The GA is ultralight (with density <3 mg cm(-3)) yet mechanically resilient because the walls of the cell closely pack in a highly ordered manner to maximize mechanical strength. The GA has been utilized as an appealing reactor for catalytic hydrogenation, which exhibited great advantages such as large oil absorption capability, exceptional catalytic activity, ease of product separation and high stability. PMID:27174450

  20. Cellular and circuit mechanisms maintain low spike co-variability and enhance population coding in somatosensory cortex

    Directory of Open Access Journals (Sweden)

    Cheng eLy

    2012-03-01

    Full Text Available The responses of cortical neurons are highly variable across repeated presentations of a stimulus. Understanding this variability is critical for theories of both sensory and motor processing, since response variance affects the accuracy of neural codes. Despite this influence, the cellular and circuit mechanisms that shape the trial-to-trial variability of population responses remain poorly understood. We used a combination of experimental and computational techniques to uncover the mechanisms underlying response variability of populations of pyramidal (E cells in layer 2/3 of rat whisker barrel cortex. Spike trains recorded from pairs of E-cells during either spontaneous activity or whisker deflected responses show similarly low levels of spiking co-variability, despite large differences in network activation between the two states. We developed network models that show how spike threshold nonlinearities dilutes E-cell spiking co-variability during spontaneous activity and low velocity whisker deflections. In contrast, during high velocity whisker deflections, cancelation mechanisms mediated by feedforward inhibition maintain low E-cell pairwise co-variability. Thus, the combination of these two mechanisms ensure low E-cell population variability over a wide range of whisker deflection velocities. Finally, we show how this active decorrelation of population variability leads to a drastic increase in the population information about whisker velocity. The canonical cellular and circuit components of our study suggest that low network variability over a broad range of neural states may generalize across the nervous system.

  1. Nanocrystallization kinetics under instantaneous growth approximation: Experiments and cellular automata simulations

    Energy Technology Data Exchange (ETDEWEB)

    Blazquez, J.S.; Millan, M.; Conde, C.F.; Conde, A. [Departamento de Fisica de la Materia Condensada, Universidad de Sevilla-ICMSE, P.O. Box 1065, 41080 Sevilla (Spain)

    2010-05-15

    Nanocrystallization kinetics is analyzed in the frame of instantaneous growth approximation, which implies that the time required for a crystallite to reach its final size is negligible with respect to the time required for the nanocrystallization process. This approach strongly simplifies the kinetic analysis and allows us to obtain the nucleation rate from both isothermal and non-isothermal nanocrystallization processes. Moreover, as no constraining mechanism is considered but the absence of growth, the results could be discussed in the frame of Johnson-Mehl-Avrami-Kolmogorov theory with a growth index equal to zero. Cellular automata simulations are in agreement with the observed kinetics and microstructure. (Abstract Copyright [2010], Wiley Periodicals, Inc.)

  2. Identification of the cellular mechanisms undelying the contribution of stress and glucocorticoids to Alzheimer's disease pathology

    OpenAIRE

    Sotiropoulos, Ioannis

    2006-01-01

    Clinical evidence suggests the involvement of stress and glucocorticoids (GC) in the etiopathogenesis of Alzheimer’s disease (AD), a disease marked by severe memory impairments as well as alterations in mood and emotional state. The experiments described in this dissertation represent an attempt to establish the cellular mechanisms through which stress and GC may impact on the development of AD. These studies focused on the hippocampus and prefrontal cortex (PFC), brain areas that are severel...

  3. Cellular Mechanisms of High Mobility Group 1 (HMGB-1) Protein Action in the Diabetic Retinopathy

    OpenAIRE

    Santos, Andrea Rachelle C.; Dvoriantchikova, Galina; Li, Yiwen; Mohammad, Ghulam; Abu El-Asrar, Ahmed M.; Wen, Rong; Ivanov, Dmitry

    2014-01-01

    Diabetic retinopathy is one of the main microvascular complications of diabetes and remains one of the leading causes of blindness worldwide. Recent studies have revealed an important role of inflammatory and proangiogenic high mobility group 1 (HMGB-1) cytokine in diabetic retinopathy. To elucidate cellular mechanisms of HMGB-1 activity in the retina, we performed this study. The histological features of diabetic retinopathy include loss of blood-vessel pericytes and endothelial cells, as we...

  4. Optimization of the diabetic nephropathy treatment with attention to the special features of cellular inflammation mechanisms

    OpenAIRE

    Щербань, Тетяна Дмитрівна

    2016-01-01

    Aim. Optimization of the diabetic nephropathy (DN) treatment in association with hypertonic disease (HD) based on the study of neutrophil chain of pathogenic cellular mechanisms of these diseases development and the special features of its clinical course.Materials and methods. There were complexly examined 86 patients with HD associated with DN and 30 patients with isolated HD. The control group was formed by 30 practically healthy persons. The activity of NO-synthases in neutrophils was det...

  5. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding

    OpenAIRE

    Tchoukalova, Yourka D.; Votruba, Susanne B; Tchkonia, Tamara; Giorgadze, Nino; Kirkland, James L.; Jensen, Michael D.

    2010-01-01

    Body fat distribution is an important predictor of the metabolic consequences of obesity, but the cellular mechanisms regulating regional fat accumulation are unknown. We assessed the changes in adipocyte size (photomicrographs) and number in response to overfeeding in upper- and lower-body s.c. fat depots of 28 healthy, normal weight adults (15 men) age 29 ± 2 y. We analyzed how these changes relate to regional fat gain (dual energy X-ray absorptiometry and computed tomography) and baseline ...

  6. Cellular and Molecular Mechanisms of Novel Therapies to Ameliorate Liver Sinusoidal Dysfunction in Cirrhotic Portal Hypertension

    OpenAIRE

    Marrone, Giusi

    2014-01-01

    Increased intrahepatic vascular resistance (IHVR), mainly due to elevated vascular tone together with the maturation of hepatic fibrosis and the drop of the hepatic endothelial function, is the main factor in the development of portal hypertension (PH) in cirrhosis. This PhD thesis investigates the cellular and molecular mechanisms necessary for the identification of new therapeutic targets and evaluates the possible cross- talk between the hepatic cells in static and physiological conditions...

  7. Cellular and molecular mechanisms of osteoporosis: current concepts and future direction treatment

    Directory of Open Access Journals (Sweden)

    A. T. Dolzhenko

    2016-01-01

    Full Text Available The article presents review of literature dedicated to the contemporary view on the cellular-molecular mechanisms of the bone remodeling and pathogenesis of the osteoporosis. The discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in process bone remodeling has made progress in understanding the mechanisms development disease and possible to development drugs of the new generation – denosumab, a fully human RANKL monoclonal antibody and inhibitor cathepsin K odanacatib that inhibits of the bone resorption.

  8. A computational model of cellular mechanisms of temporal coding in the medial geniculate body (MGB.

    Directory of Open Access Journals (Sweden)

    Cal F Rabang

    Full Text Available Acoustic stimuli are often represented in the early auditory pathway as patterns of neural activity synchronized to time-varying features. This phase-locking predominates until the level of the medial geniculate body (MGB, where previous studies have identified two main, largely segregated response types: Stimulus-synchronized responses faithfully preserve the temporal coding from its afferent inputs, and Non-synchronized responses, which are not phase locked to the inputs, represent changes in temporal modulation by a rate code. The cellular mechanisms underlying this transformation from phase-locked to rate code are not well understood. We use a computational model of a MGB thalamocortical neuron to test the hypothesis that these response classes arise from inferior colliculus (IC excitatory afferents with divergent properties similar to those observed in brain slice studies. Large-conductance inputs exhibiting synaptic depression preserved input synchrony as short as 12.5 ms interclick intervals, while maintaining low firing rates and low-pass filtering responses. By contrast, small-conductance inputs with Mixed plasticity (depression of AMPA-receptor component and facilitation of NMDA-receptor component desynchronized afferent inputs, generated a click-rate dependent increase in firing rate, and high-pass filtered the inputs. Synaptic inputs with facilitation often permitted band-pass synchrony along with band-pass rate tuning. These responses could be tuned by changes in membrane potential, strength of the NMDA component, and characteristics of synaptic plasticity. These results demonstrate how the same synchronized input spike trains from the inferior colliculus can be transformed into different representations of temporal modulation by divergent synaptic properties.

  9. Deformation Mechanisms of Gum Metals Under Nanoindentation

    Science.gov (United States)

    Sankaran, Rohini Priya

    defect structures to applied loading, we perform ex-situ nanoindentation. Nanoindentation is a convenient method as the plastic deformation is localized and probes a nominally defect free volume of the material. We subsequently characterize the defect structures in these alloys with both conventional TEM and advanced techniques such as HAADF HRSTEM and nanoprobe diffraction. These advanced techniques allow for a more thorough understanding of the observed deformation features. The main findings from this investigation are as follows. As expected we observe that a non-equilibrium phase, o, is present in the leaner beta-stabilized alloy, ST Ref-1. We do not find any direct evidence of secondary phases in STGM, and we find the beta phase in CWGM, along with lath microstructure with subgrain structure consisting of dislocation cell networks. Upon nanoindentation, we find twinning accompanied by beta nucleation on the twin boundary in ST Ref-1 samples. This result is consistent with previous findings and is reasonable considering the alloy is unstable with respect to beta transformation. We find deformation nanotwinning in cold worked gum metals under nanoindentation, which is initially surprising. We argue that when viewed as a nanocrystalline material, such a deformation mechanism is consistent with previous work, and furthermore, a deformation nanotwinned structure does not preclude an ideal shear mechanism from operating in the alloy. Lastly, we observe continuous lattice rotations in STGM under nanoindentation via nanoprobe diffraction. With this technique, for the first time we can demonstrate that the lattice rotations are truly continuous at the nanoscale. We can quantify this lattice rotation, and find that even though the rotation is large, it may be mediated by a reasonable geometrically necessary dislocation density, and note that similar rotations are typically observed in other materials under nanoindentation. HRSTEM and conventional TEM data confirm the

  10. Evolved Mechanisms Versus Underlying Conditional Relations

    Directory of Open Access Journals (Sweden)

    Astorga Miguel López

    2015-03-01

    Full Text Available The social contracts theory claims that, in social exchange circumstances, human reasoning is not necessarily led by logic, but by certain evolved mental mechanisms that are useful for catching offenders. An emblematic experiment carried out with the intention to prove this thesis is the first experiment described by Fiddick, Cosmides, and Tooby in their paper of 2000. Lopez Astorga has questioned that experiment claiming that its results depend on an underlying conditional logical form not taken into account by Fiddick, Cosmides, and Tooby. In this paper, I propose an explanation alternative to that of Lopez Astorga, which does not depend on logical forms and is based on the mental models theory. Thus, I conclude that this other alternative explanation is one more proof that the experiment in question does not demonstrate the fundamental thesis of the social contracts theory.

  11. An Underlying Geometrical Manifold for Hamiltonian Mechanics

    CERN Document Server

    Horwitz, L P; Levitan, J; Lewkowicz, M

    2015-01-01

    We show that there exists an underlying manifold with a conformal metric and compatible connection form, and a metric type Hamiltonian (which we call the geometrical picture) that can be put into correspondence with the usual Hamilton-Lagrange mechanics. The requirement of dynamical equivalence of the two types of Hamiltonians, that the momenta generated by the two pictures be equal for all times, is sufficient to determine an expansion of the conformal factor, defined on the geometrical coordinate representation, in its domain of analyticity with coefficients to all orders determined by functions of the potential of the Hamilton-Lagrange picture, defined on the Hamilton-Lagrange coordinate representation, and its derivatives. Conversely, if the conformal function is known, the potential of a Hamilton-Lagrange picture can be determined in a similar way. We show that arbitrary local variations of the orbits in the Hamilton-Lagrange picture can be generated by variations along geodesics in the geometrical pictu...

  12. Mechanisms underlying UV-induced immune suppression

    International Nuclear Information System (INIS)

    Skin cancer is the most prevalent form of human neoplasia. Estimates suggest that in excess of one million new cases of skin cancer will be diagnosed this year alone in the United States (www.cancer.org/statistics). Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer. The cost of treating non-melanoma skin cancer is estimated to be in excess of US$ 650 million a year [J.G. Chen, A.B. Fleischer, E.D. Smith, C. Kancler, N.D. Goldman, P.M. Williford, S.R. Feldman, Cost of non-melanoma skin cancer treatment in the United States, Dermatol. Surg. 27 (2001) 1035-1038], and when melanoma is included, the estimated cost of treating skin cancer in the United States is estimated to rise to US$ 2.9 billion annually (www.cancer.org/statistics). Because the morbidity and mortality associated with skin cancer is a major public health problem, it is important to understand the mechanisms underlying skin cancer development. The primary cause of skin cancer is the ultraviolet (UV) radiation found in sunlight. In addition to its carcinogenic potential, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. The focus of this manuscript will be to review the mechanisms underlying the induction of immune suppression following UV exposure. Particular attention will be directed to the role of soluble mediators in activating immune suppression

  13. Mechanisms underlying UV-induced immune suppression

    Energy Technology Data Exchange (ETDEWEB)

    Ullrich, Stephen E. [Department of Immunology, University of Texas, MD Anderson Cancer Center, South Campus Research Building 1, 7455 Fannin St., P.O. Box 301402, Houston, TX 77030-1903 (United States)]. E-mail: sullrich@mdanderson.org

    2005-04-01

    Skin cancer is the most prevalent form of human neoplasia. Estimates suggest that in excess of one million new cases of skin cancer will be diagnosed this year alone in the United States (www.cancer.org/statistics). Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer. The cost of treating non-melanoma skin cancer is estimated to be in excess of US$ 650 million a year [J.G. Chen, A.B. Fleischer, E.D. Smith, C. Kancler, N.D. Goldman, P.M. Williford, S.R. Feldman, Cost of non-melanoma skin cancer treatment in the United States, Dermatol. Surg. 27 (2001) 1035-1038], and when melanoma is included, the estimated cost of treating skin cancer in the United States is estimated to rise to US$ 2.9 billion annually (www.cancer.org/statistics). Because the morbidity and mortality associated with skin cancer is a major public health problem, it is important to understand the mechanisms underlying skin cancer development. The primary cause of skin cancer is the ultraviolet (UV) radiation found in sunlight. In addition to its carcinogenic potential, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. The focus of this manuscript will be to review the mechanisms underlying the induction of immune suppression following UV exposure. Particular attention will be directed to the role of soluble mediators in activating immune suppression.

  14. Patterns and Cellular Mechanisms of Arm Regeneration in Adult Starfish Asterias rollestoni Bell

    Institute of Scientific and Technical Information of China (English)

    FAN Tingjun; FAN Xianyuan; DU Yutang; SUN Wenjie; ZHANG Shaofeng; LI Jiaxin

    2011-01-01

    To understand the mechanisms of starfish regeneration,the arms of adult starfish Asterias rollestoni Bell were amputated and their regeneration pattems and cellular mechanisms were studied.It was found that cells in the outer epidermis and inner parietal peritoneum near the end of the stump began to dedifferentiate 4d after amputation.The dedifferentiated cells in the outer epidermis proliferated,migrated to the wound site and formed a thickened pre-epidermis which would then re-differentiate gradually into mature epidermis.The new parietal peritoneum formed on the coelomic side of wound might be from the curvely elongated parietal peritoneum,resulting from the dedifferentiated and proliferated cells by extension.Afterwards,the proliferated cells made the outer epidermis and inner parietal peritoneum invaginate into the interior dermis and formed blastema-like structures together with induced dedifferentiated dermal cells.Most interestingly,the arm regeneration in A.rollestoni was achieved synchronously by de novo arm-bud formation and growth,and arm-stump elongation.The crucial aspects of arm-bud formation included cell dedifferentiation,proliferation and migration,while those of arm-stump elongation included cell dedifferentiation,proliferation,invagination,and arm-wall-across blastema-like structure formation.The unique pattern and cellular mechanisms of amputated arm regeneration make it easier to understand the rapid regeneration process of adult starfish.This study may lay solid foundations for the research into molecular mechanisms of echinoderm regeneration.

  15. Mechanical buckling of veins under internal pressure.

    Science.gov (United States)

    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

  16. Cellular graphene aerogel combines ultralow weight and high mechanical strength: A highly efficient reactor for catalytic hydrogenation

    Science.gov (United States)

    Zhang, Bingxing; Zhang, Jianling; Sang, Xinxin; Liu, Chengcheng; Luo, Tian; Peng, Li; Han, Buxing; Tan, Xiuniang; Ma, Xue; Wang, Dong; Zhao, Ning

    2016-05-01

    The construction of three-dimensional graphene aerogels (GAs) is of great importance owing to their outstanding properties for various applications. Up to now, the combination of ultralow weight and super mechanical strength for GA remains a great challenge. Here we demonstrate the fabrication of cellular GAs by a facile, easily controlled and versatile route, i.e. the chemical reduction of graphene oxide assemblies at oil-water interface under a mild condition (70 °C). The GA is ultralight (with density resilient because the walls of the cell closely pack in a highly ordered manner to maximize mechanical strength. The GA has been utilized as an appealing reactor for catalytic hydrogenation, which exhibited great advantages such as large oil absorption capability, exceptional catalytic activity, ease of product separation and high stability.

  17. Two distinct neural mechanisms underlying indirect reciprocity.

    Science.gov (United States)

    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

  18. DMPD: Anti-inflammatory actions of PPAR ligands: new insights on cellular andmolecular mechanisms. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17981503 Anti-inflammatory actions of PPAR ligands: new insights on cellular andmol...) (.html) (.csml) Show Anti-inflammatory actions of PPAR ligands: new insights on cellular andmolecular mech...anisms. PubmedID 17981503 Title Anti-inflammatory actions of PPAR ligands: new in

  19. Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness

    International Nuclear Information System (INIS)

    The evolutionary-conserved interactions between KASH and SUN domain-containing proteins within the perinuclear space establish physical connections, called LINC complexes, between the nucleus and the cytoskeleton. Here, we show that the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. These constructs disrupt endogenous LINC complexes as indicated by the displacement of endogenous Nesprins from the nuclear envelope. We also provide evidence that KASH domains most probably fit a pocket provided by SUN domains and that post-translational modifications are dispensable for that interaction. We demonstrate that the disruption of endogenous LINC complexes affect cellular mechanical stiffness to an extent that compares to the loss of mechanical stiffness previously reported in embryonic fibroblasts derived from mouse lacking A-type lamins, a mouse model of muscular dystrophies and cardiomyopathies. These findings support a model whereby physical connections between the nucleus and the cytoskeleton are mediated by interactions between diverse combinations of Sun proteins and Nesprins through their respective evolutionary-conserved domains. Furthermore, they emphasize, for the first time, the relevance of LINC complexes in cellular mechanical stiffness suggesting a possible involvement of their disruption in various laminopathies, a group of human diseases linked to mutations of A-type lamins

  20. Cellular and molecular investigations of the adhesion and mechanics of Listeria monocytogenes

    Science.gov (United States)

    Eskhan, Asma Omar

    Atomic force microscopy has been used to quantify the adherence and mechanical properties of an array of L. monocytogenes strains and their surface biopolymers. First, eight L. monocytogenes strains that represented the two major lineages of the species were compared for their adherence and mechanics at cellular and molecular levels. Our results indicated that strains of lineage' II were characterized by higher adhesion and Young's moduli, longer and more rigid surface biopolymers and lower specific and nonspecific forces when compared to lineage' I strains. Additionally, adherence and mechanical properties of eight L. monocytogenes epidemic and environmental strains were probed. Our results pointed to that environmental and epidemic strains representative of a given lineage were similar in their adherence and mechanical properties when investigated at a cellular level. However, when the molecular properties of the strains were considered, epidemic strains were characterized by higher specific and nonspecific forces, shorter, denser and more flexible biopolymers compared to environmental strains. Second, the role of environmental pH conditions of growth on the adhesion and mechanics of a pathogenic L. monocytogenes EGDe was investigated. Our results pointed to a transition in the adhesion energies for cells cultured at pH 7. In addition, when the types of molecular forces that govern the adhesion were quantified using Poisson statistical approach and using a new proposed method, specific hydrogen-bond energies dominated the bacterial adhesion process. Such a finding is instrumental to researchers designing methods to control bacterial adhesion. Similarly, bacterial cells underwent a transition in their mechanical properties. We have shown that cells cultured at pH 7 were the most rigid compared to those cultured in lower or higher pH conditions of growth. Due to transitions observed in adherence and mechanics when cells were cultured at pH 7, we hypothesized that

  1. In vitro kinetic studies on the mechanism of oxygen-dependent cellular uptake of copper radiopharmaceuticals

    International Nuclear Information System (INIS)

    The development of hypoxia-selective radiopharmaceuticals for use as therapeutic and/or imaging agents is of vital importance for both early identification and treatment of cancer and in the design of new drugs. Radiotracers based on copper for use in positron emission tomography have received great attention due to the successful application of copper(II) bis(thiosemicarbazonato) complexes, such as [60/62/64Cu(II)ATSM] and [60/62/64Cu(II)PTSM], as markers for tumour hypoxia and blood perfusion, respectively. Recent work has led to the proposal of a revised mechanism of hypoxia-selective cellular uptake and retention of [Cu(II)ATSM]. The work presented here describes non-steady-state kinetic simulations in which the reported pO2-dependent in vitro cellular uptake and retention of [64Cu(II)ATSM] in EMT6 murine carcinoma cells has been modelled by using the revised mechanistic scheme. Non-steady-state (NSS) kinetic analysis reveals that the model is in very good agreement with the reported experimental data with a root-mean-squared error of less than 6% between the simulated and experimental cellular uptake profiles. Estimated rate constants are derived for the cellular uptake and washout (k1 = 9.8 ± 0.59 x 10-4 s-1 and k2 = 2.9 ± 0.17 x 10-3 s-1), intracellular reduction (k3 = 5.2 ± 0.31 x 10-2 s-1), reoxidation (k4 = 2.2 ± 0.13 mol-1 dm3 s-1) and proton-mediated ligand dissociation (k5 = 9.0 ± 0.54 x 10-5 s-1). Previous mechanisms focused on the reduction and reoxidation steps. However, the data suggest that the origins of hypoxia-selective retention may reside with the stability of the copper(I) anion with respect to protonation and ligand dissociation. In vitro kinetic studies using the nicotimamide adenine dinucleotide (NADH)-dependent ferredoxin reductase enzyme PuR isolated from the bacterium Rhodopseudomonas palustris have also been conducted. NADH turnover frequencies are found to be dependent on the structure of the ligand and the results confirm that

  2. Cellular automaton simulation of microstructure evolution during austenite decomposition under continuous cooling conditions

    Indian Academy of Sciences (India)

    M R Varma; R Sasikumar; S G K Pillai; P K Nair

    2001-06-01

    A two-dimensional diffusion based model is developed to describe transformation of austenite into ferrite and pearlite under continuous cooling conditions. The nucleation of ferrite is assumed to occur over grain boundaries and the nucleation of pearlite is assumed to be taking place all over the grain and at growing ferrite–austenite interfaces, when the composition and temperature conditions are favourable. A cellular automaton algorithm, with transformation rules based on this model is used for the growth of ferrite and pearlite. Model predicted results for continuous cooling transformations are verified by comparing the model predicted microstructure features with the experimental measurements for two sets of plain carbon steels of different composition and austenite grain size. Using the model, it is possible to generate results like undercooling to start ferrite and pearlite transformations, which are difficult to obtain experimentally.

  3. A mathematical model in cellular manufacturing system considering subcontracting approach under constraints

    Directory of Open Access Journals (Sweden)

    Kamran Forghani

    2012-10-01

    Full Text Available In this paper, a new mathematical model in cellular manufacturing systems (CMSs has been presented. In order to increase the performance of manufacturing system, the production quantity of parts has been considered as a decision variable, i.e. each part can be produced and outsourced, simultaneously. This extension would be minimized the unused capacity of machines. The exceptional elements (EEs are taken into account and would be totally outsourced to the external supplier in order to remove intercellular material handling cost. The problem has been formulated as a mixed-integer programming to minimize the sum of manufacturing variable costs under budget, machines capacity and demand constraints. Also, to evaluate advantages of the model, several illustrative numerical examples have been provided to compare the performance of the proposed model with the available classical approaches in the literature.

  4. Vascular Adventitia Calcification and Its Underlying Mechanism.

    Directory of Open Access Journals (Sweden)

    Na Li

    Full Text Available Previous research on vascular calcification has mainly focused on the vascular intima and media. However, we show here that vascular calcification may also occur in the adventitia. The purpose of this work is to help elucidate the pathogenic mechanisms underlying vascular calcification. The calcified lesions were examined by Von Kossa staining in ApoE-/- mice which were fed high fat diets (HFD for 48 weeks and human subjects aged 60 years and older that had died of coronary heart disease, heart failure or acute renal failure. Explant cultured fibroblasts and smooth muscle cells (SMCswere obtained from rat adventitia and media, respectively. After calcification induction, cells were collected for Alizarin Red S staining. Calcified lesions were observed in the aorta adventitia and coronary artery adventitia of ApoE-/-mice, as well as in the aorta adventitia of human subjects examined. Explant culture of fibroblasts, the primary cell type comprising the adventitia, was successfully induced for calcification after incubation with TGF-β1 (20 ng/ml + mineralization media for 4 days, and the phenotype conversion vascular adventitia fibroblasts into myofibroblasts was identified. Culture of SMCs, which comprise only a small percentage of all cells in the adventitia, in calcifying medium for 14 days resulted in significant calcification.Vascular calcification can occur in the adventitia. Adventitia calcification may arise from the fibroblasts which were transformed into myofibroblasts or smooth muscle cells.

  5. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

    International Nuclear Information System (INIS)

    Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: ► Endothelial cells mount a stress response under conditions of low serum. ► Endothelial VEGFR levels are

  6. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

    Energy Technology Data Exchange (ETDEWEB)

    Latham, Antony M.; Odell, Adam F. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Mughal, Nadeem A. [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Issitt, Theo; Ulyatt, Clare; Walker, John H. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Homer-Vanniasinkam, Shervanthi [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Ponnambalam, Sreenivasan, E-mail: s.ponnambalam@leeds.ac.uk [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom)

    2012-11-01

    Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: Black-Right-Pointing-Pointer Endothelial cells mount a stress response under conditions of low serum. Black

  7. Distinct cellular mechanisms of blood vessel fusion in the zebrafish embryo.

    Science.gov (United States)

    Herwig, Lukas; Blum, Yannick; Krudewig, Alice; Ellertsdottir, Elin; Lenard, Anna; Belting, Heinz-Georg; Affolter, Markus

    2011-11-22

    Although many of the cellular and molecular mechanisms of angiogenesis have been intensely studied [1], little is known about the processes that underlie vascular anastomosis. We have generated transgenic fish lines expressing an EGFP-tagged version of the junctional protein zona occludens 1 (ZO1) to visualize individual cell behaviors that occur during vessel fusion and lumen formation in vivo. These life observations show that endothelial cells (ECs) use two distinct morphogenetic mechanisms, cell membrane invagination and cord hollowing to generate different types of vascular tubes. During initial steps of anastomosis, cell junctions that have formed at the initial site of cell contacts expand into rings, generating a cellular interface of apical membrane compartments, as defined by the localization of the apical marker podocalyxin-2 (Pdxl2). During the cord hollowing process, these apical membrane compartments are brought together via cell rearrangements and extensive junctional remodeling, resulting in lumen coalescence and formation of a multicellular tube. Vessel fusion by membrane invagination occurs adjacent to a preexisting lumen in a proximal to distal direction and is blood-flow dependent. Here, the invaginating inner cell membrane undergoes concomitant apicobasal polarization and the vascular lumen is formed by the extension of a transcellular lumen through the EC, which forms a unicellular or seamless tube. PMID:22079115

  8. The biocompatibility of fluorescent nanodiamonds and their mechanism of cellular uptake

    Science.gov (United States)

    Vaijayanthimala, Vairakkannu; Tzeng, Yan-Kai; Chang, Huan-Cheng; Li, Chung-Leung

    2009-10-01

    The labeling of cells with fluorescent nanoparticles is promising for various biomedical applications. The objective of this study is to evaluate the biocompatibility and the mechanism of the cellular uptake of fluorescent nanodiamonds (FNDs) in cancer cells (HeLa) and pre-adipocytes (3T3-L1). With flow cytometry and the use of a battery of metabolic and cytoskeletal inhibitors, we found that the mechanism of the FND uptake in both cells is by energy-dependent clathrin-mediated endocytosis. In addition, the surface charge of FND influences its cellular uptake, as the uptake of poly-L-lysine-coated FNDs is better than that of oxidative-acid-purified FNDs at the same concentration in regular medium with or without serum. We also confirm that the proliferative potential of FND-treated and untreated cells does not exhibit any significant differences when measured at bulk cultures, and more stringently at clonal cell density. Further biocompatibility studies indicate that the in vitro differentiation of 3T3-L1 pre-adipocytes and 489-2 osteoprogenitors is not affected by the FND treatment. Our results show that FNDs are biocompatible and ideal candidates for potential applications in human stem cell research.

  9. The mechanics of cellular compartmentalization as a model for tumor spreading

    Science.gov (United States)

    Fritsch, Anatol; Pawlizak, Steve; Zink, Mareike; Kaes, Josef A.

    2012-02-01

    Based on a recently developed surgical method of Michael H"ockel, which makes use of cellular confinement to compartments in the human body, we study the mechanics of the process of cell segregation. Compartmentalization is a fundamental process of cellular organization and occurs during embryonic development. A simple model system can demonstrate the process of compartmentalization: When two populations of suspended cells are mixed, this mixture will eventually segregate into two phases, whereas mixtures of the same cell type will not. In the 1960s, Malcolm S. Steinberg formulated the so-called differential adhesion hypothesis which explains the segregation in the model system and the process of compartmentalization by differences in surface tension and adhesiveness of the interacting cells. We are interested in to which extend the same physical principles affect tumor growth and spreading between compartments. For our studies, we use healthy and cancerous breast cell lines of different malignancy as well as primary cells from human cervix carcinoma. We apply a set of techniques to study their mechanical properties and interactions. The Optical Stretcher is used for whole cell rheology, while Cell-cell-adhesion forces are directly measured with a modified AFM. In combination with 3D segregation experiments in droplet cultures we try to clarify the role of surface tension in tumor spreading.

  10. On the effects of geometry, defects, and material asymmetry on the mechanical response of shape memory alloy cellular lattice structures

    Science.gov (United States)

    Karamooz Ravari, M. R.; Nasr Esfahani, S.; Taheri Andani, M.; Kadkhodaei, M.; Ghaei, A.; Karaca, H.; Elahinia, M.

    2016-02-01

    Shape memory alloy (such as NiTi) cellular lattice structures are a new class of advanced materials with many potential applications. The cost of fabrication of these structures however is high. It is therefore necessary to develop modeling methods to predict the functional behavior of these alloys before fabrication. The main aim of the present study is to assess the effects of geometry, microstructural imperfections and material asymmetric response of dense shape memory alloys on the mechanical response of cellular structures. To this end, several cellular and dense NiTi samples are fabricated using a selective laser melting process. Both cellular and dense specimens were tested in compression in order to obtain their stress-strain response. For modeling purposes, a three -dimensional (3D) constitutive model based on microplane theory which is able to describe the material asymmetry was employed. Five finite element models based on unit cell and multi-cell methods were generated to predict the mechanical response of cellular lattices. The results show the considerable effects of the microstructural imperfections on the mechanical response of the cellular lattice structures. The asymmetric material response of the bulk material also affects the mechanical response of the corresponding cellular structure.

  11. Early Passage Dependence of Mesenchymal Stem Cell Mechanics Influences Cellular Invasion and Migration.

    Science.gov (United States)

    Spagnol, Stephen T; Lin, Wei-Chun; Booth, Elizabeth A; Ladoux, Benoit; Lazarus, Hillard M; Dahl, Kris Noel

    2016-07-01

    The cellular structures and mechanical properties of human mesenchymal stem cells (hMSCs) vary significantly during culture and with differentiation. Previously, studies to measure mechanics have provided divergent results using different quantitative parameters and mechanical models of deformation. Here, we examine hMSCs prepared for clinical use and subject them to mechanical testing conducive to the relevant deformability associated with clinical injection procedures. Micropipette aspiration of hMSCs shows deformation as a viscoelastic fluid, with little variation from cell to cell within a population. After two passages, hMSCs deform as viscoelastic solids. Further, for clinical applicability during stem cell migration in vivo, we investigated the ability of hMSCs to invade into micropillar arrays of increasing confinement from 12 to 8 μm spacing between adjacent micropillars. We find that hMSC samples with reduced deformability and cells that are more solid-like with passage are more easily able to enter the micropillar arrays. Increased cell fluidity is an advantage for injection procedures and optimization of cell selection based on mechanical properties may enhance efficacy of injected hMSC populations. However, the ability to invade and migrate within tight interstitial spaces appears to be increased with a more solidified cytoskeleton, likely from increased force generation and contractility. Thus, there may be a balance between optimal injection survival and in situ tissue invasion. PMID:26581348

  12. Finite element analysis of the mechanical properties of cellular aluminium based on micro-computed tomography

    International Nuclear Information System (INIS)

    Research highlights: → Elastic and plastic anisotropy is observed for both materials → Both show qualitatively similar characteristics with quantitative differences → Distinctly higher mechanical properties for closed-cell foam → The 'big' and 'small' models show good agreement for the closed-cell foam. - Abstract: In the present paper, the macroscopic mechanical properties of open-cell M-Pore sponge (porosity of 91-93%) and closed-cell Alporas foam (porosity of 80-86%) are investigated. The complex geometry of these cellular materials is scanned by micro-computed tomography and used in finite element (FE) analysis. The mechanical properties are determined by uni-axial compression simulations in three perpendicular directions (x-, y- and z-direction). M-Pore and Alporas exhibit the same qualitative mechanical characteristics but with quantitative differences. In both cases, strong anisotropy is observed for Young's modulus and the 0.002 offset yield stress. Furthermore, for the investigated relative density range a linear dependence between relative density and mechanical properties is found. Finally, a distinctly higher Young's modulus and 0.002 offset yield stress is observed for Alporas.

  13. Robust mechanisms of ventral furrow invagination require the combination of cellular shape changes

    International Nuclear Information System (INIS)

    Ventral furrow formation in Drosophila is the first large-scale morphogenetic movement during the life of the embryo, and is driven by co-ordinated changes in the shape of individual epithelial cells within the cellular blastoderm. Although many of the genes involved have been identified, the details of the mechanical processes that convert local changes in gene expression into whole-scale changes in embryonic form remain to be fully understood. Biologists have identified two main cell deformation modes responsible for ventral furrow invagination: constriction of the apical ends of the cells (apical wedging) and deformation along their apical–basal axes (radial lengthening/shortening). In this work, we used a computer 2D finite element model of ventral furrow formation to investigate the ability of different combinations of three plausible elementary active cell shape changes to bring about epithelial invagination: ectodermal apical–basal shortening, mesodermal apical–basal lengthening/shortening and mesodermal apical constriction. We undertook a systems analysis of the biomechanical system, which revealed many different combinations of active forces (invagination mechanisms) were able to generate a ventral furrow. Two important general features were revealed. First that combinations of shape changes are the most robust to environmental and mutational perturbation, in particular those combining ectodermal pushing and mesodermal wedging. Second, that ectodermal pushing plays a big part in all of the robust mechanisms (mesodermal forces alone do not close the furrow), and this provides evidence that it may be an important element in the mechanics of invagination in Drosophila

  14. Effects of Mechanical Properties on Tumor Invasion: Insights from a Cellular Model

    KAUST Repository

    Li, YZ

    2014-08-01

    Understanding the regulating mechanism of tumor invasion is of crucial importance for both fundamental cancer research and clinical applications. Previous in vivo experiments have shown that invasive cancer cells dissociate from the primary tumor and invade into the stroma, forming an irregular invasive morphology. Although cell movements involved in tumor invasion are ultimately driven by mechanical forces of cell-cell interactions and tumor-host interactions, how these mechanical properties affect tumor invasion is still poorly understood. In this study, we use a recently developed two-dimensional cellular model to study the effects of mechanical properties on tumor invasion. We study the effects of cell-cell adhesions as well as the degree of degradation and stiffness of extracellular matrix (ECM). Our simulation results show that cell-cell adhesion relationship must be satisfied for tumor invasion. Increased adhesion to ECM and decreased adhesion among tumor cells result in invasive tumor behaviors. When this invasive behavior occurs, ECM plays an important role for both tumor morphology and the shape of invasive cancer cells. Increased stiffness and stronger degree of degradation of ECM promote tumor invasion, generating more aggressive tumor invasive morphologies. It can also generate irregular shape of invasive cancer cells, protruding towards ECM. The capability of our model suggests it a useful tool to study tumor invasion and might be used to propose optimal treatment in clinical applications.

  15. The Signaling Mechanisms Underlying Cell Polarity and Chemotaxis

    OpenAIRE

    Wang, Fei

    2009-01-01

    Chemotaxis—the directed movement of cells in a gradient of chemoattractant—is essential for neutrophils to crawl to sites of inflammation and infection and for Dictyostelium discoideum (D. discoideum) to aggregate during morphogenesis. Chemoattractant-induced activation of spatially localized cellular signals causes cells to polarize and move toward the highest concentration of the chemoattractant. Extensive studies have been devoted to achieving a better understanding of the mechanism(s) use...

  16. Cellular intrinsic mechanism affecting the outcome of AML treated with Ara-C in a syngeneic mouse model.

    Directory of Open Access Journals (Sweden)

    Wenjun Zhao

    Full Text Available The mechanisms underlying acute myeloid leukemia (AML treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.

  17. Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death.

    Science.gov (United States)

    Narayanan, Kannan Badri; Ali, Manaf; Barclay, Barry J; Cheng, Qiang Shawn; D'Abronzo, Leandro; Dornetshuber-Fleiss, Rita; Ghosh, Paramita M; Gonzalez Guzman, Michael J; Lee, Tae-Jin; Leung, Po Sing; Li, Lin; Luanpitpong, Suidjit; Ratovitski, Edward; Rojanasakul, Yon; Romano, Maria Fiammetta; Romano, Simona; Sinha, Ranjeet K; Yedjou, Clement; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G; Ryan, Elizabeth P; Colacci, Annamaria; Hamid, Roslida A; Mondello, Chiara; Raju, Jayadev; Salem, Hosni K; Woodrick, Jordan; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Kim, Seo Yun; Bisson, William H; Lowe, Leroy; Park, Hyun Ho

    2015-06-01

    Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis. PMID:26106145

  18. Mechanism of cellular uptake and impact of ferucarbotran on macrophage physiology.

    Directory of Open Access Journals (Sweden)

    Chung-Yi Yang

    Full Text Available Superparamagnetic iron oxide (SPIO nanoparticles are contrast agents used for magnetic resonance imaging. Ferucarbotran is a clinically approved SPIO-coated carboxydextran with a diameter of about 45-60 nm. We investigated the mechanism of cellular uptake of Ferucarbotran with a cell model using the murine macrophage cell line Raw 264.7. We observed a dose-dependent uptake of these SPIO particles by spectrophotometer analysis and also a dose-dependent increase in the granularity of the macrophages as determined by flow cytometry. There was a linear correlation between the side scattering mean value and iron content (P<0.001, R(2 = 0. 8048. For evaluation of the endocytotic pathway of these ingested SPIO particles, different inhibitors of the endocytotic pathways were employed. There was a significant decrease of side scattering counts in the cells and a less significant change in signal intensity based on magnetic resonance in the phenylarsine oxide-treated macrophages. After labeling with SPIO particles, the macrophages showed an increase in the production of reactive oxygen species at 2, 24, and 48 h; a decrease in mitochondrial membrane potential at 24 h; and an increase in cell proliferation at 24 h. We concluded that Ferucarbotran was internalized into macrophages via the clathrin-mediated pathway and can change the cellular behavior of these cells after labeling.

  19. Contribution of glutathione to the control of cellular redox homeostasis under toxic metal and metalloid stress.

    Science.gov (United States)

    Hernández, Luis E; Sobrino-Plata, Juan; Montero-Palmero, M Belén; Carrasco-Gil, Sandra; Flores-Cáceres, M Laura; Ortega-Villasante, Cristina; Escobar, Carolina

    2015-05-01

    The accumulation of toxic metals and metalloids, such as cadmium (Cd), mercury (Hg), or arsenic (As), as a consequence of various anthropogenic activities, poses a serious threat to the environment and human health. The ability of plants to take up mineral nutrients from the soil can be exploited to develop phytoremediation technologies able to alleviate the negative impact of toxic elements in terrestrial ecosystems. However, we must select plant species or populations capable of tolerating exposure to hazardous elements. The tolerance of plant cells to toxic elements is highly dependent on glutathione (GSH) metabolism. GSH is a biothiol tripeptide that plays a fundamental dual role: first, as an antioxidant to mitigate the redox imbalance caused by toxic metal(loid) accumulation, and second as a precursor of phytochelatins (PCs), ligand peptides that limit the free ion cellular concentration of those pollutants. The sulphur assimilation pathway, synthesis of GSH, and production of PCs are tightly regulated in order to alleviate the phytotoxicity of different hazardous elements, which might induce specific stress signatures. This review provides an update on mechanisms of tolerance that depend on biothiols in plant cells exposed to toxic elements, with a particular emphasis on the Hg-triggered responses, and considering the contribution of hormones to their regulation. PMID:25750419

  20. A knock-in model of human epilepsy in Drosophila reveals a novel cellular mechanism associated with heat-induced seizure

    OpenAIRE

    Sun, Lei; Gilligan, Jeff; Staber, Cynthia; Schutte, Ryan J; Nguyen, Vivian; O'Dowd, Diane K.; Reenan, Robert

    2012-01-01

    Over 40 missense mutations in the human SCN1A sodium channel gene are linked to an epilepsy syndrome termed genetic epilepsy with febrile seizures plus (GEFS+). Inheritance of GEFS+ is dominant but the underlying cellular mechanisms remain poorly understood. Here we report knock-in of a GEFS+ SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semi-dominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains o...

  1. Cellular origin and developmental mechanisms during the formation of skin melanocytes

    Energy Technology Data Exchange (ETDEWEB)

    Ernfors, Patrik, E-mail: patrik.ernfors@ki.se [Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm (Sweden)

    2010-05-01

    Melanocytes are derived from the neural crest (NC), which are transient multipotent cells arising by delamination from the developing dorsal neural tube. During recent years, signaling systems and molecular mechanisms of melanocyte development have been studied in detail, but the exact diversification of the NC into melanocytes and how they migrate, expand and disperse in the skin have not been fully understood. The recent finding that Schwann cell precursors (SCPs) of the growing nerve represents a stem cell niche from which various cell types, including Schwann cells, endoneural fibroblasts and melanocytes arise has exposed new knowledge on the cellular basis for melanocyte development. This opens for the identification of new factors and reinterpretation of old data on cell fate instructive, proliferative, survival and cell homing factors participating in melanocyte development.

  2. Beyond membrane channelopathies: alternative mechanisms underlying complex human disease

    Institute of Scientific and Technical Information of China (English)

    Konstantinos Dean BOUDOULAS; Peter J MOHLER

    2011-01-01

    Over the past fifteen years, our understanding of the molecular mechanisms underlying human disease has flourished in large part due to the discovery of gene mutations linked with membrane ion channels and transporters. In fact, ion channel defects ("channelopathies" - the focus of this review series) have been associated with a spectrum of serious human disease phenotypes including cystic fibrosis, cardiac arrhythmia, diabetes, skeletal muscle defects, and neurological disorders. However, we now know that human disease, particularly excitable cell disease, may be caused by defects in non-ion channel polypeptides including in cellular components residing well beneath the plasma membrane. For example, over the past few years, a new class of potentially fatal cardiac arrhythmias has been linked with cytoplasmic proteins that include sub-membrane adapters such as ankyrin-B (ANK2),ankyrin-G (ANK3), and alpha-1 syntrophin, membrane coat proteins including caveolin-3 (CAV3), signaling platforms including yotiao (AKAPg), and cardiac enzymes (GPD1L). The focus of this review is to detail the exciting role of lamins, yet another class of gene products that have provided elegant new insight into human disease.

  3. Electrospun PCL/Gelatin composite fibrous scaffolds: mechanical properties and cellular responses.

    Science.gov (United States)

    Yao, Ruijuan; He, Jing; Meng, Guolong; Jiang, Bo; Wu, Fang

    2016-06-01

    Electrospinning of hybrid polymer has gained widespread interest by taking advantages of the biological property of the natural polymer and the mechanical property of the synthetic polymer. However, the effect of the blend ratio on the above two properties has been less reported despite the importance to balance these two properties in various tissue engineering applications. To this aim, we investigated the electrospun PCL/Gelatin composite fibrous scaffolds with different blend ratios of 4:1, 2:1, 1:1, 1:2, 1:4, respectively. The morphology of the electrospun samples was observed by SEM and the result showed that the fiber diameter distribution became more uniform with the increase of the gelatin content. The mechanical testing results indicated that the 2:1 PCL/Gelatin sample had both the highest tensile strength of 3.7 MPa and the highest elongation rate of about 90%. Surprisingly, the 2:1 PCL/Gelatin sample also showed the best mesenchymal stem cell responses in terms of attachment, spreading, and cytoskeleton organization. Such correlation might be partly due to the fact that the enhanced mechanical property, an integral part of the physical microenvironment, likely played an important role in regulating the cellular functions. Overall, our results indicated that the PCL/Gelatin sample with the blend ratio of 2:1 was a superior candidate for scaffolds for tissue engineering applications. PMID:27044505

  4. Cellular Mechanism of Inner Ear Genetic Disease, roles of Kv7.1 (KCNQ1) Channel

    Science.gov (United States)

    Mousavi Nik, Atefeh

    Potassium channels are the most diverse and widely distributed membrane protein in all living organisms. They have various roles in the body such as controlling membrane potential, cell volume, and cell migration. Many studies have shown that mutation in these channels is associated with different diseases for example: Hearing Defect, Cardiac Arrhythmia, Episodic Ataxia, Seizure and Neuromyotonia. One of the most important diseases associated with K+ channel mutations is called Jervell and Lange-Nielsen syndrome (JLNS). This disease causes bilateral congenital deafness and the patients also suffer from Long QT and they usually experience syncopal episodes in their life and eventually die as a result of cardiac arrest. The gene KCNQ1 encodes the Kv7.1 voltage gated potassium channel. This channel expresses in apical membrane of marginal cell in stria vasularis of cochlea and secret K+ ion to endolymp to keep the endocochlear potential stable, which is necessary for the inner ear to function properly. Kv7.1 channel also expresses in cardiac myocytes and mutation in this gene is associated with another syndrome called Romano-Ward syndrome (RWS). Although Romano-Ward patients have mutation in KCNQ1, similar to Jervell and Lange-Nielsen patients, they only suffer from cardiac defect, and their hearing is completely normal. Several studies identified that mutations in Kv7.1 gene is associated with JLNS and RWS, but the biophysical and cellular mechanisms of these mutations are still unknown. To determine the cellular mechanisms of JLNS and RWS, and to provide mechanistic insight on the functional outputs of JLNS versus RWS mutations, we generated several mutant forms of the human Kv7.1 ( KCNQ1) clone, using site-directed mutagenesis to define their sub-cellular localization and examined their electrophysiological properties. We identified JLNS and RWS mutations at the S4-S5-linker, the pore loop (P-loop) and the C-terminus of hKv7.1 which have been found to control

  5. Cellular Interrogation: Exploiting Cell-to-Cell Variability to Discriminate Regulatory Mechanisms in Oscillatory Signalling

    Science.gov (United States)

    Gibson, Daniel; Chang, Frederick; Gnad, Florian; Gunawardena, Jeremy

    2016-01-01

    The molecular complexity within a cell may be seen as an evolutionary response to the external complexity of the cell’s environment. This suggests that the external environment may be harnessed to interrogate the cell’s internal molecular architecture. Cells, however, are not only nonlinear and non-stationary, but also exhibit heterogeneous responses within a clonal, isogenic population. In effect, each cell undertakes its own experiment. Here, we develop a method of cellular interrogation using programmable microfluidic devices which exploits the additional information present in cell-to-cell variation, without requiring model parameters to be fitted to data. We focussed on Ca2+ signalling in response to hormone stimulation, which exhibits oscillatory spiking in many cell types and chose eight models of Ca2+ signalling networks which exhibit similar behaviour in simulation. We developed a nonlinear frequency analysis for non-stationary responses, which could classify models into groups under parameter variation, but found that this question alone was unable to distinguish critical feedback loops. We further developed a nonlinear amplitude analysis and found that the combination of both questions ruled out six of the models as inconsistent with the experimentally-observed dynamics and heterogeneity. The two models that survived the double interrogation were mathematically different but schematically identical and yielded the same unexpected predictions that we confirmed experimentally. Further analysis showed that subtle mathematical details can markedly influence non-stationary responses under parameter variation, emphasising the difficulty of finding a “correct” model. By developing questions for the pathway being studied, and designing more versatile microfluidics, cellular interrogation holds promise as a systematic strategy that can complement direct intervention by genetics or pharmacology. PMID:27367445

  6. Mechanisms underlying stage-1 TRPL channel translocation in Drosophila photoreceptors.

    Directory of Open Access Journals (Sweden)

    Minh-Ha Lieu

    Full Text Available BACKGROUND: TRP channels function as key mediators of sensory transduction and other cellular signaling pathways. In Drosophila, TRP and TRPL are the light-activated channels in photoreceptors. While TRP is statically localized in the signaling compartment of the cell (the rhabdomere, TRPL localization is regulated by light. TRPL channels translocate out of the rhabdomere in two distinct stages, returning to the rhabdomere with dark-incubation. Translocation of TRPL channels regulates their availability, and thereby the gain of the signal. Little, however, is known about the mechanisms underlying this trafficking of TRPL channels. METHODOLOGY/PRINCIPAL FINDINGS: We first examine the involvement of de novo protein synthesis in TRPL translocation. We feed flies cycloheximide, verify inhibition of protein synthesis, and test for TRPL translocation in photoreceptors. We find that protein synthesis is not involved in either stage of TRPL translocation out of the rhabdomere, but that re-localization to the rhabdomere from stage-1, but not stage-2, depends on protein synthesis. We also characterize an ex vivo eye preparation that is amenable to biochemical and genetic manipulation. We use this preparation to examine mechanisms of stage-1 TRPL translocation. We find that stage-1 translocation is: induced with ATP depletion, unaltered with perturbation of the actin cytoskeleton or inhibition of endocytosis, and slowed with increased membrane sterol content. CONCLUSIONS/SIGNIFICANCE: Our results indicate that translocation of TRPL out of the rhabdomere is likely due to protein transport, and not degradation/re-synthesis. Re-localization from each stage to the rhabdomere likely involves different strategies. Since TRPL channels can translocate to stage-1 in the absence of ATP, with no major requirement of the cytoskeleton, we suggest that stage-1 translocation involves simple diffusion through the apical membrane, which may be regulated by release of a

  7. Supersymmetric quantum mechanics under point singularities

    International Nuclear Information System (INIS)

    We provide a systematic study on the possibility of supersymmetry (SUSY) for one-dimensional quantum mechanical systems consisting of a pair of lines R or intervals [-l, l] each having a point singularity. We consider the most general singularities and walls (boundaries) at x = ±l admitted quantum mechanically, using a U(2) family of parameters to specify one singularity and similarly a U(1) family of parameters to specify one wall. With these parameter freedoms, we find that for a certain subfamily the line systems acquire an N = 1 SUSY which can be enhanced to N = 4 if the parameters are further tuned, and that these SUSY are generically broken except for a special case. The interval systems, on the other hand, can accommodate N = 2 or N = 4 SUSY, broken or unbroken, and exhibit a rich variety of (degenerate) spectra. Our SUSY systems include the familiar SUSY systems with the Dirac δ(x)-potential, and hence are extensions of the known SUSY quantum mechanics to those with general point singularities and walls. The self-adjointness of the supercharge in relation to the self-adjointness of the Hamiltonian is also discussed

  8. Comprehensive analysis of temporal alterations in cellular proteome of Bacillus subtilis under curcumin treatment.

    Directory of Open Access Journals (Sweden)

    Panga Jaipal Reddy

    Full Text Available Curcumin is a natural dietary compound with antimicrobial activity against various gram positive and negative bacteria. This study aims to investigate the proteome level alterations in Bacillus subtilis due to curcumin treatment and identification of its molecular/cellular targets to understand the mechanism of action. We have performed a comprehensive proteomic analysis of B. subtilis AH75 strain at different time intervals of curcumin treatment (20, 60 and 120 min after the drug exposure, three replicates to compare the protein expression profiles using two complementary quantitative proteomic techniques, 2D-DIGE and iTRAQ. To the best of our knowledge, this is the first comprehensive longitudinal investigation describing the effect of curcumin treatment on B. subtilis proteome. The proteomics analysis revealed several interesting targets such UDP-N-acetylglucosamine 1-carboxyvinyltransferase 1, putative septation protein SpoVG and ATP-dependent Clp protease proteolytic subunit. Further, in silico pathway analysis using DAVID and KOBAS has revealed modulation of pathways related to the fatty acid metabolism and cell wall synthesis, which are crucial for cell viability. Our findings revealed that curcumin treatment lead to inhibition of the cell wall and fatty acid synthesis in addition to differential expression of many crucial proteins involved in modulation of bacterial metabolism. Findings obtained from proteomics analysis were further validated using 5-cyano-2,3-ditolyl tetrazolium chloride (CTC assay for respiratory activity, resazurin assay for metabolic activity and membrane integrity assay by potassium and inorganic phosphate leakage measurement. The gene expression analysis of selected cell wall biosynthesis enzymes has strengthened the proteomics findings and indicated the major effect of curcumin on cell division.

  9. MECANISMOS CELULARES EN RESPUESTA AL ESTRÉS:: SIRTUINAS Cellular mechanisms in response to stress: sirtuin

    Directory of Open Access Journals (Sweden)

    Nancy Paola Echeverri-Ruíz

    2010-07-01

    Full Text Available Desde hace algún tiempo se conoce el papel de la restricción calórica sobre la longevidad y la prevención de enfermedades crónicas, pero hasta hace poco los mecanismos celulares involucrados comienzan a ser elucidados. El estrés celular se podría definir como el estado en el que la célula no presenta las condiciones óptimas de supervivencia, siendo el oxidativo un tipo de estrés en el que se generan radicales libres nocivos para las estructuras celulares. La restricción calórica podría incrementar la resistencia celular a diferentes formas de estrés. Las sirtuinas, proteínas deacetilasas de histonas tipo III, están involucradas en la relación entre balance energético y transcripción génica, permitiendo que la célula responda a la restricción calórica y sobreviva a situaciones de estrés oxidativo. En esta relación las sirtuinas regulan genes de la familia FOXO, cMYC, hTERT, p53, entre otros. La activación o silenciamiento de estos genes es importante en los procesos de apoptosis, reparación y muerte celular.The role of caloric restriction on longevity and prevention of chronic diseases has been known for some time; recently, cellular mechanisms involved are beginning to be elucidated. Cellular stress could be defined as the state in which the cell does not present optimal survival conditions; oxidative stress is a type of stress in which free radicals harmful cell structures. Caloric restriction might increase cellular resistance to various forms of stress. Sirtuins, histone deacetylases type III proteins are involved in the relationship between energy balance and gene transcription, allowing cell to respond to caloric restriction and to survive to oxidative stress. In this relationship, sirtuins regulate FOXO family genes, cMYC, hTERT, p53, among others. Activation or silencing of those genes is important in the process of apoptosis, repair and cell death

  10. Cellular mechanisms of tissue fibrosis. 6. Purinergic signaling and response in fibroblasts and tissue fibrosis.

    Science.gov (United States)

    Lu, David; Insel, Paul A

    2014-05-01

    Tissue fibrosis occurs as a result of the dysregulation of extracellular matrix (ECM) synthesis. Tissue fibroblasts, resident cells responsible for the synthesis and turnover of ECM, are regulated via numerous hormonal and mechanical signals. The release of intracellular nucleotides and their resultant autocrine/paracrine signaling have been shown to play key roles in the homeostatic maintenance of tissue remodeling and in fibrotic response post-injury. Extracellular nucleotides signal through P2 nucleotide and P1 adenosine receptors to activate signaling networks that regulate the proliferation and activity of fibroblasts, which, in turn, influence tissue structure and pathologic remodeling. An important component in the signaling and functional responses of fibroblasts to extracellular ATP and adenosine is the expression and activity of ectonucleotideases that attenuate nucleotide-mediated signaling, and thereby integrate P2 receptor- and subsequent adenosine receptor-initiated responses. Results of studies of the mechanisms of cellular nucleotide release and the effects of this autocrine/paracrine signaling axis on fibroblast-to-myofibroblast conversion and the fibrotic phenotype have advanced understanding of tissue remodeling and fibrosis. This review summarizes recent findings related to purinergic signaling in the regulation of fibroblasts and the development of tissue fibrosis in the heart, lungs, liver, and kidney. PMID:24352335

  11. Mechanism of acute cadmium toxicity in the testis of the rat: a cellular and molecular inquiry

    International Nuclear Information System (INIS)

    The more sensitive Sertoli cells were chosen as a model to investigate a molecular mechanism of toxicity. Primary rat Sertoli cells were exposed to sublethal concentrations of cadmium and the changes in [32P]-orthophosphate-labelled phosphoproteins using two-dimensional polyacrylamide gel electrophoresis were examined. Resultant autoradiograms showed a delayed dose- and time-dependent increase in intensity of two acidic proteins having identical molecular weights. These changes were most probably a result of increased synthesis of the proteins. Pretreatment of the cells with zinc, a cadmium antagonist, partially reduced the effect of cadmium. This research concludes that Sertoli cells are relatively more sensitive to the effects of cadmium than interstitial cells. A time- and dose dependent increase in [32P]-associated activity to two small Sertoli cell phosphoproteins was consistently seen after cadmium exposure, whereas no effect could be seen using essential, non-toxic metals. This response may be an early indicator in the disruption of cellular homeostasis by cadmium, and will hopefully contribute positive evidence in the search for a molecular mechanism of cadmium toxicity

  12. Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs.

    Science.gov (United States)

    Cunha-Oliveira, Teresa; Rego, Ana Cristina; Oliveira, Catarina R

    2008-06-01

    Substance abuse and addiction are the most costly of all the neuropsychiatric disorders. In the last decades, much progress has been achieved in understanding the effects of the drugs of abuse in the brain. However, efficient treatments that prevent relapse have not been developed. Drug addiction is now considered a brain disease, because the abuse of drugs affects several brain functions. Neurological impairments observed in drug addicts may reflect drug-induced neuronal dysfunction and neurotoxicity. The drugs of abuse directly or indirectly affect neurotransmitter systems, particularly dopaminergic and glutamatergic neurons. This review explores the literature reporting cellular and molecular alterations reflecting the cytotoxicity induced by amphetamines, cocaine and opiates in neuronal systems. The neurotoxic effects of drugs of abuse are often associated with oxidative stress, mitochondrial dysfunction, apoptosis and inhibition of neurogenesis, among other mechanisms. Understanding the mechanisms that underlie brain dysfunction observed in drug-addicted individuals may contribute to improve the treatment of drug addiction, which may have social and economic consequences. PMID:18440072

  13. Modeling mechanical behaviors of composites with various ratios of matrixeinclusion properties using movable cellular automaton method

    Institute of Scientific and Technical Information of China (English)

    A.Yu. SMOLIN; E.V. SHILKO; S.V. ASTAFUROV; I.S. KONOVALENKO; S.P. BUYAKOVA; S.G. PSAKHIE

    2015-01-01

    Two classes of composite materials are considered: classical metaleceramic composites with reinforcing hard inclusions as well as hard ceramics matrix with soft gel inclusions. Movable cellular automaton method is used for modeling the mechanical behaviors of such different heterogeneous materials. The method is based on particle approach and may be considered as a kind of discrete element method. The main feature of the method is the use of many-body forces of inter-element interaction within the formalism of simply deformable element approximation. It was shown that the strength of reinforcing particles and the width of particle-binder interphase boundaries had determining influence on the service characteristics of metaleceramic composite. In particular, the increasing of strength of carbide inclusions may lead to significant increase in the strength and ultimate strain of composite material. On the example of porous zirconia ceramics it was shown that the change in the mechanical properties of pore surface leads to the corresponding change in effective elastic modulus and strength limit of the ceramic sample. The less is the pore size, the more is this effect. The increase in the elastic properties of pore surface of ceramics may reduce its fracture energy.

  14. On Modeling Coverage and Rate of Random Cellular Networks under Generic Channel Fading

    OpenAIRE

    Al-Hourani, Akram; Kandeepan, Sithamparanathan

    2016-01-01

    In this paper we provide an analytic framework for computing the expected downlink coverage probability, and the associated data rate of cellular networks, where base stations are distributed in a random manner. The provided expressions are in computable integral forms that accommodate generic channel fading conditions. We develop these expressions by modelling the cellular interference using stochastic geometry analysis, then we employ them for comparing the coverage resulting from various c...

  15. Mechanisms Underlying Induction of Tolerance to Foods.

    Science.gov (United States)

    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

  16. Believing versus interacting: Behavioural and neural mechanisms underlying interpersonal coordination

    DEFF Research Database (Denmark)

    Konvalinka, Ivana; Bauer, Markus; Kilner, James;

    in joint action has investigated only one of these mechanisms at a time – low-level processes underlying joint coordination, or high-level cognitive mechanisms that give insight into how people think about another. In real interactions, interplay between these two mechanisms modulates how we interact...... into neural mechanisms underlying belief of interacting with another person as well as engaging in interaction with the responsive other....

  17. Habitats under Mechanical and Herbicide Management Regimes

    Directory of Open Access Journals (Sweden)

    Wendy-Ann P. Isaac

    2012-01-01

    Full Text Available Commelina diffusa is a colonising species of banana orchard habitats in St. Vincent in the Windward Islands of the Caribbean. In the present study, the population dynamics of C. diffusa were investigated in response to mechanical weed management with either a rotary string trimmer or glufosinate in ruderal and banana habitats. The study focused on density and size distribution of the weed over time and their response to two weed management strategies. The population dynamics of C. diffusa differed between the two habitats. Seedling establishment appeared to be an important factor influencing the dynamics of C. diffusa in banana orchards as there was little recruitment of seeds with less flower production compared with ruderal habitats where plants produced more flowers. Plants of C. diffusa in the banana orchard habitat had a longer growth cycle. In the banana orchard habitat, the C. diffusa population was greater and the plants were shorter with mechanical management than in areas treated with glufosinate. The results suggest that it is possible to manipulate the dynamics of C. diffusa in banana orchards as there is less chance of seed recruitment. Further research is necessary to refine an IPM approach for the management of C. diffusa.

  18. 3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response.

    Science.gov (United States)

    Maiti, A; Small, W; Lewicki, J P; Weisgraber, T H; Duoss, E B; Chinn, S C; Pearson, M A; Spadaccini, C M; Maxwell, R S; Wilson, T S

    2016-01-01

    3D printing of polymeric foams by direct-ink-write is a recent technological breakthrough that enables the creation of versatile compressible solids with programmable microstructure, customizable shapes, and tunable mechanical response including negative elastic modulus. However, in many applications the success of these 3D printed materials as a viable replacement for traditional stochastic foams critically depends on their mechanical performance and micro-architectural stability while deployed under long-term mechanical strain. To predict the long-term performance of the two types of foams we employed multi-year-long accelerated aging studies under compressive strain followed by a time-temperature-superposition analysis using a minimum-arc-length-based algorithm. The resulting master curves predict superior long-term performance of the 3D printed foam in terms of two different metrics, i.e., compression set and load retention. To gain deeper understanding, we imaged the microstructure of both foams using X-ray computed tomography, and performed finite-element analysis of the mechanical response within these microstructures. This indicates a wider stress variation in the stochastic foam with points of more extreme local stress as compared to the 3D printed material, which might explain the latter's improved long-term stability and mechanical performance. PMID:27117858

  19. 3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response

    Science.gov (United States)

    Maiti, A.; Small, W.; Lewicki, J. P.; Weisgraber, T. H.; Duoss, E. B.; Chinn, S. C.; Pearson, M. A.; Spadaccini, C. M.; Maxwell, R. S.; Wilson, T. S.

    2016-04-01

    3D printing of polymeric foams by direct-ink-write is a recent technological breakthrough that enables the creation of versatile compressible solids with programmable microstructure, customizable shapes, and tunable mechanical response including negative elastic modulus. However, in many applications the success of these 3D printed materials as a viable replacement for traditional stochastic foams critically depends on their mechanical performance and micro-architectural stability while deployed under long-term mechanical strain. To predict the long-term performance of the two types of foams we employed multi-year-long accelerated aging studies under compressive strain followed by a time-temperature-superposition analysis using a minimum-arc-length-based algorithm. The resulting master curves predict superior long-term performance of the 3D printed foam in terms of two different metrics, i.e., compression set and load retention. To gain deeper understanding, we imaged the microstructure of both foams using X-ray computed tomography, and performed finite-element analysis of the mechanical response within these microstructures. This indicates a wider stress variation in the stochastic foam with points of more extreme local stress as compared to the 3D printed material, which might explain the latter’s improved long-term stability and mechanical performance.

  20. 3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response

    Science.gov (United States)

    Maiti, A.; Small, W.; Lewicki, J. P.; Weisgraber, T. H.; Duoss, E. B.; Chinn, S. C.; Pearson, M. A.; Spadaccini, C. M.; Maxwell, R. S.; Wilson, T. S.

    2016-01-01

    3D printing of polymeric foams by direct-ink-write is a recent technological breakthrough that enables the creation of versatile compressible solids with programmable microstructure, customizable shapes, and tunable mechanical response including negative elastic modulus. However, in many applications the success of these 3D printed materials as a viable replacement for traditional stochastic foams critically depends on their mechanical performance and micro-architectural stability while deployed under long-term mechanical strain. To predict the long-term performance of the two types of foams we employed multi-year-long accelerated aging studies under compressive strain followed by a time-temperature-superposition analysis using a minimum-arc-length-based algorithm. The resulting master curves predict superior long-term performance of the 3D printed foam in terms of two different metrics, i.e., compression set and load retention. To gain deeper understanding, we imaged the microstructure of both foams using X-ray computed tomography, and performed finite-element analysis of the mechanical response within these microstructures. This indicates a wider stress variation in the stochastic foam with points of more extreme local stress as compared to the 3D printed material, which might explain the latter’s improved long-term stability and mechanical performance. PMID:27117858

  1. Synaptic mechanisms underlying persistent cocaine craving.

    Science.gov (United States)

    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

  2. Cellular mechanisms of activity-dependent BDNF expression in primary sensory neurons.

    Science.gov (United States)

    Vermehren-Schmaedick, A; Khanjian, R A; Balkowiec, A

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) is abundantly expressed by both developing and adult rat visceral sensory neurons from the nodose ganglion (NG) in vivo and in vitro. We have previously shown that BDNF is released from neonatal NG neurons by activity and regulates dendritic development in their postsynaptic targets in the brainstem. The current study was carried out to examine the cellular and molecular mechanisms of activity-dependent BDNF expression in neonatal rat NG neurons, using our established in vitro model of neuronal activation by electrical field stimulation with patterns that mimic neuronal activity in vivo. We show that BDNF mRNA (transcript 4) increases over threefold in response to a 4-h tonic or bursting pattern delivered at the frequency of 6 Hz, which corresponds to the normal heart rate of a newborn rat. No significant increase in BDNF expression was observed following stimulation at 1 Hz. The latter effect suggests a frequency-dependent mechanism of regulated BDNF expression. In addition to BDNF transcript 4, which is known to be regulated by activity, transcript 1 also showed significant upregulation. The increases in BDNF mRNA were followed by BDNF protein upregulation of a similar magnitude after 24h of stimulation at 6 Hz. Electrical stimulation-evoked BDNF expression was inhibited by pretreating neurons with the blocker of voltage-gated sodium channels tetrodotoxin and by removing extracellular calcium. Moreover, our data show that repetitive stimulation-evoked BDNF expression requires calcium influx through N-, but not L-type, channels. Together, our study reveals novel mechanisms through which electrical activity stimulates de novo synthesis of BDNF in sensory neurons, and points to the role of N-type calcium channels in regulating BDNF expression in sensory neurons in response to repetitive stimulation. PMID:26459016

  3. Hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5) communicates cellular iron and oxygen availability by distinct mechanisms.

    Science.gov (United States)

    Chollangi, Srinivas; Thompson, Joel W; Ruiz, Julio C; Gardner, Kevin H; Bruick, Richard K

    2012-07-01

    Iron regulatory proteins play a principal role in maintaining cellular iron homeostasis by post-transcriptionally regulating factors responsible for iron uptake, utilization, and storage. An E3 ubiquitin ligase complex containing FBXL5 targets IRP2 for proteasomal degradation under iron- and oxygen-replete conditions, whereas FBXL5 itself is degraded when iron and oxygen availability decreases. FBXL5 contains a hemerythrin-like (Hr) domain at its N terminus that mediates its own differential stability. Here, we investigated the iron- and oxygen-dependent conformational changes within FBXL5-Hr that underlie its role as a cellular sensor. As predicted, FBXL5-Hr undergoes substantive structural changes when iron becomes limiting, accounting for its switch-like behavior. However, these same changes are not observed in response to oxygen depletion, indicating that this domain accommodates two distinct sensing mechanisms. Moreover, FBXL5-Hr does not behave as a dynamic sensor that continuously samples the cellular environment, assuming conformations in equilibrium with ever-changing cellular iron levels. Instead, the isolated domain appears competent to incorporate iron only at or near the time of its own synthesis. These observations have important implications for mechanisms by which these metabolites are sensed within mammalian cells. PMID:22648410

  4. Never-ageing cellular senescence

    OpenAIRE

    Ogrunc, Müge; d’Adda di Fagagna, Fabrizio

    2011-01-01

    Cellular senescence was historically discovered as a form of cellular ageing of in vitro cultured cells. It has been under the spotlight following the evidence of oncogene-induced senescence in vivo and its role as a potent tumour suppressor mechanism. Presently, a PubMed search using keywords ‘cellular senescence and cancer’ reveals 8398 number of references (by April 2011) showing that while our knowledge of senescence keeps expanding, the complexity of the phenomenon keeps us – researchers...

  5. Cellular polarization: Interaction between extrinsic bounded noises and the wave-pinning mechanism

    Science.gov (United States)

    de Franciscis, Sebastiano; d'Onofrio, Alberto

    2013-09-01

    Cell polarization (cued or uncued) is a fundamental mechanism in cell biology. As an alternative to the classical Turing bifurcation, it has been proposed that the onset of cell polarity might arise by means of the well-known phenomenon of wave-pinning [Gamba , Proc. Natl. Acad. Sci. USAPNASA60027-842410.1073/pnas.0503974102 102, 16927 (2005)]. A particularly simple and elegant deterministic model of cell polarization based on the wave-pinning mechanism has been proposed by Edelstein-Keshet and coworkers [Biophys. J.BIOJAU0006-349510.1529/biophysj.107.120824 94, 3684 (2008)]. This model consists of a small biomolecular network where an active membrane-bound factor interconverts into its inactive form that freely diffuses in the cell cytosol. However, biomolecular networks do communicate with other networks as well as with the external world. Thus, their dynamics must be considered as perturbed by extrinsic noises. These noises may have both a spatial and a temporal correlation, and in any case they must be bounded to preserve the biological meaningfulness of the perturbed parameters. Here we numerically show that the inclusion of external spatiotemporal bounded parametric perturbations in the above wave-pinning-based model of cellular polarization may sometimes destroy the polarized state. The polarization loss depends on both the extent of temporal and spatial correlations and on the kind of noise employed. For example, an increase of the spatial correlation of the noise induces an increase of the probability of cell polarization. However, if the noise is spatially homogeneous then the polarization is lost in the majority of cases. These phenomena are independent of the type of noise. Conversely, an increase of the temporal autocorrelation of the noise induces an effect that depends on the model of noise.

  6. PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Cellular and molecular mechanisms of heat stress related to bovine ovarian function.

    Science.gov (United States)

    Roth, Z

    2015-05-01

    In light of the intensive genetic selection for high milk production and the onset of global warming, it seems that the reduced fertility of lactating cows during the summer will worsen in coming years. Although not entirely clear, the mechanism appears to be multifactorial in nature. It includes alterations in follicular development, depression of follicular dominance, and impairment of steroidogenesis and gonadotropin secretion. Heat-induced perturbations in the physiology of the follicle-enclosed oocyte have also been documented, expressed by impaired cleavage rate and reduced developmental competence. With respect to the oocyte, alterations include an increase in PUFA in the membrane, reactive oxygen species, ceramide formation and caspase activity, and induction of apoptosis via the sphingomyelin and/or mitochondrial pathways. New insight into cellular and molecular alterations has revealed that heat induces perturbations in both nuclear and cytoplasmic maturation events, such as resumption of meiosis, metaphase II plate formation, cytoskeleton rearrangement, and translocation of cortical granules. Alterations in mitochondrial distribution (i.e., low proportion of category I mitochondria) and function (i.e., low membrane potential) have recently been reported for oocytes collected during the summer. These were associated with impaired expression of both nuclear (succinate dehydrogenase subunit [SDHD], adenosine triphosphate [ATP] synthase subunit beta [ATP5B]), mitochondrially NADH dehydrogenase subunit 2 (ND2), and mitochondiral (cytochrome c oxidase subunit II [MT-CO2] and cytochrome b [MT-CYB]) genes that are crucial in the mitochondrial respiratory chain. In addition, season-induced alteration in the stored maternal mRNA has been documented, expressed by reduced transcript levels (oocyte maturation factor MOS [C-MOS], growth differentiation factor 9 [GDF9], POU domain class 5 transcription factor 1 [POU5F1], and glyceraldehyde-3-phosphate dehydrogenase

  7. Molecular and Cellular Mechanisms Elucidating Neurocognitive Basis of Functional Impairments Associated with Intellectual Disability in Down Syndrome

    Science.gov (United States)

    Rachidi, Mohammed; Lopes, Carmela

    2010-01-01

    Down syndrome, the most common genetic cause of intellectual disability, is associated with brain disorders due to chromosome 21 gene overdosage. Molecular and cellular mechanisms involved in the neuromorphological alterations and cognitive impairments are reported herein in a global model. Recent advances in Down syndrome research have lead to…

  8. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans

    Science.gov (United States)

    Abegglen, Lisa M.; Caulin, Aleah F.; Chan, Ashley; Lee, Kristy; Robinson, Rosann; Campbell, Michael S.; Kiso, Wendy K.; Schmitt, Dennis L.; Waddell, Peter J; Bhaskara, Srividya; Jensen, Shane T.; Maley, Carlo C.; Schiffman, Joshua D.

    2016-01-01

    IMPORTANCE Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. OBJECTIVE To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). DESIGN, SETTING, AND PARTICIPANTS A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. EXPOSURES Ionizing radiation and doxorubicin. MAIN OUTCOMES AND MEASURES Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. RESULTS Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95%CI, 0%–5%]; African wild dog, 8%[95%CI, 0%–16%]; lion, 2%[95%CI, 0% –7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95%CI, 3.14%–6.49%), compared with humans, who have 11% to 25%cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain

  9. Cellular automata

    CERN Document Server

    Codd, E F

    1968-01-01

    Cellular Automata presents the fundamental principles of homogeneous cellular systems. This book discusses the possibility of biochemical computers with self-reproducing capability.Organized into eight chapters, this book begins with an overview of some theorems dealing with conditions under which universal computation and construction can be exhibited in cellular spaces. This text then presents a design for a machine embedded in a cellular space or a machine that can compute all computable functions and construct a replica of itself in any accessible and sufficiently large region of t

  10. Characterization of Wave Dispersion in Viscoelastic Cellular Assemblies by Doublet Mechanics

    Institute of Scientific and Technical Information of China (English)

    JIN Yan-Fang; XIONG Chun-Yang; FANG Jing; FERRARI Mauro

    2009-01-01

    Using the Voigt model, we analyze wave propagation in viscoelastic granular media with a monatomic lattice, planar simple cubic package and cubical-tetrahedral assembly within the context of doublet mechanics. Microstrains of elongation between the doublet particles are considered in the models. Wave dispersive relations are derived from dynamic equations of the particles involved in the media, and phase velocities and attenuations of the dispersive waves are obtained for the different assemblies. Variations in these dispersion characteristics are analyzed with the changes of cell interval, modulus, and wave frequency. The relations between micro-constants and macro-parameters are presented under the condition of non-scale continuity of the media.

  11. Microstructures, mechanical behavior, cellular response, and hemocompatibility of bulk ultrafine-grained pure tantalum.

    Science.gov (United States)

    Nie, F L; Zheng, Y F; Wang, Y; Wang, J T

    2014-02-01

    Bulk ultrafine-grained (UFG) pure Ta had been successfully prepared by equal channel angular pressing (ECAP) technique till eight passes. The 1st, 2nd, 4th, and 8th ECAPed Ta samples were investigated in the current study, with the 0th ECAPed Ta sample as the microcrystalline counterpart control. The microstructure and grain size distribution were characterized by X-ray diffractometer patterns, scanning electron microscopy, and transmission electron microscopy analysis by means of histogram. Although the mechanical behavior of all the experimental samples were analyzed through uniaxial tensile measurement and microhardness test, in vitro biological interactions onto the substrates such as protein adsorption, cellular responses derived from different types of cell lines, and the activity of erythrocyte and platelets were further evaluated and specifically assessed by bicinchoninic acid assay, enzyme-linked immunosorbent assay, and the method of colorimetric reading. A superior percentage of protein adsorption can be observed on the substrate of the UFG 8th ECAPed Ta (around 90%), even above those on the tissue culture plate (control) and the other ECAPed Ta samples. Furthermore, the UFG 8th ECAPed Ta shows no cytotoxic within 4 days culture when incubated with the murine fibroblast cell lines (L929). In addition, a priority order in the growth of endothelial cells (ECV304) other than vascular smooth muscle cells was observed in the case of the UFG 8th ECAPed Ta. In terms of hemolysis rate and adhered platelets (both the amount and the individual morphology), an evolutionary outcome of preferentially enhanced hemocompatibility can be concluded for the case of the UFG 8th ECAPed Ta. PMID:23908098

  12. Molecular, Cellular, and Structural Mechanisms of Cocaine Addiction: A Key Role for MicroRNAs

    Science.gov (United States)

    Jonkman, Sietse; Kenny, Paul J

    2013-01-01

    The rewarding properties of cocaine play a key role in establishing and maintaining the drug-taking habit. However, as exposure to cocaine increases, drug use can transition from controlled to compulsive. Importantly, very little is known about the neurobiological mechanisms that control this switch in drug use that defines addiction. MicroRNAs (miRNAs) are small non-protein coding RNA transcripts that can regulate the expression of messenger RNAs that code for proteins. Because of their highly pleiotropic nature, each miRNA has the potential to regulate hundreds or even thousands of protein-coding RNA transcripts. This property of miRNAs has generated considerable interest in their potential involvement in complex psychiatric disorders such as addiction, as each miRNA could potentially influence the many different molecular and cellular adaptations that arise in response to drug use that are hypothesized to drive the emergence of addiction. Here, we review recent evidence supporting a key role for miRNAs in the ventral striatum in regulating the rewarding and reinforcing properties of cocaine in animals with limited exposure to the drug. Moreover, we discuss evidence suggesting that miRNAs in the dorsal striatum control the escalation of drug intake in rats with extended cocaine access. These findings highlight the central role for miRNAs in drug-induced neuroplasticity in brain reward systems that drive the emergence of compulsive-like drug use in animals, and suggest that a better understanding of how miRNAs control drug intake will provide new insights into the neurobiology of drug addiction. PMID:22968819

  13. Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment

    Directory of Open Access Journals (Sweden)

    Gaurav eSinghal

    2014-04-01

    Full Text Available Recent studies on environmental enrichment (EE have shown cytokines, cellular immune components (e.g. T lymphocytes, NK cells and glial cells in causal relationship to EE in bringing out changes to neurobiology and behavior. The purpose of this review is to evaluate these neuroimmune mechanisms associated with neurobiological and behavioral changes in response to different EE methods. We systematically reviewed common research databases. After applying all inclusion and exclusion criteria, 328 articles remained for this review. Physical exercise, a form of EE, elicits anti-inflammatory and neuromodulatory effects through interaction with several immune pathways including IL-6 secretion from muscle fibers, reduced expression of TLR’s on monocytes and macrophages, reduced secretion of adipokines, modulation of hippocampal T cells, priming of microglia and upregulation of MKP-1 in CNS. In contrast, immunomodulatory roles of other enrichment methods are not studied extensively. Nonetheless, studies showing reduction in the expression of IL-1β and TNF-α in response to enrichment with novel objects and accessories suggest anti-inflammatory effects of novel environment. Likewise, social enrichment, though considered a necessity for healthy behavior, results in immunosuppression in socially defeated animals. This has been attributed to reduction in T lymphocytes, NK cells and IL-10 in subordinate animals. EE through sensory stimuli has been investigated to a lesser extent and the effect on immune factors has not been evaluated yet. Discovery of this multidimensional relationship between immune system, brain functioning and EE has paved a way towards formulating environ-immuno therapies for treating psychiatric illnesses with minimal use of pharmacotherapy. While the immuno-modulatory role of physical exercise has been evaluated extensively, more research is required to investigate neuroimmune changes associated with other enrichment methods.

  14. Molecular Mechanisms Regulating Muscle Fiber Composition Under Microgravity

    Science.gov (United States)

    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

  15. Genetic Dominance & Cellular Processes

    Science.gov (United States)

    Seager, Robert D.

    2014-01-01

    In learning genetics, many students misunderstand and misinterpret what "dominance" means. Understanding is easier if students realize that dominance is not a mechanism, but rather a consequence of underlying cellular processes. For example, metabolic pathways are often little affected by changes in enzyme concentration. This means that…

  16. Multi-operator collaboration for green cellular networks under roaming price consideration

    KAUST Repository

    Ghazzai, Hakim

    2014-09-01

    This paper investigates the collaboration between multiple mobile operators to optimize the energy efficiency of cellular networks. Our framework studies the case of LTE-Advanced networks deployed in the same area and owning renewable energy generators. The objective is to reduce the CO2 emissions of cellular networks via collaborative techniques and using base station sleeping strategy while respecting the network quality of service. Low complexity and practical algorithm is employed to achieve green goals during low traffic periods. Cooperation decision criteria are also established basing on derived roaming prices and profit gains of competitive mobile operators. Our numerical results show a significant save in terms of CO2 compared to the non-collaboration case and that cooperative mobile operator exploiting renewables are more awarded than traditional operators.

  17. p16(INK4a suppression by glucose restriction contributes to human cellular lifespan extension through SIRT1-mediated epigenetic and genetic mechanisms.

    Directory of Open Access Journals (Sweden)

    Yuanyuan Li

    Full Text Available Although caloric restriction (CR has been shown to increase lifespan in various animal models, the mechanisms underlying this phenomenon have not yet been revealed. We developed an in vitro system to mimic CR by reducing glucose concentration in cell growth medium which excludes metabolic factors and allows assessment of the effects of CR at the cellular and molecular level. We monitored cellular proliferation of normal WI-38, IMR-90 and MRC-5 human lung fibroblasts and found that glucose restriction (GR can inhibit cellular senescence and significantly extend cellular lifespan compared with cells receiving normal glucose (NG in the culture medium. Moreover, GR decreased expression of p16(INK4a (p16, a well-known senescence-related gene, in all of the tested cell lines. Over-expressed p16 resulted in early replicative senescence in glucose-restricted cells suggesting a crucial role of p16 regulation in GR-induced cellular lifespan extension. The decreased expression of p16 was partly due to GR-induced chromatin remodeling through effects on histone acetylation and methylation of the p16 promoter. GR resulted in an increased expression of SIRT1, a NAD-dependent histone deacetylase, which has positive correlation with CR-induced longevity. The elevated SIRT1 was accompanied by enhanced activation of the Akt/p70S6K1 signaling pathway in response to GR. Furthermore, knockdown of SIRT1 abolished GR-induced p16 repression as well as Akt/p70S6K1 activation implying that SIRT1 may affect p16 repression through direct deacetylation effects and indirect regulation of Akt/p70S6K1 signaling. Collectively, these results provide new insights into interactions between epigenetic and genetic mechanisms on CR-induced longevity that may contribute to anti-aging approaches and also provide a general molecular model for studying CR in vitro in mammalian systems.

  18. Dosimetric applications of cellular electrophysiological changes under high- and low-LET irradiation in health physics

    International Nuclear Information System (INIS)

    The first step of interaction of radiation with any biological target occurs at the cellular level, especially at the cell membrane. This results in a Linear Energy Transfer (LET)-dependent deposition of energy at membrane substructures, where the supramolecular arrangement of components represents highly sensitive targets for ionizing radiation, e.g. the natural membrane lipid component. As part of a current research project on the influence of low level effects of ionizing radiation on biophysical cellular parameters, changes of electrical properties of irradiated cell membranes were studied for their suitability as biological dosimeters. Normal human embryonic lung cells (Flow 2002) and transformed human lung cells (WI-38/SV13) were exposed to ionizing radiation with LET ranging from 10 to over 100 keV/μm. With the use of micromanipulators, glass-micro-electrodes in a special headstage were used to determine intracellular electrical activity at different time intervals after irradiation of the cells. Population density of the irradiated cell colonies was varied in order to determine the influence of contact inhibition and intercellular communication on the observable radiation induced effect. Dose- and dose rate-dependent variation of cellular membrane resting potential and membrane resistance are discussed for both normal and malignant human cells. (author)

  19. A computational framework for 3D mechanical modeling of plant morphogenesis with cellular resolution.

    Directory of Open Access Journals (Sweden)

    Frédéric Boudon

    2015-01-01

    Full Text Available The link between genetic regulation and the definition of form and size during morphogenesis remains largely an open question in both plant and animal biology. This is partially due to the complexity of the process, involving extensive molecular networks, multiple feedbacks between different scales of organization and physical forces operating at multiple levels. Here we present a conceptual and modeling framework aimed at generating an integrated understanding of morphogenesis in plants. This framework is based on the biophysical properties of plant cells, which are under high internal turgor pressure, and are prevented from bursting because of the presence of a rigid cell wall. To control cell growth, the underlying molecular networks must interfere locally with the elastic and/or plastic extensibility of this cell wall. We present a model in the form of a three dimensional (3D virtual tissue, where growth depends on the local modulation of wall mechanical properties and turgor pressure. The model shows how forces generated by turgor-pressure can act both cell autonomously and non-cell autonomously to drive growth in different directions. We use simulations to explore lateral organ formation at the shoot apical meristem. Although different scenarios lead to similar shape changes, they are not equivalent and lead to different, testable predictions regarding the mechanical and geometrical properties of the growing lateral organs. Using flower development as an example, we further show how a limited number of gene activities can explain the complex shape changes that accompany organ outgrowth.

  20. Microstructure variation and growth mechanism of hypoeutectic Al-Si alloy solidifi ed under high pressure

    Directory of Open Access Journals (Sweden)

    Zhang Guozhi

    2009-05-01

    Full Text Available The microstructure of hypoeutectic Al-9.21wt.%Si alloy solidified under 5.5 GPa was studied. The results show that the solidifi cation microstructure is refi ned. The primary α phase is the extended solid solution. The solid solubility of Si in α phase is up to 8.26wt.%. The growth mode of the α phase is cellular, and this cellular growth mechanism is interpreted in terms of the decrease of the diffusivity and the extended solid solution under high pressure. By calculation, it can be known that the the diffusivity of solute in the liquid under normal pressure is as high as two hundred times that under high pressure. The microhardness of the hypoeutectic Al-Si alloy solidified under high pressure is higher than that of solidifi ed under normal pressure. After annealing, Si precipitates from the solid solution, the microhardness of the alloy decrease, but, still higher than that of solidifi ed under normal pressure.

  1. Behaviour of cellular foam core materials in GRP sandwich under fatigue

    Energy Technology Data Exchange (ETDEWEB)

    Aamlid, O.; Echtermeyer, A.T.; McGeorge, D.; Buene, L. [Det Norske Veritas Research AS, Hoevik (Norway)

    1993-12-31

    This paper concerns four point bend testing of sandwich beams with PVC foam cores, representative of hull panels in high speed light craft. The study focuses on the long term behavior of cellular foam core materials when the sandwich beam is subjected to fatigue loading until the specimen fails due to shear fracture or excessive shear deformations in the core. The core materials tested include the partially cross-linked PVC Divinycell H100 and H200 and the linear PVC Airex R63.80. Results from the program are presented and discussed.

  2. Rapid Disruption of Cellular Integrity of Zinc-treated Astroglia Is Regulated by p38 MAPK and Ca2+-dependent Mechanisms

    OpenAIRE

    Im, Joo-Young; Joo, Hyo-Jin; Han, Pyung-Lim

    2011-01-01

    Cultured cortical primary astroglia treated with zinc died while rapidly detached from culture plates, a distinct part of zinc-treated astroglia. In the present study, we investigated the mechanism underlying the rapid change in the morphologic integrity of zinc-treated astroglia. Among the early cellular events occurring in zinc-treated astroglia, strong activation of p38 MAPK and JNK was evident. Although inhibitors of p38 (SB203580 and SB202190) or JNK (SP600125) did not protect zinc-insul...

  3. An inhibitory interaction between viral and cellular proteins underlies the resistance of tomato to nonadapted tobamoviruses.

    Science.gov (United States)

    Ishibashi, Kazuhiro; Naito, Satoshi; Meshi, Tetsuo; Ishikawa, Masayuki

    2009-05-26

    Any individual virus can infect only a limited range of hosts, and most plant species are "nonhosts" to a given virus; i.e., all members of the species are insusceptible to the virus. In nonhost plants, the factors that control virus resistance are not genetically tractable, and how the host range of a virus is determined remains poorly understood. Tomato (Solanum lycopersicum) is a nonhost species for Tobacco mild green mosaic virus (TMGMV) and Pepper mild mottle virus (PMMoV), members of the genus Tobamovirus. Previously, we identified Tm-1, a resistance gene of tomato to another tobamovirus, Tomato mosaic virus (ToMV), and found that Tm-1 binds to ToMV replication proteins to inhibit RNA replication. Tm-1 is derived from a wild tomato species, S. habrochaites, and ToMV-susceptible tomato cultivars have the allelic gene tm-1. The tm-1 protein can neither bind to ToMV replication proteins nor inhibit ToMV multiplication. Here, we show that transgenic tobacco plants expressing tm-1 exhibit resistance to TMGMV and PMMoV. The tm-1 protein bound to the replication proteins of TMGMV and PMMoV and inhibited their RNA replication in vitro. In one of the tm-1-expressing tobacco plants, a tm-1-insensitive TMGMV mutant emerged. In tomato protoplasts, this mutant TMGMV multiplied as efficiently as ToMV. However, in tomato plants, the mutant TMGMV multiplied with lower efficiency compared to ToMV and caused systemic necrosis. These results suggest that an inhibitory interaction between the replication proteins and tm-1 underlies a multilayered resistance mechanism to TMGMV in tomato. PMID:19423673

  4. Cellular resilience.

    Science.gov (United States)

    Smirnova, Lena; Harris, Georgina; Leist, Marcel; Hartung, Thomas

    2015-01-01

    Cellular resilience describes the ability of a cell to cope with environmental changes such as toxicant exposure. If cellular metabolism does not collapse directly after the hit or end in programmed cell death, the ensuing stress responses promote a new homeostasis under stress. The processes of reverting "back to normal" and reversal of apoptosis ("anastasis") have been studied little at the cellular level. Cell types show astonishingly similar vulnerability to most toxicants, except for those that require a very specific target, metabolism or mechanism present only in specific cell types. The majority of chemicals triggers "general cytotoxicity" in any cell at similar concentrations. We hypothesize that cells differ less in their vulnerability to a given toxicant than in their resilience (coping with the "hit"). In many cases, cells do not return to the naive state after a toxic insult. The phenomena of "pre-conditioning", "tolerance" and "hormesis" describe this for low-dose exposures to toxicants that render the cell more resistant to subsequent hits. The defense and resilience programs include epigenetic changes that leave a "memory/scar" - an alteration as a consequence of the stress the cell has experienced. These memories might have long-term consequences, both positive (resistance) and negative, that contribute to chronic and delayed manifestations of hazard and, ultimately, disease. This article calls for more systematic analyses of how cells cope with toxic perturbations in the long-term after stressor withdrawal. A technical prerequisite for these are stable (organotypic) cultures and a characterization of stress response molecular networks. PMID:26536287

  5. Mechanical Properties of 3-D Printed Cellular Foams with triangular cells

    Science.gov (United States)

    Bunga, Pratap Kumar

    In the present work, poly lactic acid (PLA) is used as a model system to investigate the mechanical behavior of 3-D printed foams with triangular cells. Solid PLA tension and compression specimens and foams made of PLA were fabricated using fused deposition 3-D printing technique. The solid PLA tension specimens were characterized for their densities and found to be about 10% lower in density as compared to their bulk counter parts. The triangular foams had a relative density of about 64%. The relationships between the structure of the foams and its deformation behavior under compression along two in-plane directions were characterized. Furthermore, simple finite element models were developed to understand the observed deformation behavior of triangular foams.

  6. Molecular Mechanism Underlying Lymphatic Metastasis in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Zhiwen Xiao

    2014-01-01

    Full Text Available 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.

  7. Elucidating the cellular uptake mechanism of aptamer-functionalized graphene-isolated-Au-nanocrystals with dual-modal imaging.

    Science.gov (United States)

    Wang, Shanshan; Liu, Zhangkun; Zou, Yuxiu; Lai, Xiaofang; Ding, Ding; Chen, Long; Zhang, Liqin; Wu, Yuan; Chen, Zhuo; Tan, Weihong

    2016-05-23

    Elucidating the endocytosis and metabolism of nanoparticles in cells could improve the diagnostic sensitivity and therapeutic efficiency. In this work, we explore the cellular uptake mechanism of a biocompatible nanocrystal nanostructure, graphene-isolated-Au-nanocrystals (GIANs), by monitoring the intrinsic Raman and two-photon luminescence signals of GIANs in live cells. Aptamers functionalized on the GIAN nanostructure through simple, but strong, π-π interactions entered the cells through a clathrin-dependent pathway, while unmodified GIANs mainly entered the cells through a caveolae-mediated endocytosis pathway. Thus, it can be concluded that the mechanism of cellular uptake in these graphene-isolated-Au-nanocrystal nanostructures is determined by the presence or absence of aptamer modification. PMID:27111129

  8. RNase-L control of cellular mRNAs: roles in biologic functions and mechanisms of substrate targeting.

    Science.gov (United States)

    Brennan-Laun, Sarah E; Ezelle, Heather J; Li, Xiao-Ling; Hassel, Bret A

    2014-04-01

    RNase-L is a mediator of type 1 interferon-induced antiviral activity that has diverse and critical cellular roles, including the regulation of cell proliferation, differentiation, senescence and apoptosis, tumorigenesis, and the control of the innate immune response. Although RNase-L was originally shown to mediate the endonucleolytic cleavage of both viral and ribosomal RNAs in response to infection, more recent evidence indicates that RNase-L also functions in the regulation of cellular mRNAs as an important mechanism by which it exerts its diverse biological functions. Despite this growing body of work, many questions remain regarding the roles of mRNAs as RNase-L substrates. This review will survey known and putative mRNA substrates of RNase-L, propose mechanisms by which it may selectively cleave these transcripts, and postulate future clinical applications. PMID:24697205

  9. The Effect of Structural Design on Mechanical Properties and Cellular Response of Additive Manufactured Titanium Scaffolds

    Directory of Open Access Journals (Sweden)

    Jan Wieding

    2012-08-01

    Full Text Available Restoration of segmental defects in long bones remains a challenging task in orthopedic surgery. Although autologous bone is still the ‘Gold Standard’ because of its high biocompatibility, it has nevertheless been associated with several disadvantages. Consequently, artificial materials, such as calcium phosphate and titanium, have been considered for the treatment of bone defects. In the present study, the mechanical properties of three different scaffold designs were investigated. The scaffolds were made of titanium alloy (Ti6Al4V, fabricated by means of an additive manufacturing process with defined pore geometry and porosities of approximately 70%. Two scaffolds exhibited rectangular struts, orientated in the direction of loading. The struts for the third scaffold were orientated diagonal to the load direction, and featured a circular cross-section. Material properties were calculated from stress-strain relationships under axial compression testing. In vitro cell testing was undertaken with human osteoblasts on scaffolds fabricated using the same manufacturing process. Although the scaffolds exhibited different strut geometry, the mechanical properties of ultimate compressive strength were similar (145–164 MPa and in the range of human cortical bone. Test results for elastic modulus revealed values between 3.7 and 6.7 GPa. In vitro testing demonstrated proliferation and spreading of bone cells on the scaffold surface.

  10. Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

    OpenAIRE

    Yu, Tao; Tao, Yonghui; Yang, Meiqiang; Chen, Peng; Gao, XiaoBo; Zhang, Yanbo; Zhang,Tao; Chen, Zi; Hou, Jian; Zhang, Yan; Ruan, Kangcheng; Wang, Hongyan; Hu, Ronggui

    2014-01-01

    Global change in protein turnover (protein degradome) constitutes a central part of cellular responses to intrinsic or extrinsic stimuli. However, profiling protein degradome remains technically challenging. Recently, inhibition of the proteasome, e.g., by using bortezomib (BTZ), has emerged as a major chemotherapeutic strategy for treating multiple myeloma and other human malignancies, but systematic understanding of the mechanisms for BTZ drug action and tumor drug resistance is yet to be a...

  11. Regulation of hTERT transcription: a target of cellular and viral mechanisms for immortalization and carcinogenesis

    OpenAIRE

    Horikawa, Izumi; Michishita, Eriko; Barrett, J. Carl

    2004-01-01

    A hallmark of human cancer cells is immortal cell growth, which is associated with telomere maintenance by telomerase. The transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is a major mechanism that negatively and positively controls telomerase activity in normal and cancer cells, respectively. A growing body of data suggests that various cellular and viral factors and pathways involved in cell senescence, immortalization and carcinogenesis act on the hTERT...

  12. Complex I Disorders: Causes, Mechanisms, and Development of Treatment Strategies at the Cellular Level

    Science.gov (United States)

    Valsecchi, Federica; Koopman, Werner J. H.; Manjeri, Ganesh R.; Rodenburg, Richard J.; Smeitink, Jan A. M.; Willems, Peter H. G. M.

    2010-01-01

    Mitochondrial oxidative phosphorylation (OXPHOS) represents the final step in the conversion of nutrients into cellular energy. Genetic defects in the OXPHOS system have an incidence between 1:5,000 and 1:10,000 live births. Inherited isolated deficiency of the first complex (CI) of this system, a multisubunit assembly of 45 different proteins,…

  13. Cellular mechanisms of arrhythmias: from rate-dependent APD variations to heterocellular coupling

    OpenAIRE

    Salvarani, Nicolò

    2008-01-01

    It is well established that a variety of pathological conditions induces structural and electrical remodeling of the heart which can lead to heart failure and cardiac arrhythmias. Clinically, structural remodeling is characterized by changes in the shape, size and function of the heart. These changes are based on diverse and complex cellular reactions to injury and involve both cardiomyocytes and non-cardiomyocytes. Histopathologically, remodeling typically involves cardiomyocyte hypertrophy,...

  14. Cellular origins and differentiation control mechanisms during periodontal development and wound healing.

    Science.gov (United States)

    Pitaru, S; McCulloch, C A; Narayanan, S A

    1994-03-01

    In the context of cellular origins, odontogenic epithelium and oral epithelium are the sources for junctional epithelium during development and during wound healing respectively. In contrast, both odontogenic and non-odontogenic mesenchyme contain the progenitors for gingival fibroblasts in developing tissues while in wounded tissues, gingival fibroblasts are derived from gingival connective tissues and comprise a heterogeneous population of cells with diverse properties and functions. Periodontal ligament, bone and cementum cell populations apparently originate from dental follicle progenitor cells during development, but during wound healing derive from ancestral cells in periodontal ligament and bone. Cellular differentiation in developing periodontium is governed in part by epithelial-mesenchymal interactions that generate specific signals which regulate selective cell populations in time and space. On the other hand, differentiation during wound healing and regeneration is regulated by a vast array of extracellular matrix informational molecules and by cytokines that induce both selective and non-selective responses in the different cell lineages and their precursors. Further, several important signalling systems are irretrievably lost after development is complete. Thus, in the context of cellular origins and differentiation, developing and wounded periodontal tissues exhibit fundamental differences. Future prospects for improved healing and regeneration of periodontal tissues may derive from identification and isolation of informational molecules that are stored in connective tissue matrices. These molecules and elucidation of their functions may open new perspectives in our understanding of the biology of periodontal wound healing and may provide novel approaches to periodontal regeneration. PMID:8158503

  15. Investigation of mechanical properties for open cellular structure CoCrMo alloy fabricated by selective laser melting process

    Science.gov (United States)

    Azidin, A.; Taib, Z. A. M.; Harun, W. S. W.; Che Ghani, S. A.; Faisae, M. F.; Omar, M. A.; Ramli, H.

    2015-12-01

    Orthodontic implants have been a major focus through mechanical and biological performance in advance to fabricate shape of complex anatomical. Designing the part with a complex mechanism is one of the challenging process and addition to achieve the balance and desired mechanical performance brought to the right manufacture technique to fabricate. Metal additive manufacturing (MAM) is brought forward to the newest fabrication technology in this field. In this study, selective laser melting (SLM) process was utilized on a medical grade cobalt-chrome molybdenum (CoCrMo) alloy. The work has focused on mechanical properties of the CoCrMo open cellular structures samples with 60%, 70%, and 80% designed volume porosity that could potentially emulate the properties of human bone. It was observed that hardness values decreased as the soaking time increases except for bottom face. For compression test, 60% designed volume porosity demonstrated highest ultimate compressive strength compared to 70% and 80%.

  16. Mechanisms underlying the impacts of exotic plant invasions.

    OpenAIRE

    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 st...

  17. Cooperative Mechanism of Supply Chain Under Asymmetric Information

    Institute of Scientific and Technical Information of China (English)

    郭敏; 王红卫; 瞿坦

    2003-01-01

    The cooperative mechanism is one main issue in the decentralized supply chain system, especially in an asymmetric information structure. We analyze the non-cooperative game behavior of a 2-echelon distribution supply chain, compare the results with the system optimal solution, and give the supplier dominated cooperative mechanisms. We also analyze the validity of our contract under the asymmetric retailers' holding cost information and give some useful conclusions.

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

    Science.gov (United States)

    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.

  19. Games of School Choice under the Boston Mechanism

    OpenAIRE

    Haluk Ergin; Tayfun Sönmez

    2005-01-01

    Many school districts in the U.S. use a student assignment mechanism that we refer to as the Boston mechanism. Under this mechanism a student loses his priority at a school unless his parents rank it as their first choice. Therefore parents are given incentives to rank high on their list the schools where the student has a good chance of getting in. We characterize the Nash equilibria of the induced preference revelation game. An important policy implication of our result is that a transition...

  20. Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current

    NARCIS (Netherlands)

    Qi, Xiao Yan; Yeh, Yung-Hsin; Xiao, Ling; Burstein, Brett; Maguy, Ange; Chartier, Denis; Villeneuve, Louis R.; Brundel, Bianca J. J. M.; Dobrev, Dobromir; Nattel, Stanley

    2008-01-01

    Atrial tachycardia (AT) downregulates L-type Ca2+ current (I-CaL) and causes atrial fibrillation -promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cell

  1. Neural Circuitry and Plasticity Mechanisms Underlying Delay Eyeblink Conditioning

    Science.gov (United States)

    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…

  2. A triphasic constrained mixture model of engineered tissue formation under in vitro dynamic mechanical conditioning.

    Science.gov (United States)

    Soares, Joao S; Sacks, Michael S

    2016-04-01

    While it has become axiomatic that mechanical signals promote in vitro engineered tissue formation, the underlying mechanisms remain largely unknown. Moreover, efforts to date to determine parameters for optimal extracellular matrix (ECM) development have been largely empirical. In the present work, we propose a two-pronged approach involving novel theoretical developments coupled with key experimental data to develop better mechanistic understanding of growth and development of dense connective tissue under mechanical stimuli. To describe cellular proliferation and ECM synthesis that occur at rates of days to weeks, we employ mixture theory to model the construct constituents as a nutrient-cell-ECM triphasic system, their transport, and their biochemical reactions. Dynamic conditioning protocols with frequencies around 1 Hz are described with multi-scale methods to couple the dissimilar time scales. Enhancement of nutrient transport due to pore fluid advection is upscaled into the growth model, and the spatially dependent ECM distribution describes the evolving poroelastic characteristics of the scaffold-engineered tissue construct. Simulation results compared favorably to the existing experimental data, and most importantly, distinguish between static and dynamic conditioning regimes. The theoretical framework for mechanically conditioned tissue engineering (TE) permits not only the formulation of novel and better-informed mechanistic hypothesis describing the phenomena underlying TE growth and development, but also the exploration/optimization of conditioning protocols in a rational manner. PMID:26055347

  3. Failure mechanisms in thin rubber sheet composites under static solicitation

    Directory of Open Access Journals (Sweden)

    E. Bayraktar

    2007-03-01

    Full Text Available Purpose: Mechanical behaviour and damage mechanisms in thin rubber sheet composites were investigated under static solicitation at room temperature. Two types of rubber are used in this study; Natural rubber, NR vulcanised and reinforced by carbon black and Synthetic rubber (styrene-butadiene-rubber, SBR.Design/methodology/approach: A comprehensive study has been carried out in order to identify a threshold criterion for the damage mechanism to explain a tearing criterion for the concept of tearing energy of the elastomers and also to give a detail for the damage mechanism depending on the loading conditions. A typical type of specimen geometry of thin sheet rubber composite materials was studied under static tensile tests conducted on the smooth and notched specimens with variable depths. In this way, the effects of the plane stress on the damage mechanism are characterized depending on the rubber materials.Findings: Damage mechanisms during tensile test have been described for both of rubber types and the criteria which characterize the tearing resistance, characteristic energy for tearing (T was explained. Damage in the specimens were evaluated just at the beginning of the tearing by means of the observations in the scanning electron microscopy (SEM.Practical implications: A tearing criterion was suggested in the case of simple tension conditions by assuming large strain. In the next step of this study, a finite element analysis (FEA will be applied under the same conditions of this part in order to obtain the agreement between experimental and FEA results.Originality/value: This study propses a threshold criterion for the damage just at the beginning of the tearing for thin sheet rubber composites and gives a detail discussion for explaining the damage mechanisms by SEM results. This type of study gives many facilities for the sake of simplicity in industrial application.

  4. Designing Microfluidic Devices for Studying Cellular Responses Under Single or Coexisting Chemical/Electrical/Shear Stress Stimuli.

    Science.gov (United States)

    Chou, Tzu-Yuan; Sun, Yung-Shin; Hou, Hsien-San; Wu, Shang-Ying; Zhu, Yun; Cheng, Ji-Yen; Lo, Kai-Yin

    2016-01-01

    Microfluidic devices are capable of creating a precise and controllable cellular micro-environment of pH, temperature, salt concentration, and other physical or chemical stimuli. They have been commonly used for in vitro cell studies by providing in vivo like surroundings. Especially, how cells response to chemical gradients, electrical fields, and shear stresses has drawn many interests since these phenomena are important in understanding cellular properties and functions. These microfluidic chips can be made of glass substrates, silicon wafers, polydimethylsiloxane (PDMS) polymers, polymethylmethacrylate (PMMA) substrates, or polyethyleneterephthalate (PET) substrates. Out of these materials, PMMA substrates are cheap and can be easily processed using laser ablation and writing. Although a few microfluidic devices have been designed and fabricated for generating multiple, coexisting chemical and electrical stimuli, none of them was considered efficient enough in reducing experimental repeats, particular for screening purposes. In this report, we describe our design and fabrication of two PMMA-based microfluidic chips for investigating cellular responses, in the production of reactive oxygen species and the migration, under single or coexisting chemical/electrical/shear stress stimuli. The first chip generates five relative concentrations of 0, 1/8, 1/2, 7/8, and 1 in the culture regions, together with a shear stress gradient produced inside each of these areas. The second chip generates the same relative concentrations, but with five different electric field strengths created within each culture area. These devices not only provide cells with a precise, controllable micro-environment but also greatly increase the experimental throughput. PMID:27584698

  5. Modification of the cellular heat sensitivity of cucumber by growth under supplemental ultraviolet-B radiation

    International Nuclear Information System (INIS)

    The effect of ultraviolet B (UV-B) radiation on the thermal sensitivity of cucumber (Cucumis sativus L.) was studied using UV-B-sensitive cv Poinsett 76 and UV-B-resistant cv Ashley grown under control and elevated (300 mW m-2) UV-B radiation levels. Using both cotyledon and leaf discs, the ability of the tissue to reduce triphenyl tetrazolium chloride (TTC) was determined after treatment at 50 degrees C for various times. Semilogarithmic plots of TTC reduction as a function of time at 50 degrees were curvilinear. They were monophasic for the control cucumber and biphasic for cucumber grown in the presence of elevated UV-B. Treatment of cucumber plants at 37 degrees C for 24 h or of tissue discs at acute UV-B levels for 1 h further modified their response to elevated temperature. These results suggest that growth of cucumber under enhanced UV-B radiation levels increased its ability to withstand elevated temperatures. 19 refs., 2 figs., 2 tabs

  6. Ethanol Neurotoxicity in the Developing Cerebellum: Underlying Mechanisms and Implications

    Directory of Open Access Journals (Sweden)

    Ambrish Kumar

    2013-06-01

    Full Text Available Ethanol is the main constituent of alcoholic beverages that exerts toxicity to neuronal development. Ethanol affects synaptogenesis and prevents proper brain development. In humans, synaptogenesis takes place during the third trimester of pregnancy, and in rodents this period corresponds to the initial few weeks of postnatal development. In this period neuronal maturation and differentiation begin and neuronal cells start migrating to their ultimate destinations. Although the neuronal development of all areas of the brain is affected, the cerebellum and cerebellar neurons are more susceptible to the damaging effects of ethanol. Ethanol’s harmful effects include neuronal cell death, impaired differentiation, reduction of neuronal numbers, and weakening of neuronal plasticity. Neuronal development requires many hormones and growth factors such as retinoic acid, nerve growth factors, and cytokines. These factors regulate development and differentiation of neurons by acting through various receptors and their signaling pathways. Ethanol exposure during development impairs neuronal signaling mechanisms mediated by the N-methyl-d-aspartate (NMDA receptors, the retinoic acid receptors, and by growth factors such as brain-derived neurotrophic factor (BDNF, insulin-like growth factor 1 (IGF-I, and basic fibroblast growth factor (bFGF. In combination, these ethanol effects disrupt cellular homeostasis, reduce the survival and migration of neurons, and lead to various developmental defects in the brain. Here we review the signaling mechanisms that are required for proper neuronal development, and how these processes are impaired by ethanol resulting in harmful consequences to brain development.

  7. Cellular and molecular mechanism study of declined intestinal transit function in the cholesterol gallstone formation process of the guinea pig

    OpenAIRE

    Fan, Ying; Wu, Shuodong; YIN, ZHENHUA; Fu, Bei-Bei

    2014-01-01

    The aim of this study was to investigate the cellular and molecular mechanisms of declined intestinal transit (IT) function in the cholesterol gallstone (CG) formation process. Forty guinea pigs were divided into an experimental group (EG) and a control group (CoG), and the reverse transcription-polymerase chain reaction (RT-PCR) was performed for the analysis of c-kit and stem cell factor (scf) mRNA expression in the small bowel. In addition, immunofluorescence staining and confocal laser mi...

  8. MECHANISMS OF DAMAGING EFFECT OF MANGENESE IN TOXIC CONCENTRATIONS ON CELLULAR AND SUBCELLULAR LEVELS

    Directory of Open Access Journals (Sweden)

    Goncharenko A. V.

    2012-11-01

    Full Text Available Influence of subtoxic concentration of manganese chloride in dose equal to LD 50 on condition of plasmatic membranes (model: erythrocytes and functional activity of cell power (model: the isolated liver mitochondrion of rats was studied. It was established that manganese chloride in fixed concentration caused authentic augmentation of sorption capacity of erythrocytes towards alcian blue, influenced increasing of their spontaneous haemolysis and activation of peroxide oxidation of lipids. In experiment on the isolated mitochondrion it was proved that manganese chloride caused dissociation of an oxidizing phosphorusling and complete inhibition of respiration in concentrations of 3 and 4,5mM. These dependences testify that subtoxic concentration of manganese can damage the cell energy. Thus, this pilot research indicated damaging effect of manganese on cellular (erythrocytes and subcellular (mitochondrion levels which are realized through external functioning of membrane structures and deprived them from restoration.

  9. Mechanisms and Regulation of Intestinal Absorption of Water-soluble Vitamins: Cellular and Molecular Aspects

    DEFF Research Database (Denmark)

    Nexø, Ebba; Said, Hamid M

    2012-01-01

    The water-soluble vitamins represent a group of structurally and functionally unrelated compounds that share the common feature of being essential for normal cellular functions, growth, and development. With the exception of some endogenous production of niacin, human cells cannot synthesize thes...... deficiency. An impaired absorptive function occurs in a variety of conditions including congenital defects in the digestive or absorptive processes, intestinal diseases, drug interaction, and chronic alcohol use....... micronutrients, and thus, must obtain them from exogenous sources via intestinal absorption. The intestine, therefore, plays a critical role in maintaining and regulating normal body homeostasis of these essential nutrients, and interference with its normal absorptive function could lead to suboptimal states or...

  10. Cellular and Molecular Mechanisms of 3,3′-Diindolylmethane in Gastrointestinal Cancer

    Directory of Open Access Journals (Sweden)

    Soo Mi Kim

    2016-07-01

    Full Text Available Studies in humans have shown that 3,3′-diindolylmethane (DIM, which is found in cruciferous vegetables, such as cabbage and broccoli, is effective in the attenuation of gastrointestinal cancers. This review presents the latest findings on the use, targets, and modes of action of DIM for the treatment of human gastrointestinal cancers. DIM acts upon several cellular and molecular processes in gastrointestinal cancer cells, including apoptosis, autophagy, invasion, cell cycle regulation, metastasis, angiogenesis, and endoplasmic reticulum (ER stress. In addition, DIM increases the efficacy of other drugs or therapeutic chemicals when used in combinatorial treatment for gastrointestinal cancer. The studies to date offer strong evidence to support the use of DIM as an anticancer and therapeutic agent for gastrointestinal cancer. Therefore, this review provides a comprehensive understanding of the preventive and therapeutic properties of DIM in addition to its different perspective on the safety of DIM in clinical applications for the treatment of gastrointestinal cancers.

  11. Mechanical Analysis of Concrete Specimen under Restrained Condition

    Institute of Scientific and Technical Information of China (English)

    MA Xinwei; NIU Changren; R D Hooton

    2005-01-01

    In order to quantify the development of the tensile stresses and obtain a reliable estimation of the cracking risk, the concrete was subjected to restrained conditions. The fully restrained condition was achieved by keeping the length constant of a concrete specimen. Comparing the free shrinkage with the restrained shrinkage,tensile creep could be discriminated from shrinkage. The testing method was introduced in details, and the mechanical behaviors under tensile load were analyzed. Results show that concrete exhibits a pronounced viscoelasticity. Under restrained condition, the self induced tensile stress increases with time. The lower the water to cement ratio, the larger the tensile stress at the same age. The tensile creep of hardening concrete is much larger than that of hardened concrete. The relationships among autogenous shrinkage under free condition, elastic strain and creep under restrained condition are described, and the mathematical model for the calculation of elastic strain and creep is proposed.

  12. A possible realization of Einstein's causal theory underlying quantum mechanics

    International Nuclear Information System (INIS)

    It is shown that a new microscopic mechanics formulated earlier can be looked upon as a possible causal theory underlying quantum mechanics, which removes Einstein's famous objections against quantum theory. This approach is free from objections raised against Bohm's hidden variable theory and leads to a clear physical picture in terms of familiar concepts, if self interactions are held responsible for deviations from classical behaviour. The new level of physics unfolded by this approach may reveal novel frontiers in high-energy physics. (author)

  13. Permeability and mechanical properties of cracked glass under pressure

    International Nuclear Information System (INIS)

    Crack initiation and growth in brittle solids under tension have been extensively studied by various experimental, theoretical and numerical approaches. If has been established that dynamic brittle fracture is related to fundamental physical parameters and processes, such as crack speed, crack branching, surface roughening, and dynamic instabilities. On the other hand, less studies have been done in the area of compressive fracture despite its vital importance in geology, material science and engineering applications (such as the improvement and the insurance of the nuclear wastes storage). The present work aims to investigate thermo-mechanical cracking effects on elastic wave velocities, mechanical strength and permeability und r pressure to evaluate damage evolution, brittle failure and transport properties on a synthetic glass (SON 68), and to highlight the very different behavior of the glass amorphous structure compared to any rock structure. The original glass, produced in ideal conditions of slow cooling that prevent from any crack formation, exhibits a linear and reversible mechanical behavior and isotropic elastic velocities, as expected. It also presents a high strength as it fails at about 700 MPa of deviatoric stress for a confining pressure of 15 MPa. We choose to apply to some original glass samples a reproducible method (thermal treatment with a thermal shock of T=100,200 and 300 C) which creates cracks with a homogeneous distribution. The impact of the thermal treatment is clearly visible through the elastic wave velocity measurements as we observe crack closure under hydrostatic conditions (at about 30 MPa). For T ≥ 200 C, the glass mechanical behavior becomes non linear and records an irreversible damage. The total damage observed with the acoustic emissions in these samples underlines the combination of the thermal and the mechanical cracks which drive to the sample failure. The results obtained with pore fluid pressure show a very small

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

    Science.gov (United States)

    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

  15. Cellular Homeostasis and Aging.

    Science.gov (United States)

    Hartl, F Ulrich

    2016-06-01

    Aging and longevity are controlled by a multiplicity of molecular and cellular signaling events that interface with environmental factors to maintain cellular homeostasis. Modulation of these pathways to extend life span, including insulin-like signaling and the response to dietary restriction, identified the cellular machineries and networks of protein homeostasis (proteostasis) and stress resistance pathways as critical players in the aging process. A decline of proteostasis capacity during aging leads to dysfunction of specific cell types and tissues, rendering the organism susceptible to a range of chronic diseases. This volume of the Annual Review of Biochemistry contains a set of two reviews addressing our current understanding of the molecular mechanisms underlying aging in model organisms and humans. PMID:27050288

  16. Inter-cellular nanovesicle mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth

    Science.gov (United States)

    Kogure, Takayuki; Lin, Wen-Lang; Yan, Irene K.; Braconi, Chiara; Patel, Tushar

    2011-01-01

    Hepatocellular carcinoma (HCC) is characterized by a propensity for multifocality, growth by local spread, and dysregulation of multiple signaling pathways. These features may be determined by the tumoral microenvironment. The potential of tumor cells to modulate HCC growth and behavior by secreted proteins has been extensively studied. In contrast the potential for genetic modulation is poorly understood. We investigated the role and involvement of tumor derived nanovesicles capable of altering gene expression, and characterized their ability to modulate cell signaling and biological effects in other cells. We show that HCC cells can produce nanovesicles, exosomes, that differ in both RNA and protein content from their cells of origin. These can be taken up and internalized by other cells, and can transmit a functional transgene. The microRNA content of these exosomes was examined, and a subset that is highly enriched within exosomes was identified. A combinatorial approach to identify potential targets identified transforming growth factor β activated kinase-1 (TAK1) as the most likely candidate pathway that could be modulated by these miRNA. Loss of TAK1 has been implicated in hepatocarcinogenesis and is a biologically plausible target for inter-cellular modulation. We showed that HCC cell derived exosomes can modulate TAK1 expression and associated signaling and enhance transformed cell growth in recipient cells. Conclusion: Exosome mediated miRNA transfer is an important mechanism of inter-cellular communication in HCC cells. These observations identify a unique inter-cellular mechanism that could potentially contribute to local spread, intrahepatic metastases or multifocal growth in HCC. PMID:21721029

  17. Mechanism of Laser/light beam interaction at cellular and tissue level and study of the influential factors for the application of low level laser therapy

    OpenAIRE

    Khalid, Muhammad Zeeshan

    2016-01-01

    After the discovery of laser therapy it was realized it has useful application of wound healing and reduce pain, but due to the poor understanding of the mechanism and dose response this technique remained to be controversial for therapeutic applications. In order to understand the working and effectiveness different experiments were performed to determine the laser beam effect at the cellular and tissue level. This article discusses the mechanism of beam interaction at tissues and cellular l...

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

    Science.gov (United States)

    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

  19. Crack arrest saturation model under combined electrical and mechanical loadings

    OpenAIRE

    R.R. Bhargava; A. Setia

    2009-01-01

    Purpose: The investigation aims at proposing a model for cracked piezoelectric strip which is capable to arrest the crack.Design/methodology/approach: Under the combined effect of electrical and mechanical loadings applied at the edges of the strip, the developed saturation zone is produced at each tip of the crack. To arrest further opening of the crack, the rims of the developed saturation zones are subjected to in-plane cohesive, normal uniform constant saturation point electrical displace...

  20. Underlying mechanisms and the evolving influence of diet

    DEFF Research Database (Denmark)

    Larsen, Lesli Hingstrup

    2012-01-01

    to increased risk of developing obesity. Recently, the intestinal microbiome, the collected genome of the bacteria, also has been associated with obesity and with specific dietary profiles. The underlying mechanisms determining the susceptibility to obesity do not only include the genome but also the...... epigenome and the microbiome that can be modified by diet, and by genotype, adding to the complexity of determining the contributors to obesity....

  1. Brain mechanisms underlying sensation-seeking in humans

    OpenAIRE

    Norbury, A. E.

    2015-01-01

    Sensation-seeking is a personality trait concerned with motivation for intense and unusual sensory experiences, that has been identified as risk factor for a variety of psychopathologies with high social cost; in particular gambling and substance addictions. It has previously proved difficult to tease out neural mechanisms underlying sensation-seeking in humans, due to a lack of cognitive-behavioural paradigms probing sensation-seeking-like behaviour in the lab. The first aim of this thesis w...

  2. Mechanisms underlying reduced responsiveness of neonatal neutrophils to distinct chemoattractants

    OpenAIRE

    Weinberger, Barry; Laskin, Debra L.; Mariano, Thomas M.; Sunil, Vasanthi R.; DeCoste, Christina J.; Heck, Diane E.; Carol R. Gardner; Laskin, Jeffrey D.

    2001-01-01

    Potential mechanisms underlying impaired chemotactic responsiveness of neonatal neutrophils were investigated. Two distinct chemoattractants were compared: bacterially derived N-formyl-methionyl-leucyl-phenylalanine (fMLP) and a unique chemotactic monoclonal antibody, designated DL1.2, which binds to a neutrophil antigen with an apparent molecular mass of 120 kDa. Chemotaxis of neutrophils toward fMLP, as well as DL1.2, was reduced in neonates when compared with adult cells. This did not appe...

  3. Mechanisms underlying the antidepressant response and treatment resistance

    OpenAIRE

    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 ...

  4. Mechanisms Underlying the Antidepressant Response and Treatment Resistance

    OpenAIRE

    Marjorie Rose Levinstein; Benjamin Adam Samuels

    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 ...

  5. Mechanisms Underlying the Link between Cannabis Use and Prospective Memory

    OpenAIRE

    Carrie Cuttler; McLaughlin, Ryan J.; Peter Graf

    2012-01-01

    While the effects of cannabis use on retrospective memory have been extensively examined, only a limited number of studies have focused on the links between cannabis use and prospective memory. We conducted two studies to examine the links between cannabis use and both time-based and event-based prospective memory as well as potential mechanisms underlying these links. For the first study, 805 students completed an online survey designed to assess cannabis consumption, problems with cannabis ...

  6. The asymmetric self-assembly mechanism of adherens junctions: a cellular push–pull unit

    International Nuclear Information System (INIS)

    To form adherens junctions (AJ), cells first establish contact by sending out lamellipodia onto neighboring cells. We investigated the role of contacting cells in AJ assembly by studying an asymmetric AJ motif: finger-like AJ extending across the cell–cell interface. Using a cytoskeleton replica and immunofluorescence, we observed that actin bundles embedded in the lamellipodia are co-localized with stress fibers in the neighboring cell at the AJ. This suggests that donor lamellipodia present actin fingers, which are stabilized by acceptor lamellae via acto-myosin contractility. Indeed, we show that changes in actin network geometry promoted by Rac overexpression lead to corresponding changes in AJ morphology. Moreover, contractility inhibition and enhancement (via drugs or local traction) lead respectively to the disappearance and further growth of AJ fingers. Thus, we propose that receiving lamellae exert a local pull on AJ, promoting further polymerization of the donor actin bundles. In spite of different compositions, AJ and focal contacts both act as cellular mechanosensors

  7. [Changes of the neuronal membrane excitability as cellular mechanisms of learning and memory].

    Science.gov (United States)

    Gaĭnutdinov, Kh L; Andrianov, V V; Gaĭnutdinova, T Kh

    2011-01-01

    In the presented review given literature and results of own studies of dynamics of electrical characteristics of neurons, which change are included in processes both an elaboration of learning, and retention of the long-term memory. Literary datas and our results allow to conclusion, that long-term retention of behavioural reactions during learning is accompanied not only by changing efficiency of synaptic transmission, as well as increasing of excitability of command neurons of the defensive reflex. This means, that in the process of learning are involved long-term changes of the characteristics a membrane of certain elements of neuronal network, dependent from the metabolism of the cells. see text). Thou phenomena possible mark as cellular (electrophysiological) correlates of long-term plastic modifications of the behaviour. The analyses of having results demonstrates an important role of membrane characteristics of neurons (their excitability) and parameters an synaptic transmission not only in initial stage of learning, as well as in long-term modifications of the behaviour (long-term memory). PMID:21442956

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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)

  10. An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development

    Directory of Open Access Journals (Sweden)

    Xinglong Gu

    2016-01-01

    Full Text Available 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, whereas 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.

  11. Neural mechanisms underlying morphine withdrawal in addicted patients: a review

    Directory of Open Access Journals (Sweden)

    Nima Babhadiashar

    2015-06-01

    Full Text Available Morphine is one of the most potent alkaloid in opium, which has substantial medical uses and needs and it is the first active principle purified from herbal source. Morphine has commonly been used for relief of moderate to severe pain as it acts directly on the central nervous system; nonetheless, its chronic abuse increases tolerance and physical dependence, which is commonly known as opiate addiction. Morphine withdrawal syndrome is physiological and behavioral symptoms that stem from prolonged exposure to morphine. A majority of brain regions are hypofunctional over prolonged abstinence and acute morphine withdrawal. Furthermore, several neural mechanisms are likely to contribute to morphine withdrawal. The present review summarizes the literature pertaining to neural mechanisms underlying morphine withdrawal. Despite the fact that morphine withdrawal is a complex process, it is suggested that neural mechanisms play key roles in morphine withdrawal.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  14. Cellular and Network Mechanisms Underlying Information Processing in a Simple Sensory System

    Science.gov (United States)

    Jacobs, Gwen; Henze, Chris; Biegel, Bryan (Technical Monitor)

    2002-01-01

    Realistic, biophysically-based compartmental models were constructed of several primary sensory interneurons in the cricket cercal sensory system. A dynamic atlas of the afferent input to these cells was used to set spatio-temporal parameters for the simulated stimulus-dependent synaptic inputs. We examined the roles of dendritic morphology, passive membrane properties, and active conductances on the frequency tuning of the neurons. The sensitivity of narrow-band low pass interneurons could be explained entirely by the electronic structure of the dendritic arbors and the dynamic sensitivity of the SIZ. The dynamic characteristics of interneurons with higher frequency sensitivity required models with voltage-dependent dendritic conductances.

  15. A Role for Histone Deacetylases in the Cellular and Behavioral Mechanisms Underlying Learning and Memory

    Science.gov (United States)

    Mahgoub, Melissa; Monteggia, Lisa M.

    2014-01-01

    Histone deacetylases (HDACs) are a family of chromatin remodeling enzymes that restrict access of transcription factors to the DNA, thereby repressing gene expression. In contrast, histone acetyltransferases (HATs) relax the chromatin structure allowing for an active chromatin state and promoting gene transcription. Accumulating data have…

  16. Cellular mechanisms underlying the laxative effect of flavonol naringenin on rat constipation model.

    Directory of Open Access Journals (Sweden)

    Zi-Huan Yang

    Full Text Available BACKGROUND & AIMS: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively. METHODS/PRINCIPAL FINDINGS: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC, which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid, but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid. Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl azacyclotridecan-2-imine-hydrochloride pretreatment reduced the naringenin-induced I(SC. In addition, significant inhibition of the naringenin-induced I(SC by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group. CONCLUSIONS: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation.

  17. Cellular mechanism underlying formaldehyde-stimulated Cl- secretion in rat airway epithelium.

    Directory of Open Access Journals (Sweden)

    Yu-Li Luo

    Full Text Available BACKGROUND: Recent studies suggest that formaldehyde (FA could be synthesized endogeneously and transient receptor potential (TRP channel might be the sensor of FA. However, the physiological significance is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: The present study investigated the FA induced epithelial Cl(- secretion by activation of TRPV-1 channel located in the nerve ending fiber. Exogenously applied FA induced an increase of I(SC in intact rat trachea tissue but not in the primary cultured epithelial cells. Western blot and immunofluorescence analysis identified TRPV-1 expression in rat tracheal nerve ending. Capsazepine (CAZ, a TRPV-1 specific antagonist significantly blocked the I(SC induced by FA. The TRPV-1 agonist capsaicin (Cap induced an increase of I(SC, which was similar to the I(SC induced by FA. L-703606, an NK-1 specific inhibitor and propranolol, an adrenalin β receptor inhibitor significantly abolished the I(SC induced by FA or Cap. In the ion substitute analysis, FA could not induce I(SC in the absence of extracelluar Cl(-. The I(SC induced by FA could be blocked by the non-specific Cl(- channel inhibitor DPC and the CFTR specific inhibitor CFTR(i-172, but not by the Ca(2+-activated Cl(- channel inhibitor DIDS. Furthermore, both forskolin, an agonist of adenylate cyclase (AC and MDL-12330A, an antagonist of AC could block FA-induced I(SC. CONCLUSION: Our results suggest that FA-induced epithelial I(SC response is mediated by nerve, involving the activation of TRPV-1 and release of adrenalin as well as substance P.

  18. Cellular and Deafness Mechanisms Underlying Connexin Mutation-Induced Hearing Loss – A Common Hereditary Deafness

    OpenAIRE

    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 th...

  19. Olfactory Stem Cells, a New Cellular Model for Studying Molecular Mechanisms Underlying Familial Dysautonomia

    OpenAIRE

    Nathalie Boone; Béatrice Loriod; Aurélie Bergon; Oualid Sbai; Christine Formisano-Tréziny; Jean Gabert; Michel Khrestchatisky; Catherine Nguyen; François Féron; Axelrod, Felicia B.; El Chérif Ibrahim

    2010-01-01

    BACKGROUND: Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and mod...

  20. Fundamental molecular mechanism for the cellular uptake of guanidinium-rich molecules.

    Science.gov (United States)

    Herce, Henry D; Garcia, Angel E; Cardoso, M Cristina

    2014-12-17

    Guanidinium-rich molecules, such as cell-penetrating peptides, efficiently enter living cells in a non-endocytic energy-independent manner and transport a wide range of cargos, including drugs and biomarkers. The mechanism by which these highly cationic molecules efficiently cross the hydrophobic barrier imposed by the plasma membrane remains a fundamental open question. Here, a combination of computational results and in vitro and live-cell experimental evidence reveals an efficient energy-independent translocation mechanism for arginine-rich molecules. This mechanism unveils the essential role of guanidinium groups and two universal cell components: fatty acids and the cell membrane pH gradient. Deprotonated fatty acids in contact with the cell exterior interact with guanidinium groups, leading to a transient membrane channel that facilitates the transport of arginine-rich peptides toward the cell interior. On the cytosolic side, the fatty acids become protonated, releasing the peptides and resealing the channel. This fundamental mechanism appears to be universal across cells from different species and kingdoms. PMID:25405895

  1. Peripheral Receptor Mechanisms Underlying Orofacial Muscle Pain and Hyperalgesia

    Science.gov (United States)

    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

  2. Mechanical and electronical properties of ZnS under pressure

    Directory of Open Access Journals (Sweden)

    M. Bilge

    2008-11-01

    Full Text Available Purpose: The wide-gap semiconductor materials are very important for application in the fields of optical device technology. ZnS is wide-gap semiconductor that is attractive material due to the polymorphic structural transformation and it is suitable semiconductor for applications in infrared optics, ultraviolet laser devices, electronic image display, high-density optical memory, solar cell etc. The goal is to evaluate mechanical and electrical properties of ZnS dunder pressure.Design/methodology/approach: We report ab-initio calculations of lattice constants, bulk modulus and elastic constants of the B1 (rocksalt, B3 (zincblende and B4 (wurtzite structures of ZnS. Ab-initio calculations are based on the density functional theory (DFT within generalized gradient approximation (GGA for the exchange-correlation potential.Findings: Phase transition pressures from B4 phase to B3 phase, from B3 phase to B1 phase and from B4 phase to B1 are predicted from intersection of the enthalpy-pressure data for the three phases. These results are consistent with the experimental and other theoretical calculations. Mechanical properties of ZnS under high pressure are also calculated. It is seen that the mechanical properties of ZnS under high pressure are quite different from those ambient condition. The band structure, density of states (DOS and energy gaps are also given for B3 structure of ZnS.Research limitations/implications: The results are compared with the previous theoretical and experimental data.Originality/value: Evaluation of mechanic and electronical properties of ZnS under pressure.

  3. 'Effective inefficiency': cellular control of protein trafficking as a mechanism of post-translational regulation.

    Science.gov (United States)

    Conn, P Michael; Janovick, Jo Ann; Brothers, Shaun P; Knollman, Paul E

    2006-07-01

    The great writer and polyglot, W Somerset Maugham said, 'I'll give you my opinion of the human race in a nutshell...their heart's in the right place, but their head is a thoroughly inefficient organ.' If his words are applied to trafficking of the human pituitary gonadotropin-releasing hormone receptor, it turns out that he was more right than he knew. Paradoxically, the inefficiency of receptor trafficking to the plasma membrane can bring regulatory advantages to cells. Understanding the mechanism by which cells recognize correctly folded proteins in health and disease opens doors to new therapeutic approaches and provides a more accurate view of mechanisms of normal cell function than is presently available. PMID:16837606

  4. Cellular Mechanisms of Tissue Fibrosis. 6. Purinergic signaling and response in fibroblasts and tissue fibrosis

    OpenAIRE

    Lu, David; Insel, Paul A.

    2013-01-01

    Tissue fibrosis occurs as a result of the dysregulation of extracellular matrix (ECM) synthesis. Tissue fibroblasts, resident cells responsible for the synthesis and turnover of ECM, are regulated via numerous hormonal and mechanical signals. The release of intracellular nucleotides and their resultant autocrine/paracrine signaling have been shown to play key roles in the homeostatic maintenance of tissue remodeling and in fibrotic response post-injury. Extracellular nucleotides signal throug...

  5. Chinese Medicines Induce Cell Death: The Molecular and Cellular Mechanisms for Cancer Therapy

    OpenAIRE

    Xuanbin Wang; Yibin Feng; Ning Wang; Fan Cheung; Hor Yue Tan; Sen Zhong; Charlie Li; Seiichi Kobayashi

    2014-01-01

    Chinese medicines have long history in treating cancer. With the growing scientific evidence of biomedical researches and clinical trials in cancer therapy, they are increasingly accepted as a complementary and alternative treatment. One of the mechanisms is to induce cancer cell death. Aim. To comprehensively review the publications concerning cancer cell death induced by Chinese medicines in recent years and provide insights on anticancer drug discovery from Chinese medicines. Materials and...

  6. Molecular, Cellular, and Structural Mechanisms of Cocaine Addiction: A Key Role for MicroRNAs

    OpenAIRE

    Jonkman, Sietse; Kenny, Paul J.

    2012-01-01

    The rewarding properties of cocaine play a key role in establishing and maintaining the drug-taking habit. However, as exposure to cocaine increases, drug use can transition from controlled to compulsive. Importantly, very little is known about the neurobiological mechanisms that control this switch in drug use that defines addiction. MicroRNAs (miRNAs) are small non-protein coding RNA transcripts that can regulate the expression of messenger RNAs that code for proteins. Because of their high...

  7. Fundamental Molecular Mechanism for the Cellular Uptake of Guanidinium-Rich Molecules

    OpenAIRE

    Herce, Henry D.; Garcia, Angel E.; Cardoso, M. Cristina

    2014-01-01

    Guanidinium-rich molecules, such as cell-penetrating peptides, efficiently enter living cells in a non-endocytic energy-independent manner and transport a wide range of cargos, including drugs and biomarkers. The mechanism by which these highly cationic molecules efficiently cross the hydrophobic barrier imposed by the plasma membrane remains a fundamental open question. Here, a combination of computational results and in vitro and live-cell experimental evidence reveals an efficient energy-i...

  8. Cellular mechanisms of alpha herpesvirus egress: live cell fluorescence microscopy of pseudorabies virus exocytosis.

    OpenAIRE

    Hogue, Ian B.; Jens B Bosse; Jiun-Ruey Hu; Thiberge, Stephan Y.; Enquist, Lynn W.

    2014-01-01

    Egress of newly assembled herpesvirus particles from infected cells is a highly dynamic process involving the host secretory pathway working in concert with viral components. To elucidate the location, dynamics, and molecular mechanisms of alpha herpesvirus egress, we developed a live-cell fluorescence microscopy method to visualize the final transport and exocytosis of pseudorabies virus (PRV) particles in non-polarized epithelial cells. This method is based on total internal reflection fluo...

  9. Phytoplankton calcification as an effective mechanism to alleviate cellular calcium poisoning

    OpenAIRE

    Müller, M. N.; Barcelos e Ramos, J.; Schulz, K. G.; U. Riebesell; J. Kaźmierczak; Gallo, F.; Mackinder, L.; Li, Y; P. N. Nesterenko; T. W. Trull; Hallegraeff, G.M.

    2015-01-01

    Marine phytoplankton have developed the remarkable ability to tightly regulate the concentration of free calcium ions in the intracellular cytosol at a level of ~ 0.1 μmol L−1 in the presence of seawater Ca2+ concentrations of 10 mmol L−1. The low cytosolic calcium ion concentration is of utmost importance for proper cell signalling function. While the regulatory mechanisms responsible for the tight control of intracellular Ca2+ concentration are not completely understood, ...

  10. Phytoplankton calcification as an effective mechanism to prevent cellular calcium poisoning

    OpenAIRE

    Müller, M. N.; J. Barcelos e Ramos; Schulz, K. G.; U. Riebesell; J. Kaźmierczak; Gallo, F.; Mackinder, L.; Y. Li; P. N. Nesterenko; T. W. Trull; Hallegraeff, G.M.

    2015-01-01

    Marine phytoplankton has developed the remarkable ability to tightly regulate the concentration of free calcium ions in the intracellular cytosol at a level of ~ 0.1 μmol L−1 in the presence of seawater Ca2+ concentrations of 10 mmol L−1. The low cytosolic calcium ion concentration is of utmost importance for proper cell signalling function. While the regulatory mechanisms responsible for the tight control of intracellular Ca2+ concentration are not completely understood, ...

  11. 1. Morphological Implication on Cellular Response to Mechanical Stress in Bone.

    Science.gov (United States)

    Amizuka, Norio

    2016-08-01

    In bone, there are 3 distinct cell types: an osteoblast, a bone forming cell; an osteocyte embedded in bone matrix as a consequence of being differentiated from an osteoblast; and an osteoclast, a multinucleated giant cell responsible for bone resorption. Bone is always remodeled by replacing old bone with new bone (bone remodeling), by which bone can maintain its stiffness and flexibility. However, in an osteoporotic state, the disrupted balance between bone resorption and formation results in not only markedly reduced bone mass, but also in disorganized geometry of trabecules, which can often give rise to a bone fracture. Osteocytes located in their lacunae insert their fine cytoplasmic processes into narrow passageways referred to as osteocytic canaliculi. Neighboring osteocytes connect to each other by means of a gap junction in their cytoplasmic processes. Therefore, osteocytes and their lacunae/canaliculi appear to form functional syncytium called osteocytic lacunar canalicular system (OLCS). The geometrical distribution of OLCS is poorly arranged in immature bone, while it appears well-arranged distribution in mature bone (cortical bone), in which molecular transports and sensing mechanical stress seems to be efficient, and therefore, may be able to respond to mechanical stress. In this seminar, I will introduce our recent findings on the morphology and function of OLCS which may respond to mechanical stress. PMID:27441762

  12. (Some cellular mechanisms influencing the transcription of human endogenous retrovirus, HERV-Fc1.

    Directory of Open Access Journals (Sweden)

    Magdalena Janina Laska

    Full Text Available DNA methylation and histone acetylation are epigenetic modifications that act as regulators of gene expression. DNA methylation is considered an important mechanism for silencing of retroelements in the mammalian genome. However, the methylation of human endogenous retroviruses (HERVs is not well investigated. The aim of this study was to investigate the transcriptional potential of HERV-Fc1 proviral 5'LTR in more detail, and examined the specific influence of CpG methylation on this LTR in number of cell lines. Specifically, the role of demethylating chemicals e.g. 5-aza-2' deoxycytidine and Trichostatin-A, in inducing or reactivating expression of HERV-Fc1 specific sequences and the mechanisms were investigated. In our present study, 5-aza-dC is shown to be a powerful inducer of HERV-Fc1, and at the same time it strongly inhibits methylation of DNA. Treatment with this demethylating agent 5-aza-dC, results in significantly increased levels of HERV-Fc1 expression in cells previously not expressing HERV-Fc1, or with a very low expression level. The extent of expression of HERV-Fc1 RNAs precisely correlates with the apparent extent of demethylation of the related DNA sequences. In conclusion, the results suggest that inhibition of DNA methylation/histone deacetylase can interfere with gene silencing mechanisms affecting HERV-Fc1 expression in human cells.

  13. Energy cost and putative benefits of cellular mechanisms modulating buoyancy in aflagellate marine phytoplankton.

    Science.gov (United States)

    Lavoie, Michel; Raven, John A; Levasseur, Maurice

    2016-04-01

    Little information is available on the energetics of buoyancy modulation in aflagellate phytoplankton, which comprises the majority of autotrophic cells found in the ocean. Here, we computed for three aflagellate species of marine phytoplankton (Emiliania huxleyi, Thalassiosira pseudonana, and Ethmodiscus rex) the theoretical minimum energy cost as photons absorbed and nitrogen resource required of the key physiological mechanisms (i.e., replacement of quaternary ammonium by dimethyl-sulfoniopropionate, storage of polysaccharides, and cell wall biosynthesis) affecting the cell's vertical movement as a function of nitrogen (N) availability. These energy costs were also normalized to the capacity of each buoyancy mechanism to modulate sinking or rising rates based on Stokes' law. The three physiological mechanisms could act as ballast in the three species tested in conditions of low N availability at a low fraction (<12%) of the total photon energy cost for growth. Cell wall formation in E. huxleyi was the least costly ballast strategy, whereas in T. pseudonana, the photon energy cost of the three ballast strategies was similar. In E. rex, carbohydrate storage and mobilization appear to be energetically cheaper than modulations in organic solute synthesis to achieve vertical migration. This supports the carbohydrate-ballast strategy for vertical migration for this species, but argues against the theory of replacement of low- or high-density organic solutes. This study brings new insights into the energy cost and potential selective advantages of several strategies modulating the buoyancy of aflagellate marine phytoplankton. PMID:27037589

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

    OpenAIRE

    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 dysfu...

  15. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Directory of Open Access Journals (Sweden)

    Ana-Maria Florea

    2011-03-01

    Full Text Available Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs and might provide new therapeutic strategies and reduce side effects.

  16. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Energy Technology Data Exchange (ETDEWEB)

    Florea, Ana-Maria [Department of Neuropathology, Heinrich-Heine University, Düsseldorf (Germany); Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144, Doha (Qatar)

    2011-03-15

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

  17. Adaptive response: some underlying mechanisms and open questions

    Directory of Open Access Journals (Sweden)

    Evgeniya G. Dimova

    2008-01-01

    Full Text Available Organisms are affected by different DNA damaging agents naturally present in the environment or released as a result of human activity. Many defense mechanisms have evolved in organisms to minimize genotoxic damage. One of them is induced radioresistance or adaptive response. The adaptive response could be considered as a nonspecific phenomenon in which exposure to minimal stress could result in increased resistance to higher levels of the same or to other types of stress some hours later. A better understanding of the molecular mechanism underlying the adaptive response may lead to an improvement of cancer treatment, risk assessment and risk management strategies, radiation protection, e.g. of astronauts during long-term space flights. In this mini-review we discuss some open questions and the probable underlying mechanisms involved in adaptive response: the transcription of many genes and the activation of numerous signaling pathways that trigger cell defenses - DNA repair systems, induction of proteins synthesis, enhanced detoxification of free radicals and antioxidant production.

  18. Large Chip Production Mechanism under the Extreme Load Cutting Conditions

    Institute of Scientific and Technical Information of China (English)

    LIU Xianli; HE Genghuang; YAN Fugang; CHENG Yaonan; LIU Li

    2015-01-01

    There has existed a great deal of theory researches in term of chip production and chip breaking characteristics under conventional cutting and high speed cutting conditions, however, there isn’t sufficient research on chip formation mechanism as well as its influence on cutting state regarding large workpieces under extreme load cutting. This paper presents a model of large saw-tooth chip through applying finite element simulation method, which gives a profound analysis about the characteristics of the extreme load cutting as well as morphology and removal of the large chip. In the meantime, a calculation formula that gives a quantitative description of the saw-tooth level regarding the large chip is established on the basis of cutting experiments on high temperature and high strength steel 2.25Cr-1Mo-0.25V. The cutting experiments are carried out by using the scanning electron microscope and super depth of field electron microscope to measure and calculate the large chip produced under different cutting parameters, which can verify the validity of the established model. The calculating results show that the large saw-toothed chip is produced under the squeezing action between workpiece and cutting tools. In the meanwhile, the chip develops a hardened layer where contacts the cutting tool and the saw-tooth of the chip tend to form in transverse direction. This research creates the theoretical model for large chip and performs the cutting experiments under the extreme load cutting condition, as well as analyzes the production mechanism of the large chip in the macro and micro conditions. Therefore, the proposed research could provide theoretical guidance and technical support in improving productivity and cutting technology research.

  19. Cellular Mechanism of Newly Synthesized Indoledione Derivative-induced Immunological Death of Tumor Cell

    OpenAIRE

    Oh, Su-Jin; Ryu, Chung-Kyu; Baek, So-Young; Lee, Hyunah

    2011-01-01

    Background EY-6 is one of the newly synthesized indoledione derivatives to induce tumor cell-specific cell death. In this study, we investigated the mechanism of immunological death induced by EY-6 at mouse colon cancer cell as well as at the normal immune cell represented by dendritic cell. Methods C57BL/6 mouse syngeneic colon cancer cell MC38 was treated with EY-6, and analyzed by MTT for viability test, flow cytometry for confirming surface expressing molecules and ELISA for detection of ...

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

    Science.gov (United States)

    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. Quasi-nano wear mechanism under repeated impact contact loading

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    A new quasi-nano wear mechanism (QNWM) has been proposed in this paper based on the facts of wear curve turning under high energy impact contact loading.Its characteristic is that the wear rate of QNWM is only 1/10-1/3 that of delamination mechanism at the same energy density.The diameters of wear debris and pits on the worn surfaces fall into the quasi-nanometer scale (about 50-120 nm).The necessary and sufficient conditions,which bring about the QNWM,are:(i) the nano-structure (nano-crystalline + amorphous phase) in impact contact surface layer has formed by the intensive impact strain;(ii) the delamination wear cracking in sub-surface layer must be restrained;(iii) the microcracks of QNWM are produced in amorphous phase of surface nano-structure layer rather than in nano-crystalline.

  2. Mechanisms underlying KCNQ1channel cell volume sensitivity

    DEFF Research Database (Denmark)

    Hammami, Sofia

    Cells are constantly exposed to changes in cell volume during cell metabolism, nutrient uptake, cell proliferation, cell migration and salt and water transport. In order to cope with these perturbations, potassium channels in line with chloride channels have been shown to be likely contributors to...... the process of cell volume adjustments. A great diversity of potassium channels being members of either the 6TM, 4 TM or 2 TM K+ channel gene family have been shown to be strictly regulated by small, fast changes in cell volume. However, the precise mechanism underlying the K+ channel sensitivity to...... cell volume alterations is not yet fully understood. The KCNQ1 channel belonging to the voltage gated KCNQ family is considered a precise sensor of volume changes. The goal of this thesis was to elucidate the mechanism that induces cell volume sensitivity. Until now, a number of investigators have...

  3. Chinese Medicines Induce Cell Death: The Molecular and Cellular Mechanisms for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Xuanbin Wang

    2014-01-01

    Full Text Available Chinese medicines have long history in treating cancer. With the growing scientific evidence of biomedical researches and clinical trials in cancer therapy, they are increasingly accepted as a complementary and alternative treatment. One of the mechanisms is to induce cancer cell death. Aim. To comprehensively review the publications concerning cancer cell death induced by Chinese medicines in recent years and provide insights on anticancer drug discovery from Chinese medicines. Materials and Methods. Chinese medicines (including Chinese medicinal herbs, animal parts, and minerals were used in the study. The key words including “cancer”, “cell death”, “apoptosis”, “autophagy,” “necrosis,” and “Chinese medicine” were used in retrieval of related information from PubMed and other databases. Results. The cell death induced by Chinese medicines is described as apoptotic, autophagic, or necrotic cell death and other types with an emphasis on their mechanisms of anticancer action. The relationship among different types of cell death induced by Chinese medicines is critically reviewed and discussed. Conclusions. This review summarizes that CMs treatment could induce multiple pathways leading to cancer cell death, in which apoptosis is the dominant type. To apply these preclinical researches to clinic application will be a key issue in the future.

  4. The cytotoxicity of polycationic iron oxide nanoparticles: Common endpoint assays and alternative approaches for improved understanding of cellular response mechanism

    Directory of Open Access Journals (Sweden)

    Hoskins Clare

    2012-04-01

    Our findings indicate that common in vitro cell endpoint assays do not give detailed and complete information on cellular state and it is essential to explore novel approaches and carry out more in-depth studies to elucidate cellular response mechanism to magnetic nanoparticles.

  5. Transdifferentiation of pancreatic α-cells into insulinsecreting cells: From experimental models to underlying mechanisms

    Institute of Scientific and Technical Information of China (English)

    Jieli; Lu; Rami; Jaafer; Rémy; Bonnavion; Philippe; Bertolino; Chang-Xian; Zhang

    2014-01-01

    Pancreatic insulin-secreting β-cells are essential regulators of glucose metabolism. New strategies are cur-rently being investigated to create insulin-producing β cells to replace deficient β cells, including the differentiation of either stem or progenitor cells, and the newly uncovered transdifferentiation of mature non-β islet cell types. However, in order to correctly drive any cell to adopt a new β-cell fate, a better understanding of the in vivo mechanisms involved in the plasticity and biology of islet cells is urgently required. Here, we review the recent studies reporting the phenomenon of transdifferentiation of α cells into β cells by focusing on the major candidates and contexts revealed to be involved in adult β-cell regeneration through this process. The possible underlying mechanisms of transdifferentiation and the interactions between several key factors involved in the process are also addressed. We propose that it is of importance to further study the molecular and cellular mechanisms underlying α- to β-cell transdifferentiation, in order to make β-cell regeneration from α cells a relevant and realizable strategy for developing cell-replacement therapy.

  6. Study of mechanical properties of nanomaterials under high pressure

    Science.gov (United States)

    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.

  7. Hormesis and Cellular Quality Control: A Possible Explanation for the Molecular Mechanisms that Underlie the Benefits of Mild Stress

    OpenAIRE

    Wiegant, F.A.C.; de Poot, S A H; Boers-Trilles, V.E.; Schreij, A.M.A

    2012-01-01

    In contrast to the detrimental action of severe stress conditions, the beneficial effects of mild stress, known as hormesis, is increasingly discussed and studied. A variety of applications for hormesis in risk assessment processes, anti-ageing strategies and clinical therapies have been proposed. The molecular mechanisms underlying the phenomenon of hormesis, however, are not yet fully understood. A possible mechanism that has been proposed for hormesis, the homoeostasis overshoot hypothesis...

  8. Morphogenesis of the lymphatic vasculature: A focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels.

    Science.gov (United States)

    Kazenwadel, Jan; Harvey, Natasha L

    2016-03-01

    Lymphatic vessels serve crucial roles in the regulation of tissue fluid homeostasis, dietary lipid absorption and immune cell trafficking. Defects in lymphatic vessel morphogenesis and function have been associated with lymphedema, obesity, hypertension and tumour metastasis. Morphogenetic events important for construction of the lymphatic vasculature during development include the specification and emergence of lymphatic endothelial progenitor cells, their differentiation and assembly into interconnected vessels and vascular remodeling, ultimately giving rise to a functional vascular network. Despite the embryonic origins of lymphatic endothelial progenitor cells being long debated, work performed over the last decade had overwhelmingly supported at least a great majority of progenitor cells arising from the venous vasculature. Here, we review the most recent advances in the field of lymphatic vessel morphogenesis, with a focus on studies that have identified novel sources of embryonic lymphatic endothelial progenitor cells, together with the cellular mechanisms by which lymphatic vessels are initially assembled. PMID:26228815

  9. Behavior of duplex stainless steel casting defects under mechanical loadings

    International Nuclear Information System (INIS)

    Several components in the primary circuit of pressurized water reactors are made of cast duplex stainless steels. This material contains small casting defects, mainly shrinkage cavities, due to the manufacturing process. In safety analyses, the structural integrity of the components is studied under the most severe assumptions: presence of a large defect, accidental loadings and end-of-life material properties accounting for its thermal aging embrittlement at the service temperature. The casting defects are idealized as semi-circular surface cracks or notches that have envelope dimensions. In order to assess the real severity of the casting defects under mechanical loadings, an experimental program was carried out. It consisted of testing, under both cyclic and monotonic solicitations, three-point bend specimens containing either a natural defect (in the form of a localized cluster of cavities) or a machined notch having the dimensions of the cluster's envelope. The results show that shrinkage cavities are far less harmful than envelope notches thanks to the metal bridges between cavities. Under fatigue loadings, the generalized initiation of a cluster of cavities (defined when the cluster becomes a crack of the same global size) is reached for a number of cycles that is much higher than the one leading to the initiation of a notch. In the case of monotonic loadings, specimens with casting defects offer a very high resistance to ductile tearing. The tests are analyzed in order to develop a method that takes into account the behavior of casting defects in a more realistic fashion than by an envelope crack. Various approaches are investigated, including the search of equivalent defects or of criteria based on continuum mechanics concepts, and compared with literature data. This study shows the conservatism of current safety analyses in modeling casting defects by envelope semi-elliptical cracks and contributes to the development of alternative approaches. (orig.)

  10. Auxin apical control of the auxin polar transport and its oscillation - a suggested cellular transduction mechanism

    Directory of Open Access Journals (Sweden)

    Tomasz J. Wodzicki

    2014-02-01

    Full Text Available The proposed hypothesis concerns the transduction of auxin molecular signals arriving from the apoplast at the plasma membrane or recognized by the proteineous receptors of the responding cell, to the concentration gradients oscillating in the supracellular space, associated usually with the specific plant growth and differentiation. Acting as an agonist from outside the target cell auxin stimulates in this cell: (1 the liberation of auxin from the cytosolic pool of its conjugates directly into the basipetal efflux; (2 the synthesis of new auxin which restores the cytosolic reserve of auxin conjugates. The functioning of such a system may be effective in a series of processes initiated by the changing concentration of cytosolic calcium. The hypothesis suggests a molecular mechanism for the development and effective operation of the morphogenetic field in the supracellular space of the plant body, such as the field resulting from auxin waves discovered in cambium.

  11. Cellular Microcultures: Programming Mechanical and Physicochemical Properties of 3D Hydrogel Cellular Microcultures via Direct Ink Writing (Adv. Healthcare Mater. 9/2016).

    Science.gov (United States)

    McCracken, Joselle M; Badea, Adina; Kandel, Mikhail E; Gladman, A Sydney; Wetzel, David J; Popescu, Gabriel; Lewis, Jennifer A; Nuzzo, Ralph G

    2016-05-01

    R. Nuzzo and co-workers show on page 1025 how compositional differences in hydrogels are used to tune their cellular compliance by controlling their polymer mesh properties and subsequent uptake of the protein poly-l-lysine (green spheres in circled inset). The cover image shows pyramid micro-scaffolds prepared using direct ink writing (DIW) that differentially direct fibroblast and preosteoblast growth in 3D, depending on cell motility and surface treatment. PMID:27166616

  12. Cellular uptake of the antitumor agent Dp44mT occurs via a carrier/receptor-mediated mechanism.

    Science.gov (United States)

    Merlot, Angelica M; Pantarat, Namfon; Menezes, Sharleen V; Sahni, Sumit; Richardson, Des R; Kalinowski, Danuta S

    2013-12-01

    The chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) shows potent and selective anticancer and antimetastatic activity. However, the mechanism by which it is initially transported into cells to induce cytotoxicity is unknown. Hence, the current investigation examined the cellular uptake of ¹⁴C-Dp44mT relative to two structurally related ligands, namely the aroylhydrazone ¹⁴C-pyridoxal isonicotinoyl hydrazone (¹⁴C-PIH) and the thiosemicarbazone (¹⁴C-2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (¹⁴C-Bp4eT). In marked contrast to the cellular uptake of ¹⁴C-PIH and ¹⁴C-Bp4eT, which were linear as a function of concentration, ¹⁴C-Dp44mT uptake was saturable using SK-N-MC neuroepithelioma cells (Bmax, 4.28 × 10⁷ molecules of chelator/cell; and Kd, 2.45 μM). Together with the fact that ¹⁴C-Dp44mT uptake was temperature-dependent and significantly (P complex [Fe(¹⁴C-Dp44mT)₂] was not saturable as a function of concentration and was much greater than the ligand alone, indicating an alternate mode of transport. Studies examining the tissue distribution of ¹⁴C-Dp44mT injected intravenously into a mouse tumor model demonstrated the ¹⁴C label was primarily identified in the excretory system. Collectively, these findings examining the mechanism of Dp44mT uptake and its distribution and excretion have clinical implications for its bioavailability and uptake in vivo. PMID:24085840

  13. Linking Cellular Mechanisms to Behavior: Entorhinal Persistent Spiking and Membrane Potential Oscillations May Underlie Path Integration, Grid Cell Firing, and Episodic Memory

    Directory of Open Access Journals (Sweden)

    Michael E. Hasselmo

    2008-01-01

    Full Text Available The entorhinal cortex plays an important role in spatial memory and episodic memory functions. These functions may result from cellular mechanisms for integration of the afferent input to entorhinal cortex. This article reviews physiological data on persistent spiking and membrane potential oscillations in entorhinal cortex then presents models showing how both these cellular mechanisms could contribute to properties observed during unit recording, including grid cell firing, and how they could underlie behavioural functions including path integration. The interaction of oscillations and persistent firing could contribute to encoding and retrieval of trajectories through space and time as a mechanism relevant to episodic memory.

  14. Application of cellular mechanisms to growth and development of food producing animals.

    Science.gov (United States)

    Chung, K Y; Johnson, B J

    2008-04-01

    Postnatal skeletal muscle growth is a result of hypertrophy of existing skeletal muscle fibers in food producing animals. Accumulation of additional nuclei, as a source of DNA, to the multinucleated skeletal muscle fiber aids in fiber hypertrophy during periods of rapid skeletal muscle growth. Muscle satellite cells are recognized as the source of nuclei to support muscle hypertrophy. Exogenous growth-enhancing compounds have been used to modulate growth rate and efficiency in meat animals for over a half century. In cattle, these compounds enhance efficiency of growth by preferentially stimulating skeletal muscle growth compared with adipose tissue. There are 2 main classes of compounds approved for use in cattle in the United States, anabolic steroids and beta-adrenergic agonists (beta-AA). Administration of both trenbolone acetate and estradiol-17beta, as implants, increased carcass protein accumulation 8 to 10% in yearling steers. Muscle satellite cells isolated from steers implanted with trenbolone acetate/ estradiol-17beta had a shorter lag phase in culture compared with satellite cells isolated from control steers. Collectively, these data indicate that activation, increased proliferation, and subsequent fusion of satellite cells in muscles of implanted cattle may be an important mechanism by which anabolic steroids enhance muscle hypertrophy. Oral administration of beta-AA to ruminants does not alter DNA accumulation in skeletal muscle over a typical feeding period (28 to 42 d). Enhanced muscle hypertrophy observed due to beta-AA feeding occurs by direct, receptor-mediated changes in protein synthesis and degradation rates of skeletal muscle tissue. Proper timing of anabolic steroid administration when coupled with beta-AA feeding could result in a synergistic response in skeletal muscle growth due to the effects of anabolic steroids at increasing satellite cell activity, which then can support the rapid hypertrophic changes of the muscle fiber when exposed

  15. Mechanisms Underlying the Antidepressant Response and Treatment Resistance

    Directory of Open Access Journals (Sweden)

    Marjorie Rose Levinstein

    2014-06-01

    Full Text Available 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.

  16. Behavior of duplex stainless steel casting defects under mechanical loadings

    International Nuclear Information System (INIS)

    Several components in the primary circuit of pressurized water reactors are made of cast duplex stainless steels. This material contains small casting defects, mainly shrinkage cavities, due to the manufacturing process. In safety analyses, the structural integrity of the components is studied. In order to assess the real severity of the casting defects under mechanical loadings, an experimental program was carried out. It consisted of testing, under both cyclic and monotonic solicitations, three-point bend specimens containing either a natural defect (in the form of a localized cluster of cavities) or a machined notch having the dimensions of the cluster's envelope. The tests are analyzed in order to develop a method that takes into account the behavior of castings defects in a more realistic fashion than by an envelope crack. Various approaches are investigated, including the search of equivalent defects or of criteria based on continuum mechanics concepts, and compared with literature data. This study shows the conservatism of current safety analyses in modelling casting defects by envelope semi-elliptical cracks and contributes to the development of alternative approaches. (author)

  17. Uncoupling of oxidative phosphorylation by curcumin: Implication of its cellular mechanism of action

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Han Wern; Lim, Hwee Ying [Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260 (Singapore); Wong, Kim Ping, E-mail: bchsitkp@nus.edu.sg [Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260 (Singapore)

    2009-11-06

    Curcumin is a phytochemical isolated from the rhizome of turmeric. Recent reports have shown curcumin to have antioxidant, anti-inflammatory and anti-tumor properties as well as affecting the 5'-AMP activated protein kinase (AMPK), mTOR and STAT-3 signaling pathways. We provide evidence that curcumin acts as an uncoupler. Well-established biochemical techniques were performed on isolated rat liver mitochondria in measuring oxygen consumption, F{sub 0}F{sub 1}-ATPase activity and ATP biosynthesis. Curcumin displays all the characteristics typical of classical uncouplers like fccP and 2,4-dinitrophenol. In addition, at concentrations higher than 50 {mu}M, curcumin was found to inhibit mitochondrial respiration which is a characteristic feature of inhibitory uncouplers. As a protonophoric uncoupler and as an activator of F{sub 0}F{sub 1}-ATPase, curcumin causes a decrease in ATP biosynthesis in rat liver mitochondria. The resulting change in ATP:AMP could disrupt the phosphorylation status of the cell; this provides a possible mechanism for its activation of AMPK and its downstream mTOR and STAT-3 signaling.

  18. Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy.

    Science.gov (United States)

    Gill, Harinder; Leung, Anskar Y H; Kwong, Yok-Lam

    2016-01-01

    Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematopoietic stem cell disorders characterized by cytopenia, ineffective hematopoiesis, and progression to secondary acute myeloid leukemia in high-risk cases. Conventional prognostication relies on clinicopathological parameters supplemented by cytogenetic information. However, recent studies have shown that genetic aberrations also have critical impacts on treatment outcome. Moreover, these genetic alterations may themselves be a target for treatment. The mutation landscape in MDS is shaped by gene aberrations involved in DNA methylation (TET2, DNMT3A, IDH1/2), histone modification (ASXL1, EZH2), the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1/2), transcription (RUNX1, TP53, BCOR, PHF6, NCOR, CEBPA, GATA2), tyrosine kinase receptor signaling (JAK2, MPL, FLT3, GNAS, KIT), RAS pathways (KRAS, NRAS, CBL, NF1, PTPN11), DNA repair (ATM, BRCC3, DLRE1C, FANCL), and cohesion complexes (STAG2, CTCF, SMC1A, RAD21). A detailed understanding of the pathogenetic mechanisms leading to transformation is critical for designing single-agent or combinatorial approaches in target therapy of MDS. PMID:27023522

  19. Molecular and cellular mechanisms for the regulation of ovarian follicular function in cows.

    Science.gov (United States)

    Shimizu, Takashi

    2016-08-25

    Ovary is an important organ that houses the oocytes (reproductive cell). Oocyte growth depends on the function of follicular cells such as the granulosa and theca cells. Two-cell two gonadotropin systems are associated with oocyte growth and follicular cell functions. In addition to these systems, it is also known that several growth factors regulate oocyte growth and follicular cell functions. Vascular endothelial growth factor (VEGF) is involved in thecal vasculature during follicular development and the suppression of granulosa cell apoptosis. Metabolic factors such as insulin, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) also play critical roles in the process of follicular development and growth. These factors are associated not only with follicular development, but also with follicular cell function. Steroid hormones (estrogens, androgens, and progestins) that are secreted from follicular cells influence the function of the female genital tract and its affect the susceptibility to bacterial infection. This review covers our current understanding of the mechanisms by which gonadotrophins and/or steroid hormones regulate the growth factors in the follicular cells of the bovine ovary. In addition, this review describes the effect of endotoxin on the function of follicular cells. PMID:27097851

  20. Uncoupling of oxidative phosphorylation by curcumin: Implication of its cellular mechanism of action

    International Nuclear Information System (INIS)

    Curcumin is a phytochemical isolated from the rhizome of turmeric. Recent reports have shown curcumin to have antioxidant, anti-inflammatory and anti-tumor properties as well as affecting the 5'-AMP activated protein kinase (AMPK), mTOR and STAT-3 signaling pathways. We provide evidence that curcumin acts as an uncoupler. Well-established biochemical techniques were performed on isolated rat liver mitochondria in measuring oxygen consumption, F0F1-ATPase activity and ATP biosynthesis. Curcumin displays all the characteristics typical of classical uncouplers like fccP and 2,4-dinitrophenol. In addition, at concentrations higher than 50 μM, curcumin was found to inhibit mitochondrial respiration which is a characteristic feature of inhibitory uncouplers. As a protonophoric uncoupler and as an activator of F0F1-ATPase, curcumin causes a decrease in ATP biosynthesis in rat liver mitochondria. The resulting change in ATP:AMP could disrupt the phosphorylation status of the cell; this provides a possible mechanism for its activation of AMPK and its downstream mTOR and STAT-3 signaling.

  1. Behaviour of bcc technical superconductors under dynamic mechanical stress

    International Nuclear Information System (INIS)

    The behavior of bcc technical superconductors NbTi, NbZr and Nb under dynamic mechanical stress was investigated using two measuring techniques. In shot-sample training experiments the load was measured at which, in wire samples with a transport current applied, normal transitions occured in succesive straining cycles. Complementary, the acoustic emission from superconductors was monitored during strain at 4.2 K. A mechanism based on the formation of a stress induced shear transformation was proposed to account for the training behavior. This partially reversible shearing of the lattice is not sufficient to furnish the required energy for transition in the normal state but it may be detected by means of acoustic emission. On the other hand, a time correlation between acoustic emission and normal transition was found although training behavior and emission responded differently to the same metallurgical treatment. The experiments strongly indicate that the mechanism directly responsible for local energy release is microyielding, induced by the shear transformation. The stress relaxation which accompanies this transformation results in an increased load on the rest of the sample cross-section. Consequently microyielding caused by the transformation could occur in that region of the sample without being detected on the stress-strain curve. This would result in a sufficient release of energy to increase the sample temperature above its critical value. (orig./HP)

  2. Piezoelectric compliant mechanism energy harvesters under large base excitations

    Science.gov (United States)

    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.

  3. Autophagy as a Possible Underlying Mechanism of Nanomaterial Toxicity

    Directory of Open Access Journals (Sweden)

    Vanessa Cohignac

    2014-07-01

    Full Text Available The rapid development of nanotechnologies is raising safety concerns because of the potential effects of engineered nanomaterials on human health, particularly at the respiratory level. Since the last decades, many in vivo studies have been interested in the pulmonary effects of different classes of nanomaterials. It has been shown that some of them can induce toxic effects, essentially depending on their physico-chemical characteristics, but other studies did not identify such effects. Inflammation and oxidative stress are currently the two main mechanisms described to explain the observed toxicity. However, the exact underlying mechanism(s still remain(s unknown and autophagy could represent an interesting candidate. Autophagy is a physiological process in which cytoplasmic components are digested via a lysosomal pathway. It has been shown that autophagy is involved in the pathogenesis and the progression of human diseases, and is able to modulate the oxidative stress and pro-inflammatory responses. A growing amount of literature suggests that a link between nanomaterial toxicity and autophagy impairment could exist. In this review, we will first summarize what is known about the respiratory effects of nanomaterials and we will then discuss the possible involvement of autophagy in this toxicity. This review should help understand why autophagy impairment could be taken as a promising candidate to fully understand nanomaterials toxicity.

  4. Girdin/GIV is upregulated by cyclic tension, propagates mechanical signal transduction, and is required for the cellular proliferation and migration of MG-63 cells

    International Nuclear Information System (INIS)

    To explore how Girdin/GIV is regulated by cyclic tension and propagates downstream signals to affect cell proliferation and migration. Human osteoblast-like MG-63 cells were exposed to cyclic tension force at 4000 μstrain and 0.5 Hz for 6 h, produced by a four-point bending system. Cyclic tension force upregulated Girdin and Akt expression and phosphorylation in cultured MG-63 cells. Girdin and Akt each promoted the phosphorylation of the other under stimulated tension. In vitro MTT and transwell assays showed that Girdin and Akt are required for cell proliferation and migration during cellular quiescence. Moreover, STAT3 was determined to be essential for Girdin expression under stimulated tension force in the physiological condition, as well as for osteoblast proliferation and migration during quiescence. These findings suggest that the STAT3/Girdin/Akt pathway activates in osteoblasts in response to mechanical stimulation and may play a significant role in triggering osteoblast proliferation and migration during orthodontic treatment. - Highlights: • Tension force upregulates Girdin and Akt expression and phosphorylation. • Girdin and Akt promotes the phosphorylation of each other under tension stimulation. • Girdin and Akt are required for MG-63 cell proliferation and migration. • STAT3 is essential for Girdin expression after application of the tension forces

  5. Girdin/GIV is upregulated by cyclic tension, propagates mechanical signal transduction, and is required for the cellular proliferation and migration of MG-63 cells

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Jiang-Tian; Li, Yan; Yu, Bing; Gao, Guo-Jie; Zhou, Ting; Li, Song, E-mail: song_li59@126.com

    2015-08-21

    To explore how Girdin/GIV is regulated by cyclic tension and propagates downstream signals to affect cell proliferation and migration. Human osteoblast-like MG-63 cells were exposed to cyclic tension force at 4000 μstrain and 0.5 Hz for 6 h, produced by a four-point bending system. Cyclic tension force upregulated Girdin and Akt expression and phosphorylation in cultured MG-63 cells. Girdin and Akt each promoted the phosphorylation of the other under stimulated tension. In vitro MTT and transwell assays showed that Girdin and Akt are required for cell proliferation and migration during cellular quiescence. Moreover, STAT3 was determined to be essential for Girdin expression under stimulated tension force in the physiological condition, as well as for osteoblast proliferation and migration during quiescence. These findings suggest that the STAT3/Girdin/Akt pathway activates in osteoblasts in response to mechanical stimulation and may play a significant role in triggering osteoblast proliferation and migration during orthodontic treatment. - Highlights: • Tension force upregulates Girdin and Akt expression and phosphorylation. • Girdin and Akt promotes the phosphorylation of each other under tension stimulation. • Girdin and Akt are required for MG-63 cell proliferation and migration. • STAT3 is essential for Girdin expression after application of the tension forces.

  6. Study on the Cellular Molecular Mechanism of Intrauterine Transmission of Hepatitis B Virus

    Institute of Scientific and Technical Information of China (English)

    王健; 孙琳

    2003-01-01

    Objective: To study intrauterine transmission of HBV and its celbular molecular mechanism and influence on the fetus. Methods: A total of 46 cases of Fegnant uxnnen who suffered from HBV were divided into HBeAg (+) and HBeAg (-) groups. HBV-DNA in serum and peripheral blood mononuclear cells ( PBMC ) of 46 cases of pregnant women before delivery urns detected by polymerase chain reaction ( PCR). After placenta being delivery, HBV-DNA in serum and cord blood mononuclear cells ( CBMC) was also detected by PCR. Results: The total of positive rates of HBV-DNA in serum and PBMC of pregnant women with hepatitis B were 69.57% (32/46) and 41.30% (19/46). The positive rates of HBV-DNA in serum of cord blood and CBMC were 56.52%(26/46) and 21.74% (10/46) respectively. Among them, the positive rates of HBV-DNA inserum and PBMC of pregnant women with HBeAg (+) were 100. 00% (25/25) and 60.00% (15/25) respectively. The positive rates of HBV-DNA in serum of cord blood and CBMC were 88.00% (22/25) and 32. 00% (8/25) respectively. The positive rates of HBV-DNA in serum and PBMC of pregnant women with HBeAg (-) were 33.33%(7/21) and 19.05%(4/21) respectively. The positive rates of HBV-DNA in serum of card blood and CBMC were 19.05%(4/21) and 9.52%(2/21) resspectively. The positive rates of HBV-DNA in serum of card blood and CBMC of newborns were higher in the group of pregnant women with HBeAg (+) than those in the group of pregnant women with HBeAg (--) (P<0. O1 and P<0. 05). There was no HBV-DNA in serum, PBMC and CBMC of normal pregnant women and normal neorwles. Conclusion : The intrauterine transmission of HBV can be existent and its transmission way not only can be induced by serum but also can be induced by PBMC. The way of intrauterine transmission of HBV in-duced by PBMC was concealed. The dangerous possibility of intrauterine transmission is higher in thepregnant women with HBeAg (+) than that in the group of pregnant women with HBeAg (-).

  7. Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling.

    Directory of Open Access Journals (Sweden)

    Shinya Tasaki

    Full Text Available BACKGROUND: Mutation of the epidermal growth factor receptor (EGFR results in a discordant cell signaling, leading to the development of various diseases. However, the mechanism underlying the alteration of downstream signaling due to such mutation has not yet been completely understood at the system level. Here, we report a phosphoproteomics-based methodology for characterizing the regulatory mechanism underlying aberrant EGFR signaling using computational network modeling. METHODOLOGY/PRINCIPAL FINDINGS: Our phosphoproteomic analysis of the mutation at tyrosine 992 (Y992, one of the multifunctional docking sites of EGFR, revealed network-wide effects of the mutation on EGF signaling in a time-resolved manner. Computational modeling based on the temporal activation profiles enabled us to not only rediscover already-known protein interactions with Y992 and internalization property of mutated EGFR but also further gain model-driven insights into the effect of cellular content and the regulation of EGFR degradation. Our kinetic model also suggested critical reactions facilitating the reconstruction of the diverse effects of the mutation on phosphoproteome dynamics. CONCLUSIONS/SIGNIFICANCE: Our integrative approach provided a mechanistic description of the disorders of mutated EGFR signaling networks, which could facilitate the development of a systematic strategy toward controlling disease-related cell signaling.

  8. Crack arrest saturation model under combined electrical and mechanical loadings

    Directory of Open Access Journals (Sweden)

    R.R. Bhargava

    2009-12-01

    Full Text Available Purpose: The investigation aims at proposing a model for cracked piezoelectric strip which is capable to arrest the crack.Design/methodology/approach: Under the combined effect of electrical and mechanical loadings applied at the edges of the strip, the developed saturation zone is produced at each tip of the crack. To arrest further opening of the crack, the rims of the developed saturation zones are subjected to in-plane cohesive, normal uniform constant saturation point electrical displacement. The problem is solved using Fourier integral transform method which reduces the problem to the solution of Fredholm integral equation of the second kind. This integral equation in turn is solved numerically.Findings: The expressions are derived for different intensity factors and energy release rate. A qualitative analysis of the parameters affecting the arrest of opening of the crack and fatigue crack growth with respect to strip thickness and material constants are presented graphically.Research limitations/implications: The investigations are carried out by considering the material electrical brittle. Consequently, the zones protrude along the straight lines ahead of the crack tips. And further, the small scale electrical yielding conditions are used.Practical implications: Piezoelectric materials are widely getting used nowadays, even in day to day life like piezoelectric cigarette lighter, children toys etc. And, its advance used in technology like transducers, actuators has been already in progress. So, the aspect of cracking of piezoelectric materials are of great practical importance.Originality/value: The piezoelectric material under the combined effect of electrical and mechanical loadings gives the assessment of electrical displacement which is required to arrest the crack. The various useful interpretations are also drawn from the graphs.

  9. POSSIBLE MECHANISMS UNDERLYING THE THERAPEUTIC EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION

    Directory of Open Access Journals (Sweden)

    Alexander eChervyakov

    2015-06-01

    Full Text Available 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 (LTP and long-term depression (LTD. 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 (BDNF 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.

  10. Electron transport properties of single molecular junctions under mechanical modulations

    International Nuclear Information System (INIS)

    Electron transport behaviors of single molecular junctions are very sensitive to the atomic scale molecule-metal electrode contact interfaces, which have been difficult to control. We used a modified scanning probe microscope-break junction technique (SPM-BJT) to control the dynamics of the contacts and simultaneously monitor both the conductance and force. First, by fitting the measured data into a modified multiple tunneling barrier model, the static contact resistances, corresponding to the different contact conformations of single alkanedithiol and alkanediamine molecular junctions, were identified. Second, the changes of contact decay constant were measured under mechanical extensions of the molecular junctions, which helped to classify the different single molecular conductance sets into specific microscopic conformations of the molecule-electrode contacts. Third, by monitoring the changes of force and contact decay constant with the mechanical extensions, the changes of conductance were found to be caused by the changes of contact bond length and by the atomic reorganizations near the contact bond. This study provides a new insight into the understanding of the influences of contact conformations, especially the effect of changes of dynamic contact conformation on electron transport through single molecular junctions. (paper)

  11. Using Drosophila to discover mechanisms underlying type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Ronald W. Alfa

    2016-04-01

    Full Text Available 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.

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

    Science.gov (United States)

    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

  13. Thermal stability of nafion membranes under mechanical stress

    Energy Technology Data Exchange (ETDEWEB)

    Quintilii, M.; Struis, R. [Paul Scherrer Inst. (PSI), Villigen (Switzerland)

    1997-06-01

    The feasibility of adequately modified fluoro-ionomer membranes (NAFION{sup R}) is demonstrated for the selective separation of methanol synthesis products from the raw reactor gas at temperatures around 200{sup o}C. For an economically relevant application of this concept on a technical scale the Nafion membranes should be thin ({approx_equal}10 {mu}m) and thermally stable over a long period of time (1-2 years). In cooperation with industry (Methanol Casale SA, Lugano (CH)), we test the thermal stability of Nafion hollow fibers and supported Nafion thin sheet membranes at temperatures between 160 and 200{sup o}C under mechanical stress by applying a gas pressure difference over the membrane surface ({Delta}P{<=} 40 bar). Tests with the hollow fibers revealed that Nafion has visco-elastic properties. Tests with 50 {mu}m thin Nafion sheets supported by a porous metal carrier at 200{sup o}C and {Delta}P=39 bar showed no mechanical defects over a period of 92 days. (author) 5 figs., 4 refs.

  14. Different neurophysiological mechanisms underlying word and rule extraction from speech.

    Directory of Open Access Journals (Sweden)

    Ruth De Diego Balaguer

    Full Text Available 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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  17. Mechanism of Laser/light beam interaction at cellular and tissue level and study of the influential factors for the application of low level laser therapy

    CERN Document Server

    Khalid, Muhammad Zeeshan

    2016-01-01

    After the discovery of laser therapy it was realized it has useful application of wound healing and reduce pain, but due to the poor understanding of the mechanism and dose response this technique remained to be controversial for therapeutic applications. In order to understand the working and effectiveness different experiments were performed to determine the laser beam effect at the cellular and tissue level. This article discusses the mechanism of beam interaction at tissues and cellular level with different light sources and dosimetry principles for clinical application of low level laser therapy. Different application techniques and methods currently in use for clinical treatment has also been reviewed.

  18. Involvement of the Wnt/β-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis.

    Directory of Open Access Journals (Sweden)

    Sachiko Matsuzaki

    Full Text Available BACKGROUND: During the development and progression of endometriotic lesions, excess fibrosis may lead to scarring, chronic pain, and altered tissue function. However, the cellular and molecular mechanisms of fibrosis in endometriosis remain to be clarified. OBJECTIVES: The objective of the present study was to investigate whether the Wnt/β-catenin signaling pathway was involved in regulating the cellular and molecular mechanisms of fibrosis in endometriosis in vitro and to evaluate whether fibrosis could be prevented by targeting the Wnt/β-catenin pathway in a xenograft model of endometriosis in immunodeficient nude mice. METHODS: Seventy patients (40 with and 30 without endometriosis with normal menstrual cycles were recruited. In vitro effects of small-molecule antagonists of the Tcf/β-catenin complex (PKF 115-584 and CGP049090 on fibrotic markers (alpha smooth muscle actin, type I collagen, connective tissue growth factor, fibronectin and collagen gel contraction were evaluated in endometrial and endometriotic stromal cells from patients with endometriosis. In vitro effects of activation of the Wnt/β-catenin signaling pathway by treatment with recombinant Wnt3a on profibrotic responses were evaluated in endometrial stromal cells of patients without endometriosis. The effects of CGP049090 treatment on the fibrosis of endometriotic implants were evaluated in a xenograft model of endometriosis in immunodeficient nude mice. RESULTS: Treatment with PKF 115-584 and CGP049090 significantly decreased the expression of alpha smooth muscle actin, type I collagen, connective tissue growth factor and fibronectin mRNAs in both endometriotic and endometrial stromal cells with or without transforming growth factor-β1 stimulation. Both endometriotic and endometrial stromal cell-mediated contraction of collagen gels was significantly decreased by treatment with PKF 115-584 and CGP049090 as compared to that of untreated cells. The animal experiments

  19. Mechanical Modeling of a WIPP Drum Under Pressure

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Jeffrey A. [Sandia National Laboratories, Albuquerque, NM (United States)

    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

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

    Science.gov (United States)

    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

  1. Induction of multixenobiotic defense mechanisms in resistant Daphnia magna clones as a general cellular response to stress.

    Science.gov (United States)

    Jordão, Rita; Campos, Bruno; Lemos, Marco F L; Soares, Amadeu M V M; Tauler, Romà; Barata, Carlos

    2016-06-01

    Multixenobiotic resistance mechanisms (MXR) were recently identified in Daphnia magna. Previous results characterized gene transcripts of genes encoding and efflux activities of four putative ABCB1 and ABCC transporters that were chemically induced but showed low specificity against model transporter substrates and inhibitors, thus preventing us from distinguishing between activities of different efflux transporter types. In this study we report on the specificity of induction of ABC transporters and of the stress protein hsp70 in clones selected to be genetically resistant to ABCB1 chemical substrates. Clones resistant to mitoxantrone, ivermectin and pentachlorophenol showed distinctive transcriptional responses of transporter protein coding genes and of putative transporter dye activities. Expression of hsp70 proteins also varied across resistant clones. Clones resistant to mitoxantrone and pentachlorophenol showed high constitutive levels of hsp70. Transcriptional levels of the abcb1 gene transporter and of putative dye transporter activity were also induced to a greater extent in the pentachlorophenol resistant clone. Observed higher dye transporter activities in individuals from clones resistant to mitoxantrone and ivermectin were unrelated with transcriptional levels of the studied four abcc and abcb1 transporter genes. These findings suggest that Abcb1 induction in D. magna may be a part of a general cellular stress response. PMID:27039215

  2. Differentiation of autonomic reflex control begins with cellular mechanisms at the first synapse within the nucleus tractus solitarius

    Directory of Open Access Journals (Sweden)

    M.C. Andresen

    2004-04-01

    Full Text Available Visceral afferents send information via cranial nerves to the nucleus tractus solitarius (NTS. The NTS is the initial step of information processing that culminates in homeostatic reflex responses. Recent evidence suggests that strong afferent synaptic responses in the NTS are most often modulated by depression and this forms a basic principle of central integration of these autonomic pathways. The visceral afferent synapse is uncommonly powerful at the NTS with large unitary response amplitudes and depression rather than facilitation at moderate to high frequencies of activation. Substantial signal depression occurs through multiple mechanisms at this very first brainstem synapse onto second order NTS neurons. This review highlights new approaches to the study of these basic processes featuring patch clamp recordings in NTS brain slices and optical techniques with fluorescent tracers. The vanilloid receptor agonist, capsaicin, distinguishes two classes of second order neurons (capsaicin sensitive or capsaicin resistant that appear to reflect unmyelinated and myelinated afferent pathways. The differences in cellular properties of these two classes of NTS neurons indicate clear functional differentiation at both the pre- and postsynaptic portions of these first synapses. By virtue of their position at the earliest stage of these pathways, such mechanistic differences probably impart important differentiation in the performance over the entire reflex pathways.

  3. Suppression of cellular immunity by head and neck irradiation. Precipitating factors and reparative mechanisms in an experimental model

    International Nuclear Information System (INIS)

    A model was developed in C3H mice to investigate the immunosuppressive effects of head and neck irradiation and to explore mechanisms for repair of the defects. Mice receiving 1200 rad (12 Gy) of head and neck irradiation showed significant depression of delayed-type hypersensitivity, peripheral blood lymphocyte counts, spleen cell counts, and spleen cell production of interleukin-2. Treatment with optimal dosages of thymosin alpha 1 (T alpha-1) produced significant increases in all of these values, in some instances to levels higher than in the nonirradiated controls. In identical experiments with mice irradiated to a portal limited to the pelvic region, T alpha-1 induced only partial remission of the abnormalities. The dose response of T alpha-1 with head and neck irradiation showed a relatively limited dose range for immune restoration, a finding that warrants similar determinations in clinical trials with immunomodulating agents. The results suggest a potential clinical usefulness of T alpha-1 and also interleukin-2 in restoring cellular immunity after irradiation for head and neck cancers. The model appears to be useful for investigating immunomodulating agents before they are clinically evaluated as adjuvants with head and neck irradiation regimens

  4. Mechanisms underlying reduced fertility in anovular dairy cows.

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

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

    Institute of Scientific and Technical Information of China (English)

    Zhaoliang Zhang; Hong Liao; William J. Lucas

    2014-01-01

    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, remobiliza-tion 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 local y by the root system where hormones serve as important signaling components in terms of develop-mental 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 global y regulating a wide range of Pi deficiency responses. In this review, recent advances are evaluated in terms of progress toward developing a comprehen-sive 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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  9. Neural mechanisms underlying the induction and relief of perceptual curiosity

    Directory of Open Access Journals (Sweden)

    Marieke Jepma

    2012-02-01

    Full Text Available Curiosity is one of the most basic biological drives in both animals and humans, and has been identified as a key motive for learning and discovery. Despite the importance of curiosity and related behaviors, the topic has been largely neglected in human neuroscience; hence little is known about the neurobiological mechanisms underlying curiosity. We used functional magnetic resonance imaging (fMRI to investigate what happens in our brain during the induction and subsequent relief of perceptual curiosity. Our core findings were that (i the induction of perceptual curiosity, through the presentation of ambiguous visual input, activated the anterior insula and anterior cingulate cortex, brain regions sensitive to conflict and arousal; (ii the relief of perceptual curiosity, through visual disambiguation, activated regions of the striatum that have been related to reward processing; and (iii the relief of perceptual curiosity was associated with hippocampal activation and enhanced incidental memory. These findings provide the first demonstration of the neural basis of human perceptual curiosity. Our results provide neurobiological support for a classic psychological theory of curiosity, which holds that curiosity is an aversive condition of increased arousal whose termination is rewarding and facilitates memory.

  10. Distinct Subthreshold Mechanisms Underlying Rate-Coding Principles in Primate Auditory Cortex.

    Science.gov (United States)

    Gao, Lixia; Kostlan, Kevin; Wang, Yunyan; Wang, Xiaoqin

    2016-08-17

    A key computational principle for encoding time-varying signals in auditory and somatosensory cortices of monkeys is the opponent model of rate coding by two distinct populations of neurons. However, the subthreshold mechanisms that give rise to this computation have not been revealed. Because the rate-coding neurons are only observed in awake conditions, it is especially challenging to probe their underlying cellular mechanisms. Using a novel intracellular recording technique that we developed in awake marmosets, we found that the two types of rate-coding neurons in auditory cortex exhibited distinct subthreshold responses. While the positive-monotonic neurons (monotonically increasing firing rate with increasing stimulus repetition frequency) displayed sustained depolarization at high repetition frequency, the negative-monotonic neurons (opposite trend) instead exhibited hyperpolarization at high repetition frequency but sustained depolarization at low repetition frequency. The combination of excitatory and inhibitory subthreshold events allows the cortex to represent time-varying signals through these two opponent neuronal populations. PMID:27478016

  11. Intrapituitary mechanisms underlying the control of fertility: key players in seasonal breeding.

    Science.gov (United States)

    Tortonese, D J

    2016-07-01

    Recent studies have shown that, in conjunction with dynamic changes in the secretion of GnRH from the hypothalamus, paracrine interactions within the pituitary gland play an important role in the regulation of fertility during the annual reproductive cycle. Morphological studies have provided evidence for close associations between gonadotropes and lactotropes and gap junction coupling between these cells in a variety of species. The physiological significance of this cellular interaction was supported by subsequent studies revealing the expression of prolactin receptors in both the pars distalis and pars tuberalis regions of the pituitary. This cellular interaction is critical for adequate gonadotropin output because, in the presence of dopamine, prolactin can negatively regulate the LH response to GnRH. Receptor signaling studies showed that signal convergence at the level of protein kinase C and phospholipase C within the gonadotrope underlies the resulting inhibition of LH secretion. Although this is a conserved mechanism present in all species studied so far, in seasonal breeders such as the sheep and the horse, this mechanism is regulated by photoperiod, as it is only apparent during the long days of spring and summer. At this time of year, the nonbreeding season of the sheep coincides with the breeding season of the horse, indicating that this inhibitory system plays different roles in short- and long-day breeders. Although in the sheep, it contributes to the complete suppression of the reproductive axis, in the horse, it is likely to participate in the fine-tuning of gonadotropin output by preventing gonadotrope desensitization. The photoperiodic regulation of this inhibitory mechanism appears to rely on alterations in the folliculostellate cell population. Indeed, electron microscopic studies have recently shown increased folliculostellate cell area together with upregulation of their adherens junctions during the spring and summer. The association between

  12. Cellular Entry of Ebola Virus Involves Uptake by a Macropinocytosis-Like Mechanism and Subsequent Trafficking through Early and Late Endosomes

    OpenAIRE

    Saeed, Mohammad F.; Kolokoltsov, Andrey A.; Albrecht, Thomas; Davey, Robert A.

    2010-01-01

    Zaire ebolavirus (ZEBOV), a highly pathogenic zoonotic virus, poses serious public health, ecological and potential bioterrorism threats. Currently no specific therapy or vaccine is available. Virus entry is an attractive target for therapeutic intervention. However, current knowledge of the ZEBOV entry mechanism is limited. While it is known that ZEBOV enters cells through endocytosis, which of the cellular endocytic mechanisms used remains unclear. Previous studies have produced differing o...

  13. Mechanism of crack initiation and crack growth under thermal and mechanical fatigue loading

    International Nuclear Information System (INIS)

    The present contribution is focused on the experimental investigations and numerical simulations of the deformation behaviour and crack development in the austenitic stainless steel X6CrNiNb18-10 under thermal and mechanical cyclic loading in HCF and LCF regimes. The main objective of this research is the understanding of the basic mechanisms of fatigue damage and the development of simulation methods, which can be applied further in safety evaluations of nuclear power plant components. In this context the modelling of crack initiation and crack growth inside the material structure induced by varying thermal or mechanical loads are of particular interest. The mechanisms of crack initiation depend among other things on the type of loading, microstructure, material properties and temperature. The Nb-stabilized austenitic stainless steel in the solution-annealed condition was chosen for the investigations. Experiments with two kinds of cyclic loading - pure thermal and pure mechanical - were carried out and simulated. The fatigue behaviour of the steel X6CrNiNb18-10 under thermal loading was studied within the framework of the joint research project [4]. Interrupted thermal cyclic tests in the temperature range of 150 C to 300 C combined with non-destructive residual stress measurements (XRD) and various microscopic investigations, e.g. in SEM (Scanning Electron Microscope), were used to study the effects of thermal cyclic loading on the material. This thermal cyclic loading leads to thermal induced stresses and strains. As a result intrusions and extrusions appear inside the grains (at the surface), at which microcracks arise and evolve to a dominant crack. Finally, these microcracks cause a continuous and significant decrease of residual stresses. The fatigue behaviour of the steel X6CrNiNb18-10 under mechanical loading at room temperature was studied within the framework of the research project [5], [8]. With a combination of interrupted LCF tests and EBSD

  14. Research on Cellular Instabilities of Lean Premixed Syngas Flames under Various Hydrogen Fractions Using a Constant Volume Vessel

    Directory of Open Access Journals (Sweden)

    Hong-Meng Li

    2014-07-01

    Full Text Available An experimental study of the intrinsic instabilities of H2/CO lean (φ = 0.4 to φ = 1.0 premixed flames at different hydrogen fractions ranging from 0% to 100% at elevated pressure and room temperature was performed in a constant volume vessel using a Schlieren system. The unstretched laminar burning velocities were compared with data from the previous literature and simulated results. The results indicate that excellent agreements are obtained. The cellular instabilities of syngas-air flames were discussed and critical flame radii were measured. When hydrogen fractions are above 50%, the flame tends to be more stable as the equivalence ratio increases; however, the instability increases for flames of lower hydrogen fractions. For the premixed syngas flame with hydrogen fractions greater than 50%, the decline in cellular instabilities induced by the increase in equivalence ratio can be attributed to a reduction of diffusive-thermal instabilities rather than increased hydrodynamic instabilities. For premixed syngas flames with hydrogen fractions lower than 50%, as the equivalence ratio increases, the cellular instabilities become more evident because the enhanced hydrodynamic instabilities become the dominant effect. For premixed syngas flames, the enhancement of cellular instabilities induced by the increase in hydrogen fraction is the result of both increasing diffusive-thermal and hydrodynamic instabilities.

  15. Bronchopulmonary dysplasia: understanding of the underlying pathological mechanisms

    Directory of Open Access Journals (Sweden)

    Daniela Fanni

    2014-06-01

    better understanding of the underlying pathological mechanisms of BPD might provide insight into development of new therapeutic and preventive strategies.  Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014 · Cagliari (Italy · October 25th, 2014 · The role of the clinical pathological dialogue in problem solving Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken

  16. Alteration mechanisms of UOX spent fuel under water

    International Nuclear Information System (INIS)

    The mechanisms of spent fuel alteration in aqueous media need to be understood on the assumption of a direct disposal of the assemblies in a geological formation or for long duration storage in pool. This work is a contribution to the study of the effects of the alpha and/or beta/gamma radiolysis of water on the oxidation and the dissolution of the UO2 matrix of UOX spent fuel. The effects of the alpha radiolysis, predominant in geological disposal conditions, were quantified by using samples of UO2 doped with plutonium. The leaching experiments highlighted two types of control for the matrix alteration according to the alpha activity. The first is based on the radiolytic oxidation of the surface and leads to a continuous release of uranium in solution whereas the second is based on a control by the solubility of uranium. An activity threshold, between 18 MBq.g-1 and 33 MBq.g-1, was defined in a carbonated water. The value of this threshold is dependent on the experimental conditions and the presence or not of electro-active species such as hydrogen in the system. The effects of the alpha/beta/gamma radiolysis in relation with the storage conditions were also quantified. The experimental data obtained on spent fuel indicate that the alteration rate of the matrix based on the behaviour of tracer elements (caesium and strontium) reached a maximum value of some mg.m-2.d-1, even under very oxidizing conditions. The solubility of uranium and the nature of the secondary phases depend however on the extent of the oxidizing conditions. (author)

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Sofia Sakellaridi

    2015-03-01

    Full Text Available 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 towards the target ultimately chosen even from the beginning of the trial. This finding indicates an early cognitive selection bias for the ensuing decision process.

  19. Mechanisms underlying the link between cannabis use and prospective memory.

    Directory of Open Access Journals (Sweden)

    Carrie Cuttler

    Full Text Available While the effects of cannabis use on retrospective memory have been extensively examined, only a limited number of studies have focused on the links between cannabis use and prospective memory. We conducted two studies to examine the links between cannabis use and both time-based and event-based prospective memory as well as potential mechanisms underlying these links. For the first study, 805 students completed an online survey designed to assess cannabis consumption, problems with cannabis use indicative of a disorder, and frequency of experiencing prospective memory failures. The results showed small to moderate sized correlations between cannabis consumption, problems with cannabis use, and prospective memory. However, a series of mediation analyses revealed that correlations between problems with cannabis use and prospective memory were driven by self-reported problems with retrospective memory. For the second study, 48 non-users (who had never used cannabis, 48 experimenters (who had used cannabis five or fewer times in their lives, and 48 chronic users (who had used cannabis at least three times a week for one year were administered three objective prospective memory tests and three self-report measures of prospective memory. The results revealed no objective deficits in prospective memory associated with chronic cannabis use. In contrast, chronic cannabis users reported experiencing more internally-cued prospective memory failures. Subsequent analyses revealed that this effect was driven by self-reported problems with retrospective memory as well as by use of alcohol and other drugs. Although our samples were not fully characterized with respect to variables such as neurological disorders and family history of substance use disorders, leaving open the possibility that these variables may play a role in the detected relationships, the present findings indicate that cannabis use has a modest effect on self-reported problems with

  20. Different routes, same pathways: Molecular mechanisms under silver ion and nanoparticle exposures in the soil sentinel Eisenia fetida.

    Science.gov (United States)

    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

  1. RNase-L Control of Cellular mRNAs: Roles in Biologic Functions and Mechanisms of Substrate Targeting

    OpenAIRE

    Brennan-Laun, Sarah E.; Ezelle, Heather J.; Li, Xiao-Ling; Hassel, Bret A.

    2014-01-01

    RNase-L is a mediator of type 1 interferon-induced antiviral activity that has diverse and critical cellular roles, including the regulation of cell proliferation, differentiation, senescence and apoptosis, tumorigenesis, and the control of the innate immune response. Although RNase-L was originally shown to mediate the endonucleolytic cleavage of both viral and ribosomal RNAs in response to infection, more recent evidence indicates that RNase-L also functions in the regulation of cellular mR...

  2. The Relationship Between Bound Water and Carbohydrate Reserves in Association with Cellular Integrity in Fragaria vesca Stored Under Different Conditions

    OpenAIRE

    Blanch, Maria; Sánchez-Ballesta, M. Teresa; Escribano, M. Isabel; Merodio, Carmen

    2015-01-01

    © 2014, The Author(s). It has been recognized that high CO2 concentrations maintain the freshness of strawberries, reducing weight loss and the incidence of decay. Since strawberries have high tolerance threshold to CO2, it is of interest to know what changes occur in cellular water distribution when the threshold is reached or exceeded. Moreover, as strawberries are prone to producing exudate during storage at low temperatures, application of technologies improving water retention is needed....

  3. Mechanisms underlying the rules for associative plasticity at adult human neocortical synapses

    NARCIS (Netherlands)

    M.B. Verhoog (Matthijs); N.A. Goriounova (Natalia); J. Obermayer (Joshua); J. Stroeder (Jasper); J.J. Johannes Hjorth (J.); G. Testa-Silva (Guilherme); J.C. Baayen; C.P.J. de Kock (Christiaan); R.M. Meredith (Rhiannon); H.D. Mansvelder (Huibert)

    2013-01-01

    textabstractThe neocortex in our brain stores long-term memories by changing the strength of connections between neurons. To date, the rules and mechanisms that govern activity-induced synaptic changes at human cortical synapses are poorly understood and have not been studied directly at a cellular

  4. Mechanical response of collagen molecule under hydrostatic compression

    Energy Technology Data Exchange (ETDEWEB)

    Saini, Karanvir, E-mail: karans@iitrpr.ac.in; 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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  7. Statistical Structures Underlying Quantum Mechanics and Social Science

    OpenAIRE

    Wright, Ron

    2003-01-01

    Common observations of the unpredictability of human behavior and the influence of one question on the answer to another suggest social science experiments are probabilistic and may be mutually incompatible with one another, characteristics attributed to quantum mechanics (as distinguished from classical mechanics). This paper examines this superficial similarity in depth using the Foulis-Randall Operational Statistics language. In contradistinction to physics, social science deals with compl...

  8. Features wear nodes mechanization wing aircraft operating under dynamic loads

    Directory of Open Access Journals (Sweden)

    А.М. Хімко

    2009-03-01

    Full Text Available  The conducted researches of titanic alloy ВТ-22 at dynamic loading with cycled sliding and dynamic loading in conditions of rolling with slipping. It is established that roller jamming in the carriage increases wear of rod of mechanization of a wing to twenty times. The optimum covering for strengthening wearied sites and restoration of working surfaces of wing’s mechanization rod is defined.

  9. Cellular basis of radiation-induced fibrosis

    International Nuclear Information System (INIS)

    Fibrosis is a common sequela of both cancer treatment by radiotherapy and accidental irradiation and has been described in many tissues including skin, lung, heart and liver. The underlying mechanisms of the radiation-induced fibrosis still remain to be resolved. In the present review we tried to illustrate the basic cellular mechanisms of radiation-induced fibrosis based on the newest findings arising from molecular radiobiology and cell biology. Based on these findings the cellular mechanism of radiation-induced fibrosis can be seen as a multicellular process involving various interacting cell systems in the target organ resulting in the fibrotic phenotype of the fibroblast/fibrocyte cell system

  10. Heavy-ion radiobiology: new approaches to delineate mechanisms underlying enhanced biological effectiveness.

    Science.gov (United States)

    Blakely, E A; Kronenberg, A

    1998-11-01

    Shortly after the discovery of polonium and radium by Marie Curie and her husband and colleague, Pierre Curie, it was learned that exposure to these alpha-particle emitters produced deleterious biological effects. The mechanisms underlying the increased biological effectiveness of densely ionizing radiations, including alpha particles, neutrons and highly energetic heavy charged particles, remain an active area of investigation. In this paper, we review recent advances in several areas of the radiobiology of these densely ionizing radiations, also known as heavy ions. Advances are described in the areas of DNA damage and repair, chromosome aberrations, mutagenesis, neoplastic transformation in vitro, genomic instability, normal tissue radiobiology and carcinogenesis in vivo. We focus on technical innovations, including novel applications of pulsed-field gel electrophoresis, fluorescence in situ hybridization (FISH), linkage analysis, and studies of gene expression and protein expression. We also highlight the use of new cellular and animal systems, including those with defined DNA repair deficiencies, as well as epithelial cell model systems to assess neoplastic transformation both in vitro and in vivo. The studies reviewed herein have had a substantial impact on our understanding of the genotoxic effects of heavy ions as well as their distinct effects on tissue homeostasis. The use of these radiations in cancer therapy is also discussed. The use of both heavy-ion and proton therapy is on the upswing in several centers around the world, due to their unique energy deposition characteristics that enhance the therapeutic effect and help reduce damage to normal tissue. PMID:9806616

  11. Heavy-ion radiobiology: new approaches to delineate mechanisms underlying enhanced biological effectiveness

    Science.gov (United States)

    Blakely, E. A.; Kronenberg, A.; Chatterjee, A. (Principal Investigator)

    1998-01-01

    Shortly after the discovery of polonium and radium by Marie Curie and her husband and colleague, Pierre Curie, it was learned that exposure to these alpha-particle emitters produced deleterious biological effects. The mechanisms underlying the increased biological effectiveness of densely ionizing radiations, including alpha particles, neutrons and highly energetic heavy charged particles, remain an active area of investigation. In this paper, we review recent advances in several areas of the radiobiology of these densely ionizing radiations, also known as heavy ions. Advances are described in the areas of DNA damage and repair, chromosome aberrations, mutagenesis, neoplastic transformation in vitro, genomic instability, normal tissue radiobiology and carcinogenesis in vivo. We focus on technical innovations, including novel applications of pulsed-field gel electrophoresis, fluorescence in situ hybridization (FISH), linkage analysis, and studies of gene expression and protein expression. We also highlight the use of new cellular and animal systems, including those with defined DNA repair deficiencies, as well as epithelial cell model systems to assess neoplastic transformation both in vitro and in vivo. The studies reviewed herein have had a substantial impact on our understanding of the genotoxic effects of heavy ions as well as their distinct effects on tissue homeostasis. The use of these radiations in cancer therapy is also discussed. The use of both heavy-ion and proton therapy is on the upswing in several centers around the world, due to their unique energy deposition characteristics that enhance the therapeutic effect and help reduce damage to normal tissue.

  12. Tuning of redox regulatory mechanisms, reactive oxygen species and redox homeostasis under salinity stress

    Directory of Open Access Journals (Sweden)

    Hossain eSazzad

    2016-05-01

    Full Text Available Soil salinity is a crucial environmental constraint which limits biomass production at many sites on a global scale. Saline growth conditions cause osmotic and ionic imbalances, oxidative stress and perturb metabolism, e.g. the photosynthetic electron flow. The plant ability to tolerate salinity is determined by multiple biochemical and physiological mechanisms protecting cell functions, in particular by regulating proper water relations and maintaining ion homeostasis. Redox homeostasis is a fundamental cell property. Its regulation includes control of reactive oxygen species (ROS generation, sensing deviation from and readjustment of the cellular redox state. All these redox related functions have been recognized as decisive factors in salinity acclimation and adaptation. This review focuses on the core response of plants to overcome the challenges of salinity stress through regulation of ROS generation and detoxification systems and to maintain redox homeostasis. Emphasis is given to the role of NADH oxidase (RBOH, alternative oxidase (AOX, the plastid terminal oxidase (PTOX and the malate valve with the malate dehydrogenase isoforms under salt stress. Overwhelming evidence assigns an essential auxiliary function of ROS and redox homeostasis to salinity acclimation of plants.

  13. Coral bleaching under thermal stress: putative involvement of host/symbiont recognition mechanisms

    Directory of Open Access Journals (Sweden)

    Tambutte Sylvie

    2009-08-01

    Full Text Available Abstract Background Coral bleaching can be defined as the loss of symbiotic zooxanthellae and/or their photosynthetic pigments from their cnidarian host. This major disturbance of reef ecosystems is principally induced by increases in water temperature. Since the beginning of the 1980s and the onset of global climate change, this phenomenon has been occurring at increasing rates and scales, and with increasing severity. Several studies have been undertaken in the last few years to better understand the cellular and molecular mechanisms of coral bleaching but the jigsaw puzzle is far from being complete, especially concerning the early events leading to symbiosis breakdown. The aim of the present study was to find molecular actors involved early in the mechanism leading to symbiosis collapse. Results In our experimental procedure, one set of Pocillopora damicornis nubbins was subjected to a gradual increase of water temperature from 28°C to 32°C over 15 days. A second control set kept at constant temperature (28°C. The differentially expressed mRNA between the stressed states (sampled just before the onset of bleaching and the non stressed states (control were isolated by Suppression Subtractive Hybridization. Transcription rates of the most interesting genes (considering their putative function were quantified by Q-RT-PCR, which revealed a significant decrease in transcription of two candidates six days before bleaching. RACE-PCR experiments showed that one of them (PdC-Lectin contained a C-Type-Lectin domain specific for mannose. Immunolocalisation demonstrated that this host gene mediates molecular interactions between the host and the symbionts suggesting a putative role in zooxanthellae acquisition and/or sequestration. The second gene corresponds to a gene putatively involved in calcification processes (Pdcyst-rich. Its down-regulation could reflect a trade-off mechanism leading to the arrest of the mineralization process under stress

  14. Molecular mechanisms underlying the cholesterol-lowering effect of Ginkgo biloba extract in hepatocytes: a comparative study with Iovastatin

    Institute of Scientific and Technical Information of China (English)

    Zuo-quan XIE; Gai LIANG; Lu ZHANG; Qi WANG; Yi QU; Yang GAO; Li-bo LIN; Sai YE; Ji ZHANG; Hui WANG; Guo-ping ZHAO; Qing-hua ZHANG

    2009-01-01

    Aim: To explore the molecular mechanisms underlying the cholesterol-lowering effect of a Ginkgo biloba extract (GBE). Methods: Enzyme activity, cholesterol flux and changes in gene expression levels were assessed in cultured hepatocytes treated with GBE or Iovastatin. Results: GBE decreased the total cholesterol content in cultured hepatocytes and inhibited the activity of HMG-CoA reductase, as determined by an in vitro enzyme activity assay. In addition, GBE decreased cholesterol influx, whereas Iovastatin increased choles-terol influx. GBE treatment induced significant increases in the expression of cholesterogenic genes and genes involved in cholesterol metabolism, such as SREBF2, as determined by cDNA microarray and real-time RT-PCR. Furthermore, INSIG2, LDLR, LRP1, and LRP10 were differentially regulated by GBE and Iovastatin. The data imply that the two compounds modulate cholesterol metabolism through distinct mechanisms. Conclusion: By using a gene expression profiling approach, we were able to broaden the understanding of the molecular mechanisms by which GBE lowers cellular cholesterol levels. Specifically, we demonstrated that GBE exhibited dual effects on the cellular choles-terol pool by modulating both HMG-CoA reductase activity and inhibiting cholesterol influx.

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

    Science.gov (United States)

    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.

  16. Coping styles and behavioural flexibility: towards underlying mechanisms

    OpenAIRE

    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 attribu...

  17. Different routes, same pathways: Molecular mechanisms under silver ion and nanoparticle exposures in the soil sentinel Eisenia fetida

    International Nuclear Information System (INIS)

    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. - Highlights: • Molecular effects underlying Ag ions and NPs exposure were studied in Eisenia fetida. • Full transcriptomic study of a genetically characterised lineage. • NPs and ions presented a similar toxicodynamic response. • Internalisation of the two Ag forms by different toxicokinetic mechanisms. - Transcriptomic analyses after exposure of earthworms to silver NPs or ions showed a final common toxicodynamic response, but internalisation by different toxicokinetic mechanisms

  18. Analysis of nanoscale mechanical grasping under ambient conditions

    International Nuclear Information System (INIS)

    In this paper, in order to understand mechanical grasping at the nanoscale, contact mechanics between nanogrippers and nanoobjects is studied. Contact models are introduced to simulate elastic contacts between various profiles of a flat surface, sphere and cylinder for different types of nanoobjects and nanogrippers. Analyses and evaluation instances indicate that friction forces, commonly used in macro-grasping to overcome gravity, at the nanoscale are often insufficient to overcome the relatively strong adhesion forces when picking up the nanoobject deposited on a substrate due to the tiny contact area. For stable nanoscale grasping, nonparallel two-finger grippers with a 'V' configuration are demonstrated to have better grasping capabilities than parallel grippers. To achieve mechanical nanoscale grasping, a nanogripper constructed from two microcantilevers is presented. Experimental results for the pick-and-place manipulation of silicon nanowires validate the theoretical analyses and capabilities of the proposed nanogripper.

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

    Science.gov (United States)

    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

  20. Strain-driven criticality underlies nonlinear mechanics of fibrous networks

    CERN Document Server

    Sharma, A; Rens, R; Vahabi, M; Jansen, K A; Koenderink, G H; MacKintosh, F C

    2016-01-01

    Networks with only central force interactions are floppy when their average connectivity is below an isostatic threshold. Although such networks are mechanically unstable, they can become rigid when strained. It was recently shown that the transition from floppy to rigid states as a function of simple shear strain is continuous, with hallmark signatures of criticality (Nat. Phys. 12, 584 (2016)). The nonlinear mechanical response of collagen networks was shown to be quantitatively described within the framework of such mechanical critical phenomenon. Here, we provide a more quantitative characterization of critical behavior in subisostatic networks. Using finite size scaling we demonstrate the divergence of strain fluctuations in the network at well-defined critical strain. We show that the characteristic strain corresponding to the onset of strain stiffening is distinct from but related to this critical strain in a way that depends on critical exponents. We confirm this prediction experimentally for collagen...

  1. A novel antibody-dependent cellular cytotoxicity mechanism involved in defense against malaria requires costimulation of monocytes FcgammaRII and FcgammaRIII

    DEFF Research Database (Denmark)

    Jafarshad, Ali; Dziegiel, Morten Hanefeld; Lundquist, Rasmus; Nielsen, Leif K; Singh, Subhash; Druilhe, Pierre L

    2007-01-01

    Clinical experiments have shown that the Ab-dependent cell-mediated inhibition of Plasmodium falciparum is a major mechanism controlling malaria parasitemia and thereby symptoms. In this study, we demonstrate that a single merozoite per monocyte (MN) is sufficient to trigger optimal antiparasitic......-dependent cellular cytotoxicity and implies that all MN are not equally effective. These findings have both fundamental and practical implications, particularly for vaccine discovery....

  2. Mechanisms of antibody-dependent cellular cytotoxicity: the use of effector cells from chronic granulomatous disease patients as investigative probes.

    OpenAIRE

    Katz, P.; Simone, C B; Henkart, P A; Fauci, A S

    1980-01-01

    The present study characterized the antibody-dependent cellular cytoxicity (ADCC) of leukocyte effector cells (neutrophils, lymphocytes, and monocytes) from normal subjects and from chronic granulomatous disease (CGD) patients. CGD phagocytic cells (neutrophils and monocytes) had depressed ADCC activity against antibody-coated human erythrocyte (HRBC) targets in suspension cultures indicative of abnormal intracellular postphagocytic killing. However, when phagocytosis was prevented by using a...

  3. Dynamics of mechanical system for electromechanical integrated toroidal drive under electric disturbance

    Institute of Scientific and Technical Information of China (English)

    许立忠; 郝秀红

    2014-01-01

    Based on electromagnetics and mechanics, electromechanical coupled dynamic equations for the drive were developed. Using method of perturbation, free vibrations of the mechanical system under electric disturbance were investigated. The forced responses of the mechanical system to mechanical excitation under electric disturbance were also presented. It is known that for the system with electric disturbance, as time grows, beat occurs. When electric disturbing frequency is near to the natural frequencies of the mechanical system or their integer multiple, resonance vibrations occur. The forced responses of the mechanical system to mechanical excitation under electric disturbance are compound vibrations decided by mechanical excitation, electric disturbance and parameters of the system. The coupled resonance vibration caused by electric disturbance and mechanical excitation was discussed as well. The conditions under which above coupled resonance occurs were presented. The results show that when the difference of the excitation frequency and the perturbation frequency is equal to some order of natural frequency, coupled resonance vibrations occur.

  4. A possible mechanism of current in medium under electromagnetic wave

    Institute of Scientific and Technical Information of China (English)

    Zhang Tao

    2006-01-01

    In this paper a possible mechanism of current in medium is presented. Comparison between this current and the magnetization current was made. Expression for this current was derived. This work is helpful to understanding the interaction between medium and electromagnetic wave.

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

    Science.gov (United States)

    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

  6. Water hydraulic polymer components under irradiation. Mechanical properties

    International Nuclear Information System (INIS)

    Polymers will be used as different sealing and glide components for the hydraulic remote handling systems for lifting and moving activities in ITER. During operation these materials must maintain their properties during prolonged gamma irradiation and in the presence of water at or near room temperature. Preliminary results showed that the irradiation environment could affect the degradation process of the polymers and their hardness increase was different for irradiations carried out to 10 MGy in dry nitrogen or water. Vickers hardness tests were performed to study in detail the change in the mechanical properties of the candidate materials proposed for seals and wipers. Three different polymer materials have been tested as possible seals and O-rings: PEEK, Polyethylene (UHMW-PE), and Polyurethane. Specimens of each material have been irradiated with 60Co gamma rays up to 10 MGy in water. Following irradiation mechanical testing (tensile and microhardness) and also some microstructural observations of the fracture mode were carried out. The main results will be presented and discussed. Of the three materials, PEEK was outstanding, showing excellent mechanical behaviour for the doses and the irradiation conditions studied. Up to 10 MGy, neither hardness nor tensile strength were modified. In the case of polyethylene and polyurethane, the tensil failure mechanism varied with irradiation and give rise to lower ability for bending. However, up to 10 MGy the measured tensile strength and hardness data are acceptable for the working conditions studied. (author)

  7. Dissection of molecular mechanisms underlying speech and language disorders

    OpenAIRE

    Fisher, S

    2005-01-01

    Developmental disorders affecting speech and language are highly heritable, but very little is currently understood about the neuromolecular mechanisms that underlie these traits. Integration of data from diverse research areas, including linguistics, neuropsychology, neuroimaging, genetics, molecular neuroscience, developmental biology, and evolutionary anthropology, is becoming essential for unraveling the relevant pathways. Recent studies of the FOXP2 gene provide a case in point. Mutation...

  8. A review of mechanisms underlying anticarcinogenicity by brassica vegetables

    NARCIS (Netherlands)

    Verhoeven, D.T.H.; Verhagen, H.; Goldbohm, R.A.; Brandt, P.A. van den; Poppel, G. van

    1997-01-01

    The mechanisms by which brassica vegetables might decrease the risk of cancer are reviewed in this paper. Brassicas, including all types of cabbages, broccoli, cauliflower and Brussels sprouts, may be protective against cancer due to their relatively high glucosinolate content. Glucosinolates are us

  9. Mechanical Solder Characterisation Under High Strain Rate Conditions

    Science.gov (United States)

    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.

  10. Underlying mechanisms of transient luminous events: a review

    Directory of Open Access Journals (Sweden)

    V. V. Surkov

    2012-08-01

    Full Text Available 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.

  11. Mechanism of NBTI Recovery under Negative Voltage Stress

    International Nuclear Information System (INIS)

    Recovery phenomenon is observed under negative gate voltage stress which is smaller than the previous degradation stress. We focus on the drain current to study the degradation and recovery of negative bias temperature instability (NBTI) with a real-time method. By this method, different recovery phenomena among different size devices are observed. Under negative recovery stress, the drain current gradually recovers for the large size devices and gets into recovery saturation when long recovery time is involved. For small-size devices, a step-like recovery of drain current is observed. The recovery of the drain current is mainly caused by the holes detrapping and tunnelling back to the channel surface which are trapped in oxide. The model of hole detrapping explains the recovery under negative voltage stress reasonably. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

  12. Mechanism of NBTI Recovery under Negative Voltage Stress

    Institute of Scientific and Technical Information of China (English)

    CAO Yan-Rong; HU Shi-Gang; MA Xiao-Hua; HAO Yue

    2008-01-01

    Recovery phenomenon is observed under negative gate voltage stress which is smaller than the previous degradation stress. We focus on the drain current to study the degradation and recovery of negative bias temperature instability (NBTI) with a real-time method. By this method, different recovery phenomena among different size devices are observed. Under negative recovery stress, the drain current gradually recovers for the large size devices and gets into recovery saturation when long recovery time is involved. For small-size devices, a step-like recovery of drain current is observed. The recovery of the drain current is mainly caused by the holes detrapping and tunnelling back to the channel surface which are trapped in oxide. The model of hole detrapping explains the recovery under negative voltage stress reasonably.

  13. Mechanisms Underlying Isovolumic Contraction and Ejection Peaks in Seismocardiogram Morphology

    OpenAIRE

    Gurev, Viatcheslav; Tavakolian, Kouhyar; Constantino, Jason; Kaminska, Bozena; Blaber, Andrew P.; Trayanova, Natalia A.

    2012-01-01

    A three-dimensional (3D) finite element electromechanical model of the heart is employed in simulations of seismocardiograms (SCGs). To simulate SCGs, a previously developed 3D model of ventricular contraction is extended by adding the mechanical interaction of the heart with the chest and internal organs. The proposed model reproduces the major peaks of seismocardiographic signals during the phases of the cardiac cycle. Results indicate that SCGs record the pressure of the heart acting on th...

  14. POLYSTYRENE THERMAL AND CATALYTIC DEGRADATION MECHANISMS UNDER HYDROCRACKING CONDITIONS

    OpenAIRE

    Edwin G. Fuentes; María P. González-Marcos; Rubén López-Fonseca; José I. Gutiérrez-Ortiz; Juan R. González-Velasco

    2012-01-01

    In this study, differences between reaction mechanisms involved in thermal and catalytic processes of polystyrene degradation, 30% wt. in decalin, over Pt/Al2O3 bifunctional catalyst, are presented. Oligomers and aromatic derivates, mainly styrene, are mainly produced through the thermal process, whereas, with Pt/Al2O3, both depolymerisation and hydrogenation reactions have occured. Oligomers, in a lower concentration than in the thermal process, and aromatics, mainly ethyl benzene, are obtai...

  15. "Adaptive response" - some underlying mechanisms and open questions

    OpenAIRE

    Evgeniya G. Dimova; Bryant, Peter E.; Chankova, Stephka G

    2008-01-01

    Organisms are affected by different DNA damaging agents naturally present in the environment or released as a result of human activity. Many defense mechanisms have evolved in organisms to minimize genotoxic damage. One of them is induced radioresistance or adaptive response. The adaptive response could be considered as a nonspecific phenomenon in which exposure to minimal stress could result in increased resistance to higher levels of the same or to other types of stress some hours later. A ...

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

    Science.gov (United States)

    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) leading to negligible change in permeability after a 6-month run.

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

    Science.gov (United States)

    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. Physiological, molecular, and cellular mechanisms of impaired seawater tolerance following exposure of Atlantic salmon, Salmo salar, smolts to acid and aluminum

    Science.gov (United States)

    Monette, M.Y.; Yada, T.; Matey, V.; McCormick, S.D.

    2010-01-01

    We examined the physiological, molecular, and cellular mechanisms of impaired ion regulation in Atlantic salmon, Salmo salar, smolts following acute acid and aluminum (Al) exposure. Smolts were exposed to: control (pH 6.5, 3.4??gl-1 Al), acid and low Al (LAl: pH 5.4, 11??gl-1 Al), acid and moderate Al (MAl: pH 5.3, 42??gl-1 Al), and acid and high Al (HAl: pH 5.4, 56??gl-1 Al) for two and six days. At each time-point, smolts were sampled directly from freshwater treatment tanks and after a 24h seawater challenge. Exposure to acid/MAl and acid/HAl led to accumulation of gill Al, substantial alterations in gill morphology, reduced gill Na+/K+-ATPase (NKA) activity, and impaired ion regulation in both freshwater and seawater. Exposure to acid/MAl for six days also led to a decrease in gill mRNA expression of the apical Cl- channel (cystic fibrosis transmembrane conductance regulator I), increased apoptosis upon seawater exposure, an increase in the surface expression of mitochondria-rich cells (MRCs) within the filament epithelium of the gill, but reduced abundance of gill NKA-positive MRCs. By contrast, smolts exposed to acid and the lowest Al concentration exhibited minor gill Al accumulation, slight morphological modifications in the gill, and impaired seawater tolerance in the absence of a detectable effect on freshwater ion regulation. These impacts were accompanied by decreased cell proliferation, a slight increase in the surface expression of MRCs within the filament epithelium, but no impact on gill apoptosis or total MRC abundance was observed. However, MRCs in the gills of smolts exposed to acid/LAl exhibited morphological alterations including decreased size, staining intensity, and shape factor. We demonstrate that the seawater tolerance of Atlantic salmon smolts is extremely sensitive to acute exposure to acid and low levels of Al, and that the mechanisms underlying this depend on the time-course and severity of Al exposure. We propose that when smolts are

  19. Inhibition of cAMP-activated intestinal chloride secretion by diclofenac: cellular mechanism and potential application in cholera.

    Directory of Open Access Journals (Sweden)

    Pawin Pongkorpsakol

    2014-09-01

    Full Text Available Cyclic AMP-activated intestinal Cl- secretion plays an important role in pathogenesis of cholera. This study aimed to investigate the effect of diclofenac on cAMP-activated Cl- secretion, its underlying mechanisms, and possible application in the treatment of cholera. Diclofenac inhibited cAMP-activated Cl- secretion in human intestinal epithelial (T84 cells with IC50 of ∼ 20 µM. The effect required no cytochrome P450 enzyme-mediated metabolic activation. Interestingly, exposures of T84 cell monolayers to diclofenac, either in apical or basolateral solutions, produced similar degree of inhibitions. Analyses of the apical Cl- current showed that diclofenac reversibly inhibited CFTR Cl- channel activity (IC50 ∼ 10 µM via mechanisms not involving either changes in intracellular cAMP levels or CFTR channel inactivation by AMP-activated protein kinase and protein phosphatase. Of interest, diclofenac had no effect on Na(+-K(+ ATPases and Na(+-K(+-Cl- cotransporters, but inhibited cAMP-activated basolateral K(+ channels with IC50 of ∼ 3 µM. In addition, diclofenac suppressed Ca(2+-activated Cl- channels, inwardly rectifying Cl- channels, and Ca(2+-activated basolateral K(+ channels. Furthermore, diclofenac (up to 200 µM; 24 h of treatment had no effect on cell viability and barrier function in T84 cells. Importantly, cholera toxin (CT-induced Cl- secretion across T84 cell monolayers was effectively suppressed by diclofenac. Intraperitoneal administration of diclofenac (30 mg/kg reduced both CT and Vibrio cholerae-induced intestinal fluid secretion by ∼ 70% without affecting intestinal fluid absorption in mice. Collectively, our results indicate that diclofenac inhibits both cAMP-activated and Ca(2+-activated Cl- secretion by inhibiting both apical Cl- channels and basolateral K+ channels in intestinal epithelial cells. Diclofenac may be useful in the treatment of cholera and other types of secretory diarrheas resulting from intestinal

  20. Dislocation mechanism of deuterium retention in tungsten under plasma implantation

    International Nuclear Information System (INIS)

    We have developed a new theoretical model for deuterium (D) retention in tungsten-based alloys on the basis of its being trapped at dislocations and transported to the surface via the dislocation network with parameters determined by ab initio calculations. The model is used to explain experimentally observed trends of D retention under sub-threshold implantation, which does not produce stable lattice defects to act as traps for D in conventional models. Saturation of D retention with implantation dose and effects due to alloying of tungsten with, e.g. tantalum, are evaluated, and comparison of the model predictions with experimental observations under high-flux plasma implantation conditions is presented. (paper)

  1. Mechanical behaviour of an austenitic stainless steel under repeated impacts

    International Nuclear Information System (INIS)

    Cyclic indentation tests realised with an energy controlled spherical indenter allow a characterisation of the material behaviour under dynamic solicitations. This solicitation is, for example, able to show erosion and matting phenomenon. This test has been performed on AISI 316 stainless steels samples. Results have shown an increase of the hardness and the depth of the affected area versus the cycles number. With a micrographic optical analysis, we have detected a work hardening effect below the contact area. (authors)

  2. Comparison on cellular mechanisms of iron and cadmium accumulation in rice: prospects for cultivating Fe-rich but Cd-free rice.

    Science.gov (United States)

    Gao, Lei; Chang, Jiadong; Chen, Ruijie; Li, Hubo; Lu, Hongfei; Tao, Longxing; Xiong, Jie

    2016-12-01

    Iron (Fe) is essential for rice growth and humans consuming as their staple food but is often deficient because of insoluble Fe(III) in soil for rice growth and limited assimilation for human bodies, while cadmium (Cd) is non-essential and toxic for rice growth and humans if accumulating at high levels. Over-accumulated Cd can cause damage to human bodies. Selecting and breeding Fe-rich but Cd-free rice cultivars are ambitious, challenging and meaningful tasks for researchers. Although evidences show that the mechanisms of Fe/Cd uptake and accumulation in rice are common to some extent as a result of similar entry routes within rice, an increasing number of researchers have discovered distinct mechanisms between Fe/Cd uptake and accumulation in rice. This comprehensive review systematically elaborates and compares cellular mechanisms of Fe/Cd uptake and accumulation in rice, respectively. Mechanisms for maintaining Fe homeostasis and Cd detoxicification are also elucidated. Then, effects of different fertilizer management on Fe/Cd accumulation in rice are discussed. Finally, this review enumerates various approaches for reducing grain Cd accumulation and enhancing Fe content in rice. In summary, understanding of discrepant cellular mechanisms of Fe/Cd accumulation in rice provides guidance for cultivating Fe-fortified rice and has paved the way to develop rice that are tolerant to Cd stress, aiming at breeding Fe-rich but Cd-free rice. PMID:27502932

  3. Early-life Stress Impacts the Developing Hippocampus and Primes Seizure Occurrence: cellular, molecular, and epigenetic mechanisms

    Directory of Open Access Journals (Sweden)

    Li-Tung eHuang

    2014-02-01

    Full Text Available Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures and an increase in epileptogenesis. This article reviews the cellular and molecular changes encountered during prenatal and postnatal stress, and assesses the possible link between these changes and increases in seizure occurrence and epileptogenesis in the developing hippocampus. In addititon, the priming effect of prenatal and postnatal stress for seizures and epileptogenesis is discussed. Finally, the roles of epigenetic modifications in hippocampus and HPA axis programming, early-life stress, and epilepsy are discussed.

  4. DNA-Destabilizing Agents as an Alternative Approach for Targeting DNA: Mechanisms of Action and Cellular Consequences

    Directory of Open Access Journals (Sweden)

    Gaëlle Lenglet

    2010-01-01

    Full Text Available DNA targeting drugs represent a large proportion of the actual anticancer drug pharmacopeia, both in terms of drug brands and prescription volumes. Small DNA-interacting molecules share the ability of certain proteins to change the DNA helix's overall organization and geometrical orientation via tilt, roll, twist, slip, and flip effects. In this ocean of DNA-interacting compounds, most stabilize both DNA strands and very few display helix-destabilizing properties. These types of DNA-destabilizing effect are observed with certain mono- or bis-intercalators and DNA alkylating agents (some of which have been or are being developed as cancer drugs. The formation of locally destabilized DNA portions could interfere with protein/DNA recognition and potentially affect several crucial cellular processes, such as DNA repair, replication, and transcription. The present paper describes the molecular basis of DNA destabilization, the cellular impact on protein recognition, and DNA repair processes and the latter's relationships with antitumour efficacy.

  5. Differential Effects of Polymer-Surface Decoration on Drug Delivery, Cellular Retention, and Action Mechanisms of Functionalized Mesoporous Silica Nanoparticles.

    Science.gov (United States)

    You, Yuanyuan; Hu, Hao; He, Lizhen; Chen, Tianfeng

    2015-12-01

    Polymer-surface decoration has been found to be an effective strategy to enhance the biological activities of nanomedicine. Herein, three different types of polymers with a cancer-targeting ligand Arg-Gly-Asp peptide (RGD) have been used to decorate mesoporous silica nanoparticles (MSNs) and the functionalized nanosystems were used as drug carriers of oxaliplatin (OXA). The results showed that polymer-surface decoration of the MSNs nanosystem by poly(ethylene glycol) (PEG) and polyethyleneimine (PEI) significantly enhanced the anticancer efficacy of OXA, which was much higher than that of chitosan (CTS). This effect was closely related to the enhancement of the cellular uptake and cellular drug retention. Moreover, PEI@MSNs-OXA possessed excellent advantages in penetrating ability and inhibitory effects on SW480 spheroids that were used to simulate the in vivo tumor environments. Therefore, this study provides useful information for the rational design of a cancer-targeted MSNs nanosystem with polymer-surface decoration. PMID:26248202

  6. Advanced waterflooding in chalk reservoirs: Understanding of underlying mechanisms

    DEFF Research Database (Denmark)

    Zahid, Adeel; Sandersen, Sara Bülow; Stenby, Erling Halfdan;

    2011-01-01

    pressure. We have also observed formation of a microemulsion phase between brine and oil with the increase in sulfate ion concentration at high temperature and pressure. In addition, sulfate ions can reduce interfacial tension (IFT) between oil and water. We propose that the decrease in viscosity and...... formation of a microemulsion phase could be the possible reasons for the observed increase in oil recovery with sulfate ions at high temperature in chalk reservoirs besides the mechanism of the rock wettability alteration, which has been reported in most previous studies....

  7. Early-life Stress Impacts the Developing Hippocampus and Primes Seizure Occurrence: cellular, molecular, and epigenetic mechanisms

    OpenAIRE

    Li-Tung eHuang

    2014-01-01

    Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures...

  8. Early-life stress impacts the developing hippocampus and primes seizure occurrence: cellular, molecular, and epigenetic mechanisms

    OpenAIRE

    Huang, Li-Tung

    2014-01-01

    Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures...

  9. Contributions of mass spectrometry-based proteomics to defining cellular mechanisms and diagnostic markers for systemic lupus erythematosus

    OpenAIRE

    Korte, Erik A.; Gaffney, Patrick M.; Powell, David W.

    2012-01-01

    Systematic lupus erythematosus (SLE) is a complex disease for which molecular diagnostics are limited and pathogenesis is not clearly understood. Important information is provided in this regard by identification and characterization of more specific molecular and cellular targets in SLE immune cells and target tissue and markers of early-onset and effective response to treatment of SLE complications. In recent years, advances in proteomic technologies and applications have facilitated such d...

  10. Confocal imaging of whole vertebrate embryos reveals novel insights into molecular and cellular mechanisms of organ development

    Science.gov (United States)

    Hadel, Diana M.; Keller, Bradley B.; Sandell, Lisa L.

    2014-03-01

    Confocal microscopy has been an invaluable tool for studying cellular or sub-cellular biological processes. The study of vertebrate embryology is based largely on examination of whole embryos and organs. The application of confocal microscopy to immunostained whole mount embryos, combined with three dimensional (3D) image reconstruction technologies, opens new avenues for synthesizing molecular, cellular and anatomical analysis of vertebrate development. Optical cropping of the region of interest enables visualization of structures that are morphologically complex or obscured, and solid surface rendering of fluorescent signal facilitates understanding of 3D structures. We have applied these technologies to whole mount immunostained mouse embryos to visualize developmental morphogenesis of the mammalian inner ear and heart. Using molecular markers of neuron development and transgenic reporters of neural crest cell lineage we have examined development of inner ear neurons that originate from the otic vesicle, along with the supporting glial cells that derive from the neural crest. The image analysis reveals a previously unrecognized coordinated spatial organization between migratory neural crest cells and neurons of the cochleovestibular nerve. The images also enable visualization of early cochlear spiral nerve morphogenesis relative to the developing cochlea, demonstrating a heretofore unknown association of neural crest cells with extending peripheral neurite projections. We performed similar analysis of embryonic hearts in mouse and chick, documenting the distribution of adhesion molecules during septation of the outflow tract and remodeling of aortic arches. Surface rendering of lumen space defines the morphology in a manner similar to resin injection casting and micro-CT.

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

    Science.gov (United States)

    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.

  12. Molecular mechanisms underlying the effects of acupuncture on neuropathic pain**

    Institute of Scientific and Technical Information of China (English)

    Ziyong Ju; Huashun Cui; Xiaohui Guo; Huayuan Yang; Jinsen He; Ke Wang

    2013-01-01

    Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity fol owing chronic constriction injury, es-pecial y electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function.

  13. Cellular mechanisms of reduced sarcoplasmic reticulum Ca2+ content in L-thyroxin-induced rat ventricular hypertrophy

    Institute of Scientific and Technical Information of China (English)

    Lai-jing SONG; Guan-lei WANG; Jie LIU; Qin-ying QIU; Jing-hua OU; Yong-yuan GUAN

    2008-01-01

    Aim:To examine how the sarcoplasmic reticulum (SR) Ca2+ content changes and the underlying mechanism in L-thyroxin-induced cardiac hypertrophy. Methods:Echocardiography was used to confirm the establishment of the cardiac hypertro-phy model. The confocal microscopy and fluorescent indicator Fluo-3 was ap-plied to examine the intracellular Ca2+ concentration ([Ca2+]I), the Ca2+ sparks, and the caffeine-induced Ca2+ transient in freshly isolated cardiac ventricular myocytes. The activity of sarcolemmal and SR Ca2+-ATPase 2a (SERCA2a) in the ventricular tissue was also measured, respectively. Results:L-thyroxin (1 mg/kg injection for 10 d) induces left ventricular cardiac hypertrophy with normal myocardial function. The decreased caffeine-induced Ca2+ transient in the Ca2+-free solution was detected. The spontaneous Ca2+ sparks in hypertrophied myocytes occurred more frequently than in normal cells, with similar duration and spatial spread, but smaller amplitude. Then the basal [Ca2+]I increase was observed in quiescent left ventricular myocytes from hyperthyroidism rats. The activity of sarcolemmal and SR Ca2+-ATPase was decreased in the hypertrophied ventricle tissue. Conclusion:The results suggested that the reduced SR Ca2+ content may be associated with an increased Ca2+ leak and reduced SERCA2a activity, contributing to abnormal intracellular Ca2+ handling during hypertrophy in hyperthyroidism rats.

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

    Science.gov (United States)

    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

  15. Molecular mechanism for cavitation in water under tension

    CERN Document Server

    Menzl, Georg; Geiger, Philipp; Caupin, Frédéric; Abascal, Jose L F; Valeriani, Chantal; Dellago, Christoph

    2016-01-01

    Despite its relevance in biology and engineering, the molecular mechanism driving cavitation in water remains unknown. Using computer simulations, we investigate the structure and dynamics of vapor bubbles emerging from metastable water at negative pressures. We find that in the early stages of cavitation, bubbles are irregularly shaped and become more spherical as they grow. Nevertheless, the free energy of bubble formation can be perfectly reproduced in the framework of classical nucleation theory (CNT) if the curvature dependence of the surface tension is taken into account. Comparison of the observed bubble dynamics to the predictions of the macroscopic Rayleigh--Plesset (RP) equation, augmented with thermal fluctuations, demonstrates that the growth of nanoscale bubbles is governed by viscous forces. Combining the dynamical prefactor determined from the RP equation with the free energy of CNT yields an analytical expression for the cavitation rate that reproduces the simulation results very well over a w...

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

    Science.gov (United States)

    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

  17. Mechanisms underlying rapid aldosterone effects in the kidney.

    LENUS (Irish Health Repository)

    Thomas, Warren

    2011-03-17

    The steroid hormone aldosterone is a key regulator of electrolyte transport in the kidney and contributes to both homeostatic whole-body electrolyte balance and the development of renal and cardiovascular pathologies. Aldosterone exerts its action principally through the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues. Aldosterone also stimulates the activation of protein kinases and secondary messenger signaling cascades that act independently on specific molecular targets in the cell membrane and also modulate the transcriptional action of aldosterone through MR. This review describes current knowledge regarding the mechanisms and targets of rapid aldosterone action in the nephron and how aldosterone integrates these responses into the regulation of renal physiology.

  18. Mechanisms underlying rapid aldosterone effects in the kidney.

    LENUS (Irish Health Repository)

    Thomas, Warren

    2012-02-01

    The steroid hormone aldosterone is a key regulator of electrolyte transport in the kidney and contributes to both homeostatic whole-body electrolyte balance and the development of renal and cardiovascular pathologies. Aldosterone exerts its action principally through the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues. Aldosterone also stimulates the activation of protein kinases and secondary messenger signaling cascades that act independently on specific molecular targets in the cell membrane and also modulate the transcriptional action of aldosterone through MR. This review describes current knowledge regarding the mechanisms and targets of rapid aldosterone action in the nephron and how aldosterone integrates these responses into the regulation of renal physiology.

  19. Mechanisms underlying probucol-induced hERG-channel deficiency

    Directory of Open Access Journals (Sweden)

    Shi YQ

    2015-07-01

    Full Text Available Yuan-Qi Shi,1,* Cai-Chuan Yan,1,* Xiao Zhang,1 Meng Yan,1 Li-Rong Liu,1 Huai-Ze Geng,1 Lin Lv,1 Bao-Xin Li1,21Department of Pharmacology, Harbin Medical University, 2State-Province Key Laboratory of Biopharmaceutical Engineering, Harbin, Heilongjiang, People’s Republic of China*These authors contributed equally to this workAbstract: The hERG gene encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (IKr, which is important for cardiac repolarization. Reduction of IhERG due to genetic mutations or drug interferences causes long QT syndrome, leading to life-threatening cardiac arrhythmias (torsades de pointes or sudden death. Probucol is a cholesterol-lowering drug that could reduce hERG current by decreasing plasma membrane hERG protein expression and eventually cause long QT syndrome. Here, we investigated the mechanisms of probucol effects on IhERG and hERG-channel expression. Our data demonstrated that probucol reduces SGK1 expression, known as SGK isoform, in a concentration-dependent manner, resulting in downregulation of phosphorylated E3 ubiquitin ligase Nedd4-2 expression, but not the total level of Nedd4-2. As a result, the hERG protein reduces, due to the enhanced ubiquitination level. On the contrary, carbachol could enhance the phosphorylation level of Nedd4-2 as an alternative to SGK1, and thus rescue the ubiquitin-mediated degradation of hERG channels caused by probucol. These discoveries provide a novel mechanism of probucol-induced hERG-channel deficiency, and imply that carbachol or its analog may serve as potential therapeutic compounds for the handling of probucol cardiotoxicity.Keywords: long QT, hERG potassium channels, probucol, SGK1, Nedd4-2

  20. Mechanical behavior of enamel rods under micro-compression.

    Science.gov (United States)

    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. Uranium dioxide sintering Kinetics and mechanisms under controlled oxygen potentials

    International Nuclear Information System (INIS)

    The initial, intermediate, and final sintering stages of uranium dioxide were investigated as a function of stoichiometry and temperature by following the kinetics of the sintering reaction. Stoichiometry was controlled by means of the oxygen potential of the sintering atmosphere, which was measured continuously by solid-state oxygen sensors. Included in the kinetic study were microspheres originated from UO2 gels and UO2 pellets produced by isostatic pressing ceramic grade powders. The microspheres sintering behavior was examined using hot-stage microscopy and a specially designed high-temperature, controlled atmosphere furnace. This same furnace was employed as part of an optical dilatometer, which was utilized in the UO2 pellet sintering investigations. For controlling the deviations from stoichiometry during heat treatment, the oxygen partial pressure in the sintering atmosphere was varied by passing the gas through a Cu-Ti-Cu oxygen trap. The trap temperature determined the oxygen partial pressure of the outflowing mixture. Dry hydrogen was also used in some of the UO sub(2+x) sintering experiments. The determination of diametrial shrinkages and sintering indices was made utilizing high-speed microcinematography and ultra-microbalance techniques. It was observed that the oxygen potential has a substantial influence on the kinetics of the three sintering stages. The control of the sintering atmosphere oxygen partial pressure led to very fast densification of UO sub(2+x). Values in the interval 95.0 to 99.5% of theoretical density were reached in less than one minute. Uranium volume diffusion is the dominant mechanism in the initial and intermediate sintering stages. For the final stage, uranium grain boundary diffusion was found to be the main sintering mechanism. (Author)

  2. Mechanisms of microstructural changes of fuel under irradiation

    International Nuclear Information System (INIS)

    Nuclear fuels are subjected to high levels of radiation damage mainly due to the slowing of fission fragments, which results in substantial modifications of the initial fuel microstructure. Microstructure changes alter practically all engineering fuel properties such as atomic transport or thermomechanical properties so understanding these changes is essential to predicting the performance of fuel elements. Also, with increasing burn-up, the fuel drifts away from its initial composition as the fission process produces new chemical elements. Because nuclear fuels operate at high temperature and usually under high-temperature gradients, damage annealing, foreign atom or defect clustering and migration occur on multiple time and length scales, which make long-term predictions difficult. The end result is a fuel microstructure which may show extensive differences on the scale of a single fuel pellet. The main challenge we are faced with is, therefore, to identify the phenomena occurring on the atom scale that are liable to have macroscopic effects that will determine the microstructure changes and ultimately the life-span of a fuel element. One step towards meeting this challenge is to develop and apply experimental or modelling methods capable of connecting events that occur over very short length and timescales to changes in the fuel microstructure over engineering length and timescales. In the first part of this chapter, we provide an overview of some of the more important microstructure modifications observed in nuclear fuels. The emphasis is placed on oxide fuels because of the extensive amount of data available in relation to these materials under neutron or ion irradiation. When possible and relevant, the specifics of other types of fuels such as metallic or carbide fuels are alluded to. Throughout this chapter but more specifically in the latter part, we attempt to give examples of how modelling and experimentation at various scales can provide us with

  3. The involvement of selected membrane transport mechanisms in the cellular uptake of 177Lu-labeled bombesin, somatostatin and gastrin analogues

    International Nuclear Information System (INIS)

    Introduction: Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imaging and radiotherapy of some malignancies. However, the retention of radioactivity in the kidney may result in renal radiotoxic injury. This study seeks to evaluate the role of endocytic receptor megalin, renal SLC influx transporters and fluid phase endocytosis (FPE) in the cellular accumulation of radiolabeled peptides. Methods: In vitro transport cellular studies using megalin ligands (RAP, albumin), fluid phase endocytosis (FPE) inhibitor rottlerin and low temperature were employed to evaluate the transport mechanisms of the peptides. Cells transfected with hOAT1 or hOCT2 were used to analyze the role of these SLC transporters. Somatostatin (177Lu-DOTA-[Tyr3]octreotate, 177Lu-DOTA-[1-Nal3]octreotide), gastrin (177Lu-DOTA-sargastrin) and bombesin (177Lu-DOTA-[Pro1,Tyr4]bombesin, 177Lu-DOTA-[Lys3]bombesin, 177Lu-PCTA-[Lys3]bombesin) analogues were involved in the study. Results: RAP, albumin and low temperature decreased the accumulation of all the studied peptides significantly. With one exception, rottlerin caused the concentration dependent inhibition of the cellular accumulation of the radiopeptides. No significant differences in the uptake of the peptides between the control cells and those transfected with hOAT1 or hOCT2 were observed. Conclusion: The study showed that active transport mechanisms are decisive for the cellular accumulation in all tested 177Lu-labeled somatostatin, gastrin and bombesin analogues. Besides receptor-mediated endocytosis by megalin, FPE participates significantly in the uptake. The tested types of renal SLC transporters are not involved in this process

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

    Science.gov (United States)

    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

  5. Comparative analysis reveals the underlying mechanism of vertebrate seasonal reproduction.

    Science.gov (United States)

    Ikegami, Keisuke; Yoshimura, Takashi

    2016-02-01

    Animals utilize photoperiodic changes as a calendar to regulate seasonal reproduction. Birds have highly sophisticated photoperiodic mechanisms and functional genomics analysis in quail uncovered the signal transduction pathway regulating avian seasonal reproduction. Birds detect light with deep brain photoreceptors. Long day (LD) stimulus induces secretion of thyroid-stimulating hormone (TSH) from the pars tuberalis (PT) of the pituitary gland. PT-derived TSH locally activates thyroid hormone (TH) in the hypothalamus, which induces gonadotropin-releasing hormone (GnRH) and hence gonadotropin secretion. However, during winter, low temperatures increase serum TH for adaptive thermogenesis, which accelerates germ cell apoptosis by activating the genes involved in metamorphosis. Therefore, TH has a dual role in the regulation of seasonal reproduction. Studies using TSH receptor knockout mice confirmed the involvement of PT-derived TSH in mammalian seasonal reproduction. In addition, studies in mice revealed that the tissue-specific glycosylation of TSH diversifies its function in the circulation to avoid crosstalk. In contrast to birds and mammals, one of the molecular machineries necessary for the seasonal reproduction of fish are localized in the saccus vasculosus from the photoreceptor to the neuroendocrine output. Thus, comparative analysis is a powerful tool to uncover the universality and diversity of fundamental properties in various organisms. PMID:26050562

  6. Testing of short superconducting wire samples under mechanical stress

    International Nuclear Information System (INIS)

    It is well known that degradation and training effects are serious problems in large-scale, complex-shaped superconducting magnets. This behavior is attributed to plastic deformation of the superconductor and/or the matrix, which is produced by forces in the coil and concomitant heating. The current-carrying capacity of short superconducting samples immersed in liquid helium in a magnetic field and subjected to a tensile test was investigated. It was found that the critical current of the superconducting wire was reduced by 25 percent as a result of mechanically straining it beyond the breaking point. At approximately 60 percent of the limiting load, voltage jumps corresponding to the short time the sample was in the normal state appeared in the sample after the current was turned on. This transition occurred only once at a given load. No voltage jumps were observed in the sample up to the critical current after the current was turned on again at the same or a reduced load. These results may serve as guidelines in studying the effects of training and degradation and developing methods of eliminating them in superconducting magnets

  7. RISK FACTORS FOR PANCREATIC CANCER: UNDERLYING MECHANISMS AND POTENTIAL TARGETS

    Directory of Open Access Journals (Sweden)

    EdwinCharlesThrower

    2014-01-01

    Full Text Available 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-kB are important mechanisms that induce acute pancreatitis. 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 oncogneic 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.

  8. Coupled electrophysiological recording and single cell transcriptome analyses revealed molecular mechanisms underlying neuronal maturation

    OpenAIRE

    Chen, Xiaoying; Zhang, Kunshan; Zhou, Liqiang; Gao, Xinpei; Wang, Junbang; Yao, Yinan; He, Fei; Luo, Yuping; Yu, Yongchun; Li, Siguang; Cheng, Liming; Sun, Yi E.

    2016-01-01

    The mammalian brain is heterogeneous, containing billions of neurons and trillions of synapses forming various neural circuitries, through which sense, movement, thought, and emotion arise. The cellular heterogeneity of the brain has made it difficult to study the molecular logic of neural circuitry wiring, pruning, activation, and plasticity, until recently, transcriptome analyses with single cell resolution makes decoding of gene regulatory networks underlying aforementioned circuitry prope...

  9. Neural network mechanisms underlying stimulus driven variability reduction.

    Science.gov (United States)

    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

  10. Neural network mechanisms underlying stimulus driven variability reduction.

    Directory of Open Access Journals (Sweden)

    Gustavo Deco

    Full Text Available 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.

  11. Neural mechanism underlying autobiographical memory modulated by remoteness and emotion

    Science.gov (United States)

    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.

  12. Mechanisms underlying global stereopsis in fovea and periphery.

    Science.gov (United States)

    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

  13. Mechanical Model for Dynamic Behavior of Concrete Under Impact Loading

    Science.gov (United States)

    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).

  14. Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons.

    Science.gov (United States)

    Balkowiec, Agnieszka; Katz, David M

    2002-12-01

    Brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent modifications of neuronal connectivity and synaptic strength, including establishment of hippocampal long-term potentiation (LTP). To shed light on mechanisms underlying BDNF-dependent synaptic plasticity, the present study was undertaken to characterize release of native BDNF from newborn rat hippocampal neurons in response to physiologically relevant patterns of electrical field stimulation in culture, including tonic stimulation at 5 Hz, bursting stimulation at 25 and 100 Hz, and theta-burst stimulation (TBS). Release was measured using the ELISA in situ technique, developed in our laboratory to quantify secretion of native BDNF without the need to first overexpress the protein to nonphysiological levels. Each stimulation protocol resulted in a significant increase in BDNF release that was tetrodotoxin sensitive and occurred in the absence of glutamate receptor activation. However, 100 Hz tetanus and TBS, stimulus patterns that are most effective in inducing hippocampal LTP, were significantly more effective in releasing native BDNF than lower-frequency stimulation. For all stimulation protocols tested, removal of extracellular calcium, or blockade of N-type calcium channels, prevented BDNF release. Similarly, depletion of intracellular calcium stores with thapsigargin and treatment with dantrolene, an inhibitor of calcium release from caffeine-ryanodine-sensitive stores, markedly inhibited activity-dependent BDNF release. Our results indicate that BDNF release can encode temporal features of hippocampal neuronal activity. The dual requirement for calcium influx through N-type calcium channels and calcium mobilization from intracellular stores strongly implicates a role for calcium-induced calcium release in activity-dependent BDNF secretion. PMID:12451139

  15. Enhancement of sleep slow waves: underlying mechanisms and practical consequences.

    Directory of Open Access Journals (Sweden)

    Michele Bellesi

    2014-10-01

    Full Text Available Even modest sleep restriction, especially the loss of sleep slow wave activity, is invariably associated with slower 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 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, 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 enhancement.

  16. Compression under a mechanical counter pressure space suit glove

    Science.gov (United States)

    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, ppressure reductions. Conclusions: The MCP glove compressed the dorsum of the hand and middle finger at the design pressure.

  17. Photodegradation kinetics, products and mechanism of timolol under simulated sunlight

    International Nuclear Information System (INIS)

    Highlights: ► The indirect degradation of timolol is first investigated in fulvic acid solution. ► 3FA* and 1O2 accounted for the degradation of timolol in the aerated FA solutions. ► The presence of halides inhibited the degradation in the order of Cl− − −. ► The role of I− in the degradation was first found to be concentration-dependent. ► The photoproducts of timolol were identified by LC-DAD/ESI-MS/MS analysis. -- Abstract: The photodegradation of β-blocker timolol in fulvic acid (FA) solution was investigated under simulated sunlight. The triplet excited state of FA (3FA*) and singlet oxygen (1O2) were the main reactive species responsible for the degradation of timolol in the aerated FA solutions. Both dissolved oxygen and iodide ions (I−) are the efficient quenchers of 3FA*. The photodegradation was drastically accelerated after removing the dissolved oxygen. The presence of I− inhibited the photosensitized degradation of timolol in the deoxygenated FA solutions, whereas the role of I− in the reaction was concentration-dependent in the aerated solutions. The other halide ions such as chloride (Cl−) and bromide (Br−) exhibited less effect on the photodegradation of timolol in both aerated and deoxygenated solutions. By LC-DAD/ESI-MS/MS analysis, the photoproducts of timolol in both aerated and deoxygenated FA solutions were identified. Electron transfer interaction occurred between 3FA* and amine moiety of timolol, leading to the cleavage of C–O bond in the side chain and oxidation of the hexatomic ring. These findings suggest the photosensitized degradation was a significant pathway for the elimination of timolol in natural waters

  18. Photodegradation kinetics, products and mechanism of timolol under simulated sunlight

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yong, E-mail: ychen@hust.edu.cn [School of Environmental Science and Engineering, Huazhong University of Science and Technology, Wuhan 430074 (China); Liang, Qi; Zhou, Danna [College of Material Science and Chemical Engineering, China University of Geosciences, Wuhan 430074 (China); Wang, Zongping, E-mail: zongpingw@hust.edu.cn [School of Environmental Science and Engineering, Huazhong University of Science and Technology, Wuhan 430074 (China); Tao, Tao [School of Environmental Science and Engineering, Huazhong University of Science and Technology, Wuhan 430074 (China); Zuo, Yuegang [Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, 285 Old Westport Road, North Dartmouth, MA 02747 (United States)

    2013-05-15

    Highlights: ► The indirect degradation of timolol is first investigated in fulvic acid solution. ► {sup 3}FA{sup *} and {sup 1}O{sub 2} accounted for the degradation of timolol in the aerated FA solutions. ► The presence of halides inhibited the degradation in the order of Cl{sup −} < Br{sup −} < I{sup −}. ► The role of I{sup −} in the degradation was first found to be concentration-dependent. ► The photoproducts of timolol were identified by LC-DAD/ESI-MS/MS analysis. -- Abstract: The photodegradation of β-blocker timolol in fulvic acid (FA) solution was investigated under simulated sunlight. The triplet excited state of FA ({sup 3}FA{sup *}) and singlet oxygen ({sup 1}O{sub 2}) were the main reactive species responsible for the degradation of timolol in the aerated FA solutions. Both dissolved oxygen and iodide ions (I{sup −}) are the efficient quenchers of {sup 3}FA{sup *}. The photodegradation was drastically accelerated after removing the dissolved oxygen. The presence of I{sup −} inhibited the photosensitized degradation of timolol in the deoxygenated FA solutions, whereas the role of I{sup −} in the reaction was concentration-dependent in the aerated solutions. The other halide ions such as chloride (Cl{sup −}) and bromide (Br{sup −}) exhibited less effect on the photodegradation of timolol in both aerated and deoxygenated solutions. By LC-DAD/ESI-MS/MS analysis, the photoproducts of timolol in both aerated and deoxygenated FA solutions were identified. Electron transfer interaction occurred between {sup 3}FA{sup *} and amine moiety of timolol, leading to the cleavage of C–O bond in the side chain and oxidation of the hexatomic ring. These findings suggest the photosensitized degradation was a significant pathway for the elimination of timolol in natural waters.

  19. Particle behavior and char burnout mechanisms under pressurized combustion conditions

    Energy Technology Data Exchange (ETDEWEB)

    Bauer, C.M.; Spliethoff, H.; Hein, K.R.G.

    1999-07-01

    Combined cycle systems with coal-fired gas turbines promise highest cycle efficiencies for this fuel. Pressurized pulverized coal combustion, in particular, yields high cycle efficiencies due to the high flue gas temperatures possible. The main problem, however, is to ensure a flue gas clean enough to meet the high gas turbine standards with a dirty fuel like coal. On the one hand, a profound knowledge of the basic chemical and physical processes during fuel conversion under elevated pressures is required whereas on the other hand suitable hot gas cleaning systems need to be developed. The objective of this work was to provide experimental data to enable a detailed description of pressurized coal combustion processes. A series of experiments were performed with two German hvb coals, Ensdorf and Goettelborn, and one German brown coal, Garzweiler, using a semi-technical scale pressurized entrained flow reactor. The parameters varied in the experiments were pressure, gas temperature and bulk gas oxygen concentration. A two-color pyrometer was used for in-situ determination of particle surface temperatures and particle sizes. Flue gas composition was measured and solid residue samples taken and subsequently analyzed. The char burnout reaction rates were determinated varying the parameters pressure, gas temperature and initial oxygen concentration. Variation of residence time was achieved by taking the samples at different points along the reaction zone. The most influential parameters on char burnout reaction rates were found to be oxygen partial pressure and fuel volatile content. With increasing pressure the burn-out reactions are accelerated and are mostly controlled by product desorption and pore diffusion being the limiting processes. The char burnout process is enhanced by a higher fuel volatile content.

  20. Positive and negative regulatory mechanisms for fine-tuning cellularity and functions of medullary thymic epithelial cells

    Directory of Open Access Journals (Sweden)

    Taishin eAkiyama

    2015-09-01

    Full Text Available Self-tolerant T cells and regulatory T cells develop in the thymus. A wide variety of cell-cell interactions in the thymus is required for the differentiation, proliferation, and repertoire selection of T cells. Various secreted and cell surface molecules expressed in thymic epithelial cells mediate these processes. Moreover, cytokines expressed by cells of hematopoietic origin regulate the cellularity of thymic epithelial cells (TECs. Tumor necrosis factor (TNF family RANK ligand, lymphotoxin, and CD40 ligand, expressed in T cells and innate lymphoid cells (ILCs, promote the differentiation and proliferation of medullary TECs (mTECs that play critical roles in the induction of immune tolerance. A recent study suggests that interleukin-22 (IL-22 produced by ILCs promotes regeneration of TECs after irradiation. Intriguingly, TGF-β and osteoprotegerin limit cellularity of mTECs, thereby attenuating regulatory T cell generation. We will review recent insights into the molecular basis for cell-cell interactions regulating differentiation and proliferation of mTECs and also discuss about a perspective on use of mathematical models for understanding this complicated system.

  1. Mechanism underlying the development of unilateral spatial neglect

    International Nuclear Information System (INIS)

    To test the hypothesis that functional disturbance of the neural network involving the inferior parietal lobule (IPL), anterior cingulate gyrus (ACG), dorsolateral frontal lobe (DLF), and thalamus (TH) as components of the right hemisphere underlies the development of unilateral spatial neglect (USN), cerebral perfusion was measured by 123I-IMP SPECT in 32 patients with cerebrovascular right brain damage, 20 of whom had USN and 12 of whom did not. In analyzing the SPECT data, RI uptake in the four component regions and cerebellum (serving as a control) were estimated by symmetrically placing 'regions of interest' from both hemispheres on SPECT slices, most suitable for each region. The 'regional to cerebellar ratio' (R/CE ratio) for each component region was calculated and the values were compared. In the USN group, R/CE ratio values for each component region in the right hemisphere were significantly lower than those in the left, whereas in the non-USN group there was no right-left difference. When R/CE ratio values for each component region in the right hemisphere were compared between the USN and non-USN group, those for the IPL, ACG and TH were significantly lower in the USN group; the value for the DLF was also lower in the USN group, although the difference was not significant. Significantly lower values of R/CE for each component region in the right hemisphere were noticed when the regions showed apparent involvement on X-ray CT/MRI. Furthermore, in seven of the USN patients where lesions revealed by CT/MRI did not involve network components, the R/CE ratio values for the components in the right hemisphere were lower than those in the left; the difference was significant for the IPL, ACG and TH, but not for the DLF. It is suggested that functional disturbance of the neural network involving the IPL, ACG, DLF and TH in the right hemisphere might underlie the development of USN. (author)

  2. Corticonic models of brain mechanisms underlying cognition and intelligence

    Science.gov (United States)

    Farhat, Nabil H.

    underlying intelligence and other higher level brain functions.

  3. Microwave gallium-68 radiochemistry for kinetically stable bis(thiosemicarbazone) complexes: structural investigations and cellular uptake under hypoxia.

    Science.gov (United States)

    Alam, Israt S; Arrowsmith, Rory L; Cortezon-Tamarit, Fernando; Twyman, Frazer; Kociok-Köhn, Gabriele; Botchway, Stanley W; Dilworth, Jonathan R; Carroll, Laurence; Aboagye, Eric O; Pascu, Sofia I

    2016-01-01

    We report the microwave synthesis of several bis(thiosemicarbazones) and the rapid gallium-68 incorporation to give the corresponding metal complexes. These proved kinetically stable under 'cold' and 'hot' biological assays and were investigated using laser scanning confocal microscopy, flow cytometry and radioactive cell retention studies under normoxia and hypoxia. (68)Ga complex retention was found to be 34% higher in hypoxic cells than in normoxic cells over 30 min, further increasing to 53% at 120 min. Our data suggests that this class of gallium complexes show hypoxia selectivity suitable for imaging in living cells and in vivo tests by microPET in nude athymic mice showed that they are excreted within 1 h of their administration. PMID:26583314

  4. Evaluation of survival patterns and cellular injury of pseudomonas aeruginosa in different bottled waters stored under various conditions

    OpenAIRE

    Teixeira, Paula; Cunha, Joaquim; Albano, Helena; Ramalho, Rita; Gibbs, Paul

    2001-01-01

    Pseudomonas aeruginosa cells were inoculated into different waters and sampled after different periods of starvation in order to evaluate the influences of storage under daylight or dark conditions, the presence or absence of the autochthonous flora, the chemical composition of the water and the storage temperature, on survival Survival was investigated by plate counts on selective and nonselective agar media. Light, low temperature (4C) and presence of the autochthonous flora negatively infl...

  5. Project on Transfer Mechanism of Radioactive Source Term Under Severe Accident

    Institute of Scientific and Technical Information of China (English)

    SUN; Xue-ting; JI; Song-tao; CHEN; Lin-lin

    2012-01-01

    <正>The "Transfer mechanism of radioactive source term under severe accident" is a sub-project of the research program of "Mechanism and phenomenology of severe accident". An aerosol transfer mechanism experimental facility is built to simulate the passive containment cooling system (PCCS) of advanced pressurizer reactors to research effects to the transfer process of fission products under severe accident. An advanced CFD method is also utilized to research the effects. The objective of this project is to understand

  6. Coupled mechanical-electrical-thermal modeling for short-circuit prediction in a lithium-ion cell under mechanical abuse

    Science.gov (United States)

    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.

  7. Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes.

    Directory of Open Access Journals (Sweden)

    Mohammad F Saeed

    Full Text Available Zaire ebolavirus (ZEBOV, a highly pathogenic zoonotic virus, poses serious public health, ecological and potential bioterrorism threats. Currently no specific therapy or vaccine is available. Virus entry is an attractive target for therapeutic intervention. However, current knowledge of the ZEBOV entry mechanism is limited. While it is known that ZEBOV enters cells through endocytosis, which of the cellular endocytic mechanisms used remains unclear. Previous studies have produced differing outcomes, indicating potential involvement of multiple routes but many of these studies were performed using noninfectious surrogate systems such as pseudotyped retroviral particles, which may not accurately recapitulate the entry characteristics of the morphologically distinct wild type virus. Here we used replication-competent infectious ZEBOV as well as morphologically similar virus-like particles in specific infection and entry assays to demonstrate that in HEK293T and Vero cells internalization of ZEBOV is independent of clathrin, caveolae, and dynamin. Instead the uptake mechanism has features of macropinocytosis. The binding of virus to cells appears to directly stimulate fluid phase uptake as well as localized actin polymerization. Inhibition of key regulators of macropinocytosis including Pak1 and CtBP/BARS as well as treatment with the drug EIPA, which affects macropinosome formation, resulted in significant reduction in ZEBOV entry and infection. It is also shown that following internalization, the virus enters the endolysosomal pathway and is trafficked through early and late endosomes, but the exact site of membrane fusion and nucleocapsid penetration in the cytoplasm remains unclear. This study identifies the route for ZEBOV entry and identifies the key cellular factors required for the uptake of this filamentous virus. The findings greatly expand our understanding of the ZEBOV entry mechanism that can be applied to development of new

  8. Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes.

    Science.gov (United States)

    Saeed, Mohammad F; Kolokoltsov, Andrey A; Albrecht, Thomas; Davey, Robert A

    2010-01-01

    Zaire ebolavirus (ZEBOV), a highly pathogenic zoonotic virus, poses serious public health, ecological and potential bioterrorism threats. Currently no specific therapy or vaccine is available. Virus entry is an attractive target for therapeutic intervention. However, current knowledge of the ZEBOV entry mechanism is limited. While it is known that ZEBOV enters cells through endocytosis, which of the cellular endocytic mechanisms used remains unclear. Previous studies have produced differing outcomes, indicating potential involvement of multiple routes but many of these studies were performed using noninfectious surrogate systems such as pseudotyped retroviral particles, which may not accurately recapitulate the entry characteristics of the morphologically distinct wild type virus. Here we used replication-competent infectious ZEBOV as well as morphologically similar virus-like particles in specific infection and entry assays to demonstrate that in HEK293T and Vero cells internalization of ZEBOV is independent of clathrin, caveolae, and dynamin. Instead the uptake mechanism has features of macropinocytosis. The binding of virus to cells appears to directly stimulate fluid phase uptake as well as localized actin polymerization. Inhibition of key regulators of macropinocytosis including Pak1 and CtBP/BARS as well as treatment with the drug EIPA, which affects macropinosome formation, resulted in significant reduction in ZEBOV entry and infection. It is also shown that following internalization, the virus enters the endolysosomal pathway and is trafficked through early and late endosomes, but the exact site of membrane fusion and nucleocapsid penetration in the cytoplasm remains unclear. This study identifies the route for ZEBOV entry and identifies the key cellular factors required for the uptake of this filamentous virus. The findings greatly expand our understanding of the ZEBOV entry mechanism that can be applied to development of new therapeutics as well as

  9. Chemosensitizing effects of carbon-based nanomaterials in cancer cells: enhanced apoptosis and inhibition of proliferation as underlying mechanisms

    Science.gov (United States)

    Erdmann, Kati; Ringel, Jessica; Hampel, Silke; Rieger, Christiane; Huebner, Doreen; Wirth, Manfred P.; Fuessel, Susanne

    2014-10-01

    Recent studies have shown that carbon nanomaterials such as carbon nanofibres (CNFs) and multi-walled carbon nanotubes (CNTs) can exert antitumor activities themselves and sensitize cancer cells to conventional chemotherapeutics such as carboplatin and cisplatin. In the present study, the chemosensitizing effect of CNFs and CNTs on cancer cells of urological origin was investigated regarding the underlying mechanisms. Prostate cancer (DU-145, PC-3) and bladder cancer (EJ28) cells were treated with carbon nanomaterials (CNFs, CNTs) and chemotherapeutics (carboplatin, cisplatin) alone as well as in combination for 24 h. Forty-eight (EJ28) or 72 h (DU-145, PC-3) after the end of treatment the effects on cellular proliferation, clonogenic survival, cell death rate and cell cycle distribution were evaluated. Depending on the cell line, simultaneous administration of chemotherapeutics and carbon nanomaterials produced an additional inhibition of cellular proliferation and clonogenic survival of up to 77% and 98%, respectively, compared to the inhibitory effects of the chemotherapeutics alone. These strongly enhanced antiproliferative effects were accompanied by an elevated cell death rate, which was predominantly mediated via apoptosis and not by necrosis. The antitumor effects of combinations with CNTs were less pronounced than those with CNFs. The enhanced effects of the combinatory treatments on cellular function were mostly of additive to partly synergistic nature. Furthermore, cell cycle analysis demonstrated an arrest at the G2/M phase mediated by a monotreatment with chemotherapeutics. Following combinatory treatments, mostly less than or nearly additive increases of cell fractions in the G2/M phase could be observed. In conclusion, the pronounced chemosensitizing effects of CNFs and CNTs were mediated by an enhanced apoptosis and inhibition of proliferation. The combination of carbon-based nanomaterials and conventional chemotherapeutics represents a novel

  10. Task Group 7B: Cellular and Molecular Mechanisms of Biological Aging: The Roles of Nature, Nurture and Chance in the Maintenance of Human Healthspan

    Energy Technology Data Exchange (ETDEWEB)

    Weier, Heinz-Ulrich; Arya, Suresh; Grant, Christine; Miller, Linda; Ono, Santa Jeremy; Patil, Chris; Shay, Jerry; Topol, Eric; Torry, Michael; Weier, Heinz-Ulrich G.; Tse, Iris; Lin, Su-Ju; Miller, Richard

    2007-11-14

    The degree to which an individual organism maintains healthspan and lifespan is a function of complex interactions between genetic inheritance ('nature'), environment, including cultural inheritance (nurture) and stochastic events ('luck' or 'chance'). This task group will focus upon the role of chance because it is so poorly understood and because it appears to be of major importance in the determination of individual variations in healthspan and lifespan within species. The major factor determining variations in healthspan and lifespan between species is genetic inheritance. Broader aspects of cellular and molecular mechanisms of biological aging will also be considered, given their importance for understanding the cellular and molecular basis of successful aging. The task force will consider the cellular and molecular basis for nature, nurture and chance in healthspan and life span determination. On the basis of comparisons between identical and non-identical twins, geneticists have estimated that genes control no more than about a quarter of the inter-individual differences in lifespan (Herskind 1996). Twin studies of very old individuals, however, show substantially greater genetic contributions to Healthspan (McClearn 2004; Reed 2003). The environment clearly plays an important role in the length and the quality of life. Tobacco smoke, for example has the potential to impact upon multiple body systems in ways that appear to accelerate the rates at which those systems age (Bernhard 2007). To document the role of chance events on aging, one must rigorously control both the genetic composition of an organism and its environment. This has been done to a remarkable degree in a species of nematodes, Caenorhabditis elegans (Vanfleteren 1998). The results confirm hundreds of previous studies with a wide range of species, especially those with inbred rodents housed under apparently identical but less well controlled environments. One

  11. Physiological, molecular, and cellular mechanisms of impaired seawater tolerance following exposure of Atlantic salmon, Salmo salar, smolts to acid and aluminum

    Energy Technology Data Exchange (ETDEWEB)

    Monette, Michelle Y., E-mail: michelle.monette@yale.edu [Organismic and Evolutionary Biology Program, University of Massachusetts, Amherst, MA 01003 (United States); USGS, Conte Anadromous Fish Research Center, Turners Falls, MA 01376 (United States); Yada, Takashi [Freshwater Fisheries Research Department, National Research Institute of Fisheries Science, Nikko (Japan); Matey, Victoria [Department of Biology, San Diego State University, San Diego, CA 92182 (United States); McCormick, Stephen D. [Organismic and Evolutionary Biology Program, University of Massachusetts, Amherst, MA 01003 (United States); USGS, Conte Anadromous Fish Research Center, Turners Falls, MA 01376 (United States)

    2010-08-01

    We examined the physiological, molecular, and cellular mechanisms of impaired ion regulation in Atlantic salmon, Salmo salar, smolts following acute acid and aluminum (Al) exposure. Smolts were exposed to: control (pH 6.5, 3.4 {mu}g l{sup -1} Al), acid and low Al (LAl: pH 5.4, 11 {mu}g l{sup -1} Al), acid and moderate Al (MAl: pH 5.3, 42 {mu}g l{sup -1} Al), and acid and high Al (HAl: pH 5.4, 56 {mu}g l{sup -1} Al) for two and six days. At each time-point, smolts were sampled directly from freshwater treatment tanks and after a 24 h seawater challenge. Exposure to acid/MAl and acid/HAl led to accumulation of gill Al, substantial alterations in gill morphology, reduced gill Na{sup +}/K{sup +}-ATPase (NKA) activity, and impaired ion regulation in both freshwater and seawater. Exposure to acid/MAl for six days also led to a decrease in gill mRNA expression of the apical Cl{sup -} channel (cystic fibrosis transmembrane conductance regulator I), increased apoptosis upon seawater exposure, an increase in the surface expression of mitochondria-rich cells (MRCs) within the filament epithelium of the gill, but reduced abundance of gill NKA-positive MRCs. By contrast, smolts exposed to acid and the lowest Al concentration exhibited minor gill Al accumulation, slight morphological modifications in the gill, and impaired seawater tolerance in the absence of a detectable effect on freshwater ion regulation. These impacts were accompanied by decreased cell proliferation, a slight increase in the surface expression of MRCs within the filament epithelium, but no impact on gill apoptosis or total MRC abundance was observed. However, MRCs in the gills of smolts exposed to acid/LAl exhibited morphological alterations including decreased size, staining intensity, and shape factor. We demonstrate that the seawater tolerance of Atlantic salmon smolts is extremely sensitive to acute exposure to acid and low levels of Al, and that the mechanisms underlying this depend on the time

  12. Activation of lipid peroxidation as a mechanism of plant cell rearrangements under microgravity

    Science.gov (United States)

    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.

  13. Mechanical properties and cellular response of novel electrospun nanofibers for ligament tissue engineering: Effects of orientation and geometry.

    Science.gov (United States)

    Pauly, Hannah M; Kelly, Daniel J; Popat, Ketul C; Trujillo, Nathan A; Dunne, Nicholas J; McCarthy, Helen O; Haut Donahue, Tammy L

    2016-08-01

    Electrospun nanofibers are a promising material for ligamentous tissue engineering, however weak mechanical properties of fibers to date have limited their clinical usage. The goal of this work was to modify electrospun nanofibers to create a robust structure that mimics the complex hierarchy of native tendons and ligaments. The scaffolds that were fabricated in this study consisted of either random or aligned nanofibers in flat sheets or rolled nanofiber bundles that mimic the size scale of fascicle units in primarily tensile load bearing soft musculoskeletal tissues. Altering nanofiber orientation and geometry significantly affected mechanical properties; most notably aligned nanofiber sheets had the greatest modulus; 125% higher than that of random nanofiber sheets; and 45% higher than aligned nanofiber bundles. Modifying aligned nanofiber sheets to form aligned nanofiber bundles also resulted in approximately 107% higher yield stresses and 140% higher yield strains. The mechanical properties of aligned nanofiber bundles were in the range of the mechanical properties of the native ACL: modulus=158±32MPa, yield stress=57±23MPa and yield strain=0.38±0.08. Adipose derived stem cells cultured on all surfaces remained viable and proliferated extensively over a 7 day culture period and cells elongated on nanofiber bundles. The results of the study suggest that aligned nanofiber bundles may be useful for ligament and tendon tissue engineering based on their mechanical properties and ability to support cell adhesion, proliferation, and elongation. PMID:27082129

  14. SMTCI: Secure Multi-Trial Trust Evaluation and Cost- Effective Incentive Mechanism for Multi-Hop Cellular Networks

    Directory of Open Access Journals (Sweden)

    B.Sumathi

    2013-04-01

    Full Text Available In multi-hop cellular networks, finding an optimum and trusted route in the network through intermediate node is a major issue. At MCN, or the next-generation wireless networks, can significantly improve network performance and deployment and help implement many novel applications and services. However, when compared to wired and single-hop wireless networks, MCNs are highly vulnerable to serious security threats because packets may be relayed through integrated networks and autonomous devices. Our Proposed work has been focusing on developing secure trust based protocols for securing MCNs. Specifically, we are interested in securing route establishment and data transmission processes, establishing stable routes, and preserving users’ anonymity and location privacy. In this paperwe propose a multi-trial trust evaluation scheme, trusted node based ad hoc routing using trials to establish security accomplishes establishment of trusted networks in MANETs. We apply the same idea todevelop our proposed algorithm TBARA to rate neighbor nodes using hash values for identifying the misbehaving nodes. After the successful transmission of packets from source to destination, thedestination will send acknowledgement for the corresponding packet, upon receiving of acknowledgement incentive will be generated. It reduces the number of public-key cryptographic operations and protectagainst collusion attack.

  15. Metabolomics Reveals New Mechanisms for Pathogenesis in Barth Syndrome and Introduces Novel Roles for Cardiolipin in Cellular Function.

    Science.gov (United States)

    Sandlers, Yana; Mercier, Kelly; Pathmasiri, Wimal; Carlson, Jim; McRitchie, Susan; Sumner, Susan; Vernon, Hilary J

    2016-01-01

    Barth Syndrome is the only known Mendelian disorder of cardiolipin remodeling, with characteristic clinical features of cardiomyopathy, skeletal myopathy, and neutropenia. While the primary biochemical defects of reduced mature cardiolipin and increased monolysocardiolipin are well-described, much of the downstream biochemical dysregulation has not been uncovered, and biomarkers are limited. In order to further expand upon the knowledge of the biochemical abnormalities in Barth Syndrome, we analyzed metabolite profiles in plasma from a cohort of individuals with Barth Syndrome compared to age-matched controls via 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. A clear distinction between metabolite profiles of individuals with Barth Syndrome and controls was observed, and was defined by an array of metabolite classes including amino acids and lipids. Pathway analysis of these discriminating metabolites revealed involvement of mitochondrial and extra-mitochondrial biochemical pathways including: insulin regulation of fatty acid metabolism, lipid metabolism, biogenic amine metabolism, amino acid metabolism, endothelial nitric oxide synthase signaling, and tRNA biosynthesis. Taken together, this data indicates broad metabolic dysregulation in Barth Syndrome with wide cellular effects. PMID:27015085

  16. The cellular uptake mechanism, intracellular transportation, and exocytosis of polyamidoamine dendrimers in multidrug-resistant breast cancer cells.

    Science.gov (United States)

    Zhang, Jie; Liu, Dan; Zhang, Mengjun; Sun, Yuqi; Zhang, Xiaojun; Guan, Guannan; Zhao, Xiuli; Qiao, Mingxi; Chen, Dawei; Hu, Haiyang

    2016-01-01

    Polyamidoamine dendrimers, which can deliver drugs and genetic materials to resistant cells, are attracting increased research attention, but their transportation behavior in resistant cells remains unclear. In this paper, we performed a systematic analysis of the cellular uptake, intracellular transportation, and efflux of PAMAM-NH2 dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) using sensitive breast cancer cells (MCF-7 cells) as the control. We found that the uptake rate of PAMAM-NH2 was much lower and exocytosis of PAMAM-NH2 was much greater in MCF-7/ADR cells than in MCF-7 cells due to the elimination of PAMAM-NH2 from P-glycoprotein and the multidrug resistance-associated protein in MCF-7/ADR cells. Macropinocytosis played a more important role in its uptake in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH2 aggregated and became more degraded in the lysosomal vesicles of the MCF-7/ADR cells than in those of the MCF-7 cells. The endoplasmic reticulum and Golgi complex were found to participate in the exocytosis rather than endocytosis process of PAMAM-NH2 in both types of cells. Our findings clearly showed the intracellular transportation process of PAMAM-NH2 in MCF-7/ADR cells and provided a guide of using PAMAM-NH2 as a drug and gene vector in resistant cells. PMID:27536106

  17. Fundamental study of failure mechanisms of pressure vessels under thermo-mechanical cycling in multiphase environments

    Science.gov (United States)

    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

  18. Effects and underlying mechanisms of curcumin on the proliferation of vascular smooth muscle cells induced by Chol:MβCD

    International Nuclear Information System (INIS)

    Proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of various cardiovascular diseases. Curcumin, extracted from Curcumae longae, has been shown a variety of beneficial effects on human health, including anti-atherosclerosis by mechanisms poorly understood. In the present study, we attempted to investigate whether curcumin has any effect on VSMCs proliferation and the potential mechanisms involved. Our data showed curcumin concentration-dependently abrogated the proliferation of primary rat VSMCs induced by Chol:MβCD. To explore the underlying cellular and molecular mechanisms, we found that curcumin was capable of restoring caveolin-1 expression which was reduced by Chol:MβCD treatment. Moreover, curcumin abrogated the increment of phospho-ERK1/2 and nuclear accumulation of ERK1/2 in primary rat VSMCs induced by Chol:MβCD, which led to a suppression of AP-1 promoter activity stimulated by Chol:MβCD. In addition, curcumin was able to reverse cell cycle progression induced by Chol:MβCD, which was further supported by its down-regulation of cyclinD1 and E2F promoter activities in the presence of Chol:MβCD. Taking together, our data suggest curcumin inhibits Chol:MβCD-induced VSMCs proliferation via restoring caveolin-1 expression that leads to the suppression of over-activated ERK signaling and causes cell cycle arrest at G1/S phase. These novel findings support the beneficial potential of curcumin in cardiovascular disease.

  19. Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells.

    Science.gov (United States)

    Han, Anna; Bennett, Natalie; MacDonald, Amber; Johnstone, Megan; Whelan, Jay; Donohoe, Dallas R

    2016-08-01

    Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc. PMID:26661480

  20. By Different Cellular Mechanisms, Lymphatic Vessels Sprout by Endothelial Cell Recruitment Whereas Blood Vessels Grow by Vascular Expansion

    Science.gov (United States)

    Parsons-Wingerter, Patricia; McKay, Terri L.; Leontiev, Dmitry; Condrich, Terence K.; DiCorleto, Paul E.

    2005-01-01

    The development of effective vascular therapies requires the understanding of all modes of vessel formation contributing to vasculogenesis, angiogenesis (here termed hemangiogenesis) and lymphangiogenesis. We show that lymphangiogenesis proceeds by blind-ended vessel sprouting via recruitment of isolated endothelial progenitor cells to the tips of growing vessels, whereas hemangiogenesis occurs by non-sprouting vessel expansion from the capillary network, during middevelopment in the quail chorioallantoic membrane (CAM). Blood vessels expanded out of capillaries that displayed transient expression of alpha smooth muscle actin (alphaSMA), accompanied by mural recruitment of migratory progenitor cells expressing SMA. Lymphatics and blood vessels were identified by confocal/fluorescence microscopy of vascular endothelial growth factor (VEGF) receptors VEGFR-1 and VEGFR-2, alphaSMA (expressed on CAM blood vessels but not on lymphatics), homeobox transcription factor Prox-1 (specific to CAM lymphatic endothelium), and the quail hematopoetic/vascular marker, QH-1. Expression of VEGFR-1 was highly restricted to blood vessels (primarily capillaries). VEGFR-2 was expressed intensely in isolated hematopoietic cells, lymphatic vessels and moderately in blood vessels. Prox-1 was absent from endothelial progenitor cells prior to lymphatic recruitment. Although vascular endothelial growth factor-165 (VEGF(sub 165)) is a key regulator of numerous cellular processes in hemangiogenesis and vasculogenesis, the role of VEGF(sub 165) in lymphangiogenesis is less clear. Exogenous VEGF(sub 165) increased blood vessel density without changing endogenous modes of vascular/lymphatic vessel formation or marker expression patterns. However, VEGF(sub 165) did increase the frequency of blood vascular anastomoses and strongly induced the antimaturational dissociation of lymphatics from blood vessels, with frequent formation of homogeneous lymphatic networks.

  1. Interactivity effects in social media marketing on brand engagement: an investigation of underlying mechanisms

    NARCIS (Netherlands)

    M.L. Antheunis; G. van Noort

    2011-01-01

    Although, SNS advertising spending increases, research on SNS campaigning is still underexposed. First, this study aims to investigate the effect of SNS campaign interactivity on the receivers brand engagement, taking four underlying mechanisms into account (brand identification, campaign divergence

  2. News with an attitude: assessing the mechanisms underlying the effects of opinionated news

    NARCIS (Netherlands)

    M. Boukes; H.G. Boomgaarden; M. Moorman; C.H. de Vreese

    2014-01-01

    Opinionated news targets communities of likeminded viewers, relies on dramaturgical storytelling techniques, and shares characteristics with political satire. Accordingly, opinionated news should be understood as a specific form of political entertainment. We have investigated the mechanisms underly

  3. Mechanism of Roof Shock in Longwall Coal Mining under Surface Gully

    OpenAIRE

    Gangwei Fan; Dongsheng Zhang; Xufeng Wang

    2015-01-01

    The paper presents an interpretation on the abnormal roof shock in longwall coal mining under gullies using physical modeling, numerical modeling, and mechanical analysis. The modeling results show that the roof movement causes the shock load onto the stope in longwall coal mining under surface gully. The triggering mechanism of shock load depends on the direction of the face retreat with respect to the bottom of the surface gully. The slope tends to slide along the interface plane with a lon...

  4. Large Deflections Mechanical Analysis of a Suspended Single-Wall Carbon Nanotube under Thermoelectrical Loading

    OpenAIRE

    Assaf Ya'akobovitz; Slava Krylov; Yael Hanein

    2011-01-01

    Following the recent progress in integrating single-wall carbon nanotubes (SWCNTs) into silicon-based micro-electromechanical systems (MEMS), new modeling tools are needed to predict their behavior under different loads, including thermal, electrical and mechanical. In the present study, the mechanical behavior of SWCNTs under thermoelectrical loading is analyzed using a large deflection geometrically nonlinear string model. The effect of the resistive heating was found to have a substantial ...

  5. Mechanical behaviors and phase transition of Ho2O3 nanocrystals under high pressure

    International Nuclear Information System (INIS)

    Mechanical properties and phase transition often show quite large crystal size dependent behavior, especially at nanoscale under high pressure. Here, we have investigated Ho2O3 nanocrystals with in-situ x-ray diffraction and Raman spectroscopy under high pressure up to 33.5 GPa. When compared to the structural transition routine cubic -> monoclinic -> hexagonal phase in bulk Ho2O3 under high pressure, the nano-sized Ho2O3 shows a much higher onset transition pressure from cubic to monoclinic structure and followed by a pressure-induced-amorphization under compression. The detailed analysis on the Q (Q = 2π/d) dependent bulk moduli reveals the nanosized Ho2O3 particles consist of a clear higher compressible shell and a less compressible core. Insight into these phenomena shed lights on micro-mechanism studies of the mechanical behavior and phase evolution for nanomaterials under high pressure, in general.

  6. Mechanism of cellular uptake of HIV-TAT peptide & effects of TAT-SOD against ultraviolet induced skin damage

    OpenAIRE

    Chen, Xiaochao

    2013-01-01

    TAT peptide is one of the best-characterised cell penetrating peptides (CPPs) derived from the transactivator of transcription protein from the human immunodeficiency virus 1 (HIV-1). TAT peptide is able to cross the cell membrane and deliver various biomolecules into cells with low immunogenicity and no toxicity. However, the exact mechanism of internalization still remains a subject of controversy. Lamellar neutron scattering was used to determine the location of TAT pepti...

  7. Cellular differentiation in 3D-bioprinted mesenchymal stem cell-loaded hydrogels with varying structural and mechanical properties

    OpenAIRE

    Duarte Campos, Daniela Filipa

    2016-01-01

    Hydrogels are a promising alternative to rigid biomaterials typically used in the field of bone tissue engineering for the treatment of musculoskeletal disorders. By hydrogel-based 3D-bioprinting, the native ornamentation of cells and matrix from bone tissue could be resembled. Herein, it was hypothesized the combination of polysaccharides (agarose, alginate) with biological components (collagen, fibrinogen) would increase mechanical stiffness of printed constructs as well as support the prin...

  8. micro-mechanical experimental investigation and modelling of strain and damage of argillaceous rocks under combined hydric and mechanical loads

    International Nuclear Information System (INIS)

    The hydro-mechanical behavior of argillaceous rocks, which are possible host rocks for underground radioactive nuclear waste storage, is investigated by means of micro-mechanical experimental investigations and modellings. Strain fields at the micrometric scale of the composite structure of this rock, are measured by the combination of environmental scanning electron microscopy, in situ testing and digital image correlation technique. The evolution of argillaceous rocks under pure hydric loading is first investigated. The strain field is strongly heterogeneous and manifests anisotropy. The observed nonlinear deformation at high relative humidity (RH) is related not only to damage, but also to the nonlinear swelling of the clay mineral itself, controlled by different local mechanisms depending on RH. Irreversible deformations are observed during hydric cycles, as well as a network of microcracks located in the bulk of the clay matrix and/or at the inclusion-matrix interface. Second, the local deformation field of the material under combined hydric and mechanical loadings is quantified. Three types of deformation bands are evidenced under mechanical loading, either normal to stress direction (compaction), parallel (microcracking) or inclined (shear). Moreover, they are strongly controlled by the water content of the material: shear bands are in particular prone to appear at high RH states. In view of understanding the mechanical interactions a local scale, the material is modeled as a composite made of non-swelling elastic inclusions embedded in an elastic swelling clay matrix. The internal stress field induced by swelling strain incompatibilities between inclusions and matrix, as well as the overall deformation, is numerically computed at equilibrium but also during the transient stage associated with a moisture gradient. An analytical micro-mechanical model based on Eshelby's solution is proposed. In addition, 2D finite element computations are performed. Results

  9. Insulin resistance is a two-sided mechanism acting under opposite catabolic and anabolic conditions.

    Science.gov (United States)

    Schwartsburd, Polina

    2016-04-01

    The survival of multi-cellular organisms depends on the organism ability to maintain glucose homeostasis for time of low/high nutrient availability or high energy needs, and the ability to fight infections or stress. These effects are realized through the insulin controlled transport of blood glucose into the insulin-responsive cells such as muscle, fat and liver cells. Reduction in the ability of these cells to take glucose from the blood in response to normal circulating levels of insulin is known as insulin resistance (IR). Chronic IR is a key pathological feature of obesity, type 2 diabetes, sepsis and cancer cachexia, however temporal IR are widely met in fasting/ hibernation, pregnancy, anti-bacterial immunity, exercise and stress. Paradoxically, a certain part of the IR-cases is associated with catabolic metabolism, whereas the other is related to anabolic pathways. How can this paradoxical IR-response be explained? What is the metabolic basis of this IR variability and its physiological and pathological impacts? An answer to these questions might be achieved through the hypothesis in which IR is considered as a two-sided mechanism acting under opposite metabolic conditions (catabolism and anabolism) but with the common aim to sustain glucose homeostasis in a wide metabolic range. To test this hypothesis, I examined the main metabolic distinctions between the varied IR-cases and their dependence on the blood glucose concentration, level of the IR-threshold, and catabolic/anabolic activation. On the basis of the established interrelations, a simple model of IR-distribution has been developed. The model revealed the «U-type distribution» form with separation into two main IR-groups, each determined in the catabolic or anabolic conditions with one exception - type 2 diabetes and its paradoxical catabolic activation in anabolic conditions. The dual opposing (or complementary) role for the IR opens a new possibility for better understanding the cause and

  10. Dopamine as a potent inducer of cellular glutathione and NAD(P)H:quinone oxidoreductase 1 in PC12 neuronal cells: a potential adaptive mechanism for dopaminergic neuroprotection.

    Science.gov (United States)

    Jia, Zhenquan; Zhu, Hong; Misra, Bhaba R; Li, Yunbo; Misra, Hara P

    2008-11-01

    Dopamine auto-oxidation and the consequent formation of reactive oxygen species and electrophilic quinone molecules have been implicated in dopaminergic neuronal cell death in Parkinson's disease. We reported here that in PC12 dopaminergic neuronal cells dopamine at noncytotoxic concentrations (50-150 muM) potently induced cellular glutathione (GSH) and the phase 2 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), two critical cellular defenses in detoxification of ROS and electrophilic quinone molecules. Incubation of PC12 cells with dopamine also led to a marked increase in the mRNA levels for gamma-glutamylcysteine ligase catalytic subunit (GCLC) and NQO1. In addition, treatment of PC12 cells with dopamine resulted in a significant elevation of GSH content in the mitochondrial compartment. To determine whether treatment with dopamine at noncytotoxic concentrations, which upregulated the cellular defenses could protect the neuronal cells against subsequent lethal oxidative and electrophilic injury, PC12 cells were pretreated with dopamine (150 muM) for 24 h and then exposed to various cytotoxic concentrations of dopamine or 6-hydroxydopamine (6-OHDA). We found that pretreatment of PC12 cells with dopamine at a noncytotoxic concentration led to a remarkable protection against cytotoxicity caused by dopamine or 6-OHDA at lethal concentrations, as detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium reduction assay. In view of the critical roles of GSH and NQO1 in protecting against dopaminergic neuron degeneration, the above findings implicate that upregulation of both GSH and NQO1 by dopamine at noncytotoxic concentrations may serve as an important adaptive mechanism for dopaminergic neuroprotection. PMID:18368484

  11. Factors influencing the transfection efficiency and cellular uptake mechanisms of Pluronic P123-modified polypropyleneimine/pDNA polyplexes in multidrug resistant breast cancer cells.

    Science.gov (United States)

    Gu, Jijin; Hao, Junguo; Fang, Xiaoling; Sha, Xianyi

    2016-04-01

    Generally, the major obstacles for efficient gene delivery are cellular internalization and endosomal escape of nucleic acid such as plasmid DNA (pDNA) or small interfering RNA (siRNA). We previously developed Pluronic P123 modified polypropyleneimine (PPI)/pDNA (P123-PPI/pDNA) polyplexes as a gene delivery system. The results showed that P123-PPI/pDNA polyplexes revealed higher transfection efficiency than PPI/pDNA polyplexes in multidrug resistant breast cancer cells. As a continued effort, the present investigation on the factors influencing the transfection efficiency, cellular uptake mechanisms, and intracellular fate of P123-PPI/pDNA polyplexes is reported. The presence of P123 was the main factor influencing the transfection efficiency of P123-PPI/pDNA polyplexes in MCF-7/ADR cells, but other parameters, such as N/P ratio, FBS concentration, incubation time and temperature were important as well. The endocytic inhibitors against clathrin-mediated endocytosis (CME), caveolae-mediated endocytosis (CvME), and macropinocytosis were involved in the internalization to investigate their effects on the cellular uptake and transfection efficiency of P123-PPI/pDNA polyplexes in vitro. The data showed that the internalization of P123-PPI/pDNA polyplexes was obtained from both CME and CvME. Colocalization experiments with TRITC-transferrin (CME indicator), Alexa Fluor 555-CTB (CvME indicator), monoclonal anti-α-tubulin (microtubule indicator), and LysoTracker Green (Endosome/lysosome indicator) were carried out to confirm the internalization routes. The results showed that both CME and CvME played vital roles in the effective transfection of P123-PPI/pDNA polyplexes. Endosome/lysosome system and skeleton, including actin filament and microtubule, were necessary for the transportation after internalization. PMID:26741268

  12. Mechanisms Underlying Lexical Access in Native and Second Language Processing of Gender and Number Agreement

    Science.gov (United States)

    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…

  13. Mechanisms of shrub encroachment into Northern Chihuahuan Desert grasslands and impacts of climate change investigated using a cellular automata model

    Science.gov (United States)

    Caracciolo, Domenico; Istanbulluoglu, Erkan; Noto, Leonardo Valerio; Collins, Scott L.

    2016-05-01

    Arid and semiarid grasslands of southwestern North America have changed dramatically over the last 150 years as a result of woody plant encroachment. Overgrazing, reduced fire frequency, and climate change are known drivers of woody plant encroachment into grasslands. In this study, relatively simple algorithms for encroachment factors (i.e., grazing, grassland fires, and seed dispersal by grazers) are proposed and implemented in the ecohydrological Cellular-Automata Tree Grass Shrub Simulator (CATGraSS). CATGraSS is used in a 7.3 km2 rectangular domain located in central New Mexico along a zone of grassland to shrubland transition, where shrub encroachment is currently active. CATGraSS is calibrated and used to investigate the relative contributions of grazing, fire frequency, seed dispersal by herbivores and climate change on shrub abundance over a 150-year period of historical shrub encroachment. The impact of future climate change is examined using a model output that realistically represents current vegetation cover as initial condition, in a series of stochastic CATGraSS future climate simulations. Model simulations are found to be highly sensitive to the initial distribution of shrub cover. Encroachment factors more actively lead to shrub propagation within the domain when the model starts with randomly distributed individual shrubs. However, when shrubs are naturally evolved into clusters, the model response to encroachment factors is muted unless the effect of seed dispersal by herbivores is amplified. The relative contribution of different drivers on modeled shrub encroachment varied based on the initial shrub cover condition used in the model. When historical weather data is used, CATGraSS predicted loss of shrub and grass cover during the 1950 s drought. While future climate change is found to amplify shrub encroachment (∼13% more shrub cover by 2100), grazing remains the dominant factor promoting shrub encroachment. When we modeled future climate

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

    Science.gov (United States)

    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

  15. The cellular decision between apoptosis and autophagy

    Directory of Open Access Journals (Sweden)

    Yong-Jun Fan

    2013-03-01

    Full Text Available Apoptosis and autophagy are important molecular processes that maintain organismal and cellular homeostasis, respectively. While apoptosis fulfills its role through dismantling damaged or unwanted cells, autophagy maintains cellular homeostasis through recycling selective intracellular organelles and molecules. Yet in some conditions, autophagy can lead to cell death. Apoptosis and autophagy can be stimulated by the same stresses. Emerging evidence indicates an interplay between the core proteins in both pathways, which underlies the molecular mechanism of the crosstalk between apoptosis and autophagy. This review summarizes recent literature on molecules that regulate both the apoptotic and autophagic processes.

  16. Microtubule dysfunction by posttranslational nitrotyrosination of α-tubulin: A nitric oxide-dependent mechanism of cellular injury

    OpenAIRE

    Eiserich, Jason P.; Estévez, Alvaro G.; Bamberg, Thaddeus V.; Ye, Yao Zu; Chumley, Phillip H.; Beckman, Joseph S.; Freeman, Bruce A.

    1999-01-01

    NO2Tyr (3-Nitrotyrosine) is a modified amino acid that is formed by nitric oxide-derived species and has been implicated in the pathology of diverse human diseases. Nitration of active-site tyrosine residues is known to compromise protein structure and function. Although free NO2Tyr is produced in abundant concentrations under pathological conditions, its capacity to alter protein structure and function at the translational or posttranslational level is unknown. Here, we report that free NO2T...

  17. Integrated cellular systems

    Science.gov (United States)

    Harper, Jason C.

    The generation of new three-dimensional (3D) matrices that enable integration of biomolecular components and whole cells into device architectures, without adversely altering their morphology or activity, continues to be an expanding and challenging field of research. This research is driven by the promise that encapsulated biomolecules and cells can significantly impact areas as diverse as biocatalysis, controlled delivery of therapeutics, environmental and industrial process monitoring, early warning of warfare agents, bioelectronics, photonics, smart prosthetics, advanced physiological sensors, portable medical diagnostic devices, and tissue/organ replacement. This work focuses on the development of a fundamental understanding of the biochemical and nanomaterial mechanisms that govern the cell directed assembly and integration process. It was shown that this integration process relies on the ability of cells to actively develop a pH gradient in response to evaporation induced osmotic stress, which catalyzes silica condensation within a thin 3D volume surrounding the cells, creating a functional bio/nano interface. The mechanism responsible for introducing functional foreign membrane-bound proteins via proteoliposome addition to the silica-lipid-cell matrix was also determined. Utilizing this new understanding, 3D cellular immobilization capabilities were extended using sol-gel matrices endowed with glycerol, trehalose, and media components. The effects of these additives, and the metabolic phase of encapsulated S. cerivisiase cells, on long-term viability and the rate of inducible gene expression was studied. This enabled the entrapment of cells within a novel microfluidic platform capable of simultaneous colorimetric, fluorescent, and electrochemical detection of a single analyte, significantly improving confidence in the biosensor output. As a complementary approach, multiphoton protein lithography was utilized to engineer 3D protein matrices in which to

  18. A Review on Damage Mechanisms, Models and Calibration Methods under Various Deformation Conditions

    OpenAIRE

    Lin, Jiali; Liu, Y.; Liu, Yehan; Dean, T. A.

    2005-01-01

    Abstract The development of microdamage under the deformation conditions of high temperature creep, cold metal forming, superplastic forming, and hot metal forming has been reviewed and discussed, and typical constitutive equations developed to model the individual damage mechanisms are summarized. Based on the microstructural analysis of the key damage features for metallic materials under a wide range of ...

  19. Modeling mechanical restriction differences between car and heavy truck in two-lane cellular automata traffic flow model

    Science.gov (United States)

    Li, Xin; Li, Xingang; Xiao, Yao; Jia, Bin

    2016-06-01

    Real traffic is heterogeneous with car and truck. Due to mechanical restrictions, the car and the truck have different limited deceleration capabilities, which are important factors in safety driving. This paper extends the single lane safety driving (SD) model with limited deceleration capability to two-lane SD model, in which car-truck heterogeneous traffic is considered. A car has a larger limited deceleration capability while a heavy truck has a smaller limited deceleration capability as a result of loaded goods. Then the safety driving conditions are different as the types of the following and the leading vehicles vary. In order to eliminate the well-known plug in heterogeneous two-lane traffic, it is assumed that heavy truck has active deceleration behavior when the heavy truck perceives the forming plug. The lane-changing decisions are also determined by the safety driving conditions. The fundamental diagram, spatiotemporal diagram, and lane-changing frequency were investigated to show the effect of mechanical restriction on heterogeneous traffic flow. It was shown that there would be still three traffic phases in heterogeneous traffic condition; the active deceleration of the heavy truck could well eliminate the plug; the lane-changing frequency was low in synchronized flow; the flow and velocity would decrease as the proportion of heavy truck grows or the limited deceleration capability of heavy truck drops; and the flow could be improved with lane control measures.

  20. Electro-oxidation process and mechanism of molybdenite decomposition under ultrasonic effect

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    According to the characteristics and shortcomings of the traditional roasting process and the electro-oxidation process in the molybdenum metallurgical industry,the ultrasound electro-oxidation process was proposed to strengthen the oxidative decomposition or leaching of molybdenum.Laboratory work was carried out in an electrochemical cell with 15 nun electrode spacing at 25℃ under ultrasonic effect.The optimum conditions were found through experiments.The electro-oxidation mechanism of molybdenite decomposition under ultrasonic was investigated.A model of electro-oxidation mechanism of molybdenum under ultrasonic was given.

  1. Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae. V. Anamnestic cellular and humoral responses following challenge infection

    Energy Technology Data Exchange (ETDEWEB)

    Correa-Oliveira, R.; Sher, A.; James, S.L.

    1984-03-01

    Mice vaccinated with radiation-attenuated cercariae display low levels of cellular and humoral immune responses toward schistosomulum antigens, as measured in vitro by lymphocyte blastogenesis and quantitation of anti-larval antibodies by indirect immunofluorescence. Both responses wane with time after vaccination. However subsequent challenge infection provokes immune responses of classical anamnestic character, being both more rapid in appearance and of greater magnitude. Antigen responsive cells appear in lymph nodes draining the challenge site within 24 hours after infection. Both circulating anti-schistosomulum surface antibodies as well as cytophilic IgE anti-worm antigen antibodies increase substantially by 1 week after challenge. All of the anamnestic circulating antibodies belong to the IgG class. Those findings support the concept that vaccine-induced resistance to Schistosoma mansoni infection involves sensitized T and B lymphocytes, and point to the possible role of post-challenge anamnestic responses in the effector mechanism of parasite killing in this model.

  2. Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae. V. Anamnestic cellular and humoral responses following challenge infection

    International Nuclear Information System (INIS)

    Mice vaccinated with radiation-attenuated cercariae display low levels of cellular and humoral immune responses toward schistosomulum antigens, as measured in vitro by lymphocyte blastogenesis and quantitation of anti-larval antibodies by indirect immunofluorescence. Both responses wane with time after vaccination. However subsequent challenge infection provokes immune responses of classical anamnestic character, being both more rapid in appearance and of greater magnitude. Antigen responsive cells appear in lymph nodes draining the challenge site within 24 hours after infection. Both circulating anti-schistosomulum surface antibodies as well as cytophilic IgE anti-worm antigen antibodies increase substantially by 1 week after challenge. All of the anamnestic circulating antibodies belong to the IgG class. Those findings support the concept that vaccine-induced resistance to Schistosoma mansoni infection involves sensitized T and B lymphocytes, and point to the possible role of post-challenge anamnestic responses in the effector mechanism of parasite killing in this model

  3. Numerical investigation of aerosolized drug delivery in the human lungs under mechanical ventilator conditions

    Science.gov (United States)

    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.

  4. Report on NCI symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. II. Cellular and animal models

    Energy Technology Data Exchange (ETDEWEB)

    Fry, R.J.M.

    1984-01-01

    The point at which the common final pathway for induction of cancer by chemical carcinogens and ionizing radiation has not been identified. Although common molecular targets are suggested by recent findings about the role of oncogenes, the mechanism by which the deposition of radiation energy and the formation of adducts or other DNA lesions induced by chemicals affects the changes in the relevant targets may be quite different. The damage to DNA that plays no part in the transformation events, but that influences the stability of the genome, and therefore, the probability of subsequent changes that influence tumorigenesis may be more readily induced by some agents than others. Similarly, the degree of cytotoxic effects that disrupt tissue integrity and increase the probability of expression of initiated cells may be dependent on the type of carcinogen. Also, evidence was presented that repair of the initial lesions could be demonstrated after exposure to low-LET radiation but not after exposure to chemical carcinogens.

  5. The influence of receptor-mediated interactions on reaction-diffusion mechanisms of cellular self-organisation.

    Science.gov (United States)

    Klika, Václav; Baker, Ruth E; Headon, Denis; Gaffney, Eamonn A

    2012-04-01

    Understanding the mechanisms governing and regulating self-organisation in the developing embryo is a key challenge that has puzzled and fascinated scientists for decades. Since its conception in 1952 the Turing model has been a paradigm for pattern formation, motivating numerous theoretical and experimental studies, though its verification at the molecular level in biological systems has remained elusive. In this work, we consider the influence of receptor-mediated dynamics within the framework of Turing models, showing how non-diffusing species impact the conditions for the emergence of self-organisation. We illustrate our results within the framework of hair follicle pre-patterning, showing how receptor interaction structures can be constrained by the requirement for patterning, without the need for detailed knowledge of the network dynamics. Finally, in the light of our results, we discuss the ability of such systems to pattern outside the classical limits of the Turing model, and the inherent dangers involved in model reduction. PMID:22072186

  6. Report on NCI symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. II. Cellular and animal models

    International Nuclear Information System (INIS)

    The point at which the common final pathway for induction of cancer by chemical carcinogens and ionizing radiation has not been identified. Although common molecular targets are suggested by recent findings about the role of oncogenes, the mechanism by which the deposition of radiation energy and the formation of adducts or other DNA lesions induced by chemicals affects the changes in the relevant targets may be quite different. The damage to DNA that plays no part in the transformation events, but that influences the stability of the genome, and therefore, the probability of subsequent changes that influence tumorigenesis may be more readily induced by some agents than others. Similarly, the degree of cytotoxic effects that disrupt tissue integrity and increase the probability of expression of initiated cells may be dependent on the type of carcinogen. Also, evidence was presented that repair of the initial lesions could be demonstrated after exposure to low-LET radiation but not after exposure to chemical carcinogens

  7. Mechanisms underlying the adaptive response against spontaneous neoplastic transformation induced by low doses of low LET radiation, Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    J. Leslie Redpath, Ph.D.

    2006-01-23

    The goal of this project was to investigate mechanisms underlying the adaptive response seen following exposure of HeLa x skin fibroblast human hybrid cells to low doses of low LET radiation. It was proposed to investigate the contributions of three possible mechanisms. These were: 1. Upregulation of cellular antioxidant status. 2. Upregulation of DNA repair. 3. Upregulation of gap junction intracellular communication. We have completed the study of the role of upregulation of reduced glutathione (GSH) as a possible mechanism underlying our observed suppression of transformation frequency at low radiation doses. We have also completed our study of the possible role of upregulation of DNA repair in the observed adaptive response against neoplastic transformation. We concluded that upregulation of DNA repair may be more important in modulating transformation at the higher dose. A manuscript describing the above studies has been submitted published in Carcinogenesis 24:1961-1965, 2003. Finally, we have completed two studies of the possible role of upregulation of gap junction intercellular communication (GJIC) in modulating transformation frequency at low doses of low LET radiation. This research was published in Radiation Research 162:646-654, 2004. In order to optimize the opportunity for GJIC, we then carried out a study where confluent cultures were irradiated. The results indicated, that while the degree of low dose suppression was somewhat reduced compared to that seen for subconfluent cultures, it was not completely absent. This research has been submitted for publication. Our research program was of sufficient interest to generate two invited reviews, and five invited presentations.

  8. Research of mechanics of the compact bone microvolume and porous ceramics under uniaxial compression

    International Nuclear Information System (INIS)

    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

  9. Research of mechanics of the compact bone microvolume and porous ceramics under uniaxial compression

    Energy Technology Data Exchange (ETDEWEB)

    Kolmakova, T. V., E-mail: kolmakova@ftf.tsu.ru; Buyakova, S. P., E-mail: sbuyakova@ispms.tsc.ru; Kul’kov, S. N., E-mail: kulkov@ms.tsc.ru [Institute of Strength Physics and Materials Science of Siberian Branch of Russian Academy of Sciences (Russian Federation); National Research Tomsk State University (Russian Federation)

    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.

  10. Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu.

    Science.gov (United States)

    Cooley, S; Burns, L J; Repka, T; Miller, J S

    1999-10-01

    Treatment of advanced breast cancer with autologous stem cell transplantation is limited by a high probability of disease relapse. In clinical trials, interleukin 2 (IL-2) alone can expand natural killer (NK) cells in vivo and increase their cytotoxic activity against breast cancer cell lines, but this increase is modest. Understanding the mechanisms that mediate NK cell lysis of breast cancer targets may lead to improvements of current immunotherapy strategies. NK cells from normal donors or patients receiving subcutaneous IL-2 were tested in cytotoxicity assays against five breast cancer cell lines. The role of adhesion molecules and antibodies that interact through Fc receptors on NK cells was explored. NK cell lysis of breast cancer targets is variable and is partially dependent on recognition through ICAM-1 and CD18. While blocking CD2 slightly decreased cytotoxicity, contrary to expectations, an antibody against CD58 (the ligand for CD2), failed to block killing and instead mediated an increased cytotoxicity that correlated with target density of CD58. The CD58 antibody-enhanced killing was dependent not only on FcRgammaIII but also on CD2 and ICAM-1/CD18. To further elucidate the mechanism of this CD58 antibody-dependent cellular cytotoxicity (ADCC), another antibody was tested. Trastuzumab (Herceptin), a humanized antibody against HER2/neu, mediated potent ADCC against all the HER2/neu positive breast cancer targets. Unlike CD58 antibody-mediated ADCC, Herceptin ADCC was minimally affected by blocking antibodies to CD2 or ICAM-1/CD18, which suggests a different mechanism of action. This study shows that multiple mechanisms are involved in NK cell lysis of breast cancer targets, that none of the targets are inherently resistant to killing, and that two distinct mechanisms of ADCC can target immunotherapy to breast cancer cells. PMID:10517495

  11. A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence.

    Science.gov (United States)

    Bukhari, Syed I A; Truesdell, Samuel S; Lee, Sooncheol; Kollu, Swapna; Classon, Anthony; Boukhali, Myriam; Jain, Esha; Mortensen, Richard D; Yanagiya, Akiko; Sadreyev, Ruslan I; Haas, Wilhelm; Vasudevan, Shobha

    2016-03-01

    MicroRNAs predominantly decrease gene expression; however, specific mRNAs are translationally upregulated in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes by an FXR1a-associated microRNA-protein complex (microRNP) that lacks the microRNP repressor, GW182. Their mechanism in these conditions of decreased mTOR signaling, and therefore reduced canonical (cap-and-poly(A)-tail-mediated) translation, remains undiscovered. Our data reveal that mTOR inhibition in human THP1 cells enables microRNA-mediated activation. Activation requires shortened/no poly(A)-tail targets; polyadenylated mRNAs are partially activated upon PAIP2 overexpression, which interferes with poly(A)-bound PABP, precluding PABP-enhanced microRNA-mediated inhibition and canonical translation. Consistently, inhibition of PARN deadenylase prevents activation. P97/DAP5, a homolog of canonical translation factor, eIF4G, which lacks PABP- and cap binding complex-interacting domains, is required for activation, and thereby for the oocyte immature state. P97 interacts with 3' UTR-binding FXR1a-associated microRNPs and with PARN, which binds mRNA 5' caps, forming a specialized complex to translate recruited mRNAs in these altered canonical translation conditions. PMID:26942679

  12. The Influence of Receptor-Mediated Interactions on Reaction-Diffusion Mechanisms of Cellular Self-organisation

    KAUST Repository

    Klika, Václav

    2011-11-10

    Understanding the mechanisms governing and regulating self-organisation in the developing embryo is a key challenge that has puzzled and fascinated scientists for decades. Since its conception in 1952 the Turing model has been a paradigm for pattern formation, motivating numerous theoretical and experimental studies, though its verification at the molecular level in biological systems has remained elusive. In this work, we consider the influence of receptor-mediated dynamics within the framework of Turing models, showing how non-diffusing species impact the conditions for the emergence of self-organisation. We illustrate our results within the framework of hair follicle pre-patterning, showing how receptor interaction structures can be constrained by the requirement for patterning, without the need for detailed knowledge of the network dynamics. Finally, in the light of our results, we discuss the ability of such systems to pattern outside the classical limits of the Turing model, and the inherent dangers involved in model reduction. © 2011 Society for Mathematical Biology.

  13. The phosphoinositide 3-kinase signaling pathway in normal and malignant B cells: activation mechanisms, regulation and impact on cellular functions.

    Science.gov (United States)

    Pauls, Samantha D; Lafarge, Sandrine T; Landego, Ivan; Zhang, Tingting; Marshall, Aaron J

    2012-01-01

    The phosphoinositide 3-kinase (PI3K) pathway is a central signal transduction axis controlling normal B cell homeostasis and activation in humoral immunity. The p110δ PI3K catalytic subunit has emerged as a critical mediator of multiple B cell functions. The activity of this pathway is regulated at multiple levels, with inositol phosphatases PTEN and SHIP both playing critical roles. When deregulated, the PI3K pathway can contribute to B cell malignancies and autoantibody production. This review summarizes current knowledge on key mechanisms that activate and regulate the PI3K pathway and influence normal B cell functional responses including the development of B cell subsets, antigen presentation, immunoglobulin isotype switch, germinal center responses, and maintenance of B cell anergy. We also discuss PI3K pathway alterations reported in select B cell malignancies and highlight studies indicating the functional significance of this pathway in malignant B cell survival and growth within tissue microenvironments. Finally, we comment on early clinical trial results, which support PI3K inhibition as a promising treatment of chronic lymphocytic leukemia. PMID:22908014

  14. RNA sequencing of Populus x canadensis roots identifies key molecular mechanisms underlying physiological adaption to excess zinc.

    Directory of Open Access Journals (Sweden)

    Andrea Ariani

    Full Text Available Populus x canadensis clone I-214 exhibits a general indicator phenotype in response to excess Zn, and a higher metal uptake in roots than in shoots with a reduced translocation to aerial parts under hydroponic conditions. This physiological adaptation seems mainly regulated by roots, although the molecular mechanisms that underlie these processes are still poorly understood. Here, differential expression analysis using RNA-sequencing technology was used to identify the molecular mechanisms involved in the response to excess Zn in root. In order to maximize specificity of detection of differentially expressed (DE genes, we consider the intersection of genes identified by three distinct statistical approaches (61 up- and 19 down-regulated and validate them by RT-qPCR, yielding an agreement of 93% between the two experimental techniques. Gene Ontology (GO terms related to oxidation-reduction processes, transport and cellular iron ion homeostasis were enriched among DE genes, highlighting the importance of metal homeostasis in adaptation to excess Zn by P. x canadensis clone I-214. We identified the up-regulation of two Populus metal transporters (ZIP2 and NRAMP1 probably involved in metal uptake, and the down-regulation of a NAS4 gene involved in metal translocation. We identified also four Fe-homeostasis transcription factors (two bHLH38 genes, FIT and BTS that were differentially expressed, probably for reducing Zn-induced Fe-deficiency. In particular, we suggest that the down-regulation of FIT transcription factor could be a mechanism to cope with Zn-induced Fe-deficiency in Populus. These results provide insight into the molecular mechanisms involved in adaption to excess Zn in Populus spp., but could also constitute a starting point for the identification and characterization of molecular markers or biotechnological targets for possible improvement of phytoremediation performances of poplar trees.

  15. Hypolipidemic Activity and Antiatherosclerotic Effect of Polysaccharide of Polygonatum sibiricum in Rabbit Model and Related Cellular Mechanisms

    Directory of Open Access Journals (Sweden)

    Jun-xuan Yang

    2015-01-01

    Full Text Available Objective. To evaluate the hypolipidemic activity and antiatherosclerotic effect of polysaccharide of Polygonatum sibiricum (PPGS, which is a kind of Chinese herbal medicine using the rhizome part of the whole herb. Materials and Methods. Thirty rabbits were divided into normal control group, model control group, and PPGS subgroups of 0.8, 1.6, and 3.2 mL/kg/day under random selection. In atherosclerosis model, the effects of PPGS on diverse blood lipids, foam cells number, and aortic morphology were evaluated. In the primary culture of endothelial cells (ECs, the activities of PPGS on both ECs proliferation and ECs injury were studied as well. Results. In atherosclerosis model, the hypolipidemic activities of PPGS were mainly focused on TC, LDL-C, and Lp(a. All changes on these factors were statistically significant compared with model group (P < 0.01, except TG and HDL-C. The intimal foam cell number of PPGS subgroups (0.8, 1.6, and 3.2 mL/kg/day was significantly reduced than model control (P < 0.01. In the primary culture of endothelial cells (ECs, PPGS showed no effect on cell proliferation but preferred to protect EC from injury and apoptosis induced by H2O2 and lipopolysaccharide (LPS. Discussion and Conclusion. The antiatherosclerotic effect of PPGS may be supported by its hypolipidemic activities, improving aortic morphology, and reducing foam cells number and ECs injury.

  16. Cellular Automata

    OpenAIRE

    Bagnoli, Franco

    1998-01-01

    An introduction to cellular automata (both deterministic and probabilistic) with examples. Definition of deterministic automata, dynamical properties, damage spreading and Lyapunov exponents; probabilistic automata and Markov processes, nonequilibrium phase transitions, directed percolation, diffusion; simulation techniques, mean field. Investigation themes: life, epidemics, forest fires, percolation, modeling of ecosystems and speciation. They represent my notes for the school "Dynamical Mod...

  17. Mechanical response under contact loads of AlCrN-coated tool materials

    International Nuclear Information System (INIS)

    The mechanical behavior under contact loading of systems consisting of PVD AlCrN film deposited onto two distinct hard substrates - cemented carbides and tool steel is studied by means of indentation testing techniques, under monotonic and cyclic condition. Experimental work includes assessment of critical applied loads for emergence of circular cracks at the coating surface, as well as evaluation of both surface and subsurface damage evolution. Results indicate that both coated systems are susceptible to mechanical degradation associated with repetitive contact load. Furthermore, significant differences on contact fatigue behavior between the two studied coated systems are evidenced under consideration of cracking evolution at top surface and penetration towards the substrate. In this regard, the intrinsic mechanical properties of the substrate are pointed out as key feature for rationalizing the experimental findings

  18. Molecular mechanisms underlying the physiological responses of the cold-water coral Desmophyllum dianthus to ocean acidification

    Science.gov (United States)

    Carreiro-Silva, M.; Cerqueira, T.; Godinho, A.; Caetano, M.; Santos, R. S.; Bettencourt, R.

    2014-06-01

    Cold-water corals (CWCs) are thought to be particularly vulnerable to ocean acidification (OA) due to increased atmospheric pCO2, because they inhabit deep and cold waters where the aragonite saturation state is naturally low. Several recent studies have evaluated the impact of OA on organism-level physiological processes such as calcification and respiration. However, no studies to date have looked at the impact at the molecular level of gene expression. Here, we report results of a long-term, 8-month experiment to compare the physiological responses of the CWC Desmophyllum dianthus to OA at both the organismal and gene expression levels under two pCO2/pH treatments: ambient pCO2 (460 μatm, pHT = 8.01) and elevated pCO2 (997 μatm, pHT = 7.70). At the organismal level, no significant differences were detected in the calcification and respiration rates of D. dianthus. Conversely, significant differences were recorded in gene expression profiles, which showed an up-regulation of genes involved in cellular stress (HSP70) and immune defence (mannose-binding c-type lectin). Expression of alpha-carbonic anhydrase, a key enzyme involved in the synthesis of coral skeleton, was also significantly up-regulated in corals under elevated pCO2, indicating that D. dianthus was under physiological reconditioning to calcify under these conditions. Thus, gene expression profiles revealed physiological impacts that were not evident at the organismal level. Consequently, understanding the molecular mechanisms behind the physiological processes involved in a coral's response to elevated pCO2 is critical to assess the ability of CWCs to acclimate or adapt to future OA conditions.

  19. The New Cellular Immunology

    Science.gov (United States)

    Claman, Henry N.

    1973-01-01

    Discusses the nature of the immune response and traces many of the discoveries that have led to the present state of knowledge in immunology. The new cellular immunology is directing its efforts toward improving health by proper manipulation of the immune mechanisms of the body. (JR)

  20. Cellular and molecular basis of cerebellar development

    Science.gov (United States)

    Martinez, Salvador; Andreu, Abraham; Mecklenburg, Nora; Echevarria, Diego

    2013-01-01

    Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function. PMID:23805080