Mechanisms and circumvention of cellular resistance to cisplatin.

NARCIS (Netherlands)

Hospers, Geesiena Alberdina Petronella

1989-01-01

Cisplatin (CDDP) is an active cytostatic agent. A limitation to its effectiveness initially or appearing during cystatic treatment is the occurrence of resistance. This thesis describes mechanisms wich are responsible for acquired cellular CDDP resistance. To investigate cellular CDDP resistance, a

Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling

Science.gov (United States)

Lebensohn, Andres M; Dubey, Ramin; Neitzel, Leif R; Tacchelly-Benites, Ofelia; Yang, Eungi; Marceau, Caleb D; Davis, Eric M; Patel, Bhaven B; Bahrami-Nejad, Zahra; Travaglini, Kyle J; Ahmed, Yashi; Lee, Ethan; Carette, Jan E; Rohatgi, Rajat

2016-01-01

The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1α uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling β-catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the β-catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems. DOI: http://dx.doi.org/10.7554/eLife.21459.001 PMID:27996937

Bioinspired Cellular Structures: Additive Manufacturing and Mechanical Properties

Science.gov (United States)

Stampfl, J.; Pettermann, H. E.; Liska, R.

Biological materials (e.g., wood, trabecular bone, marine skeletons) rely heavily on the use of cellular architecture, which provides several advantages. (1) The resulting structures can bear the variety of "real life" load spectra using a minimum of a given bulk material, featuring engineering lightweight design principles. (2) The inside of the structures is accessible to body fluids which deliver the required nutrients. (3) Furthermore, cellular architectures can grow organically by adding or removing individual struts or by changing the shape of the constituting elements. All these facts make the use of cellular architectures a reasonable choice for nature. Using additive manufacturing technologies (AMT), it is now possible to fabricate such structures for applications in engineering and biomedicine. In this chapter, we present methods that allow the 3D computational analysis of the mechanical properties of cellular structures with open porosity. Various different cellular architectures including disorder are studied. In order to quantify the influence of architecture, the apparent density is always kept constant. Furthermore, it is shown that how new advanced photopolymers can be used to tailor the mechanical and functional properties of the fabricated structures.

Molecular and cellular mechanisms of cadmium carcinogenesis

International Nuclear Information System (INIS)

Waisberg, Michael; Joseph, Pius; Hale, Beverley; Beyersmann, Detmar

2003-01-01

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. Cd 2+ 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

Prediction of regulatory elements

DEFF Research Database (Denmark)

Sandelin, Albin

2008-01-01

Finding the regulatory mechanisms responsible for gene expression remains one of the most important challenges for biomedical research. A major focus in cellular biology is to find functional transcription factor binding sites (TFBS) responsible for the regulation of a downstream gene. As wet......-lab methods are time consuming and expensive, it is not realistic to identify TFBS for all uncharacterized genes in the genome by purely experimental means. Computational methods aimed at predicting potential regulatory regions can increase the efficiency of wet-lab experiments significantly. Here, methods...

Cell-Nonautonomous Mechanisms Underlying Cellular and Organismal Aging.

Science.gov (United States)

Medkour, Younes; Svistkova, Veronika; Titorenko, Vladimir I

2016-01-01

Cell-autonomous mechanisms underlying cellular and organismal aging in evolutionarily distant eukaryotes have been established; these mechanisms regulate longevity-defining processes within a single eukaryotic cell. Recent findings have provided valuable insight into cell-nonautonomous mechanisms modulating cellular and organismal aging in eukaryotes across phyla; these mechanisms involve a transmission of various longevity factors between different cells, tissues, and organisms. Herein, we review such cell-nonautonomous mechanisms of aging in eukaryotes. We discuss the following: (1) how low molecular weight transmissible longevity factors modulate aging and define longevity of cells in yeast populations cultured in liquid media or on solid surfaces, (2) how communications between proteostasis stress networks operating in neurons and nonneuronal somatic tissues define longevity of the nematode Caenorhabditis elegans by modulating the rates of aging in different tissues, and (3) how different bacterial species colonizing the gut lumen of C. elegans define nematode longevity by modulating the rate of organismal aging. Copyright © 2016. Published by Elsevier Inc.

Biochemical Factors Modulating Cellular Neurotoxicity of Methylmercury

Directory of Open Access Journals (Sweden)

Parvinder Kaur

2011-01-01

Full Text Available Methylmercury (MeHg, an environmental toxicant primarily found in fish and seafood, poses a dilemma to both consumers and regulatory authorities, given the nutritional benefits of fish consumption versus the possible adverse neurological damage. Several studies have shown that MeHg toxicity is influenced by a number of biochemical factors, such as glutathione (GSH, fatty acids, vitamins, and essential elements, but the cellular mechanisms underlying these complex interactions have not yet been fully elucidated. The objective of this paper is to outline the cellular response to dietary nutrients, as well as to describe the neurotoxic exposures to MeHg. In order to determine the cellular mechanism(s of toxicity, the effect of pretreatment with biochemical factors (e.g., N-acetyl cysteine, (NAC; diethyl maleate, (DEM; docosahexaenoic acid, (DHA; selenomethionine, SeM; Trolox and MeHg treatment on intercellular antioxidant status, MeHg content, and other endpoints was evaluated. This paper emphasizes that the protection against oxidative stress offered by these biochemical factors is among one of the major mechanisms responsible for conferring neuroprotection. It is therefore critical to ascertain the cellular mechanisms associated with various dietary nutrients as well as to determine the potential effects of neurotoxic exposures for accurately assessing the risks and benefits associated with fish consumption.

Rac1 in human diseases: The therapeutic potential of targeting Rac1 signaling regulatory mechanisms.

Science.gov (United States)

Marei, Hadir; Malliri, Angeliki

2017-07-03

Abnormal Rac1 signaling is linked to a number of debilitating human diseases, including cancer, cardiovascular diseases and neurodegenerative disorders. As such, Rac1 represents an attractive therapeutic target, yet the search for effective Rac1 inhibitors is still underway. Given the adverse effects associated with Rac1 signaling perturbation, cells have evolved several mechanisms to ensure the tight regulation of Rac1 signaling. Thus, characterizing these mechanisms can provide invaluable information regarding major cellular events that lead to aberrant Rac1 signaling. Importantly, this information can be utilized to further facilitate the development of effective pharmacological modulators that can restore normal Rac1 signaling. In this review, we focus on the pathological role of Rac1 signaling, highlighting the benefits and potential drawbacks of targeting Rac1 in a clinical setting. Additionally, we provide an overview of available compounds that target key Rac1 regulatory mechanisms and discuss future therapeutic avenues arising from our understanding of these mechanisms.

Symposium on molecular and cellular mechanisms of mutagenesis

International Nuclear Information System (INIS)

1981-01-01

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

Kinetic theory approach to modeling of cellular repair mechanisms under genome stress.

Directory of Open Access Journals (Sweden)

Jinpeng Qi

Full Text Available Under acute perturbations from outer environment, a normal cell can trigger cellular self-defense mechanism in response to genome stress. To investigate the kinetics of cellular self-repair process at single cell level further, a model of DNA damage generating and repair is proposed under acute Ion Radiation (IR by using mathematical framework of kinetic theory of active particles (KTAP. Firstly, we focus on illustrating the profile of Cellular Repair System (CRS instituted by two sub-populations, each of which is made up of the active particles with different discrete states. Then, we implement the mathematical framework of cellular self-repair mechanism, and illustrate the dynamic processes of Double Strand Breaks (DSBs and Repair Protein (RP generating, DSB-protein complexes (DSBCs synthesizing, and toxins accumulating. Finally, we roughly analyze the capability of cellular self-repair mechanism, cellular activity of transferring DNA damage, and genome stability, especially the different fates of a certain cell before and after the time thresholds of IR perturbations that a cell can tolerate maximally under different IR perturbation circumstances.

Kinetic theory approach to modeling of cellular repair mechanisms under genome stress.

Science.gov (United States)

Qi, Jinpeng; Ding, Yongsheng; Zhu, Ying; Wu, Yizhi

2011-01-01

Under acute perturbations from outer environment, a normal cell can trigger cellular self-defense mechanism in response to genome stress. To investigate the kinetics of cellular self-repair process at single cell level further, a model of DNA damage generating and repair is proposed under acute Ion Radiation (IR) by using mathematical framework of kinetic theory of active particles (KTAP). Firstly, we focus on illustrating the profile of Cellular Repair System (CRS) instituted by two sub-populations, each of which is made up of the active particles with different discrete states. Then, we implement the mathematical framework of cellular self-repair mechanism, and illustrate the dynamic processes of Double Strand Breaks (DSBs) and Repair Protein (RP) generating, DSB-protein complexes (DSBCs) synthesizing, and toxins accumulating. Finally, we roughly analyze the capability of cellular self-repair mechanism, cellular activity of transferring DNA damage, and genome stability, especially the different fates of a certain cell before and after the time thresholds of IR perturbations that a cell can tolerate maximally under different IR perturbation circumstances.

Symposium on molecular and cellular mechanisms of mutagenesis

Energy Technology Data Exchange (ETDEWEB)

1981-01-01

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. (ERB)

Cellular Mechanisms of Somatic Stem Cell Aging

Science.gov (United States)

Jung, Yunjoon

2014-01-01

Tissue homeostasis and regenerative capacity rely on rare populations of somatic stem cells endowed with the potential to self-renew and differentiate. During aging, many tissues show a decline in regenerative potential coupled with a loss of stem cell function. Cells including somatic stem cells have evolved a series of checks and balances to sense and repair cellular damage to maximize tissue function. However, during aging the mechanisms that protect normal cell function begin to fail. In this review, we will discuss how common cellular mechanisms that maintain tissue fidelity and organismal lifespan impact somatic stem cell function. We will highlight context-dependent changes and commonalities that define aging, by focusing on three age-sensitive stem cell compartments: blood, neural, and muscle. Understanding the interaction between extrinsic regulators and intrinsic effectors that operate within different stem cell compartments is likely to have important implications for identifying strategies to improve health span and treat age-related degenerative diseases. PMID:24439814

Cellular automata and statistical mechanical models

International Nuclear Information System (INIS)

Rujan, P.

1987-01-01

The authors elaborate on the analogy between the transfer matrix of usual lattice models and the master equation describing the time development of cellular automata. Transient and stationary properties of probabilistic automata are linked to surface and bulk properties, respectively, of restricted statistical mechanical systems. It is demonstrated that methods of statistical physics can be successfully used to describe the dynamic and the stationary behavior of such automata. Some exact results are derived, including duality transformations, exact mappings, disorder, and linear solutions. Many examples are worked out in detail to demonstrate how to use statistical physics in order to construct cellular automata with desired properties. This approach is considered to be a first step toward the design of fully parallel, probabilistic systems whose computational abilities rely on the cooperative behavior of their components

Cellular and Chemical Neuroscience of Mammalian Sleep

OpenAIRE

Datta, Subimal

2010-01-01

Extraordinary strides have been made toward understanding the complexities and regulatory mechanisms of sleep over the past two decades, thanks to the help of rapidly evolving technologies. At its most basic level, mammalian sleep is a restorative process of the brain and body. Beyond its primary restorative purpose, sleep is essential for a number of vital functions. Our primary research interest is to understand the cellular and molecular mechanisms underlying the regulation of sleep and it...

Dynamics and mechanisms of quantum dot nanoparticle cellular uptake

Directory of Open Access Journals (Sweden)

Telford William G

2010-06-01

Full Text Available Abstract Background The rapid growth of the nanotechnology industry and the wide application of various nanomaterials have raised concerns over their impact on the environment and human health. Yet little is known about the mechanism of cellular uptake and cytotoxicity of nanoparticles. An array of nanomaterials has recently been introduced into cancer research promising for remarkable improvements in diagnosis and treatment of the disease. Among them, quantum dots (QDs distinguish themselves in offering many intrinsic photophysical properties that are desirable for targeted imaging and drug delivery. Results We explored the kinetics and mechanism of cellular uptake of QDs with different surface coatings in two human mammary cells. Using fluorescence microscopy and laser scanning cytometry (LSC, we found that both MCF-7 and MCF-10A cells internalized large amount of QD655-COOH, but the percentage of endocytosing cells is slightly higher in MCF-7 cell line than in MCF-10A cell line. Live cell fluorescent imaging showed that QD cellular uptake increases with time over 40 h of incubation. Staining cells with dyes specific to various intracellular organelles indicated that QDs were localized in lysosomes. Transmission electron microscopy (TEM images suggested a potential pathway for QD cellular uptake mechanism involving three major stages: endocytosis, sequestration in early endosomes, and translocation to later endosomes or lysosomes. No cytotoxicity was observed in cells incubated with 0.8 nM of QDs for a period of 72 h. Conclusions The findings presented here provide information on the mechanism of QD endocytosis that could be exploited to reduce non-specific targeting, thereby improving specific targeting of QDs in cancer diagnosis and treatment applications. These findings are also important in understanding the cytotoxicity of nanomaterials and in emphasizing the importance of strict environmental control of nanoparticles.

A Model of How Different Biology Experts Explain Molecular and Cellular Mechanisms

Science.gov (United States)

Trujillo, Caleb M.; Anderson, Trevor R.; Pelaez, Nancy J.

2015-01-01

Constructing explanations is an essential skill for all science learners. The goal of this project was to model the key components of expert explanation of molecular and cellular mechanisms. As such, we asked: What is an appropriate model of the components of explanation used by biology experts to explain molecular and cellular mechanisms? Do…

Design and implementation of a novel mechanical testing system for cellular solids.

Science.gov (United States)

Nazarian, Ara; Stauber, Martin; Müller, Ralph

2005-05-01

Cellular solids constitute an important class of engineering materials encompassing both man-made and natural constructs. Materials such as wood, cork, coral, and cancellous bone are examples of cellular solids. The structural analysis of cellular solid failure has been limited to 2D sections to illustrate global fracture patterns. Due to the inherent destructiveness of 2D methods, dynamic assessment of fracture progression has not been possible. Image-guided failure assessment (IGFA), a noninvasive technique to analyze 3D progressive bone failure, has been developed utilizing stepwise microcompression in combination with time-lapsed microcomputed tomographic imaging (microCT). This method allows for the assessment of fracture progression in the plastic region, where much of the structural deformation/energy absorption is encountered in a cellular solid. Therefore, the goal of this project was to design and fabricate a novel micromechanical testing system to validate the effectiveness of the stepwise IGFA technique compared to classical continuous mechanical testing, using a variety of engineered and natural cellular solids. In our analysis, we found stepwise compression to be a valid approach for IGFA with high precision and accuracy comparable to classical continuous testing. Therefore, this approach complements the conventional mechanical testing methods by providing visual insight into the failure propagation mechanisms of cellular solids. (c) 2005 Wiley Periodicals, Inc.

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 - others: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

Osmosensory mechanisms in cellular and systemic volume regulation

DEFF Research Database (Denmark)

Pedersen, Stine Helene Falsig; Kapus, András; Hoffmann, Else K

2011-01-01

Perturbations of cellular and systemic osmolarity severely challenge the function of all organisms and are consequently regulated very tightly. Here we outline current evidence on how cells sense volume perturbations, with particular focus on mechanisms relevant to the kidneys and to extracellular...

Single nucleotide resolution RNA-seq uncovers new regulatory mechanisms in the opportunistic pathogen Streptococcus agalactiae.

Science.gov (United States)

Rosinski-Chupin, Isabelle; Sauvage, Elisabeth; Sismeiro, Odile; Villain, Adrien; Da Cunha, Violette; Caliot, Marie-Elise; Dillies, Marie-Agnès; Trieu-Cuot, Patrick; Bouloc, Philippe; Lartigue, Marie-Frédérique; Glaser, Philippe

2015-05-30

Streptococcus agalactiae, or Group B Streptococcus, is a leading cause of neonatal infections and an increasing cause of infections in adults with underlying diseases. In an effort to reconstruct the transcriptional networks involved in S. agalactiae physiology and pathogenesis, we performed an extensive and robust characterization of its transcriptome through a combination of differential RNA-sequencing in eight different growth conditions or genetic backgrounds and strand-specific RNA-sequencing. Our study identified 1,210 transcription start sites (TSSs) and 655 transcript ends as well as 39 riboswitches and cis-regulatory regions, 39 cis-antisense non-coding RNAs and 47 small RNAs potentially acting in trans. Among these putative regulatory RNAs, ten were differentially expressed in response to an acid stress and two riboswitches sensed directly or indirectly the pH modification. Strikingly, 15% of the TSSs identified were associated with the incorporation of pseudo-templated nucleotides, showing that reiterative transcription is a pervasive process in S. agalactiae. In particular, 40% of the TSSs upstream genes involved in nucleotide metabolism show reiterative transcription potentially regulating gene expression, as exemplified for pyrG and thyA encoding the CTP synthase and the thymidylate synthase respectively. This comprehensive map of the transcriptome at the single nucleotide resolution led to the discovery of new regulatory mechanisms in S. agalactiae. It also provides the basis for in depth analyses of transcriptional networks in S. agalactiae and of the regulatory role of reiterative transcription following variations of intra-cellular nucleotide pools.

Computational challenges in modeling gene regulatory events.

Science.gov (United States)

Pataskar, Abhijeet; Tiwari, Vijay K

2016-10-19

Cellular transcriptional programs driven by genetic and epigenetic mechanisms could be better understood by integrating "omics" data and subsequently modeling the gene-regulatory events. Toward this end, computational biology should keep pace with evolving experimental procedures and data availability. This article gives an exemplified account of the current computational challenges in molecular biology.

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

International Nuclear Information System (INIS)

Amin, Rupesh P.; Hamadeh, Hisham K.; Bushel, Pierre R.; Bennett, Lee; Afshari, Cynthia A.; Paules, Richard S.

2002-01-01

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

Critical protein GAPDH and its regulatory mechanisms in cancer cells

International Nuclear Information System (INIS)

Zhang, Jin-Ying; Zhang, Fan; Hong, Chao-Qun; Giuliano, Armando E.; Cui, Xiao-Jiang; Zhou, Guang-Ji; Zhang, Guo-Jun; Cui, Yu-Kun

2015-01-01

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. However, emerging evidence indicates that GAPDH is implicated in diverse functions independent of its role in energy metabolism; the expression status of GAPDH is also deregulated in various cancer cells. One of the most common effects of GAPDH is its inconsistent role in the determination of cancer cell fate. Furthermore, studies have described GAPDH as a regulator of cell death; other studies have suggested that GAPDH participates in tumor progression and serves as a new therapeutic target. However, related regulatory mechanisms of its numerous cellular functions and deregulated expression levels remain unclear. GAPDH is tightly regulated at transcriptional and posttranscriptional levels, which are involved in the regulation of diverse GAPDH functions. Several cancer-related factors, such as insulin, hypoxia inducible factor-1 (HIF-1), p53, nitric oxide (NO), and acetylated histone, not only modulate GAPDH gene expression but also affect protein functions via common pathways. Moreover, posttranslational modifications (PTMs) occurring in GAPDH in cancer cells result in new activities unrelated to the original glycolytic function of GAPDH. In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized. Mechanisms and pathways involved in GAPDH regulation and its different roles in cancer cells are also described

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

Directory of Open Access Journals (Sweden)

Kristina Kirschner

2015-03-01

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

Regulatory mechanisms of apoptosis in regularly dividing cells

Directory of Open Access Journals (Sweden)

Ribal S Darwish

2010-08-01

Full Text Available Ribal S DarwishDepartment of Anesthesiology, Division of Critical Care Medicine, University of Maryland Medical Center, Baltimore, Maryland, USAAbstract: The balance between cell survival and death is essential for normal development and homeostasis of organisms. Apoptosis is a distinct type of cell death with ultrastructural features that are consistent with an active, inherently controlled process. Abnormalities and ­dysregulation of apoptosis contribute to the pathophysiology of multiple disease processes. Apoptosis is strictly regulated by several positive and negative feedback mechanisms that regulate cell death and determine the final outcome after cell exposure to apoptotic stimuli. Mitochondria and caspases are central components of the regulatory mechanisms of ­apoptosis. Recently, noncaspase pathways of apoptosis have been explored through the studies of ­apoptosis-inducing factor and endonuclease G. Multiple difficulties in the apoptosis research relate to apoptosis detection and imaging. This article reviews current understanding of the regulatory mechanisms of apoptosis.Keywords: caspases, apoptosis-inducing factor, apoptosis inhibitory proteins, cytochrome c, mitochondria 

Regulatory Coherence and Standardization Mechanisms in the Trans-Pacific Partnership

Directory of Open Access Journals (Sweden)

Cai Phoenix X. F.

2016-12-01

Full Text Available This article posits a new taxonomy and framework for assessing regulatory coherence in the new generation of mega-regional, cross-cutting free trade agreements. Using the Trans-Pacific Partnership as the primary example, this article situates the rise of regulatory coherence within the current trade landscape, provides clear definitions of regulatory coherence, and argues that the real engine of regulatory coherence lies in the work of international standard setting organizations. This work has been little examined in the current literature. The article provides a detailed examination of the mechanics by which the Trans-Pacific Partnership promotes regulatory standardization and concludes with some normative implications and calls for future research.

Cellular mechanisms within the juxtaglomerular apparatus

DEFF Research Database (Denmark)

Briggs, J P; Skøtt, O; Schnermann, J

1990-01-01

Cl concentration at the macular densa. This change also results in inhibition of secretion of renin. The macula densa has a unique location near the terminal end of the thick ascending limb, where NaCl concentration is highly flow dependent. The cellular mechanisms by which changes in tubular fluid NaCl produce...... vasoconstriction and inhibition of renin secretion are unknown, but the anatomy of the juxtaglomerular apparatus strongly suggests that such responses may be mediated by the extraglomerular mesangial cells located in the polar cushion underlying the macula densa. Recent evidence suggests that interstitial chloride...

A Channel Allocation Mechanism for Cellular Networks

Directory of Open Access Journals (Sweden)

Chi-Hua Chen

2017-04-01

Full Text Available In cellular networks, call blocking causes lower customer satisfaction and economic loss. Therefore, the channel allocation for call block avoidance is an important issue. This study proposes a mechanism that considers the real-time traffic information (e.g., traffic flow and vehicle speed and the user behavior (e.g., call inter-arrival time and call holding time to analyze the adaptable number of communication calls in the specific cell for channel allocation. In experiments about call block probabilities (CBP, this study simulated two cases that are the situations of the whole day and traffic accident. The simulation results show that all CBPs in the scenario of whole day are less than 21.5% by using the proposed mechanism, which is better than using the static channel allocation (SCA mechanism. Moreover, all CBPs in the scenario of traffic accidents are less than 16.5% by using the proposed mechanism, which is better than using the SCA mechanism. Therefore, the proposed mechanism can decrease the number of CBPs effectively.

Global Rebalancing of Cellular Resources by Pleiotropic Point Mutations Illustrates a Multi-scale Mechanism of Adaptive Evolution

DEFF Research Database (Denmark)

Utrilla, José; O'Brien, Edward J.; Chen, Ke

2016-01-01

Pleiotropic regulatory mutations affect diverse cellular processes, posing a challenge to our understanding of genotype-phenotype relationships across multiple biological scales. Adaptive laboratory evolution (ALE) allows for such mutations to be found and characterized in the context of clear se...

Size effects in the mechanical behavior of cellular materials

NARCIS (Netherlands)

Tekoglu, C; Onck, PR

Effective mechanical properties of cellular materials depend strongly on the specimen size to the cell size ratio. Experimental studies performed on aluminium foams show that under uniaxial compression, the stiffness of these materials falls below the corresponding bulk value, when the ratio of the

The Tumorigenic Roles of the Cellular REDOX Regulatory Systems

Directory of Open Access Journals (Sweden)

Stéphanie Anaís Castaldo

2016-01-01

Full Text Available The cellular REDOX regulatory systems play a central role in maintaining REDOX homeostasis that is crucial for cell integrity, survival, and proliferation. To date, a substantial amount of data has demonstrated that cancer cells typically undergo increasing oxidative stress as the tumor develops, upregulating these important antioxidant systems in order to survive, proliferate, and metastasize under these extreme oxidative stress conditions. Since a large number of chemotherapeutic agents currently used in the clinic rely on the induction of ROS overload or change of ROS quality to kill the tumor, the cancer cell REDOX adaptation represents a significant obstacle to conventional chemotherapy. In this review we will first examine the different factors that contribute to the enhanced oxidative stress generally observed within the tumor microenvironment. We will then make a comprehensive assessment of the current literature regarding the main antioxidant proteins and systems that have been shown to be positively associated with tumor progression and chemoresistance. Finally we will make an analysis of commonly used chemotherapeutic drugs that induce ROS. The current knowledge of cancer cell REDOX adaptation raises the issue of developing novel and more effective therapies for these tumors that are usually resistant to conventional ROS inducing chemotherapy.

Active Cellular Mechanics and its Consequences for Animal Development

Science.gov (United States)

Noll, Nicholas B.

A central goal of developmental biology is to understand how an organism shapes itself, a process referred to as morphogenesis. While the molecular components critical to determining the initial body plan have been well characterized, the control of the subsequent dynamics of cellular rearrangements which ultimately shape the organism are far less understood. A major roadblock to a more complete picture of morphogenesis is the inability to measure tissue-scale mechanics throughout development and thus answer fundamental questions: How is the mechanical state of the cell regulated by local protein expression and global pattering? In what way does stress feedback onto the larger developmental program? In this dissertation, we begin to approach these questions through the introduction and analysis of a multi-scale model of epithelial mechanics which explicitly connects cytoskeletal protein activity to tissue-level stress. In Chapter 2, we introduce the discrete Active Tension Network (ATN) model of cellular mechanics. ATNs are tissues that satisfy two primary assumptions: that the mechanical balance of cells is dominated by cortical tension and that myosin actively remodels the actin cytoskeleton in a stress-dependent manner. Remarkably, the interplay of these features allows for angle-preserving, i.e. 'isogonal', dilations or contractions of local cell geometry that do not generate stress. Asymptotically this model is stabilized provided there is mechanical feedback on expression of myosin within the cell; we take this to be a strong prediction to be tested. The ATN model exposes a fundamental connection between equilibrium cell geometry and its underlying force network. In Chapter 3, we relax the tension-net approximation and demonstrate that at equilibrium, epithelial tissues with non-uniform pressure have non-trivial geometric constraints that imply the network is described by a weighted `dual' triangulation. We show that the dual triangulation encodes all

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

International Nuclear Information System (INIS)

Enrico Fermi, Università di Pisa, Largo Pontecorvo 3, I-56127 Pisa (Italy))" data-affiliation=" (Dipartimento di Fisica Enrico Fermi, Università di Pisa, Largo Pontecorvo 3, I-56127 Pisa (Italy))" >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 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.

Phytoplankton calcification as an effective mechanism to prevent 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.

2015-08-01

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, 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 time scales. For example, the Cretaceous (145 to 66 Ma ago), an era known for the high abundance of coccolithophores and the production of enormous calcium carbonate deposits, exhibited seawater calcium concentrations up to four 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 prevent cellular calcium poisoning and thereby offered a potential key evolutionary advantage, responsible for the proliferation of coccolithophores during times of high seawater calcium concentrations.

DMPD: The interferon regulatory factor family in host defense: mechanism of action. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 17502370 The interferon regulatory factor family in host defense: mechanism of acti....html) (.csml) Show The interferon regulatory factor family in host defense: mechanism of action. PubmedID 1...7502370 Title The interferon regulatory factor family in host defense: mechanism

Density-dependence as a size-independent regulatory mechanism

NARCIS (Netherlands)

De Vladar, H.P.

2006-01-01

The growth function of populations is central in biomathematics. The main dogma is the existence of density-dependence mechanisms, which can be modelled with distinct functional forms that depend on the size of the Population. One important class of regulatory functions is the theta-logistic, which

Quantitative inference of dynamic regulatory pathways via microarray data

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Chen Bor-Sen

2005-03-01

Full Text Available Abstract Background The cellular signaling pathway (network is one of the main topics of organismic investigations. The intracellular interactions between genes in a signaling pathway are considered as the foundation of functional genomics. Thus, what genes and how much they influence each other through transcriptional binding or physical interactions are essential problems. Under the synchronous measures of gene expression via a microarray chip, an amount of dynamic information is embedded and remains to be discovered. Using a systematically dynamic modeling approach, we explore the causal relationship among genes in cellular signaling pathways from the system biology approach. Results In this study, a second-order dynamic model is developed to describe the regulatory mechanism of a target gene from the upstream causality point of view. From the expression profile and dynamic model of a target gene, we can estimate its upstream regulatory function. According to this upstream regulatory function, we would deduce the upstream regulatory genes with their regulatory abilities and activation delays, and then link up a regulatory pathway. Iteratively, these regulatory genes are considered as target genes to trace back their upstream regulatory genes. Then we could construct the regulatory pathway (or network to the genome wide. In short, we can infer the genetic regulatory pathways from gene-expression profiles quantitatively, which can confirm some doubted paths or seek some unknown paths in a regulatory pathway (network. Finally, the proposed approach is validated by randomly reshuffling the time order of microarray data. Conclusion We focus our algorithm on the inference of regulatory abilities of the identified causal genes, and how much delay before they regulate the downstream genes. With this information, a regulatory pathway would be built up using microarray data. In the present study, two signaling pathways, i.e. circadian regulatory

Multiple regulatory systems coordinate DNA replication with cell growth in Bacillus subtilis.

Science.gov (United States)

Murray, Heath; Koh, Alan

2014-10-01

In many bacteria the rate of DNA replication is linked with cellular physiology to ensure that genome duplication is coordinated with growth. Nutrient-mediated growth rate control of DNA replication initiation has been appreciated for decades, however the mechanism(s) that connects these cell cycle activities has eluded understanding. In order to help address this fundamental question we have investigated regulation of DNA replication in the model organism Bacillus subtilis. Contrary to the prevailing view we find that changes in DnaA protein level are not sufficient to account for nutrient-mediated growth rate control of DNA replication initiation, although this regulation does require both DnaA and the endogenous replication origin. We go on to report connections between DNA replication and several essential cellular activities required for rapid bacterial growth, including respiration, central carbon metabolism, fatty acid synthesis, phospholipid synthesis, and protein synthesis. Unexpectedly, the results indicate that multiple regulatory systems are involved in coordinating DNA replication with cell physiology, with some of the regulatory systems targeting oriC while others act in a oriC-independent manner. We propose that distinct regulatory systems are utilized to control DNA replication in response to diverse physiological and chemical changes.

Putting theory to the test: which regulatory mechanisms can drive realistic growth of a root?

Science.gov (United States)

De Vos, Dirk; Vissenberg, Kris; Broeckhove, Jan; Beemster, Gerrit T S

2014-10-01

In recent years there has been a strong development of computational approaches to mechanistically understand organ growth regulation in plants. In this study, simulation methods were used to explore which regulatory mechanisms can lead to realistic output at the cell and whole organ scale and which other possibilities must be discarded as they result in cellular patterns and kinematic characteristics that are not consistent with experimental observations for the Arabidopsis thaliana primary root. To aid in this analysis, a 'Uniform Longitudinal Strain Rule' (ULSR) was formulated as a necessary condition for stable, unidirectional, symplastic growth. Our simulations indicate that symplastic structures are robust to differences in longitudinal strain rates along the growth axis only if these differences are small and short-lived. Whereas simple cell-autonomous regulatory rules based on counters and timers can produce stable growth, it was found that steady developmental zones and smooth transitions in cell lengths are not feasible. By introducing spatial cues into growth regulation, those inadequacies could be avoided and experimental data could be faithfully reproduced. Nevertheless, a root growth model based on previous polar auxin-transport mechanisms violates the proposed ULSR due to the presence of lateral gradients. Models with layer-specific regulation or layer-driven growth offer potential solutions. Alternatively, a model representing the known cross-talk between auxin, as the cell proliferation promoting factor, and cytokinin, as the cell differentiation promoting factor, predicts the effect of hormone-perturbations on meristem size. By down-regulating PIN-mediated transport through the transcription factor SHY2, cytokinin effectively flattens the lateral auxin gradient, at the basal boundary of the division zone, (thereby imposing the ULSR) to signal the exit of proliferation and start of elongation. This model exploration underlines the value of

The imperative for controlled mechanical stresses in unraveling cellular mechanisms of mechanotransduction

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Sorkin Adam M

2006-05-01

Full Text Available Abstract Background In vitro mechanotransduction studies are designed to elucidate cell behavior in response to a well-defined mechanical signal that is imparted to cultured cells, e.g. through fluid flow. Typically, flow rates are calculated based on a parallel plate flow assumption, to achieve a targeted cellular shear stress. This study evaluates the performance of specific flow/perfusion chambers in imparting the targeted stress at the cellular level. Methods To evaluate how well actual flow chambers meet their target stresses (set for 1 and 10 dyn/cm2 for this study at a cellular level, computational models were developed to calculate flow velocity components and imparted shear stresses for a given pressure gradient. Computational predictions were validated with micro-particle image velocimetry (μPIV experiments. Results Based on these computational and experimental studies, as few as 66% of cells seeded along the midplane of commonly implemented flow/perfusion chambers are subjected to stresses within ±10% of the target stress. In addition, flow velocities and shear stresses imparted through fluid drag vary as a function of location within each chamber. Hence, not only a limited number of cells are exposed to target stress levels within each chamber, but also neighboring cells may experience different flow regimes. Finally, flow regimes are highly dependent on flow chamber geometry, resulting in significant variation in magnitudes and spatial distributions of stress between chambers. Conclusion The results of this study challenge the basic premise of in vitro mechanotransduction studies, i.e. that a controlled flow regime is applied to impart a defined mechanical stimulus to cells. These results also underscore the fact that data from studies in which different chambers are utilized can not be compared, even if the target stress regimes are comparable.

Phytoplankton calcification as an effective mechanism to alleviate cellular calcium poisoning

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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.

The Quiescent Cellular State is Arf/p53-Dependent and Associated with H2AX Downregulation and Genome Stability

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Mitsuko Masutani

2012-05-01

Full Text Available Cancer is a disease associated with genomic instability and mutations. Excluding some tumors with specific chromosomal translocations, most cancers that develop at an advanced age are characterized by either chromosomal or microsatellite instability. However, it is still unclear how genomic instability and mutations are generated during the process of cellular transformation and how the development of genomic instability contributes to cellular transformation. Recent studies of cellular regulation and tetraploidy development have provided insights into the factors triggering cellular transformation and the regulatory mechanisms that protect chromosomes from genomic instability.

Behavioural ratings of self-regulatory mechanisms and driving behaviour after an acquired brain injury.

Science.gov (United States)

Rike, Per-Ola; Ulleberg, Pål; Schultheis, Maria T; Lundqvist, Anna; Schanke, Anne-Kristine

2014-01-01

To explore whether measurements of self-regulatory mechanisms and cognition predict driving behaviour after an acquired brain injury (ABI). Consecutive follow-up study. At baseline participants included 77 persons with stroke and 32 persons with a traumatic brain injury (TBI), all of whom completed a multidisciplinary driving assessment (MDA). A follow-up cohort of 34 persons that succeeded the MDA was included. Baseline measurements: Neuropsychological tests and measurements of self-regulatory mechanisms (BRIEF-A and UPPS Impulsive Behaviour Scale), driving behaviour (DBQ) and pre-injury driving characteristics (mileage, compensatory driving strategies and accident rates). Follow-up measurements: Post-injury driving characteristics were collected by mailed questionnaires from the participants who succeeded the MDA. A MDA, which included a medical examination, neuropsychological testing and an on-road driving test, was considered in the decision for or against granting a driver's license. Self-regulatory mechanisms and driving behaviour were examined for research purposes only. At baseline, self-regulatory mechanisms were significantly associated to aberrant driving behaviour, but not with neuropsychological data or with the outcome of the on-road driving test. Aspects of self-regulation were associated to driving behaviour at follow-up. It is recommended that self-regulatory measurements should regularly be considered in the driving assessments after ABI.

Cellular Mechanisms of Action of Drug Abuse on Olfactory Neurons

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Thomas Heinbockel

2015-12-01

Full Text Available Cannabinoids (Δ9-tetrahydrocannabinol are the active ingredient of marijuana (cannabis which is the most commonly abused illicit drug in the USA. In addition to being known and used as recreational drugs, cannabinoids are produced endogenously by neurons in the brain (endocannabinoids and serve as important signaling molecules in the nervous system and the rest of the body. Cannabinoids have been implicated in bodily processes both in health and disease. Recent pharmacological and physiological experiments have described novel aspects of classic brain signaling mechanisms or revealed unknown mechanisms of cellular communication involving the endocannabinoid system. While several forms of signaling have been described for endocannabinoids, the most distinguishing feature of endocannabinoids is their ability to act as retrograde messengers in neural circuits. Neurons in the main olfactory bulb express high levels of cannabinoid receptors. Here, we describe the cellular mechanisms and function of this novel brain signaling system in regulating neural activity at synapses in olfactory circuits. Results from basic research have the potential to provide the groundwork for translating the neurobiology of drug abuse to the realm of the pharmacotherapeutic treatment of addiction, specifically marijuana substance use disorder.

Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin

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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.

Genetic control and regulatory mechanisms of succinoglycan and curdlan biosynthesis in genus Agrobacterium.

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Wu, Dan; Li, Ang; Ma, Fang; Yang, Jixian; Xie, Yutong

2016-07-01

Agrobacterium is a genus of gram-negative bacteria that can produce several typical exopolysaccharides with commercial uses in the food and pharmaceutical fields. In particular, succinoglycan and curdlan, due to their good quality in high yield, have been employed on an industrial scale comparatively early. Exopolysaccharide biosynthesis is a multiple-step process controlled by different functional genes, and various environmental factors cause changes in exopolysaccharide biosynthesis through regulatory mechanisms. In this mini-review, we focus on the genetic control and regulatory mechanisms of succinoglycan and curdlan produced by Agrobacterium. Some key functional genes and regulatory mechanisms for exopolysaccharide biosynthesis are described, possessing a high potential for application in metabolic engineering to modify exopolysaccharide production and physicochemical properties. This review may contribute to the understanding of exopolysaccharide biosynthesis and exopolysaccharide modification by metabolic engineering methods in Agrobacterium.

Investigating the effects of ABC transporter-based acquired drug resistance mechanisms at the cellular and tissue scale.

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Liu, Cong; Krishnan, J; Xu, Xiao Yun

2013-03-01

In this paper we systematically investigate the effects of acquired drug resistance at the cellular and tissue scale, with a specific focus on ATP-binding cassette (ABC) transporter-based mechanisms and contrast this with other representative intracellular resistance mechanisms. This is done by developing in silico models wherein the drug resistance mechanism is overlaid on a coarse-grained description of apoptosis; these cellular models are coupled with interstitial drug transport, allowing for a transparent examination of the effect of acquired drug resistances at the tissue level. While ABC transporter-mediated resistance mechanisms counteract drug effect at the cellular level, its tissue-level effect is more complicated, revealing unexpected trends in tissue response as drug stimuli are systematically varied. Qualitatively different behaviour is observed in other drug resistance mechanisms. Overall the paper (i) provides insight into the tissue level functioning of a particular resistance mechanism, (ii) shows that this is very different from other resistance mechanisms of an apparently similar type, and (iii) demonstrates a concrete instance of how the functioning of a negative feedback based cellular adaptive mechanism can have unexpected higher scale effects.

Regulatory dendritic cells in autoimmunity: A comprehensive review.

Science.gov (United States)

Liu, Juan; Cao, Xuetao

2015-09-01

Dendritic cells (DCs) are professional antigen-presenting cells (APC) with significant phenotypic heterogeneity and functional plasticity. DCs play crucial roles in initiating effective adaptive immune responses for elimination of invading pathogens and also in inducing immune tolerance toward harmless components to maintain immune homeostasis. The regulatory capacity of DCs depends on their immature state and distinct subsets, yet not restricted to the immature state and one specialized subset. The tolerogenicity of DC is controlled by a complex network of environmental signals and cellular intrinsic mechanisms. Regulatory DCs play an important role in the maintenance of immunological tolerance via the induction of T cell unresponsiveness or apoptosis, and generation of regulatory T cells. DCs play essential roles in driving autoimmunity via promoting the activation of effector T cells such as T helper 1 and T helper 17 cells, and/or suppressing the generation of regulatory T cells. Besides, a breakdown of DCs-mediated tolerance due to abnormal environmental signals or breakdown of intrinsic regulatory mechanisms is closely linked with the pathogenesis of autoimmune diseases. Novel immunotherapy taking advantage of the tolerogenic potential of regulatory DCs is being developed for treatment of autoimmune diseases. In this review, we will describe the current understanding on the generation of regulatory DC and the role of regulatory DCs in promoting tolerogenic immune responses and suppressing autoimmune responses. The emerging roles of DCs dysfunction in the pathogenesis of autoimmune diseases and the potential application of regulatory DCs in the treatment of autoimmune diseases will also be discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mechanisms of cellular invasion by intracellular parasites.

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Walker, Dawn M; Oghumu, Steve; Gupta, Gaurav; McGwire, Bradford S; Drew, Mark E; Satoskar, Abhay R

2014-04-01

Numerous disease-causing parasites must invade host cells in order to prosper. Collectively, such pathogens are responsible for a staggering amount of human sickness and death throughout the world. Leishmaniasis, Chagas disease, toxoplasmosis, and malaria are neglected diseases and therefore are linked to socio-economical and geographical factors, affecting well-over half the world's population. Such obligate intracellular parasites have co-evolved with humans to establish a complexity of specific molecular parasite-host cell interactions, forming the basis of the parasite's cellular tropism. They make use of such interactions to invade host cells as a means to migrate through various tissues, to evade the host immune system, and to undergo intracellular replication. These cellular migration and invasion events are absolutely essential for the completion of the lifecycles of these parasites and lead to their for disease pathogenesis. This review is an overview of the molecular mechanisms of protozoan parasite invasion of host cells and discussion of therapeutic strategies, which could be developed by targeting these invasion pathways. Specifically, we focus on four species of protozoan parasites Leishmania, Trypanosoma cruzi, Plasmodium, and Toxoplasma, which are responsible for significant morbidity and mortality.

Mechanisms and cellular functions of intramembrane proteases.

Science.gov (United States)

Urban, Siniša

2013-12-01

The turn of the millennium coincided with the branding of a fundamentally different class of enzyme - proteases that reside immersed inside the membrane. This new field was the convergence of completely separate lines of research focused on cholesterol homeostasis, Alzheimer's disease, and developmental genetics. None intended their ultimate path, but soon became a richly-integrated fabric for an entirely new field: regulated intramembrane proteolysis. Our aim in this Special Issue is to focus on the ancient and nearly ubiquitous enzymes that catalyze this unexpected yet important reaction. The pace of progress has been dramatic, resulting in a rapidly-expanding universe of known cellular functions, and a paradigm shift in the biochemical understanding of these once heretical enzymes. More recently, the first therapeutic successes have been attained by targeting an intramembrane protease. We consider these advances and identify oncoming opportunities in four parts: growing spectra of cellular roles, insights into biochemical mechanisms, therapeutic strategies, and newly-emerging topics. Recent studies also expose challenges for the future, including non-linear relationships between substrate identification and physiological functions, and the need for potent and specific, not broad-class, inhibitors. © 2013.

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

Science.gov (United States)

Estrada, Javier; Andrew, Natalie; Gibson, Daniel; Chang, Frederick; Gnad, Florian; Gunawardena, Jeremy

2016-07-01

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.

Multiple regulatory systems coordinate DNA replication with cell growth in Bacillus subtilis.

Directory of Open Access Journals (Sweden)

Heath Murray

2014-10-01

Full Text Available In many bacteria the rate of DNA replication is linked with cellular physiology to ensure that genome duplication is coordinated with growth. Nutrient-mediated growth rate control of DNA replication initiation has been appreciated for decades, however the mechanism(s that connects these cell cycle activities has eluded understanding. In order to help address this fundamental question we have investigated regulation of DNA replication in the model organism Bacillus subtilis. Contrary to the prevailing view we find that changes in DnaA protein level are not sufficient to account for nutrient-mediated growth rate control of DNA replication initiation, although this regulation does require both DnaA and the endogenous replication origin. We go on to report connections between DNA replication and several essential cellular activities required for rapid bacterial growth, including respiration, central carbon metabolism, fatty acid synthesis, phospholipid synthesis, and protein synthesis. Unexpectedly, the results indicate that multiple regulatory systems are involved in coordinating DNA replication with cell physiology, with some of the regulatory systems targeting oriC while others act in a oriC-independent manner. We propose that distinct regulatory systems are utilized to control DNA replication in response to diverse physiological and chemical changes.

Multiple Regulatory Systems Coordinate DNA Replication with Cell Growth in Bacillus subtilis

Science.gov (United States)

Murray, Heath; Koh, Alan

2014-01-01

In many bacteria the rate of DNA replication is linked with cellular physiology to ensure that genome duplication is coordinated with growth. Nutrient-mediated growth rate control of DNA replication initiation has been appreciated for decades, however the mechanism(s) that connects these cell cycle activities has eluded understanding. In order to help address this fundamental question we have investigated regulation of DNA replication in the model organism Bacillus subtilis. Contrary to the prevailing view we find that changes in DnaA protein level are not sufficient to account for nutrient-mediated growth rate control of DNA replication initiation, although this regulation does require both DnaA and the endogenous replication origin. We go on to report connections between DNA replication and several essential cellular activities required for rapid bacterial growth, including respiration, central carbon metabolism, fatty acid synthesis, phospholipid synthesis, and protein synthesis. Unexpectedly, the results indicate that multiple regulatory systems are involved in coordinating DNA replication with cell physiology, with some of the regulatory systems targeting oriC while others act in a oriC-independent manner. We propose that distinct regulatory systems are utilized to control DNA replication in response to diverse physiological and chemical changes. PMID:25340815

Cellular mechanisms of noise-induced hearing loss.

Science.gov (United States)

Kurabi, Arwa; Keithley, Elizabeth M; Housley, Gary D; Ryan, Allen F; Wong, Ann C-Y

2017-06-01

Exposure to intense sound or noise can result in purely temporary threshold shift (TTS), or leave a residual permanent threshold shift (PTS) along with alterations in growth functions of auditory nerve output. Recent research has revealed a number of mechanisms that contribute to noise-induced hearing loss (NIHL). The principle cause of NIHL is damage to cochlear hair cells and associated synaptopathy. Contributions to TTS include reversible damage to hair cell (HC) stereocilia or synapses, while moderate TTS reflects protective purinergic hearing adaptation. PTS represents permanent damage to or loss of HCs and synapses. While the substrates of HC damage are complex, they include the accumulation of reactive oxygen species and the active stimulation of intracellular stress pathways, leading to programmed and/or necrotic cell death. Permanent damage to cochlear neurons can also contribute to the effects of NIHL, in addition to HC damage. These mechanisms have translational potential for pharmacological intervention and provide multiple opportunities to prevent HC damage or to rescue HCs and spiral ganglion neurons that have suffered injury. This paper reviews advances in our understanding of cellular mechanisms that contribute to NIHL and their potential for therapeutic manipulation. Published by Elsevier B.V.

Synthetic Biology: Tools to Design, Build, and Optimize Cellular Processes

Science.gov (United States)

Young, Eric; Alper, Hal

2010-01-01

The general central dogma frames the emergent properties of life, which make biology both necessary and difficult to engineer. In a process engineering paradigm, each biological process stream and process unit is heavily influenced by regulatory interactions and interactions with the surrounding environment. Synthetic biology is developing the tools and methods that will increase control over these interactions, eventually resulting in an integrative synthetic biology that will allow ground-up cellular optimization. In this review, we attempt to contextualize the areas of synthetic biology into three tiers: (1) the process units and associated streams of the central dogma, (2) the intrinsic regulatory mechanisms, and (3) the extrinsic physical and chemical environment. Efforts at each of these three tiers attempt to control cellular systems and take advantage of emerging tools and approaches. Ultimately, it will be possible to integrate these approaches and realize the vision of integrative synthetic biology when cells are completely rewired for biotechnological goals. This review will highlight progress towards this goal as well as areas requiring further research. PMID:20150964

Synthetic Biology: Tools to Design, Build, and Optimize Cellular Processes

Directory of Open Access Journals (Sweden)

Eric Young

2010-01-01

Full Text Available The general central dogma frames the emergent properties of life, which make biology both necessary and difficult to engineer. In a process engineering paradigm, each biological process stream and process unit is heavily influenced by regulatory interactions and interactions with the surrounding environment. Synthetic biology is developing the tools and methods that will increase control over these interactions, eventually resulting in an integrative synthetic biology that will allow ground-up cellular optimization. In this review, we attempt to contextualize the areas of synthetic biology into three tiers: (1 the process units and associated streams of the central dogma, (2 the intrinsic regulatory mechanisms, and (3 the extrinsic physical and chemical environment. Efforts at each of these three tiers attempt to control cellular systems and take advantage of emerging tools and approaches. Ultimately, it will be possible to integrate these approaches and realize the vision of integrative synthetic biology when cells are completely rewired for biotechnological goals. This review will highlight progress towards this goal as well as areas requiring further research.

Synthetic biology: tools to design, build, and optimize cellular processes.

Science.gov (United States)

Young, Eric; Alper, Hal

2010-01-01

The general central dogma frames the emergent properties of life, which make biology both necessary and difficult to engineer. In a process engineering paradigm, each biological process stream and process unit is heavily influenced by regulatory interactions and interactions with the surrounding environment. Synthetic biology is developing the tools and methods that will increase control over these interactions, eventually resulting in an integrative synthetic biology that will allow ground-up cellular optimization. In this review, we attempt to contextualize the areas of synthetic biology into three tiers: (1) the process units and associated streams of the central dogma, (2) the intrinsic regulatory mechanisms, and (3) the extrinsic physical and chemical environment. Efforts at each of these three tiers attempt to control cellular systems and take advantage of emerging tools and approaches. Ultimately, it will be possible to integrate these approaches and realize the vision of integrative synthetic biology when cells are completely rewired for biotechnological goals. This review will highlight progress towards this goal as well as areas requiring further research.

Cellular and molecular mechanisms of metformin: an overview

Science.gov (United States)

Viollet, Benoit; Guigas, Bruno; Sanz Garcia, Nieves; Leclerc, Jocelyne; Foretz, Marc; Andreelli, Fabrizio

2012-01-01

Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycemic agent now recommended as the first line oral therapy for type 2 diabetes (T2D). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory-chain complex 1. In addition, the resulting decrease in hepatic energy status activates the AMP-activated protein kinase (AMPK), a cellular metabolic sensor, providing a generally accepted mechanism for metformin action on hepatic gluconeogenic program. The demonstration that the respiratory-chain complex 1, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin was reported to restore ovarian function in polycystic ovary syndrome, reduce fatty liver and to lower microvascular and macrovascular complications associated with T2D. Its use was also recently suggested as an adjuvant treatment for cancer or gestational diabetes, and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent data from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D. PMID:22117616

Neuromodulation of hypoglossal motoneurons: cellular and developmental mechanisms.

Science.gov (United States)

Bayliss, D A; Viana, F; Talley, E M; Berger, A J

1997-11-01

Hypoglossal motoneurons (HMs) in the caudal brainstem have a respiratory-related activity pattern and contribute to control of upper airway resistance. In this review, we focus primarily on signalling mechanisms utilized by neurotransmitters to enhance HM excitability. In particular, we consider: (1) the membrane depolarization induced by a number of different putative transmitters [thyrotropin-releasing hormone (TRH), serotonin (5-HT), norepinephrine (NE)]; and (2) the inhibition of a calcium-dependent spike after hyperpolarization (AHP) by 5-HT and its effect on firing behavior. Potential functional consequences on HM behavior of these different neurotransmitter effects is discussed. In addition, we describe postnatal changes in transmitter effects and suggest potential cellular mechanisms to explain those developmental changes. Most of the data discussed are derived from in vitro electrophysiological recordings performed in preparations from neonatal and adult rats.

Cellular automata in cytoskeletal lattices

Energy Technology Data Exchange (ETDEWEB)

Smith, S A; Watt, R C; Hameroff, S R

1984-01-01

Cellular automata (CA) activities could mediate biological regulation and information processing via nonlinear electrodynamic effects in cytoskeletal lattice arrays. Frohlich coherent oscillations and other nonlinear mechanisms may effect discrete 10/sup -10/ to 10/sup -11/ s interval events which result in dynamic patterns in biolattices such as cylindrical protein polymers: microtubules (MT). Structural geometry and electrostatic forces of MT subunit dipole oscillations suggest neighbor rules among the hexagonally packed protein subunits. Computer simulations using these suggested rules and MT structural geometry demonstrate CA activities including dynamical and stable self-organizing patterns, oscillators, and traveling gliders. CA activities in MT and other cytoskeletal lattices may have important biological regulatory functions. 23 references, 6 figures, 1 table.

Cellular studies and interaction mechanisms of extremely low frequency fields

Science.gov (United States)

Liburdy, Robert P.

1995-01-01

Worldwide interest in the biological effects of ELF (extremely low frequency, level is to identify cellular responses to ELF fields, to develop a dose threshold for such interactions, and with such information to formulate and test appropriate interaction mechanisms. This review is selective and will discuss the most recent cellular studies directed at these goals which relate to power line, sinusoidal ELF fields. In these studies an interaction site at the cell membrane is by consensus a likely candidate, since changes in ion transport, ligand-receptor events such as antibody binding, and G protein activation have been reported. These changes strongly indicate that signal transduction (ST) can be influenced. Also, ELF fields are reported to influence enzyme activation, gene expression, protein synthesis, and cell proliferation, which are triggered by earlier ST events at the cell membrane. The concept of ELF fields altering early cell membrane events and thereby influencing intracellular cell function via the ST cascade is perhaps the most plausible biological framework currently being investigated for understanding ELF effects on cells. For example, the consequence of an increase due to ELF fields in mitogenesis, the final endpoint of the ST cascade, is an overall increase in the probability of mutagenesis and consequently cancer, according to the Ames epigenetic model of carcinogenesis. Consistent with this epigenetic mechanism and the ST pathway to carcinogenesis is recent evidence that ELF fields can alter breast cancer cell proliferation and can act as a copromoter in vitro. The most important dosimetric question being addressed currently is whether the electric (E) or the magnetic (B) field, or if combinations of static B and time-varying B fields represent an exposure metric for the cell. This question relates directly to understanding fundamental interaction mechanisms and to the development of a rationale for ELF dose threshold guidelines. The weight of

Molecular and cellular mechanisms of hexavalent chromium-induced lung cancer: an updated perspective.

Science.gov (United States)

Urbano, A M; Ferreira, L M R; Alpoim, M C

2012-03-01

For over a century, chromium (Cr) has found widespread industrial and commercial use, namely as a pigment, in the production of stainless steel and in chrome plating. The adverse health effects to the skin and respiratory tract of prolonged exposure to Cr have been known or suspected for a long time, but it was much more recently that the toxicity of this element was unequivocally attributed to its hexavalent state. Based on the combined results of extensive epidemiological studies, animal carcinogenicity studies and several types of other relevant data, authoritative regulatory agencies have found sufficient evidence to classify hexavalent chromium [Cr(VI)] compounds as encountered in the chromate production, chromate pigment production and chromium plating industries as carcinogenic to humans. Crucial for the development of novel strategies to prevent, detect and/or treat Cr(VI)-induced cancers is a detailed knowledge of the molecular and cellular mechanisms underlying these pathologies. Unfortunately, in spite of a considerable research effort, crucial facets of these mechanisms remain essentially unknown. This review is intended to provide a concise, integrated and critical perspective of the current state of knowledge concerning multiple aspects of Cr(VI) carcinogenesis. It will present recent theories of Cr(VI)-induced carcinogenesis and will include aspects not traditionally covered in other reviews, such as the possible involvement of the energy metabolism in this process. A brief discussion on the models that have been used in the studies of Cr(VI)-induced carcinogenicity will also be included, due to the impact of this parameter on the relevance of the results obtained.

Probabilistic cellular automata: Some statistical mechanical considerations

International Nuclear Information System (INIS)

Lebowitz, J.L.; Maes, C.; Speer, E.R.

1990-01-01

Spin systems evolving in continuous or discrete time under the action of stochastic dynamics are used to model phenomena as diverse as the structure of alloys and the functioning of neural networks. While in some cases the dynamics are secondary, designed to produce a specific stationary measure whose properties one is interested in studying, there are other cases in which the only available information is the dynamical rule. Prime examples of the former are computer simulations, via Glauber dynamics, of equilibrium Gibbs measures with a specified interaction potential. Examples of the latter include various types of majority rule dynamics used as models for pattern recognition and for error-tolerant computations. The present note discusses ways in which techniques found useful in equilibrium statistical mechanics can be applied to a particular class of models of the latter types. These are cellular automata with noise: systems in which the spins are updated stochastically at integer times, simultaneously at all sites of some regular lattice. These models were first investigated in detail in the Soviet literature of the late sixties and early seventies. They are now generally referred to as Stochastic or Probabilistic Cellular Automata (PCA), and may be considered to include deterministic automata (CA) as special limits. 16 refs., 3 figs

Cell volume homeostatic mechanisms: effectors and signalling pathways

DEFF Research Database (Denmark)

Hoffmann, E K; Pedersen, Stine Helene Falsig

2011-01-01

. Later work addressed the mechanisms through which cellular signalling pathways regulate the volume regulatory effectors or flux pathways. These studies were facilitated by the molecular identification of most of the relevant channels and transporters, and more recently also by the increased...

Transcriptome profiling reveals regulatory mechanisms underlying Corolla Senescence in Petunia

Science.gov (United States)

Genetic regulatory mechanisms that govern petal natural senescence in petunia is complicated and unclear. To identify key genes and pathways that regulate the process, we initiated a transcriptome analysis in petunia petals at four developmental time points, including petal opening without anthesis ...

Cellular and molecular mechanisms coordinating pancreas development.

Science.gov (United States)

Bastidas-Ponce, Aimée; Scheibner, Katharina; Lickert, Heiko; Bakhti, Mostafa

2017-08-15

The pancreas is an endoderm-derived glandular organ that participates in the regulation of systemic glucose metabolism and food digestion through the function of its endocrine and exocrine compartments, respectively. While intensive research has explored the signaling pathways and transcriptional programs that govern pancreas development, much remains to be discovered regarding the cellular processes that orchestrate pancreas morphogenesis. Here, we discuss the developmental mechanisms and principles that are known to underlie pancreas development, from induction and lineage formation to morphogenesis and organogenesis. Elucidating such principles will help to identify novel candidate disease genes and unravel the pathogenesis of pancreas-related diseases, such as diabetes, pancreatitis and cancer. © 2017. Published by The Company of Biologists Ltd.

A dynamic genetic-hormonal regulatory network model explains multiple cellular behaviors of the root apical meristem of Arabidopsis thaliana.

Science.gov (United States)

García-Gómez, Mónica L; Azpeitia, Eugenio; Álvarez-Buylla, Elena R

2017-04-01

The study of the concerted action of hormones and transcription factors is fundamental to understand cell differentiation and pattern formation during organ development. The root apical meristem of Arabidopsis thaliana is a useful model to address this. It has a stem cell niche near its tip conformed of a quiescent organizer and stem or initial cells around it, then a proliferation domain followed by a transition domain, where cells diminish division rate before transiting to the elongation zone; here, cells grow anisotropically prior to their final differentiation towards the plant base. A minimal model of the gene regulatory network that underlies cell-fate specification and patterning at the root stem cell niche was proposed before. In this study, we update and couple such network with both the auxin and cytokinin hormone signaling pathways to address how they collectively give rise to attractors that correspond to the genetic and hormonal activity profiles that are characteristic of different cell types along A. thaliana root apical meristem. We used a Boolean model of the genetic-hormonal regulatory network to integrate known and predicted regulatory interactions into alternative models. Our analyses show that, after adding some putative missing interactions, the model includes the necessary and sufficient components and regulatory interactions to recover attractors characteristic of the root cell types, including the auxin and cytokinin activity profiles that correlate with different cellular behaviors along the root apical meristem. Furthermore, the model predicts the existence of activity configurations that could correspond to the transition domain. The model also provides a possible explanation for apparently paradoxical cellular behaviors in the root meristem. For example, how auxin may induce and at the same time inhibit WOX5 expression. According to the model proposed here the hormonal regulation of WOX5 might depend on the cell type. Our results

A dynamic genetic-hormonal regulatory network model explains multiple cellular behaviors of the root apical meristem of Arabidopsis thaliana.

Directory of Open Access Journals (Sweden)

Mónica L García-Gómez

2017-04-01

Full Text Available The study of the concerted action of hormones and transcription factors is fundamental to understand cell differentiation and pattern formation during organ development. The root apical meristem of Arabidopsis thaliana is a useful model to address this. It has a stem cell niche near its tip conformed of a quiescent organizer and stem or initial cells around it, then a proliferation domain followed by a transition domain, where cells diminish division rate before transiting to the elongation zone; here, cells grow anisotropically prior to their final differentiation towards the plant base. A minimal model of the gene regulatory network that underlies cell-fate specification and patterning at the root stem cell niche was proposed before. In this study, we update and couple such network with both the auxin and cytokinin hormone signaling pathways to address how they collectively give rise to attractors that correspond to the genetic and hormonal activity profiles that are characteristic of different cell types along A. thaliana root apical meristem. We used a Boolean model of the genetic-hormonal regulatory network to integrate known and predicted regulatory interactions into alternative models. Our analyses show that, after adding some putative missing interactions, the model includes the necessary and sufficient components and regulatory interactions to recover attractors characteristic of the root cell types, including the auxin and cytokinin activity profiles that correlate with different cellular behaviors along the root apical meristem. Furthermore, the model predicts the existence of activity configurations that could correspond to the transition domain. The model also provides a possible explanation for apparently paradoxical cellular behaviors in the root meristem. For example, how auxin may induce and at the same time inhibit WOX5 expression. According to the model proposed here the hormonal regulation of WOX5 might depend on the cell

Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection.

Science.gov (United States)

Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio

2017-01-01

Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung.

Postischemic revascularization: from cellular and molecular mechanisms to clinical applications.

Science.gov (United States)

Silvestre, Jean-Sébastien; Smadja, David M; Lévy, Bernard I

2013-10-01

After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.

The Role of Instabilities on the Mechanical Response of Cellular Solids and Structures

National Research Council Canada - National Science Library

Kyriakides, S

1997-01-01

.... The relatively regular and periodic microstructure of these two-dimensional materials makes them excellent models for studying the mechanisms that govern the compressive response of cellular materials...

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. Copyright © 2016. Published by Elsevier B.V.

Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function.

Science.gov (United States)

Spencer, William C; Deneris, Evan S

2017-01-01

The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling

Metabolic Network Topology Reveals Transcriptional Regulatory Signatures of Type 2 Diabetes

DEFF Research Database (Denmark)

Zelezniak, Aleksej; Pers, Tune Hannes; Pinho Soares, Simao Pedro

2010-01-01

mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets...... with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites—metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment...... factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic...

Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation

Science.gov (United States)

Niessen, Carien M.; Leckband, Deborah; Yap, Alpha S.

2013-01-01

This review addresses the cellular and molecular mechanisms of cadherin-based tissue morphogenesis. Tissue physiology is profoundly influenced by the distinctive organizations of cells in organs and tissues. In metazoa, adhesion receptors of the classical cadherin family play important roles in establishing and maintaining such tissue organization. Indeed, it is apparent that cadherins participate in a range of morphogenetic events that range from support of tissue integrity to dynamic cellular rearrangements. A comprehensive understanding of cadherin-based morphogenesis must then define the molecular and cellular mechanisms that support these distinct cadherin biologies. Here we focus on four key mechanistic elements: the molecular basis for adhesion through cadherin ectodomains; the regulation of cadherin expression at the cell surface; cooperation between cadherins and the actin cytoskeleton; and regulation by cell signaling. We discuss current progress and outline issues for further research in these fields. PMID:21527735

Cellular mechanisms of estradiol-mediated sexual differentiation of the brain.

Science.gov (United States)

Wright, Christopher L; Schwarz, Jaclyn S; Dean, Shannon L; McCarthy, Margaret M

2010-09-01

Gonadal steroids organize the developing brain during a perinatal sensitive period and have enduring consequences for adult behavior. In male rodents testicular androgens are aromatized in neurons to estrogens and initiate multiple distinct cellular processes that ultimately determine the masculine phenotype. Within specific brain regions, overall cell number and dendritic morphology are the principal targets for hormonal organization. Recent advances have been made in elucidating the cellular mechanisms by which the neurological underpinnings of sexually dimorphic physiology and behavior are determined. These include estradiol-mediated prostaglandin synthesis, presynaptic release of glutamate, postsynaptic changes in glutamate receptors and changes in cell adhesion molecules. Sex differences in cell death are mediated by hormonal modulation of survival and death factors such as TNFalpha and Bcl-2/BAX. Copyright 2010 Elsevier Ltd. All rights reserved.

Cellular packing, mechanical stress and the evolution of multicellularity

Science.gov (United States)

Jacobeen, Shane; Pentz, Jennifer T.; Graba, Elyes C.; Brandys, Colin G.; Ratcliff, William C.; Yunker, Peter J.

2018-03-01

The evolution of multicellularity set the stage for sustained increases in organismal complexity1-5. However, a fundamental aspect of this transition remains largely unknown: how do simple clusters of cells evolve increased size when confronted by forces capable of breaking intracellular bonds? Here we show that multicellular snowflake yeast clusters6-8 fracture due to crowding-induced mechanical stress. Over seven weeks ( 291 generations) of daily selection for large size, snowflake clusters evolve to increase their radius 1.7-fold by reducing the accumulation of internal stress. During this period, cells within the clusters evolve to be more elongated, concomitant with a decrease in the cellular volume fraction of the clusters. The associated increase in free space reduces the internal stress caused by cellular growth, thus delaying fracture and increasing cluster size. This work demonstrates how readily natural selection finds simple, physical solutions to spatial constraints that limit the evolution of group size—a fundamental step in the evolution of multicellularity.

Genome-wide identification of regulatory elements and reconstruction of gene regulatory networks of the green alga Chlamydomonas reinhardtii under carbon deprivation.

Directory of Open Access Journals (Sweden)

Flavia Vischi Winck

Full Text Available The unicellular green alga Chlamydomonas reinhardtii is a long-established model organism for studies on photosynthesis and carbon metabolism-related physiology. Under conditions of air-level carbon dioxide concentration [CO2], a carbon concentrating mechanism (CCM is induced to facilitate cellular carbon uptake. CCM increases the availability of carbon dioxide at the site of cellular carbon fixation. To improve our understanding of the transcriptional control of the CCM, we employed FAIRE-seq (formaldehyde-assisted Isolation of Regulatory Elements, followed by deep sequencing to determine nucleosome-depleted chromatin regions of algal cells subjected to carbon deprivation. Our FAIRE data recapitulated the positions of known regulatory elements in the promoter of the periplasmic carbonic anhydrase (Cah1 gene, which is upregulated during CCM induction, and revealed new candidate regulatory elements at a genome-wide scale. In addition, time series expression patterns of 130 transcription factor (TF and transcription regulator (TR genes were obtained for cells cultured under photoautotrophic condition and subjected to a shift from high to low [CO2]. Groups of co-expressed genes were identified and a putative directed gene-regulatory network underlying the CCM was reconstructed from the gene expression data using the recently developed IOTA (inner composition alignment method. Among the candidate regulatory genes, two members of the MYB-related TF family, Lcr1 (Low-CO 2 response regulator 1 and Lcr2 (Low-CO2 response regulator 2, may play an important role in down-regulating the expression of a particular set of TF and TR genes in response to low [CO2]. The results obtained provide new insights into the transcriptional control of the CCM and revealed more than 60 new candidate regulatory genes. Deep sequencing of nucleosome-depleted genomic regions indicated the presence of new, previously unknown regulatory elements in the C. reinhardtii genome

The Effects of Chronological Age on the Cellular Mechanics of Human Dermal Fibroblasts

Science.gov (United States)

Pan, Z.; Hung, V.; Kambhampati, S.; Ge, S. R.; Rafailovich, M.; Ghosh, K.; Clark, R.; Liu, Y. J.; Nakamura, T.; Shu, X. Z.; Prestwich, G.

2006-03-01

It is often observed that older people display diminished wound healing abilities. Understanding of this phenomenon is important for many in vivo applications of tissue engineering. In this study, the cell mechanics of dermal fibroblasts from 25, 40 and 84 years old female subjects were compared. These cells were cultured on functionalized hyaluronic acid hydrogel substrates which emulated physiological conditions in dermal tissue. The deformation of the substrate caused by cellular traction forces was detected by tracing the displacement of fluorescent beads embedded in the substrate using Digital Image Speckle Correlation. Then cellular traction forces were quantitatively determined by Finite Element Method in a linear elastic model with a high spatial resolution. These results were correlated with auxiliary measurements of substrate modulus, cell modulus and migration. We found that with increasing age, the magnitude of the cellular traction forces diminished. Similarly, the ability of the cells to adapt to changes in the mechanical properties of their environment and migrate was also impaired. The interrelationship between these factors and wound healing will be discussed. This work is supported by NSF- MRSEC program.

Molecular and cellular mechanisms of tight junction dysfunction in the irritable bowel syndrome.

Science.gov (United States)

Cheng, Peng; Yao, Jianning; Wang, Chunfeng; Zhang, Lianfeng; Kong, Wuming

2015-09-01

The pathophysiological mechanisms of the irritable bowel syndrome (IBS), one of the most prevalent gastrointestinal disorders, are complex and have not been fully elucidated. The present study aimed to investigate the molecular and cellular mechanisms of tight junction (TJ) dysfunction in IBS. Intestinal tissues of IBS and non‑IBS patients were examined to observe cellular changes by cell chemical tracer electron microscopy and transmission electron microscopy, and intestinal claudin‑1 protein was detected by immunohistochemistry, western blot analysis and fluorescence quantitative polymerase chain reaction. Compared with the control group, TJ broadening and the tracer extravasation phenomenon were observed in the diarrhea‑predominant IBS group, and a greater number of neuroendocrine cells and mast cells filled with high‑density particles in the endocrine package pulp as well as a certain extent of vacuolization were present. The expression of claudin‑1 in diarrhea‑predominant IBS patients was decreased, while it was increased in constipation‑predominant IBS patients. In conclusion, the results of the present study indicated that changes in cellular structure and claudin‑1 levels were associated with Tjs in IBS.

Natural agents: cellular and molecular mechanisms of photoprotection.

Science.gov (United States)

Afaq, Farrukh

2011-04-15

The skin is the largest organ of the body that produces a flexible and self-repairing barrier and protects the body from most common potentially harmful physical, environmental, and biological insults. Solar ultraviolet (UV) radiation is one of the major environmental insults to the skin and causes multi-tiered cellular and molecular events eventually leading to skin cancer. The past decade has seen a surge in the incidence of skin cancer due to changes in life style patterns that have led to a significant increase in the amount of UV radiation that people receive. Reducing excessive exposure to UV radiation is desirable; nevertheless this approach is not easy to implement. Therefore, there is an urgent need to develop novel strategies to reduce the adverse biological effects of UV radiation on the skin. A wide variety of natural agents have been reported to possess substantial skin photoprotective effects. Numerous preclinical and clinical studies have elucidated that natural agents act by several cellular and molecular mechanisms to delay or prevent skin cancer. In this review article, we have summarized and discussed some of the selected natural agents for skin photoprotection. Copyright © 2010 Elsevier Inc. All rights reserved.

Cellular and chemical neuroscience of mammalian sleep.

Science.gov (United States)

Datta, Subimal

2010-05-01

Extraordinary strides have been made toward understanding the complexities and regulatory mechanisms of sleep over the past two decades thanks to the help of rapidly evolving technologies. At its most basic level, mammalian sleep is a restorative process of the brain and body. Beyond its primary restorative purpose, sleep is essential for a number of vital functions. Our primary research interest is to understand the cellular and molecular mechanisms underlying the regulation of sleep and its cognitive functions. Here I will reflect on our own research contributions to 50 years of extraordinary advances in the neurobiology of slow-wave sleep (SWS) and rapid eye movement (REM) sleep regulation. I conclude this review by suggesting some potential future directions to further our understanding of the neurobiology of sleep. Copyright 2010 Elsevier B.V. All rights reserved.

Cellular therapies for heart disease: unveiling the ethical and public policy challenges.

Science.gov (United States)

Raval, Amish N; Kamp, Timothy J; Hogle, Linda F

2008-10-01

Cellular therapies have emerged as a potential revolutionary treatment for cardiovascular disease. Promising preclinical results have resulted in a flurry of basic research activity and spawned multiple clinical trials worldwide. However, the optimal cell type and delivery mode have not been determined for target patient populations. Nor have the mechanisms of benefit for the range of cellular interventions been clearly defined. Experiences to date have unveiled a myriad of ethical and public policy challenges which will affect the way researchers and clinicians make decisions for both basic and clinical research. Stem cells derived from embryos are at the forefront of the ethical and political debate, raising issues of which derivation methods are morally and socially permissible to pursue, as much as which are technically feasible. Adult stem cells are less controversial; however, important challenges exist in determining study design, cell processing, delivery mode, and target patient population. Pathways to successful commercialization and hence broad accessibility of cellular therapies for heart disease are only beginning to be explored. Comprehensive, multi-disciplinary and collaborative networks involving basic researchers, clinicians, regulatory officials and policymakers are required to share information, develop research, regulatory and policy standards and enable rational and ethical cell-based treatment approaches.

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

Science.gov (United States)

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

2016-10-31

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

Resveratrol Inhibition of Cellular Respiration: New Paradigm for an Old Mechanism

Directory of Open Access Journals (Sweden)

Luis Alberto Madrigal-Perez

2016-03-01

Full Text Available Resveratrol (3,4′,5-trihydroxy-trans-stilbene, RSV has emerged as an important molecule in the biomedical area. This is due to its antioxidant and health benefits exerted in mammals. Nonetheless, early studies have also demonstrated its toxic properties toward plant-pathogenic fungi of this phytochemical. Both effects appear to be opposed and caused by different molecular mechanisms. However, the inhibition of cellular respiration is a hypothesis that might explain both toxic and beneficial properties of resveratrol, since this phytochemical: (1 decreases the production of energy of plant-pathogenic organisms, which prevents their proliferation; (2 increases adenosine monophosphate/adenosine diphosphate (AMP/ADP ratio that can lead to AMP protein kinase (AMPK activation, which is related to its health effects, and (3 increases the reactive oxygen species generation by the inhibition of electron transport. This pro-oxidant effect induces expression of antioxidant enzymes as a mechanism to counteract oxidative stress. In this review, evidence is discussed that supports the hypothesis that cellular respiration is the main target of resveratrol.

A Model of How Different Biology Experts Explain Molecular and Cellular Mechanisms

Science.gov (United States)

Trujillo, Caleb M.; Anderson, Trevor R.; Pelaez, Nancy J.

2015-01-01

Constructing explanations is an essential skill for all science learners. The goal of this project was to model the key components of expert explanation of molecular and cellular mechanisms. As such, we asked: What is an appropriate model of the components of explanation used by biology experts to explain molecular and cellular mechanisms? Do explanations made by experts from different biology subdisciplines at a university support the validity of this model? Guided by the modeling framework of R. S. Justi and J. K. Gilbert, the validity of an initial model was tested by asking seven biologists to explain a molecular mechanism of their choice. Data were collected from interviews, artifacts, and drawings, and then subjected to thematic analysis. We found that biologists explained the specific activities and organization of entities of the mechanism. In addition, they contextualized explanations according to their biological and social significance; integrated explanations with methods, instruments, and measurements; and used analogies and narrated stories. The derived methods, analogies, context, and how themes informed the development of our final MACH model of mechanistic explanations. Future research will test the potential of the MACH model as a guiding framework for instruction to enhance the quality of student explanations. PMID:25999313

Effects of temperature and cellular interactions on the mechanics and morphology of human cancer cells investigated by atomic force microscopy.

Science.gov (United States)

Li, Mi; Liu, LianQing; Xi, Ning; Wang, YueChao; Xiao, XiuBin; Zhang, WeiJing

2015-09-01

Cell mechanics plays an important role in cellular physiological activities. Recent studies have shown that cellular mechanical properties are novel biomarkers for indicating the cell states. In this article, temperature-controllable atomic force microscopy (AFM) was applied to quantitatively investigate the effects of temperature and cellular interactions on the mechanics and morphology of human cancer cells. First, AFM indenting experiments were performed on six types of human cells to investigate the changes of cellular Young's modulus at different temperatures and the results showed that the mechanical responses to the changes of temperature were variable for different types of cancer cells. Second, AFM imaging experiments were performed to observe the morphological changes in living cells at different temperatures and the results showed the significant changes of cell morphology caused by the alterations of temperature. Finally, by co-culturing human cancer cells with human immune cells, the mechanical and morphological changes in cancer cells were investigated. The results showed that the co-culture of cancer cells and immune cells could cause the distinct mechanical changes in cancer cells, but no significant morphological differences were observed. The experimental results improved our understanding of the effects of temperature and cellular interactions on the mechanics and morphology of cancer cells.

Mechanical sensitivity of Piezo1 ion channels can be tuned by cellular membrane tension

Science.gov (United States)

Lewis, Amanda H; Grandl, Jörg

2015-01-01

Piezo1 ion channels mediate the conversion of mechanical forces into electrical signals and are critical for responsiveness to touch in metazoans. The apparent mechanical sensitivity of Piezo1 varies substantially across cellular environments, stimulating methods and protocols, raising the fundamental questions of what precise physical stimulus activates the channel and how its stimulus sensitivity is regulated. Here, we measured Piezo1 currents evoked by membrane stretch in three patch configurations, while simultaneously visualizing and measuring membrane geometry. Building on this approach, we developed protocols to minimize resting membrane curvature and tension prior to probing Piezo1 activity. We find that Piezo1 responds to lateral membrane tension with exquisite sensitivity as compared to other mechanically activated channels and that resting tension can drive channel inactivation, thereby tuning overall mechanical sensitivity of Piezo1. Our results explain how Piezo1 can function efficiently and with adaptable sensitivity as a sensor of mechanical stimulation in diverse cellular contexts. DOI: http://dx.doi.org/10.7554/eLife.12088.001 PMID:26646186

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

International Nuclear Information System (INIS)

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

2016-01-01

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. (paper)

The emergence of extracellular matrix mechanics and cell traction forces as important regulators of cellular self-organization.

Science.gov (United States)

Checa, Sara; Rausch, Manuel K; Petersen, Ansgar; Kuhl, Ellen; Duda, Georg N

2015-01-01

Physical cues play a fundamental role in a wide range of biological processes, such as embryogenesis, wound healing, tumour invasion and connective tissue morphogenesis. Although it is well known that during these processes, cells continuously interact with the local extracellular matrix (ECM) through cell traction forces, the role of these mechanical interactions on large scale cellular and matrix organization remains largely unknown. In this study, we use a simple theoretical model to investigate cellular and matrix organization as a result of mechanical feedback signals between cells and the surrounding ECM. The model includes bi-directional coupling through cellular traction forces to deform the ECM and through matrix deformation to trigger cellular migration. In addition, we incorporate the mechanical contribution of matrix fibres and their reorganization by the cells. We show that a group of contractile cells will self-polarize at a large scale, even in homogeneous environments. In addition, our simulations mimic the experimentally observed alignment of cells in the direction of maximum stiffness and the building up of tension as a consequence of cell and fibre reorganization. Moreover, we demonstrate that cellular organization is tightly linked to the mechanical feedback loop between cells and matrix. Cells with a preference for stiff environments have a tendency to form chains, while cells with a tendency for soft environments tend to form clusters. The model presented here illustrates the potential of simple physical cues and their impact on cellular self-organization. It can be used in applications where cell-matrix interactions play a key role, such as in the design of tissue engineering scaffolds and to gain a basic understanding of pattern formation in organogenesis or tissue regeneration.

HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression

Science.gov (United States)

Redmond, Catherine J.; Dooley, Katharine E.; Fu, Haiqing; Gillison, Maura L.; Akagi, Keiko; Symer, David E.; Aladjem, Mirit I.

2018-01-01

Integration of human papillomavirus (HPV) genomes into cellular chromatin is common in HPV-associated cancers. Integration is random, and each site is unique depending on how and where the virus integrates. We recently showed that tandemly integrated HPV16 could result in the formation of a super-enhancer-like element that drives transcription of the viral oncogenes. Here, we characterize the chromatin landscape and genomic architecture of this integration locus to elucidate the mechanisms that promoted de novo super-enhancer formation. Using next-generation sequencing and molecular combing/fiber-FISH, we show that ~26 copies of HPV16 are integrated into an intergenic region of chromosome 2p23.2, interspersed with 25 kb of amplified, flanking cellular DNA. This interspersed, co-amplified viral-host pattern is frequent in HPV-associated cancers and here we designate it as Type III integration. An abundant viral-cellular fusion transcript encoding the viral E6/E7 oncogenes is expressed from the integration locus and the chromatin encompassing both the viral enhancer and a region in the adjacent amplified cellular sequences is strongly enriched in the super-enhancer markers H3K27ac and Brd4. Notably, the peak in the amplified cellular sequence corresponds to an epithelial-cell-type specific enhancer. Thus, HPV16 integration generated a super-enhancer-like element composed of tandem interspersed copies of the viral upstream regulatory region and a cellular enhancer, to drive high levels of oncogene expression. PMID:29364907

Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory.

Science.gov (United States)

Rahn, Elizabeth J; Guzman-Karlsson, Mikael C; David Sweatt, J

2013-10-01

Sensitization is a form of non-associative conditioning in which amplification of behavioral responses can occur following presentation of an aversive or noxious stimulus. Understanding the cellular and molecular underpinnings of sensitization has been an overarching theme spanning the field of learning and memory as well as that of pain research. In this review we examine how sensitization, both in the context of learning as well as pain processing, shares evolutionarily conserved behavioral, cellular/synaptic, and epigenetic mechanisms across phyla. First, we characterize the behavioral phenomenon of sensitization both in invertebrates and vertebrates. Particular emphasis is placed on long-term sensitization (LTS) of withdrawal reflexes in Aplysia following aversive stimulation or injury, although additional invertebrate models are also covered. In the context of vertebrates, sensitization of mammalian hyperarousal in a model of post-traumatic stress disorder (PTSD), as well as mammalian models of inflammatory and neuropathic pain is characterized. Second, we investigate the cellular and synaptic mechanisms underlying these behaviors. We focus our discussion on serotonin-mediated long-term facilitation (LTF) and axotomy-mediated long-term hyperexcitability (LTH) in reduced Aplysia systems, as well as mammalian spinal plasticity mechanisms of central sensitization. Third, we explore recent evidence implicating epigenetic mechanisms in learning- and pain-related sensitization. This review illustrates the fundamental and functional overlay of the learning and memory field with the pain field which argues for homologous persistent plasticity mechanisms in response to sensitizing stimuli or injury across phyla. Copyright © 2013 Elsevier Inc. All rights reserved.

[Regulatory Mechanisms of PD-L1 Expression and Its Role in Immune Evasion].

Science.gov (United States)

Kataoka, Keisuke

2017-11-01

Immune checkpoint blockade therapy using anti-PD-1 or anti-PD-L1 antibodies can unleash anti-tumor immunity and induce durable remission in a variety ofhuman cancers. However, the regulatory mechanisms of PD-L1 expression mediating immune evasion ofcancer cells have not been fully elucidated, including the genetic alterations causing PD-L1 overexpression. Recently, we have reported a novel genetic mechanism ofimmune evasion associated with structural variations(SVs)disrupting the 3'-untranslated region(UTR)ofthe PD-L1 gene in various malignancies, such as aggressive lymphomas and gastrointestinal cancers. Despite a heterogenous nature ofthese SVs, they are closely associated with a marked upregulation of PD-L1 expression, which augments tumor growth and escape from anti-tumor immunity. Here we present an overview of the regulatory mechanisms of PD-L1 expression in cancer cells, highlighting the genetic mechanisms of PD-L1 constitutive activation, with specific focus on PD-L1 3'-UTR disruption.

Regulatory design for RES-E support mechanisms: Learning curves, market structure, and burden-sharing

International Nuclear Information System (INIS)

Batlle, C.; Pérez-Arriaga, I.J.; Zambrano-Barragán, P.

2012-01-01

Drawing from relevant experiences in power systems around the world, this paper offers a review of existing policy support mechanisms for RES-E, with a detailed analysis of their regulatory implications. While recent studies provide an account of current RES-E support systems, in this paper we focus on some of the impacts these mechanisms have on the overall energy market structure and its performance. Given the rising importance of RES-E in systems everywhere, these impacts should no longer be overlooked. - Highlights: ► This paper offers a critical review of RES-E support mechanisms and their regulatory implications. ► The discussion focuses on how the different schemes impact the performance of the energy markets. ► We propose to redesign of current RES-E mechanisms to optimize incentives and market performance. ► Our recommendation is also to gradually move from price-based mechanisms to auctions.

The Role of Mechanical Force in Molecular and Cellular during Orthodontic Tooth Movement

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Ida Bagus Narmada

2012-10-01

Full Text Available Application of mechanical force on abnormally positioned tooth, cause changes in tooth location and transmitted to the bone ia the periodontal ligament (PDL produce orthodontic tooth movement. This force application is further way that remodeling in the area occurs. In order to develop biological strategies for enhancing this movement of teeth in bone, the underlying mechanisms of bone resorption and apposition should be understood in detail. Analysis of gingival crevicular fluid (GCF may be a good means of examining the on going molecular and cellular process associated with gingival and bone turnover during orthodontic tooth movement. If it could be possible to biologically monitor and predict the outcome of orthodontic force, then the appliance management could be based on dividual tissue response and the effectiveness of the treatment could be improved and understanding their biology is critical to finding ways to modify bone biology to move teeth faster. The present article reviewed a short introduction to some mayors advanced mechanical force in molecular and cellular biology during orthodontic tooth movement.DOI: 10.14693/jdi.v15i3.30

The biocompatibility of fluorescent nanodiamonds and their mechanism of cellular uptake

International Nuclear Information System (INIS)

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

2009-01-01

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.

The biocompatibility of fluorescent nanodiamonds and their mechanism of cellular uptake

Energy Technology Data Exchange (ETDEWEB)

Vaijayanthimala, Vairakkannu; Tzeng, Yan-Kai; Chang, Huan-Cheng [Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei 106, Taiwan (China); Li, Chung-Leung, E-mail: hcchang@po.sinica.edu.t, E-mail: chungL@gate.sinica.edu.t [Genomics Research Center, Academia Sinica, Taipei 115, Taiwan (China)

2009-10-21

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.

A conserved RNA structural element within the hepatitis B virus post-transcriptional regulatory element enhance nuclear export of intronless transcripts and repress the splicing mechanism.

Science.gov (United States)

Visootsat, Akasit; Payungporn, Sunchai; T-Thienprasert, Nattanan P

2015-12-01

Hepatitis B virus (HBV) infection is a primary cause of hepatocellular carcinoma and liver cirrhosis worldwide. To develop novel antiviral drugs, a better understanding of HBV gene expression regulation is vital. One important aspect is to understand how HBV hijacks the cellular machinery to export unspliced RNA from the nucleus. The HBV post-transcriptional regulatory element (HBV PRE) has been proposed to be the HBV RNA nuclear export element. However, the function remains controversial, and the core element is unclear. This study, therefore, aimed to identify functional regulatory elements within the HBV PRE and investigate their functions. Using bioinformatics programs based on sequence conservation and conserved RNA secondary structures, three regulatory elements were predicted, namely PRE 1151-1410, PRE 1520-1620 and PRE 1650-1684. PRE 1151-1410 significantly increased intronless and unspliced luciferase activity in both HepG2 and COS-7 cells. Likewise, PRE 1151-1410 significantly elevated intronless and unspliced HBV surface transcripts in liver cancer cells. Moreover, motif analysis predicted that PRE 1151-1410 contains several regulatory motifs. This study reported the roles of PRE 1151-1410 in intronless transcript nuclear export and the splicing mechanism. Additionally, these results provide knowledge in the field of HBV RNA regulation. Moreover, PRE 1151-1410 may be used to enhance the expression of other mRNAs in intronless reporter plasmids.

Intestinal Stem Cell Niche: The Extracellular Matrix and Cellular Components

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Laween Meran

2017-01-01

Full Text Available The intestinal epithelium comprises a monolayer of polarised columnar cells organised along the crypt-villus axis. Intestinal stem cells reside at the base of crypts and are constantly nourished by their surrounding niche for maintenance, self-renewal, and differentiation. The cellular microenvironment including the adjacent Paneth cells, stromal cells, smooth muscle cells, and neural cells as well as the extracellular matrix together constitute the intestinal stem cell niche. A dynamic regulatory network exists among the epithelium, stromal cells, and the matrix via complex signal transduction to maintain tissue homeostasis. Dysregulation of these biological or mechanical signals could potentially lead to intestinal injury and disease. In this review, we discuss the role of different intestinal stem cell niche components and dissect the interaction between dynamic matrix factors and regulatory signalling during intestinal stem cell homeostasis.

The agglomeration state of nanoparticles can influence the mechanism of their cellular internalisation.

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Halamoda-Kenzaoui, Blanka; Ceridono, Mara; Urbán, Patricia; Bogni, Alessia; Ponti, Jessica; Gioria, Sabrina; Kinsner-Ovaskainen, Agnieszka

2017-06-26

Significant progress of nanotechnology, including in particular biomedical and pharmaceutical applications, has resulted in a high number of studies describing the biological effects of nanomaterials. Moreover, a determination of so-called "critical quality attributes", that is specific physicochemical properties of nanomaterials triggering the observed biological response, has been recognised as crucial for the evaluation and design of novel safe and efficacious therapeutics. In the context of in vitro studies, a thorough physicochemical characterisation of nanoparticles (NPs), also in the biological medium, is necessary to allow a correlation with a cellular response. Following this concept, we examined whether the main and frequently reported characteristics of NPs such as size and the agglomeration state can influence the level and the mechanism of NP cellular internalization. We employed fluorescently-labelled 30 and 80 nm silicon dioxide NPs, both in agglomerated and non-agglomerated form. Using flow cytometry, transmission electron microscopy, the inhibitors of endocytosis and gene silencing we determined the most probable routes of cellular uptake for each form of tested silica NPs. We observed differences in cellular uptake depending on the size and the agglomeration state of NPs. Caveolae-mediated endocytosis was implicated particularly in the internalisation of well dispersed silica NPs but with an increase of the agglomeration state of NPs a combination of endocytic pathways with a predominant role of macropinocytosis was noted. We demonstrated that the agglomeration state of NPs is an important factor influencing the level of cell uptake and the mechanism of endocytosis of silica NPs.

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

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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.

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

Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities.

Science.gov (United States)

Gajarsa, Jason J; Kloner, Robert A

2011-01-01

As more patients survive myocardial infarctions, the incidence of heart failure increases. After an infarction, the human heart undergoes a series of structural changes, which are governed by cellular and molecular mechanisms in a pathological metamorphosis termed "remodeling." This review will discuss the current developments in our understanding of these molecular and cellular events in remodeling and the various pharmacological, cellular and device therapies used to treat, and potentially retard, this condition. Specifically, this paper will examine the neurohormonal activity of the renin-angiotensin-aldosterone axis and its molecular effects on the heart. The emerging understanding of the extra-cellular matrix and the various active molecules within it, such as the matrix metalloproteinases, elicits new appreciation for their role in cardiac remodeling and as possible future therapeutic targets. Cell therapy with stem cells is another recent therapy with great potential in improving post-infarcted hearts. Lastly, the cellular and molecular effects of left ventricular assist devices on remodeling will be reviewed. Our increasing knowledge of the cellular and molecular mechanisms underlying cardiac remodeling enables us not only to better understand how our more successful therapies, like angiotensin-converting enzyme inhibitors, work, but also to explore new therapies of the future.

Regulatory factors governing adenosine-to-inosine (A-to-I) RNA editing.

Science.gov (United States)

Hong, HuiQi; Lin, Jaymie Siqi; Chen, Leilei

2015-03-31

Adenosine-to-inosine (A-to-I) RNA editing, the most prevalent mode of transcript modification in higher eukaryotes, is catalysed by the adenosine deaminases acting on RNA (ADARs). A-to-I editing imposes an additional layer of gene regulation as it dictates various aspects of RNA metabolism, including RNA folding, processing, localization and degradation. Furthermore, editing events in exonic regions contribute to proteome diversity as translational machinery decodes inosine as guanosine. Although it has been demonstrated that dysregulated A-to-I editing contributes to various diseases, the precise regulatory mechanisms governing this critical cellular process have yet to be fully elucidated. However, integration of previous studies revealed that regulation of A-to-I editing is multifaceted, weaving an intricate network of auto- and transregulations, including the involvement of virus-originated factors like adenovirus-associated RNA. Taken together, it is apparent that tipping of any regulatory components will have profound effects on A-to-I editing, which in turn contributes to both normal and aberrant physiological conditions. A complete understanding of this intricate regulatory network may ultimately be translated into new therapeutic strategies against diseases driven by perturbed RNA editing events. Herein, we review the current state of knowledge on the regulatory mechanisms governing A-to-I editing and propose the role of other co-factors that may be involved in this complex regulatory process.

A qrr noncoding RNA deploys four different regulatory mechanisms to optimize quorum-sensing dynamics.

Science.gov (United States)

Feng, Lihui; Rutherford, Steven T; Papenfort, Kai; Bagert, John D; van Kessel, Julia C; Tirrell, David A; Wingreen, Ned S; Bassler, Bonnie L

2015-01-15

Quorum sensing is a cell-cell communication process that bacteria use to transition between individual and social lifestyles. In vibrios, homologous small RNAs called the Qrr sRNAs function at the center of quorum-sensing pathways. The Qrr sRNAs regulate multiple mRNA targets including those encoding the quorum-sensing regulatory components luxR, luxO, luxM, and aphA. We show that a representative Qrr, Qrr3, uses four distinct mechanisms to control its particular targets: the Qrr3 sRNA represses luxR through catalytic degradation, represses luxM through coupled degradation, represses luxO through sequestration, and activates aphA by revealing the ribosome binding site while the sRNA itself is degraded. Qrr3 forms different base-pairing interactions with each mRNA target, and the particular pairing strategy determines which regulatory mechanism occurs. Combined mathematical modeling and experiments show that the specific Qrr regulatory mechanism employed governs the potency, dynamics, and competition of target mRNA regulation, which in turn, defines the overall quorum-sensing response. Copyright © 2015 Elsevier Inc. All rights reserved.

Regulatory T Cells in Human Ovarian Cancer

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Dong-Jun Peng

2012-01-01

Full Text Available Multiple layers of suppressive components including regulatory T (TReg cells, suppressive antigen-presenting cells, and inhibitory cytokines form suppressive networks in the ovarian cancer microenvironment. It has been demonstrated that as a major suppressive element, TReg cells infiltrate tumor, interact with several types of immune cells, and mediate immune suppression through different molecular and cellular mechanisms. In this paper, we focus on human ovarian cancer and will discuss the nature of TReg cells including their subsets, trafficking, expansion, and function. We will briefly review the development of manipulation of TReg cells in preclinical and clinical settings.

Discrete dynamic modeling of cellular signaling networks.

Science.gov (United States)

Albert, Réka; Wang, Rui-Sheng

2009-01-01

Understanding signal transduction in cellular systems is a central issue in systems biology. Numerous experiments from different laboratories generate an abundance of individual components and causal interactions mediating environmental and developmental signals. However, for many signal transduction systems there is insufficient information on the overall structure and the molecular mechanisms involved in the signaling network. Moreover, lack of kinetic and temporal information makes it difficult to construct quantitative models of signal transduction pathways. Discrete dynamic modeling, combined with network analysis, provides an effective way to integrate fragmentary knowledge of regulatory interactions into a predictive mathematical model which is able to describe the time evolution of the system without the requirement for kinetic parameters. This chapter introduces the fundamental concepts of discrete dynamic modeling, particularly focusing on Boolean dynamic models. We describe this method step-by-step in the context of cellular signaling networks. Several variants of Boolean dynamic models including threshold Boolean networks and piecewise linear systems are also covered, followed by two examples of successful application of discrete dynamic modeling in cell biology.

Exploring associations between self-regulatory mechanisms and neuropsychological functioning and driver behaviour after brain injury.

Science.gov (United States)

Rike, Per-Ola; Johansen, Hans J; Ulleberg, Pål; Lundqvist, Anna; Schanke, Anne-Kristine

2018-04-01

The objective of this prospective one-year follow-up study was to explore the associations between self-regulatory mechanisms and neuropsychological tests as well as baseline and follow-up ratings of driver behaviour. The participants were a cohort of subjects with stroke and traumatic brain injury (TBI) who were found fit to drive after a multi-disciplinary driver assessment (baseline). Baseline measures included neuropsychological tests and ratings of self-regulatory mechanisms, i.e., executive functions (Behavior Rating Inventory of Executive Function-Adult Version; BRIEF-A) and impulsive personality traits (UPPS Impulsive Behavior Scale). The participants rated pre-injury driving behaviour on the Driver Behaviour Qestionnaire (DBQ) retrospectively at baseline and after one year of post-injury driving (follow-up). Better performance on neuropsychological tests was significantly associated with more post-injury DBQ Violations. The BRIEF-A main indexes were significantly associated with baseline and follow-up ratings of DBQ Mistakes and follow-up DBQ Inattention. UPPS (lack of) Perseverance was significantly associated with baseline DBQ Inattention, whereas UPPS Urgency was significantly associated with baseline DBQ Inexperience and post-injury DBQ Mistakes. There were no significant changes in DBQ ratings from baseline (pre-injury) to follow-up (post-injury). It was concluded that neuropsychological functioning and self-regulatory mechanisms are related to driver behaviour. Some aspects of driver behaviour do not necessarily change after brain injury, reflecting the influence of premorbid driving behaviour or impaired awareness of deficits on post-injury driving behaviour. Further evidence is required to predict the role of self-regulatory mechanisms on driver behaviour and crashes or near misses.

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 insight

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

Introduction of transplantation tolerance after total lymphoid irradiation: cellular mechanisms

International Nuclear Information System (INIS)

Strober, S.; King, D.P.; Gottlieb, M.; Hoppe, R.T.; Kaplan, H.S.

1981-01-01

High-dose fractionated total lymphoid irradiation (TLI) is a safe, routine regimen used to treat patients with lymphoid malignancies. Although few side effects are associated with the regimen, a profound suppression of cell-mediated immunity is observed for several years after therapy, as judged by both in vivo and in vitro assays. A profound immunosuppression has also been observed in mice and rats given TLI. Recently, we have achieved similar results using TLI in nonmatched bone marrow transplantation in outbred dogs. The experimental work in animals and underlying cellular mechanisms are reviewed here

Elucidating the molecular mechanisms underlying cellular response to biophysical cues using synthetic biology approaches

NARCIS (Netherlands)

Denning, Denise; Roos, Wouter H

2016-01-01

The use of synthetic surfaces and materials to influence and study cell behavior has vastly progressed our understanding of the underlying molecular mechanisms involved in cellular response to physicochemical and biophysical cues. Reconstituting cytoskeletal proteins and interfacing them with a

Electricity generation: regulatory mechanisms to incentive renewable alternative energy sources in Brazil

International Nuclear Information System (INIS)

Cavaliero, Carla Kazue Nakao; Silva, E.P. da

2005-01-01

The dissemination of renewable alternative energy sources for electricity generation has always being done through regulatory mechanisms, created and managed by the government of each country. Since these sources are more costly to generate, they have received incentives in response to worldwide environmental concerns, above all with regard to the reduction of CO 2 emissions. In Brazil, the electricity generation from renewable alternative sources is experiencing a new phase of growth. Until a short time ago, environmental appeal was the strongest incentive to these sources in Brazil but it was insufficient to attain its objective. With the electricity crisis and the rationing imposed in 2001, another important factor gained awareness: the need to diversify energy sources. Within this context, this work has the objective of analyzing the regulatory mechanisms recently developed to stimulate electricity generation from renewable alternative energy sources in Brazil by following the experience of other countries such as the United States, United Kingdom and Germany

Biomechanics of cellular solids.

Science.gov (United States)

Gibson, Lorna J

2005-03-01

Materials with a cellular structure are widespread in nature and include wood, cork, plant parenchyma and trabecular bone. Natural cellular materials are often mechanically efficient: the honeycomb-like microstructure of wood, for instance, gives it an exceptionally high performance index for resisting bending and buckling. Here we review the mechanics of a wide range of natural cellular materials and examine their role in lightweight natural sandwich structures (e.g. iris leaves) and natural tubular structures (e.g. plant stems or animal quills). We also describe two examples of engineered biomaterials with a cellular structure, designed to replace or regenerate tissue in the body.

Gene regulatory and signaling networks exhibit distinct topological distributions of motifs

Science.gov (United States)

Ferreira, Gustavo Rodrigues; Nakaya, Helder Imoto; Costa, Luciano da Fontoura

2018-04-01

The biological processes of cellular decision making and differentiation involve a plethora of signaling pathways and gene regulatory circuits. These networks in turn exhibit a multitude of motifs playing crucial parts in regulating network activity. Here we compare the topological placement of motifs in gene regulatory and signaling networks and observe that it suggests different evolutionary strategies in motif distribution for distinct cellular subnetworks.

Human equilibrative nucleoside transporter-1 knockdown tunes cellular mechanics through epithelial-mesenchymal transition in pancreatic cancer cells.

Directory of Open Access Journals (Sweden)

Yeonju Lee

Full Text Available We report cell mechanical changes in response to alteration of expression of the human equilibrative nucleoside transporter-1 (hENT1, a most abundant and widely distributed plasma membrane nucleoside transporter in human cells and/or tissues. Modulation of hENT1 expression level altered the stiffness of pancreatic cancer Capan-1 and Panc 03.27 cells, which was analyzed by atomic force microscopy (AFM and correlated to microfluidic platform. The hENT1 knockdown induced reduction of cellular stiffness in both of cells up to 70%. In addition, cellular phenotypic changes such as cell morphology, migration, and expression level of epithelial-mesenchymal transition (EMT markers were observed after hENT1 knockdown. Cells with suppressed hENT1 became elongated, migrated faster, and had reduced E-cadherin and elevated N-cadherin compared to parental cells which are consistent with epithelial-mesenchymal transition (EMT. Those cellular phenotypic changes closely correlated with changes in cellular stiffness. This study suggests that hENT1 expression level affects cellular phenotype and cell elastic behavior can be a physical biomarker for quantify hENT1 expression and detect phenotypic shift. Furthermore, cell mechanics can be a critical tool in detecting disease progression and response to therapy.

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases.

Science.gov (United States)

Kubben, Nard; Misteli, Tom

2017-10-01

Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular mechanisms that underpin physiological ageing. Their study also leads to a better understanding of the causes, drivers and potential therapeutic strategies of common diseases associated with ageing, including neurological disorders, diabetes, cardiovascular diseases and cancer. Using the rare premature ageing disorder Hutchinson-Gilford progeria syndrome as a paradigm, we discuss here the shared mechanisms between premature ageing and ageing-associated diseases, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity.

p38β, A Novel Regulatory Target of Pokemon in Hepatic Cells

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Ying Tan

2013-06-01

Full Text Available Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells.

p38β, A novel regulatory target of Pokemon in hepatic cells.

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Chen, Zhe; Liu, Feng; Zhang, Nannan; Cao, Deliang; Liu, Min; Tan, Ying; Jiang, Yuyang

2013-06-27

Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells.

High-risk medical devices, children and the FDA: regulatory challenges facing pediatric mechanical circulatory support devices.

Science.gov (United States)

Almond, Christopher S D; Chen, Eric A; Berman, Michael R; Less, Joanne R; Baldwin, J Timothy; Linde-Feucht, Sarah R; Hoke, Tracey R; Pearson, Gail D; Jenkins, Kathy; Duncan, Brian W; Zuckerman, Bram D

2007-01-01

Pediatric mechanical circulatory support is a critical unmet need in the United States. Infant- and child-sized ventricular assist devices are currently being developed largely through federal contracts and grants through the National Heart, Lung, and Blood Institute (NHLBI). Human testing and marketing of high-risk devices for children raises epidemiologic and regulatory issues that will need to be addressed. Leaders from the US Food and Drug Administration (FDA), NHLBI, academic pediatric community, and industry convened in January 2006 for the first FDA Workshop on the Regulatory Process for Pediatric Mechanical Circulatory Support Devices. The purpose was to provide the pediatric community with an overview of the federal regulatory process for high-risk medical devices and to review the challenges specific to the development and regulation of pediatric mechanical circulatory support devices. Pediatric mechanical circulatory support present significant epidemiologic, logistic, and financial challenges to industry, federal regulators, and the pediatric community. Early interactions with the FDA, shared appreciation of challenges, and careful planning will be critical to avoid unnecessary delays in making potentially life-saving devices available for children. Collaborative efforts to address these challenges are warranted.

CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms

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Deepak A. Deshpande

2018-01-01

Full Text Available Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle function and in the development of airway hyperresponsiveness. Inflammatory cytokines alter calcium (Ca2+ signaling and contractility of airway smooth muscle, which results in nonspecific airway hyperresponsiveness to agonists. In this context, Ca2+ regulatory mechanisms in airway smooth muscle and changes in these regulatory mechanisms encompass a major component of airway hyperresponsiveness. Although dynamic Ca2+ regulation is complex, phospholipase C/inositol tris-phosphate (PLC/IP3 and CD38-cyclic ADP-ribose (CD38/cADPR are two major pathways mediating agonist-induced Ca2+ regulation in airway smooth muscle. Altered CD38 expression or enhanced cyclic ADP-ribosyl cyclase activity associated with CD38 contributes to human pathologies such as asthma, neoplasia, and neuroimmune diseases. This review is focused on investigations on the role of CD38-cyclic ADP-ribose signaling in airway smooth muscle in the context of transcriptional and posttranscriptional regulation of CD38 expression. The specific roles of transcription factors NF-kB and AP-1 in the transcriptional regulation of CD38 expression and of miRNAs miR-140-3p and miR-708 in the posttranscriptional regulation and the underlying mechanisms of such regulation are discussed.

CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms

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Deshpande, Deepak A.; Guedes, Alonso G. P.; Graeff, Richard; Dogan, Soner; Subramanian, Subbaya; Walseth, Timothy F.

2018-01-01

Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle function and in the development of airway hyperresponsiveness. Inflammatory cytokines alter calcium (Ca2+) signaling and contractility of airway smooth muscle, which results in nonspecific airway hyperresponsiveness to agonists. In this context, Ca2+ regulatory mechanisms in airway smooth muscle and changes in these regulatory mechanisms encompass a major component of airway hyperresponsiveness. Although dynamic Ca2+ regulation is complex, phospholipase C/inositol tris-phosphate (PLC/IP3) and CD38-cyclic ADP-ribose (CD38/cADPR) are two major pathways mediating agonist-induced Ca2+ regulation in airway smooth muscle. Altered CD38 expression or enhanced cyclic ADP-ribosyl cyclase activity associated with CD38 contributes to human pathologies such as asthma, neoplasia, and neuroimmune diseases. This review is focused on investigations on the role of CD38-cyclic ADP-ribose signaling in airway smooth muscle in the context of transcriptional and posttranscriptional regulation of CD38 expression. The specific roles of transcription factors NF-kB and AP-1 in the transcriptional regulation of CD38 expression and of miRNAs miR-140-3p and miR-708 in the posttranscriptional regulation and the underlying mechanisms of such regulation are discussed. PMID:29576747

Neural and Cellular Mechanisms of Fear and Extinction Memory Formation

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Orsini, Caitlin A.; Maren, Stephen

2012-01-01

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 thirty 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

Regulatory mechanism of the flavoprotein Tah18-dependent nitric oxide synthesis and cell death in yeast.

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Yoshikawa, Yuki; Nasuno, Ryo; Kawahara, Nobuhiro; Nishimura, Akira; Watanabe, Daisuke; Takagi, Hiroshi

2016-07-01

Nitric oxide (NO) is a ubiquitous signaling molecule involved in the regulation of a large number of cellular functions. The regulatory mechanism of NO generation in unicellular eukaryotic yeast cells is poorly understood due to the lack of mammalian and bacterial NO synthase (NOS) orthologues, even though yeast produces NO under oxidative stress conditions. Recently, we reported that the flavoprotein Tah18, which was previously shown to transfer electrons to the iron-sulfur cluster protein Dre2, is involved in NOS-like activity in the yeast Saccharomyces cerevisiae. On the other hand, Tah18 was reported to promote apoptotic cell death after exposure to hydrogen peroxide (H2O2). Here, we showed that NOS-like activity requiring Tah18 induced cell death upon treatment with H2O2. Our experimental results also indicate that Tah18-dependent NO production and cell death are suppressed by enhancement of the interaction between Tah18 and its molecular partner Dre2. Our findings indicate that the Tah18-Dre2 complex regulates cell death as a molecular switch via Tah18-dependent NOS-like activity in response to environmental changes. Copyright © 2016 Elsevier Inc. All rights reserved.

Mammalian iron metabolism and its control by iron regulatory proteins☆

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Anderson, Cole P.; Shen, Lacy; Eisenstein, Richard S.; Leibold, Elizabeth A.

2013-01-01

Cellular iron homeostasis is maintained by iron regulatory proteins 1 and 2 (IRP1 and IRP2). IRPs bind to iron-responsive elements (IREs) located in the untranslated regions of mRNAs encoding protein involved in iron uptake, storage, utilization and export. Over the past decade, significant progress has been made in understanding how IRPs are regulated by iron-dependent and iron-independent mechanisms and the pathological consequences of IRP2 deficiency in mice. The identification of novel IREs involved in diverse cellular pathways has revealed that the IRP–IRE network extends to processes other than iron homeostasis. A mechanistic understanding of IRP regulation will likely yield important insights into the basis of disorders of iron metabolism. This article is part of a Special Issue entitled: Cell Biology of Metals. PMID:22610083

Regulatory components of carbon concentrating mechanisms in aquatic unicellular photosynthetic organisms.

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Tomar, Vandana; Sidhu, Gurpreet Kaur; Nogia, Panchsheela; Mehrotra, Rajesh; Mehrotra, Sandhya

2017-11-01

This review provides an insight into the regulation of the carbon concentrating mechanisms (CCMs) in lower organisms like cyanobacteria, proteobacteria, and algae. CCMs evolved as a mechanism to concentrate CO 2 at the site of primary carboxylating enzyme Ribulose-1, 5-bisphosphate carboxylase oxygenase (Rubisco), so that the enzyme could overcome its affinity towards O 2 which leads to wasteful processes like photorespiration. A diverse set of CCMs exist in nature, i.e., carboxysomes in cyanobacteria and proteobacteria; pyrenoids in algae and diatoms, the C 4 system, and Crassulacean acid metabolism in higher plants. Prime regulators of CCM in most of the photosynthetic autotrophs belong to the LysR family of transcriptional regulators, which regulate the activity of the components of CCM depending upon the ambient CO 2 concentrations. Major targets of these regulators are carbonic anhydrase and inorganic carbon uptake systems (CO 2 and HCO 3 - transporters) whose activities are modulated either at transcriptional level or by changes in the levels of their co-regulatory metabolites. The article provides information on the localization of the CCM components as well as their function and participation in the development of an efficient CCM. Signal transduction cascades leading to activation/inactivation of inducible CCM components on perception of low/high CO 2 stimuli have also been brought into picture. A detailed study of the regulatory components can aid in identifying the unraveled aspects of these mechanisms and hence provide information on key molecules that need to be explored to further provide a clear understanding of the mechanism under study.

Rapid construction of mechanically- confined multi- cellular structures using dendrimeric intercellular linker.

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Mo, Xuejun; Li, Qiushi; Yi Lui, Lena Wai; Zheng, Baixue; Kang, Chiang Huen; Nugraha, Bramasta; Yue, Zhilian; Jia, Rui Rui; Fu, Hong Xia; Choudhury, Deepak; Arooz, Talha; Yan, Jie; Lim, Chwee Teck; Shen, Shali; Hong Tan, Choon; Yu, Hanry

2010-10-01

Tissue constructs that mimic the in vivo cell-cell and cell-matrix interactions are especially useful for applications involving the cell- dense and matrix- poor internal organs. Rapid and precise arrangement of cells into functional tissue constructs remains a challenge in tissue engineering. We demonstrate rapid assembly of C3A cells into multi- cell structures using a dendrimeric intercellular linker. The linker is composed of oleyl- polyethylene glycol (PEG) derivatives conjugated to a 16 arms- polypropylenimine hexadecaamine (DAB) dendrimer. The positively charged multivalent dendrimer concentrates the linker onto the negatively charged cell surface to facilitate efficient insertion of the hydrophobic oleyl groups into the cellular membrane. Bringing linker- treated cells into close proximity to each other via mechanical means such as centrifugation and micromanipulation enables their rapid assembly into multi- cellular structures within minutes. The cells exhibit high levels of viability, proliferation, three- dimensional (3D) cell morphology and other functions in the constructs. We constructed defined multi- cellular structures such as rings, sheets or branching rods that can serve as potential tissue building blocks to be further assembled into complex 3D tissue constructs for biomedical applications. 2010 Elsevier Ltd. All rights reserved.

[Neuronal and hormonal regulatory mechanisms of tears production and secretion].

Science.gov (United States)

Mrugacz, Małgorzata; Zywalewska, Nella; Bakunowicz-Lazarczyk, Alina

2005-01-01

The ocular surface, tear film, lacrimal glands act as a functional unit to preserve the quality of the refractive surface of the eye, and to resist injury and protect the eye against bodily and environmental conditions. Homeostasis of this functional unit involves neuronal and hormonal regulatory mechanisms. The eye appears to be a target organ for sex hormones particulary the androgen, as they modulate the immune system and trophic functions of the lacrimal and Meibomian glands.

Regulatory mechanism of endothelin receptor B in the cerebral arteries after focal cerebral ischemia

DEFF Research Database (Denmark)

Grell, Anne-Sofie; Thigarajah, Rushani; Edvinsson, Lars

2014-01-01

BACKGROUND AND PURPOSE: Increased expression of endothelin receptor type B (ETBR), a vasoactive receptor, has recently been implied in the reduced cerebral blood flow and exacerbated neuronal damage after ischemia-reperfusion (I/R). The study explores the regulatory mechanisms of ETBR to identify...... drug targets to restore normal cerebral artery contractile function as part of successful neuroprotective therapy. METHODS: We have employed in vitro methods on human and rat cerebral arteries to study the regulatory mechanisms and the efficacy of target selective inhibitor, Mithramycin A (Mit...... the ETBR mRNA and protein levels. It also significantly reduced the ETBR mediated cerebrovascular contractility. Detailed analysis indicated that ERK1/2 mediated phosphorylation of Sp1 might be essential for ETBR transcription. CONCLUSION: Transcription factor Sp1 regulates the ETBR mediated...

Cellular Therapies Clinical Research Roadmap: lessons learned on how to move a cellular therapy into a clinical trial.

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Ouseph, Stacy; Tappitake, Darah; Armant, Myriam; Wesselschmidt, Robin; Derecho, Ivy; Draxler, Rebecca; Wood, Deborah; Centanni, John M

2015-04-01

A clinical research roadmap has been developed as a resource for researchers to identify critical areas and potential pitfalls when transitioning a cellular therapy product from the research laboratory, by means of an Investigational New Drug (IND) application, into early-phase clinical trials. The roadmap describes four key areas: basic and preclinical research, resource development, translational research and Good Manufacturing Practice (GMP) and IND assembly and submission. Basic and preclinical research identifies a new therapeutic concept and demonstrates its potential value with the use of a model of the relevant disease. During resource development, the appropriate specialists and the required expertise to bring this product into the clinic are identified (eg, researchers, regulatory specialists, GMP manufacturing staff, clinicians and clinical trials staff, etc). Additionally, the funds required to achieve this goal (or a plan to procure them) are identified. In the next phase, the plan to translate the research product into a clinical-grade therapeutic is developed. Finally regulatory approval to start the trial must be obtained. In the United States, this is done by filing an IND application with the Food and Drug Administration. The National Heart, Lung and Blood Institute-funded Production Assistance for Cellular Therapies program has facilitated the transition of a variety of cellular therapy products from the laboratory into Phase1/2 trials. The five Production Assistance for Cellular Therapies facilities have assisted investigators by performing translational studies and GMP manufacturing to ensure that cellular products met release specifications and were manufactured safely, reproducibly and at the appropriate scale. The roadmap resulting from this experience is the focus of this article. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Oxidative Damage and Cellular Defense Mechanisms in Sea Urchin Models of Aging

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Du, Colin; Anderson, Arielle; Lortie, Mae; Parsons, Rachel; Bodnar, Andrea

2013-01-01

The free radical or oxidative stress theory of aging proposes that the accumulation of oxidative cellular damage is a major contributor to the aging process and a key determinant of species longevity. This study investigates the oxidative stress theory in a novel model for aging research, the sea urchin. Sea urchins present a unique model for the study of aging due to the existence of species with tremendously different natural life spans including some species with extraordinary longevity and negligible senescence. Cellular oxidative damage, antioxidant capacity and proteasome enzyme activities were measured in the tissues of three sea urchin species: short-lived Lytechinus variegatus, long-lived Strongylocentrotus franciscanus and Strongylocentrotus purpuratus which has an intermediate lifespan. Levels of protein carbonyls and 4-hydroxynonenal (HNE) measured in tissues (muscle, nerve, esophagus, gonad, coelomocytes, ampullae) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) measured in cell-free coelomic fluid showed no general increase with age. The fluorescent age-pigment lipofuscin measured in muscle, nerve and esophagus, increased with age however it appeared to be predominantly extracellular. Antioxidant mechanisms (total antioxidant capacity, superoxide dismutase) and proteasome enzyme activities were maintained with age. In some instances, levels of oxidative damage were lower and antioxidant activity higher in cells or tissues of the long-lived species compared to the short-lived species, however further studies are required to determine the relationship between oxidative damage and longevity in these animals. Consistent with the predictions of the oxidative stress theory of aging, the results suggest that negligible senescence is accompanied by a lack of accumulation of cellular oxidative damage with age and maintenance of antioxidant capacity and proteasome enzyme activities may be important mechanisms to mitigate damage. PMID:23707327

Network analysis of transcriptomics expands regulatory landscapes in Synechococcus sp. PCC 7002

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McClure, Ryan S.; Overall, Christopher C.; McDermott, Jason E.; Hill, Eric A.; Markillie, Lye Meng; McCue, Lee Ann; Taylor, Ronald C.; Ludwig, Marcus; Bryant, Donald A.; Beliaev, Alexander S.

2016-08-27

Cyanobacterial regulation of gene expression must contend with a genome organization that lacks apparent functional context, as the majority of cellular processes and metabolic pathways are encoded by genes found at disparate locations across the genome. In addition, the fact that coordinated regulation of cyanobacterial cellular machinery takes place with significantly fewer transcription factors, compared to other Eubacteria, suggests the involvement of post-transcriptional mechanisms and regulatory adaptations which are not fully understood. Global transcript abundance from model cyanobacterium Synechococcus sp. PCC 7002 grown under 42 different conditions was analyzed using context-likelihood of relatedness. The resulting 903-gene network, which was organized into 11 modules, not only allowed classification of cyanobacterial responses to specific environmental variables but provided insight into the transcriptional network topology and led to the expansion of predicted regulons. When used in conjunction with genome sequence, the global transcript abundance allowed identification of putative post-transcriptional changes in expression as well as novel potential targets of both DNA binding proteins and asRNA regulators. The results offer a new perspective into the multi-level regulation that governs cellular adaptations of fast-growing physiologically robust cyanobacterium Synechococcus sp. PCC 7002 to changing environmental variables. It also extends a methodological knowledge-based framework for studying multi-scale regulatory mechanisms that operate in cyanobacteria. Finally, it provides valuable context for integrating systems-level data to enhance evidence-driven genomic annotation, especially in organisms where traditional context analyses cannot be implemented due to lack of operon-based functional organization.

Cellular Reparative Mechanisms of Mesenchymal Stem Cells for Retinal Diseases.

Science.gov (United States)

Ding, Suet Lee Shirley; Kumar, Suresh; Mok, Pooi Ling

2017-07-28

The use of multipotent mesenchymal stem cells (MSCs) has been reported as promising for the treatment of numerous degenerative disorders including the eye. In retinal degenerative diseases, MSCs exhibit the potential to regenerate into retinal neurons and retinal pigmented epithelial cells in both in vitro and in vivo studies. Delivery of MSCs was found to improve retinal morphology and function and delay retinal degeneration. In this review, we revisit the therapeutic role of MSCs in the diseased eye. Furthermore, we reveal the possible cellular mechanisms and identify the associated signaling pathways of MSCs in reversing the pathological conditions of various ocular disorders such as age-related macular degeneration (AMD), retinitis pigmentosa, diabetic retinopathy, and glaucoma. Current stem cell treatment can be dispensed as an independent cell treatment format or with the combination of other approaches. Hence, the improvement of the treatment strategy is largely subjected by our understanding of MSCs mechanism of action.

Intramolecular dynamics within the N-Cap-SH3-SH2 regulatory unit of the c-Abl tyrosine kinase reveal targeting to the cellular membrane.

Science.gov (United States)

de Oliveira, Guilherme A P; Pereira, Elen G; Ferretti, Giulia D S; Valente, Ana Paula; Cordeiro, Yraima; Silva, Jerson L

2013-09-27

c-Abl is a key regulator of cell signaling and is under strict control via intramolecular interactions. In this study, we address changes in the intramolecular dynamics coupling within the c-Abl regulatory unit by presenting its N-terminal segment (N-Cap) with an alternative function in the cell as c-Abl becomes activated. Using small angle x-ray scattering, nuclear magnetic resonance, and confocal microscopy, we demonstrate that the N-Cap and the Src homology (SH) 3 domain acquire μs-ms motions upon N-Cap association with the SH2-L domain, revealing a stabilizing synergy between these segments. The N-Cap-myristoyl tether likely triggers the protein to anchor to the membrane because of these flip-flop dynamics, which occur in the μs-ms time range. This segment not only presents the myristate during c-Abl inhibition but may also trigger protein localization inside the cell in a functional and stability-dependent mechanism that is lost in Bcr-Abl(+) cells, which underlie chronic myeloid leukemia. This loss of intramolecular dynamics and binding to the cellular membrane is a potential therapeutic target.

Mitochondrial and cellular mechanisms for managing lipid excess

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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.

AKAP18:PKA-RIIα structure reveals crucial anchor points for recognition of regulatory subunits of PKA.

Science.gov (United States)

Götz, Frank; Roske, Yvette; Schulz, Maike Svenja; Autenrieth, Karolin; Bertinetti, Daniela; Faelber, Katja; Zühlke, Kerstin; Kreuchwig, Annika; Kennedy, Eileen J; Krause, Gerd; Daumke, Oliver; Herberg, Friedrich W; Heinemann, Udo; Klussmann, Enno

2016-07-01

A-kinase anchoring proteins (AKAPs) interact with the dimerization/docking (D/D) domains of regulatory subunits of the ubiquitous protein kinase A (PKA). AKAPs tether PKA to defined cellular compartments establishing distinct pools to increase the specificity of PKA signalling. Here, we elucidated the structure of an extended PKA-binding domain of AKAP18β bound to the D/D domain of the regulatory RIIα subunits of PKA. We identified three hydrophilic anchor points in AKAP18β outside the core PKA-binding domain, which mediate contacts with the D/D domain. Such anchor points are conserved within AKAPs that bind regulatory RII subunits of PKA. We derived a different set of anchor points in AKAPs binding regulatory RI subunits of PKA. In vitro and cell-based experiments confirm the relevance of these sites for the interaction of RII subunits with AKAP18 and of RI subunits with the RI-specific smAKAP. Thus we report a novel mechanism governing interactions of AKAPs with PKA. The sequence specificity of each AKAP around the anchor points and the requirement of these points for the tight binding of PKA allow the development of selective inhibitors to unequivocally ascribe cellular functions to the AKAP18-PKA and other AKAP-PKA interactions. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Characterizing cellular mechanical phenotypes with mechano-node-pore sensing

Science.gov (United States)

Kim, Junghyun; Han, Sewoon; Lei, Andy; Miyano, Masaru; Bloom, Jessica; Srivastava, Vasudha; Stampfer, Martha M.; Gartner, Zev J.; LaBarge, Mark A.; Sohn, Lydia L.

2018-01-01

The mechanical properties of cells change with their differentiation, chronological age, and malignant progression. Consequently, these properties may be useful label-free biomarkers of various functional or clinically relevant cell states. Here, we demonstrate mechano-node-pore sensing (mechano-NPS), a multi-parametric single-cell-analysis method that utilizes a four-terminal measurement of the current across a microfluidic channel to quantify simultaneously cell diameter, resistance to compressive deformation, transverse deformation under constant strain, and recovery time after deformation. We define a new parameter, the whole-cell deformability index (wCDI), which provides a quantitative mechanical metric of the resistance to compressive deformation that can be used to discriminate among different cell types. The wCDI and the transverse deformation under constant strain show malignant MCF-7 and A549 cell lines are mechanically distinct from non-malignant, MCF-10A and BEAS-2B cell lines, and distinguishes between cells treated or untreated with cytoskeleton-perturbing small molecules. We categorize cell recovery time, ΔTr, as instantaneous (ΔTr ~ 0 ms), transient (ΔTr ≤ 40ms), or prolonged (ΔTr > 40ms), and show that the composition of recovery types, which is a consequence of changes in cytoskeletal organization, correlates with cellular transformation. Through the wCDI and cell-recovery time, mechano-NPS discriminates between sub-lineages of normal primary human mammary epithelial cells with accuracy comparable to flow cytometry, but without antibody labeling. Mechano-NPS identifies mechanical phenotypes that distinguishes lineage, chronological age, and stage of malignant progression in human epithelial cells. PMID:29780657

Regulatory mechanisms for absenteeism in the health sector: a systematic review of strategies and their implementation

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Kisakye AN

2016-11-01

Full Text Available Angela N Kisakye,1 Raymond Tweheyo,1 Freddie Ssengooba,1 George W Pariyo,2 Elizeus Rutebemberwa,1 Suzanne N Kiwanuka1 1Department of Health Policy Planning and Management, Makerere University School of Public Health, Kampala, Uganda; 2Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Background: A systematic review was undertaken to identify regulatory mechanisms aimed at mitigating health care worker absenteeism, to describe where and how they have been implemented as well as their possible effects. The goal was to propose potential policy options for managing the problem of absenteeism among human resources for health in low- and middle-income countries. Mechanisms described in this review are at the local workplace and broader national policy level. Methods: A comprehensive online search was conducted on EMBASE, CINAHL, PubMed, Google Scholar, Google, and Social Science Citation Index using MEDLINE search terms. Retrieved studies were uploaded onto reference manager and screened by two independent reviewers. Only publications in English were included. Data were extracted and synthesized according to the objectives of the review. Results: Twenty six of the 4,975 published articles retrieved were included. All were from high-income countries and covered all cadres of health workers. The regulatory mechanisms and possible effects include 1 organizational-level mechanisms being reported as effective in curbing absenteeism in low- and middle-income countries (LMICs; 2 prohibition of private sector activities in LMICs offering benefits but presenting a challenge for the government to monitor the health workforce; 3 contractual changes from temporary to fixed posts having been associated with no reduction in absenteeism and not being appropriate for LMICs; 4 multifaceted work interventions being implemented in most settings; 5 the possibility of using financial and incentive regulatory mechanisms

Glutathione in Cellular Redox Homeostasis: Association with the Excitatory Amino Acid Carrier 1 (EAAC1

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Koji Aoyama

2015-05-01

Full Text Available Reactive oxygen species (ROS are by-products of the cellular metabolism of oxygen consumption, produced mainly in the mitochondria. ROS are known to be highly reactive ions or free radicals containing oxygen that impair redox homeostasis and cellular functions, leading to cell death. Under physiological conditions, a variety of antioxidant systems scavenge ROS to maintain the intracellular redox homeostasis and normal cellular functions. This review focuses on the antioxidant system’s roles in maintaining redox homeostasis. Especially, glutathione (GSH is the most important thiol-containing molecule, as it functions as a redox buffer, antioxidant, and enzyme cofactor against oxidative stress. In the brain, dysfunction of GSH synthesis leading to GSH depletion exacerbates oxidative stress, which is linked to a pathogenesis of aging-related neurodegenerative diseases. Excitatory amino acid carrier 1 (EAAC1 plays a pivotal role in neuronal GSH synthesis. The regulatory mechanism of EAAC1 is also discussed.

Inferring nonlinear gene regulatory networks from gene expression data based on distance correlation.

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Xiaobo Guo

Full Text Available Nonlinear dependence is general in regulation mechanism of gene regulatory networks (GRNs. It is vital to properly measure or test nonlinear dependence from real data for reconstructing GRNs and understanding the complex regulatory mechanisms within the cellular system. A recently developed measurement called the distance correlation (DC has been shown powerful and computationally effective in nonlinear dependence for many situations. In this work, we incorporate the DC into inferring GRNs from the gene expression data without any underling distribution assumptions. We propose three DC-based GRNs inference algorithms: CLR-DC, MRNET-DC and REL-DC, and then compare them with the mutual information (MI-based algorithms by analyzing two simulated data: benchmark GRNs from the DREAM challenge and GRNs generated by SynTReN network generator, and an experimentally determined SOS DNA repair network in Escherichia coli. According to both the receiver operator characteristic (ROC curve and the precision-recall (PR curve, our proposed algorithms significantly outperform the MI-based algorithms in GRNs inference.

Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases

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Irina V. Kholodenko

2017-01-01

Full Text Available The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable.

Differential Polymer Structure Tunes Mechanism of Cellular Uptake and Transfection Routes of Poly(β-amino ester) Polyplexes in Human Breast Cancer Cells

OpenAIRE

Kim, Jayoung; Sunshine, Joel C.; Green, Jordan J.

2013-01-01

Successful gene delivery with non-viral particles has several barriers, including cellular uptake, endosomal escape, and nuclear transport. Understanding the mechanisms behind these steps is critical to enhancing the effectiveness of gene delivery. Polyplexes formed with poly(β-amino ester)s (PBAEs) have been shown to effectively transfer DNA to various cell types, but the mechanism of their cellular uptake has not been identified. This is the first study to evaluate the uptake mechanism of P...

Mutual information and the fidelity of response of gene regulatory models

International Nuclear Information System (INIS)

Tabbaa, Omar P; Jayaprakash, C

2014-01-01

We investigate cellular response to extracellular signals by using information theory techniques motivated by recent experiments. We present results for the steady state of the following gene regulatory models found in both prokaryotic and eukaryotic cells: a linear transcription-translation model and a positive or negative auto-regulatory model. We calculate both the information capacity and the mutual information exactly for simple models and approximately for the full model. We find that (1) small changes in mutual information can lead to potentially important changes in cellular response and (2) there are diminishing returns in the fidelity of response as the mutual information increases. We calculate the information capacity using Gillespie simulations of a model for the TNF-α-NF-κ B network and find good agreement with the measured value for an experimental realization of this network. Our results provide a quantitative understanding of the differences in cellular response when comparing experimentally measured mutual information values of different gene regulatory models. Our calculations demonstrate that Gillespie simulations can be used to compute the mutual information of more complex gene regulatory models, providing a potentially useful tool in synthetic biology. (paper)

Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins.

Science.gov (United States)

Flavin, William P; Bousset, Luc; Green, Zachary C; Chu, Yaping; Skarpathiotis, Stratos; Chaney, Michael J; Kordower, Jeffrey H; Melki, Ronald; Campbell, Edward M

2017-10-01

Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.

Regulatory Design of Capacity Remuneration Mechanisms in Regional and Low-Carbon Electric Power Markets

NARCIS (Netherlands)

Mastropietro, P.

2016-01-01

Capacity remuneration mechanisms (CRMs) are “climbing” regulatory agendas in all liberalised power sectors, especially in the European Union. CRMs are introduced to improve system reliability and to minimise power shortages to an economically efficient extent. These schemes will have a central role

RNA-Binding Proteins in Trichomonas vaginalis: Atypical Multifunctional Proteins Involved in a Posttranscriptional Iron Regulatory Mechanism

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Figueroa-Angulo, Elisa E.; Calla-Choque, Jaeson S.; Mancilla-Olea, Maria Inocente; Arroyo, Rossana

2015-01-01

Iron homeostasis is highly regulated in vertebrates through a regulatory system mediated by RNA-protein interactions between the iron regulatory proteins (IRPs) that interact with an iron responsive element (IRE) located in certain mRNAs, dubbed the IRE-IRP regulatory system. Trichomonas vaginalis, the causal agent of trichomoniasis, presents high iron dependency to regulate its growth, metabolism, and virulence properties. Although T. vaginalis lacks IRPs or proteins with aconitase activity, possesses gene expression mechanisms of iron regulation at the transcriptional and posttranscriptional levels. However, only one gene with iron regulation at the transcriptional level has been described. Recently, our research group described an iron posttranscriptional regulatory mechanism in the T. vaginalis tvcp4 and tvcp12 cysteine proteinase mRNAs. The tvcp4 and tvcp12 mRNAs have a stem-loop structure in the 5'-coding region or in the 3'-UTR, respectively that interacts with T. vaginalis multifunctional proteins HSP70, α-Actinin, and Actin under iron starvation condition, causing translation inhibition or mRNA stabilization similar to the previously characterized IRE-IRP system in eukaryotes. Herein, we summarize recent progress and shed some light on atypical RNA-binding proteins that may participate in the iron posttranscriptional regulation in T. vaginalis. PMID:26703754

Bridging time scales in cellular decision making with a stochastic bistable switch

Directory of Open Access Journals (Sweden)

Waldherr Steffen

2010-08-01

Full Text Available Abstract Background Cellular transformations which involve a significant phenotypical change of the cell's state use bistable biochemical switches as underlying decision systems. Some of these transformations act over a very long time scale on the cell population level, up to the entire lifespan of the organism. Results In this work, we aim at linking cellular decisions taking place on a time scale of years to decades with the biochemical dynamics in signal transduction and gene regulation, occuring on a time scale of minutes to hours. We show that a stochastic bistable switch forms a viable biochemical mechanism to implement decision processes on long time scales. As a case study, the mechanism is applied to model the initiation of follicle growth in mammalian ovaries, where the physiological time scale of follicle pool depletion is on the order of the organism's lifespan. We construct a simple mathematical model for this process based on experimental evidence for the involved genetic mechanisms. Conclusions Despite the underlying stochasticity, the proposed mechanism turns out to yield reliable behavior in large populations of cells subject to the considered decision process. Our model explains how the physiological time constant may emerge from the intrinsic stochasticity of the underlying gene regulatory network. Apart from ovarian follicles, the proposed mechanism may also be of relevance for other physiological systems where cells take binary decisions over a long time scale.

Regulatory requirements to the thermal-hydraulic and thermal-mechanical computer codes

International Nuclear Information System (INIS)

Vitkova, M.; Kalchev, B.; Stefanova, S.

2006-01-01

The paper presents an overview of the regulatory requirements to the thermal-hydraulic and thermal-mechanical computer codes, which are used for safety assessment of the fuel design and the fuel utilization. Some requirements to the model development, verification and validation of the codes and analysis of code uncertainties are also define. Questions concerning Quality Assurance during development and implementation of the codes as well as preparation of a detailed verification and validation plan are briefly discussed

Daratumumab depletes CD38sup>+> immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma

DEFF Research Database (Denmark)

Krejcik, Jakub; Casneuf, Tineke; Nijhof, Inger S

2016-01-01

target non-plasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from two daratumumab monotherapy studies were analyzed before and during therapy......Daratumumab targets CD38-expressing myeloma cells through a variety of immune-mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with cross-linking. These mechanisms may also...... and at relapse. Regulatory B cells (Bregs) and myeloid-derived suppressor cells (MDSCs), previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified...

Timing Embryo Segmentation: Dynamics and Regulatory Mechanisms of the Vertebrate Segmentation Clock

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Resende, Tatiana P.; Andrade, Raquel P.; Palmeirim, Isabel

2014-01-01

All vertebrate species present a segmented body, easily observed in the vertebrate column and its associated components, which provides a high degree of motility to the adult body and efficient protection of the internal organs. The sequential formation of the segmented precursors of the vertebral column during embryonic development, the somites, is governed by an oscillating genetic network, the somitogenesis molecular clock. Herein, we provide an overview of the molecular clock operating during somite formation and its underlying molecular regulatory mechanisms. Human congenital vertebral malformations have been associated with perturbations in these oscillatory mechanisms. Thus, a better comprehension of the molecular mechanisms regulating somite formation is required in order to fully understand the origin of human skeletal malformations. PMID:24895605

Cellular and Molecular Pathways Leading to External Root Resorption

Science.gov (United States)

Iglesias-Linares, A.; Hartsfield, J.K.

2016-01-01

External apical root resorption during orthodontic treatment implicates specific molecular pathways that orchestrate nonphysiologic cellular activation. To date, a substantial number of in vitro and in vivo molecular, genomic, and proteomic studies have supplied data that provide new insights into root resorption. Recent mechanisms and developments reviewed here include the role of the cellular component—specifically, the balance of CD68+, iNOS+ M1- and CD68+, CD163+ M2-like macrophages associated with root resorption and root surface repair processes linked to the expression of the M1-associated proinflammatory cytokine tumor necrosis factor, inducible nitric oxide synthase, the M1 activator interferon γ, the M2 activator interleukin 4, and M2-associated anti-inflammatory interleukin 10 and arginase I. Insights into the role of mesenchymal dental pulp cells in attenuating dentin resorption in homeostasis are also reviewed. Data on recently deciphered molecular pathways are reviewed at the level of (1) clastic cell adhesion in the external apical root resorption process and the specific role of α/β integrins, osteopontin, and related extracellular matrix proteins; (2) clastic cell fusion and activation by the RANKL/RANK/OPG and ATP-P2RX7-IL1 pathways; and (3) regulatory mechanisms of root resorption repair by cementum at the proteomic and transcriptomic levels. PMID:27811065

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

Energy Technology Data Exchange (ETDEWEB)

Holland, Jason P; Bell, Stephen G; Wong, Luet-Lok; Dilworth, Jonathan R [Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA (United Kingdom); Giansiracusa, Jeffrey H [Department of Mathematics, Mathematical Institute, University of Oxford, 24-29 St Giles' , Oxford, OX1 3LB (United Kingdom)], E-mail: hollanj3@mskcc.org, E-mail: jasonpholland@gmail.com

2009-04-07

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 [{sup 60/62/64}Cu(II)ATSM] and [{sup 60/62/64}Cu(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 pO{sub 2}-dependent in vitro cellular uptake and retention of [{sup 64}Cu(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 (k{sub 1} = 9.8 {+-} 0.59 x 10{sup -4} s{sup -1} and k{sub 2} = 2.9 {+-} 0.17 x 10{sup -3} s{sup -1}), intracellular reduction (k{sub 3} = 5.2 {+-} 0.31 x 10{sup -2} s{sup -1}), reoxidation (k{sub 4} = 2.2 {+-} 0.13 mol{sup -1} dm{sup 3} s{sup -1}) and proton-mediated ligand dissociation (k{sub 5} = 9.0 {+-} 0.54 x 10{sup -5} s{sup -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

Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms.

Science.gov (United States)

Stenmark, Kurt R; Fagan, Karen A; Frid, Maria G

2006-09-29

Chronic hypoxic exposure induces changes in the structure of pulmonary arteries, as well as in the biochemical and functional phenotypes of each of the vascular cell types, from the hilum of the lung to the most peripheral vessels in the alveolar wall. The magnitude and the specific profile of the changes depend on the species, sex, and the developmental stage at which the exposure to hypoxia occurred. Further, hypoxia-induced changes are site specific, such that the remodeling process in the large vessels differs from that in the smallest vessels. The cellular and molecular mechanisms vary and depend on the cellular composition of vessels at particular sites along the longitudinal axis of the pulmonary vasculature, as well as on local environmental factors. Each of the resident vascular cell types (ie, endothelial, smooth muscle, adventitial fibroblast) undergo site- and time-dependent alterations in proliferation, matrix protein production, expression of growth factors, cytokines, and receptors, and each resident cell type plays a specific role in the overall remodeling response. In addition, hypoxic exposure induces an inflammatory response within the vessel wall, and the recruited circulating progenitor cells contribute significantly to the structural remodeling and persistent vasoconstriction of the pulmonary circulation. The possibility exists that the lung or lung vessels also contain resident progenitor cells that participate in the remodeling process. Thus the hypoxia-induced remodeling of the pulmonary circulation is a highly complex process where numerous interactive events must be taken into account as we search for newer, more effective therapeutic interventions. This review provides perspectives on each of the aforementioned areas.

Structural imprints in vivo decode RNA regulatory mechanisms.

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Spitale, Robert C; Flynn, Ryan A; Zhang, Qiangfeng Cliff; Crisalli, Pete; Lee, Byron; Jung, Jong-Wha; Kuchelmeister, Hannes Y; Batista, Pedro J; Torre, Eduardo A; Kool, Eric T; Chang, Howard Y

2015-03-26

Visualizing the physical basis for molecular behaviour inside living cells is a great challenge for biology. RNAs are central to biological regulation, and the ability of RNA to adopt specific structures intimately controls every step of the gene expression program. However, our understanding of physiological RNA structures is limited; current in vivo RNA structure profiles include only two of the four nucleotides that make up RNA. Here we present a novel biochemical approach, in vivo click selective 2'-hydroxyl acylation and profiling experiment (icSHAPE), which enables the first global view, to our knowledge, of RNA secondary structures in living cells for all four bases. icSHAPE of the mouse embryonic stem cell transcriptome versus purified RNA folded in vitro shows that the structural dynamics of RNA in the cellular environment distinguish different classes of RNAs and regulatory elements. Structural signatures at translational start sites and ribosome pause sites are conserved from in vitro conditions, suggesting that these RNA elements are programmed by sequence. In contrast, focal structural rearrangements in vivo reveal precise interfaces of RNA with RNA-binding proteins or RNA-modification sites that are consistent with atomic-resolution structural data. Such dynamic structural footprints enable accurate prediction of RNA-protein interactions and N(6)-methyladenosine (m(6)A) modification genome wide. These results open the door for structural genomics of RNA in living cells and reveal key physiological structures controlling gene expression.

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

International Nuclear Information System (INIS)

Miyazaki, Yukihiro; Marangoni, Alejandro G

2014-01-01

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 × 10 9 Pa and E L (PW) = 1.64 × 10 9 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)

Regulatory mechanisms for absenteeism in the health sector: a systematic review of strategies and their implementation

Science.gov (United States)

Kisakye, Angela N; Tweheyo, Raymond; Ssengooba, Freddie; Pariyo, George W; Rutebemberwa, Elizeus; Kiwanuka, Suzanne N

2016-01-01

Background A systematic review was undertaken to identify regulatory mechanisms aimed at mitigating health care worker absenteeism, to describe where and how they have been implemented as well as their possible effects. The goal was to propose potential policy options for managing the problem of absenteeism among human resources for health in low- and middle-income countries. Mechanisms described in this review are at the local workplace and broader national policy level. Methods A comprehensive online search was conducted on EMBASE, CINAHL, PubMed, Google Scholar, Google, and Social Science Citation Index using MEDLINE search terms. Retrieved studies were uploaded onto reference manager and screened by two independent reviewers. Only publications in English were included. Data were extracted and synthesized according to the objectives of the review. Results Twenty six of the 4,975 published articles retrieved were included. All were from high-income countries and covered all cadres of health workers. The regulatory mechanisms and possible effects include 1) organizational-level mechanisms being reported as effective in curbing absenteeism in low- and middle-income countries (LMICs); 2) prohibition of private sector activities in LMICs offering benefits but presenting a challenge for the government to monitor the health workforce; 3) contractual changes from temporary to fixed posts having been associated with no reduction in absenteeism and not being appropriate for LMICs; 4) multifaceted work interventions being implemented in most settings; 5) the possibility of using financial and incentive regulatory mechanisms in LMICs; 6) health intervention mechanisms reducing absenteeism when integrated with exercise programs; and 7) attendance by legislation during emergencies being criticized for violating human rights in the United States and not being effective in curbing absenteeism. Conclusion Most countries have applied multiple strategies to mitigate health care

Regulatory mechanisms for absenteeism in the health sector: a systematic review of strategies and their implementation.

Science.gov (United States)

Kisakye, Angela N; Tweheyo, Raymond; Ssengooba, Freddie; Pariyo, George W; Rutebemberwa, Elizeus; Kiwanuka, Suzanne N

2016-01-01

A systematic review was undertaken to identify regulatory mechanisms aimed at mitigating health care worker absenteeism, to describe where and how they have been implemented as well as their possible effects. The goal was to propose potential policy options for managing the problem of absenteeism among human resources for health in low- and middle-income countries. Mechanisms described in this review are at the local workplace and broader national policy level. A comprehensive online search was conducted on EMBASE, CINAHL, PubMed, Google Scholar, Google, and Social Science Citation Index using MEDLINE search terms. Retrieved studies were uploaded onto reference manager and screened by two independent reviewers. Only publications in English were included. Data were extracted and synthesized according to the objectives of the review. Twenty six of the 4,975 published articles retrieved were included. All were from high-income countries and covered all cadres of health workers. The regulatory mechanisms and possible effects include 1) organizational-level mechanisms being reported as effective in curbing absenteeism in low- and middle-income countries (LMICs); 2) prohibition of private sector activities in LMICs offering benefits but presenting a challenge for the government to monitor the health workforce; 3) contractual changes from temporary to fixed posts having been associated with no reduction in absenteeism and not being appropriate for LMICs; 4) multifaceted work interventions being implemented in most settings; 5) the possibility of using financial and incentive regulatory mechanisms in LMICs; 6) health intervention mechanisms reducing absenteeism when integrated with exercise programs; and 7) attendance by legislation during emergencies being criticized for violating human rights in the United States and not being effective in curbing absenteeism. Most countries have applied multiple strategies to mitigate health care worker absenteeism. The success of these

Ciona intestinalis notochord as a new model to investigate the cellular and molecular mechanisms of tubulogenesis.

Science.gov (United States)

Denker, Elsa; Jiang, Di

2012-05-01

Biological tubes are a prevalent structural design across living organisms. They provide essential functions during the development and adult life of an organism. Increasing progress has been made recently in delineating the cellular and molecular mechanisms underlying tubulogenesis. This review aims to introduce ascidian notochord morphogenesis as an interesting model system to study the cell biology of tube formation, to a wider cell and developmental biology community. We present fundamental morphological and cellular events involved in notochord morphogenesis, compare and contrast them with other more established tubulogenesis model systems, and point out some unique features, including bipolarity of the notochord cells, and using cell shape changes and cell rearrangement to connect lumens. We highlight some initial findings in the molecular mechanisms of notochord morphogenesis. Based on these findings, we present intriguing problems and put forth hypotheses that can be addressed in future studies. Copyright © 2012 Elsevier Ltd. All rights reserved.

An examination of adaptive cellular protective mechanisms using a multi-stage carcinogenesis model

International Nuclear Information System (INIS)

Schollnberger, H.; Stewart, R. D.; Mitchel, R. E. J.; Hofmann, W.

2004-01-01

A multi-stage cancer model that describes the putative rate-limiting steps in carcinogenesis was developed and used to investigate the potential impact on lung cancer incidence of the hormesis mechanisms suggested by Feinendegen and Pollycove. In this deterministic cancer model, radiation and endogenous processes damage the DNA of target cells in the lung. Some fraction of the misrepaired our unrepaired DNA damage induces genomic instability and, ultimately, leads to the accumulation of malignant cells. The model accounts for cell birth and death processes. Ita also includes a rate of malignant transformation and a lag period for tumour formation. Cellular defence mechanisms are incorporated into the model by postulating dose and dose rate dependent radical scavenging. The accuracy of DNA damage repair also depends on dose and dose rate. Sensitivity studies were conducted to identify critical model inputs and to help define the shapes of the cumulative lung cancer incidence curves that may arise when dose and dose rate dependent cellular defence mechanisms are incorporated into a multi-stage cancer model. For lung cancer, both linear no-threshold (LNT) and non-LNT shaped responses can be obtained. The reported studied clearly show that it is critical to know whether or not and to what extent multiply damaged DNA sites are formed by endogenous processes. Model inputs that give rise to U-shaped responses are consistent with an effective cumulative lung cancer incidence threshold that may be as high as 300 mGy (4 mGy per year for 75 years). (Author) 11 refs

[Russian/German contacts in discussion on cellular mechanisms of aging and lifespan (author's transl)].

Science.gov (United States)

Duplenko, J K

1980-01-01

This is a brief review of the discussions which took place in natural literature at the end of XIX, and the beginning of XX century concerning the problems of cellular mechanism of aging, animal lifespan, death of metazoa and immortality of protozoa. The participation of German and Russian natural scientists in the discussion of cardinal gerontological questions is specially considered. The close relationship between the gerontological conceptions and the evolutionary ideas is emphasized. The author has established historical continuity of the above conceptions and modern evolutionary approaches to the predetermination of species' lifespan and mechanisms of aging.

Cellular and molecular mechanisms of alcohol-induced osteopenia.

Science.gov (United States)

Luo, Zhenhua; Liu, Yao; Liu, Yitong; Chen, Hui; Shi, Songtao; Liu, Yi

2017-12-01

Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs.

Biochemical and cellular mechanisms of low-dose effects

International Nuclear Information System (INIS)

Feinendegen, L.E.; Booz, J.; Muehlensiepen, H.

1988-01-01

The question of health effects from small radiation doses remains open. Individual cells, when being hit by single elemental doses - in low-dose irradiation - react acutely and temporarily by altering control of enzyme activity, as is demonstrated for the case of thymidine kinase. This response is not constant in that it provides a temporary protection of enzyme activity against a second irradiation, by a mechanism likely to be via improved detoxification of intracellular radicals. It must be considered that in the low-dose region radiation may also exert protection against other challenges involving radicals, causing a net beneficial effect by temporarily shielding the hit cell against radicals produced by metabolism. Since molecular alterations leading to late effects are considered a consequence of the initial cellular response, late effects from small radiation doses do not necessarily adhere to a linear dose-effect relationship. The reality of the linear relationship between the risk of late effects from high doses to small doses is an assumption, for setting dose limits, but it must not be taken for predicting health detriment from low doses. (author)

Mechanical characterization of disordered and anisotropic cellular monolayers

Science.gov (United States)

Nestor-Bergmann, Alexander; Johns, Emma; Woolner, Sarah; Jensen, Oliver E.

2018-05-01

We consider a cellular monolayer, described using a vertex-based model, for which cells form a spatially disordered array of convex polygons that tile the plane. Equilibrium cell configurations are assumed to minimize a global energy defined in terms of cell areas and perimeters; energy is dissipated via dynamic area and length changes, as well as cell neighbor exchanges. The model captures our observations of an epithelium from a Xenopus embryo showing that uniaxial stretching induces spatial ordering, with cells under net tension (compression) tending to align with (against) the direction of stretch, but with the stress remaining heterogeneous at the single-cell level. We use the vertex model to derive the linearized relation between tissue-level stress, strain, and strain rate about a deformed base state, which can be used to characterize the tissue's anisotropic mechanical properties; expressions for viscoelastic tissue moduli are given as direct sums over cells. When the base state is isotropic, the model predicts that tissue properties can be tuned to a regime with high elastic shear resistance but low resistance to area changes, or vice versa.

Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies.

Science.gov (United States)

Brattsand, R; Linden, M

1996-01-01

Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in

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

International Nuclear Information System (INIS)

Stewart-Hutchinson, P.J.; Hale, Christopher M.; Wirtz, Denis; Hodzic, Didier

2008-01-01

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

Cellular dynamical mechanisms for encoding the time and place of events along spatiotemporal trajectories in episodic memory.

Science.gov (United States)

Hasselmo, Michael E; Giocomo, Lisa M; Brandon, Mark P; Yoshida, Motoharu

2010-12-31

Understanding the mechanisms of episodic memory requires linking behavioral data and lesion effects to data on the dynamics of cellular membrane potentials and population interactions within brain regions. Linking behavior to specific membrane channels and neurochemicals has implications for therapeutic applications. Lesions of the hippocampus, entorhinal cortex and subcortical nuclei impair episodic memory function in humans and animals, and unit recording data from these regions in behaving animals indicate episodic memory processes. Intracellular recording in these regions demonstrates specific cellular properties including resonance, membrane potential oscillations and bistable persistent spiking that could underlie the encoding and retrieval of episodic trajectories. A model presented here shows how intrinsic dynamical properties of neurons could mediate the encoding of episodic memories as complex spatiotemporal trajectories. The dynamics of neurons allow encoding and retrieval of unique episodic trajectories in multiple continuous dimensions including temporal intervals, personal location, the spatial coordinates and sensory features of perceived objects and generated actions, and associations between these elements. The model also addresses how cellular dynamics could underlie unit firing data suggesting mechanisms for coding continuous dimensions of space, time, sensation and action. Copyright © 2010 Elsevier B.V. All rights reserved.

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

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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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A Transcriptional Regulatory Mechanism Finely Tunes the Firing of Type VI Secretion System in Response to Bacterial Enemies.

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Lazzaro, Martina; Feldman, Mario F; García Véscovi, Eleonora

2017-08-22

The ability to detect and measure danger from an environmental signal is paramount for bacteria to respond accordingly, deploying strategies that halt or counteract potential cellular injury and maximize survival chances. Type VI secretion systems (T6SSs) are complex bacterial contractile nanomachines able to target toxic effectors into neighboring bacteria competing for the same colonization niche. Previous studies support the concept that either T6SSs are constitutively active or they fire effectors in response to various stimuli, such as high bacterial density, cell-cell contact, nutrient depletion, or components from dead sibling cells. For Serratia marcescens , it has been proposed that its T6SS is stochastically expressed, with no distinction between harmless or aggressive competitors. In contrast, we demonstrate that the Rcs regulatory system is responsible for finely tuning Serratia T6SS expression levels, behaving as a transcriptional rheostat. When confronted with harmless bacteria, basal T6SS expression levels suffice for Serratia to eliminate the competitor. A moderate T6SS upregulation is triggered when, according to the aggressor-prey ratio, an unbalanced interplay between homologous and heterologous effectors and immunity proteins takes place. Higher T6SS expression levels are achieved when Serratia is challenged by a contender like Acinetobacter , which indiscriminately fires heterologous effectors able to exert lethal cellular harm, threatening the survival of the Serratia population. We also demonstrate that Serratia 's RcsB-dependent T6SS regulatory mechanism responds not to general stress signals but to the action of specific effectors from competitors, displaying an exquisite strategy to weigh risks and keep the balance between energy expenditure and fitness costs. IMPORTANCE Serratia marcescens is among the health-threatening pathogens categorized by the WHO as research priorities to develop alternative antimicrobial strategies, and it was

A conserved regulatory mechanism in bifunctional biotin protein ligases.

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Wang, Jingheng; Beckett, Dorothy

2017-08-01

Class II bifunctional biotin protein ligases (BirA), which catalyze post-translational biotinylation and repress transcription initiation, are broadly distributed in eubacteria and archaea. However, it is unclear if these proteins all share the same molecular mechanism of transcription regulation. In Escherichia coli the corepressor biotinoyl-5'-AMP (bio-5'-AMP), which is also the intermediate in biotin transfer, promotes operator binding and resulting transcription repression by enhancing BirA dimerization. Like E. coli BirA (EcBirA), Staphylococcus aureus, and Bacillus subtilis BirA (Sa and BsBirA) repress transcription in vivo in a biotin-dependent manner. In this work, sedimentation equilibrium measurements were performed to investigate the molecular basis of this biotin-responsive transcription regulation. The results reveal that, as observed for EcBirA, Sa, and BsBirA dimerization reactions are significantly enhanced by bio-5'-AMP binding. Thus, the molecular mechanism of the Biotin Regulatory System is conserved in the biotin repressors from these three organisms. © 2017 The Protein Society.

A cellular and regulatory map of the cholinergic nervous system of C. elegans

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Pereira, Laura; Kratsios, Paschalis; Serrano-Saiz, Esther; Sheftel, Hila; Mayo, Avi E; Hall, David H; White, John G; LeBoeuf, Brigitte; Garcia, L Rene; Alon, Uri; Hobert, Oliver

2015-01-01

Nervous system maps are of critical importance for understanding how nervous systems develop and function. We systematically map here all cholinergic neuron types in the male and hermaphrodite C. elegans nervous system. We find that acetylcholine (ACh) is the most broadly used neurotransmitter and we analyze its usage relative to other neurotransmitters within the context of the entire connectome and within specific network motifs embedded in the connectome. We reveal several dynamic aspects of cholinergic neurotransmitter identity, including a sexually dimorphic glutamatergic to cholinergic neurotransmitter switch in a sex-shared interneuron. An expression pattern analysis of ACh-gated anion channels furthermore suggests that ACh may also operate very broadly as an inhibitory neurotransmitter. As a first application of this comprehensive neurotransmitter map, we identify transcriptional regulatory mechanisms that control cholinergic neurotransmitter identity and cholinergic circuit assembly. DOI: http://dx.doi.org/10.7554/eLife.12432.001 PMID:26705699

Rearrangement of Upstream Sequences of the hTERT Gene During Cellular Immortalization

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Zhao, Yuanjun; Wang, Shuwen; Popova, Evgenya Y.; Grigoryev, Sergei A.; Zhu, Jiyue

2010-01-01

Telomerase expression, resulting from transcriptional activation of the hTERT gene, allows cells to acquire indefinite proliferative potential during cellular immortalization and tumorigenesis. However, mechanisms of hTERT gene activation in many immortal cell lines and cancer cells are poorly understood. Here, we report our studies on hTERT activation using genetically related pairs of telomerase-negative (Tel−) and -positive (Tel+) fibroblast lines. First, whereas transiently transfected plasmid reporters did not recapitulate the endogenous hTERT promoter, the promoter in chromosomally integrated bacterial artificial chromosome (BAC) reporters was activated in a subset of Tel+ cells, indicating that activation of the hTERT promoter required native chromatin context and/or distal regulatory elements. Second, the hTERT gene, located near the telomere of chromosome 5p, was translocated in all three Tel+ cell lines but not in their parental pre-crisis cells and Tel− immortal siblings. The breakage points were mapped to regions upstream of the hTERT promoter, indicating that the hTERT gene was the target of these chromosomal rearrangements. In two Tel+ cell lines, translocation of the endogenous hTERT gene appeared to be the major mechanism of its activation as the activity of hTERT promoter in many chromosomally integrated BAC reporters, with intact upstream and downstream neighboring loci, remained relatively low. Therefore, our results suggest that rearrangement of upstream sequences is an important new mechanism of hTERT promoter activation during cellular immortalization. The chromosomal rearrangements likely occurred during cellular crisis and facilitated by telomere dysfunction. Such translocations allowed the hTERT promoter to escape from the native condensed chromatin environment. PMID:19672873

Relation of murine thoracic aortic structural and cellular changes with aging to passive and active mechanical properties.

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Wheeler, Jason B; Mukherjee, Rupak; Stroud, Robert E; Jones, Jeffrey A; Ikonomidis, John S

2015-02-25

Maintenance of the structure and mechanical properties of the thoracic aorta contributes to aortic function and is dependent on the composition of the extracellular matrix and the cellular content within the aortic wall. Age-related alterations in the aorta include changes in cellular content and composition of the extracellular matrix; however, the precise roles of these age-related changes in altering aortic mechanical function are not well understood. Thoracic aortic rings from the descending segment were harvested from C57BL/6 mice aged 6 and 21 months. Thoracic aortic diameter and wall thickness were higher in the old mice. Cellular density was reduced in the medial layer of aortas from the old mice; concomitantly, collagen content was higher in old mice, but elastin content was similar between young and old mice. Stress relaxation, an index of compliance, was reduced in aortas from old mice and correlated with collagen fraction. Contractility of the aortic rings following potassium stimulation was reduced in old versus young mice. Furthermore, collagen gel contraction by aortic smooth muscle cells was reduced with age. These results demonstrate that numerous age-related structural changes occurred in the thoracic aorta and were related to alterations in mechanical properties. Aortic contractility decreased with age, likely because of a reduction in medial cell number in addition to a smooth muscle contractile deficit. Together, these unique findings provide evidence that the age-related changes in structure and mechanical function coalesce to provide an aortic substrate that may be predisposed to aortopathies. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Nitric oxide-mediated modulation of iron regulatory proteins: implication for cellular iron homeostasis.

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Kim, Sangwon; Ponka, Prem

2002-01-01

Iron regulatory proteins (IRP1 and IRP2) control the synthesis of transferrin receptors (TfR) and ferritin by binding to iron-responsive elements (IREs) that are located in the 3' untranslated region (UTR) and the 5' UTR of their respective mRNAs. Cellular iron levels affect binding of IRPs to IREs and consequently expression of TfR and ferritin. Moreover, NO(.), a redox species of nitric oxide that interacts primarily with iron, can activate IRP1 RNA-binding activity resulting in an increase in TfR mRNA levels and a decrease in ferritin synthesis. We have shown that treatment of RAW 264.7 cells (a murine macrophage cell line) with NO(+) (nitrosonium ion, which causes S-nitrosylation of thiol groups) resulted in a rapid decrease in RNA-binding of IRP2, followed by IRP2 degradation, and these changes were associated with a decrease in TfR mRNA levels and a dramatic increase in ferritin synthesis. Moreover, we demonstrated that stimulation of RAW 264.7 cells with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) increased IRP1 binding activity, whereas RNA-binding of IRP2 decreased and was followed by a degradation of this protein. Furthermore, the decrease of IRP2 binding/protein levels was associated with a decrease in TfR mRNA levels and an increase in ferritin synthesis in LPS/IFN-gamma-treated cells, and these changes were prevented by inhibitors of inducible nitric oxide synthase. These results suggest that NO(+)-mediated degradation of IRP2 plays a major role in iron metabolism during inflammation.

Activation of counter-regulatory mechanisms in a rat renal acute rejection model

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Salomon Daniel R

2008-02-01

Full Text Available Abstract Background Microarray analysis provides a powerful approach to identify gene expression alterations following transplantation. In patients the heterogeneity of graft specimens, co-morbidity, co-medications and the challenges in sample collection and preparation complicate conclusions regarding the underlying mechanisms of graft injury, rejection and immune regulation. Results We used a rat kidney transplantation model with strict transplant and sample preparation procedures to analyze genome wide changes in gene expression four days after syngeneic and allogeneic transplantation. Both interventions were associated with substantial changes in gene expression. After allogeneic transplantation, genes and pathways related to transport and metabolism were predominantly down-regulated consistent with rejection-mediated graft injury and dysfunction. Up-regulated genes were primarily related to the acute immune response including antigen presentation, T-cell receptor signaling, apoptosis, interferon signaling and complement cascades. We observed a cytokine and chemokine expression profile consistent with activation of a Th1-cell response. A novel finding was up-regulation of several regulatory and protective genes after allogeneic transplantation, specifically IL10, Bcl2a1, C4bpa, Ctla4, HO-1 and the SOCS family. Conclusion Our data indicate that in parallel with the predicted activation of immune response and tissue injury pathways, there is simultaneous activation of pathways for counter regulatory and protective mechanisms that would balance and limit the ongoing inflammatory/immune responses. The pathophysiological mechanisms behind and the clinical consequences of alterations in expression of these gene classes in acute rejection, injury and dysfunction vs. protection and immunoregulation, prompt further analyses and open new aspects for therapeutic approaches.

Origami interleaved tube cellular materials

International Nuclear Information System (INIS)

Cheung, Kenneth C; Tachi, Tomohiro; Calisch, Sam; Miura, Koryo

2014-01-01

A novel origami cellular material based on a deployable cellular origami structure is described. The structure is bi-directionally flat-foldable in two orthogonal (x and y) directions and is relatively stiff in the third orthogonal (z) direction. While such mechanical orthotropicity is well known in cellular materials with extruded two dimensional geometry, the interleaved tube geometry presented here consists of two orthogonal axes of interleaved tubes with high interfacial surface area and relative volume that changes with fold-state. In addition, the foldability still allows for fabrication by a flat lamination process, similar to methods used for conventional expanded two dimensional cellular materials. This article presents the geometric characteristics of the structure together with corresponding kinematic and mechanical modeling, explaining the orthotropic elastic behavior of the structure with classical dimensional scaling analysis. (paper)

Origami interleaved tube cellular materials

Science.gov (United States)

Cheung, Kenneth C.; Tachi, Tomohiro; Calisch, Sam; Miura, Koryo

2014-09-01

A novel origami cellular material based on a deployable cellular origami structure is described. The structure is bi-directionally flat-foldable in two orthogonal (x and y) directions and is relatively stiff in the third orthogonal (z) direction. While such mechanical orthotropicity is well known in cellular materials with extruded two dimensional geometry, the interleaved tube geometry presented here consists of two orthogonal axes of interleaved tubes with high interfacial surface area and relative volume that changes with fold-state. In addition, the foldability still allows for fabrication by a flat lamination process, similar to methods used for conventional expanded two dimensional cellular materials. This article presents the geometric characteristics of the structure together with corresponding kinematic and mechanical modeling, explaining the orthotropic elastic behavior of the structure with classical dimensional scaling analysis.

Regulatory Myeloid Cells in Transplantation

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Rosborough, Brian R.; Raïch-Regué, Dàlia; Turnquist, Heth R.; Thomson, Angus W.

2013-01-01

Regulatory myeloid cells (RMC) are emerging as novel targets for immunosuppressive (IS) agents and hold considerable promise as cellular therapeutic agents. Herein, we discuss the ability of regulatory macrophages (Mreg), regulatory dendritic cells (DCreg) and myeloid-derived suppressor cells (MDSC) to regulate alloimmunity, their potential as cellular therapeutic agents and the IS agents that target their function. We consider protocols for the generation of RMC and the selection of donor- or recipient-derived cells for adoptive cell therapy. Additionally, the issues of cell trafficking and antigen (Ag) specificity following RMC transfer are discussed. Improved understanding of the immunobiology of these cells has increased the possibility of moving RMC into the clinic to reduce the burden of current IS agents and promote Ag-specific tolerance. In the second half of this review, we discuss the influence of established and experimental IS agents on myeloid cell populations. IS agents believed historically to act primarily on T cell activation and proliferation are emerging as important regulators of RMC function. Better insights into the influence of IS agents on RMC will enhance our ability to develop cell therapy protocols to promote the function of these cells. Moreover, novel IS agents may be designed to target RMC in situ to promote Ag-specific immune regulation in transplantation and usher in a new era of immune modulation exploiting cells of myeloid origin. PMID:24092382

Immune regulation in Chandipura virus infection: characterization of CD4+ T regulatory cells from infected mice

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Shahir Prajakta

2011-05-01

Full Text Available Abstract Back ground Chandipura virus produces acute infection in mice. During infection drastic reduction of CD4+, CD8+ and CD19 + cell was noticed. Depletion of lymphocytes also noticed in spleen. The reduction may be due to the regulatory mechanism of immune system to prevent the bystander host tissue injury. There are several mechanisms like generation of regulatory cells, activation induced cell death (ACID etc were indicated to control the activation and maintain cellular homeostasis. Role of regulatory cells in homeostasis has been described in several viral diseases. This study was undertaken to characterize CD4+T regulatory cells from the infected mice. Method In this study we purified the CD4+ T cells from Chandipura virus infected susceptible Balb/c mice. CD4+ T regulatory cells were identified by expression of cell surface markers CD25, CD127 and CTLA-4 and intracellular markers Foxp3, IL-10 and TGF-beta. Antigen specificity and ability to suppress the proliferation of other lymphocytes were studied in vitro by purified CD4+CD25+T regulatory cells from infected mice. The proliferation was calculated by proliferation module of Flow Jo software. Expression of death receptors on regulatory cells were studied by flowcytometer. Results The CD4+ T cells isolated from infected mice expressed characteristic markers of regulatory phenotype at all post infective hours tested. The CD4+ T regulatory cells were proliferated when stimulated with Chandipura virus antigen. The regulatory cells did not suppress the proliferation of splenocytes stimulated with anti CD3 antibody when co cultured with them. Interesting observation was, while purification of CD4+ T cells by negative selection, the population of cells negative for CD4 also co purified along with CD4+ T cell. Flow cytometry analysis and light microscopy revealed that CD4 negative cells were of different size and shape (atypical compared to the normal lymphocytes. Greater percentage of

Cellular Mechanisms Underlying Behavioral State-Dependent Bidirectional Modulation of Motor Cortex Output

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Julia Schiemann

2015-05-01

Full Text Available Neuronal activity in primary motor cortex (M1 correlates with behavioral state, but the cellular mechanisms underpinning behavioral state-dependent modulation of M1 output remain largely unresolved. Here, we performed in vivo patch-clamp recordings from layer 5B (L5B pyramidal neurons in awake mice during quiet wakefulness and self-paced, voluntary movement. We show that L5B output neurons display bidirectional (i.e., enhanced or suppressed firing rate changes during movement, mediated via two opposing subthreshold mechanisms: (1 a global decrease in membrane potential variability that reduced L5B firing rates (L5Bsuppressed neurons, and (2 a coincident noradrenaline-mediated increase in excitatory drive to a subpopulation of L5B neurons (L5Benhanced neurons that elevated firing rates. Blocking noradrenergic receptors in forelimb M1 abolished the bidirectional modulation of M1 output during movement and selectively impaired contralateral forelimb motor coordination. Together, our results provide a mechanism for how noradrenergic neuromodulation and network-driven input changes bidirectionally modulate M1 output during motor behavior.

Cosserat modeling of cellular solids

NARCIS (Netherlands)

Onck, P.R.

Cellular solids inherit their macroscopic mechanical properties directly from the cellular microstructure. However, the characteristic material length scale is often not small compared to macroscopic dimensions, which limits the applicability of classical continuum-type constitutive models. Cosserat

Coordination of frontline defense mechanisms under severe oxidative stress.

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

2010-07-01

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

Heart Rate Variability: New Perspectives on Physiological Mechanisms, Assessment of Self-regulatory Capacity, and Health risk.

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McCraty, Rollin; Shaffer, Fred

2015-01-01

Heart rate variability, the change in the time intervals between adjacent heartbeats, is an emergent property of interdependent regulatory systems that operates on different time scales to adapt to environmental and psychological challenges. This article briefly reviews neural regulation of the heart and offers some new perspectives on mechanisms underlying the very low frequency rhythm of heart rate variability. Interpretation of heart rate variability rhythms in the context of health risk and physiological and psychological self-regulatory capacity assessment is discussed. The cardiovascular regulatory centers in the spinal cord and medulla integrate inputs from higher brain centers with afferent cardiovascular system inputs to adjust heart rate and blood pressure via sympathetic and parasympathetic efferent pathways. We also discuss the intrinsic cardiac nervous system and the heart-brain connection pathways, through which afferent information can influence activity in the subcortical, frontocortical, and motor cortex areas. In addition, the use of real-time HRV feedback to increase self-regulatory capacity is reviewed. We conclude that the heart's rhythms are characterized by both complexity and stability over longer time scales that reflect both physiological and psychological functional status of these internal self-regulatory systems.

Antibody dependent cellular phagocytosis by macrophages is a novel mechanism of action of elotuzumab.

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Kurdi, Ahmed T; Glavey, Siobhan V; Bezman, Natalie A; Jhatakia, Amy; Guerriero, Jennifer L; Manier, Salomon; Moschetta, Michele; Mishima, Yuji; Roccaro, Aldo; Detappe, Alexandre; Liu, Chia-Jen; Sacco, Antonio; Huynh, Daisy; Tai, Yu-Tzu; Robbins, Michael D; Azzi, Jamil; Ghobrial, Irene M

2018-04-13

Elotuzumab, a recently approved antibody for the treatment of multiple myeloma (MM), has been shown to stimulate Fcγ receptor (FcγR)-mediated antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells towards myeloma cells. The modulatory effects of elotuzumab on other effector cells in the tumor microenvironment, however, has not been fully explored. Antibody dependent cellular phagocytosis (ADCP) is a mechanism by which macrophages contribute to anti-tumor potency of monoclonal antibodies. Herein, we studied the NK cell independent effect of elotuzumab on tumor associated macrophages (TAMs) using a xenograft tumor model deficient in NK and adaptive immune cells. We demonstrate significant anti-tumor efficacy of single agent elotuzumab in immunocompromised xenograft models of multiple myeloma, which is in part mediated by Fc-FcγR interaction of elotuzumab with macrophages. Elotuzumab is shown in this study to induce phenotypic activation of macrophages in-vivo and mediates ADCP of myeloma cells though a FcγR dependent manner in-vitro. Together, these findings propose a novel immune mediated mechanism by which elotuzumab exerts anti-myeloma activity and helps to provide rationale for combination therapies that can enhance macrophage activity. Copyright ©2018, American Association for Cancer Research.

Zeno's paradox in quantum cellular automata

Energy Technology Data Exchange (ETDEWEB)

Groessing, G [Atominst. der Oesterreichischen Universitaeten, Vienna (Austria); Zeilinger, A [Inst. fuer Experimentalphysik, Univ. Innsbruck (Austria)

1991-07-01

The effect of Zeno's paradox in quantum theory is demonstrated with the aid of quantum mechanical cellular automata. It is shown that the degree of non-unitarity of the cellular automaton evolution and the frequency of consecutive measurements of cellular automaton states are operationally indistinguishable. (orig.).

Zeno's paradox in quantum cellular automata

International Nuclear Information System (INIS)

Groessing, G.; Zeilinger, A.

1991-01-01

The effect of Zeno's paradox in quantum theory is demonstrated with the aid of quantum mechanical cellular automata. It is shown that the degree of non-unitarity of the cellular automaton evolution and the frequency of consecutive measurements of cellular automaton states are operationally indistinguishable. (orig.)

Cellular and Molecular Mechanisms in Perioperative Hepatic Protection: A Review of Current Interventions

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Zahra Talebi

2017-05-01

Full Text Available Liver is one of the most important organs needing great concern during the perioperative period. There are a number of different mechanisms that interact with liver cells and might affect their integrity and cell live. Though these mechanisms are not all the same, there is a great common point: all affect the metabolic pathways of the liver. Ischemia, anesthetic drug effects and other perioperative insults may affect the liver. Disturbance in an organ’s blood flow is an inherent part of diverse surgical procedures, which leads to lack of oxygen and nutrient supply. These ischemic periods can be particularly long in case of liver surgeries, such as resection of large hepatic tumors, management of hepatic trauma and liver transplant. Once the blood flow and oxygen supply are restored, the interruption of blood flow affects the oxygen dependent cells in liver, which require mitochondrial oxidative phosphorylation for their metabolism. Molecular mechanisms such as Redox status, ionic interchange disturbances as well as different mediators and cells like KC, SEC, dendritic cells, leukocytes, and lymphocytes, are involved in the process ultimately leading to cell death by apoptosis and necrosis. This review provides an overview on the cellular and molecular mechanisms involved in liver injuries, categorizing these mechanisms in 3 different classes: preoperative mechanisms, intraoperative mechanisms and postoperative mechanisms. Each of them are discussed in a different part of the manuscript

Mechanisms regulating skin immunity and inflammation.

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

2014-05-01

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

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

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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.

Sexual Experience in Female Rodents: Cellular Mechanisms and Functional Consequences

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Meisel, Robert L.; Mullins, Amanda J.

2007-01-01

The neurobiology of female sexual behavior has largely focused on mechanisms of hormone action on nerve cells and how these effects translate into the display of copulatory motor patterns. Of equal importance, though less studied, are some of the consequences of engaging in sexual behavior, including the rewarding properties of sexual interactions and how sexual experience alters copulatory efficiency. This review summarizes the effects of sexual experience on reward processes and copulation in female Syrian hamsters. Neural correlates of these sexual interactions include long-term cellular changes in dopamine transmission and postsynaptic signaling pathways related to neuronal plasticity (e.g., dendritic spine formation). Taken together, these studies suggest that sexual experience enhances the reinforcing properties of sexual behavior, which has the coincident outcome of increasing copulatory efficiency in a way that can increase reproductive success. PMID:16978593

The Molecular and Cellular Mechanisms of Axon Guidance in Mossy Fiber Sprouting

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Ryuta Koyama

2018-05-01

Full Text Available The question of whether mossy fiber sprouting is epileptogenic has not been resolved; both sprouting-induced recurrent excitatory and inhibitory circuit hypotheses have been experimentally (but not fully supported. Therefore, whether mossy fiber sprouting is a potential therapeutic target for epilepsy remains under debate. Moreover, the axon guidance mechanisms of mossy fiber sprouting have attracted the interest of neuroscientists. Sprouting of mossy fibers exhibits several uncommon axonal growth features in the basically non-plastic adult brain. For example, robust branching of axonal collaterals arises from pre-existing primary mossy fiber axons. Understanding the branching mechanisms in adulthood may contribute to axonal regeneration therapies in neuroregenerative medicine in which robust axonal re-growth is essential. Additionally, because granule cells are produced throughout life in the neurogenic dentate gyrus, it is interesting to examine whether the mossy fibers of newly generated granule cells follow the pre-existing trajectories of sprouted mossy fibers in the epileptic brain. Understanding these axon guidance mechanisms may contribute to neuron transplantation therapies, for which the incorporation of transplanted neurons into pre-existing neural circuits is essential. Thus, clarifying the axon guidance mechanisms of mossy fiber sprouting could lead to an understanding of central nervous system (CNS network reorganization and plasticity. Here, we review the molecular and cellular mechanisms of axon guidance in mossy fiber sprouting by discussing mainly in vitro studies.

Cellular Signaling in Health and Disease

CERN Document Server

Beckerman, Martin

2009-01-01

In today’s world, three great classes of non-infectious diseases – the metabolic syndromes (such as type 2 diabetes and atherosclerosis), the cancers, and the neurodegenerative disorders – have risen to the fore. These diseases, all associated with increasing age of an individual, have proven to be remarkably complex and difficult to treat. This is because, in large measure, when the cellular signaling pathways responsible for maintaining homeostasis and health of the body become dysregulated, they generate equally stable disease states. As a result the body may respond positively to a drug, but only for a while and then revert back to the disease state. Cellular Signaling in Health and Disease summarizes our current understanding of these regulatory networks in the healthy and diseased states, showing which molecular components might be prime targets for drug interventions. This is accomplished by presenting models that explain in mechanistic, molecular detail how a particular part of the cellular sign...

Advanced in study of cellular and molecular mechanisms of radiation effects on central nervous system

International Nuclear Information System (INIS)

Zhang Wei; Tu Yu; Wang Lili

2008-01-01

Along with radiation treatment extensively applied, radiation injury also is valued gradually. The effect of radiation to the cellular and molecular of central nervous system (CNS) is a complicated and moderately advanced process and the mechanism is remains incompletely clear yet. Inquiring into the possible mechanism of the CNS including the injury and the restoration of neuron, neuroglia cells, endotheliocyte cell and blood-brain barrier and the molecular level of change induced by radiation, so as to provide beneficial thought for preventing and curing radiation injury clinically. Some neuroprotective strategies are also addressed in the review. (authors)

Mechanisms of Plastic Deformation in Collagen Networks Induced by Cellular Forces.

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Ban, Ehsan; Franklin, J Matthew; Nam, Sungmin; Smith, Lucas R; Wang, Hailong; Wells, Rebecca G; Chaudhuri, Ovijit; Liphardt, Jan T; Shenoy, Vivek B

2018-01-23

Contractile cells can reorganize fibrous extracellular matrices and form dense tracts of fibers between neighboring cells. These tracts guide the development of tubular tissue structures and provide paths for the invasion of cancer cells. Here, we studied the mechanisms of the mechanical plasticity of collagen tracts formed by contractile premalignant acinar cells and fibroblasts. Using fluorescence microscopy and second harmonic generation, we quantified the collagen densification, fiber alignment, and strains that remain within the tracts after cellular forces are abolished. We explained these observations using a theoretical fiber network model that accounts for the stretch-dependent formation of weak cross-links between nearby fibers. We tested the predictions of our model using shear rheology experiments. Both our model and rheological experiments demonstrated that increasing collagen concentration leads to substantial increases in plasticity. We also considered the effect of permanent elongation of fibers on network plasticity and derived a phase diagram that classifies the dominant mechanisms of plasticity based on the rate and magnitude of deformation and the mechanical properties of individual fibers. Plasticity is caused by the formation of new cross-links if moderate strains are applied at small rates or due to permanent fiber elongation if large strains are applied over short periods. Finally, we developed a coarse-grained model for plastic deformation of collagen networks that can be employed to simulate multicellular interactions in processes such as morphogenesis, cancer invasion, and fibrosis. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

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.

Cellular and Molecular Mechanisms of Diabetic Atherosclerosis: Herbal Medicines as a Potential Therapeutic Approach

Directory of Open Access Journals (Sweden)

Jinfan Tian

2017-01-01

Full Text Available An increasing number of patients diagnosed with diabetes mellitus eventually develop severe coronary atherosclerosis disease. Both type 1 and type 2 diabetes mellitus increase the risk of cardiovascular disease associated with atherosclerosis. The cellular and molecular mechanisms affecting the incidence of diabetic atherosclerosis are still unclear, as are appropriate strategies for the prevention and treatment of diabetic atherosclerosis. In this review, we discuss progress in the study of herbs as potential therapeutic agents for diabetic atherosclerosis.

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.

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.

Gender Inequality and Reflexive Law: The Potential of different regulatory Mechanisms for making Employment Rights effective

OpenAIRE

Deakin, S.; McLaughlin, C.; Chai, D.H.

2011-01-01

We review the different regulatory mechanisms which have been used in the UK context to promote gender equality in employment over the past decade, including legal enforcement based on claimant-led litigation, collective bargaining, pay audits, and shareholder pressure. Evidence is drawn from case studies examining the effects of these different mechanisms on organisations in the public and private sectors, and from econometric analysis of the impact of stock market pressures on firms' human ...

Cellular Signal Mechanisms of Reward-Related Plasticity in the Hippocampus

Directory of Open Access Journals (Sweden)

Masako Isokawa

2012-01-01

Full Text Available The hippocampus has the extraordinary capacity to process and store information. Consequently, there is an intense interest in the mechanisms that underline learning and memory. Synaptic plasticity has been hypothesized to be the neuronal substrate for learning. Ca2+ and Ca2+-activated kinases control cellular processes of most forms of hippocampal synapse plasticity. In this paper, I aim to integrate our current understanding of Ca2+-mediated synaptic plasticity and metaplasticity in motivational and reward-related learning in the hippocampus. I will introduce two representative neuromodulators that are widely studied in reward-related learning (e.g., ghrelin and endocannabinoids and show how they might contribute to hippocampal neuron activities and Ca2+-mediated signaling processes in synaptic plasticity. Additionally, I will discuss functional significance of these two systems and their signaling pathways for its relevance to maladaptive reward learning leading to addiction.

Do Surface Porosity and Pore Size Influence Mechanical Properties and Cellular Response to PEEK?

Science.gov (United States)

Torstrick, F Brennan; Evans, Nathan T; Stevens, Hazel Y; Gall, Ken; Guldberg, Robert E

2016-11-01

Despite its widespread use in orthopaedic implants such as soft tissue fasteners and spinal intervertebral implants, polyetheretherketone (PEEK) often suffers from poor osseointegration. Introducing porosity can overcome this limitation by encouraging bone ingrowth; however, the corresponding decrease in implant strength can potentially reduce the implant's ability to bear physiologic loads. We have previously shown, using a single pore size, that limiting porosity to the surface of PEEK implants preserves strength while supporting in vivo osseointegration. However, additional work is needed to investigate the effect of pore size on both the mechanical properties and cellular response to PEEK. (1) Can surface porous PEEK (PEEK-SP) microstructure be reliably controlled? (2) What is the effect of pore size on the mechanical properties of PEEK-SP? (3) Do surface porosity and pore size influence the cellular response to PEEK? PEEK-SP was created by extruding PEEK through NaCl crystals of three controlled ranges: 200 to 312, 312 to 425, and 425 to 508 µm. Micro-CT was used to characterize the microstructure of PEEK-SP. Tensile, fatigue, and interfacial shear tests were performed to compare the mechanical properties of PEEK-SP with injection-molded PEEK (PEEK-IM). The cellular response to PEEK-SP, assessed by proliferation, alkaline phosphatase activity, vascular endothelial growth factor production, and calcium content of osteoblast, mesenchymal stem cell, and preosteoblast (MC3T3-E1) cultures, was compared with that of machined smooth PEEK and Ti6Al4V. Micro-CT analysis showed that PEEK-SP layers possessed pores that were 284 ± 35 µm, 341 ± 49 µm, and 416 ± 54 µm for each pore size group. Porosity and pore layer depth ranged from 61% to 69% and 303 to 391 µm, respectively. Mechanical testing revealed tensile strengths > 67 MPa and interfacial shear strengths > 20 MPa for all three pore size groups. All PEEK-SP groups exhibited > 50% decrease

Modeling cellular systems

CERN Document Server

Matthäus, Franziska; Pahle, Jürgen

2017-01-01

This contributed volume comprises research articles and reviews on topics connected to the mathematical modeling of cellular systems. These contributions cover signaling pathways, stochastic effects, cell motility and mechanics, pattern formation processes, as well as multi-scale approaches. All authors attended the workshop on "Modeling Cellular Systems" which took place in Heidelberg in October 2014. The target audience primarily comprises researchers and experts in the field, but the book may also be beneficial for graduate students.

The regulatory mechanism in the U.S. lessons learned

International Nuclear Information System (INIS)

Roberts, T.M.

1987-01-01

The U.S. Nuclear Regulatory Commission is responsible for the regulation of the commercial uses of nuclear power in the United States in order to protect the public health and safety. The NRC has undertaken a number of initiatives to incorporate the experience gained from the over 25 years of commercial nuclear power plant operation. These initiatives are aimed at improving the regulatory structure currently in place by providing for a more predictable and stable regulatory environment and by more efficiently and effectively focusing the activities of utilities on the safe operation of their facilities. (author)

Differential polymer structure tunes mechanism of cellular uptake and transfection routes of poly(β-amino ester) polyplexes in human breast cancer cells.

Science.gov (United States)

Kim, Jayoung; Sunshine, Joel C; Green, Jordan J

2014-01-15

Successful gene delivery with nonviral particles has several barriers, including cellular uptake, endosomal escape, and nuclear transport. Understanding the mechanisms behind these steps is critical to enhancing the effectiveness of gene delivery. Polyplexes formed with poly(β-amino ester)s (PBAEs) have been shown to effectively transfer DNA to various cell types, but the mechanism of their cellular uptake has not been identified. This is the first study to evaluate the uptake mechanism of PBAE polyplexes and the dependence of cellular uptake on the end group and molecular weight of the polymer. We synthesized three different analogues of PBAEs with the same base polymer poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) (B4S4) but with small changes in the end group or molecular weight. We quantified the uptake and transfection efficiencies of the pDNA polyplexes formulated from these polymers in hard-to-transfect triple negative human breast cancer cells (MDA-MB 231). All polymers formed positively charged (10-17 mV) nanoparticles of ∼200 nm in size. Cellular internalization of all three formulations was inhibited the most (60-90% decrease in cellular uptake) by blocking caveolae-mediated endocytosis. Greater inhibition was shown with polymers that had a 1-(3-aminopropyl)-4-methylpiperazine end group (E7) than the others with a 2-(3-aminopropylamino)-ethanol end group (E6) or higher molecular weight. However, caveolae-mediated endocytosis was generally not as efficient as clathrin-mediated endocytosis in leading to transfection. These findings indicate that PBAE polyplexes can be used to transfect triple negative human breast cancer cells and that small changes to the same base polymer can modulate their cellular uptake and transfection routes.

pH Regulatory Transporters in Pancreatic Ductal Adenocarcinoma

DEFF Research Database (Denmark)

Kong, Su Chii

The abnormal features of hypoxia and altered metabolisms in solid tumours lead to an increased glycolysis that is uncoupled from oxidative phosphorylation in the TCA cycle. Tumoural cells often exhibit dysregulated expressions and activities of various membrane pH regulatory transporters to cope...... with the elevated acid production from this glycolysis, as well as from cellular ATP hydrolysis, sequentially creating a favourable intracellular pH and hostile acidic tumour microenvironment, fortify the tumour cells with highly invasive, metastatic and drug resistant phenotype. In current work, we study...... proliferation was found to be decreased while apoptosis was increased with concanamycin A treatment, indicative of V-ATPases being involved in PDAC cell survival mechanisms as well. Comprehending pH regulation in tumour cells might provide insights in preventing tumourigenesis by pH disruptions. Data presented...

CMRegNet-An interspecies reference database for corynebacterial and mycobacterial regulatory networks

DEFF Research Database (Denmark)

Abreu, Vinicius A C; Almeida, Sintia; Tiwari, Sandeep

2015-01-01

gene regulatory network can lead to various practical applications, creating a greater understanding of how organisms control their cellular behavior. DESCRIPTION: In this work, we present a new database, CMRegNet for the gene regulatory networks of Corynebacterium glutamicum ATCC 13032......Net to date the most comprehensive database of regulatory interactions of CMNR bacteria. The content of CMRegNet is publicly available online via a web interface found at http://lgcm.icb.ufmg.br/cmregnet ....

Molecular and Cellular Mechanisms of Shigella flexneri Dissemination.

Science.gov (United States)

Agaisse, Hervé

2016-01-01

The intracellular pathogen Shigella flexneri is the causative agent of bacillary dysentery in humans. The disease is characterized by bacterial invasion of intestinal cells, dissemination within the colonic epithelium through direct spread from cell to cell, and massive inflammation of the intestinal mucosa. Here, we review the mechanisms supporting S. flexneri dissemination. The dissemination process primarily relies on actin assembly at the bacterial pole, which propels the pathogen throughout the cytosol of primary infected cells. Polar actin assembly is supported by polar expression of the bacterial autotransporter family member IcsA, which recruits the N-WASP/ARP2/3 actin assembly machinery. As motile bacteria encounter cell-cell contacts, they form plasma membrane protrusions that project into adjacent cells. In addition to the ARP2/3-dependent actin assembly machinery, protrusion formation relies on formins and myosins. The resolution of protrusions into vacuoles occurs through the collapse of the protrusion neck, leading to the formation of an intermediate membrane-bound compartment termed vacuole-like protrusions (VLPs). VLP formation requires tyrosine kinase and phosphoinositide signaling in protrusions, which relies on the integrity of the bacterial type 3 secretion system (T3SS). The T3SS is also required for escaping double membrane vacuoles through the activity of the T3SS translocases IpaB and IpaC, and the effector proteins VirA and IcsB. Numerous factors supporting envelope biogenesis contribute to IcsA exposure and maintenance at the bacterial pole, including LPS synthesis, membrane proteases, and periplasmic chaperones. Although less characterized, the assembly and function of the T3SS in the context of bacterial dissemination also relies on factors supporting envelope biogenesis. Finally, the dissemination process requires the adaptation of the pathogen to various cellular compartments through transcriptional and post-transcriptional mechanisms.

Molecular and Cellular mechanisms of Shigella flexneri dissemination

Directory of Open Access Journals (Sweden)

Herve eAgaisse

2016-03-01

Full Text Available The intracellular pathogen Shigella flexneri is the causative agent of bacillary dysentery in humans. The disease is characterized by bacterial invasion of intestinal cells, dissemination within the colonic epithelium through direct spread from cell to cell, and massive inflammation of the intestinal mucosa. Here, we review the mechanisms supporting S. flexneri dissemination. The dissemination process primarily relies on actin assembly at the bacterial pole, which propels the pathogen throughout the cytosol of primary infected cells. Polar actin assembly is supported by polar expression of the bacterial autotransporter family member IcsA, which recruits the N-WASP/ARP2/3 actin assembly machinery. As motile bacteria encounter cell-cell contacts, they form plasma membrane protrusions that project into adjacent cells. In addition to the ARP2/3-dependent actin assembly machinery, protrusion formation relies on formins and myosins. The resolution of protrusions into vacuoles occurs through the collapse of the protrusion neck, leading to the formation of an intermediate membrane-bound compartment termed vacuole-like protrusions (VLPs. VLP formation requires tyrosine kinase and phosphoinositide signaling in protrusions, which relies on the integrity of the bacterial type 3 secretion system (T3SS. The T3SS is also required for escaping double membrane vacuoles through the activity of the T3SS translocases IpaB and IpaC, and the effector proteins VirA and IcsB. Numerous factors supporting envelope biogenesis contribute to IcsA exposure and maintenance at the bacterial pole, including LPS synthesis, membrane proteases, and periplasmic chaperones. Although less characterized, the assembly and function of the T3SS in the context of bacterial dissemination also relies on factors supporting envelope biogenesis. Finally, the dissemination process requires the adaptation of the pathogen to various cellular compartments through transcriptional and post

State of the Art of Fuzzy Methods for Gene Regulatory Networks Inference

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Tuqyah Abdullah Al Qazlan

2015-01-01

Full Text Available To address one of the most challenging issues at the cellular level, this paper surveys the fuzzy methods used in gene regulatory networks (GRNs inference. GRNs represent causal relationships between genes that have a direct influence, trough protein production, on the life and the development of living organisms and provide a useful contribution to the understanding of the cellular functions as well as the mechanisms of diseases. Fuzzy systems are based on handling imprecise knowledge, such as biological information. They provide viable computational tools for inferring GRNs from gene expression data, thus contributing to the discovery of gene interactions responsible for specific diseases and/or ad hoc correcting therapies. Increasing computational power and high throughput technologies have provided powerful means to manage these challenging digital ecosystems at different levels from cell to society globally. The main aim of this paper is to report, present, and discuss the main contributions of this multidisciplinary field in a coherent and structured framework.

Quantifying cellular mechanics and adhesion in renal tubular injury using single cell force spectroscopy.

Science.gov (United States)

Siamantouras, Eleftherios; Hills, Claire E; Squires, Paul E; Liu, Kuo-Kang

2016-05-01

Tubulointerstitial fibrosis represents the major underlying pathology of diabetic nephropathy where loss of cell-to-cell adhesion is a critical step. To date, research has predominantly focussed on the loss of cell surface molecular binding events that include altered protein ligation. In the current study, atomic force microscopy single cell force spectroscopy (AFM-SCFS) was used to quantify changes in cellular stiffness and cell adhesion in TGF-β1 treated kidney cells of the human proximal tubule (HK2). AFM indentation of TGF-β1 treated HK2 cells showed a significant increase (42%) in the elastic modulus (stiffness) compared to control. Fluorescence microscopy confirmed that increased cell stiffness is accompanied by reorganization of the cytoskeleton. The corresponding changes in stiffness, due to F-actin rearrangement, affected the work of detachment by changing the separation distance between two adherent cells. Overall, our novel data quantitatively demonstrate a correlation between cellular elasticity, adhesion and early morphologic/phenotypic changes associated with tubular injury. Diabetes affects many patients worldwide. One of the long term problems is diabetic nephropathy. Here, the authors utilized atomic force microscopy single cell force spectroscopy (AFM- SCFS) to study cellular stiffness and cell adhesion after TGF1 treatment in human proximal tubule kidney cells. The findings would help further understand the overall disease mechanism in diabetic patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Dynamic behavior of cellular materials and cellular structures: Experiments and modeling

Science.gov (United States)

Gao, Ziyang

Cellular solids, including cellular materials and cellular structures (CMS), have attracted people's great interests because of their low densities and novel physical, mechanical, thermal, electrical and acoustic properties. They offer potential for lightweight structures, energy absorption, thermal management, etc. Therefore, the studies of cellular solids have become one of the hottest research fields nowadays. From energy absorption point of view, any plastically deformed structures can be divided into two types (called type I and type II), and the basic cells of the CMS may take the configurations of these two types of structures. Accordingly, separated discussions are presented in this thesis. First, a modified 1-D model is proposed and numerically solved for a typical type II structure. Good agreement is achieved with the previous experimental data, hence is used to simulate the dynamic behavior of a type II chain. Resulted from different load speeds, interesting collapse modes are observed, and the parameters which govern the cell's post-collapse behavior are identified through a comprehensive non-dimensional analysis on general cellular chains. Secondly, the MHS specimens are chosen as an example of type I foam materials because of their good uniformity of the cell geometry. An extensive experimental study was carried out, where more attention was paid to their responses to dynamic loadings. Great enhancement of the stress-strain curve was observed in dynamic cases, and the energy absorption capacity is found to be several times higher than that of the commercial metal foams. Based on the experimental study, finite elemental simulations and theoretical modeling are also conducted, achieving good agreements and demonstrating the validities of those models. It is believed that the experimental, numerical and analytical results obtained in the present study will certainly deepen the understanding of the unsolved fundamental issues on the mechanical behavior of

Mechanisms of cellular synchronization in the vascular wall. Mechanisms of vasomotion

DEFF Research Database (Denmark)

Matchkov, Vladimir

2010-01-01

. The presence of chloride channels in virtually all living cells is an essential problem as well as the dependence of ion channel properties on the complex interaction of many cellular proteins. I was the first who coupled the endogenous chloride current to one of four known bestrophin isoforms. PCR and Western...

Effects of Matrix Alignment and Mechanical Constraints on Cellular Behavior in 3D Engineered Microtissues

Science.gov (United States)

Bose, Prasenjit; Eyckmans, Jeroen; Chen, Christopher; Reich, Daniel

The adhesion of cells to the extracellular matrix (ECM) plays a crucial role in a variety of cellular functions. The main building blocks of the ECM are 3D networks of fibrous proteins whose structure and alignments varies with tissue type. However, the impact of ECM alignment on cellular behaviors such as cell adhesion, spreading, extension and mechanics remains poorly understood. We present results on the development of a microtissue-based system that enables control of the structure, orientation, and degree of fibrillar alignment in 3D fibroblast-populated collagen gels. The tissues self-assemble from cell-laden collagen gels placed in micro-fabricated wells containing sets of elastic pillars. The contractile action of the cells leads to controlled alignment of the fibrous collagen, depending on the number and location of the pillars in each well. The pillars are elastic, and are utilized to measure the contractile forces of the microtissues, and by incorporating magnetic material in selected pillars, time-varying forces can be applied to the tissues for dynamic stimulation and measurement of mechanical properties. Results on the effects of varying pillar shape, spacing, location, and stiffness on microtissue organization and contractility will be presented. This work is supported by NSF CMMI-1463011.

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.

Multiple post-transcriptional regulatory mechanisms in ferritin gene expression

International Nuclear Information System (INIS)

Mattia, E.; Den Blaauwen, J.; Van Renswoude, J.; Ashwell, G.

1989-01-01

The authors have investigated the mechanisms involved in the regulation of ferritin biosynthesis in K562 human erythroleukemia cells during prolonged exposure to iron. They show that, upon addition of hemin (an efficient iron donor) to the cell culture, the rate of ferritin biosynthesis reaches a maximum after a few hours and then decreases. During a 24-hr incubation with the iron donor the concentrations of total ferritin heavy (H) and light (L) subunit mRNAs rise 2- to 5-fold and 2- to 3-fold, respectively, over the control values, while the amount of the protein increases 10- to 30-fold. The hemin-induced increment in ferritin subunit mRNA is not prevented by deferoxamine, suggesting that it is not directly mediated by chelatable iron. In vitro nuclear transcription analyses performed on nuclei isolated from control cells and cells grown in the presence of hemin indicate that the rates of synthesis of H- and L-subunit mRNAs remain constant. They conclude that iron-induced ferritin biosynthesis is governed by multiple post-transcriptional regulatory mechanisms. They propose that exposure of cells to iron leads to stabilization of ferritin mRNAs, in addition to activation and translation of stored H-and L-subunit mRNAs

Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats

International Nuclear Information System (INIS)

Rashid, Kahkashan; Sil, Parames C.

2015-01-01

The phytochemical, curcumin, has been reported to play many beneficial roles. However, under diabetic conditions, the detail mechanism of its beneficial action in the glucose homeostasis regulatory organ, pancreas, is poorly understood. The present study has been designed and carried out to explore the role of curcumin in the pancreatic tissue of STZ induced and cellular stress mediated diabetes in eight weeks old male Wistar rats. Diabetes was induced with a single intraperitoneal dose of STZ (65 mg/kg body weight). Post to diabetes induction, animals were treated with curcumin at a dose of 100 mg/kg body weight for eight weeks. Underlying molecular and cellular mechanism was determined using various biochemical assays, DNA fragmentation, FACS, histology, immunoblotting and ELISA. Treatment with curcumin reduced blood glucose level, increased plasma insulin and mitigated oxidative stress related markers. In vivo and in vitro experimental results revealed increased levels of proinflammatory cytokines (TNF-α, IL1-β and IFN-γ), reduced level of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2) along with enhanced levels of signaling molecules of ER stress dependent and independent apoptosis (cleaved Caspase-12/9/8/3) in STZ administered group. Treatment with curcumin ameliorated all the adverse changes and helps the organ back to its normal physiology. Results suggest that curcumin protects pancreatic beta-cells by attenuating inflammatory responses, and inhibiting ER/mitochondrial dependent and independent pathways of apoptosis and crosstalk between them. This uniqueness and absence of any detectable adverse effect proposes the possibility of using this molecule as an effective protector in the cellular stress mediated diabetes mellitus. - Highlights: • STZ induced cellular stress plays a vital role in pancreatic dysfunction. • Cellular stress causes inflammation, pancreatic islet cell death and diabetes. • Deregulation of Nrf-2

Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats

Energy Technology Data Exchange (ETDEWEB)

Rashid, Kahkashan; Sil, Parames C., E-mail: parames@jcbose.ac.in

2015-02-01

The phytochemical, curcumin, has been reported to play many beneficial roles. However, under diabetic conditions, the detail mechanism of its beneficial action in the glucose homeostasis regulatory organ, pancreas, is poorly understood. The present study has been designed and carried out to explore the role of curcumin in the pancreatic tissue of STZ induced and cellular stress mediated diabetes in eight weeks old male Wistar rats. Diabetes was induced with a single intraperitoneal dose of STZ (65 mg/kg body weight). Post to diabetes induction, animals were treated with curcumin at a dose of 100 mg/kg body weight for eight weeks. Underlying molecular and cellular mechanism was determined using various biochemical assays, DNA fragmentation, FACS, histology, immunoblotting and ELISA. Treatment with curcumin reduced blood glucose level, increased plasma insulin and mitigated oxidative stress related markers. In vivo and in vitro experimental results revealed increased levels of proinflammatory cytokines (TNF-α, IL1-β and IFN-γ), reduced level of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2) along with enhanced levels of signaling molecules of ER stress dependent and independent apoptosis (cleaved Caspase-12/9/8/3) in STZ administered group. Treatment with curcumin ameliorated all the adverse changes and helps the organ back to its normal physiology. Results suggest that curcumin protects pancreatic beta-cells by attenuating inflammatory responses, and inhibiting ER/mitochondrial dependent and independent pathways of apoptosis and crosstalk between them. This uniqueness and absence of any detectable adverse effect proposes the possibility of using this molecule as an effective protector in the cellular stress mediated diabetes mellitus. - Highlights: • STZ induced cellular stress plays a vital role in pancreatic dysfunction. • Cellular stress causes inflammation, pancreatic islet cell death and diabetes. • Deregulation of Nrf-2

Retrievability of high-level nuclear waste from geologic repositories - Regulatory and rock mechanics/design considerations

International Nuclear Information System (INIS)

Tanious, N.S.; Nataraja, M.S.; Daemen, J.J.K.

1987-01-01

Retrievability of nuclear waste from high-level geologic repositories is one of the performance objectives identified in 10CFR60 (Code of Federal Regulations, 1985). 10CFR60.111 states that the geologic repository operations area shall be designed to preserve the option of waste retrieval. In designing the repository operations area, rock mechanics considerations play a major role especially in evaluating the feasibility of retrieval operations. This paper discusses generic considerations affecting retrievability as they relate to repository design, construction, and operation, with emphasis on regulatory and rock mechanics aspects

Epigenetics and Cellular Metabolism

OpenAIRE

Wenyi Xu; Fengzhong Wang; Zhongsheng Yu; Fengjiao Xin

2016-01-01

Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the proce...

Cellular Force Microscopy for in Vivo Measurements of Plant Tissue Mechanics1[W][OA

Science.gov (United States)

Routier-Kierzkowska, Anne-Lise; Weber, Alain; Kochova, Petra; Felekis, Dimitris; Nelson, Bradley J.; Kuhlemeier, Cris; Smith, Richard S.

2012-01-01

Although growth and morphogenesis are controlled by genetics, physical shape change in plant tissue results from a balance between cell wall loosening and intracellular pressure. Despite recent work demonstrating a role for mechanical signals in morphogenesis, precise measurement of mechanical properties at the individual cell level remains a technical challenge. To address this challenge, we have developed cellular force microscopy (CFM), which combines the versatility of classical microindentation techniques with the high automation and resolution approaching that of atomic force microscopy. CFM’s large range of forces provides the possibility to map the apparent stiffness of both plasmolyzed and turgid tissue as well as to perform micropuncture of cells using very high stresses. CFM experiments reveal that, within a tissue, local stiffness measurements can vary with the level of turgor pressure in an unexpected way. Altogether, our results highlight the importance of detailed physically based simulations for the interpretation of microindentation results. CFM’s ability to be used both to assess and manipulate tissue mechanics makes it a method of choice to unravel the feedbacks between mechanics, genetics, and morphogenesis. PMID:22353572

Modulation of the mechanical properties of ventricular extracellular matrix hydrogels with a carbodiimide crosslinker and investigation of their cellular compatibility

Directory of Open Access Journals (Sweden)

Kyohei Fujita

2018-01-01

Full Text Available Hydrogels made from the cardiac extracellular matrix (ECM as two-dimensional (2D or 3D cell-culture substrates have beneficial biochemical effects on the differentiation of stem cells into cardiomyocytes. The mechanical properties of the substrates that match those of the host tissues have been identified as critical biophysical cues for coaxing the tissue-specific differentiation of stem cells. The objectives of the present study are (1 to fabricate hydrogels comprising pure ventricular ECM (vECM, (2 to make the gels possess mechanical properties similar to those of the decellularized ventricular tissue, and (3 to evaluate the cellular compatibility of the hydrogels. In order to achieve these aims, (1 a simplified protocol was developed to produce vECM solution easily and rapidly, (2 N-(3-Dimethylaminopropyl-N’-ethylcarbodiimide hydrochloride (EDAC was chosen to crosslink the hydrogels made from the vECM solution to enhance their mechanical properties and stabilize the microstructure of the gels, (3 rat embryonic fibroblasts or cardiomyocytes were cultured on these gels to determine the cellular compatibility of the gels. In particular, the nonlinearity and viscoelasticity of the gels were characterized quantitatively using a newly proposed nonlinear Kelvin model. The results showed that EDAC treatment allowed modulation of the mechanical properties of the gels to the same level as those of decellularized ventricular tissue in terms of the equilibrium elasticity and relaxation coefficient. Cell culture confirmed the cellular compatibility of the gels. Furthermore, an empirical relationship between the equilibrium elastic modulus of the gels and the vECM and EDAC concentrations was derived, which is important to tailor the mechanical properties of the gels. Finally, the influence of the mechanical properties of the gels on the behavior of cultured fibroblasts and cardiomyocytes was discussed.

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

Directory of Open Access Journals (Sweden)

Arturo Blazquez-Navarro

2018-05-01

Full Text Available BK virus (BKV associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

Science.gov (United States)

Blazquez-Navarro, Arturo; Schachtner, Thomas; Stervbo, Ulrik; Sefrin, Anett; Stein, Maik; Westhoff, Timm H; Reinke, Petra; Klipp, Edda; Babel, Nina; Neumann, Avidan U; Or-Guil, Michal

2018-05-01

BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

Unraveling the cellular and molecular mechanisms of repetitive magnetic stimulation

Directory of Open Access Journals (Sweden)

Florian eMüller-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.

Cellular and molecular mechanisms in malignant transformation of diploid rodent and human cells by radiation

International Nuclear Information System (INIS)

Borek, C.

1985-01-01

The development of cell culture systems has made it possible to probe into the effects of radiation at a cellular and molecular level, under defined conditions where homeostatic mechanisms do not prevail. Using in vitro systems free of host-medicated influences, one can assess qualitatively and quantitatively dose-related and time-dependent interactions of radiation with single cells and to evaluate the influences of agents that may enhance or inhibit the oncogenic potential of radiation. These systems are useful in pragmatic studies where dose response relationships and cancer risk estimates are assessed with particular focus on the low dose range of radiation where epidemiological and animal studies are limiting. The in vitro systems serve well also in mechanistic studies where cellular and molecular processes underlying transformation can be elucidated and where the role of modulating factors which determine the frequency and quality of these events can be investigated

Transcription regulatory networks analysis using CAGE

KAUST Repository

Tegnér, Jesper N.

2009-10-01

Mapping out cellular networks in general and transcriptional networks in particular has proved to be a bottle-neck hampering our understanding of biological processes. Integrative approaches fusing computational and experimental technologies for decoding transcriptional networks at a high level of resolution is therefore of uttermost importance. Yet, this is challenging since the control of gene expression in eukaryotes is a complex multi-level process influenced by several epigenetic factors and the fine interplay between regulatory proteins and the promoter structure governing the combinatorial regulation of gene expression. In this chapter we review how the CAGE data can be integrated with other measurements such as expression, physical interactions and computational prediction of regulatory motifs, which together can provide a genome-wide picture of eukaryotic transcriptional regulatory networks at a new level of resolution. © 2010 by Pan Stanford Publishing Pte. Ltd. All rights reserved.

Regulatory mechanisms of RNA function: emerging roles of DNA repair enzymes.

Science.gov (United States)

Jobert, Laure; Nilsen, Hilde

2014-07-01

The acquisition of an appropriate set of chemical modifications is required in order to establish correct structure of RNA molecules, and essential for their function. Modification of RNA bases affects RNA maturation, RNA processing, RNA quality control, and protein translation. Some RNA modifications are directly involved in the regulation of these processes. RNA epigenetics is emerging as a mechanism to achieve dynamic regulation of RNA function. Other modifications may prevent or be a signal for degradation. All types of RNA species are subject to processing or degradation, and numerous cellular mechanisms are involved. Unexpectedly, several studies during the last decade have established a connection between DNA and RNA surveillance mechanisms in eukaryotes. Several proteins that respond to DNA damage, either to process or to signal the presence of damaged DNA, have been shown to participate in RNA quality control, turnover or processing. Some enzymes that repair DNA damage may also process modified RNA substrates. In this review, we give an overview of the DNA repair proteins that function in RNA metabolism. We also discuss the roles of two base excision repair enzymes, SMUG1 and APE1, in RNA quality control.

Transcriptional regulatory network triggered by oxidative signals configures the early response mechanisms of japonica rice to chilling stress

KAUST Repository

Yun, Kil-Young; Park, Myoung Ryoul; Mohanty, Bijayalaxmi; Herath, Venura; Xu, Fuyu; Mauleon, Ramil; Wijaya, Edward; Bajic, Vladimir B.; Bruskiewich, Richard; de los Reyes, Benildo G

2010-01-01

-plant level analyses established a holistic view of chilling stress response mechanism of japonica rice. Early response regulatory network triggered by oxidative signals is critical for prolonged survival under sub-optimal temperature. Integration of stress

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

International Nuclear Information System (INIS)

Latham, Antony M.; Odell, Adam F.; Mughal, Nadeem A.; Issitt, Theo; Ulyatt, Clare; Walker, John H.; Homer-Vanniasinkam, Shervanthi; Ponnambalam, Sreenivasan

2012-01-01

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: ► Endothelial cells mount a stress response under conditions of low serum. ► Endothelial VEGFR levels are

Molecular biological mechanism II. Molecular mechanisms of cell cycle regulation

International Nuclear Information System (INIS)

Jung, T.

2000-01-01

The cell cycle in eukaryotes is regulated by central cell cycle controlling protein kinase complexes. These protein kinase complexes consist of a catalytic subunit from the cyclin-dependent protein kinase family (CDK), and a regulatory subunit from the cyclin family. Cyclins are characterised by their periodic cell cycle related synthesis and destruction. Each cell cycle phase is characterised by a specific set of CDKs and cyclins. The activity of CDK/cyclin complexes is mainly regulated on four levels. It is controlled by specific phosphorylation steps, the synthesis and destruction of cyclins, the binding of specific inhibitor proteins, and by active control of their intracellular localisation. At several critical points within the cell cycle, named checkpoints, the integrity of the cellular genome is monitored. If damage to the genome or an unfinished prior cell cycle phase is detected, the cell cycle progression is stopped. These cell cycle blocks are of great importance to secure survival of cells. Their primary importance is to prevent the manifestation and heritable passage of a mutated genome to daughter cells. Damage sensing, DNA repair, cell cycle control and apoptosis are closely linked cellular defence mechanisms to secure genome integrity. Disregulation in one of these defence mechanisms are potentially correlated with an increased cancer risk and therefore in at least some cases with an increased radiation sensitivity. (orig.) [de

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

International Nuclear Information System (INIS)

Veyhl, C.; Belova, I.V.; Murch, G.E.; Fiedler, T.

2011-01-01

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.

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

OpenAIRE

Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Amankwah, Ernest K.; Qu, Xiaotao; Tsai, Ya-Yu; Jim, Heather S. L.; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia

2015-01-01

Background\\ud \\ud Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contribu...

MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma

Science.gov (United States)

Beckers, Anneleen; Van Peer, Gert; Carter, Daniel R.; Gartlgruber, Moritz; Herrmann, Carl; Agarwal, Saurabh; Helsmoortel, Hetty H.; Althoff, Kristina; Molenaar, Jan J.; Cheung, Belamy B.; Schulte, Johannes H.; Benoit, Yves; Shohet, Jason M.; Westermann, Frank; Marshall, Glenn M.; Vandesompele, Jo; De Preter, Katleen; Speleman, Frank

2016-01-01

LIN28B has been identified as an oncogene in various tumor entities, including neuroblastoma, a childhood cancer that originates from neural crest-derived cells, and is characterized by amplification of the MYCN oncogene. Recently, elevated LIN28B expression levels were shown to contribute to neuroblastoma tumorigenesis via let-7 dependent de-repression of MYCN. However, additional insight in the regulation of LIN28B in neuroblastoma is lacking. Therefore, we have performed a comprehensive analysis of the regulation of LIN28B in neuroblastoma, with a specific focus on the contribution of miRNAs. We show that MYCN regulates LIN28B expression in neuroblastoma tumors via two distinct parallel mechanisms. First, through an unbiased LIN28B-3′UTR reporter screen, we found that miR-26a-5p and miR-26b-5p regulate LIN28B expression. Next, we demonstrated that MYCN indirectly affects the expression of miR-26a-5p, and hence regulates LIN28B, therefor establishing a MYCN-miR-26a-5p-LIN28B regulatory axis. Second, we provide evidence that MYCN regulates LIN28B expression via interaction with the LIN28B promotor, establishing a direct MYCN-LIN28B regulatory axis. We believe that these findings mark LIN28B as an important effector of the MYCN oncogenic phenotype and underlines the importance of MYCN-regulated miRNAs in establishing the MYCN-driven oncogenic process. PMID:26123663

Sordaria macrospora, a model organism to study fungal cellular development.

Science.gov (United States)

Engh, Ines; Nowrousian, Minou; Kück, Ulrich

2010-12-01

During the development of multicellular eukaryotes, the processes of cellular growth and organogenesis are tightly coordinated. Since the 1940s, filamentous fungi have served as genetic model organisms to decipher basic mechanisms underlying eukaryotic cell differentiation. Here, we focus on Sordaria macrospora, a homothallic ascomycete and important model organism for developmental biology. During its sexual life cycle, S. macrospora forms three-dimensional fruiting bodies, a complex process involving the formation of different cell types. S. macrospora can be used for genetic, biochemical and cellular experimental approaches since diverse tools, including fluorescence microscopy, a marker recycling system and gene libraries, are available. Moreover, the genome of S. macrospora has been sequenced and allows functional genomics analyses. Over the past years, our group has generated and analysed a number of developmental mutants which has greatly enhanced our fundamental understanding about fungal morphogenesis. In addition, our recent research activities have established a link between developmental proteins and conserved signalling cascades, ultimately leading to a regulatory network controlling differentiation processes in a eukaryotic model organism. This review summarizes the results of our recent findings, thus advancing current knowledge of the general principles and paradigms underpinning eukaryotic cell differentiation and development. Copyright © 2010 Elsevier GmbH. All rights reserved.

Measuring the correlation between cell mechanics and myofibroblastic differentiation during maturation of 3D microtissues

Science.gov (United States)

Zhao, Ruogang; Wang, Weigang; Boudou, Thomas; Chen, Christopher; Reich, Daniel

2013-03-01

Tissue stiffness and cellular contractility are two of the most important biomechanical factors regulating pathological transitions of encapsulated cells, such as the differentiation of fibroblasts into myofibroblasts - a key event contributing to tissue fibrosis. However, a quantitative correlation between tissue stiffness and cellular contraction and myofibroblast differentiation has not yet been established in 3D environments, mainly due to the lack of suitable 3D tissue culture models that allow both tissue remodeling and simultaneous measurement of the cell/tissue mechanics. To address this, we have developed a magnetic microtissue tester system that allows the remodeling of arrays of cell-laden 3D collagen microtissues and the measurement of cell and tissue mechanics using magnetically actuated elastomeric microcantilevers. By measuring the development of cell/tissue mechanical properties and the expression level of α-smooth muscle actin (α-SMA, a marker for myofibroblast differentiation) during a 6 day culture period, we found microtissue stiffness increased by 45% and α-SMA expression increased by 38%, but tissue contraction forces only increased by 10%, indicating that tissue stiffness may be the predominant mechanical factor for regulation of myofibroblast differentiation. This study provides new quantitative insight into the regulatory effect of cell and tissue mechanics on cellular function. Supported in part by NIH grant HL090747

Controlling cellular P-TEFb activity by the HIV-1 transcriptional transactivator Tat.

Directory of Open Access Journals (Sweden)

Lisa Muniz

Full Text Available The human immunodeficiency virus 1 (HIV-1 transcriptional transactivator (Tat is essential for synthesis of full-length transcripts from the integrated viral genome by RNA polymerase II (Pol II. Tat recruits the host positive transcription elongation factor b (P-TEFb to the HIV-1 promoter through binding to the transactivator RNA (TAR at the 5'-end of the nascent HIV transcript. P-TEFb is a general Pol II transcription factor; its cellular activity is controlled by the 7SK small nuclear RNA (snRNA and the HEXIM1 protein, which sequester P-TEFb into transcriptionally inactive 7SK/HEXIM/P-TEFb snRNP. Besides targeting P-TEFb to HIV transcription, Tat also increases the nuclear level of active P-TEFb through promoting its dissociation from the 7SK/HEXIM/P-TEFb RNP by an unclear mechanism. In this study, by using in vitro and in vivo RNA-protein binding assays, we demonstrate that HIV-1 Tat binds with high specificity and efficiency to an evolutionarily highly conserved stem-bulge-stem motif of the 5'-hairpin of human 7SK snRNA. The newly discovered Tat-binding motif of 7SK is structurally and functionally indistinguishable from the extensively characterized Tat-binding site of HIV TAR and importantly, it is imbedded in the HEXIM-binding elements of 7SK snRNA. We show that Tat efficiently replaces HEXIM1 on the 7SK snRNA in vivo and therefore, it promotes the disassembly of the 7SK/HEXIM/P-TEFb negative transcriptional regulatory snRNP to augment the nuclear level of active P-TEFb. This is the first demonstration that HIV-1 specifically targets an important cellular regulatory RNA, most probably to promote viral transcription and replication. Demonstration that the human 7SK snRNA carries a TAR RNA-like Tat-binding element that is essential for the normal transcriptional regulatory function of 7SK questions the viability of HIV therapeutic approaches based on small drugs blocking the Tat-binding site of HIV TAR.

Regulatory mechanisms of metabolic flexibility in the dark-eyed junco (Junco hyemalis).

Science.gov (United States)

Stager, Maria; Swanson, David L; Cheviron, Zachary A

2015-03-01

Small temperate birds reversibly modify their aerobic performance to maintain thermoregulatory homeostasis under seasonally changing environmental conditions and these physiological adjustments may be attributable to changes in the expression of genes in the underlying regulatory networks. Here, we report the results of an experimental procedure designed to gain insight into the fundamental mechanisms of metabolic flexibility in the dark-eyed junco (Junco hyemalis). We combined genomic transcriptional profiles with measures of metabolic enzyme activities and whole-animal thermogenic performance from juncos exposed to four 6-week acclimation treatments that varied in temperature (cold, 3°C; warm, 24°C) and photoperiod (short day, 8 h light:16 h dark; long day, 16 h light:8 h dark). Cold-acclimated birds increased thermogenic capacity compared with warm-acclimated birds, and this enhanced performance was associated with upregulation of genes involved in muscle hypertrophy, angiogenesis, and lipid transport and oxidation, as well as with catabolic enzyme activities. These physiological changes occurred over ecologically relevant timescales, suggesting that birds make regulatory adjustments to interacting, hierarchical pathways in order to seasonally enhance thermogenic capacity. © 2015. Published by The Company of Biologists Ltd.

A microfluidic-enabled mechanical microcompressor for the immobilization of live single- and multi-cellular specimens.

Science.gov (United States)

Yan, Yingjun; Jiang, Liwei; Aufderheide, Karl J; Wright, Gus A; Terekhov, Alexander; Costa, Lino; Qin, Kevin; McCleery, W Tyler; Fellenstein, John J; Ustione, Alessandro; Robertson, J Brian; Johnson, Carl Hirschie; Piston, David W; Hutson, M Shane; Wikswo, John P; Hofmeister, William; Janetopoulos, Chris

2014-02-01

A microcompressor is a precision mechanical device that flattens and immobilizes living cells and small organisms for optical microscopy, allowing enhanced visualization of sub-cellular structures and organelles. We have developed an easily fabricated device, which can be equipped with microfluidics, permitting the addition of media or chemicals during observation. This device can be used on both upright and inverted microscopes. The apparatus permits micrometer precision flattening for nondestructive immobilization of specimens as small as a bacterium, while also accommodating larger specimens, such as Caenorhabditis elegans, for long-term observations. The compressor mount is removable and allows easy specimen addition and recovery for later observation. Several customized specimen beds can be incorporated into the base. To demonstrate the capabilities of the device, we have imaged numerous cellular events in several protozoan species, in yeast cells, and in Drosophila melanogaster embryos. We have been able to document previously unreported events, and also perform photobleaching experiments, in conjugating Tetrahymena thermophila.

The Unexplored Mechanisms and Regulatory Functions of Ribosomal Translocation

Science.gov (United States)

Alejo, Jose Luis

In every cell, protein synthesis is carried out by the ribosome, a complex macromolecular RNA-protein assembly. Decades of structural and kinetic studies have increased our understanding of ribosome initiation, decoding, translocation and termination. Yet, the underlying mechanism of these fundamental processes has yet to be fully delineated. Hence, the molecular basis of regulation remains obscure. Here, single-molecule fluorescence methods are applied to decipher the mechanism and regulatory roles of the multi-step process of directional substrate translocation on the ribosome that accompanies every round of protein synthesis. In Chapter 1, single-molecule fluorescence resonance energy transfer (smFRET) is introduced as a tool for studying bacterial ribosome translocation. Chapter 2 details the experimental methods. In Chapter 3, the elongation factor G(EF-G)-catalyzed movement of substrates through the ribosome is examined from several perspectives or signals reporting on various degrees of freedom of ribosome dynamics. Two ribosomal states interconvert in the presence of EF-G(GDP), displaying novel head domain motions, until relocking takes place. In Chapter 4, in order to test if the mentioned fluctuations leading to relocking are correlated to the engagement of the P-site by the peptidyl-tRNA, the translocation of miscoded tRNAs is studied. Severe defects in the relocking stages of translocation reveal the correlation between this new stage of translocation and P-site tRNA engagement.

Numerical Investigation on the Propagation Mechanism of Steady Cellular Detonations in Curved Channels

International Nuclear Information System (INIS)

Li Jian; Ning Jian-Guo; Zhao Hui; Wang Cheng; Hao Li

2015-01-01

The propagation mechanism of steady cellular detonations in curved channels is investigated numerically with a detailed chemical reaction mechanism. The numerical results demonstrate that as the radius of the curvature decreases, detonation fails near the inner wall due to the strong expansion effect. As the radius of the curvature increases, the detonation front near the inner wall can sustain an underdriven detonation. In the case where detonation fails, a transverse detonation downstream forms and re-initiates the quenched detonation as it propagates toward the inner wall. Two kinds of propagation modes exist as the detonation is propagating in the curved channel. One is that the detonation fails first, and then a following transverse detonation initiates the quenched detonation and this process repeats itself. The other one is that without detonation failure and re-initiation, a steady detonation exists which consists of an underdriven detonation front near the inner wall subject to the diffraction and an overdriven detonation near the outer wall subject to the compression. (paper)

Identification of cellular responses to low-dose radiation by antibody array in human B-lymphoblasts IM-9 cells

Energy Technology Data Exchange (ETDEWEB)

Eom, Hyeon Soo; Kim, Ji Young; Nam, Seon Young [Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro and Nuclear Power Co. LTD., Seoul (Korea, Republic of)

2017-04-15

The low-dose radiation (LDR)-induced various responses can reduce genetic mutation, enhance cell survival, and increase infection resistance (1). The antibody array for global analysis of phosphorylated proteins might be very useful to study signaling networks of LDR-induced cellular responses (2). Therefore, global analysis of phospho- proteins in cells exposed to radiation is important to understand the signaling mechanisms induced by changes of protein phosphorylation which lead to various biological effects by radiation. The aim is to explore the possibility of LDR-specific signaling for various beneficial effects and elucidate the potential signaling pathways representing LDR responses. Our results suggest that LDR did not affect cell death and that the increased proteins phosphorylation by LDR might be involved in various cellular responses for cell homeostasis. These results might be useful to further studies aimed at investigating potential regulatory markers that represent responses to LDR.

Identification of cellular responses to low-dose radiation by antibody array in human B-lymphoblasts IM-9 cells

International Nuclear Information System (INIS)

Eom, Hyeon Soo; Kim, Ji Young; Nam, Seon Young

2017-01-01

The low-dose radiation (LDR)-induced various responses can reduce genetic mutation, enhance cell survival, and increase infection resistance (1). The antibody array for global analysis of phosphorylated proteins might be very useful to study signaling networks of LDR-induced cellular responses (2). Therefore, global analysis of phospho- proteins in cells exposed to radiation is important to understand the signaling mechanisms induced by changes of protein phosphorylation which lead to various biological effects by radiation. The aim is to explore the possibility of LDR-specific signaling for various beneficial effects and elucidate the potential signaling pathways representing LDR responses. Our results suggest that LDR did not affect cell death and that the increased proteins phosphorylation by LDR might be involved in various cellular responses for cell homeostasis. These results might be useful to further studies aimed at investigating potential regulatory markers that represent responses to LDR

A new type of sandwich panel with periodic cellular metal cores and its mechanical performances

International Nuclear Information System (INIS)

Lim, Chae-Hong; Jeon, Insu; Kang, Ki-Ju

2009-01-01

Many studies have been performed on the mechanical properties and optimization of truss PCMs (periodic cellular metals), but those on the fabrication process, which is one of key factors determining the survivability of PCMs in the market, have been relatively limited. This study introduces a new idea on the fabrication of quasi Kagome truss cored sandwich panels, which is based on the expanded-metal process. And the mechanical behavior of the sandwich panels is to be evaluated. The mechanical strengths and failure mechanisms under compression and bending load are estimated based on elementary mechanics of materials, and the optimal design is derived. Its validity is proved by comparison with the results of experiments. The results showed that the new idea is promising with respect to all three requirements, i.e., the morphology, fabrication cost, and raw materials. The simple mechanical analysis was sufficiently effective and accurate for estimating the performance and failure mode of the sandwich panels. In the experiments, sandwich panel specimens of three different designs were compared in their bending behaviors to demonstrate sensitivity of geometric parameters. Namely, although all the designs had little difference in their load capacity-per-weight, the failure mechanisms and the behaviors after a peak load were totally different.

Targeting Cellular Stress Mechanisms and Metabolic Homeostasis by Chinese Herbal Drugs for Neuroprotection

Directory of Open Access Journals (Sweden)

Hsiao-Chien Ting

2018-01-01

Full Text Available Traditional Chinese medicine has been practiced for centuries in East Asia. Herbs are used to maintain health and cure disease. Certain Chinese herbs are known to protect and improve the brain, memory, and nervous system. To apply ancient knowledge to modern science, some major natural therapeutic compounds in herbs were extracted and evaluated in recent decades. Emerging studies have shown that herbal compounds have neuroprotective effects or can ameliorate neurodegenerative diseases. To understand the mechanisms of herbal compounds that protect against neurodegenerative diseases, we summarize studies that discovered neuroprotection by herbal compounds and compound-related mechanisms in neurodegenerative disease models. Those compounds discussed herein show neuroprotection through different mechanisms, such as cytokine regulation, autophagy, endoplasmic reticulum (ER stress, glucose metabolism, and synaptic function. The interleukin (IL-1β and tumor necrosis factor (TNF-α signaling pathways are inhibited by some compounds, thus attenuating the inflammatory response and protecting neurons from cell death. As to autophagy regulation, herbal compounds show opposite regulatory effects in different neurodegenerative models. Herbal compounds that inhibit ER stress prevent neuronal death in neurodegenerative diseases. Moreover, there are compounds that protect against neuronal death by affecting glucose metabolism and synaptic function. Since the progression of neurodegenerative diseases is complicated, and compound-related mechanisms for neuroprotection differ, therapeutic strategies may need to involve multiple compounds and consider the type and stage of neurodegenerative diseases.

Characterizing heterogeneous cellular responses to perturbations.

Science.gov (United States)

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

2008-12-09

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

Mechanism of cellular secretion studied by high resolution soft-x-ray microscopy

International Nuclear Information System (INIS)

Loo, B.W. Jr.; Meyer-Ilse, W.; Rothman, S.S.

1997-01-01

The secretion of proteins is a fundamental cellular process. The physical and biochemical mechanisms that underlie this process have been studied with the view that they can serve as a general model for how cells transport many different substances to and through their various compartments and to the external environment. In this work, the authors study the secretion of digestive enzymes by the acinar cell of the mammalian pancreas. This is the classical system for studying such processes. The proteins that digest food are stored in approximately micrometer sized vesicles, zymogen granules, within these cells. There are two explanations for how these proteins are transported from within the granules to the exterior of the cell during the process of secretion. One proposes that whole granules are lost from the cell in discrete events, and the other proposes that partial and gradual emptying of the granules accounts for protein secretion. Of course, both mechanisms may occur. The authors are attempting to assess to what degree each of these mechanisms account for protein secretion by the organ. In order to do so, the authors have been determining whether physical changes in the granules, such as mass loss, occur during secretion as the second model predicts, or if there is a simple reduction in the number of granules as predicted by the first model

Regulatory capital requirements and bail in mechanisms

NARCIS (Netherlands)

Joosen, B.P.M.; Haentjens, M.; Wessels, B.

2015-01-01

With the introduction of the Capital Requirements Regulation (CRR) in the European Union, the qualitative requirements for bank regulatory capital have changed. These changes aim at implementing in Europe the Basel III principles for better bank capital that is able to absorb losses of banks,

Elucidating the biosynthetic and regulatory mechanisms of flavonoid-derived bioactive components in Epimedium sagittatum

Directory of Open Access Journals (Sweden)

Wenjun eHuang

2015-09-01

Full Text Available Herba epimedii (Epimedium, a traditional Chinese medicine, has been widely used as a kidney tonic and antirheumatic medicine for thousands of years. In Epimedium, flavonoids have been demonstrated to be the main bioactive components (BCs. However, the molecular biosynthetic and regulatory mechanisms of flavonoid-derived BCs remain obscure. In this study, we isolated twelve structural genes and two putative transcription factors (TFs in the flavonoid pathway. Phytochemical analysis showed that the total content of four representative BCs (epimedin A, B, C and icariin decreased slightly or dramatically in two lines of E. sagittatum during leaf development. Transcriptional analysis revealed that two R2R3-MYB TFs (EsMYBA1 and EsMYBF1, together with a bHLH TF (EsGL3 and WD40 protein (EsTTG1, were supposed to coordinately regulate the anthocyanin and flavonol-derived BCs biosynthesis in leaves. Overexpression of EsFLS (flavonol synthase in tobacco resulted in increased flavonols content and decreased anthocyanins content in flowers. Moreover, EsMYB12 negatively correlated with the accumulation of the four BCs, and might act as a transcriptional repressor in the flavonoid pathway. Therefore, the anthocyanin pathway may coordinate with the flavonol-derived BCs pathway in Epimedium leaves. A better understanding of the flavonoid biosynthetic and regulatory mechanisms in E. sagittatum will facilitate functional characterization, metabolic engineering and molecular breeding studies of Epimedium species.

Plant RNA Regulatory Network and RNA Granules in Virus Infection

Directory of Open Access Journals (Sweden)

Kristiina Mäkinen

2017-12-01

their individual components contribute to these processes. In this review we discuss the roles of cellular RNA regulatory mechanisms and RNA granules in plant virus infection in the light of current knowledge and compare the findings to those made in animal virus studies.

Plant RNA Regulatory Network and RNA Granules in Virus Infection.

Science.gov (United States)

Mäkinen, Kristiina; Lõhmus, Andres; Pollari, Maija

2017-01-01

components contribute to these processes. In this review we discuss the roles of cellular RNA regulatory mechanisms and RNA granules in plant virus infection in the light of current knowledge and compare the findings to those made in animal virus studies.

Using Cellular Proteins to Reveal Mechanisms of HIV Infection | Center for Cancer Research

Science.gov (United States)

A vital step in HIV infection is the insertion of viral DNA into the genome of the host cell. In order for the insertion to occur, viral nucleic acid must be transported through the membrane that separates the main cellular compartment (the cytoplasm) from the nucleus, where the host DNA is located. Scientists are actively studying the mechanism used to transport viral DNA into the nucleus in the hopes of targeting this step with future anti-HIV treatments. Up to this point, researchers have identified some of the viral components that play a role in nuclear transport, but they have not determined how viral interactions with other molecules in the cell contribute to the process.

Cellular senescence and organismal aging.

Science.gov (United States)

Jeyapalan, Jessie C; Sedivy, John M

2008-01-01

Cellular senescence, first observed and defined using in vitro cell culture studies, is an irreversible cell cycle arrest which can be triggered by a variety of factors. Emerging evidence suggests that cellular senescence acts as an in vivo tumor suppression mechanism by limiting aberrant proliferation. It has also been postulated that cellular senescence can occur independently of cancer and contribute to the physiological processes of normal organismal aging. Recent data have demonstrated the in vivo accumulation of senescent cells with advancing age. Some characteristics of senescent cells, such as the ability to modify their extracellular environment, could play a role in aging and age-related pathology. In this review, we examine current evidence that links cellular senescence and organismal aging.

Trans-acting translational regulatory RNA binding proteins.

Science.gov (United States)

Harvey, Robert F; Smith, Tom S; Mulroney, Thomas; Queiroz, Rayner M L; Pizzinga, Mariavittoria; Dezi, Veronica; Villenueva, Eneko; Ramakrishna, Manasa; Lilley, Kathryn S; Willis, Anne E

2018-05-01

The canonical molecular machinery required for global mRNA translation and its control has been well defined, with distinct sets of proteins involved in the processes of translation initiation, elongation and termination. Additionally, noncanonical, trans-acting regulatory RNA-binding proteins (RBPs) are necessary to provide mRNA-specific translation, and these interact with 5' and 3' untranslated regions and coding regions of mRNA to regulate ribosome recruitment and transit. Recently it has also been demonstrated that trans-acting ribosomal proteins direct the translation of specific mRNAs. Importantly, it has been shown that subsets of RBPs often work in concert, forming distinct regulatory complexes upon different cellular perturbation, creating an RBP combinatorial code, which through the translation of specific subsets of mRNAs, dictate cell fate. With the development of new methodologies, a plethora of novel RNA binding proteins have recently been identified, although the function of many of these proteins within mRNA translation is unknown. In this review we will discuss these methodologies and their shortcomings when applied to the study of translation, which need to be addressed to enable a better understanding of trans-acting translational regulatory proteins. Moreover, we discuss the protein domains that are responsible for RNA binding as well as the RNA motifs to which they bind, and the role of trans-acting ribosomal proteins in directing the translation of specific mRNAs. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes Translation > Translation Regulation Translation > Translation Mechanisms. © 2018 Medical Research Council and University of Cambridge. WIREs RNA published by Wiley Periodicals, Inc.

Radiation, nitric oxide and cellular death

International Nuclear Information System (INIS)

Dubner, D.; Perez, M.R. Del; Michelin, S.C.; Gisone, P.A.

1997-01-01

The mechanisms of radiation induced cellular death constitute an objective of research ever since the first biological effects of radiation were first observed. The explosion of information produced in the last 20 years calls for a careful analysis due to the apparent contradictory data related to the cellular system studied and the range of doses used. This review focuses on the role of the active oxygen species, in particular the nitric oxides, in its relevance as potential mediator of radiation induced cellular death

Sub-cellular mRNA localization modulates the regulation of gene expression by small RNAs in bacteria

Science.gov (United States)

Teimouri, Hamid; Korkmazhan, Elgin; Stavans, Joel; Levine, Erel

2017-10-01

Small non-coding RNAs can exert significant regulatory activity on gene expression in bacteria. In recent years, substantial progress has been made in understanding bacterial gene expression by sRNAs. However, recent findings that demonstrate that families of mRNAs show non-trivial sub-cellular distributions raise the question of how localization may affect the regulatory activity of sRNAs. Here we address this question within a simple mathematical model. We show that the non-uniform spatial distributions of mRNA can alter the threshold-linear response that characterizes sRNAs that act stoichiometrically, and modulate the hierarchy among targets co-regulated by the same sRNA. We also identify conditions where the sub-cellular organization of cofactors in the sRNA pathway can induce spatial heterogeneity on sRNA targets. Our results suggest that under certain conditions, interpretation and modeling of natural and synthetic gene regulatory circuits need to take into account the spatial organization of the transcripts of participating genes.

A High-Level Petri Net Framework for Genetic Regulatory Networks

Directory of Open Access Journals (Sweden)

Banks Richard

2007-12-01

Full Text Available To understand the function of genetic regulatory networks in the development of cellular systems, we must not only realise the individual network entities, but also the manner by which they interact. Multi-valued networks are a promising qualitative approach for modelling such genetic regulatory networks, however, at present they have limited formal analysis techniques and tools. We present a flexible formal framework for modelling and analysing multi-valued genetic regulatory networks using high-level Petri nets and logic minimization techniques. We demonstrate our approach with a detailed case study in which part of the genetic regulatory network responsible for the carbon starvation stress response in Escherichia coli is modelled and analysed. We then compare and contrast this multivalued model to a corresponding Boolean model and consider their formal relationship.

Tracking of time-varying genomic regulatory networks with a LASSO-Kalman smoother

OpenAIRE

Khan, Jehandad; Bouaynaya, Nidhal; Fathallah-Shaykh, Hassan M

2014-01-01

It is widely accepted that cellular requirements and environmental conditions dictate the architecture of genetic regulatory networks. Nonetheless, the status quo in regulatory network modeling and analysis assumes an invariant network topology over time. In this paper, we refocus on a dynamic perspective of genetic networks, one that can uncover substantial topological changes in network structure during biological processes such as developmental growth. We propose a novel outlook on the inf...

Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

Science.gov (United States)

Huppert, Jula; Closhen, Dorothea; Croxford, Andrew; White, Robin; Kulig, Paulina; Pietrowski, Eweline; Bechmann, Ingo; Becher, Burkhard; Luhmann, Heiko J; Waisman, Ari; Kuhlmann, Christoph R W

2010-04-01

Recently T-helper 17 (Th17) cells were demonstrated to disrupt the blood-brain barrier (BBB) by the action of IL-17A. The aim of the present study was to examine the mechanisms that underlie IL-17A-induced BBB breakdown. Barrier integrity was analyzed in the murine brain endothelial cell line bEnd.3 by measuring the electrical resistance values using electrical call impedance sensing technology. Furthermore, in-cell Western blots, fluorescence imaging, and monocyte adhesion and transendothelial migration assays were performed. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. IL-17A induced NADPH oxidase- or xanthine oxidase-dependent reactive oxygen species (ROS) production. The resulting oxidative stress activated the endothelial contractile machinery, which was accompanied by a down-regulation of the tight junction molecule occludin. Blocking either ROS formation or myosin light chain phosphorylation or applying IL-17A-neutralizing antibodies prevented IL-17A-induced BBB disruption. Treatment of mice with EAE using ML-7, an inhibitor of the myosin light chain kinase, resulted in less BBB disruption at the spinal cord and less infiltration of lymphocytes via the BBB and subsequently reduced the clinical characteristics of EAE. These observations indicate that IL-17A accounts for a crucial step in the development of EAE by impairing the integrity of the BBB, involving augmented production of ROS.-Huppert, J., Closhen, D., Croxford, A., White, R., Kulig, P., Pietrowski, E., Bechmann, I., Becher, B., Luhmann, H. J., Waisman, A., Kuhlmann, C. R. W. Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

Conditional bistability, a generic cellular mnemonic mechanism for robust and flexible working memory computations.

Science.gov (United States)

Rodriguez, Guillaume; Sarazin, Matthieu; Clemente, Alexandra; Holden, Stephanie; Paz, Jeanne T; Delord, Bruno

2018-04-30

Persistent neural activity, the substrate of working memory, is thought to emerge from synaptic reverberation within recurrent networks. However, reverberation models do not robustly explain fundamental dynamics of persistent activity, including high-spiking irregularity, large intertrial variability, and state transitions. While cellular bistability may contribute to persistent activity, its rigidity appears incompatible with persistent activity labile characteristics. Here, we unravel in a cellular model a form of spike-mediated conditional bistability that is robust, generic and provides a rich repertoire of mnemonic computations. Under asynchronous synaptic inputs of the awakened state, conditional bistability generates spiking/bursting episodes, accounting for the irregularity, variability and state transitions characterizing persistent activity. This mechanism has likely been overlooked because of the sub-threshold input it requires and we predict how to assess it experimentally. Our results suggest a reexamination of the role of intrinsic properties in the collective network dynamics responsible for flexible working memory. SIGNIFICANCE STATEMENT This study unravels a novel form of intrinsic neuronal property, i.e. conditional bistability. We show that, thanks of its conditional character, conditional bistability favors the emergence of flexible and robust forms of persistent activity in PFC neural networks, in opposition to previously studied classical forms of absolute bistability. Specifically, we demonstrate for the first time that conditional bistability 1) is a generic biophysical spike-dependent mechanism of layer V pyramidal neurons in the PFC and that 2) it accounts for essential neurodynamical features for the organisation and flexibility of PFC persistent activity (the large irregularity and intertrial variability of the discharge and its organization under discrete stable states), which remain unexplained in a robust fashion by current models

Cellular dynamical mechanisms for encoding the time and place of events along spatiotemporal trajectories in episodic memory

OpenAIRE

Hasselmo, Michael E.; Giocomo, Lisa M.; Yoshida, Motoharu

2009-01-01

Understanding the mechanisms of episodic memory requires linking behavioural data and lesion effects to data on the dynamics of cellular membrane potentials and population interactions within these brain regions. Linking behavior to specific membrane channels and neurochemicals has implications for therapeutic applications. Lesions of the hippocampus, entorhinal cortex and subcortical nuclei impair episodic memory function in humans and animals, and unit recording data from these regions in b...

Computational and molecular dissection of an X-box cis-Regulatory module

OpenAIRE

Warrington, Timothy Burton

2015-01-01

Ciliopathies are a class of human diseases marked by dysfunction of the cellular organelle, cilia. While many of the molecular components that make up cilia have been identified and studied, comparatively little is understood about the transcriptional regulation of genes encoding these components. The conserved transcription factor Regulatory Factor X (RFX)/DAF-19, which acts through binding to the cis-regulatory motif known as X-box, has been shown to regulate ciliary genes in many animals f...

Unraveling the cellular response to oxidative stress in the endoplasmic reticulum

DEFF Research Database (Denmark)

Hansen, Henning Gram

, disulfide bonds are predominantly generated by the two isoforms of the ER oxidoreductin-1 (Ero1) family: Ero1α and Ero1β. Both enzymes oxidize the active-site cysteines in protein disulfide isomerases (PDIs), which in turn introduce disulfide bonds into newly synthesized proteins. Ero1 is re......-oxidized by molecular oxygen and this step generates hydrogen peroxide: a reactive oxygen species. Intramolecular disulfide bonds tightly regulate the oxidase activity of Ero1α. Whereas the regulatory mechanisms that regulate Ero1α activity are well understood, the overall cellular response to oxidative stress....... Interestingly, depletion of GPx8 in cells induced expression of an antioxidant response marker only in the presence of Ero1. These findings imply that GPx8 is an important scavenger of Ero1-generated hydrogen peroxide, and thus provides a critical function in negotiating oxidative stress originating from...

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

NARCIS (Netherlands)

Chornokur, G.; Lin, H.Y.; Tyrer, J.P.; Lawrenson, K.; Dennis, J.; Amankwah, E.K.; Qu, X.; Tsai, Y.Y.; Jim, H.S.; Chen, Z.; Chen, A.Y.; Permuth-Wey, J.; Aben, K.; Anton-Culver, H.; Antonenkova, N.; Bruinsma, F.; Bandera, E.V.; Bean, Y.T.; Beckmann, M.W.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bunker, C.H.; Butzow, R.; Campbell, I.G.; Carty, K.; Chang-Claude, J.; Cook, L.S.; Cramer, D.W; Cunningham, J.M.; Cybulski, C.; Dansonka-Mieszkowska, A.; Bois, A. du; Despierre, E.; Dicks, E.; Doherty, J.A.; Dork, T.; Durst, M.; Easton, D.F.; Eccles, D.M.; Edwards, R.P.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goodman, M.T.; Gronwald, J.; Harrington, P.; Harter, P.; Hein, A.; Heitz, F.; Hildebrandt, M.A.T.; Hillemanns, P.; Hogdall, C.K.; Hogdall, E.; Hosono, S.; Jakubowska, A.; Jensen, A.; Ji, B.T.; Karlan, B.Y.; Kelemen, L.E.; Kellar, M.; Kiemeney, L.A.L.M.; Krakstad, C.; Kjaer, S.K.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lim, B.K.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.A.G.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; McNeish, I.; Menon, U.; Milne, R.L.; Modugno, F.; Moysich, K.B.; Ness, R.B.; Nevanlinna, H.; Eilber, U.; Odunsi, K.; Olson, S.H.; Orlow, I., et al.

2015-01-01

BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As

Dose response relationship in anti-stress gene regulatory networks.

Science.gov (United States)

Zhang, Qiang; Andersen, Melvin E

2007-03-02

To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on

Dose response relationship in anti-stress gene regulatory networks.

Directory of Open Access Journals (Sweden)

Qiang Zhang

2007-03-01

Full Text Available To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear depends on changes in the specific values of local response coefficients (gains distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear

Force control for mechanoinduction of impedance variation in cellular organisms

International Nuclear Information System (INIS)

Nam, Joo Hoo; Chen, Peter C Y; Lu, Zhe; Luo, Hong; Lin, Wei; Ge, Ruowen

2010-01-01

Constantly exposed to various forms of mechanical forces inherent in their physical environment (such as gravity, stress induced by fluid flow or cell–cell interactions, etc), cellular organisms sense such forces and convert them into biochemical signals through the processes of mechanosensing and mechanotransduction that eventually lead to biological changes. The effect of external forces on the internal structures and activities in a cellular organism may manifest in changes its physical properties, such as impedance. Studying variation in the impedance of a cellular organism induced by the application of an external mechanical force represents a meaningful endeavor (from a biosystems perspective) in exploring the complex mechanosensing and mechanotransduction mechanisms that govern the behavior of a cellular organism under the influence of external mechanical stimuli. In this paper we describe the development of an explicit force-feedback control system for exerting an indentation force on a cellular organism while simultaneously measuring its impedance. To demonstrate the effectiveness of this force-control system, we have conducted experiments using zebrafish embryos as a test model of a cellular organism. We report experimental results demonstrating that the application of a properly controlled external force leads to a significant change in the impedance of a zebrafish embryo. These results offer support for a plausible explanation that activities of pore canals in the chorion are responsible for the observed change in impedance.

Take it of leave it : Mechanisms underlying bacterial bistable regulatory networks

NARCIS (Netherlands)

Siebring, Jeroen; Sorg, Robin; Herber, Martijn; Kuipers, Oscar; Filloux, Alain A.M.

2012-01-01

Bistable switches occur in regulatory networks that can exist in two distinct stable states. Such networks allow distinct switching of individual cells. In bacteria these switches coexist with regulatory networks that respond gradually to environmental input. Bistable switches play key roles in high

A general mechanism for intracellular toxicity of metal-containing nanoparticles

Science.gov (United States)

Sabella, Stefania; Carney, Randy P.; Brunetti, Virgilio; Malvindi, Maria Ada; Al-Juffali, Noura; Vecchio, Giuseppe; Janes, Sam M.; Bakr, Osman M.; Cingolani, Roberto; Stellacci, Francesco; Pompa, Pier Paolo

2014-05-01

The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment - where particles are abundantly internalized - is responsible for the cascading events associated with nanoparticles-induced intracellular toxicity. We call this mechanism a ``lysosome-enhanced Trojan horse effect'' since, in the case of nanoparticles, the protective cellular machinery designed to degrade foreign objects is actually responsible for their toxicity. To test our hypothesis, we compare the toxicity of similar gold particles whose main difference is in the internalization pathways. We show that particles known to pass directly through cell membranes become more toxic when modified so as to be mostly internalized by endocytosis. Furthermore, using experiments with chelating and lysosomotropic agents, we found that the toxicity mechanism for different metal containing NPs (such as metallic, metal oxide, and semiconductor NPs) is mainly associated with the release of the corresponding toxic ions. Finally, we show that particles unable to release toxic ions (such as stably coated NPs, or diamond and silica NPs) are not harmful to intracellular environments.The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment - where

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

Directory of Open Access Journals (Sweden)

Тетяна Дмитрівна Щербань

2016-02-01

Full Text Available 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 detected by Green colorimetric methods using Griess reagent. The expression of ІСАМ-1 (CD54, CD11b-integrin and inducible NO-synthase on neutrophils was detected by the indirect immunocytochemical method. Oxygen-depending activity of neutrophils was assessed in NBT-test.Results. Expression of adhesive molecules of CD54and CD11b-integrin on neutrophils of peripheral blood essentially increases (р <0,001 in patients with DN in association with HD comparing with isolated HD and the control group.At associated pathology on the background of high oxygen-depending activity of neutrophils its functional reserve decreases that results in intensification of inflammatory processes in kidneys (р<0,001.In comorbid patients chronization of pathological process results in imbalance of NO-synthases system in neutrophils: on the background of decrease of activity of constituent NO-synthases the expression and activity of inducible NO-synthase increase (р<0,001 .The use of L-arginine hydrochloride in the complex therapy of patients with DN associated with HD intensifies organoprotective effect of basal therapy, results in facilitation of the clinical course, decreases albuminuria, corrects the functional indices of neutrophils and diminishes imbalance in NO-synthases system.Conclusions. In patients with DN in association with HD the neutrophil chain of cellular inflammation mechanisms are activated: expression of adhesive molecules grows, oxygen-depending metabolism is

On the evolution of the regulatory guidance for seismic qualification of electric and active mechanical equipment for nuclear power plants

International Nuclear Information System (INIS)

Ng, Ching Hang; Chen, Pei-Ying

2009-01-01

All electric and active mechanical equipment important to safety for nuclear power plants must be seismically qualified by testing, analysis, or combined analysis and testing. The general requirements for seismic qualification of electric and active mechanical equipment in nuclear power plants are delineated in Appendix S, 'Earthquake Engineering Criteria for Nuclear Power Plants,' to Title 10, Part 50, 'Domestic Licensing of Production and Utilization Facilities,' of the Code of Federal Regulations (10 CFR Part 50), item 52.47(20) of 10 CFR 52.47, 'Contents of Applications; Technical Information,' and Appendix A, 'Seismic and Geologic Siting Criteria for Nuclear Power Plants,' to 10 CFR Part 100, 'Reactor Site Criteria.' The United States Nuclear Regulatory Commission (NRC) issued Revision 2 of Regulatory Guide (RG) 1.100, 'Seismic Qualification of Electric and Mechanical for Nuclear Power Plants' in 1988, which endorsed, with restrictions, exceptions, and clarifications, Institute of Electrical and Electronics Engineers (IEEE) Standard 344-1987 'IEEE Recommended Practice for Seismic Qualification of Class 1E Equipment for Nuclear Power Generating Stations,' for use in seismic qualification of both electric and mechanical equipment. In 2008, the staff at the NRC drafted Revision 3 of RG 1.100 to endorse, with restrictions, exceptions, and clarifications, the IEEE Std 344-2004 and the American Society of Mechanical Engineers (ASME) QME-1-2007 'Qualification of Active Mechanical Equipment Used in Nuclear Power Plants.' IEEE Std 344-2004 was an update of Std 344-1987 and ASME QME-1-2007 was an update of QME-1-2002. The major changes in IEEE Std 344-2004 and ASME QME-1-2007 include the update and expansion of criteria and procedures describing the use of experience data as a method for seismic qualification of Class 1E electric equipment (including I and C components) as well as active mechanical equipment. In this paper, the staff will compare the draft Revision 3 to

A nucleator arms race: cellular control of actin assembly.

Science.gov (United States)

Campellone, Kenneth G; Welch, Matthew D

2010-04-01

For over a decade, the actin-related protein 2/3 (ARP2/3) complex, a handful of nucleation-promoting factors and formins were the only molecules known to directly nucleate actin filament formation de novo. However, the past several years have seen a surge in the discovery of mammalian proteins with roles in actin nucleation and dynamics. Newly recognized nucleation-promoting factors, such as WASP and SCAR homologue (WASH), WASP homologue associated with actin, membranes and microtubules (WHAMM), and junction-mediating regulatory protein (JMY), stimulate ARP2/3 activity at distinct cellular locations. Formin nucleators with additional biochemical and cellular activities have also been uncovered. Finally, the Spire, cordon-bleu and leiomodin nucleators have revealed new ways of overcoming the kinetic barriers to actin polymerization.

Involvement of Sib Proteins in the Regulation of Cellular Adhesion in Dictyostelium discoideum▿ †

OpenAIRE

Cornillon, Sophie; Froquet, Romain; Cosson, Pierre

2008-01-01

Molecular mechanisms ensuring cellular adhesion have been studied in detail in Dictyostelium amoebae, but little is known about the regulation of cellular adhesion in these cells. Here, we show that cellular adhesion is regulated in Dictyostelium, notably by the concentration of a cellular secreted factor accumulating in the medium. This constitutes a quorum-sensing mechanism allowing coordinated regulation of cellular adhesion in a Dictyostelium population. In order to understand the mechani...

Ethical Decision Making, Therapeutic Boundaries, and Communicating Using Online Technology and Cellular Phones

Science.gov (United States)

Yonan, Jesay; Bardick, Angela D.; Willment, Jo-Anne H.

2011-01-01

Cellular telephones and social networking sites pose new challenges to the maintenance of therapeutic boundaries. One such difficulty is the possible development of dual relationships between clients and counselling professionals as a result of communicating by these means. Most regulatory bodies advise professional counsellors and psychologists…

Regulatory framework and development perspectives of the mechanism of public participation in the management of Russia’s forests

Directory of Open Access Journals (Sweden)

Nikolay Mikhaylovich Shmatkov

2014-03-01

Full Text Available The article dwells on the current state of the regulatory framework of the Russian Federation and the mechanism of public participation in forest management. The examples of addressing the problems of public participation in forest management in individual regions are disclosed. The article deals with the issues concerning the provision of in-interests of the local population through the voluntary forest certification system under the FSC scheme. Recommendations on improving the mechanism of public participation in solving the forest management issues are suggested

Perspectives on Regulatory T Cell Therapies.

Science.gov (United States)

Probst-Kepper, Michael; Kröger, Andrea; Garritsen, Henk S P; Buer, Jan

2009-01-01

Adoptive transfer in animal models clearly indicate an essential role of CD4+ CD25+ FOXP3+ regulatory T (T(reg)) cells in prevention and treatment of autoimmune and graft-versus-host disease. Thus, T(reg) cell therapies and development of drugs that specifically enhance T(reg) cell function and development represent promising tools to establish dominant tolerance. So far, lack of specific markers to differentiate human T(reg) cells from activated CD4+ CD25+ effector T cells, which also express FOXP3 at different levels, hampered such an approach. Recent identification of the orphan receptor glycoprotein-A repetitions predominant (GARP or LRRC32) as T(reg) cell-specific key molecule that dominantly controls FOXP3 via a positive feedback loop opens up new perspectives for molecular and cellular therapies. This brief review focuses on the role of GARP as a safeguard of a complex regulatory network of human T(reg) cells and its implications for regulatory T cell therapies in autoimmunity and graft-versus-host disease.

Role of Sodium Bicarbonate Cotransporters in Intracellular pH Regulation and Their Regulatory Mechanisms in Human Submandibular Glands.

Science.gov (United States)

Namkoong, Eun; Shin, Yong-Hwan; Bae, Jun-Seok; Choi, Seulki; Kim, Minkyoung; Kim, Nahyun; Hwang, Sung-Min; Park, Kyungpyo

2015-01-01

Sodium bicarbonate cotransporters (NBCs) are involved in the pH regulation of salivary glands. However, the roles and regulatory mechanisms among different NBC isotypes have not been rigorously evaluated. We investigated the roles of two different types of NBCs, electroneutral (NBCn1) and electrogenic NBC (NBCe1), with respect to pH regulation and regulatory mechanisms using human submandibular glands (hSMGs) and HSG cells. Intracellular pH (pHi) was measured and the pHi recovery rate from cell acidification induced by an NH4Cl pulse was recorded. Subcellular localization and protein phosphorylation were determined using immunohistochemistry and co-immunoprecipitation techniques. We determined that NBCn1 is expressed on the basolateral side of acinar cells and the apical side of duct cells, while NBCe1 is exclusively expressed on the apical membrane of duct cells. The pHi recovery rate in hSMG acinar cells, which only express NBCn1, was not affected by pre-incubation with 5 μM PP2, an Src tyrosine kinase inhibitor. However, in HSG cells, which express both NBCe1 and NBCn1, the pHi recovery rate was inhibited by PP2. The apparent difference in regulatory mechanisms for NBCn1 and NBCe1 was evaluated by artificial overexpression of NBCn1 or NBCe1 in HSG cells, which revealed that the pHi recovery rate was only inhibited by PP2 in cells overexpressing NBCe1. Furthermore, only NBCe1 was significantly phosphorylated and translocated by NH4Cl, which was inhibited by PP2. Our results suggest that both NBCn1 and NBCe1 play a role in pHi regulation in hSMG acinar cells, and also that Src kinase does not regulate the activity of NBCn1.

Role of Sodium Bicarbonate Cotransporters in Intracellular pH Regulation and Their Regulatory Mechanisms in Human Submandibular Glands.

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Eun Namkoong

Full Text Available Sodium bicarbonate cotransporters (NBCs are involved in the pH regulation of salivary glands. However, the roles and regulatory mechanisms among different NBC isotypes have not been rigorously evaluated. We investigated the roles of two different types of NBCs, electroneutral (NBCn1 and electrogenic NBC (NBCe1, with respect to pH regulation and regulatory mechanisms using human submandibular glands (hSMGs and HSG cells. Intracellular pH (pHi was measured and the pHi recovery rate from cell acidification induced by an NH4Cl pulse was recorded. Subcellular localization and protein phosphorylation were determined using immunohistochemistry and co-immunoprecipitation techniques. We determined that NBCn1 is expressed on the basolateral side of acinar cells and the apical side of duct cells, while NBCe1 is exclusively expressed on the apical membrane of duct cells. The pHi recovery rate in hSMG acinar cells, which only express NBCn1, was not affected by pre-incubation with 5 μM PP2, an Src tyrosine kinase inhibitor. However, in HSG cells, which express both NBCe1 and NBCn1, the pHi recovery rate was inhibited by PP2. The apparent difference in regulatory mechanisms for NBCn1 and NBCe1 was evaluated by artificial overexpression of NBCn1 or NBCe1 in HSG cells, which revealed that the pHi recovery rate was only inhibited by PP2 in cells overexpressing NBCe1. Furthermore, only NBCe1 was significantly phosphorylated and translocated by NH4Cl, which was inhibited by PP2. Our results suggest that both NBCn1 and NBCe1 play a role in pHi regulation in hSMG acinar cells, and also that Src kinase does not regulate the activity of NBCn1.

In silico analysis of cis-acting regulatory elements in 5' regulatory regions of sucrose transporter gene families in rice (Oryza sativa Japonica) and Arabidopsis thaliana.

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Ibraheem, Omodele; Botha, Christiaan E J; Bradley, Graeme

2010-12-01

The regulation of gene expression involves a multifarious regulatory system. Each gene contains a unique combination of cis-acting regulatory sequence elements in the 5' regulatory region that determines its temporal and spatial expression. Cis-acting regulatory elements are essential transcriptional gene regulatory units; they control many biological processes and stress responses. Thus a full understanding of the transcriptional gene regulation system will depend on successful functional analyses of cis-acting elements. Cis-acting regulatory elements present within the 5' regulatory region of the sucrose transporter gene families in rice (Oryza sativa Japonica cultivar-group) and Arabidopsis thaliana, were identified using a bioinformatics approach. The possible cis-acting regulatory elements were predicted by scanning 1.5kbp of 5' regulatory regions of the sucrose transporter genes translational start sites, using Plant CARE, PLACE and Genomatix Matinspector professional databases. Several cis-acting regulatory elements that are associated with plant development, plant hormonal regulation and stress response were identified, and were present in varying frequencies within the 1.5kbp of 5' regulatory region, among which are; A-box, RY, CAT, Pyrimidine-box, Sucrose-box, ABRE, ARF, ERE, GARE, Me-JA, ARE, DRE, GA-motif, GATA, GT-1, MYC, MYB, W-box, and I-box. This result reveals the probable cis-acting regulatory elements that possibly are involved in the expression and regulation of sucrose transporter gene families in rice and Arabidopsis thaliana during cellular development or environmental stress conditions. Copyright © 2010 Elsevier Ltd. All rights reserved.

Density-dependence as a size-independent regulatory mechanism.

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de Vladar, Harold P

2006-01-21

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

Epigenetics and Cellular Metabolism

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Wenyi Xu

2016-01-01

Full Text Available Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc. is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well.

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain.

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Santoro, Antonietta; Spinelli, Chiara Carmela; Martucciello, Stefania; Nori, Stefania Lucia; Capunzo, Mario; Puca, Annibale Alessandro; Ciaglia, Elena

2018-03-01

Ongoing studies evidence cellular senescence in undifferentiated and specialized cells from tissues of all ages. Although it is believed that senescence plays a wider role in several stress responses in the mature age, its participation in certain physiological and pathological processes throughout life is coming to light. The "senescence machinery" has been observed in all brain cell populations, including components of innate immunity (e.g., microglia and astrocytes). As the beneficial versus detrimental implications of senescence is an open question, we aimed to analyze the contribution of immune responses in regulatory mechanisms governing its distinct functions in healthy (development, organogenesis, danger patrolling events) and diseased brain (glioma, neuroinflammation, neurodeneration), and the putative connection between cellular and molecular events governing the 2 states. Particularly this review offers new insights into the complex roles of senescence both as a chronological event as age advances, and as a molecular mechanism of brain homeostasis through the important contribution of innate immune responses and their crosstalk with neighboring cells in brain parenchyma. We also highlight the impact of the recently described glymphatic system and brain lymphatic vasculature in the interplay between peripheral and central immune surveillance and its potential implication during aging. This will open new ways to understand brain development, its deterioration during aging, and the occurrence of several oncological and neurodegenerative diseases. ©2018 Society for Leukocyte Biology.

Integration of Bacterial Small RNAs in Regulatory Networks.

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Nitzan, Mor; Rehani, Rotem; Margalit, Hanah

2017-05-22

Small RNAs (sRNAs) are central regulators of gene expression in bacteria, controlling target genes posttranscriptionally by base pairing with their mRNAs. sRNAs are involved in many cellular processes and have unique regulatory characteristics. In this review, we discuss the properties of regulation by sRNAs and how it differs from and combines with transcriptional regulation. We describe the global characteristics of the sRNA-target networks in bacteria using graph-theoretic approaches and review the local integration of sRNAs in mixed regulatory circuits, including feed-forward loops and their combinations, feedback loops, and circuits made of an sRNA and another regulator, both derived from the same transcript. Finally, we discuss the competition effects in posttranscriptional regulatory networks that may arise over shared targets, shared regulators, and shared resources and how they may lead to signal propagation across the network.

Regulatory T Cells: Potential Target in Anticancer Immunotherapy

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Chi-Mou Juang

2007-09-01

Full Text Available The concept of regulatory T cells was first described in the early 1970s, and regulatory T cells were called suppressive T cells at that time. Studies that followed have demonstrated that these suppressive T cells negatively regulated tumor immunity and contributed to tumor growth in mice. Despite the importance of these studies, there was extensive skepticism about the existence of these cells, and the concept of suppressive T cells left the center stage of immunologic research for decades. Interleukin-2 receptor α-chain, CD25, was first demonstrated in 1995 to serve as a phenotypic marker for CD4+ regulatory cells. Henceforth, research of regulatory T cells boomed. Regulatory T cells are involved in the pathogenesis of cancer, autoimmune disease, transplantation immunology, and immune tolerance in pregnancy. Recent evidence has demonstrated that regulatory T cellmediated immunosuppression is one of the crucial tumor immune evasion mechanisms and the main obstacle of successful cancer immunotherapy. The mechanism and the potential clinical application of regulatory T cells in cancer immunotherapy are discussed.

Non-Chemical Distant Cellular Interactions as a potential confounder of Cell Biology Experiments

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Ashkan eFarhadi

2014-10-01

Full Text Available Distant cells can communicate with each other through a variety of methods. Two such methods involve electrical and/or chemical mechanisms. Non-chemical, distant cellular interactions may be another method of communication that cells can use to modify the behavior of other cells that are mechanically separated. Moreover, non-chemical, distant cellular interactions may explain some cases of confounding effects in Cell Biology experiments. In this article, we review non-chemical, distant cellular interactions studies to try to shed light on the mechanisms in this highly unconventional field of cell biology. Despite the existence of several theories that try to explain the mechanism of non-chemical, distant cellular interactions, this phenomenon is still speculative. Among candidate mechanisms, electromagnetic waves appear to have the most experimental support. In this brief article, we try to answer a few key questions that may further clarify this mechanism.

Resistin enhances the expansion of regulatory T cells through modulation of dendritic cells

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Han Seung

2010-06-01

Full Text Available Abstract Background Resistin, a member of adipokine family, is known to be involved in the modulation of immune responses including inflammatory activity. Interestingly, resistin is secreted by adipocytes in mice and rats whereas it is secreted by leukocytes in humans. However, the mechanism behind the effect of resistin on the expansion of regulatory T cells (Tregs remains poorly understood. Therefore, we examined regulatory effect of resistin on the induction and cellular modification of Tregs. Results Both protein and mRNA expression of FoxP3, a representative marker of Tregs, increased in a dose-dependent manner when peripheral blood mononuclear cells were treated with resistin. At the same time, resistin had no direct effect on the induction of FoxP3 in CD4+ T cells, suggesting an indirect role through other cells type(s. Since DCs are an important player in the differentiation of T cells, we focused on the role of DCs in the modulation of Tregs by resistin. Resistin suppressed the expression of interferon regulatory factor (IRF-1 and its target cytokines, IL-6, IL-23p19 and IL-12p40, in DCs. Furthermore, FoxP3 expression is increased in CD4+ T cells when co-cultured with DCs and concomitantly treated with resistin. Conclusion Our results suggest that resistin induces expansion of functional Tregs only when co-cultured with DCs.

CoryneRegNet: an ontology-based data warehouse of corynebacterial transcription factors and regulatory networks.

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Baumbach, Jan; Brinkrolf, Karina; Czaja, Lisa F; Rahmann, Sven; Tauch, Andreas

2006-02-14

The application of DNA microarray technology in post-genomic analysis of bacterial genome sequences has allowed the generation of huge amounts of data related to regulatory networks. This data along with literature-derived knowledge on regulation of gene expression has opened the way for genome-wide reconstruction of transcriptional regulatory networks. These large-scale reconstructions can be converted into in silico models of bacterial cells that allow a systematic analysis of network behavior in response to changing environmental conditions. CoryneRegNet was designed to facilitate the genome-wide reconstruction of transcriptional regulatory networks of corynebacteria relevant in biotechnology and human medicine. During the import and integration process of data derived from experimental studies or literature knowledge CoryneRegNet generates links to genome annotations, to identified transcription factors and to the corresponding cis-regulatory elements. CoryneRegNet is based on a multi-layered, hierarchical and modular concept of transcriptional regulation and was implemented by using the relational database management system MySQL and an ontology-based data structure. Reconstructed regulatory networks can be visualized by using the yFiles JAVA graph library. As an application example of CoryneRegNet, we have reconstructed the global transcriptional regulation of a cellular module involved in SOS and stress response of corynebacteria. CoryneRegNet is an ontology-based data warehouse that allows a pertinent data management of regulatory interactions along with the genome-scale reconstruction of transcriptional regulatory networks. These models can further be combined with metabolic networks to build integrated models of cellular function including both metabolism and its transcriptional regulation.

[Translational/regulatory science researches of NIHS for regenerative medicine and cellular therapy products].

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Sato, Yoji

2014-01-01

In 2013, the Japanese Diet passed the Regenerative Medicine Promotion Act and the revisions to the Pharmaceutical Affairs Act, which was also renamed as the Therapeutic Products Act (TPA). One of the aims of the new/revised Acts is to promote the development and translation of and access to regenerative/cellular therapies. In the TPA, a product derived from processing cells is categorized as a subgroup of "regenerative medicine, cellular therapy and gene therapy products" (RCGPs), products distinct from pharmaceuticals and medical devices, allowing RCGPs to obtain a conditional and time- limited marketing authorization much earlier than that under the conventional system. To foster not only RCGPs, but also innovative pharmaceuticals and medical devices, the Ministry of Health, Labour and Welfare recently launched Translational Research Program for Innovative Pharmaceuticals, Medical Devices and RCGPs. This mini-review introduces contributions of the National Institute of Health Sciences (NIHS) to research projects on RCGPs in the Program.

Integrative Genetic and Epigenetic Analysis Uncovers Regulatory Mechanisms of Autoimmune Disease.

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Shooshtari, Parisa; Huang, Hailiang; Cotsapas, Chris

2017-07-06

Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk. These associations are preferentially located in non-coding DNA regions and in particular in tissue-specific DNase I hypersensitivity sites (DHSs). While these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk. To do so we have departed from standard practice by identifying regulatory regions which replicate across samples and connect them to the genes they control through robust re-analysis of public data. We find significant evidence of regulatory potential in 78/301 (26%) risk loci across nine autoimmune and inflammatory diseases, and we find that individual genes are targeted by these effects in 53/78 (68%) of these. Thus, we are able to generate testable mechanistic hypotheses of the molecular changes that drive disease risk. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

The New Cellular Immunology

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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)

Genetic Dominance & Cellular Processes

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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…

Cellular plasticity enables adaptation to unforeseen cell-cycle rewiring challenges.

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Katzir, Yair; Stolovicki, Elad; Stern, Shay; Braun, Erez

2012-01-01

The fundamental dynamics of the cell cycle, underlying cell growth and reproduction, were previously found to be robust under a wide range of environmental and internal perturbations. This property was commonly attributed to its network structure, which enables the coordinated interactions among hundreds of proteins. Despite significant advances in deciphering the components and autonomous interactions of this network, understanding the interfaces of the cell cycle with other major cellular processes is still lacking. To gain insight into these interfaces, we used the process of genome-rewiring in yeast by placing an essential metabolic gene HIS3 from the histidine biosynthesis pathway, under the exclusive regulation of different cell-cycle promoters. In a medium lacking histidine and under partial inhibition of the HIS3p, the rewired cells encountered an unforeseen multitasking challenge; the cell-cycle regulatory genes were required to regulate the essential histidine-pathway gene in concert with the other metabolic demands, while simultaneously driving the cell cycle through its proper temporal phases. We show here that chemostat cell populations with rewired cell-cycle promoters adapted within a short time to accommodate the inhibition of HIS3p and stabilized a new phenotypic state. Furthermore, a significant fraction of the population was able to adapt and grow into mature colonies on plates under such inhibiting conditions. The adapted state was shown to be stably inherited across generations. These adaptation dynamics were accompanied by a non-specific and irreproducible genome-wide transcriptional response. Adaptation of the cell-cycle attests to its multitasking capabilities and flexible interface with cellular metabolic processes and requirements. Similar adaptation features were found in our previous work when rewiring HIS3 to the GAL system and switching cells from galactose to glucose. Thus, at the basis of cellular plasticity is the emergence of a yet

An Organismal Model for Gene Regulatory Networks in the Gut-Associated Immune Response

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Katherine M. Buckley

2017-10-01

Full Text Available The gut epithelium is an ancient site of complex communication between the animal immune system and the microbial world. While elements of self-non-self receptors and effector mechanisms differ greatly among animal phyla, some aspects of recognition, regulation, and response are broadly conserved. A gene regulatory network (GRN approach provides a means to investigate the nature of this conservation and divergence even as more peripheral functional details remain incompletely understood. The sea urchin embryo is an unparalleled experimental model for detangling the GRNs that govern embryonic development. By applying this theoretical framework to the free swimming, feeding larval stage of the purple sea urchin, it is possible to delineate the conserved regulatory circuitry that regulates the gut-associated immune response. This model provides a morphologically simple system in which to efficiently unravel regulatory connections that are phylogenetically relevant to immunity in vertebrates. Here, we review the organism-wide cellular and transcriptional immune response of the sea urchin larva. A large set of transcription factors and signal systems, including epithelial expression of interleukin 17 (IL17, are important mediators in the activation of the early gut-associated response. Many of these have homologs that are active in vertebrate immunity, while others are ancient in animals but absent in vertebrates or specific to echinoderms. This larval model provides a means to experimentally characterize immune function encoded in the sea urchin genome and the regulatory interconnections that control immune response and resolution across the tissues of the organism.

Croatian energy regulatory council - independent Croatian regulatory body

International Nuclear Information System (INIS)

Klepo, M.

2002-01-01

By means of approving five energy laws, the Republic of Croatia established an appropriate legislative framework for energy sector regulation. A series of sub-law acts is presently being elaborated as well as some additional documents in order to bring about transparent and non-discriminatory provisions for the establishment of electric energy, gas, oil/oil derivatives and thermal energy markets, i.e. for the introduction and management of market activities and public services. A considerable share of these activities relates to the definition of transparent regulatory mechanisms that would guarantee the implementation of regulation rules based on the law, and be carried out by the independent regulatory body - Croatian Energy Regulatory Council. The Council's rights and obligations include firm executive functions, which present obligations to every energy entity. A dissatisfied party may set in motion a settlement of dispute, if it maintains that the decisions are not based on the law or reveal a flaw in the procedure. Therefore, it is the Council's priority to always make careful and law-abiding decisions. This paper gives insight into the regulatory framework elements based on the laws including the Council's organisational structure and non-profit entities that will prepare act proposals for the Council and perform other professional activities. (author)

Cellular stress-induced up-regulation of FMRP promotes cell survival by modulating PI3K-Akt phosphorylation cascades

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Wells David

2011-02-01

Full Text Available Abstract Background Fragile X syndrome (FXS, the most commonly inherited mental retardation and single gene cause of autistic spectrum disorder, occurs when the Fmr1 gene is mutated. The product of Fmr1, fragile X linked mental retardation protein (FMRP is widely expressed in HeLa cells, however the roles of FMRP within HeLa cells were not elucidated, yet. Interacting with a diverse range of mRNAs related to cellular survival regulatory signals, understanding the functions of FMRP in cellular context would provide better insights into the role of this interesting protein in FXS. Using HeLa cells treated with etoposide as a model, we tried to determine whether FMRP could play a role in cell survival. Methods Apoptotic cell death was induced by etoposide treatment on Hela cells. After we transiently modulated FMRP expression (silencing or enhancing by using molecular biotechnological methods such as small hairpin RNA virus-induced knock down and overexpression using transfection with FMRP expression vectors, cellular viability was measured using propidium iodide staining, TUNEL staining, and FACS analysis along with the level of activation of PI3K-Akt pathway by Western blot. Expression level of FMRP and apoptotic regulator BcL-xL was analyzed by Western blot, RT-PCR and immunocytochemistry. Results An increased FMRP expression was measured in etoposide-treated HeLa cells, which was induced by PI3K-Akt activation. Without FMRP expression, cellular defence mechanism via PI3K-Akt-Bcl-xL was weakened and resulted in an augmented cell death by etoposide. In addition, FMRP over-expression lead to the activation of PI3K-Akt signalling pathway as well as increased FMRP and BcL-xL expression, which culminates with the increased cell survival in etoposide-treated HeLa cells. Conclusions Taken together, these results suggest that FMRP expression is an essential part of cellular survival mechanisms through the modulation of PI3K, Akt, and Bcl-xL signal

FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1.

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Carsten C Scholz

2016-01-01

Full Text Available The asparagine hydroxylase, factor inhibiting HIF (FIH, confers oxygen-dependence upon the hypoxia-inducible factor (HIF, a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1 is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit.

Emotion: The Self-regulatory Sense.

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Peil, Katherine T

2014-03-01

While emotion is a central component of human health and well-being, traditional approaches to understanding its biological function have been wanting. A dynamic systems model, however, broadly redefines and recasts emotion as a primary sensory system-perhaps the first sensory system to have emerged, serving the ancient autopoietic function of "self-regulation." Drawing upon molecular biology and revelations from the field of epigenetics, the model suggests that human emotional perceptions provide an ongoing stream of "self-relevant" sensory information concerning optimally adaptive states between the organism and its immediate environment, along with coupled behavioral corrections that honor a universal self-regulatory logic, one still encoded within cellular signaling and immune functions. Exemplified by the fundamental molecular circuitry of sensorimotor control in the E coli bacterium, the model suggests that the hedonic (affective) categories emerge directly from positive and negative feedback processes, their good/bad binary appraisals relating to dual self-regulatory behavioral regimes-evolutionary purposes, through which organisms actively participate in natural selection, and through which humans can interpret optimal or deficit states of balanced being and becoming. The self-regulatory sensory paradigm transcends anthropomorphism, unites divergent theoretical perspectives and isolated bodies of literature, while challenging time-honored assumptions. While suppressive regulatory strategies abound, it suggests that emotions are better understood as regulating us, providing a service crucial to all semantic language, learning systems, evaluative decision-making, and fundamental to optimal physical, mental, and social health.

Emotion: The Self-regulatory Sense

Science.gov (United States)

2014-01-01

While emotion is a central component of human health and well-being, traditional approaches to understanding its biological function have been wanting. A dynamic systems model, however, broadly redefines and recasts emotion as a primary sensory system—perhaps the first sensory system to have emerged, serving the ancient autopoietic function of “self-regulation.” Drawing upon molecular biology and revelations from the field of epigenetics, the model suggests that human emotional perceptions provide an ongoing stream of “self-relevant” sensory information concerning optimally adaptive states between the organism and its immediate environment, along with coupled behavioral corrections that honor a universal self-regulatory logic, one still encoded within cellular signaling and immune functions. Exemplified by the fundamental molecular circuitry of sensorimotor control in the E coli bacterium, the model suggests that the hedonic (affective) categories emerge directly from positive and negative feedback processes, their good/bad binary appraisals relating to dual self-regulatory behavioral regimes—evolutionary purposes, through which organisms actively participate in natural selection, and through which humans can interpret optimal or deficit states of balanced being and becoming. The self-regulatory sensory paradigm transcends anthropomorphism, unites divergent theoretical perspectives and isolated bodies of literature, while challenging time-honored assumptions. While suppressive regulatory strategies abound, it suggests that emotions are better understood as regulating us, providing a service crucial to all semantic language, learning systems, evaluative decision-making, and fundamental to optimal physical, mental, and social health. PMID:24808986

Mechanics rules cell biology

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Wang James HC

2010-07-01

Full Text Available Abstract Cells in the musculoskeletal system are subjected to various mechanical forces in vivo. Years of research have shown that these mechanical forces, including tension and compression, greatly influence various cellular functions such as gene expression, cell proliferation and differentiation, and secretion of matrix proteins. Cells also use mechanotransduction mechanisms to convert mechanical signals into a cascade of cellular and molecular events. This mini-review provides an overview of cell mechanobiology to highlight the notion that mechanics, mainly in the form of mechanical forces, dictates cell behaviors in terms of both cellular mechanobiological responses and mechanotransduction.

Interplay of cis- and trans-regulatory mechanisms in the spliceosomal RNA helicase Brr2.

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Absmeier, Eva; Becke, Christian; Wollenhaupt, Jan; Santos, Karine F; Wahl, Markus C

2017-01-02

RNA helicase Brr2 is implicated in multiple phases of pre-mRNA splicing and thus requires tight regulation. Brr2 can be auto-inhibited via a large N-terminal region folding back onto its helicase core and auto-activated by a catalytically inactive C-terminal helicase cassette. Furthermore, it can be regulated in trans by the Jab1 domain of the Prp8 protein, which can inhibit Brr2 by intermittently inserting a C-terminal tail in the enzyme's RNA-binding tunnel or activate the helicase after removal of this tail. Presently it is unclear, whether these regulatory mechanisms functionally interact and to which extent they are evolutionarily conserved. Here, we report crystal structures of Saccharomyces cerevisiae and Chaetomium thermophilum Brr2-Jab1 complexes, demonstrating that Jab1-based inhibition of Brr2 presumably takes effect in all eukaryotes but is implemented via organism-specific molecular contacts. Moreover, the structures show that Brr2 auto-inhibition can act in concert with Jab1-mediated inhibition, and suggest that the N-terminal region influences how the Jab1 C-terminal tail interacts at the RNA-binding tunnel. Systematic RNA binding and unwinding studies revealed that the N-terminal region and the Jab1 C-terminal tail specifically interfere with accommodation of double-stranded and single-stranded regions of an RNA substrate, respectively, mutually reinforcing each other. Additionally, such analyses show that regulation based on the N-terminal region requires the presence of the inactive C-terminal helicase cassette. Together, our results outline an intricate system of regulatory mechanisms, which control Brr2 activities during snRNP assembly and splicing.

Toxin-antitoxin systems and regulatory mechanisms in Mycobacterium tuberculosis.

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Slayden, Richard A; Dawson, Clinton C; Cummings, Jason E

2018-06-01

There has been a significant reduction in annual tuberculosis incidence since the World Health Organization declared tuberculosis a global health threat. However, treatment of M. tuberculosis infections requires lengthy multidrug therapeutic regimens to achieve a durable cure. The development of new drugs that are active against resistant strains and phenotypically diverse organisms continues to present the greatest challenge in the future. Numerous phylogenomic analyses have revealed that the Mtb genome encodes a significantly expanded repertoire of toxin-antitoxin (TA) loci that makes up the Mtb TA system. A TA loci is a two-gene operon encoding a 'toxin' protein that inhibits bacterial growth and an interacting 'antitoxin' partner that neutralizes the inhibitory activity of the toxin. The presence of multiple chromosomally encoded TA loci in Mtb raises important questions in regard to expansion, regulation and function. Thus, the functional roles of TA loci in Mtb pathogenesis have received considerable attention over the last decade. The cumulative results indicate that they are involved in regulating adaptive responses to stresses associated with the host environment and drug treatment. Here we review the TA families encoded in Mtb, discuss the duplication of TA loci in Mtb, regulatory mechanism of TA loci, and phenotypic heterogeneity and pathogenesis.

[Motivation and Emotional States: Structural Systemic, Neurochemical, Molecular and Cellular Mechanisms].

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Bazyan, A S

2016-01-01

The structural, systemic, neurochemical, molecular and cellular mechanisms of organization and coding motivation and emotional states are describe. The GABA and glutamatergic synaptic systems of basal ganglia form a neural network and participate in the implementation of voluntary behavior. Neuropeptides, neurohormones and paracrine neuromodulators involved in the organization of motivation and emotional states, integrated with synaptic systems, controlled by neural networks and organizing goal-directed behavior. Structural centers for united and integrated of information in voluntary and goal-directed behavior are globus pallidus. Substantia nigra pars reticulata switches the information from corticobasal networks to thalamocortical networks, induces global dopaminergic (DA) signal and organize interaction of mesolimbic and nigostriatnoy DA systems controlled by prefrontal and motor cortex. Together with the motor cortex, substantia nigra displays information in the brainstem and spinal cord to implementation of behavior. Motivation states are formed in the interaction of neurohormonal and neuropeptide systems by monoaminergic systems of brain. Emotional states are formed by monoaminergic systems of the mid-brain, where the leading role belongs to the mesolimbic DA system. The emotional and motivation state of the encoded specific epigenetic molecular and chemical pattern of neuron.

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

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Miyakawa, Takuya; Tanokura, Masaru

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

The induction and regulation of radiogenic transformation in vitro: Cellular and molecular mechanisms

International Nuclear Information System (INIS)

Borek, C.

1987-01-01

Rodent and human cells in culture, transformed in vitro by ionizing radiation, ultraviolet light, or chemicals into malignant cells afford us the opportunity to probe into early and late events in the neoplastic process at a cellular and molecular level. Transformation can be regarded as an abnormal expression of cellular genes. The initiating agents disrupt the integrity of the genetic apparatus altering DNA in ways that result in the activation of cellular transforming genes (oncogenes) during some stage of the neoplastic process. Events associated with initiation and promotion may overlap to some degree, but in order for them to occur, cellular permissive conditions must prevail. Permissive factors include thyroid and steroid hormones, specific states of differentiation, certain stages in the cell cycle, specific genetic impairment, and inadequate antioxidants. Genetically susceptible cells require physiological states conducive to transformation. These may differ with age, tissue, and species and in part may be responsible for the observed lower sensitivity of human cells to transformation

Formation of cellular structure in beryllium at plastic working

International Nuclear Information System (INIS)

Papirov, I.I.; Nikolaenko, A.A.; Shokurov, V.S.; Pikalov, A.I.

2013-01-01

Conditions of cellular structure formation are investigated at various kinds of deformation and heat treatment of beryllium ingots. It is shown that the cellular structure plays the important role in formation of complex of physical mechanical properties of beryllium. Influence of impurity, various conditions of deformation (temperature, squeezing degree) and heat treatments on substructure, texture and mechanical properties of metal is investigated. Optimum conditions of rolling and heat treatments of beryllium are defined. The way of sign-variable cyclic deformation of beryllium ingots is offered for reception quasi-isotropic fine-grained metal. Physical-mechanical properties of ultra fine-grained metal are studied

Viral and cellular SOS-regulated motor proteins: dsDNA translocation mechanisms with divergent functions.

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Wolfe, Annie; Phipps, Kara; Weitao, Tao

2014-01-01

DNA damage attacks on bacterial cells have been known to activate the SOS response, a transcriptional response affecting chromosome replication, DNA recombination and repair, cell division and prophage induction. All these functions require double-stranded (ds) DNA translocation by ASCE hexameric motors. This review seeks to delineate the structural and functional characteristics of the SOS response and the SOS-regulated DNA translocases FtsK and RuvB with the phi29 bacteriophage packaging motor gp16 ATPase as a prototype to study bacterial motors. While gp16 ATPase, cellular FtsK and RuvB are similarly comprised of hexameric rings encircling dsDNA and functioning as ATP-driven DNA translocases, they utilize different mechanisms to accomplish separate functions, suggesting a convergent evolution of these motors. The gp16 ATPase and FtsK use a novel revolution mechanism, generating a power stroke between subunits through an entropy-DNA affinity switch and pushing dsDNA inward without rotation of DNA and the motor, whereas RuvB seems to employ a rotation mechanism that remains to be further characterized. While FtsK and RuvB perform essential tasks during the SOS response, their roles may be far more significant as SOS response is involved in antibiotic-inducible bacterial vesiculation and biofilm formation as well as the perspective of the bacteria-cancer evolutionary interaction.

CoryneRegNet: An ontology-based data warehouse of corynebacterial transcription factors and regulatory networks

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Czaja Lisa F

2006-02-01

Full Text Available Abstract Background The application of DNA microarray technology in post-genomic analysis of bacterial genome sequences has allowed the generation of huge amounts of data related to regulatory networks. This data along with literature-derived knowledge on regulation of gene expression has opened the way for genome-wide reconstruction of transcriptional regulatory networks. These large-scale reconstructions can be converted into in silico models of bacterial cells that allow a systematic analysis of network behavior in response to changing environmental conditions. Description CoryneRegNet was designed to facilitate the genome-wide reconstruction of transcriptional regulatory networks of corynebacteria relevant in biotechnology and human medicine. During the import and integration process of data derived from experimental studies or literature knowledge CoryneRegNet generates links to genome annotations, to identified transcription factors and to the corresponding cis-regulatory elements. CoryneRegNet is based on a multi-layered, hierarchical and modular concept of transcriptional regulation and was implemented by using the relational database management system MySQL and an ontology-based data structure. Reconstructed regulatory networks can be visualized by using the yFiles JAVA graph library. As an application example of CoryneRegNet, we have reconstructed the global transcriptional regulation of a cellular module involved in SOS and stress response of corynebacteria. Conclusion CoryneRegNet is an ontology-based data warehouse that allows a pertinent data management of regulatory interactions along with the genome-scale reconstruction of transcriptional regulatory networks. These models can further be combined with metabolic networks to build integrated models of cellular function including both metabolism and its transcriptional regulation.

Efficient Reverse-Engineering of a Developmental Gene Regulatory Network

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Cicin-Sain, Damjan; Ashyraliyev, Maksat; Jaeger, Johannes

2012-01-01

Understanding the complex regulatory networks underlying development and evolution of multi-cellular organisms is a major problem in biology. Computational models can be used as tools to extract the regulatory structure and dynamics of such networks from gene expression data. This approach is called reverse engineering. It has been successfully applied to many gene networks in various biological systems. However, to reconstitute the structure and non-linear dynamics of a developmental gene network in its spatial context remains a considerable challenge. Here, we address this challenge using a case study: the gap gene network involved in segment determination during early development of Drosophila melanogaster. A major problem for reverse-engineering pattern-forming networks is the significant amount of time and effort required to acquire and quantify spatial gene expression data. We have developed a simplified data processing pipeline that considerably increases the throughput of the method, but results in data of reduced accuracy compared to those previously used for gap gene network inference. We demonstrate that we can infer the correct network structure using our reduced data set, and investigate minimal data requirements for successful reverse engineering. Our results show that timing and position of expression domain boundaries are the crucial features for determining regulatory network structure from data, while it is less important to precisely measure expression levels. Based on this, we define minimal data requirements for gap gene network inference. Our results demonstrate the feasibility of reverse-engineering with much reduced experimental effort. This enables more widespread use of the method in different developmental contexts and organisms. Such systematic application of data-driven models to real-world networks has enormous potential. Only the quantitative investigation of a large number of developmental gene regulatory networks will allow us to

Sub-cellular distribution and translocation of TRP channels.

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Toro, Carlos A; Arias, Luis A; Brauchi, Sebastian

2011-01-01

Cellular electrical activity is the result of a highly complex processes that involve the activation of ion channel proteins. Ion channels make pores on cell membranes that rapidly transit between conductive and non-conductive states, allowing different ions to flow down their electrochemical gradients across cell membranes. In the case of neuronal cells, ion channel activity orchestrates action potentials traveling through axons, enabling electrical communication between cells in distant parts of the body. Somatic sensation -our ability to feel touch, temperature and noxious stimuli- require ion channels able to sense and respond to our peripheral environment. Sensory integration involves the summing of various environmental cues and their conversion into electrical signals. Members of the Transient Receptor Potential (TRP) family of ion channels have emerged as important mediators of both cellular sensing and sensory integration. The regulation of the spatial and temporal distribution of membrane receptors is recognized as an important mechanism for controlling the magnitude of the cellular response and the time scale on which cellular signaling occurs. Several studies have shown that this mechanism is also used by TRP channels to modulate cellular response and ultimately fulfill their physiological function as sensors. However, the inner-working of this mode of control for TRP channels remains poorly understood. The question of whether TRPs intrinsically regulate their own vesicular trafficking or weather the dynamic regulation of TRP channel residence on the cell surface is caused by extrinsic changes in the rates of vesicle insertion or retrieval remain open. This review will examine the evidence that sub-cellular redistribution of TRP channels plays an important role in regulating their activity and explore the mechanisms that control the trafficking of vesicles containing TRP channels.

Long-term potentiation in the amygdala: a cellular mechanism of fear learning and memory.

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Sigurdsson, Torfi; Doyère, Valérie; Cain, Christopher K; LeDoux, Joseph E

2007-01-01

Much of the research on long-term potentiation (LTP) is motivated by the question of whether changes in synaptic strength similar to LTP underlie learning and memory. Here we discuss findings from studies on fear conditioning, a form of associative learning whose neural circuitry is relatively well understood, that may be particularly suited for addressing this question. We first review the evidence suggesting that fear conditioning is mediated by changes in synaptic strength at sensory inputs to the lateral nucleus of the amygdala. We then discuss several outstanding questions that will be important for future research on the role of synaptic plasticity in fear learning. The results gained from these studies may shed light not only on fear conditioning, but may also help unravel more general cellular mechanisms of learning and memory.

Cellular dynamics of bovine aortic smooth muscle cells measured using MEMS force sensors

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Tsukagoshi, Takuya; Nguyen, Thanh-Vinh; Hirayama Shoji, Kayoko; Takahashi, Hidetoshi; Matsumoto, Kiyoshi; Shimoyama, Isao

2018-04-01

Adhesive cells perceive the mechanical properties of the substrates to which they adhere, adjusting their cellular mechanical forces according to their biological characteristics. This mechanical interaction subsequently affects the growth, locomotion, and differentiation of the cell. However, little is known about the detailed mechanism that underlies this interaction between adherent cells and substrates because dynamically measuring mechanical phenomena is difficult. Here, we utilize microelectromechamical systems force sensors that can measure cellular traction forces with high temporal resolution (~2.5 µs) over long periods (~3 h). We found that the cellular dynamics reflected physical phenomena with time scales from milliseconds to hours, which contradicts the idea that cellular motion is slow. A single focal adhesion (FA) generates an average force of 7 nN, which disappears in ms via the action of trypsin-ethylenediaminetetraacetic acid. The force-changing rate obtained from our measurements suggests that the time required for an FA to decompose was nearly proportional to the force acting on the FA.

Adaptive pressure-controlled cellular structures for shape morphing I: design and analysis

International Nuclear Information System (INIS)

Luo, Quantian; Tong, Liyong

2013-01-01

This work investigates adaptive bio-inspired pressure cellular structures for shape morphing. Optimum designs for cellular structures with void and pressure cells are proposed and then structural analyses are conducted. In the present design, a unit cell is comprised of straight and curved walls. When compressed air is pumped into a pressure cell, the curved walls deform in bending due to the pressure difference in two adjacent cells that leads to overall structural deformation in extension. One-dimensional actuation strain up to 35% can be theoretically achieved. In part I, we present basic design concepts and cellular mechanics. Unlike conventional structural analysis for cellular structures, a statically indeterminate unit cell is considered and novel analytical formulations are derived for the present pressurized cellular structures in linear and nonlinear analyses. In part II, we will present experimental testing and finite element analysis to demonstrate the feasibility of the present pressurized cellular actuators for morphing wings and to validate the present cellular mechanics formulations. (paper)

Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in Multiple Sclerosis

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Torrealdea Javier

2011-07-01

Full Text Available Abstract Background The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS. Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e.g. failure in central tolerance, activation by pathogens that are able to trigger the immune system. Results The model represents five concepts: central tolerance (T-cell generation by the thymus, T-cell activation, T-cell memory, cross-regulation (negative feedback between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and/or dose, and on the underlying dynamic of the immune system. Conclusion The relapsing dynamic in MS

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

International Nuclear Information System (INIS)

Florea, Ana-Maria; Büsselberg, Dietrich

2011-01-01

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

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.

Quantum features of natural cellular automata

International Nuclear Information System (INIS)

Elze, Hans-Thomas

2016-01-01

Cellular automata can show well known features of quantum mechanics, such as a linear rule according to which they evolve and which resembles a discretized version of the Schrödinger equation. This includes corresponding conservation laws. The class of “natural” Hamiltonian cellular automata is based exclusively on integer-valued variables and couplings and their dynamics derives from an Action Principle. They can be mapped reversibly to continuum models by applying Sampling Theory. Thus, “deformed” quantum mechanical models with a finite discreteness scale l are obtained, which for l → 0 reproduce familiar continuum results. We have recently demonstrated that such automata can form “multipartite” systems consistently with the tensor product structures of nonrelativistic many-body quantum mechanics, while interacting and maintaining the linear evolution. Consequently, the Superposition Principle fully applies for such primitive discrete deterministic automata and their composites and can produce the essential quantum effects of interference and entanglement. (paper)

Cellular concrete: a potential load-bearing insulation for cryogenic applications

International Nuclear Information System (INIS)

Richard, T.G.; Dobogai, J.A.; Gerhardt, T.D.; Young, W.C.

1975-01-01

The need for low cost, low thermal conductivity, high strength insulation suitable for cryogenic applications is becoming more evident. An investigation of the potential of cellular concretes to fulfill this function was initiated. A review of the thermal and mechanical characteristics of foamed plastics and cellular concrete is presented along with relative cost comparisons. Test data from preliminary investigations is presented to define the influence of material constituents, density, and temperature on the mechanical and thermal response of cellular concrete. Specimen densities range from 0.64 to 1.44 gr/cc. The influence of temperature variations from 22 0 C to -196 0 C is reported for selected densities

Synchronous versus asynchronous modeling of gene regulatory networks.

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Garg, Abhishek; Di Cara, Alessandro; Xenarios, Ioannis; Mendoza, Luis; De Micheli, Giovanni

2008-09-01

In silico modeling of gene regulatory networks has gained some momentum recently due to increased interest in analyzing the dynamics of biological systems. This has been further facilitated by the increasing availability of experimental data on gene-gene, protein-protein and gene-protein interactions. The two dynamical properties that are often experimentally testable are perturbations and stable steady states. Although a lot of work has been done on the identification of steady states, not much work has been reported on in silico modeling of cellular differentiation processes. In this manuscript, we provide algorithms based on reduced ordered binary decision diagrams (ROBDDs) for Boolean modeling of gene regulatory networks. Algorithms for synchronous and asynchronous transition models have been proposed and their corresponding computational properties have been analyzed. These algorithms allow users to compute cyclic attractors of large networks that are currently not feasible using existing software. Hereby we provide a framework to analyze the effect of multiple gene perturbation protocols, and their effect on cell differentiation processes. These algorithms were validated on the T-helper model showing the correct steady state identification and Th1-Th2 cellular differentiation process. The software binaries for Windows and Linux platforms can be downloaded from http://si2.epfl.ch/~garg/genysis.html.

Mammalian synthetic biology for studying the cell.

Science.gov (United States)

Mathur, Melina; Xiang, Joy S; Smolke, Christina D

2017-01-02

Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology. © 2017 Mathur et al.

Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity

International Nuclear Information System (INIS)

Catania, Annunziata; Iavarone, Carlo; Carlomagno, Stella M.; Chiariello, Mario

2006-01-01

Histone deacetylases (HDACs) are key regulatory enzymes involved in the control of gene expression and their inhibition by specific drugs has been widely correlated to cell cycle arrest, terminal differentiation, and apoptosis. Here, we investigated whether HDAC activity was required for PDGF-dependent signal transduction and cellular proliferation. Exposure of PDGF-stimulated NIH3T3 fibroblasts to the HDAC inhibitor trichostatin A (TSA) potently repressed the expression of a group of genes correlated to PDGF-dependent cellular growth and pro-survival activity. Moreover, we show that TSA interfered with STAT3-dependent transcriptional activity induced by PDGF. Still, neither phosphorylation nor nuclear translocation and DNA-binding in vitro and in vivo of STAT3 were affected by using TSA to interfere with PDGF stimulation. Finally, TSA treatment resulted in the suppression of PDGF-dependent cellular proliferation without affecting cellular survival of NIH3T3 cells. Our data indicate that inhibition of HDAC activity antagonizes the mitogenic effect of PDGF, suggesting that these drugs may specifically act on the expression of STAT-dependent, PDGF-responsive genes

Regulatory design governing progression of population growth phases in bacteria.

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Agustino Martínez-Antonio

Full Text Available It has long been noted that batch cultures inoculated with resting bacteria exhibit a progression of growth phases traditionally labeled lag, exponential, pre-stationary and stationary. However, a detailed molecular description of the mechanisms controlling the transitions between these phases is lacking. A core circuit, formed by a subset of regulatory interactions involving five global transcription factors (FIS, HNS, IHF, RpoS and GadX, has been identified by correlating information from the well- established transcriptional regulatory network of Escherichia coli and genome-wide expression data from cultures in these different growth phases. We propose a functional role for this circuit in controlling progression through these phases. Two alternative hypotheses for controlling the transition between the growth phases are first, a continuous graded adjustment to changing environmental conditions, and second, a discontinuous hysteretic switch at critical thresholds between growth phases. We formulate a simple mathematical model of the core circuit, consisting of differential equations based on the power-law formalism, and show by mathematical and computer-assisted analysis that there are critical conditions among the parameters of the model that can lead to hysteretic switch behavior, which--if validated experimentally--would suggest that the transitions between different growth phases might be analogous to cellular differentiation. Based on these provocative results, we propose experiments to test the alternative hypotheses.

Regulatory design governing progression of population growth phases in bacteria.

Science.gov (United States)

Martínez-Antonio, Agustino; Lomnitz, Jason G; Sandoval, Santiago; Aldana, Maximino; Savageau, Michael A

2012-01-01

It has long been noted that batch cultures inoculated with resting bacteria exhibit a progression of growth phases traditionally labeled lag, exponential, pre-stationary and stationary. However, a detailed molecular description of the mechanisms controlling the transitions between these phases is lacking. A core circuit, formed by a subset of regulatory interactions involving five global transcription factors (FIS, HNS, IHF, RpoS and GadX), has been identified by correlating information from the well- established transcriptional regulatory network of Escherichia coli and genome-wide expression data from cultures in these different growth phases. We propose a functional role for this circuit in controlling progression through these phases. Two alternative hypotheses for controlling the transition between the growth phases are first, a continuous graded adjustment to changing environmental conditions, and second, a discontinuous hysteretic switch at critical thresholds between growth phases. We formulate a simple mathematical model of the core circuit, consisting of differential equations based on the power-law formalism, and show by mathematical and computer-assisted analysis that there are critical conditions among the parameters of the model that can lead to hysteretic switch behavior, which--if validated experimentally--would suggest that the transitions between different growth phases might be analogous to cellular differentiation. Based on these provocative results, we propose experiments to test the alternative hypotheses.

Oct4 targets regulatory nodes to modulate stem cell function.

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Pearl A Campbell

2007-06-01

Full Text Available Stem cells are characterized by two defining features, the ability to self-renew and to differentiate into highly specialized cell types. The POU homeodomain transcription factor Oct4 (Pou5f1 is an essential mediator of the embryonic stem cell state and has been implicated in lineage specific differentiation, adult stem cell identity, and cancer. Recent description of the regulatory networks which maintain 'ES' have highlighted a dual role for Oct4 in the transcriptional activation of genes required to maintain self-renewal and pluripotency while concomitantly repressing genes which facilitate lineage specific differentiation. However, the molecular mechanism by which Oct4 mediates differential activation or repression at these loci to either maintain stem cell identity or facilitate the emergence of alternate transcriptional programs required for the realization of lineage remains to be elucidated. To further investigate Oct4 function, we employed gene expression profiling together with a robust statistical analysis to identify genes highly correlated to Oct4. Gene Ontology analysis to categorize overrepresented genes has led to the identification of themes which may prove essential to stem cell identity, including chromatin structure, nuclear architecture, cell cycle control, DNA repair, and apoptosis. Our experiments have identified previously unappreciated roles for Oct4 for firstly, regulating chromatin structure in a state consistent with self-renewal and pluripotency, and secondly, facilitating the expression of genes that keeps the cell poised to respond to cues that lead to differentiation. Together, these data define the mechanism by which Oct4 orchestrates cellular regulatory pathways to enforce the stem cell state and provides important insight into stem cell function and cancer.

Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes.

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Mohammad F Saeed

2010-09-01

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

Elastomeric Cellular Structure Enhanced by Compressible Liquid Filler

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Sun, Yueting; Xu, Xiaoqing; Xu, Chengliang; Qiao, Yu; Li, Yibing

2016-05-01

Elastomeric cellular structures provide a promising solution for energy absorption. Their flexible and resilient nature is particularly relevant to protection of human bodies. Herein we develop an elastomeric cellular structure filled with nanoporous material functionalized (NMF) liquid. Due to the nanoscale infiltration in NMF liquid and its interaction with cell walls, the cellular structure has a much enhanced mechanical performance, in terms of loading capacity and energy absorption density. Moreover, it is validated that the structure is highly compressible and self-restoring. Its hyper-viscoelastic characteristics are elucidated.

Proceedings of the signature series event of the international society for cellular therapy: "Advancements in cellular therapies and regenerative medicine in digestive diseases," London, United Kingdom, May 3, 2017.

Science.gov (United States)

Ciccocioppo, Rachele; Dos Santos, Claudia C; Baumgart, Daniel C; Cangemi, Giuseppina C; Cardinale, Vincenzo; Ciacci, Carolina; De Coppi, Paolo; Haldar, Debashis; Klersy, Catherine; Nostro, M Cristina; Ott, Michael; Piemonti, Lorenzo; Tomei, Alice A; Uygun, Basak; Vetrano, Stefania; Orlando, Giuseppe

2018-03-01

A summary of the First Signature Series Event, "Advancements in Cellular Therapies and Regenerative Medicine for Digestive Diseases," held on May 3, 2017, in London, United Kingdom, is presented. Twelve speakers from three continents covered major topics in the areas of cellular therapy and regenerative medicine applied to liver and gastrointestinal medicine as well as to diabetes mellitus. Highlights from their presentations, together with an overview of the global impact of digestive diseases and a proposal for a shared online collection and data-monitoring platform tool, are included in this proceedings. Although growing evidence demonstrate the feasibility and safety of exploiting cell-based technologies for the treatment of digestive diseases, regulatory and methodological obstacles will need to be overcome before the successful implementation in the clinic of these novel attractive therapeutic strategies. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Immunohistochemical distribution of regulatory peptides in the human fetal adenohypophysis

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Reyes, R; Valladares, F; Gutiérrez, R; González, M; Bello, A R

2008-01-01

We have studied here the cellular distribution of several regulatory peptides in hormone-producing cells of the human pituitary during the fetal period. Immunohistochemistry was used to show the expression of several regulatory peptides, namely Angiotensin-II, Neurotensin and Galanin, at successive gestational stages and their co-localization with hormones in the human fetal adenohypophysis. Somatotrophs, gonadotrophs and thyrotrophs were differentiated earliest. At gestational week 9, Angiotensin-II immunoreactivity was co-localized only with growth hormone immunoreactivity in somatotrophs, one of the first hormone-producing cells to differentiate. This co-localization remained until week 37. Neurotensin immunoreactivity was present in gonadotrophs and thyrotrophs in week 23, after FSH and TSH hormone differentiation. Galanin immunoreactivity was present in all hormone-producing cell types except corticotrophs. The different pro-opiomelanocortin-derived peptides were detected at different stages of gestation and adrenocorticotrophic hormone immunoreaction was the last to be detected. Our results show an interesting relationship between regulatory peptides and hormones during human fetal development, which could imply that these peptides play a regulatory role in the development of pituitary function. PMID:18510508

Cellular and exosome mediated molecular defense mechanism in bovine granulosa cells exposed to oxidative stress.

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Mohammed Saeed-Zidane

Full Text Available Various environmental insults including diseases, heat and oxidative stress could lead to abnormal growth, functions and apoptosis in granulosa cells during ovarian follicle growth and oocyte maturation. Despite the fact that cells exposed to oxidative stress are responding transcriptionally, the potential release of transcripts associated with oxidative stress response into extracellular space through exosomes is not yet determined. Therefore, here we aimed to investigate the effect of oxidative stress in bovine granulosa cells in vitro on the cellular and exosome mediated defense mechanisms. Bovine granulosa cells were aspirated from ovarian follicles and cultured in DMEM/F-12 Ham culture medium supplemented with 10% exosome-depleted fetal bovine serum. In the first experiment sub-confluent cells were treated with 5 μM H2O2 for 40 min to induce oxidative stress. Thereafter, cells were subjected to ROS and mitochondrial staining, cell proliferation and cell cycle assays. Furthermore, gene and protein expression analysis were performed in H2O2-challenged versus control group 24 hr post-treatment using qRT-PCR and immune blotting or immunocytochemistry assay, respectively. Moreover, exosomes were isolated from spent media using ultracentrifugation procedure, and subsequently used for RNA isolation and qRT-PCR. In the second experiment, exosomes released by granulosa cells under oxidative stress (StressExo or those released by granulosa cells without oxidative stress (NormalExo were co-incubated with bovine granulosa cells in vitro to proof the potential horizontal transfer of defense molecules from exosomes to granulosa cells and investigate any phenotype changes. Exposure of bovine granulosa cells to H2O2 induced the accumulation of ROS, reduced mitochondrial activity, increased expression of Nrf2 and its downstream antioxidant genes (both mRNA and protein, altered the cell cycle transitions and induced cellular apoptosis. Granulosa cells

A general mechanism for intracellular toxicity of metal-containing nanoparticles

KAUST Repository

Sabella, Stefania

2014-04-09

The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment-where particles are abundantly internalized-is responsible for the cascading events associated with nanoparticles-induced intracellular toxicity. We call this mechanism a "lysosome-enhanced Trojan horse effect" since, in the case of nanoparticles, the protective cellular machinery designed to degrade foreign objects is actually responsible for their toxicity. To test our hypothesis, we compare the toxicity of similar gold particles whose main difference is in the internalization pathways. We show that particles known to pass directly through cell membranes become more toxic when modified so as to be mostly internalized by endocytosis. Furthermore, using experiments with chelating and lysosomotropic agents, we found that the toxicity mechanism for different metal containing NPs (such as metallic, metal oxide, and semiconductor NPs) is mainly associated with the release of the corresponding toxic ions. Finally, we show that particles unable to release toxic ions (such as stably coated NPs, or diamond and silica NPs) are not harmful to intracellular environments. The Royal Society of Chemistry 2014.

A general mechanism for intracellular toxicity of metal-containing nanoparticles

KAUST Repository

Sabella, Stefania; Carney, Randy P.; Brunetti, Virgilio; Malvindi, Maria Ada; Al-Juffali, Noura; Vecchio, Giuseppe; Janes, Sam M.; Bakr, Osman; Cingolani, Roberto; Stellacci, Francesco; Pompa, Pier Paolo

2014-01-01

The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment-where particles are abundantly internalized-is responsible for the cascading events associated with nanoparticles-induced intracellular toxicity. We call this mechanism a "lysosome-enhanced Trojan horse effect" since, in the case of nanoparticles, the protective cellular machinery designed to degrade foreign objects is actually responsible for their toxicity. To test our hypothesis, we compare the toxicity of similar gold particles whose main difference is in the internalization pathways. We show that particles known to pass directly through cell membranes become more toxic when modified so as to be mostly internalized by endocytosis. Furthermore, using experiments with chelating and lysosomotropic agents, we found that the toxicity mechanism for different metal containing NPs (such as metallic, metal oxide, and semiconductor NPs) is mainly associated with the release of the corresponding toxic ions. Finally, we show that particles unable to release toxic ions (such as stably coated NPs, or diamond and silica NPs) are not harmful to intracellular environments. The Royal Society of Chemistry 2014.

Regulatory agencies and regulatory risk

OpenAIRE

Knieps, Günter; Weiß, Hans-Jörg

2008-01-01

The aim of this paper is to show that regulatory risk is due to the discretionary behaviour of regulatory agencies, caused by a too extensive regulatory mandate provided by the legislator. The normative point of reference and a behavioural model of regulatory agencies based on the positive theory of regulation are presented. Regulatory risk with regard to the future behaviour of regulatory agencies is modelled as the consequence of the ex ante uncertainty about the relative influence of inter...

The Biology of Autoimmune Response in the Scurfy Mice that Lack the CD4+Foxp3+ Regulatory T-Cells.

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Ju, Shyr-Te; Sharma, Rahul; Gaskin, Felicia; Kung, John T; Fu, Shu Man

2012-04-04

Due to a mutation in the Foxp3 transcription factor, Scurfy mice lack regulatory T-cells that maintain self-tolerance of the immune system. They develop multi-organ inflammation (MOI) and die around four weeks old. The affected organs are skin, tail, lungs and liver. In humans, endocrine and gastrointestinal inflammation are also observed, hence the disease is termed IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. The three week period of fatal MOI offers a useful autoimmune model in which the controls by genetics, T-cell subsets, cytokines, and effector mechanisms could be efficiently investigated. In this report, we will review published work, summarize our recent studies of Scurfy double mutants lacking specific autoimmune-related genes, discuss the cellular and cytokine controls by these genes on MOI, the organ-specificities of the MOI controlled by environments, and the effector mechanisms regulated by specific Th cytokines, including several newly identified control mechanisms for organ-specific autoimmune response.

A viral microRNA functions as an ortholog of cellular miR-155

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Gottwein, Eva; Mukherjee, Neelanjan; Sachse, Christoph; Frenzel, Corina; Majoros, William H.; Chi, Jen-Tsan A.; Braich, Ravi; Manoharan, Muthiah; Soutschek, Jürgen; Ohler, Uwe; Cullen, Bryan R.

2008-01-01

All metazoan eukaryotes express microRNAs (miRNAs), ∼22 nt regulatory RNAs that can repress the expression of mRNAs bearing complementary sequences1. Several DNA viruses also express miRNAs in infected cells, suggesting a role in viral replication and pathogenesis2. While specific viral miRNAs have been shown to autoregulate viral mRNAs3,4 or downregulate cellular mRNAs5,6, the function of the majority of viral miRNAs remains unknown. Here, we report that the miR-K12−11 miRNA encoded by Kaposi's Sarcoma Associated Herpesvirus (KSHV) shows significant homology to cellular miR-155, including the entire miRNA “seed” region7. Using a range of assays, we demonstrate that expression of physiological levels of miR-K12−11 or miR-155 results in the downregulation of an extensive set of common mRNA targets, including genes with known roles in cell growth regulation. Our findings indicate that viral miR-K12−11 functions as an ortholog of cellular miR-155 and has likely evolved to exploit a pre-existing gene regulatory pathway in B-cells. Moreover, the known etiological role of miR-155 in B-cell transformation8-10 suggests that miR-K12−11 may contribute to the induction of KSHV-positive B-cell tumors in infected patients. PMID:18075594

Transcriptional regulatory network triggered by oxidative signals configures the early response mechanisms of japonica rice to chilling stress

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Wijaya Edward

2010-01-01

Full Text Available Abstract Background The transcriptional regulatory network involved in low temperature response leading to acclimation has been established in Arabidopsis. In japonica rice, which can only withstand transient exposure to milder cold stress (10°C, an oxidative-mediated network has been proposed to play a key role in configuring early responses and short-term defenses. The components, hierarchical organization and physiological consequences of this network were further dissected by a systems-level approach. Results Regulatory clusters responding directly to oxidative signals were prominent during the initial 6 to 12 hours at 10°C. Early events mirrored a typical oxidative response based on striking similarities of the transcriptome to disease, elicitor and wounding induced processes. Targets of oxidative-mediated mechanisms are likely regulated by several classes of bZIP factors acting on as1/ocs/TGA-like element enriched clusters, ERF factors acting on GCC-box/JAre-like element enriched clusters and R2R3-MYB factors acting on MYB2-like element enriched clusters. Temporal induction of several H2O2-induced bZIP, ERF and MYB genes coincided with the transient H2O2 spikes within the initial 6 to 12 hours. Oxidative-independent responses involve DREB/CBF, RAP2 and RAV1 factors acting on DRE/CRT/rav1-like enriched clusters and bZIP factors acting on ABRE-like enriched clusters. Oxidative-mediated clusters were activated earlier than ABA-mediated clusters. Conclusion Genome-wide, physiological and whole-plant level analyses established a holistic view of chilling stress response mechanism of japonica rice. Early response regulatory network triggered by oxidative signals is critical for prolonged survival under sub-optimal temperature. Integration of stress and developmental responses leads to modulated growth and vigor maintenance contributing to a delay of plastic injuries.

Transcriptional regulatory network triggered by oxidative signals configures the early response mechanisms of japonica rice to chilling stress

KAUST Repository

Yun, Kil-Young

2010-01-25

Background: The transcriptional regulatory network involved in low temperature response leading to acclimation has been established in Arabidopsis. In japonica rice, which can only withstand transient exposure to milder cold stress (10C), an oxidative-mediated network has been proposed to play a key role in configuring early responses and short-term defenses. The components, hierarchical organization and physiological consequences of this network were further dissected by a systems-level approach.Results: Regulatory clusters responding directly to oxidative signals were prominent during the initial 6 to 12 hours at 10C. Early events mirrored a typical oxidative response based on striking similarities of the transcriptome to disease, elicitor and wounding induced processes. Targets of oxidative-mediated mechanisms are likely regulated by several classes of bZIP factors acting on as1/ocs/TGA-like element enriched clusters, ERF factors acting on GCC-box/JAre-like element enriched clusters and R2R3-MYB factors acting on MYB2-like element enriched clusters.Temporal induction of several H2O2-induced bZIP, ERF and MYB genes coincided with the transient H2O2spikes within the initial 6 to 12 hours. Oxidative-independent responses involve DREB/CBF, RAP2 and RAV1 factors acting on DRE/CRT/rav1-like enriched clusters and bZIP factors acting on ABRE-like enriched clusters. Oxidative-mediated clusters were activated earlier than ABA-mediated clusters.Conclusion: Genome-wide, physiological and whole-plant level analyses established a holistic view of chilling stress response mechanism of japonica rice. Early response regulatory network triggered by oxidative signals is critical for prolonged survival under sub-optimal temperature. Integration of stress and developmental responses leads to modulated growth and vigor maintenance contributing to a delay of plastic injuries. 2010 Yun et al; licensee BioMed Central Ltd.

Functional Analysis of In-frame Indel ARID1A Mutations Reveals New Regulatory Mechanisms of Its Tumor Suppressor Functions

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Bin Guan

2012-10-01

Full Text Available AT-rich interactive domain 1A (ARID1A has emerged as a new tumor suppressor in which frequent somatic mutations have been identified in several types of human cancers. Although most ARID1A somatic mutations are frame-shift or nonsense mutations that contribute to mRNA decay and loss of protein expression, 5% of ARID1A mutations are in-frame insertions or deletions (indels that involve only a small stretch of peptides. Naturally occurring in-frame indel mutations provide unique and useful models to explore the biology and regulatory role of ARID1A. In this study, we analyzed indel mutations identified in gynecological cancers to determine how these mutations affect the tumor suppressor function of ARID1A. Our results demonstrate that all in-frame mutants analyzed lost their ability to inhibit cellular proliferation or activate transcription of CDKN1A, which encodes p21, a downstream effector of ARID1A. We also showed that ARID1A is a nucleocytoplasmic protein whose stability depends on its subcellular localization. Nuclear ARID1A is less stable than cytoplasmic ARID1A because ARID1A is rapidly degraded by the ubiquitin-proteasome system in the nucleus. In-frame deletions affecting the consensus nuclear export signal reduce steady-state protein levels of ARID1A. This defect in nuclear exportation leads to nuclear retention and subsequent degradation. Our findings delineate a mechanism underlying the regulation of ARID1A subcellular distribution and protein stability and suggest that targeting the nuclear ubiquitin-proteasome system can increase the amount of the ARID1A protein in the nucleus and restore its tumor suppressor functions.

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

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Yuanyuan Li

2011-02-01

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.

A novel mechanism involved in the coupling of mitochondrial biogenesis to oxidative phosphorylation

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Jelena Ostojić

2014-01-01

Full Text Available Mitochondria are essential organelles that are central to a multitude of cellular processes, including oxidative phosphorylation (OXPHOS, which produces most of the ATP in animal cells. Thus it is important to understand not only the mechanisms and biogenesis of this energy production machinery but also how it is regulated in both physiological and pathological contexts. A recent study by Ostojić et al. [Cell Metabolism (2013 18, 567-577] has uncovered a regulatory loop by which the biogenesis of a major enzyme of the OXPHOS pathway, the respiratory complex III, is coupled to the energy producing activity of the mitochondria.

Distinct gene regulatory programs define the inhibitory effects of liver X receptors and PPARG on cancer cell proliferation.

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Savic, Daniel; Ramaker, Ryne C; Roberts, Brian S; Dean, Emma C; Burwell, Todd C; Meadows, Sarah K; Cooper, Sara J; Garabedian, Michael J; Gertz, Jason; Myers, Richard M

2016-07-11

The liver X receptors (LXRs, NR1H2 and NR1H3) and peroxisome proliferator-activated receptor gamma (PPARG, NR1C3) nuclear receptor transcription factors (TFs) are master regulators of energy homeostasis. Intriguingly, recent studies suggest that these metabolic regulators also impact tumor cell proliferation. However, a comprehensive temporal molecular characterization of the LXR and PPARG gene regulatory responses in tumor cells is still lacking. To better define the underlying molecular processes governing the genetic control of cellular growth in response to extracellular metabolic signals, we performed a comprehensive, genome-wide characterization of the temporal regulatory cascades mediated by LXR and PPARG signaling in HT29 colorectal cancer cells. For this analysis, we applied a multi-tiered approach that incorporated cellular phenotypic assays, gene expression profiles, chromatin state dynamics, and nuclear receptor binding patterns. Our results illustrate that the activation of both nuclear receptors inhibited cell proliferation and further decreased glutathione levels, consistent with increased cellular oxidative stress. Despite a common metabolic reprogramming, the gene regulatory network programs initiated by these nuclear receptors were widely distinct. PPARG generated a rapid and short-term response while maintaining a gene activator role. By contrast, LXR signaling was prolonged, with initial, predominantly activating functions that transitioned to repressive gene regulatory activities at late time points. Through the use of a multi-tiered strategy that integrated various genomic datasets, our data illustrate that distinct gene regulatory programs elicit common phenotypic effects, highlighting the complexity of the genome. These results further provide a detailed molecular map of metabolic reprogramming in cancer cells through LXR and PPARG activation. As ligand-inducible TFs, these nuclear receptors can potentially serve as attractive therapeutic

Pathogenesis and pharmacologic treatment of obesity: the role of energy regulatory mechanism.

Science.gov (United States)

Manulu, Mangatas S M; Sutanegara, I N Dwi

2006-01-01

Obesity has become a worldwide public health problem affecting millions of people. This is a chronic, stigmatized, and costly disease, rarely curable and is increasing in prevalence to a point today where we define obesity as an epidemic disease that not only in developed but also on developing countries. The pathogenesis of obesity is largely unknown, especially about energy regulatory mechanism that involved wide area of neuroendocrinology that is very interesting but very complex and makes internists "refuse" to learn. Obesity occurs through a longstanding imbalance between energy intake and energy expenditure, influenced by a complex biologic system that regulates appetite and adiposity. Obesity influences the pathogenesis of hypertension, type 2 diabetes, dyslipidemia, kidney, heart, and cerebrovascular disease. It is very wise for every internist to learn the pathogenesis and treatment of this worldwide diseases. Until now, the available treatments, including drugs, are palliative and are effective only while the treatment is being actively used; and besides so many side effects reported.

Cost-benefit and regulatory decision making

International Nuclear Information System (INIS)

Harvie, J.

1996-01-01

The Atomic Energy Control Board is investigating the feasibility of developing methods for factoring cost-benefit considerations into its regulatory decision-making. This initiative results, in part, from the federal government policy requiring cost-benefit considerations to be taken into account in regulatory processes, and from the recommendations of an Advisory Panel on Regulatory Review in 1993, submitted to the Minister of Natural Resources Canada. One of these recommendations stated: 'that mechanisms be developed to examine cost benefit issues and work towards some consensus of opinion among stake holders: a task force on the subject could be an appropriate starting point'. (author)

SUMO modification of Stra13 is required for repression of cyclin D1 expression and cellular growth arrest.

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Yaju Wang

Full Text Available Stra13, a basic helix-loop-helix (bHLH transcription factor is involved in myriad biological functions including cellular growth arrest, differentiation and senescence. However, the mechanisms by which its transcriptional activity and function are regulated remain unclear. In this study, we provide evidence that post-translational modification of Stra13 by Small Ubiquitin-like Modifier (SUMO dramatically potentiates its ability to transcriptionally repress cyclin D1 and mediate G(1 cell cycle arrest in fibroblast cells. Mutation of SUMO acceptor lysines 159 and 279 located in the C-terminal repression domain has no impact on nuclear localization; however, it abrogates association with the co-repressor histone deacetylase 1 (HDAC1, attenuates repression of cyclin D1, and prevents Stra13-mediated growth suppression. HDAC1, which promotes cellular proliferation and cell cycle progression, antagonizes Stra13 sumoylation-dependent growth arrest. Our results uncover an unidentified regulatory axis between Stra13 and HDAC1 in progression through the G(1/S phase of the cell cycle, and provide new mechanistic insights into regulation of Stra13-mediated transcriptional repression by sumoylation.

Structure reveals regulatory mechanisms of a MaoC-like hydratase from Phytophthora capsici involved in biosynthesis of polyhydroxyalkanoates (PHAs).

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Wang, Huizheng; Zhang, Kai; Zhu, Jie; Song, Weiwei; Zhao, Li; Zhang, Xiuguo

2013-01-01

Polyhydroxyalkanoates (PHAs) have attracted increasing attention as "green plastic" due to their biodegradable, biocompatible, thermoplastic, and mechanical properties, and considerable research has been undertaken to develop low cost/high efficiency processes for the production of PHAs. MaoC-like hydratase (MaoC), which belongs to (R)-hydratase involved in linking the β-oxidation and the PHA biosynthetic pathways, has been identified recently. Understanding the regulatory mechanisms of (R)-hydratase catalysis is critical for efficient production of PHAs that promise synthesis an environment-friendly plastic. We have determined the crystal structure of a new MaoC recognized from Phytophthora capsici. The crystal structure of the enzyme was solved at 2.00 Å resolution. The structure shows that MaoC has a canonical (R)-hydratase fold with an N-domain and a C-domain. Supporting its dimerization observed in structure, MaoC forms a stable homodimer in solution. Mutations that disrupt the dimeric MaoC result in a complete loss of activity toward crotonyl-CoA, indicating that dimerization is required for the enzymatic activity of MaoC. Importantly, structure comparison reveals that a loop unique to MaoC interacts with an α-helix that harbors the catalytic residues of MaoC. Deletion of the loop enhances the enzymatic activity of MaoC, suggesting its inhibitory role in regulating the activity of MaoC. The data in our study reveal the regulatory mechanism of an (R)-hydratase, providing information on enzyme engineering to produce low cost PHAs.

Simulating molecular mechanisms of the MDM2-mediated regulatory interactions: a conformational selection model of the MDM2 lid dynamics.

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Gennady M Verkhivker

Full Text Available Diversity and complexity of MDM2 mechanisms govern its principal function as the cellular antagonist of the p53 tumor suppressor. Structural and biophysical studies have demonstrated that MDM2 binding could be regulated by the dynamics of a pseudo-substrate lid motif. However, these experiments and subsequent computational studies have produced conflicting mechanistic models of MDM2 function and dynamics. We propose a unifying conformational selection model that can reconcile experimental findings and reveal a fundamental role of the lid as a dynamic regulator of MDM2-mediated binding. In this work, structure, dynamics and energetics of apo-MDM2 are studied as a function of posttranslational modifications and length of the lid. We found that the dynamic equilibrium between "closed" and "semi-closed" lid forms may be a fundamental characteristic of MDM2 regulatory interactions, which can be modulated by phosphorylation, phosphomimetic mutation as well as by the lid size. Our results revealed that these factors may regulate p53-MDM2 binding by fine-tuning the thermodynamic equilibrium between preexisting conformational states of apo-MDM2. In agreement with NMR studies, the effect of phosphorylation on MDM2 interactions was more pronounced with the truncated lid variant that favored the thermodynamically dominant closed form. The phosphomimetic mutation S17D may alter the lid dynamics by shifting the thermodynamic equilibrium towards the ensemble of "semi-closed" conformations. The dominant "semi-closed" lid form and weakened dependence on the phosphorylation seen in simulations with the complete lid can provide a rationale for binding of small p53-based mimetics and inhibitors without a direct competition with the lid dynamics. The results suggested that a conformational selection model of preexisting MDM2 states may provide a robust theoretical framework for understanding MDM2 dynamics. Probing biological functions and mechanisms of MDM2

The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism.

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Lill, Roland; Hoffmann, Bastian; Molik, Sabine; Pierik, Antonio J; Rietzschel, Nicole; Stehling, Oliver; Uzarska, Marta A; Webert, Holger; Wilbrecht, Claudia; Mühlenhoff, Ulrich

2012-09-01

Mitochondria play a key role in iron metabolism in that they synthesize heme, assemble iron-sulfur (Fe/S) proteins, and participate in cellular iron regulation. Here, we review the latter two topics and their intimate connection. The mitochondrial Fe/S cluster (ISC) assembly machinery consists of 17 proteins that operate in three major steps of the maturation process. First, the cysteine desulfurase complex Nfs1-Isd11 as the sulfur donor cooperates with ferredoxin-ferredoxin reductase acting as an electron transfer chain, and frataxin to synthesize an [2Fe-2S] cluster on the scaffold protein Isu1. Second, the cluster is released from Isu1 and transferred toward apoproteins with the help of a dedicated Hsp70 chaperone system and the glutaredoxin Grx5. Finally, various specialized ISC components assist in the generation of [4Fe-4S] clusters and cluster insertion into specific target apoproteins. Functional defects of the core ISC assembly machinery are signaled to cytosolic or nuclear iron regulatory systems resulting in increased cellular iron acquisition and mitochondrial iron accumulation. In fungi, regulation is achieved by iron-responsive transcription factors controlling the expression of genes involved in iron uptake and intracellular distribution. They are assisted by cytosolic multidomain glutaredoxins which use a bound Fe/S cluster as iron sensor and additionally perform an essential role in intracellular iron delivery to target metalloproteins. In mammalian cells, the iron regulatory proteins IRP1, an Fe/S protein, and IRP2 act in a post-transcriptional fashion to adjust the cellular needs for iron. Thus, Fe/S protein biogenesis and cellular iron metabolism are tightly linked to coordinate iron supply and utilization. This article is part of a Special Issue entitled: Cell Biology of Metals. Copyright © 2012 Elsevier B.V. All rights reserved.

Phenotypic stability and plasticity in GMP-derived cells as determined by their underlying regulatory network.

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Ramírez, Carlos; Mendoza, Luis

2018-04-01

Blood cell formation has been recognized as a suitable system to study celular differentiation mainly because of its experimental accessibility, and because it shows characteristics such as hierarchical and gradual bifurcated patterns of commitment, which are present in several developmental processes. Although hematopoiesis has been extensively studied and there is a wealth of molecular and cellular data about it, it is not clear how the underlying molecular regulatory networks define or restrict cellular differentiation processes. Here, we infer the molecular regulatory network that controls the differentiation of a blood cell subpopulation derived from the granulocyte-monocyte precursor (GMP), comprising monocytes, neutrophils, eosinophils, basophils and mast cells. We integrate published qualitative experimental data into a model to describe temporal expression patterns observed in GMP-derived cells. The model is implemented as a Boolean network, and its dynamical behavior is studied. Steady states of the network can be clearly identified with the expression profiles of monocytes, mast cells, neutrophils, basophils, and eosinophils, under wild-type and mutant backgrounds. All scripts are publicly available at https://github.com/caramirezal/RegulatoryNetworkGMPModel. lmendoza@biomedicas.unam.mx. Supplementary data are available at Bioinformatics online.

Cellular and Molecular Basis of Cerebellar Development

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Salvador eMartinez

2013-06-01

Full Text Available 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.

Cellular plasticity enables adaptation to unforeseen cell-cycle rewiring challenges.

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Yair Katzir

Full Text Available The fundamental dynamics of the cell cycle, underlying cell growth and reproduction, were previously found to be robust under a wide range of environmental and internal perturbations. This property was commonly attributed to its network structure, which enables the coordinated interactions among hundreds of proteins. Despite significant advances in deciphering the components and autonomous interactions of this network, understanding the interfaces of the cell cycle with other major cellular processes is still lacking. To gain insight into these interfaces, we used the process of genome-rewiring in yeast by placing an essential metabolic gene HIS3 from the histidine biosynthesis pathway, under the exclusive regulation of different cell-cycle promoters. In a medium lacking histidine and under partial inhibition of the HIS3p, the rewired cells encountered an unforeseen multitasking challenge; the cell-cycle regulatory genes were required to regulate the essential histidine-pathway gene in concert with the other metabolic demands, while simultaneously driving the cell cycle through its proper temporal phases. We show here that chemostat cell populations with rewired cell-cycle promoters adapted within a short time to accommodate the inhibition of HIS3p and stabilized a new phenotypic state. Furthermore, a significant fraction of the population was able to adapt and grow into mature colonies on plates under such inhibiting conditions. The adapted state was shown to be stably inherited across generations. These adaptation dynamics were accompanied by a non-specific and irreproducible genome-wide transcriptional response. Adaptation of the cell-cycle attests to its multitasking capabilities and flexible interface with cellular metabolic processes and requirements. Similar adaptation features were found in our previous work when rewiring HIS3 to the GAL system and switching cells from galactose to glucose. Thus, at the basis of cellular plasticity is

Cellular recycling of proteins in seed dormancy alleviation and germination

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Krystyna Oracz

2016-07-01

Full Text Available Each step of the seed-to-seed cycle of plant development including seed germination is characterized by a specific set of proteins. The continual renewal and/or replacement of these biomolecules are crucial for optimal plant adaptation. As proteins are the main effectors inside the cells, their levels need to be tightly regulated. This is partially achieved by specific proteolytic pathways via multicatalytic protease complexes defined as 20S and 26S proteasomes. In plants, the 20S proteasome is responsible for degradation of carbonylated proteins, while the 26S being a part of ubiquitin-proteasome pathway (UPP is known to be involved in proteolysis of phytohormone signaling regulators. On the other hand, the role of translational control of plant development is also well documented, especially in the context of pollen tube growth and light signaling. Despite the current progress that has been made in seed biology, the sequence of cellular events that determine if the seed can germinate or not are still far from complete understanding. The role and mechanisms of regulation of proteome composition during processes occurring in the plant’s photosynthetic tissues have been well characterized since many years, but in nonphotosynthetic seeds it has emerged as a tempting research task only since the last decade. This review discusses the recent discoveries providing insights into the role of protein turnover in seed dormancy alleviation, and germination, with a focus on the control of translation and proteasomal proteolysis. The presented novel data of translatome profiling in seeds highlighted that post-transcriptional regulation of germination results from a timely regulated initiation of translation. In addition, the importance of 26S proteasome in the degradation of regulatory elements of cellular signaling and that of the 20S complex in proteolysis of specific carbonylated proteins in hormonal- and light-dependent processes occurring in seeds is

Cellular regulation of the structure and function of aortic valves

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Ismail El-Hamamsy

2010-01-01

Full Text Available The aortic valve was long considered a passive structure that opens and closes in response to changes in transvalvular pressure. Recent evidence suggests that the aortic valve performs highly sophisticated functions as a result of its unique microscopic structure. These functions allow it to adapt to its hemodynamic and mechanical environment. Understanding the cellular and molecular mechanisms involved in normal valve physiology is essential to elucidate the mechanisms behind valve disease. We here review the structure and developmental biology of aortic valves; we examine the role of its cellular parts in regulating its function and describe potential pathophysiological and clinical implications.

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism.

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Hasan, Maroof; Gonugunta, Vijay K; Dobbs, Nicole; Ali, Aktar; Palchik, Guillermo; Calvaruso, Maria A; DeBerardinis, Ralph J; Yan, Nan

2017-01-24

Three-prime repair exonuclease 1 knockout (Trex1 -/- ) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 -/- mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1 -/- background, and many metabolic defects persist in Trex1 -/- Irf3 -/- cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1 -/- mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1 -/- cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.

Algorithmic crystal chemistry: A cellular automata approach

International Nuclear Information System (INIS)

Krivovichev, S. V.

2012-01-01

Atomic-molecular mechanisms of crystal growth can be modeled based on crystallochemical information using cellular automata (a particular case of finite deterministic automata). In particular, the formation of heteropolyhedral layered complexes in uranyl selenates can be modeled applying a one-dimensional three-colored cellular automaton. The use of the theory of calculations (in particular, the theory of automata) in crystallography allows one to interpret crystal growth as a computational process (the realization of an algorithm or program with a finite number of steps).

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

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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.

Mechanism of oral tolerance induction to therapeutic proteins.

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Wang, Xiaomei; Sherman, Alexandra; Liao, Gongxian; Leong, Kam W; Daniell, Henry; Terhorst, Cox; Herzog, Roland W

2013-06-15

Oral tolerance is defined as the specific suppression of humoral and/or cellular immune responses to an antigen by administration of the same antigen through the oral route. Due to its absence of toxicity, easy administration, and antigen specificity, oral tolerance is a very attractive approach to prevent unwanted immune responses that cause a variety of diseases or that complicate treatment of a disease. Many researchers have induced oral tolerance to efficiently treat autoimmune and inflammatory diseases in different animal models. However, clinical trials yielded limited success. Thus, understanding the mechanisms of oral tolerance induction to therapeutic proteins is critical for paving the way for clinical development of oral tolerance protocols. This review will summarize progress on understanding the major underlying tolerance mechanisms and contributors, including antigen presenting cells, regulatory T cells, cytokines, and signaling pathways. Potential applications, examples for therapeutic proteins and disease targets, and recent developments in delivery methods are discussed. Copyright © 2012 Elsevier B.V. All rights reserved.

Sequence-based model of gap gene regulatory network.

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Kozlov, Konstantin; Gursky, Vitaly; Kulakovskiy, Ivan; Samsonova, Maria

2014-01-01

The detailed analysis of transcriptional regulation is crucially important for understanding biological processes. The gap gene network in Drosophila attracts large interest among researches studying mechanisms of transcriptional regulation. It implements the most upstream regulatory layer of the segmentation gene network. The knowledge of molecular mechanisms involved in gap gene regulation is far less complete than that of genetics of the system. Mathematical modeling goes beyond insights gained by genetics and molecular approaches. It allows us to reconstruct wild-type gene expression patterns in silico, infer underlying regulatory mechanism and prove its sufficiency. We developed a new model that provides a dynamical description of gap gene regulatory systems, using detailed DNA-based information, as well as spatial transcription factor concentration data at varying time points. We showed that this model correctly reproduces gap gene expression patterns in wild type embryos and is able to predict gap expression patterns in Kr mutants and four reporter constructs. We used four-fold cross validation test and fitting to random dataset to validate the model and proof its sufficiency in data description. The identifiability analysis showed that most model parameters are well identifiable. We reconstructed the gap gene network topology and studied the impact of individual transcription factor binding sites on the model output. We measured this impact by calculating the site regulatory weight as a normalized difference between the residual sum of squares error for the set of all annotated sites and for the set with the site of interest excluded. The reconstructed topology of the gap gene network is in agreement with previous modeling results and data from literature. We showed that 1) the regulatory weights of transcription factor binding sites show very weak correlation with their PWM score; 2) sites with low regulatory weight are important for the model output; 3

N6-methyladenosine mediates the cellular proliferation and apoptosis via microRNAs in arsenite-transformed cells.

Science.gov (United States)

Gu, Shiyan; Sun, Donglei; Dai, Huangmei; Zhang, Zunzhen

2018-04-20

N 6 -methyladenosine (m 6 A) modification is implicated to play an important role in cellular biological processes, but its regulatory mechanisms in arsenite-induced carcinogenesis are largely unknown. Here, human bronchial epithelial (HBE) cells were chronically treated with 2.5 μM arsenite sodium (NaAsO 2 ) for about 13 weeks and these cells were identified with malignant phenotype which was demonstrated by increased levels of cellular proliferation, percentages of plate colony formation and soft agar clone formation, and high potential of resistance to apoptotic induction. Our results firstly demonstrated that m 6 A modification on RNA was significantly increased in arsenite-transformed cells and this modification may be synergistically regulated by methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), Wilms tumor 1-associated protein (WTAP) and Fat mass and obesity-associated protein (FTO). In addition, knocking down of METTL3 in arsenite-transformed cells can dramatically reverse the malignant phenotype, which was manifested by lower percentages of clone and colony formation as well as higher rates of apoptotic induction. Given the critical roles of miRNAs in cellular proliferation and apoptosis, miRNAs regulated by m 6 A in arsenite-transformed cells were analyzed by Venn diagram and KEGG pathway in this study. The results showed that these m 6 A-mediated miRNAs can regulate pathways which are closely associated with cellular proliferation and apoptosis, implicating that these miRNAs may be the critical bridge by which m 6 A mediates dysregulation of cell survival and apoptosis in arsenite-transformed cells. Taken together, our results firstly demonstrated the significant role of m 6 A in the prevention of tumor occurrence and progression induced by arsenite. Copyright © 2018 Elsevier B.V. All rights reserved.

Metallic powder-bed based 3D printing of cellular scaffolds for orthopaedic implants: A state-of-the-art review on manufacturing, topological design, mechanical properties and biocompatibility.

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Tan, X P; Tan, Y J; Chow, C S L; Tor, S B; Yeong, W Y

2017-07-01

Metallic cellular scaffold is one of the best choices for orthopaedic implants as a replacement of human body parts, which could improve life quality and increase longevity for the people needed. Unlike conventional methods of making cellular scaffolds, three-dimensional (3D) printing or additive manufacturing opens up new possibilities to fabricate those customisable intricate designs with highly interconnected pores. In the past decade, metallic powder-bed based 3D printing methods emerged and the techniques are becoming increasingly mature recently, where selective laser melting (SLM) and selective electron beam melting (SEBM) are the two representatives. Due to the advantages of good dimensional accuracy, high build resolution, clean build environment, saving materials, high customisability, etc., SLM and SEBM show huge potential in direct customisable manufacturing of metallic cellular scaffolds for orthopaedic implants. Ti-6Al-4V to date is still considered to be the optimal materials for producing orthopaedic implants due to its best combination of biocompatibility, corrosion resistance and mechanical properties. This paper presents a state-of-the-art overview mainly on manufacturing, topological design, mechanical properties and biocompatibility of cellular Ti-6Al-4V scaffolds via SLM and SEBM methods. Current manufacturing limitations, topological shortcomings, uncertainty of biocompatible test were sufficiently discussed herein. Future perspectives and recommendations were given at the end. Copyright © 2017 Elsevier B.V. All rights reserved.

Multi-cellular logistics of collective cell migration.

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Masataka Yamao

Full Text Available During development, the formation of biological networks (such as organs and neuronal networks is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes "collective migration," whereas strong noise from non-migratory cells causes "dispersive migration." Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems.

Epigenetic mechanisms and associated brain circuits in the regulation of positive emotions: A role for transposable elements.

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Gaudi, Simona; Guffanti, Guia; Fallon, James; Macciardi, Fabio

2016-10-15

Epigenetic programming and reprogramming are at the heart of cellular differentiation and represent developmental and evolutionary mechanisms in both germline and somatic cell lines. Only about 2% of our genome is composed of protein-coding genes, while the remaining 98%, once considered "junk" DNA, codes for regulatory/epigenetic elements that control how genes are expressed in different tissues and across time from conception to death. While we already know that epigenetic mechanisms are at play in cancer development and in regulating metabolism (cellular and whole body), the role of epigenetics in the developing prenatal and postnatal brain, and in maintaining a proper brain activity throughout the various stages of life, in addition to having played a critical role in human evolution, is a relatively new domain of knowledge. Here we present the current state-of-the-art techniques and results of these studies within the domain of emotions, and then speculate on how genomic and epigenetic mechanisms can modify and potentially alter our emotional (limbic) brain and affect our social interactions. J. Comp. Neurol. 524:2944-2954, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Cellular Restriction Factors of Feline Immunodeficiency Virus

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Zielonka, Jörg; Münk, Carsten

2011-01-01

Lentiviruses are known for their narrow cell- and species-tropisms, which are determined by cellular proteins whose absence or presence either support viral replication (dependency factors, cofactors) or inhibit viral replication (restriction factors). Similar to Human immunodeficiency virus type 1 (HIV-1), the cat lentivirus Feline immunodeficiency virus (FIV) is sensitive to recently discovered cellular restriction factors from non-host species that are able to stop viruses from replicating. Of particular importance are the cellular proteins APOBEC3, TRIM5α and tetherin/BST-2. In general, lentiviruses counteract or escape their species’ own variant of the restriction factor, but are targeted by the orthologous proteins of distantly related species. Most of the knowledge regarding lentiviral restriction factors has been obtained in the HIV-1 system; however, much less is known about their effects on other lentiviruses. We describe here the molecular mechanisms that explain how FIV maintains its replication in feline cells, but is largely prevented from cross-species infections by cellular restriction factors. PMID:22069525

SILICOMB PEEK Kirigami cellular structures: mechanical response and energy dissipation through zero and negative stiffness

International Nuclear Information System (INIS)

Virk, K; Marsh, M; Monti, A; Trehard, T; Hazra, K; Boba, K; Remillat, C D L; Scarpa, F; Farrow, I R

2013-01-01

The work describes the manufacturing, testing and parametric analysis of cellular structures exhibiting zero Poisson’s ratio-type behaviour, together with zero and negative stiffness effects. The cellular structures are produced in flat panels and curved configurations, using a combination of rapid prototyping techniques and Kirigami (Origami and cutting) procedures for PEEK (Polyether Ether Ketone) thermoplastic composites. The curved cellular configurations show remarkable large deformation behaviours, with zero and negative stiffness regimes depending also on the strain rate applied. These unusual stiffness characteristics lead to a large increase of energy absorption during cyclic tests. (paper)

WetA bridges cellular and chemical development in Aspergillus flavus.

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Ming-Yueh Wu

Full Text Available Bridging cellular reproduction and survival is essential for all life forms. Aspergillus fungi primarily reproduce by forming asexual spores called conidia, whose formation and maturation is governed by the central genetic regulatory circuit BrlA→AbaA→WetA. Here, we report that WetA is a multi-functional regulator that couples spore differentiation and survival, and governs proper chemical development in Aspergillus flavus. The deletion of wetA results in the formation of conidia with defective cell walls and no intra-cellular trehalose, leading to reduced stress tolerance, a rapid loss of viability, and disintegration of spores. WetA is also required for normal vegetative growth, hyphal branching, and production of aflatoxins. Targeted and genome-wide expression analyses reveal that WetA exerts feedback control of brlA and that 5,700 genes show altered mRNA levels in the mutant conidia. Functional category analyses of differentially expressed genes in ΔwetA RNA-seq data indicate that WetA contributes to spore integrity and maturity by properly regulating the metabolic pathways of trehalose, chitin, α-(1,3-glucan, β-(1,3-glucan, melanin, hydrophobins, and secondary metabolism more generally. Moreover, 160 genes predicted to encode transcription factors are differentially expressed by the absence of wetA, suggesting that WetA may play a global regulatory role in conidial development. Collectively, we present a comprehensive model for developmental control that bridges spore differentiation and survival in A. flavus.

Radiation and the regulatory landscape of neo2-Darwinism

International Nuclear Information System (INIS)

Rollo, C. David

2006-01-01

Several recently revealed features of eukaryotic genomes were not predicted by earlier evolutionary paradigms, including the relatively small number of genes, the very large amounts of non-functional code and its quarantine in heterochromatin, the remarkable conservation of many functionally important genes across relatively enormous phylogenetic distances, and the prevalence of extra-genomic information associated with chromatin structure and histone proteins. All of these emphasize a paramount role for regulatory evolution, which is further reinforced by recent perspectives highlighting even higher-order regulation governing epigenetics and development (EVO-DEVO). Modern neo 2 -Darwinism, with its emphasis on regulatory mechanisms and regulatory evolution provides new vision for understanding radiation biology, particularly because free radicals and redox states are central to many regulatory mechanisms and free radicals generated by radiation mimic and amplify endogenous signalling. This paper explores some of these aspects and their implications for low-dose radiation biology

Radiation and the regulatory landscape of neo2-Darwinism.

Science.gov (United States)

Rollo, C David

2006-05-11

Several recently revealed features of eukaryotic genomes were not predicted by earlier evolutionary paradigms, including the relatively small number of genes, the very large amounts of non-functional code and its quarantine in heterochromatin, the remarkable conservation of many functionally important genes across relatively enormous phylogenetic distances, and the prevalence of extra-genomic information associated with chromatin structure and histone proteins. All of these emphasize a paramount role for regulatory evolution, which is further reinforced by recent perspectives highlighting even higher-order regulation governing epigenetics and development (EVO-DEVO). Modern neo2-Darwinism, with its emphasis on regulatory mechanisms and regulatory evolution provides new vision for understanding radiation biology, particularly because free radicals and redox states are central to many regulatory mechanisms and free radicals generated by radiation mimic and amplify endogenous signalling. This paper explores some of these aspects and their implications for low-dose radiation biology.

Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites

Science.gov (United States)

Brautigam, Chad A; Xing, Wenmin; Yang, Sheng; Henry, Lisa; Doolittle, Lynda K; Walz, Thomas

2017-01-01

The Rho GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization, which underpins diverse cellular processes. Here we report the structure of a WRC-Rac1 complex determined by cryo-electron microscopy. Surprisingly, Rac1 is not located at the binding site on the Sra1 subunit of the WRC previously identified by mutagenesis and biochemical data. Rather, it binds to a distinct, conserved site on the opposite end of Sra1. Biophysical and biochemical data on WRC mutants confirm that Rac1 binds to both sites, with the newly identified site having higher affinity and both sites required for WRC activation. Our data reveal that the WRC is activated by simultaneous engagement of two Rac1 molecules, suggesting a mechanism by which cells may sense the density of active Rac1 at membranes to precisely control actin assembly. PMID:28949297

Perceptions of regulatory approaches

International Nuclear Information System (INIS)

Halin, Magnus; Leinonen, Ruusaliisa

2012-01-01

Ms. Ruusaliisa Leinonen and Mr. Magnus Halin from Fortum gave a joint presentation on industry perceptions of regulatory oversight of LMfS/SC. It was concluded that an open culture of discussion exists between the regulator (STUK) and the licensee, based on the common goal of nuclear safety. An example was provided of on how regulatory interventions helped foster improvements to individual and collective dose rate trends, which had remained static. Regulatory interventions included discussions on the ALARA concept to reinforce the requirement to continuously strive for improvements in safety performance. Safety culture has also been built into regulatory inspections in recent years. Training days have also been organised by the regulatory body to help develop a shared understanding of safety culture between licensee and regulatory personnel. Fortum has also developed their own training for managers and supervisors. Training and ongoing discussion on LMfS/SC safety culture is considered particularly important because both Fortum and the regulatory body are experiencing an influx of new staff due to the demographic profile of their organisations. It was noted that further work is needed to reach a common understanding of safety culture on a practical level (e.g., for a mechanic setting to work), and in relation to the inspection criteria used by the regulator. The challenges associated with companies with a mix of energy types were also discussed. This can make it more difficult to understand responsibilities and decision making processes, including the role of the parent body organisation. It also makes communication more challenging due to increased complexity and a larger number of stakeholders

Antibody-dependent cellular cytotoxicity and skin disease

International Nuclear Information System (INIS)

Norris, D.A.; Lee, L.A.

1985-01-01

Antibody dependent cellular cytotoxicity (ADCC) is a recently described mechanism of immunologic lysis in which cellular targets sensitized by specific antibodies are efficiently and selectively lysed by Fc receptor (FcR) bearing nonspecific effectors. Immunoglobulins of various classes (IgG, IgM, IgA, IgE) and various cellular effectors (large granular lymphocytes, monocyte/macrophages, T lymphocytes, neutrophils, and eosinophils) can induce ADCC in vitro, and the importance of ADCC in vivo is being tested experimentally in resistance to viral, bacterial, and parasitic infection, in tumor surveillance, in allograft rejection, and in inflammatory diseases. There is much indirect evidence that ADCC may be the mechanism of damage of different cellular targets in skin diseases, but the best direct evidence concerns immunologic keratinocyte damage, especially in cutaneous lupus erythematosus (LE). The authors have shown that keratinocytes of several species are highly susceptible to lymphocyte and monocyte-mediated ADCC, but not to neutrophil or eosinophil ADCC in vitro using two different cytotoxicity assays. In contrast, complement was a relatively ineffective mediator of lysis of metabolically intact keratinocyte targets. Patients with certain cutaneous lupus syndromes have serum antibodies capable of inducing monocyte and lymphocyte ADCC of targets coated with extractable nuclear antigens. The authors have shown that these antigens apparently move to the cell membrane of keratinocytes in vitro following ultraviolet irradiation. In an animal model, they have shown that antibodies to SSA/Ro bind to human keratinocytes in vivo, especially after ultraviolet irradiation

Structure reveals regulatory mechanisms of a MaoC-like hydratase from Phytophthora capsici involved in biosynthesis of polyhydroxyalkanoates (PHAs.

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Huizheng Wang

Full Text Available Polyhydroxyalkanoates (PHAs have attracted increasing attention as "green plastic" due to their biodegradable, biocompatible, thermoplastic, and mechanical properties, and considerable research has been undertaken to develop low cost/high efficiency processes for the production of PHAs. MaoC-like hydratase (MaoC, which belongs to (R-hydratase involved in linking the β-oxidation and the PHA biosynthetic pathways, has been identified recently. Understanding the regulatory mechanisms of (R-hydratase catalysis is critical for efficient production of PHAs that promise synthesis an environment-friendly plastic.We have determined the crystal structure of a new MaoC recognized from Phytophthora capsici. The crystal structure of the enzyme was solved at 2.00 Å resolution. The structure shows that MaoC has a canonical (R-hydratase fold with an N-domain and a C-domain. Supporting its dimerization observed in structure, MaoC forms a stable homodimer in solution. Mutations that disrupt the dimeric MaoC result in a complete loss of activity toward crotonyl-CoA, indicating that dimerization is required for the enzymatic activity of MaoC. Importantly, structure comparison reveals that a loop unique to MaoC interacts with an α-helix that harbors the catalytic residues of MaoC. Deletion of the loop enhances the enzymatic activity of MaoC, suggesting its inhibitory role in regulating the activity of MaoC.The data in our study reveal the regulatory mechanism of an (R-hydratase, providing information on enzyme engineering to produce low cost PHAs.

The cellular automaton interpretation of quantum mechanics

CERN Document Server

't Hooft, Gerard

2016-01-01

This book presents the deterministic view of quantum mechanics developed by Nobel Laureate Gerard 't Hooft. Dissatisfied with the uncomfortable gaps in the way conventional quantum mechanics meshes with the classical world, 't Hooft has revived the old hidden variable ideas, but now in a much more systematic way than usual. In this, quantum mechanics is viewed as a tool rather than a theory. The book presents examples of models that are classical in essence, but can be analysed by the use of quantum techniques, and argues that even the Standard Model, together with gravitational interactions, might be viewed as a quantum mechanical approach to analysing a system that could be classical at its core. He shows how this approach, even though it is based on hidden variables, can be plausibly reconciled with Bell's theorem, and how the usual objections voiced against the idea of ‘superdeterminism' can be overcome, at least in principle. This framework elegantly explains - and automatically cures - the problems of...

Cellular potts models multiscale extensions and biological applications

CERN Document Server

Scianna, Marco

2013-01-01

A flexible, cell-level, and lattice-based technique, the cellular Potts model accurately describes the phenomenological mechanisms involved in many biological processes. Cellular Potts Models: Multiscale Extensions and Biological Applications gives an interdisciplinary, accessible treatment of these models, from the original methodologies to the latest developments. The book first explains the biophysical bases, main merits, and limitations of the cellular Potts model. It then proposes several innovative extensions, focusing on ways to integrate and interface the basic cellular Potts model at the mesoscopic scale with approaches that accurately model microscopic dynamics. These extensions are designed to create a nested and hybrid environment, where the evolution of a biological system is realistically driven by the constant interplay and flux of information between the different levels of description. Through several biological examples, the authors demonstrate a qualitative and quantitative agreement with t...

A cellular backline: specialization of host membranes for defence.

Science.gov (United States)

Faulkner, Christine

2015-03-01

In plant-pathogen interactions, the host plasma membrane serves as a defence front for pathogens that invade from the extracellular environment. As such, the lipid bilayer acts as a scaffold that targets and delivers defence responses to the site of attack. During pathogen infection, numerous changes in plasma membrane composition, organization, and structure occur. There is increasing evidence that this facilitates the execution of a variety of responses, highlighting the regulatory role membranes play in cellular responses. Membrane microdomains such as lipid rafts are hypothesized to create signalling platforms for receptor signalling in response to pathogen perception and for callose synthesis. Further, the genesis of pathogen-associated structures such as papillae and the extra-haustorial membrane necessitates polarization of membranes and membrane trafficking pathways. Unlocking the mechanisms by which this occurs will enable greater understanding of how targeted defences, some of which result in resistance, are executed. This review will survey some of the changes that occur in host membranes during pathogen attack and how these are associated with the generation of defence responses. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Posttraumatic Stress Disorder Disturbs Coronary Tone and Its Regulatory Mechanisms.

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Lazuko, Svetlana S; Kuzhel, Olga P; Belyaeva, Lyudmila E; Manukhina, Eugenia B; Fred Downey, H; Tseilikman, Olga B; Komelkova, Maria V; Tseilikman, Vadim E

2018-01-01

Posttraumatic stress disorder (PTSD) is associated with myocardial injury, but changes in coronary regulatory mechanisms in PTSD have not been investigated. This study evaluated the effect of PTSD-inducing stress on coronary tone and its regulation by nitric oxide (NO) and voltage-gated K + channels. PTSD was induced by exposing rats to predator stress, 15 min daily for 10 days, followed by 14 stress-free days. Presence of PTSD was confirmed by the elevated plus-maze test. Coronary tone was evaluated from changes in coronary perfusion pressure of Langendorff isolated hearts. Predator stress induced significant decreases in coronary tone of isolated hearts and in blood pressure of intact rats. L-NAME, a non-selective NO synthase (NOS) inhibitor, but not S-MT, a selective iNOS inhibitor, and increased coronary tone of control rats. In PTSD rats, both L-NAME and S-MT increased coronary tone. Therefore, the stress-induced coronary vasodilation resulted from NO overproduction by both iNOS and eNOS. NOS induction was apparently due to systemic inflammation as evidenced by increased serum interleukin-1β and C-reactive protein in PTSD rats. Decreased corticosterone in PTSD rats may have contributed to inflammation and its effect on coronary tone. PTSD was also associated with voltage-gated K + channel dysfunction, which would have also reduced coronary tone.

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.

The similia principle: results obtained in a cellular model system.

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Wiegant, Fred; Van Wijk, Roeland

2010-01-01

This paper describes the results of a research program focused on the beneficial effect of low dose stress conditions that were applied according to the similia principle to cells previously disturbed by more severe stress conditions. In first instance, we discuss criteria for research on the similia principle at the cellular level. Then, the homologous ('isopathic') approach is reviewed, in which the initial (high dose) stress used to disturb cellular physiology and the subsequent (low dose) stress are identical. Beneficial effects of low dose stress are described in terms of increased cellular survival capacity and at the molecular level as an increase in the synthesis of heat shock proteins (hsps). Both phenomena reflect a stimulation of the endogenous cellular self-recovery capacity. Low dose stress conditions applied in a homologous approach stimulate the synthesis of hsps and enhance survival in comparison with stressed cells that were incubated in the absence of low dose stress conditions. Thirdly, the specificity of the low dose stress condition is described where the initial (high dose) stress is different in nature from the subsequently applied (low dose) stress; the heterologous or 'heteropathic' approach. The results support the similia principle at the cellular level and add to understanding of how low dose stress conditions influence the regulatory processes underlying self-recovery. In addition, the phenomenon of 'symptom aggravation' which is also observed at the cellular level, is discussed in the context of self-recovery. Finally, the difference in efficiency between the homologous and the heterologous approach is discussed; a perspective is indicated for further research; and the relationship between studies on the similia principle and the recently introduced concept of 'postconditioning hormesis' is emphasized. Copyright 2009 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.

The Effects Radiation on Cellular Components of the Immune

International Nuclear Information System (INIS)

Zubaidah-Alatas

2001-01-01

The immune system describes the body's ability to defend itself against various foreign intruders named as antigens by calling on an immune mechanism. Antigens penetration into body activate the body's immune system that may be humoral response, cellular response, or both. The immune response is primarily mediated by two cell types, lymphocyte and macrophage. This paper will discuss the cellular component of immune system and the radiation effects on various cells involved in system. Moreover, the effects of radiation on humoral and cellular responses and the relation among immunity, cancer and radiotherapy are also described. (author)

Cost-benefit considerations in regulatory decision-making

International Nuclear Information System (INIS)

Harvie, J.D.

1996-01-01

The Atomic Energy Control Board is investigating the feasibility of developing methods for factoring cost-benefit considerations into its regulatory decision-making. This initiative results, in part, from the federal government policy requiring cost-benefit considerations to be taken into account in regulatory processes, and from the recommendations of an Advisory Panel on Regulatory Review in 1993, submitted to the Minister of Natural Resources Canada. One of these recommendations stated: 'that mechanisms be developed to examine cost-benefit issues and work towards some consensus of opinion among stakeholders; a task force on the subject could be an appropriate starting point'. (author)

Reconstruction and analysis of transcription factor-miRNA co-regulatory feed-forward loops in human cancers using filter-wrapper feature selection.

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Chen Peng

Full Text Available BACKGROUND: As one of the most common types of co-regulatory motifs, feed-forward loops (FFLs control many cell functions and play an important role in human cancers. Therefore, it is crucial to reconstruct and analyze cancer-related FFLs that are controlled by transcription factor (TF and microRNA (miRNA simultaneously, in order to find out how miRNAs and TFs cooperate with each other in cancer cells and how they contribute to carcinogenesis. Current FFL studies rely on predicted regulation information and therefore suffer the false positive issue in prediction results. More critically, FFLs generated by existing approaches cannot represent the dynamic and conditional regulation relationship under different experimental conditions. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we proposed a novel filter-wrapper feature selection method to accurately identify co-regulatory mechanism by incorporating prior information from predicted regulatory interactions with parallel miRNA/mRNA expression datasets. By applying this method, we reconstructed 208 and 110 TF-miRNA co-regulatory FFLs from human pan-cancer and prostate datasets, respectively. Further analysis of these cancer-related FFLs showed that the top-ranking TF STAT3 and miRNA hsa-let-7e are key regulators implicated in human cancers, which have regulated targets significantly enriched in cellular process regulations and signaling pathways that are involved in carcinogenesis. CONCLUSIONS/SIGNIFICANCE: In this study, we introduced an efficient computational approach to reconstruct co-regulatory FFLs by accurately identifying gene co-regulatory interactions. The strength of the proposed feature selection method lies in the fact it can precisely filter out false positives in predicted regulatory interactions by quantitatively modeling the complex co-regulation of target genes mediated by TFs and miRNAs simultaneously. Moreover, the proposed feature selection method can be generally applied to

Tissue Engineering Strategies for Myocardial Regeneration: Acellular Versus Cellular Scaffolds?

Science.gov (United States)

Domenech, Maribella; Polo-Corrales, Lilliana; Ramirez-Vick, Jaime E; Freytes, Donald O

2016-12-01

Heart disease remains one of the leading causes of death in industrialized nations with myocardial infarction (MI) contributing to at least one fifth of the reported deaths. The hypoxic environment eventually leads to cellular death and scar tissue formation. The scar tissue that forms is not mechanically functional and often leads to myocardial remodeling and eventual heart failure. Tissue engineering and regenerative medicine principles provide an alternative approach to restoring myocardial function by designing constructs that will restore the mechanical function of the heart. In this review, we will describe the cellular events that take place after an MI and describe current treatments. We will also describe how biomaterials, alone or in combination with a cellular component, have been used to engineer suitable myocardium replacement constructs and how new advanced culture systems will be required to achieve clinical success.

Phononic Band Gaps in 2D Quadratic and 3D Cubic Cellular Structures.

Science.gov (United States)

Warmuth, Franziska; Körner, Carolin

2015-12-02

The static and dynamic mechanical behaviour of cellular materials can be designed by the architecture of the underlying unit cell. In this paper, the phononic band structure of 2D and 3D cellular structures is investigated. It is shown how the geometry of the unit cell influences the band structure and eventually leads to full band gaps. The mechanism leading to full band gaps is elucidated. Based on this knowledge, a 3D cellular structure with a broad full band gap is identified. Furthermore, the dependence of the width of the gap on the geometry parameters of the unit cell is presented.

Cellular strategies to cope with protein aggregation

NARCIS (Netherlands)

Scior, Annika; Juenemann, Katrin; Kirstein, Janine

2016-01-01

Nature has evolved several mechanisms to detoxify intracellular protein aggregates that arise upon proteotoxic challenges. These include the controlled deposition of misfolded proteins at distinct cellular sites, the protein disaggregation and refolding by molecular chaperones and/or degradation of

Uncovering a Dual Regulatory Role for Caspases During Endoplasmic Reticulum Stress-induced Cell Death.

Science.gov (United States)

Anania, Veronica G; Yu, Kebing; Gnad, Florian; Pferdehirt, Rebecca R; Li, Han; Ma, Taylur P; Jeon, Diana; Fortelny, Nikolaus; Forrest, William; Ashkenazi, Avi; Overall, Christopher M; Lill, Jennie R

2016-07-01

Many diseases are associated with endoplasmic reticulum (ER) stress, which results from an accumulation of misfolded proteins. This triggers an adaptive response called the "unfolded protein response" (UPR), and prolonged exposure to ER stress leads to cell death. Caspases are reported to play a critical role in ER stress-induced cell death but the underlying mechanisms by which they exert their effect continue to remain elusive. To understand the role caspases play during ER stress, a systems level approach integrating analysis of the transcriptome, proteome, and proteolytic substrate profile was employed. This quantitative analysis revealed transcriptional profiles for most human genes, provided information on protein abundance for 4476 proteins, and identified 445 caspase substrates. Based on these data sets many caspase substrates were shown to be downregulated at the protein level during ER stress suggesting caspase activity inhibits their cellular function. Additionally, RNA sequencing revealed a role for caspases in regulation of ER stress-induced transcriptional pathways and gene set enrichment analysis showed expression of multiple gene targets of essential transcription factors to be upregulated during ER stress upon inhibition of caspases. Furthermore, these transcription factors were degraded in a caspase-dependent manner during ER stress. These results indicate that caspases play a dual role in regulating the cellular response to ER stress through both post-translational and transcriptional regulatory mechanisms. Moreover, this study provides unique insight into progression of the unfolded protein response into cell death, which may help identify therapeutic strategies to treat ER stress-related diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Frequency-dependent micromechanics of cellularized biopolymer networks

Science.gov (United States)

Jones, Chris; Kim, Jihan; McIntyre, David; Sun, Bo

Mechanical interactions between cells and the extracellular matrix (ECM) influence many cellular behaviors such as growth, differentiation, and migration. These are dynamic processes in which the cells actively remodel the ECM. Reconstituted collagen gel is a common model ECM for studying cell-ECM interactions in vitro because collagen is the most abundant component of mammalian ECM and gives the ECM its material stiffness. We embed micron-sized particles in collagen and use holographic optical tweezers to apply forces to the particles in multiple directions and over a range of frequencies up to 10 Hz. We calculate the local compliance and show that it is dependent on both the direction and frequency of the applied force. Performing the same measurement on many particles allows us to characterize the spatial inhomogeneity of the mechanical properties and shows that the compliance decreases at higher frequencies. Performing these measurements on cell-populated collagen gels shows that cellular remodeling of the ECM changes the mechanical properties of the collagen and we investigate whether this change is dependent on the local strain and distance from nearby cells.

Cellular glutathione prevents cytolethality of monomethylarsonic acid

International Nuclear Information System (INIS)

Sakurai, Teruaki; Kojima, Chikara; Ochiai, Masayuki; Ohta, Takami; Sakurai, Masumi H.; Waalkes, Michael P.; Fujiwara, Kitao

2004-01-01

Inorganic arsenicals are clearly toxicants and carcinogens in humans. In mammals, including humans, inorganic arsenic often undergoes methylation, forming compounds such as monomethylarsonic acid (MMAs V ) and dimethylarsinic acid (DMAs V ). However, much less information is available on the in vitro toxic potential or mechanisms of these methylated arsenicals, especially MMAs V . We studied the molecular mechanisms of in vitro cytolethality of MMAs V using a rat liver epithelial cell line (TRL 1215). MMAs V was not cytotoxic in TRL 1215 cells even at concentrations exceeding 10 mM, but it became weakly cytotoxic and induced both necrotic and apoptotic cell death when cellular reduced glutathione (GSH) was depleted with the glutathione synthase inhibitor, L-buthionine-[S,R]-sulfoximine (BSO), or the glutathione reductase inhibitor, carmustine. Similar results were observed in the other mammalian cells, such as human skin TIG-112 cells, chimpanzee skin CRT-1609 cells, and mouse metallothionein (MT) positive and MT negative embryonic cells. Ethacrynic acid (EA), an inhibitor of glutathione S-transferase (GST) that catalyses GSH-substrate conjugation, also enhanced the cytolethality of MMAs V , but aminooxyacetic acid (AOAA), an inhibitor of β-lyase that catalyses the final breakdown of GSH-substrate conjugates, had no effect. Both the cellular GSH levels and the cellular GST activity were increased by the exposure to MMAs V in TRL 1215 cells. On the other hand, the addition of exogenous extracellular GSH enhanced the cytolethality of MMAs V , although cellular GSH levels actually prevented the cytolethality of combined MMAs V and exogenous GSH. These findings indicate that human arsenic metabolite MMAs V is not a highly toxic compound in mammalian cells, and the level of cellular GSH is critical to its eventual toxic effects

Parameters and characteristics governing cellular internalization and trans-barrier trafficking of nanostructures

Directory of Open Access Journals (Sweden)

Murugan K

2015-03-01

Full Text Available Karmani Murugan, Yahya E Choonara, Pradeep Kumar, Divya Bijukumar, Lisa C du Toit, Viness Pillay Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Abstract: Cellular internalization and trans-barrier transport of nanoparticles can be manipulated on the basis of the physicochemical and mechanical characteristics of nanoparticles. Research has shown that these factors significantly influence the uptake of nanoparticles. Dictating these characteristics allows for the control of the rate and extent of cellular uptake, as well as delivering the drug-loaded nanosystem intra-cellularly, which is imperative for drugs that require a specific cellular level to exert their effects. Additionally, physicochemical characteristics of the nanoparticles should be optimal for the nanosystem to bypass the natural restricting phenomena of the body and act therapeutically at the targeted site. The factors at the focal point of emerging smart nanomedicines include nanoparticle size, surface charge, shape, hydrophobicity, surface chemistry, and even protein and ligand conjugates. Hence, this review discusses the mechanism of internalization of nanoparticles and ideal nanoparticle characteristics that allow them to evade the biological barriers in order to achieve optimal cellular uptake in different organ systems. Identifying these parameters assists with the progression of nanomedicine as an outstanding vector of pharmaceuticals. Keywords: nanoparticles, transport mechanisms, cellular uptake, size, shape, charge

Gravitational Effects on Cellular Flame Structure

Science.gov (United States)

Dunsky, C. M.; Fernandez-Pello, A. C.

1991-01-01

An experimental investigation has been conducted of the effect of gravity on the structure of downwardly propagating, cellular premixed propane-oxygen-nitrogen flames anchored on a water-cooled porous-plug burner. The flame is subjected to microgravity conditions in the NASA Lewis 2.2-second drop tower, and flame characteristics are recorded on high-speed film. These are compared to flames at normal gravity conditions with the same equivalence ratio, dilution index, mixture flow rate, and ambient pressure. The results show that the cellular instability band, which is located in the rich mixture region, changes little under the absence of gravity. Lifted normal-gravity flames near the cellular/lifted limits, however, are observed to become cellular when gravity is reduced. Observations of a transient cell growth period following ignition point to heat loss as being an important mechanism in the overall flame stability, dominating the stabilizing effect of buoyancy for these downwardly-propagating burner-anchored flames. The pulsations that are observed in the plume and diffusion flame generated downstream of the premixed flame in the fuel rich cases disappear in microgravity, verifying that these fluctuations are gravity related.

Cellular mechanisms in drug - radiation interaction

International Nuclear Information System (INIS)

Trott, K.R.

1979-01-01

Some cytotoxic drugs, especially those belonging to the group of antibiotics and antimetabolites, sensitize the cells having survived drug treatment to the subsequent irradiation by either increasing the slope of the radiation dose response curves or by decreasing extrapolation number. Bleomycin was found to interact with radiation in L-cells and FM3A cells, but not in HeLa-cells. The data with EMT-6 cells suggest that the interaction depends on drug dose: no interaction occurred after the exposure to bleomycin which killed only 20 - 40% of the cells; yet the exposure to bleomycin which killed 90% of the cells in addition sensitized the surviving cells by the DMF of 1.3. The sensitization found 24 hr after the exposure of HeLa cells to methotrexate was due to cell synchronization. Other cytostatic drugs were found to synchronize proliferating cells even better. Therefore, the fluctuation of radiosensitivity has been commonly observed after the termination of exposure to these drugs. Preirradiation may lead to the change in drug dose response curves. The recruitment of resting cells into cycle occurs hours or days later, in some irradiated normal and malignant tissues. Since many cytostatic drugs are far more active in proliferating cells than in resting cells, the recruitment after irradiation may lead to the sudden increase in drug sensitivity, days after the irradiation. No single, simple theory seems to exist to classify and predict the cellular response to combined modality treatment. (Yamashita, S.)

α -Actinin TvACTN3 of Trichomonas vaginalis is an RNA-binding protein that could participate in its posttranscriptional iron regulatory mechanism.

Science.gov (United States)

Calla-Choque, Jaeson Santos; Figueroa-Angulo, Elisa Elvira; Ávila-González, Leticia; Arroyo, Rossana

2014-01-01

Trichomonas vaginalis is a sexually transmitted flagellated protist parasite responsible for trichomoniasis. This parasite is dependent on high levels of iron, favoring its growth and multiplication. Iron also differentially regulates some trichomonad virulence properties by unknown mechanisms. However, there is evidence to support the existence of gene regulatory mechanisms at the transcriptional and posttranscriptional levels that are mediated by iron concentration in T. vaginalis. Thus, the goal of this study was to identify an RNA-binding protein in T. vaginalis that interacts with the tvcp4 RNA stem-loop structure, which may participate in a posttranscriptional iron regulatory mechanism mediated by RNA-protein interactions. We performed RNA electrophoretic mobility shift assay (REMSA) and supershift, UV cross-linking, Northwestern blot, and western blot (WB) assays using cytoplasmic protein extracts from T. vaginalis with the tvcp4 RNA hairpin structure as a probe. We identified a 135-kDa protein isolated by the UV cross-linking assays as α-actinin 3 (TvACTN3) by MALDI-TOF-MS that was confirmed by LS-MS/MS and de novo sequencing. TvACTN3 is a cytoplasmic protein that specifically binds to hairpin RNA structures from trichomonads and humans when the parasites are grown under iron-depleted conditions. Thus, TvACTN3 could participate in the regulation of gene expression by iron in T. vaginalis through a parallel posttranscriptional mechanism similar to that of the IRE/IRP system.

The potential regulatory roles of NAD(+) and its metabolism in autophagy.

Science.gov (United States)

Zhang, Dong-Xia; Zhang, Jia-Ping; Hu, Jiong-Yu; Huang, Yue-Sheng

2016-04-01

(Macro)autophagy mediates the bulk degradation of defective organelles, long-lived proteins and protein aggregates in lysosomes and plays a critical role in cellular and tissue homeostasis. Defective autophagy processes have been found to contribute to a variety of metabolic diseases. However, the regulatory mechanisms of autophagy are not fully understood. Increasing data indicate that nicotinamide adenine nucleotide (NAD(+)) homeostasis correlates intimately with autophagy. NAD(+) is a ubiquitous coenzyme that functions primarily as an electron carrier of oxidoreductase in multiple redox reactions. Both NAD(+) homeostasis and its metabolism are thought to play critical roles in regulating autophagy. In this review, we discuss how the regulation of NAD(+) and its metabolism can influence autophagy. We focus on the regulation of NAD(+)/NADH homeostasis and the effects of NAD(+) consumption by poly(ADP-ribose) (PAR) polymerase-1 (PARP-1), NAD(+)-dependent deacetylation by sirtuins and NAD(+) metabolites on autophagy processes and the underlying mechanisms. Future studies should provide more direct evidence for the regulation of autophagy processes by NAD(+). A better understanding of the critical roles of NAD(+) and its metabolites on autophagy will shed light on the complexity of autophagy regulation, which is essential for the discovery of new therapeutic tools for autophagy-related diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Evasion of Apoptosis as a Cellular Stress Response in Cancer

Directory of Open Access Journals (Sweden)

Simone Fulda

2010-01-01

Full Text Available One of the hallmarks of human cancers is the intrinsic or acquired resistance to apoptosis. Evasion of apoptosis can be part of a cellular stress response to ensure the cell's survival upon exposure to stressful stimuli. Apoptosis resistance may contribute to carcinogenesis, tumor progression, and also treatment resistance, since most current anticancer therapies including chemotherapy as well as radio- and immunotherapies primarily act by activating cell death pathways including apoptosis in cancer cells. Hence, a better understanding of the molecular mechanisms regarding how cellular stress stimuli trigger antiapoptotic mechanisms and how this contributes to tumor resistance to apoptotic cell death is expected to provide the basis for a rational approach to overcome apoptosis resistance mechanisms in cancers.

Lysine acetylation targets protein complexes and co-regulates major cellular functions

DEFF Research Database (Denmark)

Choudhary, Chuna Ram; Kumar, Chanchal; Gnad, Florian

2009-01-01

Lysine acetylation is a reversible posttranslational modification of proteins and plays a key role in regulating gene expression. Technological limitations have so far prevented a global analysis of lysine acetylation's cellular roles. We used high-resolution mass spectrometry to identify 3600......, cell cycle, splicing, nuclear transport, and actin nucleation. Acetylation impaired phosphorylation-dependent interactions of 14-3-3 and regulated the yeast cyclin-dependent kinase Cdc28. Our data demonstrate that the regulatory scope of lysine acetylation is broad and comparable with that of other...

Can complex cellular processes be governed by simple linear rules?

Science.gov (United States)

Selvarajoo, Kumar; Tomita, Masaru; Tsuchiya, Masa

2009-02-01

Complex living systems have shown remarkably well-orchestrated, self-organized, robust, and stable behavior under a wide range of perturbations. However, despite the recent generation of high-throughput experimental datasets, basic cellular processes such as division, differentiation, and apoptosis still remain elusive. One of the key reasons is the lack of understanding of the governing principles of complex living systems. Here, we have reviewed the success of perturbation-response approaches, where without the requirement of detailed in vivo physiological parameters, the analysis of temporal concentration or activation response unravels biological network features such as causal relationships of reactant species, regulatory motifs, etc. Our review shows that simple linear rules govern the response behavior of biological networks in an ensemble of cells. It is daunting to know why such simplicity could hold in a complex heterogeneous environment. Provided physical reasons can be explained for these phenomena, major advancement in the understanding of basic cellular processes could be achieved.

Differential and Cooperative Cell Adhesion Regulates Cellular Pattern in Sensory Epithelia.

Science.gov (United States)

Togashi, Hideru

2016-01-01

Animal tissues are composed of multiple cell types arranged in complex and elaborate patterns. In sensory epithelia, including the auditory epithelium and olfactory epithelium, different types of cells are arranged in unique mosaic patterns. These mosaic patterns are evolutionarily conserved, and are thought to be important for hearing and olfaction. Recent progress has provided accumulating evidence that the cellular pattern formation in epithelia involves cell rearrangements, movements, and shape changes. These morphogenetic processes are largely mediated by intercellular adhesion systems. Differential adhesion and cortical tension have been proposed to promote cell rearrangements. Many different types of cells in tissues express various types of cell adhesion molecules. Although cooperative mechanisms between multiple adhesive systems are likely to contribute to the production of complex cell patterns, our current understanding of the cooperative roles between multiple adhesion systems is insufficient to entirely explain the complex mechanisms underlying cellular patterning. Recent studies have revealed that nectins, in cooperation with cadherins, are crucial for the mosaic cellular patterning in sensory organs. The nectin and cadherin systems are interacted with one another, and these interactions provide cells with differential adhesive affinities for complex cellular pattern formations in sensory epithelia, which cannot be achieved by a single mechanism.

Repair and mutagenesis in procaryotes as cellular responses to ambiental agents

International Nuclear Information System (INIS)

Gomes, R.A.

1982-01-01

The correct and incorrect mechanisms of DNA repair are discussed, as well as the cellular responses induced by the DNA lesions; the reductone mollecular effects; the cellular interactions among irradiated populations of microorganisms and the utilization of microbial assays for the detection of oncogenic activities of chemicals. (M.A.) [pt

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...... at the molecular level and has led to the discovery that the rates of mistranslation in vivo are not fixed but instead are variable. In this Review we describe the different steps in translation quality control and their variations under different growth conditions and between species though a comparison...

Cellular and Molecular Mechanisms of Anterior Chamber-Associated Immune Deviation (ACAID: What We Have Learned from Knockout Mice

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Julie Vendomèle

2017-11-01

Full Text Available Anterior chamber-associated immune deviation (ACAID is a well-known phenomenon that can occur after an antigen is introduced without any danger signal into the anterior chamber of a murine eye. It is reported to lead to an antigen-specific immune deviation throughout the body. Despite the relatively little evidence of this phenomenon in humans, it has been suggested as a potential prophylactic strategy in allograft rejections and in several autoimmune diseases. Cellular and molecular mechanisms of ACAID have been explored in different murine models mainly as proofs of concept, first by direct analyses of immune components in normal immunocompetent settings and by cell transfer experiments. Later, use of knockout (KO mice has helped considerably to decipher ACAID mechanisms. However, several factors raise questions about the reliability and validity of studies using KO murine models. This mini-review summarizes results obtained with KO mice and discusses their advantages, their potential weaknesses, and their potential methods for further progress.

Epigenetic Regulatory Mechanisms Induced by Resveratrol

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Guilherme Felipe Santos Fernandes

2017-11-01

Full Text Available Resveratrol (RVT is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. Nevertheless, the mechanism of action of RVT in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. In this paper, we analyze the biological activities exhibited by RVT with a focus on the epigenetic mechanisms, especially those related to DNA methyltransferase (DNMT, histone deacetylase (HDAC and lysine-specific demethylase-1 (LSD1.

Regulatory dendritic cell therapy: from rodents to clinical application

OpenAIRE

Raïch-Regué, Dalia; Glancy, Megan; Thomson, Angus W.

2013-01-01

Dendritic cells (DC) are highly-specialized, bone marrow-derived antigen-presenting cells that induce or regulate innate and adaptive immunity. Regulatory or “tolerogenic” DC play a crucial role in maintaining self tolerance in the healthy steady-state. These regulatory innate immune cells subvert naïve or memory T cell responses by various mechanisms. Regulatory DC (DCreg) also exhibit the ability to induce or restore T cell tolerance in many animal models of autoimmune disease or transplant...

Cellular Restriction Factors of Feline Immunodeficiency Virus

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Carsten Münk

2011-10-01

Full Text Available Lentiviruses are known for their narrow cell- and species-tropisms, which are determined by cellular proteins whose absence or presence either support viral replication (dependency factors, cofactors or inhibit viral replication (restriction factors. Similar to Human immunodeficiency virus type 1 (HIV-1, the cat lentivirus Feline immunodeficiency virus (FIV is sensitive to recently discovered cellular restriction factors from non-host species that are able to stop viruses from replicating. Of particular importance are the cellular proteins APOBEC3, TRIM5α and tetherin/BST-2. In general, lentiviruses counteract or escape their species’ own variant of the restriction factor, but are targeted by the orthologous proteins of distantly related species. Most of the knowledge regarding lentiviral restriction factors has been obtained in the HIV-1 system; however, much less is known about their effects on other lentiviruses. We describe here the molecular mechanisms that explain how FIV maintains its replication in feline cells, but is largely prevented from cross-species infections by cellular restriction factors.

Radiation and the regulatory landscape of neo{sup 2}-Darwinism

Energy Technology Data Exchange (ETDEWEB)

Rollo, C. David [Department of Biology, Life Sciences Building, 1280 Main St. West, Hamilton, Ont., Canada L8S 4K1 (Canada)]. E-mail: rollocd@mcmaster.ca

2006-05-11

Several recently revealed features of eukaryotic genomes were not predicted by earlier evolutionary paradigms, including the relatively small number of genes, the very large amounts of non-functional code and its quarantine in heterochromatin, the remarkable conservation of many functionally important genes across relatively enormous phylogenetic distances, and the prevalence of extra-genomic information associated with chromatin structure and histone proteins. All of these emphasize a paramount role for regulatory evolution, which is further reinforced by recent perspectives highlighting even higher-order regulation governing epigenetics and development (EVO-DEVO). Modern neo{sup 2}-Darwinism, with its emphasis on regulatory mechanisms and regulatory evolution provides new vision for understanding radiation biology, particularly because free radicals and redox states are central to many regulatory mechanisms and free radicals generated by radiation mimic and amplify endogenous signalling. This paper explores some of these aspects and their implications for low-dose radiation biology.

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.

The cellular mastermind(?) – Mechanotransduction and the nucleus

Science.gov (United States)

Kaminski, Ashley; Fedorchak, Gregory R.; Lammerding, Jan

2015-01-01

Cells respond to mechanical stimulation by activation of specific signaling pathways and genes that allow the cell to adapt to its dynamic physical environment. How cells sense the various mechanical inputs and translate them into biochemical signals remains an area of active investigation. Recent reports suggest that the cell nucleus may be directly implicated in this cellular mechanotransduction process. In this chapter, we discuss how forces applied to the cell surface and cytoplasm induce changes in nuclear structure and organization, which could directly affect gene expression, while also highlighting the complex interplay between nuclear structural proteins and transcriptional regulators that may further modulate mechanotransduction signaling. Taken together, these findings paint a picture of the nucleus as a central hub in cellular mechanotransduction—both structurally and biochemically—with important implications in physiology and disease. PMID:25081618

Genomic stability during cellular reprogramming: Mission impossible?

Energy Technology Data Exchange (ETDEWEB)

Joest, Mathieu von; Búa Aguín, Sabela; Li, Han, E-mail: han.li@pasteur.fr

2016-06-15

The generation of induced pluripotent stem cells (iPSCs) from adult somatic cells is one of the most exciting discoveries in recent biomedical research. It holds tremendous potential in drug discovery and regenerative medicine. However, a series of reports highlighting genomic instability in iPSCs raises concerns about their clinical application. Although the mechanisms cause genomic instability during cellular reprogramming are largely unknown, several potential sources have been suggested. This review summarizes current knowledge on this active research field and discusses the latest efforts to alleviate the genomic insults during cellular reprogramming to generate iPSCs with enhanced quality and safety.

Small RNA-Controlled Gene Regulatory Networks in Pseudomonas putida

DEFF Research Database (Denmark)

Bojanovic, Klara

evolved numerous mechanisms to controlgene expression in response to specific environmental signals. In addition to two-component systems, small regulatory RNAs (sRNAs) have emerged as major regulators of gene expression. The majority of sRNAs bind to mRNA and regulate their expression. They often have...... multiple targets and are incorporated into large regulatory networks and the RNA chaper one Hfq in many cases facilitates interactions between sRNAs and their targets. Some sRNAs also act by binding to protein targets and sequestering their function. In this PhD thesis we investigated the transcriptional....... Detailed insights into the mechanisms through which P. putida responds to different stress conditions and increased understanding of bacterial adaptation in natural and industrial settings were gained. Additionally, we identified genome-wide transcription start sites, andmany regulatory RNA elements...

Ligation of TLR7 on CD19(+) CD1d(hi) B cells suppresses allergic lung inflammation via regulatory T cells.

Science.gov (United States)

Khan, Adnan R; Amu, Sylvie; Saunders, Sean P; Hams, Emily; Blackshields, Gordon; Leonard, Martin O; Weaver, Casey T; Sparwasser, Tim; Sheils, Orla; Fallon, Padraic G

2015-06-01

B cells have been described as having the capacity to regulate cellular immune responses and suppress inflammatory processes. One such regulatory B-cell population is defined as IL-10-producing CD19(+) CD1d(hi) cells. Previous work has identified an expansion of these cells in mice infected with the helminth, Schistosoma mansoni. Here, microarray analysis of CD19(+) CD1d(hi) B cells from mice infected with S. mansoni demonstrated significantly increased Tlr7 expression, while CD19(+) CD1d(hi) B cells from uninfected mice also demonstrated elevated Tlr7 expression. Using IL-10 reporter, Il10(-/-) and Tlr7(-/-) mice, we formally demonstrate that TLR7 ligation of CD19(+) CD1d(hi) B cells increases their capacity to produce IL-10. In a mouse model of allergic lung inflammation, the adoptive transfer of TLR7-elicited CD19(+) CD1d(hi) B cells reduced airway inflammation and associated airway hyperresponsiveness. Using DEREG mice to deplete FoxP3(+) T regulatory cells in allergen-sensitized mice, we show that that TLR7-elicited CD19(+) CD1d(hi) B cells suppress airway hyperresponsiveness via a T regulatory cell dependent mechanism. These studies identify that TLR7 stimulation leads to the expansion of IL-10-producing CD19(+) CD1d(hi) B cells, which can suppress allergic lung inflammation via T regulatory cells. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Regulatory immune cells and functions in autoimmunity and transplantation immunology.

Science.gov (United States)

Papp, Gabor; Boros, Peter; Nakken, Britt; Szodoray, Peter; Zeher, Margit

2017-05-01

In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation. In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies. Copyright © 2017 Elsevier B.V. All rights reserved.

Dual Nature of Translational Control by Regulatory BC RNAs ▿

Science.gov (United States)

Eom, Taesun; Berardi, Valerio; Zhong, Jun; Risuleo, Gianfranco; Tiedge, Henri

2011-01-01

In higher eukaryotes, increasing evidence suggests, gene expression is to a large degree controlled by RNA. Regulatory RNAs have been implicated in the management of neuronal function and plasticity in mammalian brains. However, much of the molecular-mechanistic framework that enables neuronal regulatory RNAs to control gene expression remains poorly understood. Here, we establish molecular mechanisms that underlie the regulatory capacity of neuronal BC RNAs in the translational control of gene expression. We report that regulatory BC RNAs employ a two-pronged approach in translational control. One of two distinct repression mechanisms is mediated by C-loop motifs in BC RNA 3′ stem-loop domains. These C-loops bind to eIF4B and prevent the factor's interaction with 18S rRNA of the small ribosomal subunit. In the second mechanism, the central A-rich domains of BC RNAs target eIF4A, specifically inhibiting its RNA helicase activity. Thus, BC RNAs repress translation initiation in a bimodal mechanistic approach. As BC RNA functionality has evolved independently in rodent and primate lineages, our data suggest that BC RNA translational control was necessitated and implemented during mammalian phylogenetic development of complex neural systems. PMID:21930783

Cellular and molecular specificity of pituitary gland physiology.

Science.gov (United States)

Perez-Castro, Carolina; Renner, Ulrich; Haedo, Mariana R; Stalla, Gunter K; Arzt, Eduardo

2012-01-01

The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.

Protein tyrosine phosphatases: regulatory mechanisms.

NARCIS (Netherlands)

den Hertog, J.; Ostman, A.; Bohmer, F.D.

2008-01-01

Protein-tyrosine phosphatases are tightly controlled by various mechanisms, ranging from differential expression in specific cell types to restricted subcellular localization, limited proteolysis, post-translational modifications affecting intrinsic catalytic activity, ligand binding and

Electrical stimulation of the substantia nigra reticulata : Detection of neuronal extracellular GABA in the ventromedial thalamus and its regulatory mechanism using microdialysis in awake rats

NARCIS (Netherlands)

Timmerman, W; Westerink, B.H.C.

A combination of electrical stimulation and microdialysis was used to study the nigrothalamic gamma aminobutyric acid (GABA)ergic system and its regulatory mechanisms in awake rats. Extracellular GABA levels in the ventromedial nucleus of the thalamus were detected in S-min fractions collected

Inhibitors Alter the Stochasticity of Regulatory Proteins to Force Cells to Switch to the Other State in the Bistable System.

Science.gov (United States)

Jhang, Wun-Sin; Lo, Shih-Chiang; Yeh, Chen-Chao; Shu, Che-Chi

2017-06-30

The cellular behaviors under the control of genetic circuits are subject to stochastic fluctuations, or noise. The stochasticity in gene regulation, far from a nuisance, has been gradually appreciated for its unusual function in cellular activities. In this work, with Chemical Master Equation (CME), we discovered that the addition of inhibitors altered the stochasticity of regulatory proteins. For a bistable system of a mutually inhibitory network, such a change of noise led to the migration of cells in the bimodal distribution. We proposed that the consumption of regulatory protein caused by the addition of inhibitor is not the only reason for pushing cells to the specific state; the change of the intracellular stochasticity is also the main cause for the redistribution. For the level of the inhibitor capable of driving 99% of cells, if there is no consumption of regulatory protein, 88% of cells were guided to the specific state. It implied that cells were pushed, by the inhibitor, to the specific state due to the change of stochasticity.

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

DEFF Research Database (Denmark)

Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P

2015-01-01

. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC......BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes...... and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted...

Origami-based cellular metamaterial with auxetic, bistable, and self-locking properties

Science.gov (United States)

Kamrava, Soroush; Mousanezhad, Davood; Ebrahimi, Hamid; Ghosh, Ranajay; Vaziri, Ashkan

2017-04-01

We present a novel cellular metamaterial constructed from Origami building blocks based on Miura-ori fold. The proposed cellular metamaterial exhibits unusual properties some of which stemming from the inherent properties of its Origami building blocks, and others manifesting due to its unique geometrical construction and architecture. These properties include foldability with two fully-folded configurations, auxeticity (i.e., negative Poisson’s ratio), bistability, and self-locking of Origami building blocks to construct load-bearing cellular metamaterials. The kinematics and force response of the cellular metamaterial during folding were studied to investigate the underlying mechanisms resulting in its unique properties using analytical modeling and experiments.

Flaw tolerance vs. performance: A tradeoff in metallic glass cellular structures

International Nuclear Information System (INIS)

Chen, Wen; Liu, Ze; Robinson, Hannah Mae; Schroers, Jan

2014-01-01

Stochastic cellular structures are prevalent in nature and engineering materials alike. They are difficult to manipulate and study systematically and almost always contain imperfections. To design and characterize various degrees of imperfections in perfect periodic, stochastic and natural cellular structures, we fabricate a broad range of metallic glass cellular structures from perfectly periodic to highly stochastic by using a novel artificial microstructure approach based on thermoplastic replication of metallic glasses. For these cellular structures, precisely controlled imperfections are implemented and their effects on the mechanical response are evaluated. It is found that the mechanical performance of the periodic structures is generally superior to that of the stochastic structures. However, the stochastic structures experience a much higher tolerance to flaws than the periodic structure, especially in the plastic regime. The different flaw tolerance is explained by the stress distribution within the various structures, which leads to an overall 'strain-hardening' behavior of the stochastic structure compared to a 'strain-softening' behavior in the periodic structure. Our findings reveal how structure, 'strain-hardening' and flaw tolerance are microscopically related in structural materials

Induction of Osmoadaptive Mechanisms and Modulation of Cellular Physiology Help Bacillus licheniformis Strain SSA 61 Adapt to Salt Stress

Energy Technology Data Exchange (ETDEWEB)

Paul, Sangeeta; Aggarwal, Chetana; Thakur, Jyoti Kumar; Bandeppa, G. S.; Khan, Md. Aslam; Pearson, Lauren M.; Babnigg, Gyorgy; Giometti, Carol S.; Joachimiak, Andrzej

2015-01-06

Bacillus licheniformis strain SSA 61, originally isolated from Sambhar salt lake, was observed to grow even in the presence of 25 % salt stress. Osmoadaptive mechanisms of this halotolerant B. licheniformis strain SSA 61, for long-term survival and growth under salt stress, were determined. Proline was the preferentially accumulated compatible osmolyte. There was also increased accumulation of antioxidants ascorbic acid and glutathione. Among the different antioxidative enzymes assayed, superoxide dismutase played the most crucial role in defense against salt-induced stress in the organism. Adaptation to stress by the organism involved modulation of cellular physiology at various levels. There was enhanced expression of known proteins playing essential roles in stress adaptation, such as chaperones DnaK and GroEL, and general stress protein YfkM and polynucleotide phosphorylase/polyadenylase. Proteins involved in amino acid biosynthetic pathway, ribosome structure, and peptide elongation were also overexpressed. Salt stress-induced modulation of expression of enzymes involved in carbon metabolism was observed. There was up-regulation of a number of enzymes involved in generation of NADH and NADPH, indicating increased cellular demand for both energy and reducing power.

DNA replication stress: from molecular mechanisms to human disease.

Science.gov (United States)

Muñoz, Sergio; Méndez, Juan

2017-02-01

The genome of proliferating cells must be precisely duplicated in each cell division cycle. Chromosomal replication entails risks such as the possibility of introducing breaks and/or mutations in the genome. Hence, DNA replication requires the coordinated action of multiple proteins and regulatory factors, whose deregulation causes severe developmental diseases and predisposes to cancer. In recent years, the concept of "replicative stress" (RS) has attracted much attention as it impinges directly on genomic stability and offers a promising new avenue to design anticancer therapies. In this review, we summarize recent progress in three areas: (1) endogenous and exogenous factors that contribute to RS, (2) molecular mechanisms that mediate the cellular responses to RS, and (3) the large list of diseases that are directly or indirectly linked to RS.

The elasticity and failure of fluid-filled cellular solids: Theory and experiment

Science.gov (United States)

Warner, M.; Thiel, B. L.; Donald, A. M.

2000-02-01

We extend and apply theories of filled foam elasticity and failure to recently available data on foods. The predictions of elastic modulus and failure mode dependence on internal pressure and on wall integrity are borne out by photographic evidence of distortion and failure under compressive loading and under the localized stress applied by a knife blade, and by mechanical data on vegetables differing only in their turgor pressure. We calculate the dry modulus of plate-like cellular solids and the cross over between dry-like and fully fluid-filled elastic response. The bulk elastic properties of limp and aging cellular solids are calculated for model systems and compared with our mechanical data, which also show two regimes of response. The mechanics of an aged, limp beam is calculated, thus offering a practical procedure for comparing experiment and theory. This investigation also thereby offers explanations of the connection between turgor pressure and crispness and limpness of cellular materials.

The elasticity and failure of fluid-filled cellular solids: theory and experiment.

Science.gov (United States)

Warner, M; Thiel, B L; Donald, A M

2000-02-15

We extend and apply theories of filled foam elasticity and failure to recently available data on foods. The predictions of elastic modulus and failure mode dependence on internal pressure and on wall integrity are borne out by photographic evidence of distortion and failure under compressive loading and under the localized stress applied by a knife blade, and by mechanical data on vegetables differing only in their turgor pressure. We calculate the dry modulus of plate-like cellular solids and the cross over between dry-like and fully fluid-filled elastic response. The bulk elastic properties of limp and aging cellular solids are calculated for model systems and compared with our mechanical data, which also show two regimes of response. The mechanics of an aged, limp beam is calculated, thus offering a practical procedure for comparing experiment and theory. This investigation also thereby offers explanations of the connection between turgor pressure and crispness and limpness of cellular materials.

Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities

Energy Technology Data Exchange (ETDEWEB)

Edelbrock, Michael A., E-mail: Edelbrock@findlay.edu [The University of Findlay, 1000 North Main Street, Findlay, OH 45840 (United States); Kaliyaperumal, Saravanan, E-mail: Saravanan.Kaliyaperumal@hms.harvard.edu [Division of Comparative Medicine and Pathology, New England Primate Research Center, One Pine Hill Drive, Southborough, MA 01772 (United States); Williams, Kandace J., E-mail: Kandace.williams@utoledo.edu [University of Toledo College of Medicine and Life Sciences, Department of Biochemistry and Cancer Biology, 3000 Transverse Dr., Toledo, OH 43614 (United States)

2013-03-15

The field of DNA mismatch repair (MMR) has rapidly expanded after the discovery of the MutHLS repair system in bacteria. By the mid 1990s yeast and human homologues to bacterial MutL and MutS had been identified and their contribution to hereditary non-polyposis colorectal cancer (HNPCC; Lynch syndrome) was under intense investigation. The human MutS homologue 6 protein (hMSH6), was first reported in 1995 as a G:T binding partner (GTBP) of hMSH2, forming the hMutSα mismatch-binding complex. Signal transduction from each DNA-bound hMutSα complex is accomplished by the hMutLα heterodimer (hMLH1 and hPMS2). Molecular mechanisms and cellular regulation of individual MMR proteins are now areas of intensive research. This review will focus on molecular mechanisms associated with mismatch binding, as well as emerging evidence that MutSα, and in particular, MSH6, is a key protein in MMR-dependent DNA damage response and communication with other DNA repair pathways within the cell. MSH6 is unstable in the absence of MSH2, however it is the DNA lesion-binding partner of this heterodimer. MSH6, but not MSH2, has a conserved Phe-X-Glu motif that recognizes and binds several different DNA structural distortions, initiating different cellular responses. hMSH6 also contains the nuclear localization sequences required to shuttle hMutSα into the nucleus. For example, upon binding to O{sup 6}meG:T, MSH6 triggers a DNA damage response that involves altered phosphorylation within the N-terminal disordered domain of this unique protein. While many investigations have focused on MMR as a post-replication DNA repair mechanism, MMR proteins are expressed and active in all phases of the cell cycle. There is much more to be discovered about regulatory cellular roles that require the presence of MutSα and, in particular, MSH6.

Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities

International Nuclear Information System (INIS)

Edelbrock, Michael A.; Kaliyaperumal, Saravanan; Williams, Kandace J.

2013-01-01

The field of DNA mismatch repair (MMR) has rapidly expanded after the discovery of the MutHLS repair system in bacteria. By the mid 1990s yeast and human homologues to bacterial MutL and MutS had been identified and their contribution to hereditary non-polyposis colorectal cancer (HNPCC; Lynch syndrome) was under intense investigation. The human MutS homologue 6 protein (hMSH6), was first reported in 1995 as a G:T binding partner (GTBP) of hMSH2, forming the hMutSα mismatch-binding complex. Signal transduction from each DNA-bound hMutSα complex is accomplished by the hMutLα heterodimer (hMLH1 and hPMS2). Molecular mechanisms and cellular regulation of individual MMR proteins are now areas of intensive research. This review will focus on molecular mechanisms associated with mismatch binding, as well as emerging evidence that MutSα, and in particular, MSH6, is a key protein in MMR-dependent DNA damage response and communication with other DNA repair pathways within the cell. MSH6 is unstable in the absence of MSH2, however it is the DNA lesion-binding partner of this heterodimer. MSH6, but not MSH2, has a conserved Phe-X-Glu motif that recognizes and binds several different DNA structural distortions, initiating different cellular responses. hMSH6 also contains the nuclear localization sequences required to shuttle hMutSα into the nucleus. For example, upon binding to O 6 meG:T, MSH6 triggers a DNA damage response that involves altered phosphorylation within the N-terminal disordered domain of this unique protein. While many investigations have focused on MMR as a post-replication DNA repair mechanism, MMR proteins are expressed and active in all phases of the cell cycle. There is much more to be discovered about regulatory cellular roles that require the presence of MutSα and, in particular, MSH6

Hierarchical structure and modules in the Escherichia coli transcriptional regulatory network revealed by a new top-down approach

Directory of Open Access Journals (Sweden)

Buer Jan

2004-12-01

Full Text Available Abstract Background Cellular functions are coordinately carried out by groups of genes forming functional modules. Identifying such modules in the transcriptional regulatory network (TRN of organisms is important for understanding the structure and function of these fundamental cellular networks and essential for the emerging modular biology. So far, the global connectivity structure of TRN has not been well studied and consequently not applied for the identification of functional modules. Moreover, network motifs such as feed forward loop are recently proposed to be basic building blocks of TRN. However, their relationship to functional modules is not clear. Results In this work we proposed a top-down approach to identify modules in the TRN of E. coli. By studying the global connectivity structure of the regulatory network, we first revealed a five-layer hierarchical structure in which all the regulatory relationships are downward. Based on this regulatory hierarchy, we developed a new method to decompose the regulatory network into functional modules and to identify global regulators governing multiple modules. As a result, 10 global regulators and 39 modules were identified and shown to have well defined functions. We then investigated the distribution and composition of the two basic network motifs (feed forward loop and bi-fan motif in the hierarchical structure of TRN. We found that most of these network motifs include global regulators, indicating that these motifs are not basic building blocks of modules since modules should not contain global regulators. Conclusion The transcriptional regulatory network of E. coli possesses a multi-layer hierarchical modular structure without feedback regulation at transcription level. This hierarchical structure builds the basis for a new and simple decomposition method which is suitable for the identification of functional modules and global regulators in the transcriptional regulatory network of E

Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6

Energy Technology Data Exchange (ETDEWEB)

Penrose, Harrison; Heller, Sandra; Cable, Chloe [Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112 (United States); Makboul, Rania [Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112 (United States); Pathology Department, Assiut University, Assiut (Egypt); Chadalawada, Gita; Chen, Ying [Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112 (United States); Crawford, Susan E. [Department of Pathology, Saint Louis University School of Medicine, 1402 South Grand Blvd, Saint Louis, MO 63104 (United States); Savkovic, Suzana D., E-mail: ssavkovi@tulane.edu [Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112 (United States)

2016-01-15

The proliferation of colon cancer cells is mediated in part by epidermal growth factor receptor (EGFR) signaling and requires sustained levels of cellular energy to meet its high metabolic needs. Intracellular lipid droplets (LDs) are a source of energy used for various cellular functions and they are elevated in density in human cancer, yet their regulation and function are not well understood. Here, in human colon cancer cells, EGF stimulates increases in LD density, which depends on EGFR expression and activation as well as the individual cellular capacity for lipid synthesis. Increases in LDs are blockaded by inhibition of PI3K/mTOR and PGE2 synthesis, supporting their dependency on select upstream pathways. In colon cancer cells, silencing of the FOXO3 transcription factor leads to down regulation of SIRT6, a negative regulator of lipid synthesis, and consequent increases in the LD coat protein PLIN2, revealing that increases in LDs depend on loss of FOXO3/SIRT6. Moreover, EGF stimulates loss of FOXO3/SIRT6, which is blockaded by the inhibition of upstream pathways as well as lipid synthesis, revealing existence of a negative regulatory loop between LDs and FOXO3/SIRT6. Elevated LDs are utilized by EGF treatment and their depletion through the inhibition of lipid synthesis or silencing of PLIN2 significantly attenuates proliferation. This novel mechanism of proliferative EGFR signaling leading to elevated LD density in colon cancer cells could potentially be therapeutically targeted for the treatment of tumor progression. - Highlights: • In colon cancer cells, EGFR activation leads to increases in LD density. • EGFR signaling includes PI3K/mTOR and PGE2 leading to lipid synthesis. • Increases in LDs are controlled by a negative regulatory loop with FOXO3/SIRT6. • EGFR mediated colon cancer cell proliferation depends on increased LD density.

Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6

International Nuclear Information System (INIS)

Penrose, Harrison; Heller, Sandra; Cable, Chloe; Makboul, Rania; Chadalawada, Gita; Chen, Ying; Crawford, Susan E.; Savkovic, Suzana D.

2016-01-01

The proliferation of colon cancer cells is mediated in part by epidermal growth factor receptor (EGFR) signaling and requires sustained levels of cellular energy to meet its high metabolic needs. Intracellular lipid droplets (LDs) are a source of energy used for various cellular functions and they are elevated in density in human cancer, yet their regulation and function are not well understood. Here, in human colon cancer cells, EGF stimulates increases in LD density, which depends on EGFR expression and activation as well as the individual cellular capacity for lipid synthesis. Increases in LDs are blockaded by inhibition of PI3K/mTOR and PGE2 synthesis, supporting their dependency on select upstream pathways. In colon cancer cells, silencing of the FOXO3 transcription factor leads to down regulation of SIRT6, a negative regulator of lipid synthesis, and consequent increases in the LD coat protein PLIN2, revealing that increases in LDs depend on loss of FOXO3/SIRT6. Moreover, EGF stimulates loss of FOXO3/SIRT6, which is blockaded by the inhibition of upstream pathways as well as lipid synthesis, revealing existence of a negative regulatory loop between LDs and FOXO3/SIRT6. Elevated LDs are utilized by EGF treatment and their depletion through the inhibition of lipid synthesis or silencing of PLIN2 significantly attenuates proliferation. This novel mechanism of proliferative EGFR signaling leading to elevated LD density in colon cancer cells could potentially be therapeutically targeted for the treatment of tumor progression. - Highlights: • In colon cancer cells, EGFR activation leads to increases in LD density. • EGFR signaling includes PI3K/mTOR and PGE2 leading to lipid synthesis. • Increases in LDs are controlled by a negative regulatory loop with FOXO3/SIRT6. • EGFR mediated colon cancer cell proliferation depends on increased LD density.

Mechanical and mechanobiological influences on bone fracture repair : identifying important cellular characteristics

NARCIS (Netherlands)

Isaksson, H.E.

2007-01-01

Fracture repair is a complex and multifactorial process, which involves a well-programmed series of cellular and molecular events that result in a combination of intramembranous and endochondral bone formation. The vast majority of fractures is treated successfully. They heal through ‘secondary

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.

Molecular and cellular mechanisms of pulmonary fibrosis

Science.gov (United States)

2012-01-01

Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease. PMID:22824096

Regulatory focus affects physician risk tolerance.

Science.gov (United States)

Veazie, Peter J; McIntosh, Scott; Chapman, Benjamin P; Dolan, James G

2014-01-01

Risk tolerance is a source of variation in physician decision-making. This variation, if independent of clinical concerns, can result in mistaken utilization of health services. To address such problems, it will be helpful to identify nonclinical factors of risk tolerance, particularly those amendable to intervention-regulatory focus theory suggests such a factor. This study tested whether regulatory focus affects risk tolerance among primary care physicians. Twenty-seven primary care physicians were assigned to promotion-focused or prevention-focused manipulations and compared on the Risk Taking Attitudes in Medical Decision Making scale using a randomization test. Results provide evidence that physicians assigned to the promotion-focus manipulation adopted an attitude of greater risk tolerance than the physicians assigned to the prevention-focused manipulation (p = 0.01). The Cohen's d statistic was conventionally large at 0.92. Results imply that situational regulatory focus in primary care physicians affects risk tolerance and may thereby be a nonclinical source of practice variation. Results also provide marginal evidence that chronic regulatory focus is associated with risk tolerance (p = 0.05), but the mechanism remains unclear. Research and intervention targeting physician risk tolerance may benefit by considering situational regulatory focus as an explanatory factor.

Memory functions reveal structural properties of gene regulatory networks

Science.gov (United States)

Perez-Carrasco, Ruben

2018-01-01

Gene regulatory networks (GRNs) control cellular function and decision making during tissue development and homeostasis. Mathematical tools based on dynamical systems theory are often used to model these networks, but the size and complexity of these models mean that their behaviour is not always intuitive and the underlying mechanisms can be difficult to decipher. For this reason, methods that simplify and aid exploration of complex networks are necessary. To this end we develop a broadly applicable form of the Zwanzig-Mori projection. By first converting a thermodynamic state ensemble model of gene regulation into mass action reactions we derive a general method that produces a set of time evolution equations for a subset of components of a network. The influence of the rest of the network, the bulk, is captured by memory functions that describe how the subnetwork reacts to its own past state via components in the bulk. These memory functions provide probes of near-steady state dynamics, revealing information not easily accessible otherwise. We illustrate the method on a simple cross-repressive transcriptional motif to show that memory functions not only simplify the analysis of the subnetwork but also have a natural interpretation. We then apply the approach to a GRN from the vertebrate neural tube, a well characterised developmental transcriptional network composed of four interacting transcription factors. The memory functions reveal the function of specific links within the neural tube network and identify features of the regulatory structure that specifically increase the robustness of the network to initial conditions. Taken together, the study provides evidence that Zwanzig-Mori projections offer powerful and effective tools for simplifying and exploring the behaviour of GRNs. PMID:29470492

Regulatory elements involved in tax-mediated transactivation of the HTLV-I LTR.

Science.gov (United States)

Seeler, J S; Muchardt, C; Podar, M; Gaynor, R B

1993-10-01

HTLV-I is the etiologic agent of adult T-cell leukemia. In this study, we investigated the regulatory elements and cellular transcription factors which function in modulating HTLV-I gene expression in response to the viral transactivator protein, tax. Transfection experiments into Jurkat cells of a variety of site-directed mutants in the HTLV-1 LTR indicated that each of the three motifs A, B, and C within the 21-bp repeats, the binding sites for the Ets family of proteins, and the TATA box all influenced the degree of tax-mediated activation. Tax is also able to activate gene expression of other viral and cellular promoters. Tax activation of the IL-2 receptor and the HIV-1 LTR is mediated through NF-kappa B motifs. Interestingly, sequences in the 21-bp repeat B and C motifs contain significant homology with NF-kappa B regulatory elements. We demonstrated that an NF-kappa B binding protein, PRDII-BF1, but not the rel protein, bound to the B and C motifs in the 21-bp repeat. PRDII-BF1 was also able to stimulate activation of HTLV-I gene expression by tax. The role of the Ets proteins on modulating tax activation was also studied. Ets 1 but not Ets 2 was capable of increasing the degree of tax activation of the HTLV-I LTR. These results suggest that tax activates gene expression by either direct or indirect interaction with several cellular transcription factors that bind to the HTLV-I LTR.

Building hospital capacity planning mechanisms in Poland: The impact of 2016/2017 regulatory changes.

Science.gov (United States)

Dubas-Jakóbczyk, Katarzyna; Sowada, Christoph; Domagała, Alicja; Więckowska, Barbara

2018-02-07

Capacity planning is a crucial component of modern health care governance. The aim of this paper is to analyze the requirements that need to be met to build effective hospital capacity planning mechanisms in Poland. In this context, the recent regulatory changes strongly influencing hospital sector functioning, including introduction of health care needs maps, capital investment assessment, and hospital network regulations, are analyzed. Some possible ways forward, based on review of international experiences in hospital capacity planning, are discussed. Applied methods include literature review and analysis of statistical data as well as desk analysis of key national regulations related to hospital sector. Results indicate that at the system level, the process of capacity planning involves 4 elements: capital investment in facilities, equipment, and technology; service delivery; allocation of staff; and financial resources. For hospital capacity planning to be effective, the strategic decision at the macrolevel must be complemented by appropriate management of individual hospitals. The major challenge of building hospital capacity planning mechanism in Poland is imbedding it into the overall health system strategy. Because of the lack of such a strategy, the practical implementation of the ad hoc changes, which have been introduced, shows some inconsistencies. The regulations implemented between 2016 and 2017 provided a basis for hospital capacity planning, yet still need evaluation and adjustments. Also, including a mechanism for human resources planning is of crucial importance. The regulations should provide incentives for reducing oversized hospital infrastructure with simultaneous development of the long-term and coordinated care models. Copyright © 2018 John Wiley & Sons, Ltd.

A Regulatory RNA Inducing Transgenerationally Inherited Phenotypes

DEFF Research Database (Denmark)

Jensen, Lea Møller

. The variation in Arabidopsis enables different regulatory networks and mechanisms to shape the phenotypic characteristics. The thesis describes the identification of regulatory RNA encoded by an enzyme encoding gene. The RNA regulates by inducing transgenerationally inherited phenotypes. The function of the RNA...... is dependent on the genetic background illustrating that polymorphisms are found in either interactors or target genes of the RNA. Furthermore, the RNA provides a mechanistic link between accumulation of glucosinolate and onset of flowering....

Interrogating the topological robustness of gene regulatory circuits by randomization.

Directory of Open Access Journals (Sweden)

Bin Huang

2017-03-01

Full Text Available One of the most important roles of cells is performing their cellular tasks properly for survival. Cells usually achieve robust functionality, for example, cell-fate decision-making and signal transduction, through multiple layers of regulation involving many genes. Despite the combinatorial complexity of gene regulation, its quantitative behavior has been typically studied on the basis of experimentally verified core gene regulatory circuitry, composed of a small set of important elements. It is still unclear how such a core circuit operates in the presence of many other regulatory molecules and in a crowded and noisy cellular environment. Here we report a new computational method, named random circuit perturbation (RACIPE, for interrogating the robust dynamical behavior of a gene regulatory circuit even without accurate measurements of circuit kinetic parameters. RACIPE generates an ensemble of random kinetic models corresponding to a fixed circuit topology, and utilizes statistical tools to identify generic properties of the circuit. By applying RACIPE to simple toggle-switch-like motifs, we observed that the stable states of all models converge to experimentally observed gene state clusters even when the parameters are strongly perturbed. RACIPE was further applied to a proposed 22-gene network of the Epithelial-to-Mesenchymal Transition (EMT, from which we identified four experimentally observed gene states, including the states that are associated with two different types of hybrid Epithelial/Mesenchymal phenotypes. Our results suggest that dynamics of a gene circuit is mainly determined by its topology, not by detailed circuit parameters. Our work provides a theoretical foundation for circuit-based systems biology modeling. We anticipate RACIPE to be a powerful tool to predict and decode circuit design principles in an unbiased manner, and to quantitatively evaluate the robustness and heterogeneity of gene expression.

Cellular Response to Ionizing Radiation: A MicroRNA Story

Science.gov (United States)

Halimi, Mohammad; Asghari, S. Mohsen; Sariri, Reyhaneh; Moslemi, Dariush; Parsian, Hadi

2012-01-01

MicroRNAs (miRNAs) represent a class of small non-coding RNA molecules that regulate gene expression at the post-transcriptional level. They play a crucial role in diverse cellular pathways. Ionizing radiation (IR) is one of the most important treatment protocols for patients that suffer from cancer and affects directly or indirectly cellular integration. Recently it has been discovered that microRNA-mediated gene regulation interferes with radio-related pathways in ionizing radiation. Here, we review the recent discoveries about miRNAs in cellular response to IR. Thoroughly understanding the mechanism of miRNAs in radiation response, it will be possible to design new strategies for improving radiotherapy efficiency and ultimately cancer treatment. PMID:24551775

Regulatory governance of telecommunications liberalisation in Taiwan

International Nuclear Information System (INIS)

Cheng, Kuo-Tai; Hebenton, Bill

2008-01-01

This paper examines the changing role of government and market in regulating the telecommunications sector from since 1996 in Taiwan. It contextualises the theoretical aspects of regulatory governance for institutional design and practices, and reviews the concepts and mechanisms for appraising privatisation and regulatory systems. Using a conceptual framework for researching privatisation and regulation, it describes the process and issues pertinent to telecommunications liberalisation and privatisation in Taiwan, supported by a brief presentation of theoretical points of view as well as practitioners' views. The paper presents results concerning criteria for appraising privatisation and regulatory governance and considers policy lessons that can be learned from the experiences of the Taiwanese telecommunications sector's liberalisation. (author)

Regulatory governance of telecommunications liberalisation in Taiwan

Energy Technology Data Exchange (ETDEWEB)

Cheng, Kuo-Tai [Department of Regional Studies in Humanity and Social Sciences, National Hsin-Chu University of Education, No. 521 Nan-Da Road, Hsin-Chu 300 (China); Hebenton, Bill [School of Law, University of Manchester, M13 9PP (United Kingdom)

2008-12-15

This paper examines the changing role of government and market in regulating the telecommunications sector from since 1996 in Taiwan. It contextualises the theoretical aspects of regulatory governance for institutional design and practices, and reviews the concepts and mechanisms for appraising privatisation and regulatory systems. Using a conceptual framework for researching privatisation and regulation, it describes the process and issues pertinent to telecommunications liberalisation and privatisation in Taiwan, supported by a brief presentation of theoretical points of view as well as practitioners' views. The paper presents results concerning criteria for appraising privatisation and regulatory governance and considers policy lessons that can be learned from the experiences of the Taiwanese telecommunications sector's liberalisation. (author)

Similarities of cellular receptors for interferon and cortisol

International Nuclear Information System (INIS)

Filipic, B.; Schauer, P.; Likar, M.

1977-01-01

Cellular receptors are molecules located on the cell membrane. Their function is to bind different molecules to the cell surface. These molecules can penetrate into the cytoplasm and trigger cellular changes. One kind of such bound molecules are interferons and corticosteroids. Until very recently very little was known about interferon's receptors on the cell surface, mechanisms of interferon's binding to them or about kinetics of such binding. On the basis of results published elsewhere and on the basis of experimental results, the authors suggest: receptors for interferon and cortisol are glycoproteins located on the cell surface, in analogy with PHA receptors they are chemically sialoglycoproteins, binding kinetics of cortisol and interferon is similar, interferon and cortisol compete for cellular receptors, binding of cortisol or interferon is dependent on allosteric configuration of receptor molecules. (author)

Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease

Science.gov (United States)

Anderson, Mark E.; Birren, Susan J.; Fukuda, Keiichi; Herring, Neil; Hoover, Donald B.; Kanazawa, Hideaki; Paterson, David J.; Ripplinger, Crystal M.

2016-01-01

Abstract The nervous system and cardiovascular system develop in concert and are functionally interconnected in both health and disease. This white paper focuses on the cellular and molecular mechanisms that underlie neural–cardiac interactions during development, during normal physiological function in the mature system, and during pathological remodelling in cardiovascular disease. The content on each subject was contributed by experts, and we hope that this will provide a useful resource for newcomers to neurocardiology as well as aficionados. PMID:27060296

Molecular and cellular mechanisms of muscle aging and sarcopenia and effects of electrical stimulation in seniors

Directory of Open Access Journals (Sweden)

Laura Barberi

2015-08-01

Full Text Available The prolongation of skeletal muscle strength in aging and neuromuscular disease has been the objective of numerous studies employing a variety of approaches. It is generally accepted that cumulative failure to repair damage related to an overall decrease in anabolic processes is a primary cause of functional impairment in muscle. The functional performance of skeletal muscle tissues declines during post- natal life and it is compromised in different diseases, due to an alteration in muscle fiber composition and an overall decrease in muscle integrity as fibrotic invasions replace functional contractile tissue. Characteristics of skeletal muscle aging and diseases include a conspicuous reduction in myofiber plasticity (due to the progressive loss of muscle mass and in particular of the most powerful fast fibers, alteration in muscle-specific transcriptional mechanisms, and muscle atrophy. An early decrease in protein synthetic rates is followed by a later increase in protein degradation, to affect biochemical, physiological, and morphological parameters of muscle fibers during the aging process. Alterations in regenerative pathways also compromise the functionality of muscle tissues. In this review we will give an overview of the work on molecular and cellular mechanisms of aging and sarcopenia and the effects of electrical stimulation in seniors.

Pathologic Cellular Events in Smoking-Related Pancreatitis

Energy Technology Data Exchange (ETDEWEB)

Thrower, Edwin [Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520 (United States); Veterans Affairs Connecticut Healthcare, West Haven, CT 06516 (United States)

2015-04-29

Pancreatitis, a debilitating inflammatory disorder, results from pancreatic injury. Alcohol abuse is the foremost cause, although cigarette smoking has recently surfaced as a distinct risk factor. The mechanisms by which cigarette smoke and its toxins initiate pathological cellular events leading to pancreatitis, have not been clearly defined. Although cigarette smoke is composed of more than 4000 compounds, it is mainly nicotine and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which have been extensively studied with respect to pancreatic diseases. This review summarizes these research findings and highlights cellular pathways which may be of relevance in initiation and progression of smoking-related pancreatitis.

Cellular Mechanosensing: Getting to the nucleus of it all

Science.gov (United States)

Fedorchak, Gregory R.; Kaminski, Ashley; Lammerding, Jan

2014-01-01

Cells respond to mechanical forces by activating specific genes and signaling pathways that allow the cells to adapt to their physical environment. Examples include muscle growth in response to exercise, bone remodeling based on their mechanical load, or endothelial cells aligning under fluid shear stress. While the involved downstream signaling pathways and mechanoresponsive genes are generally well characterized, many of the molecular mechanisms of the initiating ‘mechanosensing’ remain still elusive. In this review, we discuss recent findings and accumulating evidence suggesting that the cell nucleus plays a crucial role in cellular mechanotransduction, including processing incoming mechanoresponsive signals and even directly responding to mechanical forces. Consequently, mutations in the involved proteins or changes in nuclear envelope composition can directly impact mechanotransduction signaling and contribute to the development and progression of a variety of human diseases, including muscular dystrophy, cancer, and the focus of this review, dilated cardiomyopathy. Improved insights into the molecular mechanisms underlying nuclear mechanotransduction, brought in part by the emergence of new technologies to study intracellular mechanics at high spatial and temporal resolution, will not only result in a better understanding of cellular mechanosensing in normal cells but may also lead to the development of novel therapies in the many diseases linked to defects in nuclear envelope proteins. PMID:25008017

Control of Metastatic Progression by microRNA Regulatory Networks

Science.gov (United States)

Pencheva, Nora; Tavazoie, Sohail F.

2015-01-01

Aberrant microRNA (miRNA) expression is a defining feature of human malignancy. Specific miRNAs have been identified as promoters or suppressors of metastatic progression. These miRNAs control metastasis through divergent or convergent regulation of metastatic gene pathways. Some miRNA regulatory networks govern cell-autonomous cancer phenotypes, while others modulate the cell-extrinsic composition of the metastatic microenvironment. The use of small RNAs as probes into the molecular and cellular underpinnings of metastasis holds promise for the identification of candidate genes for potential therapeutic intervention. PMID:23728460