Exposure to social defeat stress in adolescence improves the working memory and anxiety-like behavior of adult female rats with intrauterine growth restriction, independently of hippocampal neurogenesis.

PubMed

Furuta, Miyako; Ninomiya-Baba, Midori; Chiba, Shuichi; Funabashi, Toshiya; Akema, Tatsuo; Kunugi, Hiroshi

2015-04-01

Intrauterine growth restriction (IUGR) is a risk factor for memory impairment and emotional disturbance during growth and adulthood. However, this risk might be modulated by environmental factors during development. Here we examined whether exposing adolescent male and female rats with thromboxane A2-induced IUGR to social defeat stress (SDS) affected their working memory and anxiety-like behavior in adulthood. We also used BrdU staining to investigate hippocampal cellular proliferation and BrdU and NeuN double staining to investigate neural differentiation in female IUGR rats. In the absence of adolescent stress, IUGR female rats, but not male rats, scored significantly lower in the T-maze test of working memory and exhibited higher anxiety-like behavior in the elevated-plus maze test compared with controls. Adolescent exposure to SDS abolished these behavioral impairments in IUGR females. In the absence of adolescent stress, hippocampal cellular proliferation was significantly higher in IUGR females than in non-IUGR female controls and was not influenced by adolescent exposure to SDS. Hippocampal neural differentiation was equivalent in non-stressed control and IUGR females. Neural differentiation was significantly increased by adolescent exposure to SDS in controls but not in IUGR females. There was no significant difference in the serum corticosterone concentrations between non-stressed control and IUGR females; however, adolescent exposure to SDS significantly increased serum corticosterone concentration in control females but not in IUGR females. These results demonstrate that adolescent exposure to SDS improves behavioral impairment independent of hippocampal neurogenesis in adult rats with IUGR. Copyright © 2015 Elsevier Inc. All rights reserved.

Remote Control of Cellular Functions: The Role of Smart Nanomaterials in the Medicine of the Future.

PubMed

Genchi, Giada Graziana; Marino, Attilio; Grillone, Agostina; Pezzini, Ilaria; Ciofani, Gianni

2017-05-01

The remote control of cellular functions through smart nanomaterials represents a biomanipulation approach with unprecedented potential applications in many fields of medicine, ranging from cancer therapy to tissue engineering. By actively responding to external stimuli, smart nanomaterials act as real nanotransducers able to mediate and/or convert different forms of energy into both physical and chemical cues, fostering specific cell behaviors. This report describes those classes of nanomaterials that have mostly paved the way to a "wireless" control of biological phenomena, focusing the discussion on some examples close to the clinical practice. In particular, magnetic fields, light irradiation, ultrasound, and pH will be presented as means to manipulate the cellular fate, due to the peculiar physical/chemical properties of some smart nanoparticles, thus providing realistic examples of "nanorobots" approaching the visionary ideas of Richard Feynman. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

2D spatially controlled polymer micro patterning for cellular behavior studies

NASA Astrophysics Data System (ADS)

Dinca, V.; Palla-Papavlu, A.; Paraico, I.; Lippert, T.; Wokaun, A.; Dinescu, M.

2011-04-01

A simple and effective method to functionalize glass surfaces that enable polymer micropatterning and subsequent spatially controlled adhesion of cells is reported in this paper. The method involves the application of laser induced forward transfer (LIFT) to achieve polymer patterning in a single step onto cell repellent substrates (i.e. polyethyleneglycol (PEG)). This approach was used to produce micron-size polyethyleneimine (PEI)-patterns alternating with cell-repellent areas. The focus of this work is the ability of SH-SY5Y human neuroblastoma cells to orient, migrate, and produce organized cellular arrangements on laser generated PEI patterns.

Complex Ordered Patterns in Mechanical Instability Induced Geometrically Frustrated Triangular Cellular Structures

NASA Astrophysics Data System (ADS)

Kang, Sung Hoon; Shan, Sicong; Košmrlj, Andrej; Noorduin, Wim L.; Shian, Samuel; Weaver, James C.; Clarke, David R.; Bertoldi, Katia

2014-03-01

Geometrical frustration arises when a local order cannot propagate throughout the space because of geometrical constraints. This phenomenon plays a major role in many systems leading to disordered ground-state configurations. Here, we report a theoretical and experimental study on the behavior of buckling-induced geometrically frustrated triangular cellular structures. To our surprise, we find that buckling induces complex ordered patterns which can be tuned by controlling the porosity of the structures. Our analysis reveals that the connected geometry of the cellular structure plays a crucial role in the generation of ordered states in this frustrated system.

Calibrating cellular automaton models for pedestrians walking through corners

NASA Astrophysics Data System (ADS)

Dias, Charitha; Lovreglio, Ruggiero

2018-05-01

Cellular Automata (CA) based pedestrian simulation models have gained remarkable popularity as they are simpler and easier to implement compared to other microscopic modeling approaches. However, incorporating traditional floor field representations in CA models to simulate pedestrian corner navigation behavior could result in unrealistic behaviors. Even though several previous studies have attempted to enhance CA models to realistically simulate pedestrian maneuvers around bends, such modifications have not been calibrated or validated against empirical data. In this study, two static floor field (SFF) representations, namely 'discrete representation' and 'continuous representation', are calibrated for CA-models to represent pedestrians' walking behavior around 90° bends. Trajectory data collected through a controlled experiment are used to calibrate these model representations. Calibration results indicate that although both floor field representations can represent pedestrians' corner navigation behavior, the 'continuous' representation fits the data better. Output of this study could be beneficial for enhancing the reliability of existing CA-based models by representing pedestrians' corner navigation behaviors more realistically.

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

PubMed

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.

A Macro-to-Micro Interface for the Control of Cellular Organization

PubMed Central

Hui, Elliot E.; Li, Chun; Agrawal, Amit; Bhatia, Sangeeta N.

2015-01-01

The spatial organization of cellular communities plays a fundamental role in determining intercellular communication and emergent behavior. However, few tools exist to modulate tissue organization at the scale of individual cells, particularly in the case of dynamic manipulation. Micromechanical reconfigurable culture achieves dynamic control of tissue organization by culturing adherent cells on microfabricated plates that can be shifted to reorganize the arrangement of the cells. While biological studies utilizing this approach have been previously reported, this paper focuses on the engineering of the device, including the mechanism for translating manual manipulation to precise microscale position control, fault-tolerant design for manufacture, and the synthetic-to-living interface. PMID:26167106

EphA2 Is a Potential Player of Malignant Cellular Behavior in Non-Metastatic Renal Cell Carcinoma Cells but Not in Metastatic Renal Cell Carcinoma Cells.

PubMed

Cho, Min Chul; Cho, Sung Yong; Yoon, Cheol Yong; Lee, Seung Bae; Kwak, Cheol; Kim, Hyeon Hoe; Jeong, Hyeon

2015-01-01

To investigate the role of EphA2 in malignant cellular behavior in renal cell carcinoma (RCC) cells and whether FAK/RhoA signaling can act as downstream effectors of EphA2 on RCC cells. Expression of EphA2 protein in non-metastatic RCC (Caki-2 and A498), metastatic RCC cells (Caki-1 and ACHN), HEK-293 cells and prostate cancer cells (PC-3 and DU-145; positive controls of EphA2 expression) was evaluated by Western blot. Changes in mRNA or protein expression of EphA2, FAK or membrane-bound RhoA following EphA2, FAK or RhoA small interfering RNA (siRNA) transfection were determined by reverse transcription polymerase chain reaction or Western blot. The effect of siRNA treatment on cellular viability, apoptosis and invasion was analyzed by cell counting kit-8, Annexin-V and modified Matrigel-Boyden assays, respectively. In all RCC cell lines, the expression of EphA2 protein was detectable at variable levels; however, in HEK-293 cells, EphA2 expression was very low. Treatment with EphA2 siRNA significantly reduced the expression of EphA2 mRNA and protein in all RCC cell lines. For non-metastatic RCC cells (Caki-2 and A498) but not metastatic RCC cells (Caki-1 and ACHN), cellular viability, invasiveness, resistance to apoptosis, expression of membrane-bound RhoA protein and FAK phosphorylation were significantly decreased in EphA2 siRNA-treated cells compared to the control. In non-metastatic RCC cells, FAK siRNA significantly attenuated the invasiveness, resistance to apoptosis, as well as expression of membrane-bound RhoA protein without changing protein expression of EphA2. RhoA siRNA significantly decreased the malignant cellular behavior and expression of membrane-bound RhoA protein without changing EphA2 protein expression or FAK phosphorylation. Our data provide the first functional evidence that the EphA2/FAK/RhoA signaling pathway plays a critical role in the malignant cellular behavior of RCC and appears to be functional particularly in the early stage of malignant progression of non-metastatic RCC.

Microfabricated Nanotopological Surfaces for Study of Adhesion-dependent Cell mechanosensitivity**

PubMed Central

Chen, Weiqiang; Sun, Yubing

2014-01-01

Cells display high sensitivity and exhibit diverse responses to the intrinsic nanotopography of the extracellular matrix through their nanoscale cellular sensing machinery. Here, we reported a simple microfabrication method for precise control and spatial patterning of the local nanoroughness on glass surfaces using photolithography and reactive ion etching (RIE). Using RIE-generated nanorough glass surfaces, we demonstrated that local nanoroughness could provide a potent biophysical signal to regulate a diverse array of NIH/3T3 fibroblast behaviors, including cell morphology, adhesion, proliferation and migration. We further showed that cellular responses to nanotopography might be regulated by cell adhesion signaling and actin cytoskeleton remodeling. To further investigate the role of cytoskeleton contractility in nanoroughness sensing, we applied the RIE method to generate nanoroughness on the tops of an array of elastomeric poly-dimethylsiloxane (PDMS) microposts. We utilized the PDMS microposts as force sensors and demonstrated that nanoroughness could indeed regulate the cytoskeleton contractility of NIH/3T3 fibroblasts. Our results suggested that a feedback regulation and mechano-chemical integration mechanism involving adhesion signaling, actin cytoskeleton, and intracellular mechanosensory components might play an important role in regulating mechanosensitive behaviors of NIH/3T3 fibroblasts. The capability to control and further predict cellular responses to nanoroughness might suggest novel methods for developing biomaterials mimicking nanotopographic structures in vivo and suitable local cellular microenvironments for functional tissue engineering. PMID:22887768

Cellular behavior controlled by bio-inspired and geometry-tunable nanohairs.

PubMed

Heo, Chaejeong; Jeong, Chanho; Im, Hyeon Seong; Kim, Jong Uk; Woo, Juhyun; Lee, Ji Yeon; Park, Byeonghak; Suh, Minah; Kim, Tae-Il

2017-11-23

A cicada wing has a biocidal feature of rupturing the membrane of cells, while the cactus spine can transmit a water drop to the stem of the plant. Both of these properties have evolved from their respective unique structures. Here, we endeavor to develop geometry-controllable nanohairs that mimic the cicada's wing-like vertical hairs and the cactus spine-like stooped hairs, and to quantitatively characterize the cell migration behavior of the hairy structures. It was found that the neuroblastoma cells are highly sensitive to the variation of surfaces: flat, vertical, and stooped nanohairs (100 nm diameter and 900 nm height). The cells on the vertical hairs showed significantly decreased proliferation. It was found that the behavior of cells cultured on stooped nanohairs is strongly influenced by the direction of the stooped pattern of hairs when we quantitatively measured the migration of cells on flat, vertical, and stooped structures. However, the cells on the flat structures showed random movement and the cells on the vertical nanohairs restricted the nanohair movement. Cells on the stooped structure showed higher forward migration preference compared to that of the other structures. Furthermore, we found that these cellular behaviors on the different patterns of nanohairs were affected by intracellular actin flament change. Consistent with these results, the vertical and stooped structures can facilitate the control of cell viability and guide directional migration for biomedical applications such as organogenesis.

Comparison of the adolescent and adult mouse prefrontal cortex proteome

PubMed Central

Small, Amanda T.; Spanos, Marina; Burrus, Brainard M.

2017-01-01

Adolescence is a developmental period characterized by unique behavioral phenotypes (increased novelty seeking, risk taking, sociability and impulsivity) and increased risk for destructive behaviors, impaired decision making and psychiatric illness. Adaptive and maladaptive adolescent traits have been associated with development of the medial prefrontal cortex (mPFC), a brain region that mediates regulatory control of behavior. However, the molecular changes that underlie brain development and behavioral vulnerability have not been fully characterized. Using high-throughput 2D DIGE spot profiling with identification by MALDI-TOF mass spectrometry, we identified 62 spots in the PFC that exhibited age-dependent differences in expression. Identified proteins were associated with diverse cellular functions, including intracellular signaling, synaptic plasticity, cellular organization and metabolism. Separate Western blot analyses confirmed age-related changes in DPYSL2, DNM1, STXBP1 and CFL1 in the mPFC and expanded these findings to the dorsal striatum, nucleus accumbens, motor cortex, amygdala and ventral tegmental area. Ingenuity Pathway Analysis (IPA) identified functional interaction networks enriched with proteins identified in the proteomics screen, linking age-related alterations in protein expression to cellular assembly and development, cell signaling and behavior, and psychiatric illness. These results provide insight into potential molecular components of adolescent cortical development, implicating structural processes that begin during embryonic development as well as plastic adaptations in signaling that may work in concert to bring the cortex, and other brain regions, into maturity. PMID:28570644

Rapid Neocortical Dynamics: Cellular and Network Mechanisms

PubMed Central

Haider, Bilal; McCormick, David A.

2011-01-01

The highly interconnected local and large-scale networks of the neocortical sheet rapidly and dynamically modulate their functional connectivity according to behavioral demands. This basic operating principle of the neocortex is mediated by the continuously changing flow of excitatory and inhibitory synaptic barrages that not only control participation of neurons in networks but also define the networks themselves. The rapid control of neuronal responsiveness via synaptic bombardment is a fundamental property of cortical dynamics that may provide the basis of diverse behaviors, including sensory perception, motor integration, working memory, and attention. PMID:19409263

Laser-based nanoengineering of surface topographies for biomedical applications

NASA Astrophysics Data System (ADS)

Schlie, Sabrina; Fadeeva, Elena; Koroleva, Anastasia; Ovsianikov, Aleksandr; Koch, Jürgen; Ngezahayo, Anaclet; Chichkov, Boris. N.

2011-04-01

In this study femtosecond laser systems were used for nanoengineering of special surface topographies in silicon and titanium. Besides the control of feature sizes, we demonstrated that laser structuring caused changes in material wettability due to a reduced surface contact area. These laser-engineered topographies were tested for their capability to control cellular behavior of human fibroblasts, SH-SY5Y neuroblastoma cells, and MG-63 osteoblasts. We found that fibroblasts reduced cell growth on the structures, while the other cell types proliferated at the same rate. These findings make laser-surface structuring very attractive for biomedical applications. Finally, to explain the results the correlation between topography and the biophysics of cellular adhesion, which is the key step of selective cell control, is discussed.

Agent-based modeling of autophagy reveals emergent regulatory behavior of spatio-temporal autophagy dynamics.

PubMed

Börlin, Christoph S; Lang, Verena; Hamacher-Brady, Anne; Brady, Nathan R

2014-09-10

Autophagy is a vesicle-mediated pathway for lysosomal degradation, essential under basal and stressed conditions. Various cellular components, including specific proteins, protein aggregates, organelles and intracellular pathogens, are targets for autophagic degradation. Thereby, autophagy controls numerous vital physiological and pathophysiological functions, including cell signaling, differentiation, turnover of cellular components and pathogen defense. Moreover, autophagy enables the cell to recycle cellular components to metabolic substrates, thereby permitting prolonged survival under low nutrient conditions. Due to the multi-faceted roles for autophagy in maintaining cellular and organismal homeostasis and responding to diverse stresses, malfunction of autophagy contributes to both chronic and acute pathologies. We applied a systems biology approach to improve the understanding of this complex cellular process of autophagy. All autophagy pathway vesicle activities, i.e. creation, movement, fusion and degradation, are highly dynamic, temporally and spatially, and under various forms of regulation. We therefore developed an agent-based model (ABM) to represent individual components of the autophagy pathway, subcellular vesicle dynamics and metabolic feedback with the cellular environment, thereby providing a framework to investigate spatio-temporal aspects of autophagy regulation and dynamic behavior. The rules defining our ABM were derived from literature and from high-resolution images of autophagy markers under basal and activated conditions. Key model parameters were fit with an iterative method using a genetic algorithm and a predefined fitness function. From this approach, we found that accurate prediction of spatio-temporal behavior required increasing model complexity by implementing functional integration of autophagy with the cellular nutrient state. The resulting model is able to reproduce short-term autophagic flux measurements (up to 3 hours) under basal and activated autophagy conditions, and to measure the degree of cell-to-cell variability. Moreover, we experimentally confirmed two model predictions, namely (i) peri-nuclear concentration of autophagosomes and (ii) inhibitory lysosomal feedback on mTOR signaling. Agent-based modeling represents a novel approach to investigate autophagy dynamics, function and dysfunction with high biological realism. Our model accurately recapitulates short-term behavior and cell-to-cell variability under basal and activated conditions of autophagy. Further, this approach also allows investigation of long-term behaviors emerging from biologically-relevant alterations to vesicle trafficking and metabolic state.

Social Stress Engages Opioid Regulation of Locus Coeruleus Norepinephrine Neurons and Induces a State of Cellular and Physical Opiate Dependence

PubMed Central

Chaijale, Nayla N; Curtis, Andre L; Wood, Susan K; Zhang, Xiao-Yan; Bhatnagar, Seema; Reyes, Beverly AS; Van Bockstaele, Elisabeth J; Valentino, Rita J

2013-01-01

Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus–norepinephrine (LC–NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased μ-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors. PMID:23660707

Social stress engages opioid regulation of locus coeruleus norepinephrine neurons and induces a state of cellular and physical opiate dependence.

PubMed

Chaijale, Nayla N; Curtis, Andre L; Wood, Susan K; Zhang, Xiao-Yan; Bhatnagar, Seema; Reyes, Beverly As; Van Bockstaele, Elisabeth J; Valentino, Rita J

2013-09-01

Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased μ-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors.

Inferring the Limit Behavior of Some Elementary Cellular Automata

NASA Astrophysics Data System (ADS)

Ruivo, Eurico L. P.; de Oliveira, Pedro P. B.

Cellular automata locally define dynamical systems, discrete in space, time and in the state variables, capable of displaying arbitrarily complex global emergent behavior. One core question in the study of cellular automata refers to their limit behavior, that is, to the global dynamical features in an infinite time evolution. Previous works have shown that for finite time evolutions, the dynamics of one-dimensional cellular automata can be described by regular languages and, therefore, by finite automata. Such studies have shown the existence of growth patterns in the evolution of such finite automata for some elementary cellular automata rules and also inferred the limit behavior of such rules based upon the growth patterns; however, the results on the limit behavior were obtained manually, by direct inspection of the structures that arise during the time evolution. Here we present the formalization of an automatic method to compute such structures. Based on this, the rules of the elementary cellular automata space were classified according to the existence of a growth pattern in their finite automata. Also, we present a method to infer the limit graph of some elementary cellular automata rules, derived from the analysis of the regular expressions that describe their behavior in finite time. Finally, we analyze some attractors of two rules for which we could not compute the whole limit set.

Cell–material interactions on biphasic polyurethane matrix

PubMed Central

Dicesare, Patrick; Fox, Wade M.; Hill, Michael J.; Krishnan, G. Rajesh; Yang, Shuying; Sarkar, Debanjan

2013-01-01

Cell–matrix interaction is a key regulator for controlling stem cell fate in regenerative tissue engineering. These interactions are induced and controlled by the nanoscale features of extracellular matrix and are mimicked on synthetic matrices to control cell structure and functions. Recent studies have shown that nanostructured matrices can modulate stem cell behavior and exert specific role in tissue regeneration. In this study, we have demonstrated that nanostructured phase morphology of synthetic matrix can control adhesion, proliferation, organization and migration of human mesenchymal stem cells (MSCs). Nanostructured biodegradable polyurethanes (PU) with segmental composition exhibit biphasic morphology at nanoscale dimensions and can control cellular features of MSCs. Biodegradable PU with polyester soft segment and hard segment composed of aliphatic diisocyanates and dipeptide chain extender were designed to examine the effect polyurethane phase morphology. By altering the polyurethane composition, morphological architecture of PU was modulated and its effect was examined on MSC. Results show that MSCs can sense the nanoscale morphology of biphasic polyurethane matrix to exhibit distinct cellular features and, thus, signifies the relevance of matrix phase morphology. The role of nanostructured phases of a synthetic matrix in controlling cell–matrix interaction provides important insights for regulation of cell behavior on synthetic matrix and, therefore, is an important tool for engineering tissue regeneration. PMID:23255285

Live imaging of mouse secondary palate fusion

PubMed Central

Kim, Seungil; Prochazka, Jan; Bush, Jeffrey O.

2017-01-01

LONG ABSTRACT The fusion of the secondary palatal shelves to form the intact secondary palate is a key process in mammalian development and its disruption can lead to cleft secondary palate, a common congenital anomaly in humans. Secondary palate fusion has been extensively studied leading to several proposed cellular mechanisms that may mediate this process. However, these studies have been mostly performed on fixed embryonic tissues at progressive timepoints during development or in fixed explant cultures analyzed at static timepoints. Static analysis is limited for the analysis of dynamic morphogenetic processes such a palate fusion and what types of dynamic cellular behaviors mediate palatal fusion is incompletely understood. Here we describe a protocol for live imaging of ex vivo secondary palate fusion in mouse embryos. To examine cellular behaviors of palate fusion, epithelial-specific Keratin14-cre was used to label palate epithelial cells in ROSA26-mTmGflox reporter embryos. To visualize filamentous actin, Lifeact-mRFPruby reporter mice were used. Live imaging of secondary palate fusion was performed by dissecting recently-adhered secondary palatal shelves of embryonic day (E) 14.5 stage embryos and culturing in agarose-containing media on a glass bottom dish to enable imaging with an inverted confocal microscope. Using this method, we have detected a variety of novel cellular behaviors during secondary palate fusion. An appreciation of how distinct cell behaviors are coordinated in space and time greatly contributes to our understanding of this dynamic morphogenetic process. This protocol can be applied to mutant mouse lines, or cultures treated with pharmacological inhibitors to further advance understanding of how secondary palate fusion is controlled. PMID:28784960

Human development VIII: a theory of "deep" quantum chemistry and cell consciousness: quantum chemistry controls genes and biochemistry to give cells and higher organisms consciousness and complex behavior.

PubMed

Ventegodt, Søren; Hermansen, Tyge Dahl; Flensborg-Madsen, Trine; Nielsen, Maj Lyck; Merrick, Joav

2006-11-14

Deep quantum chemistry is a theory of deeply structured quantum fields carrying the biological information of the cell, making it able to remember, intend, represent the inner and outer world for comparison, understand what it "sees", and make choices on its structure, form, behavior and division. We suggest that deep quantum chemistry gives the cell consciousness and all the qualities and abilities related to consciousness. We use geometric symbolism, which is a pre-mathematical and philosophical approach to problems that cannot yet be handled mathematically. Using Occam's razor we have started with the simplest model that works; we presume this to be a many-dimensional, spiral fractal. We suggest that all the electrons of the large biological molecules' orbitals make one huge "cell-orbital", which is structured according to the spiral fractal nature of quantum fields. Consciousness of single cells, multi cellular structures as e.g. organs, multi-cellular organisms and multi-individual colonies (like ants) and human societies can thus be explained by deep quantum chemistry. When biochemical activity is strictly controlled by the quantum-mechanical super-orbital of the cell, this orbital can deliver energetic quanta as biological information, distributed through many fractal levels of the cell to guide form and behavior of an individual single or a multi-cellular organism. The top level of information is the consciousness of the cell or organism, which controls all the biochemical processes. By this speculative work inspired by Penrose and Hameroff we hope to inspire other researchers to formulate more strict and mathematically correct hypothesis on the complex and coherence nature of matter, life and consciousness.

Human Development VIII: A Theory of “Deep” Quantum Chemistry and Cell Consciousness: Quantum Chemistry Controls Genes and Biochemistry to Give Cells and Higher Organisms Consciousness and Complex Behavior

PubMed Central

Ventegodt, Søren; Hermansen, Tyge Dahl; Flensborg-Madsen, Trine; Nielsen, Maj Lyck; Merrick, Joav

2006-01-01

Deep quantum chemistry is a theory of deeply structured quantum fields carrying the biological information of the cell, making it able to remember, intend, represent the inner and outer world for comparison, understand what it “sees”, and make choices on its structure, form, behavior and division. We suggest that deep quantum chemistry gives the cell consciousness and all the qualities and abilities related to consciousness. We use geometric symbolism, which is a pre-mathematical and philosophical approach to problems that cannot yet be handled mathematically. Using Occams razor we have started with the simplest model that works; we presume this to be a many-dimensional, spiral fractal. We suggest that all the electrons of the large biological molecules orbitals make one huge “cell-orbital”, which is structured according to the spiral fractal nature of quantum fields. Consciousness of single cells, multi cellular structures as e.g. organs, multi-cellular organisms and multi-individual colonies (like ants) and human societies can thus be explained by deep quantum chemistry. When biochemical activity is strictly controlled by the quantum-mechanical super-orbital of the cell, this orbital can deliver energetic quanta as biological information, distributed through many fractal levels of the cell to guide form and behavior of an individual single or a multi-cellular organism. The top level of information is the consciousness of the cell or organism, which controls all the biochemical processes. By this speculative work inspired by Penrose and Hameroff we hope to inspire other researchers to formulate more strict and mathematically correct hypothesis on the complex and coherence nature of matter, life and consciousness. PMID:17115084

Neural and behavioral mechanisms of proactive and reactive inhibition

PubMed Central

Meyer, Heidi C.

2016-01-01

Response inhibition is an important component of adaptive behavior. Substantial prior research has focused on reactive inhibition, which refers to the cessation of a motor response that is already in progress. More recently, a growing number of studies have begun to examine mechanisms underlying proactive inhibition, whereby preparatory processes result in a response being withheld before it is initiated. It has become apparent that proactive inhibition is an essential component of the overall ability to regulate behavior and has implications for the success of reactive inhibition. Moreover, successful inhibition relies on learning the meaning of specific environmental cues that signal when a behavioral response should be withheld. Proactive inhibitory control is mediated by stopping goals, which reflect the desired outcome of inhibition and include information about how and when inhibition should be implemented. However, little is known about the circuits and cellular processes that encode and represent features in the environment that indicate the necessity for proactive inhibition or how these representations are implemented in response inhibition. In this article, we will review the brain circuits and systems involved in implementing inhibitory control through both reactive and proactive mechanisms. We also comment on possible cellular mechanisms that may contribute to inhibitory control processes, noting that substantial further research is necessary in this regard. Furthermore, we will outline a number of ways in which the temporal dynamics underlying the generation of the proactive inhibitory signal may be particularly important for parsing out the neurobiological correlates that contribute to the learning processes underlying various aspects of inhibitory control. PMID:27634142

Neuroendocrine control of seasonal plasticity in the auditory and vocal systems of fish

PubMed Central

Forlano, Paul M.; Sisneros, Joseph A.; Rohmann, Kevin N.; Bass, Andrew H.

2014-01-01

Seasonal changes in reproductive-related vocal behavior are widespread among fishes. This review highlights recent studies of the vocal plainfin midshipman fish, Porichthys notatus, a neuroethological model system used for the past two decades to explore neural and endocrine mechanisms of vocal-acoustic social behaviors shared with tetrapods. Integrative approaches combining behavior, neurophysiology, neuropharmacology, neuroanatomy, and gene expression methodologies have taken advantage of simple, stereotyped and easily quantifiable behaviors controlled by discrete neural networks in this model system to enable discoveries such as the first demonstration of adaptive seasonal plasticity in the auditory periphery of a vertebrate as well as rapid steroid and neuropeptide effects on vocal physiology and behavior. This simple model system has now revealed cellular and molecular mechanisms underlying seasonal and steroid-driven auditory and vocal plasticity in the vertebrate brain. PMID:25168757

Emerging roles for neurosteroids in sexual behavior and function.

PubMed

King, Steven R

2008-01-01

Although gonadal and adrenal steroids heavily impact sexual function at the level of the brain, the nervous system also produces its own steroids de novo that may regulate sexual behavior and reproduction. Current evidence points to important roles for neurosteroids in sexual and gender-typical behaviors, control of ovulation, and behaviors that strongly influence sexual interest and motivation like aggression, anxiety and depression. At the cellular level, neurosteroids act through stimulating rapid changes in excitability and direct activation of membrane receptors in neurons. Thus, unlike peripheral steroids, neurosteroids can have immediate and specific effects on select neuronal pathways to regulate sexual function.

Surface topography and chemistry shape cellular behavior on wide band-gap semiconductors.

PubMed

Bain, Lauren E; Collazo, Ramon; Hsu, Shu-Han; Latham, Nicole Pfiester; Manfra, Michael J; Ivanisevic, Albena

2014-06-01

The chemical stability and electrical properties of gallium nitride make it a promising material for the development of biocompatible electronics, a range of devices including biosensors as well as interfaces for probing and controlling cellular growth and signaling. To improve the interface formed between the probe material and the cell or biosystem, surface topography and chemistry can be applied to modify the ways in which the device interacts with its environment. PC12 cells are cultured on as-grown planar, unidirectionally polished, etched nanoporous and nanowire GaN surfaces with and without a physisorbed peptide sequence that promotes cell adhesion. While cells demonstrate preferential adhesion to roughened surfaces over as-grown flat surfaces, the topography of that roughness also influences the morphology of cellular adhesion and differentiation in neurotypic cells. Addition of the peptide sequence generally contributes further to cellular adhesion and promotes development of stereotypic long, thin neurite outgrowths over alternate morphologies. The dependence of cell behavior on both the topographic morphology and surface chemistry is thus demonstrated, providing further evidence for the importance of surface modification for modulating bio-inorganic interfaces. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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.

Neuromodulation of hypoglossal motoneurons: cellular and developmental mechanisms.

PubMed

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.

Molecular substrates of action control in cortico-striatal circuits.

PubMed

Shiflett, Michael W; Balleine, Bernard W

2011-09-15

The purpose of this review is to describe the molecular mechanisms in the striatum that mediate reward-based learning and action control during instrumental conditioning. Experiments assessing the neural bases of instrumental conditioning have uncovered functional circuits in the striatum, including dorsal and ventral striatal sub-regions, involved in action-outcome learning, stimulus-response learning, and the motivational control of action by reward-associated cues. Integration of dopamine (DA) and glutamate neurotransmission within these striatal sub-regions is hypothesized to enable learning and action control through its role in shaping synaptic plasticity and cellular excitability. The extracellular signal regulated kinase (ERK) appears to be particularly important for reward-based learning and action control due to its sensitivity to combined DA and glutamate receptor activation and its involvement in a range of cellular functions. ERK activation in striatal neurons is proposed to have a dual role in both the learning and performance factors that contribute to instrumental conditioning through its regulation of plasticity-related transcription factors and its modulation of intrinsic cellular excitability. Furthermore, perturbation of ERK activation by drugs of abuse may give rise to behavioral disorders such as addiction. Copyright © 2011 Elsevier Ltd. All rights reserved.

Toxicity evaluations of nanoclays and thermally degraded byproducts through spectroscopical and microscopical approaches

PubMed Central

Wagner, Alixandra; Eldawud, Reem; White, Andrew; Agarwal, Sushant; Stueckle, Todd A.; Sierros, Konstantinos A.; Rojanasakul, Yon; Gupta, Rakesh K.; Dinu, Cerasela Zoica

2016-01-01

Background Montmorillonite is a type of nanoclay that originates from the clay fraction of the soil and is incorporated into polymers to form nanocomposites with enhanced mechanical strength, barrier, and flammability properties used for food packaging, automotive, and medical devices. However, with implementation in such consumer applications, the interaction of montmorillonite-based composites or derived byproducts with biological systems needs to be investigated. Methods Herein we examined the potential of Cloisite Na+ (pristine) and Cloisite 30B (organically modified montmorillonite nanoclay) and their thermally degraded byproducts’ to induce toxicity in model human lung epithelial cells. The experimental set-up mimicked biological exposure in manufacturing and disposal areas and employed cellular treatments with occupationally relevant doses of nanoclays previously characterized using spectroscopical and microscopical approaches. For nanoclay-cellular interactions and for cellular analyses respectively, biosensorial-based analytical platforms were used, with induced cellular changes being confirmed via live cell counts, viability assays, and cell imaging. Results Our analysis of byproducts’ chemical and physical properties revealed both structural and functional changes. Real-time high throughput analyses of exposed cellular systems confirmed that nanoclay induced significant toxic effects, with Cloisite 30B showing time-dependent decreases in live cell count and cellular viability relative to control and pristine nanoclay, respectively. Byproducts produced less toxic effects; all treatments caused alterations in the cell morphology upon exposure. Conclusions Our morphological, behavioral, and viability cellular changes show that nanoclays have the potential to produce toxic effects when used both in manufacturing or disposal environments. General significance The reported toxicological mechanisms prove the extensibility of a biosensorial-based platform for cellular behavior analysis upon treatment with a variety of nanomaterials. PMID:27612663

A Compact Synchronous Cellular Model of Nonlinear Calcium Dynamics: Simulation and FPGA Synthesis Results.

PubMed

Soleimani, Hamid; Drakakis, Emmanuel M

2017-06-01

Recent studies have demonstrated that calcium is a widespread intracellular ion that controls a wide range of temporal dynamics in the mammalian body. The simulation and validation of such studies using experimental data would benefit from a fast large scale simulation and modelling tool. This paper presents a compact and fully reconfigurable cellular calcium model capable of mimicking Hopf bifurcation phenomenon and various nonlinear responses of the biological calcium dynamics. The proposed cellular model is synthesized on a digital platform for a single unit and a network model. Hardware synthesis, physical implementation on FPGA, and theoretical analysis confirm that the proposed cellular model can mimic the biological calcium behaviors with considerably low hardware overhead. The approach has the potential to speed up large-scale simulations of slow intracellular dynamics by sharing more cellular units in real-time. To this end, various networks constructed by pipelining 10 k to 40 k cellular calcium units are compared with an equivalent simulation run on a standard PC workstation. Results show that the cellular hardware model is, on average, 83 times faster than the CPU version.

Mechanosensitive Gold Colloidal Membranes Mediated by Supramolecular Interfacial Self-Assembly.

PubMed

Coelho, João Paulo; Mayoral, María José; Camacho, Luis; Martín-Romero, María T; Tardajos, Gloria; López-Montero, Iván; Sanz, Eduardo; Ávila-Brande, David; Giner-Casares, Juan José; Fernández, Gustavo; Guerrero-Martínez, Andrés

2017-01-25

The ability to respond toward mechanical stimuli is a fundamental property of biological organisms at both the macroscopic and cellular levels, yet it has been considerably less observed in artificial supramolecular and colloidal homologues. An archetypal example in this regard is cellular mechanosensation, a process by which mechanical forces applied on the cell membrane are converted into biochemical or electrical signals through nanometer-scale changes in molecular conformations. In this article, we report an artificial gold nanoparticle (Au NP)-discrete π-conjugated molecule hybrid system that mimics the mechanical behavior of biological membranes and is able to self-assemble into colloidal gold nanoclusters or membranes in a controlled and reversible fashion by changing the concentration or the mechanical force (pressure) applied. This has been achieved by rational design of a small π-conjugated thiolated molecule that controls, to a great extent, the hierarchy levels involved in Au NP clustering by enabling reversible, cooperative non-covalent (π-π, solvophobic, and hydrogen bonding) interactions. In addition, the Au NP membranes have the ability to entrap and release aromatic guest molecules reversibly (K b = 5.0 × 10 5 M -1 ) for several cycles when subjected to compression-expansion experiments, in close analogy to the behavior of cellular mechanosensitive channels. Not only does our hybrid system represent the first example of a reversible colloidal membrane, but it also can be controlled by a dynamic mechanical stimulus using a new supramolecular surface-pressure-controlled strategy. This approach holds great potential for the development of multiple colloidal assemblies within different research fields.

Multiaxial behavior of foams - Experiments and modeling

NASA Astrophysics Data System (ADS)

Maheo, Laurent; Guérard, Sandra; Rio, Gérard; Donnard, Adrien; Viot, Philippe

2015-09-01

Cellular materials are strongly related to pressure level inside the material. It is therefore important to use experiments which can highlight (i) the pressure-volume behavior, (ii) the shear-shape behavior for different pressure level. Authors propose to use hydrostatic compressive, shear and combined pressure-shear tests to determine cellular materials behavior. Finite Element Modeling must take into account these behavior specificities. Authors chose to use a behavior law with a Hyperelastic, a Viscous and a Hysteretic contributions. Specific developments has been performed on the Hyperelastic one by separating the spherical and the deviatoric part to take into account volume change and shape change characteristics of cellular materials.

Enantioselective cellular uptake of chiral semiconductor nanocrystals

NASA Astrophysics Data System (ADS)

Martynenko, I. V.; Kuznetsova, V. A.; Litvinov, I. K.; Orlova, A. O.; Maslov, V. G.; Fedorov, A. V.; Dubavik, A.; Purcell-Milton, F.; Gun'ko, Yu K.; Baranov, A. V.

2016-02-01

The influence of the chirality of semiconductor nanocrystals, CdSe/ZnS quantum dots (QDs) capped with L- and D-cysteine, on the efficiency of their uptake by living Ehrlich Ascite carcinoma cells is studied by spectral- and time-resolved fluorescence microspectroscopy. We report an evident enantioselective process where cellular uptake of the L-Cys QDs is almost twice as effective as that of the D-Cys QDs. This finding paves the way for the creation of novel approaches to control the biological properties and behavior of nanomaterials in living cells.

Memory in Microbes: Quantifying History-Dependent Behavior in a Bacterium

PubMed Central

Bischofs, Ilka; Price, Gavin; Keasling, Jay; Arkin, Adam P.

2008-01-01

Memory is usually associated with higher organisms rather than bacteria. However, evidence is mounting that many regulatory networks within bacteria are capable of complex dynamics and multi-stable behaviors that have been linked to memory in other systems. Moreover, it is recognized that bacteria that have experienced different environmental histories may respond differently to current conditions. These “memory” effects may be more than incidental to the regulatory mechanisms controlling acclimation or to the status of the metabolic stores. Rather, they may be regulated by the cell and confer fitness to the organism in the evolutionary game it participates in. Here, we propose that history-dependent behavior is a potentially important manifestation of memory, worth classifying and quantifying. To this end, we develop an information-theory based conceptual framework for measuring both the persistence of memory in microbes and the amount of information about the past encoded in history-dependent dynamics. This method produces a phenomenological measure of cellular memory without regard to the specific cellular mechanisms encoding it. We then apply this framework to a strain of Bacillus subtilis engineered to report on commitment to sporulation and degradative enzyme (AprE) synthesis and estimate the capacity of these systems and growth dynamics to ‘remember’ 10 distinct cell histories prior to application of a common stressor. The analysis suggests that B. subtilis remembers, both in short and long term, aspects of its cell history, and that this memory is distributed differently among the observables. While this study does not examine the mechanistic bases for memory, it presents a framework for quantifying memory in cellular behaviors and is thus a starting point for studying new questions about cellular regulation and evolutionary strategy. PMID:18324309

Virtual tissues in toxicology.

PubMed

Shah, Imran; Wambaugh, John

2010-02-01

New approaches are vital for efficiently evaluating human health risk of thousands of chemicals in commerce. In vitro models offer a high-throughput approach for assaying chemical-induced molecular and cellular changes; however, bridging these perturbations to in vivo effects across chemicals, dose, time, and species remains challenging. Technological advances in multiresolution imaging and multiscale simulation are making it feasible to reconstruct tissues in silico. In toxicology, these "virtual" tissues (VT) aim to predict histopathological outcomes from alterations of cellular phenotypes that are controlled by chemical-induced perturbations in molecular pathways. The behaviors of thousands of heterogeneous cells in tissues are simulated discretely using agent-based modeling (ABM), in which computational "agents" mimic cell interactions and cellular responses to the microenvironment. The behavior of agents is constrained by physical laws and biological rules derived from experimental evidence. VT extend compartmental physiologic models to simulate both acute insults as well as the chronic effects of low-dose exposure. Furthermore, agent behavior can encode the logic of signaling and genetic regulatory networks to evaluate the role of different pathways in chemical-induced injury. To extrapolate toxicity across species, chemicals, and doses, VT require four main components: (a) organization of prior knowledge on physiologic events to define the mechanistic rules for agent behavior, (b) knowledge on key chemical-induced molecular effects, including activation of stress sensors and changes in molecular pathways that alter the cellular phenotype, (c) multiresolution quantitative and qualitative analysis of histologic data to characterize and measure chemical-, dose-, and time-dependent physiologic events, and (d) multiscale, spatiotemporal simulation frameworks to effectively calibrate and evaluate VT using experimental data. This investigation presents the motivation, implementation, and application of VT with examples from hepatotoxicity and carcinogenesis.

Prior Cocaine Exposure Disrupts Extinction of Fear Conditioning

ERIC Educational Resources Information Center

Gugsa, Nishan; Schoenbaum, Geoffrey; Burke, Kathryn A.; Franz, Theresa M.

2006-01-01

Psychostimulant exposure has been shown to cause molecular and cellular changes in prefrontal cortex. It has been hypothesized that these drug-induced changes might affect the operation of prefrontal-limbic circuits, disrupting their normal role in controlling behavior and thereby leading to compulsive drug-seeking. To test this hypothesis, we…

Manipulating the antigen-specific immune response by the hydrophobicity of amphiphilic poly(γ-glutamic acid) nanoparticles.

PubMed

Shima, Fumiaki; Akagi, Takami; Uto, Tomofumi; Akashi, Mitsuru

2013-12-01

The new generation vaccines are safe but poorly immunogenic, and thus they require the use of adjuvants. However, conventional vaccine adjuvants fail to induce potent cellular immunity, and their toxicity and side-effects hinder the clinical use. Therefore, a vaccine adjuvant which is safe and can induce an antigen-specific cellular immunity-biased immune response is urgently required. In the development of nanoparticle-based vaccine adjuvants, the hydrophobicity is one of the most important factors. It could control the interaction between the encapsulated antigens and/or nanoparticles with immune cells. In this study, nanoparticles (NPs) composed of amphiphilic poly(γ-glutamic acid)-graft-L-phenylalanine ethyl ester (γ-PGA-Phe) with various grafting degrees of hydrophobic side chains were prepared to evaluate the effect of hydrophobicity of vaccine carriers on the antigen encapsulation behavior, cellular uptake, activation of dendritic cells (DCs), and induction of antigen-specific cellular immunity-biased immune responses. These NPs could efficiently encapsulate antigens, and the uptake amount of the encapsulated antigen by DCs was dependent on the hydrophobicity of γ-PGA-Phe NPs. Moreover, the activation potential of the DCs and the induction of antigen-specific cellular immunity were correlated with the hydrophobicity of γ-PGA-Phe NPs. By controlling the hydrophobicity of antigen-encapsulated γ-PGA-Phe NPs, the activation potential of DCs was able to manipulate about 5 to 30-hold than the conventional vaccine, and the cellular immunity was about 10 to 40-hold. These results suggest that the hydrophobicity of NPs is a key factor for changing the interaction between NPs and immune cells, and thus the induction of cellular immunity-biased immune response could be achieved by controlling the hydrophobicity of them. Copyright © 2013 Elsevier Ltd. All rights reserved.

Preface: cardiac control pathways: signaling and transport phenomena.

PubMed

Sideman, Samuel

2008-03-01

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

Emergent 1d Ising Behavior in AN Elementary Cellular Automaton Model

NASA Astrophysics Data System (ADS)

Kassebaum, Paul G.; Iannacchione, Germano S.

The fundamental nature of an evolving one-dimensional (1D) Ising model is investigated with an elementary cellular automaton (CA) simulation. The emergent CA simulation employs an ensemble of cells in one spatial dimension, each cell capable of two microstates interacting with simple nearest-neighbor rules and incorporating an external field. The behavior of the CA model provides insight into the dynamics of coupled two-state systems not expressible by exact analytical solutions. For instance, state progression graphs show the causal dynamics of a system through time in relation to the system's entropy. Unique graphical analysis techniques are introduced through difference patterns, diffusion patterns, and state progression graphs of the 1D ensemble visualizing the evolution. All analyses are consistent with the known behavior of the 1D Ising system. The CA simulation and new pattern recognition techniques are scalable (in both dimension, complexity, and size) and have many potential applications such as complex design of materials, control of agent systems, and evolutionary mechanism design.

Stem cell behavior on tailored porous oxide surface coatings.

PubMed

Lavenus, Sandrine; Poxson, David J; Ogievetsky, Nika; Dordick, Jonathan S; Siegel, Richard W

2015-07-01

Nanoscale surface topographies are known to have a profound influence on cell behavior, including cell guidance, migration, morphology, proliferation, and differentiation. In this study, we have observed the behavior of human mesenchymal stem cells cultured on a range of tailored porous SiO2 and TiO2 nanostructured surface coatings fabricated via glancing angle electron-beam deposition. By controlling the physical vapor deposition angle during fabrication, we could control systematically the deposited coating porosity, along with associated topographic features. Immunocytochemistry and image analysis quantitatively revealed the number of adherent cells, as well as their basic cellular morphology, on these surfaces. Signaling pathway studies showed that even with subtle changes in nanoscale surface structures, the behavior of mesenchymal stem cells was strongly influenced by the precise surface structures of these porous coatings. Copyright © 2015 Elsevier Ltd. All rights reserved.

Body weight, metabolism and clock genes

PubMed Central

2010-01-01

Biological rhythms are present in the lives of almost all organisms ranging from plants to more evolved creatures. These oscillations allow the anticipation of many physiological and behavioral mechanisms thus enabling coordination of rhythms in a timely manner, adaption to environmental changes and more efficient organization of the cellular processes responsible for survival of both the individual and the species. Many components of energy homeostasis exhibit circadian rhythms, which are regulated by central (suprachiasmatic nucleus) and peripheral (located in other tissues) circadian clocks. Adipocyte plays an important role in the regulation of energy homeostasis, the signaling of satiety and cellular differentiation and proliferation. Also, the adipocyte circadian clock is probably involved in the control of many of these functions. Thus, circadian clocks are implicated in the control of energy balance, feeding behavior and consequently in the regulation of body weight. In this regard, alterations in clock genes and rhythms can interfere with the complex mechanism of metabolic and hormonal anticipation, contributing to multifactorial diseases such as obesity and diabetes. The aim of this review was to define circadian clocks by describing their functioning and role in the whole body and in adipocyte metabolism, as well as their influence on body weight control and the development of obesity. PMID:20712885

Electronic platform for real-time multi-parametric analysis of cellular behavior post-exposure to single-walled carbon nanotubes

PubMed Central

Eldawud, Reem; Wagner, Alixandra; Dong, Chenbo; Rojansakul, Yon; Dinu, Cerasela Zoica

2016-01-01

Single-walled carbon nanotubes (SWCNTs) implementation in a variety of biomedical applications from bioimaging, to controlled drug delivery and cellular-directed alignment for muscle myofiber fabrication, has raised awareness of their potential toxicity. Nanotubes structural aspects which resemble asbestos, as well as their ability to induce cyto and genotoxicity upon interaction with biological systems by generating reactive oxygen species or inducing membrane damage, just to name a few, have led to focused efforts aimed to assess associated risks prior their user implementation. In this study, we employed a non-invasive and real-time electric cell impedance sensing (ECIS) platform to monitor behavior of lung epithelial cells upon exposure to a library of SWCNTs with user-defined physicochemical properties. Using the natural sensitivity of the cells, we evaluated SWCNT-induced cellular changes in relation to cell attachment, cell–cell interactions and cell viability respectively. Our methods have the potential to lead to the development of standardized assays for risk assessment of other nanomaterials as well as risk differentiation based on the nanomaterials surface chemistry, purity and agglomeration state. PMID:25913448

Fine tuning of Rac1 and RhoA alters cuspal shapes by remolding the cellular geometry

PubMed Central

Li, Liwen; Tang, Qinghuang; Nakamura, Takashi; Suh, Jun-Gyo; Ohshima, Hayato; Jung, Han-Sung

2016-01-01

The anatomic and functional combinations of cusps and lophs (ridges) define the tooth shape of rodent molars, which distinguishes species. The species-specific cusp patterns result from the spatiotemporal induction of enamel knots (EKs), which require precisely controlled cellular behavior to control the epithelial invagination. Despite the well-defined roles of EK in cusp patterning, the determinants of the ultimate cuspal shapes and involvement of epithelial cellular geometry are unknown. Using two typical tooth patterns, the lophodont in gerbils and the bunodont in mice, we showed that the cuspal shape is determined by the dental epithelium at the cap stage, whereas the cellular geometry in the inner dental epithelium (IDE) is correlated with the cuspal shape. Intriguingly, fine tuning Rac1 and RhoA interconvert cuspal shapes between two species by remolding the cellular geometry. Either inhibition of Rac1 or ectopic expression of RhoA could region-distinctively change the columnar shape of IDE cells in gerbils to drive invagination to produce cusps. Conversely, RhoA reduction in mice inhibited invagination and developed lophs. Furthermore, we found that Rac1 and RhoA modulate the choices of cuspal shape by coordinating adhesion junctions, actin distribution, and fibronectin localization to drive IDE invagination. PMID:27892530

Production, properties, and applications of hydrocolloid cellular solids.

PubMed

Nussinovitch, Amos

2005-02-01

Many common synthetic and edible materials are, in fact, cellular solids. When classifying the structure of cellular solids, a few variables, such as open vs. closed cells, flexible vs. brittle cell walls, cell-size distribution, cell-wall thickness, cell shape, the uniformity of the structure of the cellular solid and the different scales of length are taken into account. Compressive stress-strain relationships of most cellular solids can be easily identified according to their characteristic sigmoid shape, reflecting three deformation mechanisms: (i) elastic distortion under small strains, (ii) collapse and/or fracture of the cell walls, and (iii) densification. Various techniques are used to produce hydrocolloid (gum) cellular solids. The products of these include (i) sponges, obtained when the drying gel contains the occasionally produced gas bubbles; (ii) sponges produced by the immobilization of microorganisms; (iii) solid foams produced by drying foamed solutions or gels containing oils, and (iv) hydrocolloid sponges produced by enzymatic reactions. The porosity of the manufactured cellular solid is subject to change and depends on its composition and the processing technique. The porosity is controlled by a range of methods and the resulting surface structures can be investigated by microscopy and analyzed using fractal methods. Models used to describe stress-strain behaviors of hydrocolloid cellular solids as well as multilayered products and composites are discussed in detail in this manuscript. Hydrocolloid cellular solids have numerous purposes, simple and complex, ranging from dried texturized fruits to carriers of vitamins and other essential micronutrients. They can also be used to control the acoustic response of specific dry food products, and have a great potential for future use in countless different fields, from novel foods and packaging to medicine and medical care, daily commodities, farming and agriculture, and the environmental, chemical, and even electronic industries.

Biobehavioral Influences on Cancer Progression

PubMed Central

Costanzo, Erin S.; Sood, Anil K.; Lutgendorf, Susan K.

2010-01-01

Synopsis This review focuses on the contributions of stress-related behavioral factors to cancer growth and metastasis and the biobehavioral mechanisms underlying these relationships. We describe behavioral factors that are important in modulation of the stress response and the pivotal role of neuroendocrine regulation in the downstream alteration of physiological pathways relevant to cancer control, including the cellular immune response, inflammation, and tumor angiogenesis, invasion, and cell-signaling pathways. Consequences for cancer progression and metastasis, as well as quality of life, are delineated. Finally, behavioral and pharmacological interventions for cancer patients with the potential to alter these biobehavioral pathways are discussed. PMID:21094927

Patient-derived iPSCs show premature neural differentiation and neuron-type specific phenotypes relevant to neurodevelopment

PubMed Central

Yeh, Erika; Dao, Dang Q.; Wu, Zhi Y.; Kandalam, Santoshi M.; Camacho, Federico M.; Tom, Curtis; Zhang, Wandong; Krencik, Robert; Rauen, Katherine A.; Ullian, Erik M.; Weiss, Lauren A.

2017-01-01

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events. PMID:29158583

The effects of carbon nanotubes on lung and dermal cellular behaviors

PubMed Central

Luanpitpong, Sudjit; Wang, Liying; Rojanasakul, Yon

2016-01-01

Carbon nanotubes (CNTs) hold great promise to create new and better products, but their adverse health effect is a major concern. Human exposure to CNTs is primarily through inhalation and dermal contact, especially during the manufacturing and handling processes. Numerous animal studies have demonstrated the potential pulmonary and dermal hazards associated with CNT exposure, while in vitro studies have assessed the effects of CNT exposure on various cellular behaviors and have been used to perform mechanistic studies. In this review, we provide an overview of the pathological effects of CNTs and examine the acute and chronic effects of CNT exposure on lung and dermal cellular behaviors, beyond the generally discussed cytotoxicity. We then examine the linkage of cellular behaviors and disease pathogenesis, and discuss the pertinent mechanisms. PMID:24981653

Differential regulation of striatal motor behavior and related cellular responses by dopamine D2L and D2S isoforms.

PubMed

Radl, Daniela; Chiacchiaretta, Martina; Lewis, Robert G; Brami-Cherrier, Karen; Arcuri, Ludovico; Borrelli, Emiliana

2018-01-02

The dopamine D2 receptor (D2R) is a major component of the dopamine system. D2R-mediated signaling in dopamine neurons is involved in the presynaptic regulation of dopamine levels. Postsynaptically, i.e., in striatal neurons, D2R signaling controls complex functions such as motor activity through regulation of cell firing and heterologous neurotransmitter release. The presence of two isoforms, D2L and D2S, which are generated by a mechanism of alternative splicing of the Drd2 gene, raises the question of whether both isoforms may equally control presynaptic and postsynaptic events. Here, we addressed this question by comparing behavioral and cellular responses of mice with the selective ablation of either D2L or D2S isoform. We establish that the presence of either D2L or D2S can support postsynaptic functions related to the control of motor activity in basal conditions. On the contrary, absence of D2S but not D2L prevents the inhibition of tyrosine hydroxylase phosphorylation and, thereby, of dopamine synthesis, supporting a major presynaptic role for D2S. Interestingly, boosting dopamine signaling in the striatum by acute cocaine administration reveals that absence of D2L, but not of D2S, strongly impairs the motor and cellular response to the drug, in a manner similar to the ablation of both isoforms. These results suggest that when the dopamine system is challenged, D2L signaling is required for the control of striatal circuits regulating motor activity. Thus, our findings show that D2L and D2S share similar functions in basal conditions but not in response to stimulation of the dopamine system.

NASA space biology accomplishments, 1983-84

NASA Technical Reports Server (NTRS)

Halstead, T. W.; Dutcher, F. R.; Pleasant, L. G.

1984-01-01

Approximately 42 project summaries from NASA's Space Biology Program are presented. Emphasis is placed on gravitational effects on plant and animal life. The identification of gravity perception; the effects of weightlessness on genetic integrity, cellular differentiation, reproduction, development, growth, maturation, and senescence; and how gravity affects and controls physiology, morphology, and behavior of organisms are studied.

Biomolecular engineering of intracellular switches in eukaryotes

PubMed Central

Pastuszka, M.K.; Mackay, J.A.

2010-01-01

Tools to selectively and reversibly control gene expression are useful to study and model cellular functions. When optimized, these cellular switches can turn a protein's function “on” and “off” based on cues designated by the researcher. These cues include small molecules, drugs, hormones, and even temperature variations. Here we review three distinct areas in gene expression that are commonly targeted when designing cellular switches. Transcriptional switches target gene expression at the level of mRNA polymerization, with examples including the tetracycline gene induction system as well as nuclear receptors. Translational switches target the process of turning the mRNA signal into protein, with examples including riboswitches and RNA interference. Post-translational switches control how proteins interact with one another to attenuate or relay signals. Examples of post-translational modification include dimerization and intein splicing. In general, the delay times between switch and effect decreases from transcription to translation to post-translation; furthermore, the fastest switches may offer the most elegant opportunities to influence and study cell behavior. We discuss the pros and cons of these strategies, which directly influence their usefulness to study and implement drug targeting at the tissue and cellular level. PMID:21209849

Cellular membrane trafficking of mesoporous silica nanoparticles

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

Fang, I-Ju

This dissertation mainly focuses on the investigation of the cellular membrane trafficking of mesoporous silica nanoparticles. We are interested in the study of endocytosis and exocytosis behaviors of mesoporous silica nanoparticles with desired surface functionality. The relationship between mesoporous silica nanoparticles and membrane trafficking of cells, either cancerous cells or normal cells was examined. Since mesoporous silica nanoparticles were applied in many drug delivery cases, the endocytotic efficiency of mesoporous silica nanoparticles needs to be investigated in more details in order to design the cellular drug delivery system in the controlled way. It is well known that cells can engulfmore » some molecules outside of the cells through a receptor-ligand associated endocytosis. We are interested to determine if those biomolecules binding to cell surface receptors can be utilized on mesoporous silica nanoparticle materials to improve the uptake efficiency or govern the mechanism of endocytosis of mesoporous silica nanoparticles. Arginine-glycine-aspartate (RGD) is a small peptide recognized by cell integrin receptors and it was reported that avidin internalization was highly promoted by tumor lectin. Both RGD and avidin were linked to the surface of mesoporous silica nanoparticle materials to investigate the effect of receptor-associated biomolecule on cellular endocytosis efficiency. The effect of ligand types, ligand conformation and ligand density were discussed in Chapter 2 and 3. Furthermore, the exocytosis of mesoporous silica nanoparticles is very attractive for biological applications. The cellular protein sequestration study of mesoporous silica nanoparticles was examined for further information of the intracellular pathway of endocytosed mesoporous silica nanoparticle materials. The surface functionality of mesoporous silica nanoparticle materials demonstrated selectivity among the materials and cancer and normal cell lines. We aimed to determine the specific organelle that mesoporous silica nanoparticles could approach via the identification of harvested proteins from exocytosis process. Based on the study of endo- and exocytosis behavior of mesoporous silica nanoparticle materials, we can design smarter drug delivery vehicles for cancer therapy that can be effectively controlled. The destination, uptake efficiency and the cellular distribution of mesoporous silica nanoparticle materials can be programmable. As a result, release mechanism and release rate of drug delivery systems can be a well-controlled process. The deep investigation of an endo- and exocytosis study of mesoporous silica nanoparticle materials promotes the development of drug delivery applications.« less

Cellular Analogs of Operant Behavior.

DTIC Science & Technology

1992-07-31

confirmed at the behavioral level in parallel studies of hippocampal and intravenous self-administration. The results are consistent with the hypothesis...research is to elucidate the cellular reinforcement mechanisms underlying goal-directed or operant behavior. The specific aim here was to study the... studies and behavioral operant conditioning studies . Most of the research reported was initiated and completed in the present project period. Also

Control of cancer-related signal transduction networks

NASA Astrophysics Data System (ADS)

Albert, Reka

2013-03-01

Intra-cellular signaling networks are crucial to the maintenance of cellular homeostasis and for cell behavior (growth, survival, apoptosis, movement). Mutations or alterations in the expression of elements of cellular signaling networks can lead to incorrect behavioral decisions that could result in tumor development and/or the promotion of cell migration and metastasis. Thus, mitigation of the cascading effects of such dysregulations is an important control objective. My group at Penn State is collaborating with wet-bench biologists to develop and validate predictive models of various biological systems. Over the years we found that discrete dynamic modeling is very useful in molding qualitative interaction information into a predictive model. We recently demonstrated the effectiveness of network-based targeted manipulations on mitigating the disease T cell large granular lymphocyte (T-LGL) leukemia. The root of this disease is the abnormal survival of T cells which, after successfully fighting an infection, should undergo programmed cell death. We synthesized the relevant network of within-T-cell interactions from the literature, integrated it with qualitative knowledge of the dysregulated (abnormal) states of several network components, and formulated a Boolean dynamic model. The model indicated that the system possesses a steady state corresponding to the normal cell death state and a T-LGL steady state corresponding to the abnormal survival state. For each node, we evaluated the restorative manipulation consisting of maintaining the node in the state that is the opposite of its T-LGL state, e.g. knocking it out if it is overexpressed in the T-LGL state. We found that such control of any of 15 nodes led to the disappearance of the T-LGL steady state, leaving cell death as the only potential outcome from any initial condition. In four additional cases the probability of reaching the T-LGL state decreased dramatically, thus these nodes are also possible control targets. Our collaborators validated two of these predicted control mechanisms experimentally. Our work suggests that external control of a single node can be a fruitful therapeutic strategy.

Cellular and multicellular form and function.

PubMed

Liu, Wendy F; Chen, Christopher S

2007-11-10

Engineering artificial tissue constructs requires the appropriate spatial arrangement of cells within scaffolds. The introduction of microengineering tools to the biological community has provided a valuable set of techniques to manipulate the cellular environment, and to examine how cell structure affects cellular function. Using micropatterning techniques, investigators have found that the geometric presentation of cell-matrix adhesions are important regulators of various cell behaviors including cell growth, proliferation, differentiation, polarity and migration. Furthermore, the presence of neighboring cells in multicellular aggregates has a significant impact on the proliferative and differentiated state of cells. Using microengineering tools, it will now be possible to manipulate the various environmental factors for practical applications such as engineering tissue constructs with greater control over the physical structure and spatial arrangement of cells within their surrounding microenvironment.

A rationally designed six-residue swap generates comparability in the aggregation behavior of α-synuclein and β-synuclein.

PubMed

Roodveldt, Cintia; Andersson, August; De Genst, Erwin J; Labrador-Garrido, Adahir; Buell, Alexander K; Dobson, Christopher M; Tartaglia, Gian Gaetano; Vendruscolo, Michele

2012-11-06

The aggregation process of α-synuclein, a protein closely associated with Parkinson's disease, is highly sensitive to sequence variations. It is therefore of great importance to understand the factors that define the aggregation propensity of specific mutational variants as well as their toxic behavior in the cellular environment. In this context, we investigated the extent to which the aggregation behavior of α-synuclein can be altered to resemble that of β-synuclein, an aggregation-resistant homologue of α-synuclein not associated with disease, by swapping residues between the two proteins. Because of the vast number of possible swaps, we have applied a rational design procedure to single out a mutational variant, called α2β, in which two short stretches of the sequence in the NAC region have been replaced in α-synuclein from β-synuclein. We find not only that the aggregation rate of α2β is close to that of β-synuclein, being much lower than that of α-synuclein, but also that α2β effectively changes the cellular toxicity of α-synuclein to a value similar to that of β-synuclein upon exposure of SH-SY5Y cells to preformed oligomers. Remarkably, control experiments on the corresponding mutational variant of β-synuclein, called β2α, confirmed that the mutations that we have identified also shift the aggregation behavior of this protein toward that of α-synuclein. These results demonstrate that it is becoming possible to control in quantitative detail the sequence code that defines the aggregation behavior and toxicity of α-synuclein.

Core Principles of Bacterial Autoinducer Systems

PubMed Central

2015-01-01

SUMMARY Autoinduction (AI), the response to self-produced chemical signals, is widespread in the bacterial world. This process controls vastly different target functions, such as luminescence, nutrient acquisition, and biofilm formation, in different ways and integrates additional environmental and physiological cues. This diversity raises questions about unifying principles that underlie all AI systems. Here, we suggest that such core principles exist. We argue that the general purpose of AI systems is the homeostatic control of costly cooperative behaviors, including, but not limited to, secreted public goods. First, costly behaviors require preassessment of their efficiency by cheaper AI signals, which we encapsulate in a hybrid “push-pull” model. The “push” factors cell density, diffusion, and spatial clustering determine when a behavior becomes effective. The relative importance of each factor depends on each species' individual ecological context and life history. In turn, “pull” factors, often stress cues that reduce the activation threshold, determine the cellular demand for the target behavior. Second, control is homeostatic because AI systems, either themselves or through accessory mechanisms, not only initiate but also maintain the efficiency of target behaviors. Third, AI-controlled behaviors, even seemingly noncooperative ones, are generally cooperative in nature, when interpreted in the appropriate ecological context. The escape of individual cells from biofilms, for example, may be viewed as an altruistic behavior that increases the fitness of the resident population by reducing starvation stress. The framework proposed here helps appropriately categorize AI-controlled behaviors and allows for a deeper understanding of their ecological and evolutionary functions. PMID:25694124

Advances in molecular labeling, high throughput imaging and machine intelligence portend powerful functional cellular biochemistry tools.

PubMed

Price, Jeffrey H; Goodacre, Angela; Hahn, Klaus; Hodgson, Louis; Hunter, Edward A; Krajewski, Stanislaw; Murphy, Robert F; Rabinovich, Andrew; Reed, John C; Heynen, Susanne

2002-01-01

Cellular behavior is complex. Successfully understanding systems at ever-increasing complexity is fundamental to advances in modern science and unraveling the functional details of cellular behavior is no exception. We present a collection of prospectives to provide a glimpse of the techniques that will aid in collecting, managing and utilizing information on complex cellular processes via molecular imaging tools. These include: 1) visualizing intracellular protein activity with fluorescent markers, 2) high throughput (and automated) imaging of multilabeled cells in statistically significant numbers, and 3) machine intelligence to analyze subcellular image localization and pattern. Although not addressed here, the importance of combining cell-image-based information with detailed molecular structure and ligand-receptor binding models cannot be overlooked. Advanced molecular imaging techniques have the potential to impact cellular diagnostics for cancer screening, clinical correlations of tissue molecular patterns for cancer biology, and cellular molecular interactions for accelerating drug discovery. The goal of finally understanding all cellular components and behaviors will be achieved by advances in both instrumentation engineering (software and hardware) and molecular biochemistry. Copyright 2002 Wiley-Liss, Inc.

Transient expression of protein tyrosine phosphatases encoded in Cotesia plutellae bracovirus inhibits insect cellular immune responses

NASA Astrophysics Data System (ADS)

Ibrahim, Ahmed M. A.; Kim, Yonggyun

2008-01-01

Several immunosuppressive factors are associated with parasitism of an endoparasitoid wasp, Cotesia plutellae, on the diamondback moth, Plutella xylostella. C. plutellae bracovirus (CpBV) encodes a large number of putative protein tyrosine phosphatases (PTPs), which may play a role in inhibiting host cellular immunity. To address this inhibitory hypothesis of CpBV-PTPs, we performed transient expression of individual CpBV-PTPs in hemocytes of the beet armyworm, Spodoptera exigua, and analyzed their cellular immune responses. Two different forms of CpBV-PTPs were chosen and cloned into a eukaryotic expression vector under the control of the p10 promoter of baculovirus: one with the normal cysteine active site (CpBV-PTP1) and the other with a mutated active site (CpBV-PTP5). The hemocytes transfected with CpBV-PTP1 significantly increased in PTP activity compared to control hemocytes, but those with CpBV-PTP5 exhibited a significant decrease in the PTP activity. All transfected hemocytes exhibited a significant reduction in both cell spreading and encapsulation activities compared to control hemocytes. Co-transfection of CpBV-PTP1 together with its double-stranded RNA reduced the messenger RNA (mRNA) level of CpBV-PTP1 and resulted in recovery of both hemocyte behaviors. This is the first report demonstrating that the polydnaviral PTPs can manipulate PTP activity of the hemocytes to interrupt cellular immune responses.

Investigating the interplay between substrate stiffness and ligand chemistry in directing mesenchymal stem cell differentiation within 3D macro-porous substrates.

PubMed

Haugh, Matthew G; Vaughan, Ted J; Madl, Christopher M; Raftery, Rosanne M; McNamara, Laoise M; O'Brien, Fergal J; Heilshorn, Sarah C

2018-07-01

Dimensionality can have a profound impact on stiffness-mediated differentiation of mesenchymal stem cells (MSCs). However, while we have begun to understand cellular response when encapsulated within 3D substrates, the behavior of cells within macro-porous substrates is relatively underexplored. The goal of this study was to determine the influence of macro-porous topographies on stiffness-mediated differentiation of MSCs. We developed macro-porous recombinant elastin-like protein (ELP) substrates that allow independent control of mechanical properties and ligand chemistry. We then used computational modeling to probe the impact of pore topography on the mechanical stimulus that cells are exposed to within these substrates, and finally we investigated stiffness induced biases towards adipogenic and osteogenic differentiation of MSCs within macro-porous substrates. Computational modeling revealed that there is significant heterogeneity in the mechanical stimuli that cells are exposed to within porous substrates and that this heterogeneity is predominantly due to the wide range of possible cellular orientations within the pores. Surprisingly, MSCs grown within 3D porous substrates respond to increasing substrate stiffness by up-regulating both osteogenesis and adipogenesis. These results demonstrate that within porous substrates the behavior of MSCs diverges from previously observed responses to substrate stiffness, emphasizing the importance of topography as a determinant of cellular behavior. Copyright © 2018 Elsevier Ltd. All rights reserved.

Distinct Domains of CheA Confer Unique Functions in Chemotaxis and Cell Length in Azospirillum brasilense Sp7.

PubMed

Gullett, Jessica M; Bible, Amber; Alexandre, Gladys

2017-07-01

Chemotaxis is the movement of cells in response to gradients of diverse chemical cues. Motile bacteria utilize a conserved chemotaxis signal transduction system to bias their motility and navigate through a gradient. A central regulator of chemotaxis is the histidine kinase CheA. This cytoplasmic protein interacts with membrane-bound receptors, which assemble into large polar arrays, to propagate the signal. In the alphaproteobacterium Azospirillum brasilense , Che1 controls transient increases in swimming speed during chemotaxis, but it also biases the cell length at division. However, the exact underlying molecular mechanisms for Che1-dependent control of multiple cellular behaviors are not known. Here, we identify specific domains of the CheA1 histidine kinase implicated in modulating each of these functions. We show that CheA1 is produced in two isoforms: a membrane-anchored isoform produced as a fusion with a conserved seven-transmembrane domain of unknown function (TMX) at the N terminus and a soluble isoform similar to prototypical CheA. Site-directed and deletion mutagenesis combined with behavioral assays confirm the role of CheA1 in chemotaxis and implicate the TMX domain in mediating changes in cell length. Fluorescence microscopy further reveals that the membrane-anchored isoform is distributed around the cell surface while the soluble isoform localizes at the cell poles. Together, the data provide a mechanism for the role of Che1 in controlling multiple unrelated cellular behaviors via acquisition of a new domain in CheA1 and production of distinct functional isoforms. IMPORTANCE Chemotaxis provides a significant competitive advantage to bacteria in the environment, and this function has been transferred laterally multiple times, with evidence of functional divergence in different genomic contexts. The molecular principles that underlie functional diversification of chemotaxis in various genomic contexts are unknown. Here, we provide a molecular mechanism by which a single CheA protein controls two unrelated functions: chemotaxis and cell length. Acquisition of this multifunctionality is seemingly a recent evolutionary event. The findings illustrate a mechanism by which chemotaxis function may be co-opted to regulate additional cellular functions. Copyright © 2017 American Society for Microbiology.

Distinct Domains of CheA Confer Unique Functions in Chemotaxis and Cell Length in Azospirillum brasilense Sp7

PubMed Central

Gullett, Jessica M.

2017-01-01

ABSTRACT Chemotaxis is the movement of cells in response to gradients of diverse chemical cues. Motile bacteria utilize a conserved chemotaxis signal transduction system to bias their motility and navigate through a gradient. A central regulator of chemotaxis is the histidine kinase CheA. This cytoplasmic protein interacts with membrane-bound receptors, which assemble into large polar arrays, to propagate the signal. In the alphaproteobacterium Azospirillum brasilense, Che1 controls transient increases in swimming speed during chemotaxis, but it also biases the cell length at division. However, the exact underlying molecular mechanisms for Che1-dependent control of multiple cellular behaviors are not known. Here, we identify specific domains of the CheA1 histidine kinase implicated in modulating each of these functions. We show that CheA1 is produced in two isoforms: a membrane-anchored isoform produced as a fusion with a conserved seven-transmembrane domain of unknown function (TMX) at the N terminus and a soluble isoform similar to prototypical CheA. Site-directed and deletion mutagenesis combined with behavioral assays confirm the role of CheA1 in chemotaxis and implicate the TMX domain in mediating changes in cell length. Fluorescence microscopy further reveals that the membrane-anchored isoform is distributed around the cell surface while the soluble isoform localizes at the cell poles. Together, the data provide a mechanism for the role of Che1 in controlling multiple unrelated cellular behaviors via acquisition of a new domain in CheA1 and production of distinct functional isoforms. IMPORTANCE Chemotaxis provides a significant competitive advantage to bacteria in the environment, and this function has been transferred laterally multiple times, with evidence of functional divergence in different genomic contexts. The molecular principles that underlie functional diversification of chemotaxis in various genomic contexts are unknown. Here, we provide a molecular mechanism by which a single CheA protein controls two unrelated functions: chemotaxis and cell length. Acquisition of this multifunctionality is seemingly a recent evolutionary event. The findings illustrate a mechanism by which chemotaxis function may be co-opted to regulate additional cellular functions. PMID:28416707

Rational Design of Semiconductor Nanostructures for Functional Subcellular Interfaces.

PubMed

Parameswaran, Ramya; Tian, Bozhi

2018-05-15

One of the fundamental questions guiding research in the biological sciences is how cellular systems process complex physical and environmental cues and communicate with each other across multiple length scales. Importantly, aberrant signal processing in these systems can lead to diseases that can have devastating impacts on human lives. Biophysical studies in the past several decades have demonstrated that cells can respond to not only biochemical cues but also mechanical and electrical ones. Thus, the development of new materials that can both sense and modulate all of these pathways is necessary. Semiconducting nanostructures are an emerging class of discovery platforms and tools that can push the limits of our ability to modulate and sense biological behaviors for both fundamental research and clinical applications. These materials are of particular interest for interfacing with cellular systems due to their matched dimension with subcellular components (e.g., cytoskeletal filaments), and easily tunable properties in the electrical, optical and mechanical regimes. Rational design via traditional or new approaches, such as nanocasting and mesoscale chemical lithography, can allow us to control micro- and nanoscale features in nanowires to achieve new biointerfaces. Both processes endogenous to the target cell and properties of the material surface dictate the character of these interfaces. In this Account, we focus on (1) approaches for the rational design of semiconducting nanowires that exhibit unique structures for biointerfaces, (2) recent fundamental discoveries that yield robust biointerfaces at the subcellular level, (3) intracellular electrical and mechanical sensing, and (4) modulation of cellular behaviors through material topography and remote physical stimuli. In the first section, we discuss new approaches for the synthetic control of micro- and nanoscale features of these materials. In the second section, we focus on achieving biointerfaces with these rationally designed materials either intra- or extracellularly. We last delve into the use of these materials in sensing mechanical forces and electrical signals in various cellular systems as well as in instructing cellular behaviors. Future research in this area may shift the paradigm in fundamental biophysical research and biomedical applications through (1) the design and synthesis of new semiconductor-based materials and devices that interact specifically with targeted cells, (2) the clarification of many developmental, physiological, and anatomical aspects of cellular communications, (3) an understanding of how signaling between cells regulates synaptic development (e.g., information like this would offer new insight into how the nervous system works and provide new targets for the treatment of neurological diseases), (4) and the creation of new cellular materials that have the potential to open up completely new areas of application, such as in hybrid information processing systems.

Living Toroids - Cells on Toroidal Surfaces

NASA Astrophysics Data System (ADS)

Chang, Ya-Wen; Angelini, Thomas; Marquez, Samantha; Kim, Harold; Fernandez-Nieves, Alberto

2014-03-01

Cellular environment influences a multitude of cellular functions by providing chemical and physical signals that modulate cell behavior, dynamics, development, and eventually survival. Substrate mechanics has been recognized as one of the important physical cues that governs cell behavior at single cell level as well as in collective cell motion. Past research has suggested several contact-guided behaviors to be the result of surface curvature. However, studies on the effect of curvature are relatively scarce likely due to the difficulty in generating substrates with well-defined curvature. Here we describe the generation of toroidal droplets, which unlike spherical droplets, have regions of both positive and negative Gaussian curvature. Additionally, the range of curvatures can be controlled by varying the size and aspect ratio of the torus. Cells are either encapsulated inside toroidal droplets or located on toroidal hydrogel surfaces. Preliminary studies use B. Subtilis to study the organization of bacteria biofilms. When confined in droplets surrounded by yield-stress fluid, bacteria self-organize into heterogeneous biofilm at fluid- substrate interface. It is found that the surface curvature in the sub-millimeter scale has little effect on biofilm architecture.

Fracture mechanics of cellular glass

NASA Technical Reports Server (NTRS)

Zwissler, J. G.; Adams, M. A.

1981-01-01

The fracture mechanics of cellular glasses (for the structural substrate of mirrored glass for solr concentrator reflecting panels) are discussed. Commercial and developmental cellular glasses were tested and analyzed using standard testing techniques and models developed from linear fracture mechanics. Two models describing the fracture behavior of these materials were developed. Slow crack growth behavior in cellular glass was found to be more complex than that encountered in dense glasses or ceramics. The crack velocity was found to be strongly dependent upon water vapor transport to the tip of the moving crack. The existence of a static fatigue limit was not conclusively established, however, it is speculated that slow crack growth behavior in Region 1 may be slower, by orders of magnitude, than that found in dense glasses.

Micromechanics of Amorphous Metal/Polymer Hybrid Structures with 3D Cellular Architectures: Size Effects, Buckling Behavior, and Energy Absorption Capability.

PubMed

Mieszala, Maxime; Hasegawa, Madoka; Guillonneau, Gaylord; Bauer, Jens; Raghavan, Rejin; Frantz, Cédric; Kraft, Oliver; Mischler, Stefano; Michler, Johann; Philippe, Laetitia

2017-02-01

By designing advantageous cellular geometries and combining the material size effects at the nanometer scale, lightweight hybrid microarchitectured materials with tailored structural properties are achieved. Prior studies reported the mechanical properties of high strength cellular ceramic composites, obtained by atomic layer deposition. However, few studies have examined the properties of similar structures with metal coatings. To determine the mechanical performance of polymer cellular structures reinforced with a metal coating, 3D laser lithography and electroless deposition of an amorphous layer of nickel-boron (NiB) is used for the first time to produce metal/polymer hybrid structures. In this work, the mechanical response of microarchitectured structures is investigated with an emphasis on the effects of the architecture and the amorphous NiB thickness on their deformation mechanisms and energy absorption capability. Microcompression experiments show an enhancement of the mechanical properties with the NiB thickness, suggesting that the deformation mechanism and the buckling behavior are controlled by the brittle-to-ductile transition in the NiB layer. In addition, the energy absorption properties demonstrate the possibility of tuning the energy absorption efficiency with adequate designs. These findings suggest that microarchitectured metal/polymer hybrid structures are effective in producing materials with unique property combinations. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cell phone data and travel behavior research: symposium summary report

DOT National Transportation Integrated Search

2014-07-01

This report summarizes the key themes from a symposium held on February 12, 2014, to discuss opportunities and challenges using cellular location data for national travel behavior analysis. Participants discussed the availability of cellular data and...

Cellular control lies in the balance of forces

NASA Technical Reports Server (NTRS)

Chicurel, M. E.; Chen, C. S.; Ingber, D. E.

1998-01-01

Mechanical tension generated within the cytoskeleton of living cells is emerging as a critical regulator of biological function in diverse situations ranging from the control of chromosome movement to the morphogenesis of the vertebrate brain. In this article, we review recent advances that have been made in terms of understanding how cells generate, transmit and sense mechanical tension, as well as how they use these forces to control their shape and behavior. An integrated view of cell regulation that incorporates mechanics and structure as well as chemistry is beginning to emerge.

Brushes, cables, and anchors: recent insights into multiscale assembly and mechanics of cellular structural networks.

PubMed

Lele, Tanmay P; Kumar, Sanjay

2007-01-01

The remarkable ability of living cells to sense, process, and respond to mechanical stimuli in their environment depends on the rapid and efficient interconversion of mechanical and chemical energy at specific times and places within the cell. For example, application of force to cells leads to conformational changes in specific mechanosensitive molecules which then trigger cellular signaling cascades that may alter cellular structure, mechanics, and migration and profoundly influence gene expression. Similarly, the sensitivity of cells to mechanical stresses is governed by the composition, architecture, and mechanics of the cellular cytoskeleton and extracellular matrix (ECM), which are in turn driven by molecular-scale forces between the constituent biopolymers. Understanding how these mechanochemical systems coordinate over multiple length and time scales to produce orchestrated cell behaviors represents a fundamental challenge in cell biology. Here, we review recent advances in our understanding of these complex processes in three experimental systems: the assembly of axonal neurofilaments, generation of tensile forces by actomyosin stress fiber bundles, and mechanical control of adhesion assembly.

Cerebellar learning properties are modulated by the CRF receptor in granular cells.

PubMed

Ezra-Nevo, Gili; Prestori, Francesca; Locatelli, Francesca; Soda, Teresa; Ten Brinke, Michiel M; Engel, Mareen; Boele, Henk-Jan; Botta, Laura; Leshkowitz, Dena; Ramot, Assaf; Tsoory, Michael; Biton, Inbal E; Deussing, Jan; D'Angelo, Egidio; De Zeeuw, Chris I; Chen, Alon

2018-06-22

Corticotropin-releasing factor (CRF) and its type 1 receptor (CRFR 1 ) play an important role in the responses to stressful challenges. Despite the well-established expression of CRFR 1 in granular cells (GrCs), its role in procedural motor performance and memory formation remains elusive. To investigate the role of CRFR 1 expression in cerebellar GrCs, we used a mouse model depleted of CRFR 1 in these cells. We detected changes in the cellular learning mechanisms in GrCs depleted of CRFR 1 in that they showed changes in intrinsic excitability and long-term synaptic plasticity. Moreover, male mice depleted of CRFR 1 specifically in GrCs showed accelerated Pavlovian associative eye-blink conditioning, but no differences in baseline motor performance, locomotion or fear and anxiety-related behaviors. Last, we analyzed cerebella transcriptome of KO and control mice and detected prominent alterations in the expression of calcium signaling pathways components. Our findings shed light on the interplay between stress-related central mechanisms and cerebellar motor conditioning, highlighting the role of the CRF system in regulating particular forms of cerebellar learning. SIGNIFICANCE STATEMENT Although it is known that CRFR 1 is highly expressed in the cerebellum, little attention has been given to its role in cerebellar functions in the behaving animal. Moreover, most of the attention was directed to the effect of CRF on Purkinje cells at the cellular level, and to this date, almost no data exist on the role of this stress-related receptor in other cerebellar structures. Here, we explored the behavioral and cellular effect of GrCs specific ablation of CRFR 1 We found a profound effect on learning, both at the cellular and behavioral levels, without affecting baseline motor skills. Copyright © 2018 the authors.

Polysaccharide-based hydrogels with tunable composition as 3D cell culture systems.

PubMed

Gentilini, Roberta; Munarin, Fabiola; Bloise, Nora; Secchi, Eleonora; Visai, Livia; Tanzi, Maria Cristina; Petrini, Paola

2018-04-01

To date, cell cultures have been created either on 2-dimensional (2D) polystyrene surfaces or in 3-dimensional (3D) systems, which do not offer a controlled chemical composition, and which lack the soft environment encountered in vivo and the chemical stimuli that promote cell proliferation and allow complex cellular behavior. In this study, pectin-based hydrogels were developed and are proposed as versatile cell culture systems. Pectin-based hydrogels were produced by internally crosslinking pectin with calcium carbonate at different initial pH, aiming to control crosslinking kinetics and degree. Additionally, glucose and glutamine were added as additives, and their effects on the viscoelastic properties of the hydrogels and on cell viability were investigated. Pectin hydrogels showed in high cell viability and shear-thinning behavior. Independently of hydrogel composition, an initial swelling was observed, followed by a low percentage of weight variation and a steady-state stage. The addition of glucose and glutamine to pectin-based hydrogels rendered higher cell viability up to 90%-98% after 1 hour of incubation, and these hydrogels were maintained for up to 7 days of culture, yet no effect on viscoelastic properties was detected. Pectin-based hydrogels that offer tunable composition were developed successfully. They are envisioned as synthetic extracellular matrix (ECM) either to study complex cellular behaviors or to be applied as tissue engineering substitutes.

In Search of Cellular Immunophenotypes in the Blood of Children with Autism

PubMed Central

Ashwood, Paul; Corbett, Blythe A.; Kantor, Aaron; Schulman, Howard; Van de Water, Judy; Amaral, David G.

2011-01-01

Background Autism is a neurodevelopmental disorder characterized by impairments in social behavior, communication difficulties and the occurrence of repetitive or stereotyped behaviors. There has been substantial evidence for dysregulation of the immune system in autism. Methods We evaluated differences in the number and phenotype of circulating blood cells in young children with autism (n = 70) compared with age-matched controls (n = 35). Children with a confirmed diagnosis of autism (4–6 years of age) were further subdivided into low (IQ<68, n = 35) or high functioning (IQ≥68, n = 35) groups. Age- and gender-matched typically developing children constituted the control group. Six hundred and forty four primary and secondary variables, including cell counts and the abundance of cell surface antigens, were assessed using microvolume laser scanning cytometry. Results There were multiple differences in immune cell populations between the autism and control groups. The absolute number of B cells per volume of blood was over 20% higher for children with autism and the absolute number of NK cells was about 40% higher. Neither of these variables showed significant difference between the low and high functioning autism groups. While the absolute number of T cells was not different across groups, a number of cellular activation markers, including HLA-DR and CD26 on T cells, and CD38 on B cells, were significantly higher in the autism group compared to controls. Conclusions These results support previous findings that immune dysfunction may occur in some children with autism. Further evaluation of the nature of the dysfunction and how it may play a role in the etiology of autism or in facets of autism neuropathology and/or behavior are needed. PMID:21573236

Ionic channels: natural nanotubes described by the drift diffusion equations

NASA Astrophysics Data System (ADS)

Eisenberg, Bob

2000-05-01

Ionic channels are a large class of proteins with holes down their middle that control a wide range of cellular functions important in health and disease. Ionic channels can be analysed using a combination of the Poisson and drift diffusion equations familiar from computational electronics because their behavior is dominated by the electrical properties of their simple structure.

A positional code and anisotropic forces control tissue remodeling in Drosophila

NASA Astrophysics Data System (ADS)

Zallen, Jennifer

A major challenge in developmental biology is to understand how tissue-scale changes in organism structure arise from events that occur on a cellular and molecular level. We are using cell biological, biophysical, and quantitative live-embryo imaging approaches to understand how genes encode the forces that shape tissues, and to identify the mechanisms that modulate cell behavior in response to local forces. In many animals, the elongated head-to-tail body axis is achieved by rapid and coordinated movements of hundreds of cells. We found that in the fruit fly, these cell movements are regulated by subcellular asymmetries in the localization of proteins that generate contractile and adhesive forces between cells. Asymmetries in the force-generating machinery are in turn controlled by a positional code of spatial information provided by an ancient family of Toll-related receptors that are widely used for pathogen recognition by the innate immune system. I will describe how this spatial system systematically orients local cell movements and collective rosette-like clusters in the Drosophila embryo. Rosettes have now also been shown to shape the body axis in chicks, frogs, and mice, demonstrating that rosette behaviors are a general mechanism linking cellular asymmetry to tissue reorganization.

Dynamic Manipulation of Hydrogels to Control Cell Behavior: A Review

PubMed Central

Vats, Kanika

2013-01-01

For many tissue engineering applications and studies to understand how materials fundamentally affect cellular functions, it is important to have the ability to synthesize biomaterials that can mimic elements of native cell–extracellular matrix interactions. Hydrogels possess many properties that are desirable for studying cell behavior. For example, hydrogels are biocompatible and can be biochemically and mechanically altered by exploiting the presentation of cell adhesive epitopes or by changing hydrogel crosslinking density. To establish physical and biochemical tunability, hydrogels can be engineered to alter their properties upon interaction with external driving forces such as pH, temperature, electric current, as well as exposure to cytocompatible irradiation. Additionally, hydrogels can be engineered to respond to enzymes secreted by cells, such as matrix metalloproteinases and hyaluronidases. This review details different strategies and mechanisms by which biomaterials, specifically hydrogels, can be manipulated dynamically to affect cell behavior. By employing the appropriate combination of stimuli and hydrogel composition and architecture, cell behavior such as adhesion, migration, proliferation, and differentiation can be controlled in real time. This three-dimensional control in cell behavior can help create programmable cell niches that can be useful for fundamental cell studies and in a variety of tissue engineering applications. PMID:23541134

Microengineering hydrogels for stem cell bioengineering and tissue regeneration.

PubMed

Wheeldon, Ian; Ahari, Amirhossein F; Khademhosseini, Ali

2010-12-01

The integration of microfabrication technologies with advanced biomaterials has led to the development of powerful tools to control the cellular microenvironment and the microarchitecture of engineered tissue constructs. Here we review this area, with a focus on the work accomplished in our laboratory. In particular, we discuss techniques to develop hydrogel microstructures for controlling cell aggregate formation to regulate stem cell behavior as well as a bottom-up and a top-down microengineering approach to creating biomimic tissue-like structures.

Microengineering hydrogels for stem cell bioengineering and tissue regeneration

PubMed Central

Wheeldon, Ian; Ahari, Amirhossein F.; Khademhosseini, Ali

2010-01-01

The integration of microfabrication technologies with advanced biomaterials has led to the development of powerful tools to control the cellular microenvironment and the microarchitecture of engineered tissue constructs. Here we review this area, with a focus on the work accomplished in our laboratory. In particular, we discuss techniques to develop hydrogel microstructures for controlling cell aggregate formation to regulate stem cell behavior as well as a bottom-up and a top-down microengineering approach to creating biomimic tissue-like structures. PMID:21344063

Convergence behavior of delayed discrete cellular neural network without periodic coefficients.

PubMed

Wang, Jinling; Jiang, Haijun; Hu, Cheng; Ma, Tianlong

2014-05-01

In this paper, we study convergence behaviors of delayed discrete cellular neural networks without periodic coefficients. Some sufficient conditions are derived to ensure all solutions of delayed discrete cellular neural network without periodic coefficients converge to a periodic function, by applying mathematical analysis techniques and the properties of inequalities. Finally, some examples showing the effectiveness of the provided criterion are given. Copyright © 2014 Elsevier Ltd. All rights reserved.

Algorithm for cellular reprogramming.

PubMed

Ronquist, Scott; Patterson, Geoff; Muir, Lindsey A; Lindsly, Stephen; Chen, Haiming; Brown, Markus; Wicha, Max S; Bloch, Anthony; Brockett, Roger; Rajapakse, Indika

2017-11-07

The day we understand the time evolution of subcellular events at a level of detail comparable to physical systems governed by Newton's laws of motion seems far away. Even so, quantitative approaches to cellular dynamics add to our understanding of cell biology. With data-guided frameworks we can develop better predictions about, and methods for, control over specific biological processes and system-wide cell behavior. Here we describe an approach for optimizing the use of transcription factors (TFs) in cellular reprogramming, based on a device commonly used in optimal control. We construct an approximate model for the natural evolution of a cell-cycle-synchronized population of human fibroblasts, based on data obtained by sampling the expression of 22,083 genes at several time points during the cell cycle. To arrive at a model of moderate complexity, we cluster gene expression based on division of the genome into topologically associating domains (TADs) and then model the dynamics of TAD expression levels. Based on this dynamical model and additional data, such as known TF binding sites and activity, we develop a methodology for identifying the top TF candidates for a specific cellular reprogramming task. Our data-guided methodology identifies a number of TFs previously validated for reprogramming and/or natural differentiation and predicts some potentially useful combinations of TFs. Our findings highlight the immense potential of dynamical models, mathematics, and data-guided methodologies for improving strategies for control over biological processes. Copyright © 2017 the Author(s). Published by PNAS.

Modeling oscillations and spiral waves in Dictyostelium populations

NASA Astrophysics Data System (ADS)

Noorbakhsh, Javad; Schwab, David J.; Sgro, Allyson E.; Gregor, Thomas; Mehta, Pankaj

2015-06-01

Unicellular organisms exhibit elaborate collective behaviors in response to environmental cues. These behaviors are controlled by complex biochemical networks within individual cells and coordinated through cell-to-cell communication. Describing these behaviors requires new mathematical models that can bridge scales—from biochemical networks within individual cells to spatially structured cellular populations. Here we present a family of "multiscale" models for the emergence of spiral waves in the social amoeba Dictyostelium discoideum. Our models exploit new experimental advances that allow for the direct measurement and manipulation of the small signaling molecule cyclic adenosine monophosphate (cAMP) used by Dictyostelium cells to coordinate behavior in cellular populations. Inspired by recent experiments, we model the Dictyostelium signaling network as an excitable system coupled to various preprocessing modules. We use this family of models to study spatially unstructured populations of "fixed" cells by constructing phase diagrams that relate the properties of population-level oscillations to parameters in the underlying biochemical network. We then briefly discuss an extension of our model that includes spatial structure and show how this naturally gives rise to spiral waves. Our models exhibit a wide range of novel phenomena. including a density-dependent frequency change, bistability, and dynamic death due to slow cAMP dynamics. Our modeling approach provides a powerful tool for bridging scales in modeling of Dictyostelium populations.

Physical probing of cells

NASA Astrophysics Data System (ADS)

Rehfeldt, Florian; Schmidt, Christoph F.

2017-11-01

In the last two decades, it has become evident that the mechanical properties of the microenvironment of biological cells are as important as traditional biochemical cues for the control of cellular behavior and fate. The field of cell and matrix mechanics is quickly growing and so is the development of the experimental approaches used to study active and passive mechanical properties of cells and their surroundings. Within this topical review we will provide a brief overview, on the one hand, over how cellular mechanics can be probed physically, how different geometries allow access to different cellular properties, and, on the other hand, how forces are generated in cells and transmitted to the extracellular environment. We will describe the following experimental techniques: atomic force microscopy, traction force microscopy, magnetic tweezers, optical stretcher and optical tweezers pointing out both their advantages and limitations. Finally, we give an outlook on the future of the physical probing of cells.

Integrative systems control approach for reactivating Kaposi's sarcoma-associated herpesvirus (KSHV) with combinatory drugs

PubMed Central

Sun, Chien-Pin; Usui, Takane; Yu, Fuqu; Al-Shyoukh, Ibrahim; Shamma, Jeff; Sun, Ren; Ho, Chih-Ming

2009-01-01

Cells serve as basic units of life and represent intricate biological molecular systems. The vast number of cellular molecules with their signaling and regulatory circuitries forms an intertwined network. In this network, each pathway interacts non-linearly with others through different intermediates. Thus, the challenge of manipulating cellular functions for desired outcomes, such as cancer eradication and controlling viral infection lies within the integrative system of regulatory circuitries. By using a closed-loop system control scheme, we can efficiently analyze biological signaling networks and manipulate their behavior through multiple stimulations on a collection of pathways. Specifically, we aimed to maximize the reactivation of Kaposi's Sarcoma-associated Herpesvirus (KSHV) in a Primary Effusion Lymphoma cell line. The advantage of this approach is that it is well-suited to study complex integrated systems; it circumvents the need for detailed information of individual signaling components; and it investigates the network as a whole by utilizing key systemic outputs as indicators. PMID:19851479

Integrative systems control approach for reactivating Kaposi's sarcoma-associated herpesvirus (KSHV) with combinatory drugs.

PubMed

Sun, Chien-Pin; Usui, Takane; Yu, Fuqu; Al-Shyoukh, Ibrahim; Shamma, Jeff; Sun, Ren; Ho, Chih-Ming

2009-01-01

Cells serve as basic units of life and represent intricate biological molecular systems. The vast number of cellular molecules with their signaling and regulatory circuitries forms an intertwined network. In this network, each pathway interacts non-linearly with others through different intermediates. Thus, the challenge of manipulating cellular functions for desired outcomes, such as cancer eradication and controlling viral infection lies within the integrative system of regulatory circuitries. By using a closed-loop system control scheme, we can efficiently analyze biological signaling networks and manipulate their behavior through multiple stimulations on a collection of pathways. Specifically, we aimed to maximize the reactivation of Kaposi's Sarcoma-associated Herpesvirus (KSHV) in a Primary Effusion Lymphoma cell line. The advantage of this approach is that it is well-suited to study complex integrated systems; it circumvents the need for detailed information of individual signaling components; and it investigates the network as a whole by utilizing key systemic outputs as indicators.

Effects of age and the use of hands-free cellular phones on driving behavior and task performance.

PubMed

Liu, Yung-Ching; Ou, Yang-Kun

2011-12-01

This study used a driving simulator to investigate the effect of using a Bluetooth hands-free cellular phone earpiece on the driving behavior of two age groups. Forty-eight participants (24 aged 20-26 and 24 aged 65-73) were examined to assess their performance on the following divided-attention tasks under 2 driving load conditions (high and low): (1) attempting to maintain the speed limit and (2) using a cellular phone while driving. The length of the call conversation (long vs. short) and the conversational content (complex vs. simple) were manipulated as within-subject independent variables. The driving behavior of the participants, their task reaction times and accuracy, and subjective ratings were collected as dependent variables. The results indicate that under low driving loads, short talk times, and simple conversational content, the driving behavior of the participants showed low variance in the vehicle's mean speed. In contrast, complex conversation had a significantly negative impact on driving behavior. Notably, under a low driving load, motorists' driving behaviors, measured in lateral acceleration, caused significantly smaller variance in complex conversations compared to no call and simple conversations. The use of a hands-free cellular phone affected the performance (acceleration, lane deviation, reaction time, and accuracy) of older drivers significantly more than younger drivers. While performing divided attention tasks, the accuracy of the older drivers was 66.3 percent and that of the younger drivers was 96.3 percent. Although this study did not find a clear impact of cellular phone use on the driving behavior of younger drivers, their divided-attention task reaction times and accuracy were better under no-call than calling conditions. This study indicates that the use of hands-free cellular phones could significantly affect the safety of driving among the older and present risks, although lesser, for younger drivers.

Entrainment and Control of Bacterial Populations: An in Silico Study over a Spatially Extended Agent Based Model.

PubMed

Mina, Petros; Tsaneva-Atanasova, Krasimira; Bernardo, Mario di

2016-07-15

We extend a spatially explicit agent based model (ABM) developed previously to investigate entrainment and control of the emergent behavior of a population of synchronized oscillating cells in a microfluidic chamber. Unlike most of the work in models of control of cellular systems which focus on temporal changes, we model individual cells with spatial dependencies which may contribute to certain behavioral responses. We use the model to investigate the response of both open loop and closed loop strategies, such as proportional control (P-control), proportional-integral control (PI-control) and proportional-integral-derivative control (PID-control), to heterogeinities and growth in the cell population, variations of the control parameters and spatial effects such as diffusion in the spatially explicit setting of a microfluidic chamber setup. We show that, as expected from the theory of phase locking in dynamical systems, open loop control can only entrain the cell population in a subset of forcing periods, with a wide variety of dynamical behaviors obtained outside these regions of entrainment. Closed-loop control is shown instead to guarantee entrainment in a much wider region of control parameter space although presenting limitations when the population size increases over a certain threshold. In silico tracking experiments are also performed to validate the ability of classical control approaches to achieve other reference behaviors such as a desired constant output or a linearly varying one. All simulations are carried out in BSim, an advanced agent-based simulator of microbial population which is here extended ad hoc to include the effects of control strategies acting onto the population.

Role of cellular adhesions in tissue dynamics spectroscopy

NASA Astrophysics Data System (ADS)

Merrill, Daniel A.; An, Ran; Turek, John; Nolte, David

2014-02-01

Cellular adhesions play a critical role in cell behavior, and modified expression of cellular adhesion compounds has been linked to various cancers. We tested the role of cellular adhesions in drug response by studying three cellular culture models: three-dimensional tumor spheroids with well-developed cellular adhesions and extracellular matrix (ECM), dense three-dimensional cell pellets with moderate numbers of adhesions, and dilute three-dimensional cell suspensions in agarose having few adhesions. Our technique for measuring the drug response for the spheroids and cell pellets was biodynamic imaging (BDI), and for the suspensions was quasi-elastic light scattering (QELS). We tested several cytoskeletal chemotherapeutic drugs (nocodazole, cytochalasin-D, paclitaxel, and colchicine) on three cancer cell lines chosen from human colorectal adenocarcinoma (HT-29), human pancreatic carcinoma (MIA PaCa-2), and rat osteosarcoma (UMR-106) to exhibit differences in adhesion strength. Comparing tumor spheroid behavior to that of cell suspensions showed shifts in the spectral motion of the cancer tissues that match predictions based on different degrees of cell-cell contacts. The HT-29 cell line, which has the strongest adhesions in the spheroid model, exhibits anomalous behavior in some cases. These results highlight the importance of using three-dimensional tissue models in drug screening with cellular adhesions being a contributory factor in phenotypic differences between the drug responses of tissue and cells.

Fibrous Hydrogels for Cell Encapsulation: A Modular and Supramolecular Approach.

PubMed

Włodarczyk-Biegun, Małgorzata K; Farbod, Kambiz; Werten, Marc W T; Slingerland, Cornelis J; de Wolf, Frits A; van den Beucken, Jeroen J J P; Leeuwenburgh, Sander C G; Cohen Stuart, Martien A; Kamperman, Marleen

2016-01-01

Artificial 3-dimensional (3D) cell culture systems, which mimic the extracellular matrix (ECM), hold great potential as models to study cellular processes under controlled conditions. The natural ECM is a 3D structure composed of a fibrous hydrogel that provides both mechanical and biochemical cues to instruct cell behavior. Here we present an ECM-mimicking genetically engineered protein-based hydrogel as a 3D cell culture system that combines several key features: (1) Mild and straightforward encapsulation meters (1) ease of ut I am not so sure.encapsulation of the cells, without the need of an external crosslinker. (2) Supramolecular assembly resulting in a fibrous architecture that recapitulates some of the unique mechanical characteristics of the ECM, i.e. strain-stiffening and self-healing behavior. (3) A modular approach allowing controlled incorporation of the biochemical cue density (integrin binding RGD domains). We tested the gels by encapsulating MG-63 osteoblastic cells and found that encapsulated cells not only respond to higher RGD density, but also to overall gel concentration. Cells in 1% and 2% (weight fraction) protein gels showed spreading and proliferation, provided a relative RGD density of at least 50%. In contrast, in 4% gels very little spreading and proliferation occurred, even for a relative RGD density of 100%. The independent control over both mechanical and biochemical cues obtained in this modular approach renders our hydrogels suitable to study cellular responses under highly defined conditions.

Segregation of Clock and Non-Clock Regulatory Functions of REV-ERB.

PubMed

Butler, Andrew A; Burris, Thomas P

2015-08-04

The molecular clock is a master controller of circadian cellular processes that affect growth, metabolic homeostasis, and behavior. A report in Science by Zhang et al. (2015) redefines our understanding of how Rev-erba acts as an internal feedback inhibitor that modulates activity of the core clock while simultaneously regulating tissue-specific metabolic processes. Copyright © 2015 Elsevier Inc. All rights reserved.

Optimization of industrial microorganisms: recent advances in synthetic dynamic regulators.

PubMed

Min, Byung Eun; Hwang, Hyun Gyu; Lim, Hyun Gyu; Jung, Gyoo Yeol

2017-01-01

Production of biochemicals by industrial fermentation using microorganisms requires maintaining cellular production capacity, because maximal productivity is economically important. High-productivity microbial strains can be developed using static engineering, but these may not maintain maximal productivity throughout the culture period as culture conditions and cell states change dynamically. Additionally, economic reasons limit heterologous protein expression using inducible promoters to prevent metabolic burden for commodity chemical and biofuel production. Recently, synthetic and systems biology has been used to design genetic circuits, precisely controlling gene expression or influencing genetic behavior toward a desired phenotype. Development of dynamic regulators can maintain cellular phenotype in a maximum production state in response to factors including cell concentration, oxygen, temperature, pH, and metabolites. Herein, we introduce dynamic regulators of industrial microorganism optimization and discuss metabolic flux fine control by dynamic regulators in response to metabolites or extracellular stimuli, robust production systems, and auto-induction systems using quorum sensing.

Fabrication of biomimetic nanomaterials and their effect on cell behavior

NASA Astrophysics Data System (ADS)

Porri, Teresa Jane

Cells in vivo respond to an intricate combination of chemical and mechanical signals. The corneal epithelium, a structure which prevents the admission of bacteria and undesirable molecules into the eye, grows on a basement membrane which presents both nanoscale topographic and adhesive chemical signals. An effective approach to biomaterials design takes advantage of the synergistic effects of the multiple cellular inputs which are available to engineer cell-substrate interactions. We have previously demonstrated the effects of nanoscale topography on a variety of corneal epithelial cell behaviors. To gain a better understanding of cell-level control in vivo, we employ a systems-level approach which looks at the effect of nanoscale topography in conjunction with a biomimetic surface chemistry. First, we discuss a novel method of fabricating nanoscale topography through templated electroless deposition of gold into PVP-coated polycarbonate membranes. This technique creates nanowires of gold with an uniform outer diameter that is dependent upon the size of the pores in the membrane used, and a nanowire length that is dependent upon the extent of etching into the polymer membrane. The gold nanowires can be modified with self-assembled monolayers (SAMs) of alkanethiols. Using these substrates, we study the effect of topographic length scale and surface chemistry on cells attached to a discontinuous nanoscale topography, and find a transition in cellular behavior at a length scale (between 600 and 2000 nm inter-wire spacing) that is commensurate with the transition length scale seen on surfaces presenting continuous grooves and ridges. Secondly, we study the effect of non-fouling peptide-modified SAMs on cellular behavior. We examine the effect of co-presented RGD and AG73 peptides and show that cell spreading is a function of the relative ratios of RGD and AG73 present on the surface. Finally, we explore the combinatorial effects of biologically relevant chemistry with anisotropic nanoscale topography with dimensions that vary from the micron to the nanoscale. We show that integrin binding, syndecan binding, and topographic length scale each independently influence epithelial cell response to nanoscale features, lending a high degree of control over cell morphologic responses.

Thickness sensing of hMSCs on collagen gel directs stem cell fate

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

Leong, Wen Shing; Tay, Chor Yong; Yu, Haiyang

Research highlights: {yields} hMSCs appeared to sense thin collagen gel (130 {mu}m) with higher effective modulus as compared to thick gel (1440 {mu}m). {yields} Control of collagen gel thickness can modulate cellular behavior, even stem cell fate (neuronal vs. Quiescent). {yields} Distinct cellular behavior of hMSCs on thin and thick collagen gel suggests long range interaction of hMSCs with collagen gel. -- Abstract: Mechanically compliant substrate provides crucial biomechanical cues for multipotent stem cells to regulate cellular fates such as differentiation, proliferation and maintenance of their phenotype. Effective modulus of which cells sense is not only determined by intrinsic mechanicalmore » properties of the substrate, but also the thickness of substrate. From our study, it was found that interference from underlying rigid support at hundreds of microns away could induce significant cellular response. Human mesenchymal stem cells (hMSCs) were cultured on compliant biological gel, collagen type I, of different thickness but identical ECM composition and local stiffness. The cells sensed the thin gel (130 {mu}m) as having a higher effective modulus than the thick gel (1440 {mu}m) and this was reflected in their changes in morphology, actin fibers structure, proliferation and tissue specific gene expression. Commitment into neuronal lineage was observed on the thin gel only. Conversely, the thick gel (1440 {mu}m) was found to act like a substrate with lower effective modulus that inhibited actin fiber polymerization. Stem cells on the thick substrate did not express tissue specific genes and remained at their quiescent state. This study highlighted the need to consider not only the local modulus but also the thickness of biopolymer gel coating during modulation of cellular responses.« less

Cellular stress induces a protective sleep-like state in C. elegans.

PubMed

Hill, Andrew J; Mansfield, Richard; Lopez, Jessie M N G; Raizen, David M; Van Buskirk, Cheryl

2014-10-20

Sleep is recognized to be ancient in origin, with vertebrates and invertebrates experiencing behaviorally quiescent states that are regulated by conserved genetic mechanisms. Despite its conservation throughout phylogeny, the function of sleep remains debated. Hypotheses for the purpose of sleep include nervous-system-specific functions such as modulation of synaptic strength and clearance of metabolites from the brain, as well as more generalized cellular functions such as energy conservation and macromolecule biosynthesis. These models are supported by the identification of synaptic and metabolic processes that are perturbed during prolonged wakefulness. It remains to be seen whether perturbations of cellular homeostasis in turn drive sleep. Here we show that under conditions of cellular stress, including noxious heat, cold, hypertonicity, and tissue damage, the nematode Caenorhabditis elegans engages a behavioral quiescence program. The stress-induced quiescent state displays properties of sleep and is dependent on the ALA neuron, which mediates the conserved soporific effect of epidermal growth factor (EGF) ligand overexpression. We characterize heat-induced quiescence in detail and show that it is indeed dependent on components of EGF signaling, providing physiological relevance to the behavioral effects of EGF family ligands. We find that after noxious heat exposure, quiescence-defective animals show elevated expression of cellular stress reporter genes and are impaired for survival, demonstrating the benefit of stress-induced behavioral quiescence. These data provide evidence that cellular stress can induce a protective sleep-like state in C. elegans and suggest that a deeply conserved function of sleep is to mitigate disruptions of cellular homeostasis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Emergence of tissue mechanics from cellular processes: shaping a fly wing

NASA Astrophysics Data System (ADS)

Merkel, Matthias; Etournay, Raphael; Popovic, Marko; Nandi, Amitabha; Brandl, Holger; Salbreux, Guillaume; Eaton, Suzanne; Jülicher, Frank

Nowadays, biologistsare able to image biological tissueswith up to 10,000 cells in vivowhere the behavior of each individual cell can be followed in detail.However, how precisely large-scale tissue deformation and stresses emerge from cellular behavior remains elusive. Here, we study this question in the developing wing of the fruit fly. To this end, we first establish a geometrical framework that exactly decomposes tissue deformation into contributions by different kinds of cellular processes. These processes comprise cell shape changes, cell neighbor exchanges, cell divisions, and cell extrusions. As the key idea, we introduce a tiling of the cellular network into triangles. This approach also reveals that tissue deformation can also be created by correlated cellular motion. Based on quantifications using these concepts, we developed a novel continuum mechanical model for the fly wing. In particular, our model includes active anisotropic stresses and a delay in the response of cell rearrangements to material stresses. A different approach to study the emergence of tissue mechanics from cellular behavior are cell-based models. We characterize the properties of a cell-based model for 3D tissues that is a hybrid between single particle models and the so-called vertex models.

Feeding behavior of Aplysia: a model system for comparing cellular mechanisms of classical and operant conditioning.

PubMed

Baxter, Douglas A; Byrne, John H

2006-01-01

Feeding behavior of Aplysia provides an excellent model system for analyzing and comparing mechanisms underlying appetitive classical conditioning and reward operant conditioning. Behavioral protocols have been developed for both forms of associative learning, both of which increase the occurrence of biting following training. Because the neural circuitry that mediates the behavior is well characterized and amenable to detailed cellular analyses, substantial progress has been made toward a comparative analysis of the cellular mechanisms underlying these two forms of associative learning. Both forms of associative learning use the same reinforcement pathway (the esophageal nerve, En) and the same reinforcement transmitter (dopamine, DA). In addition, at least one cellular locus of plasticity (cell B51) is modified by both forms of associative learning. However, the two forms of associative learning have opposite effects on B51. Classical conditioning decreases the excitability of B51, whereas operant conditioning increases the excitability of B51. Thus, the approach of using two forms of associative learning to modify a single behavior, which is mediated by an analytically tractable neural circuit, is revealing similarities and differences in the mechanisms that underlie classical and operant conditioning.

Nanolithographic control of the spatial organization of cellular adhesion receptors at the single-molecule level

PubMed Central

Schvartzman, Mark; Palma, Matteo; Sable, Julia; Abramson, Justin; Hu, Xian; Sheetz, Michael P.; Wind, Shalom J.

2011-01-01

The ability to control the placement of individual molecules promises to enable a wide range of applications and is a key challenge in nanoscience and nanotechnology. Many biological interactions, in particular, are sensitive to the precise geometric arrangement of proteins. We have developed a technique which combines molecular-scale nanolithography with site-selective biochemistry to create biomimetic arrays of individual protein binding sites. The binding sites can be arranged in heterogeneous patterns of virtually any possible geometry with a nearly unlimited number of degrees of freedom. We have used these arrays to explore how the geometric organization of the extracellular matrix (ECM) binding ligand RGD (Arg-Gly-Asp) affects cell adhesion and spreading. Systematic variation of spacing, density and cluster size of individual integrin binding sites was used to elicit different cell behavior. Cell spreading assays on arrays of different geometric arrangements revealed a dramatic increase in spreading efficiency when at least 4 liganded sites were spaced within 60 nm or less, with no dependence on global density. This points to the existence of a minimal matrix adhesion unit for fibronectin defined in space and stoichiometry. Developing an understanding of the ECM geometries that activate specific cellular functional complexes is a critical step toward controlling cell behavior. Potential practical applications range from new therapeutic treatments to the rational design of tissue scaffolds that can optimize healing without scarring. More broadly, spatial control at the single-molecule level can elucidate factors controlling individual molecular interactions and can enable synthesis of new systems based on molecular-scale architectures. PMID:21319842

Controlling fertilization and cAMP signaling in sperm by optogenetics.

PubMed

Jansen, Vera; Alvarez, Luis; Balbach, Melanie; Strünker, Timo; Hegemann, Peter; Kaupp, U Benjamin; Wachten, Dagmar

2015-01-20

Optogenetics is a powerful technique to control cellular activity by light. The light-gated Channelrhodopsin has been widely used to study and manipulate neuronal activity in vivo, whereas optogenetic control of second messengers in vivo has not been examined in depth. In this study, we present a transgenic mouse model expressing a photoactivated adenylyl cyclase (bPAC) in sperm. In transgenic sperm, bPAC mimics the action of the endogenous soluble adenylyl cyclase (SACY) that is required for motility and fertilization: light-stimulation rapidly elevates cAMP, accelerates the flagellar beat, and, thereby, changes swimming behavior of sperm. Furthermore, bPAC replaces endogenous adenylyl cyclase activity. In mutant sperm lacking the bicarbonate-stimulated SACY activity, bPAC restored motility after light-stimulation and, thereby, enabled sperm to fertilize oocytes in vitro. We show that optogenetic control of cAMP in vivo allows to non-invasively study cAMP signaling, to control behaviors of single cells, and to restore a fundamental biological process such as fertilization.

In situ sensing and modeling of molecular events at the cellular level

NASA Astrophysics Data System (ADS)

Yang, Ruiguo

We developed the Atomic Force Microscopy (AFM) based nanorobot in combination with other nanomechanical sensors for the investigation of cell signaling pathways. The AFM nanorobotics hinge on the superior spatial resolution of AFM in imaging and extends it into the measurement of biological processes and manipulation of biological matters. A multiple input single output control system was designed and implemented to solve the issues of nanomanipulation of biological materials, feedback, response frequency and nonlinearity. The AFM nanorobotic system therefore provide the human-directed position, velocity and force control with high frequency feedback, and more importantly it can feed the operator with the real-time imaging of manipulation result from the fast-imaging based local scanning. The use of the system has taken the study of cellular process at the molecular scale into a new level. The cellular response to the physiological conditions can be significantly manifested in cellular mechanics. Dynamic mechanical property has been regarded as biomarkers, sometimes even regulators of the signaling and physiological processes, thus the name mechanobiology. We sought to characterize the relationship between the structural dynamics and the molecular dynamics and the role of them in the regulation of cell behavior. We used the AFM nanorobotics to investigate the mechanical properties in real-time of cells that are stimulated by different chemical species. These reagents could result in similar ion channel responses but distinctive mechanical behaviors. We applied these measurement results to establish a model that describes the cellular stimulation and the mechanical property change, a "two-hit" model that comprises the loss of cell adhesion and the initiation of cell apoptosis. The first hit was verified by functional experiments: depletion of Calcium and nanosurgery to disrupt the cellular adhesion. The second hit was tested by a labeling of apoptotic markers that were revealed by flow cytometry. The model would then be able to decipher qualitatively the molecular dynamics infolded in the regulation of cell behavior. To decipher the signaling pathway quantitatively, we employed a nanomechanical sensor at the bottom of the cell, quartz crystal microbalance with energy dissipation monitoring (QCM-D) to monitor the change at the basal area of the cell. This would provide the real time focal adhesion information and would be used in accordance with the AFM measurement data on the top of the cell to build a more complete mechanical profile during the antibody induced signaling process. We developed a model from a systematic control perspective that considers the signaling cascade at certain stimulation as the controller and the mechanical and structural interaction of the cell as the plant. We firstly derived the plant model based on QCM-D and AFM measurement processes. A signaling pathway model was built on a grey box approach where part of the pathway map was delineated in detail while others were condensed into a single reaction. The model parameters were obtained by extracting the mechanical response from the experiment. The model refinements were conducted by testing a series of inhibition mechanisms and comparing the simulation data with the experimental data. The model was then used to predict the existences of certain reactions that are qualitatively reported in the literature.

Multi-Cellular Logistics of Collective Cell Migration

PubMed Central

Yamao, Masataka; Naoki, Honda; Ishii, Shin

2011-01-01

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. PMID:22205934

Correlation of Emulsion Structure with Cellular Uptake Behavior of Encapsulated Bioactive Nutrients: Influence of Droplet Size and Interfacial Structure.

PubMed

Lu, Wei; Kelly, Alan L; Maguire, Pierce; Zhang, Hongzhou; Stanton, Catherine; Miao, Song

2016-11-16

In this study, an in vitro Caco-2 cell culture assay was employed to evaluate the correlation between emulsion structure and cellular uptake of encapsulated β-carotene. After 4 h of incubation, an emulsion stabilized with whey protein isolate showed the highest intracellular accumulation of β-carotene (1.06 μg), followed by that stabilized with sodium caseinate (0.60 μg) and Tween 80 (0.20 μg), which are 13-, 7.5-, and 2.5-fold higher than that of free β-carotene (0.08 μg), respectively. Emulsions with small droplet size (239 ± 5 nm) showed a higher cellular uptake of β-carotene (1.56 μg) than emulsiond with large droplet size (489 ± 9 nm) (0.93 μg) (p < 0.01). The results suggested that delivery in an emulsion significantly improved the cellular uptake of β-carotene and thus potentially its bioavailability; uptake was closely correlated with the interfacial composition and droplet size of emulsions. The findings support the potential for achieving optimal controlled and targeted delivery of bioactive nutrients by structuring emulsions.

Cell Selective Apoptosis Induced by Polymorphic Alteration of Self-Assembled Silica Nanowebs.

PubMed

Keshavarz, Meysam; Tan, Bo; Venkatakrishnan, Krishnan

2017-02-22

The biocompatibility of silicon-based nanomaterials makes them suitable for biophysical and biomedical applications. However, the application of silicon-based nanomaterials has been mainly restricted to nanoparticles (NPs) as a potential drug carrier and the extracellular matrix (ECM) as a platform for cell adhesion and proliferation. Here, we introduce silica NPs self-assembled into a 3D nanoweb architecture that was shown to inherit the therapeutic and proliferative attributes of both NPs and ECMs. The self-assembled silica nanoweb (SNW) has, therefore, not only shown targeted druglike behavior in HeLa cells without the use of biomarkers but has also shown ECM characteristics. The ECM characteristics of SNWs enhanced the cellular attraction and proliferation by which fibroblasts exhibited tissuelike behavior, and HeLa cells underwent an intensified induction of apoptosis. These properties are tailored by the alteration of the polymorphic heterogeneities of the SNW as a novel nanobiointerface for exceptional apoptosis induction through the enhancement of cellular attraction, which, to the best of our knowledge, has not been previously reported. These attributes enable selective functionality with which cancerous HeLa and mammalian fibroblast cells were affected differently. Moreover, simultaneous control of the packing index and crystallinity of the SNWs, to which the cells had been attracted, possessed the additional advantage of modulating the selective functionality of this nanobiointerface. These polymorphic characteristics were tailored by the alteration of the crystallinity of the synthesized SNW via precision control of the ionization level of the silicon substrate, whose requisite ionization energy was generated by an ultrashort pulsed laser. Our results showed that the therapeutic functionality of the SNW-plated template can be elucidated via the endocytosis of amorphous SNWs. Because of the efficient cellular attraction and remarkable contrast in the cellular response to the SNW-plated template, we expect that these findings will provide new insights and opportunities for designing and engineering novel cell-material interfaces for advanced biomedical applications in cancer research.

Chemistry with spatial control using particles and streams†

PubMed Central

Kalinin, Yevgeniy V.; Murali, Adithya

2012-01-01

Spatial control of chemical reactions, with micro- and nanometer scale resolution, has important consequences for one pot synthesis, engineering complex reactions, developmental biology, cellular biochemistry and emergent behavior. We review synthetic methods to engineer this spatial control using chemical diffusion from spherical particles, shells and polyhedra. We discuss systems that enable both isotropic and anisotropic chemical release from isolated and arrayed particles to create inhomogeneous and spatially patterned chemical fields. In addition to such finite chemical sources, we also discuss spatial control enabled with laminar flow in 2D and 3D microfluidic networks. Throughout the paper, we highlight applications of spatially controlled chemistry in chemical kinetics, reaction-diffusion systems, chemotaxis and morphogenesis. PMID:23145348

Neuronal control of energy homeostasis

PubMed Central

Gao, Qian; Horvath, Tamas L.

2013-01-01

Neuronal control of body energy homeostasis is the key mechanism by which animals and humans regulate their long-term energy balance. Various hypothalamic neuronal circuits (which include the hypothalamic melanocortin, midbrain dopamine reward and caudal brainstem autonomic feeding systems) control energy intake and expenditure to maintain body weight within a narrow range for long periods of a life span. Numerous peripheral metabolic hormones and nutrients target these structures providing feedback signals that modify the default “settings” of neuronal activity to accomplish this balance. A number of molecular genetic tools for manipulating individual components of brain energy homeostatic machineries, in combination with anatomical, electrophysiological, pharmacological and behavioral techniques, have been developed, which provide a means for elucidating the complex molecular and cellular mechanisms of feeding behavior and metabolism. This review will highlight some of these advancements and focus on the neuronal circuitries of energy homeostasis. PMID:18061579

Rapid control of male typical behaviors by brain-derived estrogens

PubMed Central

Cornil, Charlotte A.; Ball, Gregory F.; Balthazart, Jacques

2012-01-01

Beside their genomic mode of action, estrogens also activate a variety of cellular signaling pathways through non-genomic mechanisms. Until recently, little was known regarding the functional significance of such actions in males and the mechanism that control local estrogen concentration with a spatial and time resolution compatible with these non-genomic actions had rarely been examined. Here, we review evidence that estrogens rapidly modulate a variety of behaviors in male vertebrates. Then, we present in vitro work supporting the existence of a control mechanism of local brain estrogen synthesis by aromatase along with in vivo evidence that rapid changes in aromatase activity also occur in a region-specific manner in response to changes in the social or environmental context. Finally, we suggest that the brain estrogen provision may also play a significant role in females. Together these data bolster the hypothesis that brain-derived estrogens should be considered as neuromodulators. PMID:22983088

Reward, interrupted: Inhibitory control and its relevance to addictions.

PubMed

Jentsch, James David; Pennington, Zachary T

2014-01-01

There are broad individual differences in the ability to voluntarily and effortfully suppress motivated, reward-seeking behaviors, and this review presents the hypothesis that these individual differences are relevant to addictive disorders. On one hand, cumulative experience with drug abuse appears to alter the molecular, cellular and circuit mechanisms that mediate inhibitory abilities, leading to increasingly uncontrolled patterns of drug-seeking and -taking. On the other, native inter-individual differences in inhibitory control are apparently a risk factor for aspects of drug-reinforced responding and substance use disorders. In both cases, the behavioral manifestation of poor inhibitory abilities is linked to relatively low striatal dopamine D2-like receptor availability, and evidence is accumulating for a more direct contribution of striatopallidal neurons to cognitive control processes. Mechanistic research is now identifying genes upstream of dopamine transmission that mediate these relationships, as well as the involvement of other neurotransmitter systems, acting alone and in concert with dopamine. The reviewed research stands poised to identify new mechanisms that can be targeted by pharmacotherapies and/or by behavioral interventions that are designed to prevent or treat addictive behaviors and associated behavioral pathology. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Copyright © 2013 Elsevier Ltd. All rights reserved.

New advances in probing cell–extracellular matrix interactions

PubMed Central

2017-01-01

The extracellular matrix (ECM) provides structural and biochemical support to cells within tissues. An emerging body of evidence has established that the ECM plays a key role in cell mechanotransduction – the study of coupling between mechanical inputs and cellular phenotype – through either mediating transmission of forces to the cells, or presenting mechanical cues that guide cellular behaviors. Recent progress in cell mechanotransduction research has been facilitated by advances of experimental tools, particularly microtechnologies, engineered biomaterials, and imaging and analytical methods. Microtechnologies have enabled the design and fabrication of controlled physical microenvironments for the study and measurement of cell–ECM interactions. Advances in engineered biomaterials have allowed researchers to develop synthetic ECMs that mimic tissue microenvironments and investigate the impact of altered physicochemical properties on various cellular processes. Finally, advanced imaging and spectroscopy techniques have facilitated the visualization of the complex interaction between cells and ECM in vitro and in living tissues. This review will highlight the application of recent innovations in these areas to probing cell–ECM interactions. We believe cross-disciplinary approaches, combining aspects of the different technologies reviewed here, will inspire innovative ideas to further elucidate the secrets of ECM-mediated cell control. PMID:28352896

Altered Connexin 43 and Connexin 45 protein expression in the heart as a function of social and environmental stress in the prairie vole.

PubMed

Grippo, Angela J; Moffitt, Julia A; Henry, Matthew K; Firkins, Rachel; Senkler, Jonathan; McNeal, Neal; Wardwell, Joshua; Scotti, Melissa-Ann L; Dotson, Ashley; Schultz, Rachel

2015-01-01

Exposure to social and environmental stressors may influence behavior as well as autonomic and cardiovascular regulation, potentially leading to depressive disorders and cardiac dysfunction including elevated sympathetic drive, reduced parasympathetic function, and ventricular arrhythmias. The cellular mechanisms that underlie these interactions are not well understood. One mechanism may involve alterations in the expression of Connexin43 (Cx43) and Connexin45 (Cx45), gap junction proteins in the heart that play an important role in ensuring efficient cell-to-cell coupling and the maintenance of cardiac rhythmicity. The present study investigated the hypothesis that long-term social isolation, combined with mild environmental stressors, would produce both depressive behaviors and altered Cx43 and Cx45 expression in the left ventricle of prairie voles - a socially monogamous rodent model. Adult, female prairie voles were exposed to either social isolation (n = 22) or control (paired, n = 23) conditions (4 weeks), alone or in combination with chronic mild stress (CMS) (1 week). Social isolation, versus paired control conditions, produced significantly (p < 0.05) increased depressive behaviors in a 5-min forced swim test, and CMS exacerbated (p < 0.05) these behaviors. Social isolation (alone) reduced (p < 0.05) total Cx43 expression in the left ventricle; whereas CMS (but not isolation) increased (p < 0.05) total Cx45 expression and reduced (p < 0.05) the Cx43/Cx45 ratio, measured via Western blot analysis. The present findings provide insight into potential cellular mechanisms underlying altered cardiac rhythmicity associated with social and environmental stress in the prairie vole.

Lasting Adaptations in Social Behavior Produced by Social Disruption and Inhibition of Adult Neurogenesis

PubMed Central

Opendak, Maya; Offit, Lily; Monari, Patrick; Schoenfeld, Timothy J.; Sonti, Anup N.; Cameron, Heather A.

2016-01-01

Research on social instability has focused on its detrimental consequences, but most people are resilient and respond by invoking various coping strategies. To investigate cellular processes underlying such strategies, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Social disruption produced a preference for familiar over novel conspecifics, a change that did not involve global memory impairments or increased anxiety. Using the neuropeptide oxytocin as a tool to increase neurogenesis in the hippocampus of disrupted rats restored preference for novel conspecifics to predisruption levels. Conversely, reducing the number of new neurons by limited inhibition of adult neurogenesis in naive transgenic GFAP–thymidine kinase rats resulted in social behavior similar to disrupted rats. Together, these results provide novel mechanistic evidence that social disruption shapes behavior in a potentially adaptive way, possibly by reducing adult neurogenesis in the hippocampus. SIGNIFICANCE STATEMENT To investigate cellular processes underlying adaptation to social instability, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Unexpectedly, these changes were accompanied by changes in social strategies without evidence of impairments in cognition or anxiety regulation. Restoring adult neurogenesis in disrupted rats using oxytocin and conditionally suppressing the production of new neurons in socially naive GFAP–thymidine kinase rats showed that loss of 6-week-old neurons may be responsible for adaptive changes in social behavior. PMID:27358459

Surfing along Filopodia: A Particle Transport Revealed by Molecular-Scale Fluctuation Analyses

PubMed Central

Kohler, Felix; Rohrbach, Alexander

2015-01-01

Filopodia perform cellular functions such as environmental sensing or cell motility, but they also grab for particles and withdraw them leading to an increased efficiency of phagocytic uptake. Remarkably, withdrawal of micron-sized particles is also possible without noticeable movements of the filopodia. Here, we demonstrate that polystyrene beads connected by optical tweezers to the ends of adherent filopodia of J774 macrophages, are transported discontinuously toward the cell body. After a typical resting time of 1–2 min, the cargo is moved with alternating velocities, force constants, and friction constants along the surface of the filopodia. This surfing-like behavior along the filopodium is recorded by feedback-controlled interferometric three-dimensional tracking of the bead motions at 10–100 kHz. We measured transport velocities of up to 120 nm/s and transport forces of ∼70 pN. Small changes in position, fluctuation width, and temporal correlation, which are invisible in conventional microscopy, indicate molecular reorganization of transport-relevant proteins in different phases of the entire transport process. A detailed analysis implicates a controlled particle transport with fingerprints of a nanoscale unbinding/binding behavior. The manipulation and analysis methods presented in our study may also be helpful in other fields of cellular biophysics. PMID:25954870

Dynamic Call Admission Control Scheme Based on Predictive User Mobility Behavior for Cellular Networks

NASA Astrophysics Data System (ADS)

Intarasothonchun, Silada; Thipchaksurat, Sakchai; Varakulsiripunth, Ruttikorn; Onozato, Yoshikuni

In this paper, we propose a modified scheme of MSODB and PMS, called Predictive User Mobility Behavior (PUMB) to improve performance of resource reservation and call admission control for cellular networks. This algorithm is proposed in which bandwidth is allocated more efficiently to neighboring cells by key mobility parameters in order to provide QoS guarantees for transferring traffic. The probability is used to form a cluster of cells and the shadow cluster, where a mobile unit is likely to visit. When a mobile unit may change the direction and migrate to the cell that does not belong to its shadow cluster, we can support it by making efficient use of predicted nonconforming call. Concomitantly, to ensure continuity of on-going calls with better utilization of resources, bandwidth is borrowed from predicted nonconforming calls and existing adaptive calls without affecting the minimum QoS guarantees. The performance of the PUMB is demonstrated by simulation results in terms of new call blocking probability, handoff call dropping probability, bandwidth utilization, call successful probability, and overhead message transmission when arrival rate and speed of mobile units are varied. Our results show that PUMB provides the better performances comparing with those of MSODB and PMS under different traffic conditions.

Nanofiber Orientation and Surface Functionalization Modulate Human Mesenchymal Stem Cell Behavior In Vitro

PubMed Central

Kolambkar, Yash M.; Bajin, Mehmet; Wojtowicz, Abigail; Hutmacher, Dietmar W.; García, Andrés J.

2014-01-01

Electrospun nanofiber meshes have emerged as a new generation of scaffold membranes possessing a number of features suitable for tissue regeneration. One of these features is the flexibility to modify their structure and composition to orchestrate specific cellular responses. In this study, we investigated the effects of nanofiber orientation and surface functionalization on human mesenchymal stem cell (hMSC) migration and osteogenic differentiation. We used an in vitro model to examine hMSC migration into a cell-free zone on nanofiber meshes and mitomycin C treatment to assess the contribution of proliferation to the observed migration. Poly (ɛ-caprolactone) meshes with oriented topography were created by electrospinning aligned nanofibers on a rotating mandrel, while randomly oriented controls were collected on a stationary collector. Both aligned and random meshes were coated with a triple-helical, type I collagen-mimetic peptide, containing the glycine-phenylalanine-hydroxyproline-glycine-glutamate-arginine (GFOGER) motif. Our results indicate that nanofiber GFOGER peptide functionalization and orientation modulate cellular behavior, individually, and in combination. GFOGER significantly enhanced the migration, proliferation, and osteogenic differentiation of hMSCs on nanofiber meshes. Aligned nanofiber meshes displayed increased cell migration along the direction of fiber orientation compared to random meshes; however, fiber alignment did not influence osteogenic differentiation. Compared to each other, GFOGER coating resulted in a higher proliferation-driven cell migration, whereas fiber orientation appeared to generate a larger direct migratory effect. This study demonstrates that peptide surface modification and topographical cues associated with fiber alignment can be used to direct cellular behavior on nanofiber mesh scaffolds, which may be exploited for tissue regeneration. PMID:24020454

Cannabinoid Receptor Signaling in Central Regulation of Feeding Behavior: A Mini-Review.

PubMed

Koch, Marco

2017-01-01

Cannabinoids are lipid messengers that modulate a variety of physiological processes and modify the generation of specific behaviors. In this regard, the cannabinoid receptor type 1 (CB 1 ) represents the most relevant target molecule of cannabinoids so far. One main function of central CB 1 signaling is to maintain whole body energy homeostasis. Thus, cannabinoids functionally interact with classical neurotransmitters in neural networks that control energy metabolism and feeding behavior. The promotion of CB 1 signaling can increase appetite and stimulate feeding, while blockade of CB 1 suppresses hunger and induces hypophagia. However, in order to treat overeating, pharmacological blockade of CB 1 by the inverse agonist rimonabant not only suppressed feeding but also resulted in psychiatric side effects. Therefore, research within the last decade focused on deciphering the underlying cellular and molecular mechanisms of central cannabinoid signaling that control feeding and other behaviors, with the overall aim still being the identification of specific targets to develop safe pharmacological interventions for the treatment of obesity. Today, many studies unraveled the subcellular localization of CB 1 and the function of cannabinoids in neurons and glial cells within circumscribed brain regions that represent integral parts of neural circuitries controlling feeding behavior. Here, these novel experimental findings will be summarized and recent advances in understanding the mechanisms of CB 1 -dependent cannabinoid signaling being relevant for central regulation of feeding behavior will be highlighted. Finally, presumed alternative pathways of cannabinoids that are not driven by CB 1 activation but also contributing to control of feeding behavior will be introduced.

Cannabinoid Receptor Signaling in Central Regulation of Feeding Behavior: A Mini-Review

PubMed Central

Koch, Marco

2017-01-01

Cannabinoids are lipid messengers that modulate a variety of physiological processes and modify the generation of specific behaviors. In this regard, the cannabinoid receptor type 1 (CB1) represents the most relevant target molecule of cannabinoids so far. One main function of central CB1 signaling is to maintain whole body energy homeostasis. Thus, cannabinoids functionally interact with classical neurotransmitters in neural networks that control energy metabolism and feeding behavior. The promotion of CB1 signaling can increase appetite and stimulate feeding, while blockade of CB1 suppresses hunger and induces hypophagia. However, in order to treat overeating, pharmacological blockade of CB1 by the inverse agonist rimonabant not only suppressed feeding but also resulted in psychiatric side effects. Therefore, research within the last decade focused on deciphering the underlying cellular and molecular mechanisms of central cannabinoid signaling that control feeding and other behaviors, with the overall aim still being the identification of specific targets to develop safe pharmacological interventions for the treatment of obesity. Today, many studies unraveled the subcellular localization of CB1 and the function of cannabinoids in neurons and glial cells within circumscribed brain regions that represent integral parts of neural circuitries controlling feeding behavior. Here, these novel experimental findings will be summarized and recent advances in understanding the mechanisms of CB1-dependent cannabinoid signaling being relevant for central regulation of feeding behavior will be highlighted. Finally, presumed alternative pathways of cannabinoids that are not driven by CB1 activation but also contributing to control of feeding behavior will be introduced. PMID:28596721

Injectable, cellular-scale optoelectronics with applications for wireless optogenetics.

PubMed

Kim, Tae-il; McCall, Jordan G; Jung, Yei Hwan; Huang, Xian; Siuda, Edward R; Li, Yuhang; Song, Jizhou; Song, Young Min; Pao, Hsuan An; Kim, Rak-Hwan; Lu, Chaofeng; Lee, Sung Dan; Song, Il-Sun; Shin, Gunchul; Al-Hasani, Ream; Kim, Stanley; Tan, Meng Peun; Huang, Yonggang; Omenetto, Fiorenzo G; Rogers, John A; Bruchas, Michael R

2013-04-12

Successful integration of advanced semiconductor devices with biological systems will accelerate basic scientific discoveries and their translation into clinical technologies. In neuroscience generally, and in optogenetics in particular, the ability to insert light sources, detectors, sensors, and other components into precise locations of the deep brain yields versatile and important capabilities. Here, we introduce an injectable class of cellular-scale optoelectronics that offers such features, with examples of unmatched operational modes in optogenetics, including completely wireless and programmed complex behavioral control over freely moving animals. The ability of these ultrathin, mechanically compliant, biocompatible devices to afford minimally invasive operation in the soft tissues of the mammalian brain foreshadow applications in other organ systems, with potential for broad utility in biomedical science and engineering.

Fluorescent Reporters and Biosensors for Probing the Dynamic Behavior of Protein Kinases

PubMed Central

González-Vera, Juan A.; Morris, May C.

2015-01-01

Probing the dynamic activities of protein kinases in real-time in living cells constitutes a major challenge that requires specific and sensitive tools tailored to meet the particular demands associated with cellular imaging. The development of genetically-encoded and synthetic fluorescent biosensors has provided means of monitoring protein kinase activities in a non-invasive fashion in their native cellular environment with high spatial and temporal resolution. Here, we review existing technologies to probe different dynamic features of protein kinases and discuss limitations where new developments are required to implement more performant tools, in particular with respect to infrared and near-infrared fluorescent probes and strategies which enable improved signal-to-noise ratio and controlled activation of probes. PMID:28248276

A Novel Approach to Primary Cell Culture for Octopus vulgaris Neurons

PubMed Central

Maselli, Valeria; Xu, Fenglian; Syed, Naweed I.; Polese, Gianluca; Di Cosmo, Anna

2018-01-01

Octopus vulgaris is a unique model system for studying complex behaviors in animals. It has a large and centralized nervous system made up of lobes that are involved in controlling various sophisticated behaviors. As such, it may be considered as a model organism for untangling the neuronal mechanisms underlying behaviors—including learning and memory. However, despite considerable efforts, Octopus lags behind its other counterparts vis-à-vis its utility in deciphering the cellular, molecular and synaptic mechanisms underlying various behaviors. This study represents a novel approach designed to establish a neuronal cell culture protocol that makes this species amenable to further exploitation as a model system. Here we developed a protocol that enables dissociation of neurons from two specific Octopus' brain regions, the vertical-superior frontal system and the optic lobes, which are involved in memory, learning, sensory integration and adult neurogenesis. In particular, cells dissociated with enzyme papain and cultured on Poly-D-Lysine-coated dishes with L15-medium and fetal bovine serum yielded high neuronal survival, axon growth, and re-growth after injury. This model was also explored to define optimal culture conditions and to demonstrate the regenerative capabilities of adult Octopus neurons after axotomy. This study thus further underscores the importance of Octopus neurons as a model system for deciphering fundamental molecular and cellular mechanism of complex brain function and underlying behaviors. PMID:29666582

Cellular resolution functional imaging in behaving rats using voluntary head restraint

PubMed Central

Scott, Benjamin B.; Brody, Carlos D.; Tank, David W.

2013-01-01

SUMMARY High-throughput operant conditioning systems for rodents provide efficient training on sophisticated behavioral tasks. Combining these systems with technologies for cellular resolution functional imaging would provide a powerful approach to study neural dynamics during behavior. Here we describe an integrated two-photon microscope and behavioral apparatus that allows cellular resolution functional imaging of cortical regions during epochs of voluntary head restraint. Rats were trained to initiate periods of restraint up to 8 seconds in duration, which provided the mechanical stability necessary for in vivo imaging while allowing free movement between behavioral trials. A mechanical registration system repositioned the head to within a few microns, allowing the same neuronal populations to be imaged on each trial. In proof-of-principle experiments, calcium dependent fluorescence transients were recorded from GCaMP-labeled cortical neurons. In contrast to previous methods for head restraint, this system can also be incorporated into high-throughput operant conditioning systems. PMID:24055015

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

NASA Astrophysics Data System (ADS)

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 cellular solids and make substantial contributions to the theoretical advance of impact dynamics.

Intracellular cargo delivery by virus capsid protein-based vehicles: From nano to micro.

PubMed

Gao, Ding; Lin, Xiu-Ping; Zhang, Zhi-Ping; Li, Wei; Men, Dong; Zhang, Xian-En; Cui, Zong-Qiang

2016-02-01

Cellular delivery is an important concern for the efficiency of medicines and sensors for disease diagnoses and therapy. However, this task is quite challenging. Self-assembly virus capsid proteins might be developed as building blocks for multifunctional cellular delivery vehicles. In this work, we found that SV40 VP1 (Simian virus 40 major capsid protein) could function as a new cell-penetrating protein. The VP1 protein could carry foreign proteins into cells in a pentameric structure. A double color structure, with red QDs (Quantum dots) encapsulated by viral capsids fused with EGFP, was created for imaging cargo delivery and release from viral capsids. The viral capsids encapsulating QDs were further used for cellular delivery of micron-sized iron oxide particles (MPIOs). MPIOs were efficiently delivered into live cells and controlled by a magnetic field. Therefore, our study built virus-based cellular delivery systems for different sizes of cargos: protein molecules, nanoparticles, and micron-sized particles. Much research is being done to investigate methods for efficient and specific cellular delivery of drugs, proteins or genetic material. In this article, the authors describe their approach in using self-assembly virus capsid proteins SV40 VP1 (Simian virus 40 major capsid protein). The cell-penetrating behavior provided excellent cellular delivery and should give a new method for biomedical applications. Copyright © 2015 Elsevier Inc. All rights reserved.

A single amino acid residue controls Ca2+ signaling by an octopamine receptor from Drosophila melanogaster

PubMed Central

Hoff, Max; Balfanz, Sabine; Ehling, Petra; Gensch, Thomas; Baumann, Arnd

2011-01-01

Rhythmic activity of cells and cellular networks plays an important role in physiology. In the nervous system oscillations of electrical activity and/or second messenger concentrations are important to synchronize neuronal activity. At the molecular level, rhythmic activity can be initiated by different routes. We have recently shown that an octopamine-activated G-protein-coupled receptor (GPCR; DmOctα1Rb, CG3856) from Drosophila initiates Ca2+ oscillations. Here, we have unraveled the molecular basis of cellular Ca2+ signaling controlled by the DmOctα1Rb receptor using a combination of pharmacological intervention, site-directed mutagenesis, and functional cellular Ca2+ imaging on heterologously expressed receptors. Phosphorylation of a single amino acid residue in the third intracellular loop of the GPCR by PKC is necessary and sufficient to desensitize the receptor. From its desensitized state, DmOctα1Rb is resensitized by dephosphorylation, and a new Ca2+ signal occurs on octopamine stimulation. Our findings show that transient changes of the receptor's surface profile have a strong effect on its physiological signaling properties. We expect that the detailed knowledge of DmOctα1Rb-dependent signal transduction fosters the identification of specific drugs that can be used for GPCR-mediated pest control, since octopamine serves important physiological and behavioral functions in arthropods.—Hoff M., Balfanz, S., Ehling, P., Gensch, T., Baumann, A. A single amino acid residue controls Ca2+ signaling by an octopamine receptor from Drosophila melanogaster. PMID:21478261

Prior cocaine exposure disrupts extinction of fear conditioning

PubMed Central

Burke, Kathryn A.; Franz, Theresa M.; Gugsa, Nishan; Schoenbaum, Geoffrey

2008-01-01

Psychostimulant exposure has been shown to cause molecular and cellular changes in prefrontal cortex. It has been hypothesized that these drug-induced changes might affect the operation of prefrontal-limbic circuits, disrupting their normal role in controlling behavior and thereby leading to compulsive drug-seeking. To test this hypothesis, we tested cocaine-treated rats in a fear conditioning, inflation, and extinction task, known to depend on medial prefrontal cortex and amygdala. Cocaine-treated rats conditioned and inflated similar to saline controls but displayed slower extinction learning. These results support the hypothesis that control processes in the medial prefrontal cortex are impaired by cocaine exposure. PMID:16847305

Prior cocaine exposure disrupts extinction of fear conditioning.

PubMed

Burke, Kathryn A; Franz, Theresa M; Gugsa, Nishan; Schoenbaum, Geoffrey

2006-01-01

Psychostimulant exposure has been shown to cause molecular and cellular changes in prefrontal cortex. It has been hypothesized that these drug-induced changes might affect the operation of prefrontal-limbic circuits, disrupting their normal role in controlling behavior and thereby leading to compulsive drug-seeking. To test this hypothesis, we tested cocaine-treated rats in a fear conditioning, inflation, and extinction task, known to depend on medial prefrontal cortex and amygdala. Cocaine-treated rats conditioned and inflated similar to saline controls but displayed slower extinction learning. These results support the hypothesis that control processes in the medial prefrontal cortex are impaired by cocaine exposure.

A single amino acid residue controls Ca2+ signaling by an octopamine receptor from Drosophila melanogaster.

PubMed

Hoff, Max; Balfanz, Sabine; Ehling, Petra; Gensch, Thomas; Baumann, Arnd

2011-07-01

Rhythmic activity of cells and cellular networks plays an important role in physiology. In the nervous system oscillations of electrical activity and/or second messenger concentrations are important to synchronize neuronal activity. At the molecular level, rhythmic activity can be initiated by different routes. We have recently shown that an octopamine-activated G-protein-coupled receptor (GPCR; DmOctα1Rb, CG3856) from Drosophila initiates Ca(2+) oscillations. Here, we have unraveled the molecular basis of cellular Ca(2+) signaling controlled by the DmOctα1Rb receptor using a combination of pharmacological intervention, site-directed mutagenesis, and functional cellular Ca(2+) imaging on heterologously expressed receptors. Phosphorylation of a single amino acid residue in the third intracellular loop of the GPCR by PKC is necessary and sufficient to desensitize the receptor. From its desensitized state, DmOctα1Rb is resensitized by dephosphorylation, and a new Ca(2+) signal occurs on octopamine stimulation. Our findings show that transient changes of the receptor's surface profile have a strong effect on its physiological signaling properties. We expect that the detailed knowledge of DmOctα1Rb-dependent signal transduction fosters the identification of specific drugs that can be used for GPCR-mediated pest control, since octopamine serves important physiological and behavioral functions in arthropods.

Graphene oxide scaffold accelerates cellular proliferative response and alveolar bone healing of tooth extraction socket.

PubMed

Nishida, Erika; Miyaji, Hirofumi; Kato, Akihito; Takita, Hiroko; Iwanaga, Toshihiko; Momose, Takehito; Ogawa, Kosuke; Murakami, Shusuke; Sugaya, Tsutomu; Kawanami, Masamitsu

2016-01-01

Graphene oxide (GO) consisting of a carbon monolayer has been widely investigated for tissue engineering platforms because of its unique properties. For this study, we fabricated a GO-applied scaffold and assessed the cellular and tissue behaviors in the scaffold. A preclinical test was conducted to ascertain whether the GO scaffold promoted bone induction in dog tooth extraction sockets. For this study, GO scaffolds were prepared by coating the surface of a collagen sponge scaffold with 0.1 and 1 µg/mL GO dispersion. Scaffolds were characterized using scanning electron microscopy (SEM), physical testing, cell seeding, and rat subcutaneous implant testing. Then a GO scaffold was implanted into a dog tooth extraction socket. Histological observations were made at 2 weeks postsurgery. SEM observations show that GO attached to the surface of collagen scaffold struts. The GO scaffold exhibited an interconnected structure resembling that of control subjects. GO application improved the physical strength, enzyme resistance, and adsorption of calcium and proteins. Cytocompatibility tests showed that GO application significantly increased osteoblastic MC3T3-E1 cell proliferation. In addition, an assessment of rat subcutaneous tissue response revealed that implantation of 1 µg/mL GO scaffold stimulated cellular ingrowth behavior, suggesting that the GO scaffold exhibited good biocompatibility. The tissue ingrowth area and DNA contents of 1 µg/mL GO scaffold were, respectively, approximately 2.5-fold and 1.4-fold greater than those of the control. Particularly, the infiltration of ED2-positive (M2) macrophages and blood vessels were prominent in the GO scaffold. Dog bone-formation tests showed that 1 µg/mL GO scaffold implantation enhanced bone formation. New bone formation following GO scaffold implantation was enhanced fivefold compared to that in control subjects. These results suggest that GO was biocompatible and had high bone-formation capability for the scaffold. The GO scaffold is expected to be beneficial for bone tissue engineering therapy.

Multiscale computational modeling reveals a critical role for TNF-α receptor 1 dynamics in tuberculosis granuloma formation.

PubMed

Fallahi-Sichani, Mohammad; El-Kebir, Mohammed; Marino, Simeone; Kirschner, Denise E; Linderman, Jennifer J

2011-03-15

Multiple immune factors control host responses to Mycobacterium tuberculosis infection, including the formation of granulomas, which are aggregates of immune cells whose function may reflect success or failure of the host to contain infection. One such factor is TNF-α. TNF-α has been experimentally characterized to have the following activities in M. tuberculosis infection: macrophage activation, apoptosis, and chemokine and cytokine production. Availability of TNF-α within a granuloma has been proposed to play a critical role in immunity to M. tuberculosis. However, in vivo measurement of a TNF-α concentration gradient and activities within a granuloma are not experimentally feasible. Further, processes that control TNF-α concentration and activities in a granuloma remain unknown. We developed a multiscale computational model that includes molecular, cellular, and tissue scale events that occur during granuloma formation and maintenance in lung. We use our model to identify processes that regulate TNF-α concentration and cellular behaviors and thus influence the outcome of infection within a granuloma. Our model predicts that TNF-αR1 internalization kinetics play a critical role in infection control within a granuloma, controlling whether there is clearance of bacteria, excessive inflammation, containment of bacteria within a stable granuloma, or uncontrolled growth of bacteria. Our results suggest that there is an interplay between TNF-α and bacterial levels in a granuloma that is controlled by the combined effects of both molecular and cellular scale processes. Finally, our model elucidates processes involved in immunity to M. tuberculosis that may be new targets for therapy.

Biomaterial design for specific cellular interactions: Role of surface functionalization and geometric features

NASA Astrophysics Data System (ADS)

Kolhar, Poornima

The areas of drug delivery and tissue engineering have experienced extraordinary growth in recent years with the application of engineering principles and their potential to support and improve the field of medicine. The tremendous progress in nanotechnology and biotechnology has lead to this explosion of research and development in biomedical applications. Biomaterials can now be engineered at a nanoscale and their specific interactions with the biological tissues can be modulated. Various design parameters are being established and researched for design of drug-delivery carriers and scaffolds to be implanted into humans. Nanoparticles made from versatile biomaterial can deliver both small-molecule drugs and various classes of bio-macromolecules, such as proteins and oligonucleotides. Similarly in the field of tissue engineering, current approaches emphasize nanoscale control of cell behavior by mimicking the natural extracellular matrix (ECM) unlike, traditional scaffolds. Drug delivery and tissue engineering are closely connected fields and both of these applications require materials with exceptional physical, chemical, biological, and biomechanical properties to provide superior therapy. In the current study the surface functionalization and the geometric features of the biomaterials has been explored. In particular, a synthetic surface for culture of human embryonic stem cells has been developed, demonstrating the importance of surface functionalization in maintaining the pluripotency of hESCs. In the second study, the geometric features of the drug delivery carriers are investigated and the polymeric nanoneedles mediated cellular permeabilization and direct cytoplasmic delivery is reported. In the third study, the combined effect of surface functionalization and geometric modification of carriers for vascular targeting is enunciated. These studies illustrate how the biomaterials can be designed to achieve various cellular behaviors and control the interactions with cells in vivo .

Procedures for Behavioral Experiments in Head-Fixed Mice

PubMed Central

Guo, Zengcai V.; Hires, S. Andrew; Li, Nuo; O'Connor, Daniel H.; Komiyama, Takaki; Ophir, Eran; Huber, Daniel; Bonardi, Claudia; Morandell, Karin; Gutnisky, Diego; Peron, Simon; Xu, Ning-long; Cox, James; Svoboda, Karel

2014-01-01

The mouse is an increasingly prominent model for the analysis of mammalian neuronal circuits. Neural circuits ultimately have to be probed during behaviors that engage the circuits. Linking circuit dynamics to behavior requires precise control of sensory stimuli and measurement of body movements. Head-fixation has been used for behavioral research, particularly in non-human primates, to facilitate precise stimulus control, behavioral monitoring and neural recording. However, choice-based, perceptual decision tasks by head-fixed mice have only recently been introduced. Training mice relies on motivating mice using water restriction. Here we describe procedures for head-fixation, water restriction and behavioral training for head-fixed mice, with a focus on active, whisker-based tactile behaviors. In these experiments mice had restricted access to water (typically 1 ml/day). After ten days of water restriction, body weight stabilized at approximately 80% of initial weight. At that point mice were trained to discriminate sensory stimuli using operant conditioning. Head-fixed mice reported stimuli by licking in go/no-go tasks and also using a forced choice paradigm using a dual lickport. In some cases mice learned to discriminate sensory stimuli in a few trials within the first behavioral session. Delay epochs lasting a second or more were used to separate sensation (e.g. tactile exploration) and action (i.e. licking). Mice performed a variety of perceptual decision tasks with high performance for hundreds of trials per behavioral session. Up to four months of continuous water restriction showed no adverse health effects. Behavioral performance correlated with the degree of water restriction, supporting the importance of controlling access to water. These behavioral paradigms can be combined with cellular resolution imaging, random access photostimulation, and whole cell recordings. PMID:24520413

ChainMail based neural dynamics modeling of soft tissue deformation for surgical simulation.

PubMed

Zhang, Jinao; Zhong, Yongmin; Smith, Julian; Gu, Chengfan

2017-07-20

Realistic and real-time modeling and simulation of soft tissue deformation is a fundamental research issue in the field of surgical simulation. In this paper, a novel cellular neural network approach is presented for modeling and simulation of soft tissue deformation by combining neural dynamics of cellular neural network with ChainMail mechanism. The proposed method formulates the problem of elastic deformation into cellular neural network activities to avoid the complex computation of elasticity. The local position adjustments of ChainMail are incorporated into the cellular neural network as the local connectivity of cells, through which the dynamic behaviors of soft tissue deformation are transformed into the neural dynamics of cellular neural network. Experiments demonstrate that the proposed neural network approach is capable of modeling the soft tissues' nonlinear deformation and typical mechanical behaviors. The proposed method not only improves ChainMail's linear deformation with the nonlinear characteristics of neural dynamics but also enables the cellular neural network to follow the principle of continuum mechanics to simulate soft tissue deformation.

Cellular registration without behavioral recall of olfactory sensory input under general anesthesia.

PubMed

Samuelsson, Andrew R; Brandon, Nicole R; Tang, Pei; Xu, Yan

2014-04-01

Previous studies suggest that sensory information is "received" but not "perceived" under general anesthesia. Whether and to what extent the brain continues to process sensory inputs in a drug-induced unconscious state remain unclear. One hundred seven rats were randomly assigned to 12 different anesthesia and odor exposure paradigms. The immunoreactivities of the immediate early gene products c-Fos and Egr1 as neural activity markers were combined with behavioral tests to assess the integrity and relationship of cellular and behavioral responsiveness to olfactory stimuli under a surgical plane of ketamine-xylazine general anesthesia. The olfactory sensory processing centers could distinguish the presence or absence of experimental odorants even when animals were fully anesthetized. In the anesthetized state, the c-Fos immunoreactivity in the higher olfactory cortices revealed a difference between novel and familiar odorants similar to that seen in the awake state, suggesting that the anesthetized brain functions beyond simply receiving external stimulation. Reexposing animals to odorants previously experienced only under anesthesia resulted in c-Fos immunoreactivity, which was similar to that elicited by familiar odorants, indicating that previous registration had occurred in the anesthetized brain. Despite the "cellular memory," however, odor discrimination and forced-choice odor-recognition tests showed absence of behavioral recall of the registered sensations, except for a longer latency in odor recognition tests. Histologically distinguishable registration of sensory processing continues to occur at the cellular level under ketamine-xylazine general anesthesia despite the absence of behavioral recognition, consistent with the notion that general anesthesia causes disintegration of information processing without completely blocking cellular communications.

Cellular Registration Without Behavioral Recall Of Olfactory Sensory Input Under General Anesthesia

PubMed Central

Samuelsson, Andrew R.; Brandon, Nicole R.; Tang, Pei; Xu, Yan

2014-01-01

Background Previous studies suggest that sensory information is “received” but not “perceived” under general anesthesia. Whether and to what extent the brain continues to process sensory inputs in a drug-induced unconscious state remain unclear. Methods 107 rats were randomly assigned to 12 different anesthesia and odor exposure paradigms. The immunoreactivities of the immediate early gene products c-Fos and Egr1 as neural activity markers were combined with behavioral tests to assess the integrity and relationship of cellular and behavioral responsiveness to olfactory stimuli under a surgical plane of ketamine-xylazine general anesthesia. Results The olfactory sensory processing centers can distinguish the presence or absence of experimental odorants even when animals were fully anesthetized. In the anesthetized state, the c-Fos immunoreactivity in the higher olfactory cortices revealed a difference between novel and familiar odorants similar to that seen in the awake state, suggesting that the anesthetized brain functions beyond simply receiving external stimulation. Re-exposing animals to odorants previously experienced only under anesthesia resulted in c-Fos immunoreactivity similar to that elicited by familiar odorants, indicating that previous registration had occurred in the anesthetized brain. Despite the “cellular memory,” however, odor discrimination and forced-choice odor-recognition tests showed absence of behavioral recall of the registered sensations, except for a longer latency in odor recognition tests. Conclusions Histologically distinguishable registration of sensory process continues to occur at cellular level under ketamine-xylazine general anesthesia despite the absence of behavioral recognition, consistent with the notion that general anesthesia causes disintegration of information processing without completely blocking cellular communications. PMID:24694846

Modeling Alveolar Epithelial Cell Behavior In Spatially Designed Hydrogel Microenvironments

NASA Astrophysics Data System (ADS)

Lewis, Katherine Jean Reeder

The alveolar epithelium consists of two cell phenotypes, elongated alveolar type I cells (AT1) and rounded alveolar type II cells (ATII), and exists in a complex three-dimensional environment as a polarized cell layer attached to a thin basement membrane and enclosing a roughly spherical lumen. Closely surrounding the alveolar cysts are capillary endothelial cells as well as interstitial pulmonary fibroblasts. Many factors are thought to influence alveolar epithelial cell differentiation during lung development and wound repair, including physical and biochemical signals from the extracellular matrix (ECM), and paracrine signals from the surrounding mesenchyme. In particular, disrupted signaling between the alveolar epithelium and local fibroblasts has been implicated in the progression of several pulmonary diseases. However, given the complexity of alveolar tissue architecture and the multitude of signaling pathways involved, designing appropriate experimental platforms for this biological system has been difficult. In order to isolate key factors regulating cellular behavior, the researcher ideally should have control over biophysical properties of the ECM, as well as the ability to organize multiple cell types within the scaffold. This thesis aimed to develop a 3D synthetic hydrogel platform to control alveolar epithelial cyst formation, which could then be used to explore how extracellular cues influence cell behavior in a tissue-relevant cellular arrangement. To accomplish this, a poly(ethylene glycol) (PEG) hydrogel network containing enzymatically-degradable crosslinks and bioadhesive pendant peptides was employed as a base material for encapsulating primary alveolar epithelial cells. First, an array of microwells of various cross-sectional shapes was photopatterned into a PEG gel containing photo-labile crosslinks, and primary ATII cells were seeded into the wells to examine the role of geometric confinement on differentiation and multicellular arrangement. Aggregate formation in these microwells motivated us to develop a templating technique to create hollow cyst-like epithelial structures within PEG hydrogels. Photodegradable microspheres were used to form spherical epithelial layers, which were then encapsulated in a PEG hydrogel followed by template erosion with cytocompatible light. With these model alveoli, we investigated the interplay between the epithelium and mesenchyme by co-encapsulating healthy and diseased pulmonary fibroblasts with healthy and diseased epithelial cysts and measuring important cellular behaviors (i.e. proliferation, migration, and protein expression). This model of alveolar tissue represents a significant advance in culture platforms available to researchers interested in identifying the mechanisms involved in disease progression and for testing potential therapeutics in a controlled, tissue-appropriate setting.

Exact results of 1D traffic cellular automata: The low-density behavior of the Fukui-Ishibashi model

NASA Astrophysics Data System (ADS)

Salcido, Alejandro; Hernández-Zapata, Ernesto; Carreón-Sierra, Susana

2018-03-01

The maximum entropy states of the cellular automata models for traffic flow in a single-lane with no anticipation are presented and discussed. The exact analytical solutions for the low-density behavior of the stochastic Fukui-Ishibashi traffic model were obtained and compared with computer simulations of the model. An excellent agreement was found.

Identification of non-visual photomotor response cells in the vertebrate hindbrain

PubMed Central

Kokel, David; Dunn, Timothy W.; Ahrens, Misha B.; Alshut, Rüdiger; Cheung, Chung Yan J.; Saint-Amant, Louis; Bruni, Giancarlo; Mateus, Rita; van Ham, Tjakko J.; Shiraki, Tomoya; Fukada, Yoshitaka; Kojima, Daisuke; Yeh, Jing-Ruey J.; Mikut, Ralf; von Lintig, Johannes; Engert, Florian; Peterson, Randall T.

2013-01-01

Non-visual photosensation enables animals to sense light without sight. However, the cellular and molecular mechanisms of non-visual photobehaviors are poorly understood, especially in vertebrate animals. Here, we describe the photomotor response (PMR), a robust and reproducible series of motor behaviors in zebrafish that is elicited by visual wavelengths of light, but does not require the eyes, pineal gland or other canonical deep-brain photoreceptive organs. Unlike the relatively slow effects of canonical non-visual pathways, motor circuits are strongly and quickly (seconds) recruited during the PMR behavior. We find that the hindbrain is both necessary and sufficient to drive these behaviors. Using in vivo calcium imaging, we identify a discrete set of neurons within the hindbrain whose responses to light mirror the PMR behavior. Pharmacological inhibition of the visual cycle blocks PMR behaviors, suggesting that opsin-based photoreceptors control this behavior. These data represent the first known light-sensing circuit in the vertebrate hindbrain. PMID:23447595

SIFamide Translates Hunger Signals into Appetitive and Feeding Behavior in Drosophila.

PubMed

Martelli, Carlotta; Pech, Ulrike; Kobbenbring, Simon; Pauls, Dennis; Bahl, Britta; Sommer, Mirjam Vanessa; Pooryasin, Atefeh; Barth, Jonas; Arias, Carmina Warth Perez; Vassiliou, Chrystalleni; Luna, Abud Jose Farca; Poppinga, Haiko; Richter, Florian Gerhard; Wegener, Christian; Fiala, André; Riemensperger, Thomas

2017-07-11

Animal behavior is, on the one hand, controlled by neuronal circuits that integrate external sensory stimuli and induce appropriate motor responses. On the other hand, stimulus-evoked or internally generated behavior can be influenced by motivational conditions, e.g., the metabolic state. Motivational states are determined by physiological parameters whose homeostatic imbalances are signaled to and processed within the brain, often mediated by modulatory peptides. Here, we investigate the regulation of appetitive and feeding behavior in the fruit fly, Drosophila melanogaster. We report that four neurons in the fly brain that release SIFamide are integral elements of a complex neuropeptide network that regulates feeding. We show that SIFamidergic cells integrate feeding stimulating (orexigenic) and feeding suppressant (anorexigenic) signals to appropriately sensitize sensory circuits, promote appetitive behavior, and enhance food intake. Our study advances the cellular dissection of evolutionarily conserved signaling pathways that convert peripheral metabolic signals into feeding-related behavior. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Microfluidics-Based in Vivo Mimetic Systems for the Study of Cellular Biology

PubMed Central

2015-01-01

Conspectus The human body is a complex network of molecules, organelles, cells, tissues, and organs: an uncountable number of interactions and transformations interconnect all the system’s components. In addition to these biochemical components, biophysical components, such as pressure, flow, and morphology, and the location of all of these interactions play an important role in the human body. Technical difficulties have frequently limited researchers from observing cellular biology as it occurs within the human body, but some state-of-the-art analytical techniques have revealed distinct cellular behaviors that occur only in the context of the interactions. These types of findings have inspired bioanalytical chemists to provide new tools to better understand these cellular behaviors and interactions. What blocks us from understanding critical biological interactions in the human body? Conventional approaches are often too naïve to provide realistic data and in vivo whole animal studies give complex results that may or may not be relevant for humans. Microfluidics offers an opportunity to bridge these two extremes: while these studies will not model the complexity of the in vivo human system, they can control the complexity so researchers can examine critical factors of interest carefully and quantitatively. In addition, the use of human cells, such as cells isolated from donated blood, captures human-relevant data and limits the use of animals in research. In addition, researchers can adapt these systems easily and cost-effectively to a variety of high-end signal transduction mechanisms, facilitating high-throughput studies that are also spatially, temporally, or chemically resolved. These strengths should allow microfluidic platforms to reveal critical parameters in the human body and provide insights that will help with the translation of pharmacological advances to clinical trials. In this Account, we describe selected microfluidic innovations within the last 5 years that focus on modeling both biophysical and biochemical interactions in cellular communication, such as flow and cell–cell networks. We also describe more advanced systems that mimic higher level biological networks, such as organ on-a-chip and animal on-a-chip models. Since the first papers in the early 1990s, interest in the bioanalytical use of microfluidics has grown significantly. Advances in micro-/nanofabrication technology have allowed researchers to produce miniaturized, biocompatible assay platforms suitable for microfluidic studies in biochemistry and chemical biology. Well-designed microfluidic platforms can achieve quick, in vitro analyses on pico- and femtoliter volume samples that are temporally, spatially, and chemically resolved. In addition, controlled cell culture techniques using a microfluidic platform have produced biomimetic systems that allow researchers to replicate and monitor physiological interactions. Pioneering work has successfully created cell–fluid, cell–cell, cell–tissue, tissue–tissue, even organ-like level interfaces. Researchers have monitored cellular behaviors in these biomimetic microfluidic environments, producing validated model systems to understand human pathophysiology and to support the development of new therapeutics. PMID:24555566

Microfluidics-based in vivo mimetic systems for the study of cellular biology.

PubMed

Kim, Donghyuk; Wu, Xiaojie; Young, Ashlyn T; Haynes, Christy L

2014-04-15

The human body is a complex network of molecules, organelles, cells, tissues, and organs: an uncountable number of interactions and transformations interconnect all the system's components. In addition to these biochemical components, biophysical components, such as pressure, flow, and morphology, and the location of all of these interactions play an important role in the human body. Technical difficulties have frequently limited researchers from observing cellular biology as it occurs within the human body, but some state-of-the-art analytical techniques have revealed distinct cellular behaviors that occur only in the context of the interactions. These types of findings have inspired bioanalytical chemists to provide new tools to better understand these cellular behaviors and interactions. What blocks us from understanding critical biological interactions in the human body? Conventional approaches are often too naïve to provide realistic data and in vivo whole animal studies give complex results that may or may not be relevant for humans. Microfluidics offers an opportunity to bridge these two extremes: while these studies will not model the complexity of the in vivo human system, they can control the complexity so researchers can examine critical factors of interest carefully and quantitatively. In addition, the use of human cells, such as cells isolated from donated blood, captures human-relevant data and limits the use of animals in research. In addition, researchers can adapt these systems easily and cost-effectively to a variety of high-end signal transduction mechanisms, facilitating high-throughput studies that are also spatially, temporally, or chemically resolved. These strengths should allow microfluidic platforms to reveal critical parameters in the human body and provide insights that will help with the translation of pharmacological advances to clinical trials. In this Account, we describe selected microfluidic innovations within the last 5 years that focus on modeling both biophysical and biochemical interactions in cellular communication, such as flow and cell-cell networks. We also describe more advanced systems that mimic higher level biological networks, such as organ on-a-chip and animal on-a-chip models. Since the first papers in the early 1990s, interest in the bioanalytical use of microfluidics has grown significantly. Advances in micro-/nanofabrication technology have allowed researchers to produce miniaturized, biocompatible assay platforms suitable for microfluidic studies in biochemistry and chemical biology. Well-designed microfluidic platforms can achieve quick, in vitro analyses on pico- and femtoliter volume samples that are temporally, spatially, and chemically resolved. In addition, controlled cell culture techniques using a microfluidic platform have produced biomimetic systems that allow researchers to replicate and monitor physiological interactions. Pioneering work has successfully created cell-fluid, cell-cell, cell-tissue, tissue-tissue, even organ-like level interfaces. Researchers have monitored cellular behaviors in these biomimetic microfluidic environments, producing validated model systems to understand human pathophysiology and to support the development of new therapeutics.

Effect of psychological tension on pedestrian counter flow via an extended cost potential field cellular automaton model

NASA Astrophysics Data System (ADS)

Li, Xingli; Guo, Fang; Kuang, Hua; Zhou, Huaguo

2017-12-01

Psychology tells us that the different level of tension may lead to different behavior variation for individuals. In this paper, an extended cost potential field cellular automaton is proposed to simulate pedestrian counter flow under an emergency by considering behavior variation of pedestrian induced by psychological tension. A quantitative formula is introduced to describe behavioral changes caused by psychological tension, which also leads to the increasing cost of discomfort. The numerical simulations are performed under the periodic boundary condition and show that the presented model can capture some essential features of pedestrian counter flow, such as lane formation and segregation phenomenon for normal condition. Furthermore, an interesting feature is found that when pedestrians are in an extremely nervous state, a stable lane formation will be broken by a disordered mixture flow. The psychological nervousness under an emergency is not always negative to moving efficiency and a moderate level of tension will delay the occurrence of jamming phase. In addition, a larger asymmetrical ratio of left walkers to right walkers will improve the critical density related to the jamming phase and retard the occurrence of completely jammed phase. These findings will be helpful in pedestrian control and management under an emergency.

Growth and Decay in Life-Like Cellular Automata

NASA Astrophysics Data System (ADS)

Eppstein, David

Since the study of life began, many have asked: is it unique in the universe, or are there other interesting forms of life elsewhere? Before we can answer that question, we should ask others: What makes life special? If we happen across another system with life-like behavior, how would we be able to recognize it? We are speaking, of course, of the mathematical systems of cellular automata, of the fascinating patterns that have been discovered and engineered in Conway's Game of Life, and of the possible existence of other cellular automaton rules with equally complex behavior to that of Life.

Organelles – understanding noise and heterogeneity in cell biology at an intermediate scale

PubMed Central

Chang, Amy Y.

2017-01-01

ABSTRACT Many studies over the years have shown that non-genetic mechanisms for producing cell-to-cell variation can lead to highly variable behaviors across genetically identical populations of cells. Most work to date has focused on gene expression noise as the primary source of phenotypic heterogeneity, yet other sources may also contribute. In this Commentary, we explore organelle-level heterogeneity as a potential secondary source of cellular ‘noise’ that contributes to phenotypic heterogeneity. We explore mechanisms for generating organelle heterogeneity and present evidence of functional links between organelle morphology and cellular behavior. Given the many instances in which molecular-level heterogeneity has been linked to phenotypic heterogeneity, we posit that organelle heterogeneity may similarly contribute to overall phenotypic heterogeneity and underline the importance of studying organelle heterogeneity to develop a more comprehensive understanding of phenotypic heterogeneity. Finally, we conclude with a discussion of the medical challenges associated with phenotypic heterogeneity and outline how improved methods for characterizing and controlling this heterogeneity may lead to improved therapeutic strategies and outcomes for patients. PMID:28183729

Secreting and sensing the same molecule allows cells to achieve versatile social behaviors

PubMed Central

Youk, Hyun; Lim, Wendell A.

2014-01-01

Cells that secrete and sense the same signaling molecule are ubiquitous. To uncover the functional capabilities of the core ‘secrete-and-sense’ circuit motif shared by these cells, we engineered yeast to secrete and sense the mating pheromone. Perturbing each circuit element revealed parameters that control the degree to which the cell communicated with itself versus with its neighbors. This tunable interplay of self- and neighbor-communication enables cells to span a diverse repertoire of cellular behaviors. These include a cell being asocial by responding only to itself, social through quorum sensing and an isogenic population of cells splitting into social and asocial subpopulations. A mathematical model explained these behaviors. The versatility of the secrete-and-sense circuit motif may explain its recurrence across species. PMID:24503857

A Focus on Reward Prediction and the Lateral Habenula: Functional Alterations and the Behavioral Outcomes Induced by Drugs of Abuse.

PubMed

Graziane, Nicholas M; Neumann, Peter A; Dong, Yan

2018-01-01

The lateral habenula (LHb) regulates reward learning and controls the updating of reward-related information. Drugs of abuse have the capacity to hijack the cellular and neurocircuit mechanisms mediating reward learning, forming non-adaptable, compulsive behaviors geared toward obtaining illicit substances. Here, we discuss current findings demonstrating how drugs of abuse alter intrinsic and synaptic LHb neuronal function. Additionally, we discuss evidence for how drug-induced LHb alterations may affect the ability to predict reward, potentially facilitating an addiction-like state. Altogether, we combine ex vivo and in vivo results for an overview of how drugs of abuse alter LHb function and how these functional alterations affect the ability to learn and update behavioral responses to hedonic external stimuli.

Nanoscale tissue engineering: spatial control over cell-materials interactions

PubMed Central

Wheeldon, Ian; Farhadi, Arash; Bick, Alexander G.; Jabbari, Esmaiel; Khademhosseini, Ali

2011-01-01

Cells interact with the surrounding environment by making tens to hundreds of thousands of nanoscale interactions with extracellular signals and features. The goal of nanoscale tissue engineering is to harness the interactions through nanoscale biomaterials engineering in order to study and direct cellular behaviors. Here, we review the nanoscale tissue engineering technologies for both two- and three-dimensional studies (2- and 3D), and provide a holistic overview of the field. Techniques that can control the average spacing and clustering of cell adhesion ligands are well established and have been highly successful in describing cell adhesion and migration in 2D. Extension of these engineering tools to 3D biomaterials has created many new hydrogel and nanofiber scaffolds technologies that are being used to design in vitro experiments with more physiologically relevant conditions. Researchers are beginning to study complex cell functions in 3D, however, there is a need for biomaterials systems that provide fine control over the nanoscale presentation of bioactive ligands in 3D. Additionally, there is a need for 2- and 3D techniques that can control the nanoscale presentation of multiple bioactive ligands and the temporal changes in cellular microenvironment. PMID:21451238

Study of living single cells in culture: automated recognition of cell behavior.

PubMed

Bodin, P; Papin, S; Meyer, C; Travo, P

1988-07-01

An automated system capable of analyzing the behavior, in real time, of single living cells in culture, in a noninvasive and nondestructive way, has been developed. A large number of cell positions in single culture dishes were recorded using a computer controlled, robotized microscope. During subsequent observations, binary images obtained from video image analysis of the microscope visual field allowed the identification of the recorded cells. These cells could be revisited automatically every few minutes. Long-term studies of the behavior of cells make possible the analysis of cellular locomotary and mitotic activities as well as determination of cell shape (chosen from a defined library) for several hours or days in a fully automated way with observations spaced up to 30 minutes. Short-term studies of the behavior of cells permit the study, in a semiautomatic way, of acute effects of drugs (5 to 15 minutes) on changes of surface area and length of cells.

The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with Premenstrual Dysphoric Disorder

PubMed Central

Dubey, Neelima; Hoffman, Jessica F.; Schuebel, Kornel; Yuan, Qiaoping; Martinez, Pedro E.; Nieman, Lynnette K.; Rubinow, David R.; Schmidt, Peter J.; Goldman, David

2016-01-01

Clinical evidence suggests that mood and behavioral symptoms in Premenstrual Dysphoric Disorder (PMDD), a common, recently recognized, psychiatric condition among women, reflect abnormal responsivity to ovarian steroids. This differential sensitivity could be due to an unrecognized aspect of hormonal signaling or a difference in cellular response. In this study, lymphoblastoid cell line cultures (LCLs) from women with PMDD and asymptomatic Controls were compared via whole transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and following hormone treatment. The women with PMDD manifested ovarian steroid-triggered behavioral sensitivity during a hormone suppression and add-back clinical trial, and Controls did not, leading us to hypothesize that women with PMDD might differ in their cellular response to ovarian steroids. In untreated LCLs, our results overall suggest a divergence between mRNA (e.g., gene transcription) and protein (e.g., RNA translation in proteins) for the same genes. Pathway analysis of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) in untreated LCLs from women with PMDD, with more than half of these genes over-expressed as compared to Controls, and with significant effects for MTF2, PHF19, and SIRT1 (p<0.05). RNA and protein expression of the 13 ESC/E(Z) complex genes were individually quantitated. This pattern of increased ESC/E(Z) mRNA expression was confirmed in a larger cohort by qRT-PCR. In contrast, protein expression of ESC/E(Z) genes was decreased in untreated PMDD LCLs with MTF2, PHF19, and SIRT1 all significantly decreased (p<0.05). Finally, mRNA expression of several ESC/E(Z) complex genes were increased by progesterone in Controls only, and decreased by estradiol in PMDD LCLs. These findings demonstrate that LCLs from women with PMDD manifest a cellular difference in ESC/E(Z) complex function both in the untreated condition and in response to ovarian hormones. Dysregulation of ESC/E(Z) complex function could contribute to PMDD. PMID:28044059

Oscillatory cellular patterns in three-dimensional directional solidification

NASA Astrophysics Data System (ADS)

Tourret, D.; Debierre, J.-M.; Song, Y.; Mota, F. L.; Bergeon, N.; Guérin, R.; Trivedi, R.; Billia, B.; Karma, A.

2015-10-01

We present a phase-field study of oscillatory breathing modes observed during the solidification of three-dimensional cellular arrays in microgravity. Directional solidification experiments conducted onboard the International Space Station have allowed us to observe spatially extended homogeneous arrays of cells and dendrites while minimizing the amount of gravity-induced convection in the liquid. In situ observations of transparent alloys have revealed the existence, over a narrow range of control parameters, of oscillations in cellular arrays with a period ranging from about 25 to 125 min. Cellular patterns are spatially disordered, and the oscillations of individual cells are spatiotemporally uncorrelated at long distance. However, in regions displaying short-range spatial ordering, groups of cells can synchronize into oscillatory breathing modes. Quantitative phase-field simulations show that the oscillatory behavior of cells in this regime is linked to a stability limit of the spacing in hexagonal cellular array structures. For relatively high cellular front undercooling (i.e., low growth velocity or high thermal gradient), a gap appears in the otherwise continuous range of stable array spacings. Close to this gap, a sustained oscillatory regime appears with a period that compares quantitatively well with experiment. For control parameters where this gap exists, oscillations typically occur for spacings at the edge of the gap. However, after a change of growth conditions, oscillations can also occur for nearby values of control parameters where this gap just closes and a continuous range of spacings exists. In addition, sustained oscillations at to the opening of this stable gap exhibit a slow periodic modulation of the phase-shift among cells with a slower period of several hours. While long-range coherence of breathing modes can be achieved in simulations for a perfect spatial arrangement of cells as initial condition, global disorder is observed in both three-dimensional experiments and simulations from realistic noisy initial conditions. In the latter case, erratic tip-splitting events promoted by large-amplitude oscillations contribute to maintaining the long-range array disorder, unlike in thin-sample experiments where long-range coherence of oscillations is experimentally observable.

Oscillatory cellular patterns in three-dimensional directional solidification

DOE PAGES

Tourret, D.; Debierre, J. -M.; Song, Y.; ...

2015-09-11

We present a phase-field study of oscillatory breathing modes observed during the solidification of three-dimensional cellular arrays in micro-gravity. Directional solidification experiments conducted onboard the International Space Station have allowed for the first time to observe spatially extended homogeneous arrays of cells and dendrites while minimizing the amount of gravity-induced convection in the liquid. In situ observations of transparent alloys have revealed the existence, over a narrow range of control parameters, of oscillations in cellular arrays with a period ranging from about 25 to 125 minutes. Cellular patterns are spatially disordered, and the oscillations of individual cells are spatiotemporally uncorrelatedmore » at long distance. However, in regions displaying short-range spatial ordering, groups of cells can synchronize into oscillatory breathing modes. Quantitative phase-field simulations show that the oscillatory behavior of cells in this regime is linked to a stability limit of the spacing in hexagonal cellular array structures. For relatively high cellular front undercooling (\\ie low growth velocity or high thermal gradient), a gap appears in the otherwise continuous range of stable array spacings. Close to this gap, a sustained oscillatory regime appears with a period that compares quantitatively well with experiment. For control parameters where this gap exist, oscillations typically occur for spacings at the edge of the gap. However, after a change of growth conditions, oscillations can also occur for nearby values of control parameters where this gap just closes and a continuous range of spacings exists. In addition, sustained oscillations at to the opening of this stable gap exhibit a slow periodic modulation of the phase-shift among cells with a slower period of several hours. While long-range coherence of breathing modes can be achieved in simulations for a perfect spatial arrangement of cells as initial condition, global disorder is observed in both three-dimensional experiments and simulations from realistic noisy initial conditions. The, erratic tip splitting events promoted by large amplitude oscillations contribute to maintaining the long-range array disorder, unlike in thin sample experiments where long-range coherence of oscillations is experimentally observable.« less

Oscillatory cellular patterns in three-dimensional directional solidification

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

Tourret, D.; Debierre, J. -M.; Song, Y.

We present a phase-field study of oscillatory breathing modes observed during the solidification of three-dimensional cellular arrays in micro-gravity. Directional solidification experiments conducted onboard the International Space Station have allowed for the first time to observe spatially extended homogeneous arrays of cells and dendrites while minimizing the amount of gravity-induced convection in the liquid. In situ observations of transparent alloys have revealed the existence, over a narrow range of control parameters, of oscillations in cellular arrays with a period ranging from about 25 to 125 minutes. Cellular patterns are spatially disordered, and the oscillations of individual cells are spatiotemporally uncorrelatedmore » at long distance. However, in regions displaying short-range spatial ordering, groups of cells can synchronize into oscillatory breathing modes. Quantitative phase-field simulations show that the oscillatory behavior of cells in this regime is linked to a stability limit of the spacing in hexagonal cellular array structures. For relatively high cellular front undercooling (\\ie low growth velocity or high thermal gradient), a gap appears in the otherwise continuous range of stable array spacings. Close to this gap, a sustained oscillatory regime appears with a period that compares quantitatively well with experiment. For control parameters where this gap exist, oscillations typically occur for spacings at the edge of the gap. However, after a change of growth conditions, oscillations can also occur for nearby values of control parameters where this gap just closes and a continuous range of spacings exists. In addition, sustained oscillations at to the opening of this stable gap exhibit a slow periodic modulation of the phase-shift among cells with a slower period of several hours. While long-range coherence of breathing modes can be achieved in simulations for a perfect spatial arrangement of cells as initial condition, global disorder is observed in both three-dimensional experiments and simulations from realistic noisy initial conditions. The, erratic tip splitting events promoted by large amplitude oscillations contribute to maintaining the long-range array disorder, unlike in thin sample experiments where long-range coherence of oscillations is experimentally observable.« less

Data-driven modeling reveals cell behaviors controlling self-organization during Myxococcus xanthus development

PubMed Central

Cotter, Christopher R.; Schüttler, Heinz-Bernd; Igoshin, Oleg A.; Shimkets, Lawrence J.

2017-01-01

Collective cell movement is critical to the emergent properties of many multicellular systems, including microbial self-organization in biofilms, embryogenesis, wound healing, and cancer metastasis. However, even the best-studied systems lack a complete picture of how diverse physical and chemical cues act upon individual cells to ensure coordinated multicellular behavior. Known for its social developmental cycle, the bacterium Myxococcus xanthus uses coordinated movement to generate three-dimensional aggregates called fruiting bodies. Despite extensive progress in identifying genes controlling fruiting body development, cell behaviors and cell–cell communication mechanisms that mediate aggregation are largely unknown. We developed an approach to examine emergent behaviors that couples fluorescent cell tracking with data-driven models. A unique feature of this approach is the ability to identify cell behaviors affecting the observed aggregation dynamics without full knowledge of the underlying biological mechanisms. The fluorescent cell tracking revealed large deviations in the behavior of individual cells. Our modeling method indicated that decreased cell motility inside the aggregates, a biased walk toward aggregate centroids, and alignment among neighboring cells in a radial direction to the nearest aggregate are behaviors that enhance aggregation dynamics. Our modeling method also revealed that aggregation is generally robust to perturbations in these behaviors and identified possible compensatory mechanisms. The resulting approach of directly combining behavior quantification with data-driven simulations can be applied to more complex systems of collective cell movement without prior knowledge of the cellular machinery and behavioral cues. PMID:28533367

Cellular energy metabolism in T-lymphocytes.

PubMed

Gaber, Timo; Strehl, Cindy; Sawitzki, Birgit; Hoff, Paula; Buttgereit, Frank

2015-01-01

Energy homeostasis is a hallmark of cell survival and maintenance of cell function. Here we focus on the impact of cellular energy metabolism on T-lymphocyte differentiation, activation, and function in health and disease. We describe the role of transcriptional and posttranscriptional regulation of lymphocyte metabolism on immune functions of T cells. We also summarize the current knowledge about T-lymphocyte adaptations to inflammation and hypoxia, and the impact on T-cell behavior of pathophysiological hypoxia (as found in tumor tissue, chronically inflamed joints in rheumatoid arthritis and during bone regeneration). A better understanding of the underlying mechanisms that control immune cell metabolism and immune response may provide therapeutic opportunities to alter the immune response under conditions of either immunosuppression or inflammation, potentially targeting infections, vaccine response, tumor surveillance, autoimmunity, and inflammatory disorders.

Micropattern array with gradient size (µPAGS) plastic surfaces fabricated by PDMS (polydimethylsiloxane) mold-based hot embossing technique for investigation of cell-surface interaction.

PubMed

Choi, Min Jin; Park, Ju Young; Cha, Kyoung Je; Rhie, Jong-Won; Cho, Dong-Woo; Kim, Dong Sung

2012-12-01

Recently, it was found that the variations of physical environment significantly affect cell behaviors including cell proliferation, migration and differentiation. Through a plastic surface with controlled mechanical properties such as stiffness, one can change the orientation and migration of cells in a particular direction, thereby determining cell behaviors. In this study, we demonstrate a polydimethylsiloxane (PDMS) mold-based hot embossing technique for rapid, simple and low-cost replication of polystyrene (PS) surfaces having micropatterns. The PDMS mold was fabricated by UV-photolithography followed by PDMS casting; the elastomeric properties of PDMS enabled us to obtain conformal contact of the PDMS mold to a PS surface and to create high transcription quality of micropatterns on the PS surface. Two different types of circular micropillar and microwell arrays were successfully replicated on the PS surfaces based on the suggested technique. The micropatterns were designed to have various diameters (2-150 µm), spacings (2-160 µm) and heights (1.4, 2.4, 8.2 and 14.9 µm), so as to generate the gradient of physical properties on the surface. Experimental parametric studies indicated that (1) the embossing temperature became a critical processing parameter as the aspect ratio of micropattern increased and (2) the PDMS mold-based hot embossing could successfully replicate micropatterns, even having an aspect ratio of 2.7 for micropattern diameter of 6 µm, with an optimal processing condition (embossing pressure and temperature of 0.4 MPa and 130 °C, respectively) in this study. We carried out cell experiments with adipose-derived stem cells on the replicated PS surface with the height of 1.4 µm to investigate cellular behaviors in response to the micropattern array with gradient size. Cellular experiment results showed that the micropillar-arrayed surface improved cell proliferation as compared with the microwell-arrayed surface. We could also estimate the ranges of pattern sizes having the desired effects on the cellular behaviors.

Transcript, protein and metabolite temporal dynamics in the CAM plant Agave

DOE PAGES

Abraham, Paul E.; Yin, Hengfu; Borland, Anne M.; ...

2016-11-21

Already a proven mechanism for drought resilience, crassulacean acid metabolism (CAM) is a specialized type of photosynthesis that maximizes water-use efficiency (WUE) via an inverse (compared to C 3 and C 4 photosynthesis-performing species) day/night pattern of stomatal closure/opening to shift CO 2 uptake to the night, when evapotranspiration rates are low. A systems-level understanding of temporal molecular and metabolic controls is needed to define the cellular behavior that underpins CAM. Here, we report high-resolution temporal behaviors of transcript, protein and metabolite abundances across a CAM diel cycle and, where applicable, compare those observations to the well-established C 3 modelmore » plant, Arabidopsis thaliana. A mechanistic finding that emerged is that CAM operates with a diel redox poise that is shifted relative to that in Arabidopsis thaliana. Moreover, we identified widespread rescheduled expression of genes associated with signal transduction mechanisms that regulate stomatal opening/closing. Controlled production and degradation of transcripts and proteins represents a timing mechanism by which to regulate cellular function, yet how this molecular timekeeping regulates CAM physiology remains unclear. In this paper, we provide new insights into complex post-transcriptional and -translational hierarchies that govern CAM in Agave. These data sets together provide a resource to inform efforts to engineer more water-use efficient CAM pathway traits into economically valuable C 3 crops.« less

Transcript, protein and metabolite temporal dynamics in the CAM plant Agave

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

Abraham, Paul E.; Yin, Hengfu; Borland, Anne M.

Already a proven mechanism for drought resilience, crassulacean acid metabolism (CAM) is a specialized type of photosynthesis that maximizes water-use efficiency (WUE) via an inverse (compared to C 3 and C 4 photosynthesis-performing species) day/night pattern of stomatal closure/opening to shift CO 2 uptake to the night, when evapotranspiration rates are low. A systems-level understanding of temporal molecular and metabolic controls is needed to define the cellular behavior that underpins CAM. Here, we report high-resolution temporal behaviors of transcript, protein and metabolite abundances across a CAM diel cycle and, where applicable, compare those observations to the well-established C 3 modelmore » plant, Arabidopsis thaliana. A mechanistic finding that emerged is that CAM operates with a diel redox poise that is shifted relative to that in Arabidopsis thaliana. Moreover, we identified widespread rescheduled expression of genes associated with signal transduction mechanisms that regulate stomatal opening/closing. Controlled production and degradation of transcripts and proteins represents a timing mechanism by which to regulate cellular function, yet how this molecular timekeeping regulates CAM physiology remains unclear. In this paper, we provide new insights into complex post-transcriptional and -translational hierarchies that govern CAM in Agave. These data sets together provide a resource to inform efforts to engineer more water-use efficient CAM pathway traits into economically valuable C 3 crops.« less

Multiscale Feature Analysis of Salivary Gland Branching Morphogenesis

PubMed Central

Baydil, Banu; Daley, William P.; Larsen, Melinda; Yener, Bülent

2012-01-01

Pattern formation in developing tissues involves dynamic spatio-temporal changes in cellular organization and subsequent evolution of functional adult structures. Branching morphogenesis is a developmental mechanism by which patterns are generated in many developing organs, which is controlled by underlying molecular pathways. Understanding the relationship between molecular signaling, cellular behavior and resulting morphological change requires quantification and categorization of the cellular behavior. In this study, tissue-level and cellular changes in developing salivary gland in response to disruption of ROCK-mediated signaling by are modeled by building cell-graphs to compute mathematical features capturing structural properties at multiple scales. These features were used to generate multiscale cell-graph signatures of untreated and ROCK signaling disrupted salivary gland organ explants. From confocal images of mouse submandibular salivary gland organ explants in which epithelial and mesenchymal nuclei were marked, a multiscale feature set capturing global structural properties, local structural properties, spectral, and morphological properties of the tissues was derived. Six feature selection algorithms and multiway modeling of the data was performed to identify distinct subsets of cell graph features that can uniquely classify and differentiate between different cell populations. Multiscale cell-graph analysis was most effective in classification of the tissue state. Cellular and tissue organization, as defined by a multiscale subset of cell-graph features, are both quantitatively distinct in epithelial and mesenchymal cell types both in the presence and absence of ROCK inhibitors. Whereas tensor analysis demonstrate that epithelial tissue was affected the most by inhibition of ROCK signaling, significant multiscale changes in mesenchymal tissue organization were identified with this analysis that were not identified in previous biological studies. We here show how to define and calculate a multiscale feature set as an effective computational approach to identify and quantify changes at multiple biological scales and to distinguish between different states in developing tissues. PMID:22403724

Time-spatial model on the dynamics of the proliferation of Aedes aegypti

NASA Astrophysics Data System (ADS)

Gouvêa, Maury Meirelles, Jr.

2017-03-01

Some complex physical systems, such as cellular regulation, ecosystems, and societies, can be represented by local interactions between agents. Then, complex behaviors may emerge. A cellular automaton is a discrete dynamic system with these features. Among the several complex systems, epidemic diseases are given special attention by researchers with respect to their dynamics. Understanding the behavior of an epidemic may well benefit a society. For instance, different proliferation scenarios may be produced and a prevention policy set. This paper presents a new simulation method of the time-spatial spread of the Dengue mosquito with a cellular automaton. Thus, it will be possible to create different dissemination scenarios and preventive policies for these in several regions. Simulations were performed with different initial conditions and parameters as a result of which the behavior of the proposed method was characterized.

“Engineering Substrate Micro- and Nanotopography to Control Cell Function”

PubMed Central

Bettinger, Christopher J; Langer, Robert; Borenstein, Jeffrey T

2010-01-01

Lead-In The interaction of mammalian cells with nanoscale topography has proven to be an important signaling modality in controlling cell function. Naturally occurring nanotopographic structures within the extracellular matrix present surrounding cells with mechanotransductive cues that influence local migration, cell polarization, and other functions. Synthetically nanofabricated topography can also influence cell morphology, alignment, adhesion, migration, proliferation, and cytoskeleton organization. Here we review the use of in vitro synthetic cell-nanotopography interactions to control cell behavior and influence complex cellular processes including stem cell differentiation and tissue organization. Future challenges and opportunities in cell-nanotopography engineering will also be discussed including the elucidation of mechanisms and applications in tissue engineering. PMID:19492373

Feeding Behaviors in Cellular Slime Molds: A Microbial System To Study Competition.

ERIC Educational Resources Information Center

Bozzone, Donna M.

1997-01-01

Describes a laboratory project for first-year biology students that examines competition among various cellular slime molds. After a brief introduction to the topic of competition and basic life history information about cellular slime molds, students choose a question and design original experiments to seek an answer. (Author/AIM)

Reversible online control of habitual behavior by optogenetic perturbation of medial prefrontal cortex

PubMed Central

Smith, Kyle S.; Virkud, Arti; Deisseroth, Karl; Graybiel, Ann M.

2012-01-01

Habits tend to form slowly but, once formed, can have great stability. We probed these temporal characteristics of habitual behaviors by intervening optogenetically in forebrain habit circuits as rats performed well-ingrained habitual runs in a T-maze. We trained rats to perform a maze habit, confirmed the habitual behavior by devaluation tests, and then, during the maze runs (ca. 3 s), we disrupted population activity in a small region in the medial prefrontal cortex, the infralimbic cortex. In accordance with evidence that this region is necessary for the expression of habits, we found that this cortical disruption blocked habitual behavior. Notably, however, this blockade of habitual performance occurred on line, within an average of three trials (ca. 9 s of inhibition), and as soon as during the first trial (<3 s). During subsequent weeks of training, the rats acquired a new behavioral pattern. When we again imposed the same cortical perturbation, the rats regained the suppressed maze-running that typified the original habit, and, simultaneously, the more recently acquired habit was blocked. These online changes occurred within an average of two trials (ca. 6 s of infralimbic inhibition). Measured changes in generalized performance ability and motivation to consume reward were unaffected. This immediate toggling between breaking old habits and returning to them demonstrates that even semiautomatic behaviors are under cortical control and that this control occurs online, second by second. These temporal characteristics define a framework for uncovering cellular transitions between fixed and flexible behaviors, and corresponding disturbances in pathologies. PMID:23112197

Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology.

PubMed

Gadad, Bharathi S; Li, Wenhao; Yazdani, Umar; Grady, Stephen; Johnson, Trevor; Hammond, Jacob; Gunn, Howard; Curtis, Britni; English, Chris; Yutuc, Vernon; Ferrier, Clayton; Sackett, Gene P; Marti, C Nathan; Young, Keith; Hewitson, Laura; German, Dwight C

2015-10-06

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Some anecdotal reports suggest that ASD is related to exposure to ethyl mercury, in the form of the vaccine preservative, thimerosal, and/or receiving the measles, mumps, rubella (MMR) vaccine. Using infant rhesus macaques receiving thimerosal-containing vaccines (TCVs) following the recommended pediatric vaccine schedules from the 1990s and 2008, we examined behavior, and neuropathology in three brain regions found to exhibit neuropathology in postmortem ASD brains. No neuronal cellular or protein changes in the cerebellum, hippocampus, or amygdala were observed in animals following the 1990s or 2008 vaccine schedules. Analysis of social behavior in juvenile animals indicated that there were no significant differences in negative behaviors between animals in the control and experimental groups. These data indicate that administration of TCVs and/or the MMR vaccine to rhesus macaques does not result in neuropathological abnormalities, or aberrant behaviors, like those observed in ASD.

Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology

PubMed Central

Gadad, Bharathi S.; Li, Wenhao; Yazdani, Umar; Grady, Stephen; Johnson, Trevor; Hammond, Jacob; Gunn, Howard; Curtis, Britni; English, Chris; Yutuc, Vernon; Ferrier, Clayton; Sackett, Gene P.; Marti, C. Nathan; Young, Keith; Hewitson, Laura; German, Dwight C.

2015-01-01

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Some anecdotal reports suggest that ASD is related to exposure to ethyl mercury, in the form of the vaccine preservative, thimerosal, and/or receiving the measles, mumps, rubella (MMR) vaccine. Using infant rhesus macaques receiving thimerosal-containing vaccines (TCVs) following the recommended pediatric vaccine schedules from the 1990s and 2008, we examined behavior, and neuropathology in three brain regions found to exhibit neuropathology in postmortem ASD brains. No neuronal cellular or protein changes in the cerebellum, hippocampus, or amygdala were observed in animals following the 1990s or 2008 vaccine schedules. Analysis of social behavior in juvenile animals indicated that there were no significant differences in negative behaviors between animals in the control and experimental groups. These data indicate that administration of TCVs and/or the MMR vaccine to rhesus macaques does not result in neuropathological abnormalities, or aberrant behaviors, like those observed in ASD. PMID:26417083

A Continuum Damage Mechanics Model for the Static and Cyclic Fatigue of Cellular Composites

PubMed Central

Huber, Otto

2017-01-01

The fatigue behavior of a cellular composite with an epoxy matrix and glass foam granules is analyzed and modeled by means of continuum damage mechanics. The investigated cellular composite is a particular type of composite foam, and is very similar to syntactic foams. In contrast to conventional syntactic foams constituted by hollow spherical particles (balloons), cellular glass, mineral, or metal place holders are combined with the matrix material (metal or polymer) in the case of cellular composites. A microstructural investigation of the damage behavior is performed using scanning electron microscopy. For the modeling of the fatigue behavior, the damage is separated into pure static and pure cyclic damage and described in terms of the stiffness loss of the material using damage models for cyclic and creep damage. Both models incorporate nonlinear accumulation and interaction of damage. A cycle jumping procedure is developed, which allows for a fast and accurate calculation of the damage evolution for constant load frequencies. The damage model is applied to examine the mean stress effect for cyclic fatigue and to investigate the frequency effect and the influence of the signal form in the case of static and cyclic damage interaction. The calculated lifetimes are in very good agreement with experimental results. PMID:28809806

Adaptive Control Model Reveals Systematic Feedback and Key Molecules in Metabolic Pathway Regulation

PubMed Central

Moffitt, Richard A.; Merrill, Alfred H.; Wang, May D.

2011-01-01

Abstract Robust behavior in metabolic pathways resembles stabilized performance in systems under autonomous control. This suggests we can apply control theory to study existing regulation in these cellular networks. Here, we use model-reference adaptive control (MRAC) to investigate the dynamics of de novo sphingolipid synthesis regulation in a combined theoretical and experimental case study. The effects of serine palmitoyltransferase over-expression on this pathway are studied in vitro using human embryonic kidney cells. We report two key results from comparing numerical simulations with observed data. First, MRAC simulations of pathway dynamics are comparable to simulations from a standard model using mass action kinetics. The root-sum-square (RSS) between data and simulations in both cases differ by less than 5%. Second, MRAC simulations suggest systematic pathway regulation in terms of adaptive feedback from individual molecules. In response to increased metabolite levels available for de novo sphingolipid synthesis, feedback from molecules along the main artery of the pathway is regulated more frequently and with greater amplitude than from other molecules along the branches. These biological insights are consistent with current knowledge while being new that they may guide future research in sphingolipid biology. In summary, we report a novel approach to study regulation in cellular networks by applying control theory in the context of robust metabolic pathways. We do this to uncover potential insight into the dynamics of regulation and the reverse engineering of cellular networks for systems biology. This new modeling approach and the implementation routines designed for this case study may be extended to other systems. Supplementary Material is available at www.liebertonline.com/cmb. PMID:21314456

Dynamic and coordinated single-molecular interactions at TM4SF5-enriched microdomains guide invasive behaviors in 2- and 3-dimensional environments.

PubMed

Kim, Hye-Jin; Kwon, Sojung; Nam, Seo Hee; Jung, Jae Woo; Kang, Minkyung; Ryu, Jihye; Kim, Ji Eon; Cheong, Jin-Gyu; Cho, Chang Yun; Kim, Somi; Song, Dae-Geun; Kim, Yong-Nyun; Kim, Tai Young; Jung, Min-Kyo; Lee, Kyung-Min; Pack, Chan-Gi; Lee, Jung Weon

2017-04-01

Membrane proteins sense extracellular cues and transduce intracellular signaling to coordinate directionality and speed during cellular migration. They are often localized to specific regions, as with lipid rafts or tetraspanin-enriched microdomains; however, the dynamic interactions of tetraspanins with diverse receptors within tetraspanin-enriched microdomains on cellular surfaces remain largely unexplored. Here, we investigated effects of tetraspan(in) TM4SF5 (transmembrane 4 L6 family member 5)-enriched microdomains (T 5 ERMs) on the directionality of cell migration. Physical association of TM4SF5 with epidermal growth factor receptor (EGFR) and integrin α5 was visualized by live fluorescence cross-correlation spectroscopy and higher-resolution microscopy at the leading edge of migratory cells, presumably forming TM4SF5-enriched microdomains. Whereas TM4SF5 and EGFR colocalized at the migrating leading region more than at the rear, TM4SF5 and integrin α5 colocalized evenly throughout cells. Cholesterol depletion and disruption in TM4SF5 post-translational modifications, including N -glycosylation and palmitoylation, altered TM4SF5 interactions and cellular localization, which led to less cellular migration speed and directionality in 2- or 3-dimensional conditions. TM4SF5 controlled directional cell migration and invasion, and importantly, these TM4SF5 functions were dependent on cholesterol, TM4SF5 post-translational modifications, and EGFR and integrin α5 activity. Altogether, we showed that TM4SF5 dynamically interacted with EGFR and integrin α5 in migratory cells to control directionality and invasion.-Kim, H.-J., Kwon, S., Nam, S. H., Jung, J. W., Kang, M., Ryu, J., Kim, J. E., Cheong, J.-G., Cho, C. Y., Kim, S., Song, D.-G., Kim, Y.-N., Kim, T. Y., Jung, M.-K., Lee, K.-M., Pack, C.-G., Lee, J. W. Dynamic and coordinated single-molecular interactions at TM4SF5-enriched microdomains guide invasive behaviors in 2- and 3-dimensional environments. © FASEB.

Hydrophobic Drug-Loaded PEGylated Magnetic Liposomes for Drug-Controlled Release

NASA Astrophysics Data System (ADS)

Hardiansyah, Andri; Yang, Ming-Chien; Liu, Ting-Yu; Kuo, Chih-Yu; Huang, Li-Ying; Chan, Tzu-Yi

2017-05-01

Less targeted and limited solubility of hydrophobic-based drug are one of the serious obstacles in drug delivery system. Thus, new strategies to enhance the solubility of hydrophobic drug and controlled release behaviors would be developed. Herein, curcumin, a model of hydrophobic drug, has been loaded into PEGylated magnetic liposomes as a drug carrier platform for drug controlled release system. Inductive magnetic heating (hyperthermia)-stimulated drug release, in vitro cellular cytotoxicity assay of curcumin-loaded PEGylated magnetic liposomes and cellular internalization-induced by magnetic guidance would be investigated. The resultant of drug carriers could disperse homogeneously in aqueous solution, showing a superparamagnetic characteristic and could inductive magnetic heating with external high-frequency magnetic field (HFMF). In vitro curcumin release studies confirmed that the drug carriers exhibited no significant release at 37 °C, whereas exhibited rapid releasing at 45 °C. However, it would display enormous (three times higher) curcumin releasing under the HFMF exposure, compared with that without HFMF exposure at 45 °C. In vitro cytotoxicity test shows that curcumin-loaded PEGylated magnetic liposomes could efficiently kill MCF-7 cells in parallel with increasing curcumin concentration. Fluorescence microscopy observed that these drug carriers could internalize efficiently into the cellular compartment of MCF-7 cells. Thus, it would be anticipated that the novel hydrophobic drug-loaded PEGylated magnetic liposomes in combination with inductive magnetic heating are promising to apply in the combination of chemotherapy and thermotherapy for cancer therapy.

The cell's view of animal body-plan evolution.

PubMed

Lyons, Deirdre C; Martindale, Mark Q; Srivastava, Mansi

2014-10-01

An adult animal's form is shaped by the collective behavior of cells during embryonic development. To understand the forces that drove the divergence of animal body-plans, evolutionary developmental biology has focused largely on studying genetic networks operating during development. However, it is less well understood how these networks modulate characteristics at the cellular level, such as the shape, polarity, or migration of cells. We organized the "Cell's view of animal body plan evolution" symposium for the 2014 The Society for Integrative and Comparative Biology meeting with the explicit goal of bringing together researchers studying the cell biology of embryonic development in diverse animal taxa. Using a broad range of established and emerging technologies, including live imaging, single-cell analysis, and mathematical modeling, symposium participants revealed mechanisms underlying cells' behavior, a few of which we highlight here. Shape, adhesion, and movements of cells can be modulated over the course of evolution to alter adult body-plans and a major theme explored during the symposium was the role of actomyosin in coordinating diverse behaviors of cells underlying morphogenesis in a myriad of contexts. Uncovering whether conserved or divergent genetic mechanisms guide the contractility of actomyosin in these systems will be crucial to understanding the evolution of the body-plans of animals from a cellular perspective. Many speakers presented research describing developmental phenomena in which cell division and tissue growth can control the form of the adult, and other presenters shared work on studying cell-fate specification, an important source of novelty in animal body-plans. Participants also presented studies of regeneration in annelids, flatworms, acoels, and cnidarians, and provided a unifying view of the regulation of cellular behavior during different life-history stages. Additionally, several presentations highlighted technological advances that glean mechanistic insights from new and emerging model systems, thereby providing the phylogenetic breadth so essential for studying animal evolution. Thus, we propose that an explicit study of cellular phenomena is now possible for a wide range of taxa, and that it will be highly informative for understanding the evolution of animal body-plans. © The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

Cellular automata with object-oriented features for parallel molecular network modeling.

PubMed

Zhu, Hao; Wu, Yinghui; Huang, Sui; Sun, Yan; Dhar, Pawan

2005-06-01

Cellular automata are an important modeling paradigm for studying the dynamics of large, parallel systems composed of multiple, interacting components. However, to model biological systems, cellular automata need to be extended beyond the large-scale parallelism and intensive communication in order to capture two fundamental properties characteristic of complex biological systems: hierarchy and heterogeneity. This paper proposes extensions to a cellular automata language, Cellang, to meet this purpose. The extended language, with object-oriented features, can be used to describe the structure and activity of parallel molecular networks within cells. Capabilities of this new programming language include object structure to define molecular programs within a cell, floating-point data type and mathematical functions to perform quantitative computation, message passing capability to describe molecular interactions, as well as new operators, statements, and built-in functions. We discuss relevant programming issues of these features, including the object-oriented description of molecular interactions with molecule encapsulation, message passing, and the description of heterogeneity and anisotropy at the cell and molecule levels. By enabling the integration of modeling at the molecular level with system behavior at cell, tissue, organ, or even organism levels, the program will help improve our understanding of how complex and dynamic biological activities are generated and controlled by parallel functioning of molecular networks. Index Terms-Cellular automata, modeling, molecular network, object-oriented.

Long-distance communication by specialized cellular projections during pigment pattern development and evolution

PubMed Central

Eom, Dae Seok; Bain, Emily J; Patterson, Larissa B; Grout, Megan E; Parichy, David M

2015-01-01

Changes in gene activity are essential for evolutionary diversification. Yet, elucidating the cellular behaviors that underlie modifications to adult form remains a profound challenge. We use neural crest-derived adult pigmentation of zebrafish and pearl danio to uncover cellular bases for alternative pattern states. We show that stripes in zebrafish require a novel class of thin, fast cellular projection to promote Delta-Notch signaling over long distances from cells of the xanthophore lineage to melanophores. Projections depended on microfilaments and microtubules, exhibited meandering trajectories, and stabilized on target cells to which they delivered membraneous vesicles. By contrast, the uniformly patterned pearl danio lacked such projections, concomitant with Colony stimulating factor 1-dependent changes in xanthophore differentiation that likely curtail signaling available to melanophores. Our study reveals a novel mechanism of cellular communication, roles for differentiation state heterogeneity in pigment cell interactions, and an unanticipated morphogenetic behavior contributing to a striking difference in adult form. DOI: http://dx.doi.org/10.7554/eLife.12401.001 PMID:26701906

Cellular automatons applied to gas dynamic problems

NASA Technical Reports Server (NTRS)

Long, Lyle N.; Coopersmith, Robert M.; Mclachlan, B. G.

1987-01-01

This paper compares the results of a relatively new computational fluid dynamics method, cellular automatons, with experimental data and analytical results. This technique has been shown to qualitatively predict fluidlike behavior; however, there have been few published comparisons with experiment or other theories. Comparisons are made for a one-dimensional supersonic piston problem, Stokes first problem, and the flow past a normal flat plate. These comparisons are used to assess the ability of the method to accurately model fluid dynamic behavior and to point out its limitations. Reasonable results were obtained for all three test cases, but the fundamental limitations of cellular automatons are numerous. It may be misleading, at this time, to say that cellular automatons are a computationally efficient technique. Other methods, based on continuum or kinetic theory, would also be very efficient if as little of the physics were included.

Tensegrity II. How structural networks influence cellular information processing networks

NASA Technical Reports Server (NTRS)

Ingber, Donald E.

2003-01-01

The major challenge in biology today is biocomplexity: the need to explain how cell and tissue behaviors emerge from collective interactions within complex molecular networks. Part I of this two-part article, described a mechanical model of cell structure based on tensegrity architecture that explains how the mechanical behavior of the cell emerges from physical interactions among the different molecular filament systems that form the cytoskeleton. Recent work shows that the cytoskeleton also orients much of the cell's metabolic and signal transduction machinery and that mechanical distortion of cells and the cytoskeleton through cell surface integrin receptors can profoundly affect cell behavior. In particular, gradual variations in this single physical control parameter (cell shape distortion) can switch cells between distinct gene programs (e.g. growth, differentiation and apoptosis), and this process can be viewed as a biological phase transition. Part II of this article covers how combined use of tensegrity and solid-state mechanochemistry by cells may mediate mechanotransduction and facilitate integration of chemical and physical signals that are responsible for control of cell behavior. In addition, it examines how cell structural networks affect gene and protein signaling networks to produce characteristic phenotypes and cell fate transitions during tissue development.

A new simulation system of traffic flow based on cellular automata principle

NASA Astrophysics Data System (ADS)

Shan, Junru

2017-05-01

Traffic flow is a complex system of multi-behavior so it is difficult to give a specific mathematical equation to express it. With the rapid development of computer technology, it is an important method to study the complex traffic behavior by simulating the interaction mechanism between vehicles and reproduce complex traffic behavior. Using the preset of multiple operating rules, cellular automata is a kind of power system which has discrete time and space. It can be a good simulation of the real traffic process and a good way to solve the traffic problems.

Using Long-Term Time-Lapse Imaging of Mammalian Cell Cycle Progression for Laboratory Instruction and Analysis

ERIC Educational Resources Information Center

Hinchcliffe, Edward H.

2005-01-01

Cinemicrography--the capture of moving cellular sequences through the microscope--has been influential in revealing the dynamic nature of cellular behavior. One of the more dramatic cellular events is mitosis, the division of sister chromatids into two daughter cells. Mitosis has been extensively studied in a variety of organisms, both…

Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment.

PubMed

Alboni, S; van Dijk, R M; Poggini, S; Milior, G; Perrotta, M; Drenth, T; Brunello, N; Wolfer, D P; Limatola, C; Amrein, I; Cirulli, F; Maggi, L; Branchi, I

2017-04-01

Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic-pituitary-adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

On the spatial dynamics and oscillatory behavior of a predator-prey model based on cellular automata and local particle swarm optimization.

PubMed

Molina, Mario Martínez; Moreno-Armendáriz, Marco A; Carlos Seck Tuoh Mora, Juan

2013-11-07

A two-dimensional lattice model based on Cellular Automata theory and swarm intelligence is used to study the spatial and population dynamics of a theoretical ecosystem. It is found that the social interactions among predators provoke the formation of clusters, and that by increasing the mobility of predators the model enters into an oscillatory behavior. © 2013 Elsevier Ltd. All rights reserved.

Learning to swim, again: Axon regeneration in fish.

PubMed

Rasmussen, Jeffrey P; Sagasti, Alvaro

2017-01-01

Damage to the central nervous system (CNS) of fish can often be repaired to restore function, but in mammals recovery from CNS injuries usually fails due to a lack of axon regeneration. The relatively growth-permissive environment of the fish CNS may reflect both the absence of axon inhibitors found in the mammalian CNS and the presence of pro-regenerative environmental factors. Despite their different capacities for axon regeneration, many of the physiological processes, intrinsic molecular pathways, and cellular behaviors that control an axon's ability to regrow are conserved between fish and mammals. Fish models have thus been useful both for identifying factors differing between mammals and fish that may account for differences in CNS regeneration and for characterizing conserved intrinsic pathways that regulate axon regeneration in all vertebrates. The majority of adult axon regeneration studies have focused on the optic nerve or spinal axons of the teleosts goldfish and zebrafish, which have been productive models for identifying genes associated with axon regeneration, cellular mechanisms of circuit reestablishment, and the basis of functional recovery. Lampreys, which are jawless fish lacking myelin, have provided an opportunity to study regeneration of well defined spinal cord circuits. Newer larval zebrafish models offer numerous genetic tools and the ability to monitor the dynamic behaviors of extrinsic cell types regulating axon regeneration in live animals. Recent advances in imaging and gene editing methods are making fish models yet more powerful for investigating the cellular and molecular underpinnings of axon regeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

New views on the neural crest epithelial-mesenchymal transition and neuroepithelial interkinetic nuclear migration

PubMed Central

Erickson, Carol A

2009-01-01

By developing a technique for imaging the avian neural crest epithelial-mesenchymal transition (EMT), we have discovered cellular behaviors that challenge current thinking on this important developmental event, including the probability that complete disassembly of the adherens junctions may not control whether or not a neural epithelial cell undergoes an EMT. Further, neural crest cells can adopt multiple modes of cell motility in order to emigrate from the neuroepithelium. We also gained insights into interkinetic nuclear migration (INM). For example, the movement of the nucleus from the basal to apical domain may not require microtubule motors nor an intact nuclear envelope, and the nucleus does not always need to reach the apical surface in order for cytokinesis to occur. These studies illustrate the value of live-cell imaging to elucidate cellular processes. PMID:20195454

Single-Cell and Single-Molecule Analysis of Gene Expression Regulation.

PubMed

Vera, Maria; Biswas, Jeetayu; Senecal, Adrien; Singer, Robert H; Park, Hye Yoon

2016-11-23

Recent advancements in single-cell and single-molecule imaging technologies have resolved biological processes in time and space that are fundamental to understanding the regulation of gene expression. Observations of single-molecule events in their cellular context have revealed highly dynamic aspects of transcriptional and post-transcriptional control in eukaryotic cells. This approach can relate transcription with mRNA abundance and lifetimes. Another key aspect of single-cell analysis is the cell-to-cell variability among populations of cells. Definition of heterogeneity has revealed stochastic processes, determined characteristics of under-represented cell types or transitional states, and integrated cellular behaviors in the context of multicellular organisms. In this review, we discuss novel aspects of gene expression of eukaryotic cells and multicellular organisms revealed by the latest advances in single-cell and single-molecule imaging technology.

A Three-Dimensional Computational Model of Collagen Network Mechanics

PubMed Central

Lee, Byoungkoo; Zhou, Xin; Riching, Kristin; Eliceiri, Kevin W.; Keely, Patricia J.; Guelcher, Scott A.; Weaver, Alissa M.; Jiang, Yi

2014-01-01

Extracellular matrix (ECM) strongly influences cellular behaviors, including cell proliferation, adhesion, and particularly migration. In cancer, the rigidity of the stromal collagen environment is thought to control tumor aggressiveness, and collagen alignment has been linked to tumor cell invasion. While the mechanical properties of collagen at both the single fiber scale and the bulk gel scale are quite well studied, how the fiber network responds to local stress or deformation, both structurally and mechanically, is poorly understood. This intermediate scale knowledge is important to understanding cell-ECM interactions and is the focus of this study. We have developed a three-dimensional elastic collagen fiber network model (bead-and-spring model) and studied fiber network behaviors for various biophysical conditions: collagen density, crosslinker strength, crosslinker density, and fiber orientation (random vs. prealigned). We found the best-fit crosslinker parameter values using shear simulation tests in a small strain region. Using this calibrated collagen model, we simulated both shear and tensile tests in a large linear strain region for different network geometry conditions. The results suggest that network geometry is a key determinant of the mechanical properties of the fiber network. We further demonstrated how the fiber network structure and mechanics evolves with a local formation, mimicking the effect of pulling by a pseudopod during cell migration. Our computational fiber network model is a step toward a full biomechanical model of cellular behaviors in various ECM conditions. PMID:25386649

Systems Dynamic Modeling of the Stomatal Guard Cell Predicts Emergent Behaviors in Transport, Signaling, and Volume Control1[W][OA

PubMed Central

Chen, Zhong-Hua; Hills, Adrian; Bätz, Ulrike; Amtmann, Anna; Lew, Virgilio L.; Blatt, Michael R.

2012-01-01

The dynamics of stomatal movements and their consequences for photosynthesis and transpirational water loss have long been incorporated into mathematical models, but none have been developed from the bottom up that are widely applicable in predicting stomatal behavior at a cellular level. We previously established a systems dynamic model incorporating explicitly the wealth of biophysical and kinetic knowledge available for guard cell transport, signaling, and homeostasis. Here we describe the behavior of the model in response to experimentally documented changes in primary pump activities and malate (Mal) synthesis imposed over a diurnal cycle. We show that the model successfully recapitulates the cyclic variations in H+, K+, Cl−, and Mal concentrations in the cytosol and vacuole known for guard cells. It also yields a number of unexpected and counterintuitive outputs. Among these, we report a diurnal elevation in cytosolic-free Ca2+ concentration and an exchange of vacuolar Cl− with Mal, both of which find substantiation in the literature but had previously been suggested to require additional and complex levels of regulation. These findings highlight the true predictive power of the OnGuard model in providing a framework for systems analysis of stomatal guard cells, and they demonstrate the utility of the OnGuard software and HoTSig library in exploring fundamental problems in cellular physiology and homeostasis. PMID:22635112

Environmental Enrichment Rescues Postnatal Neurogenesis Defect in the Male and Female Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Chakrabarti, Lina; Scafidi, Joseph; Gallo, Vittorio; Haydar, Tarik F.

2011-01-01

Down syndrome (DS), the most frequent genetic cause of intellectual disability and developmental delay, results from impaired neural stem cell proliferation and differentiation. Impaired neurogenesis in the neocortex, hippocampus and cerebellum is believed to be the underlying cause of learning and behavioral deficits in the Ts65Dn mouse model of DS. Aggressive sensorimotor and cognitive therapies have shown promise in mitigating the cognitive disabilities in DS but these behavioral therapies have not yet been investigated at the cellular level. Here, using the Ts65Dn mouse model of DS, we demonstrate that a combination of environmental enrichment and physical exercise starting in juvenile mice (postnatal day 18) markedly increases cell proliferation, neurogenesis and gliogenesis in the hippocampal dentate gyrus (DG) and the forebrain subventricular zone (SVZ) of both male and female mice. Enrichment and exercise increased the rate of Ts65Dn DG neurogenesis to be comparable to that of the nonenriched euploid group, while the effect on SVZ neurogenesis was reduced and seen only after prolonged exposure. These results clearly indicate that in a comprehensive stimulatory environment, the postnatal DS brain has the intrinsic capability of improving neurogenesis and gliogenesis to the levels of normal matched controls and that this cellular response underlies the cognitive improvement seen following behavioral therapies. PMID:21865665

Speed and segmentation control mechanisms characterized in rhythmically-active circuits created from spinal neurons produced from genetically-tagged embryonic stem cells

PubMed Central

Sternfeld, Matthew J; Hinckley, Christopher A; Moore, Niall J; Pankratz, Matthew T; Hilde, Kathryn L; Driscoll, Shawn P; Hayashi, Marito; Amin, Neal D; Bonanomi, Dario; Gifford, Wesley D; Sharma, Kamal; Goulding, Martyn; Pfaff, Samuel L

2017-01-01

Flexible neural networks, such as the interconnected spinal neurons that control distinct motor actions, can switch their activity to produce different behaviors. Both excitatory (E) and inhibitory (I) spinal neurons are necessary for motor behavior, but the influence of recruiting different ratios of E-to-I cells remains unclear. We constructed synthetic microphysical neural networks, called circuitoids, using precise combinations of spinal neuron subtypes derived from mouse stem cells. Circuitoids of purified excitatory interneurons were sufficient to generate oscillatory bursts with properties similar to in vivo central pattern generators. Inhibitory V1 neurons provided dual layers of regulation within excitatory rhythmogenic networks - they increased the rhythmic burst frequency of excitatory V3 neurons, and segmented excitatory motor neuron activity into sub-networks. Accordingly, the speed and pattern of spinal circuits that underlie complex motor behaviors may be regulated by quantitatively gating the intra-network cellular activity ratio of E-to-I neurons. DOI: http://dx.doi.org/10.7554/eLife.21540.001 PMID:28195039

Direct measurement of local material properties within living embryonic tissues

NASA Astrophysics Data System (ADS)

Serwane, Friedhelm; Mongera, Alessandro; Rowghanian, Payam; Kealhofer, David; Lucio, Adam; Hockenbery, Zachary; Campàs, Otger

The shaping of biological matter requires the control of its mechanical properties across multiple scales, ranging from single molecules to cells and tissues. Despite their relevance, measurements of the mechanical properties of sub-cellular, cellular and supra-cellular structures within living embryos pose severe challenges to existing techniques. We have developed a technique that uses magnetic droplets to measure the mechanical properties of complex fluids, including in situ and in vivo measurements within living embryos ,across multiple length and time scales. By actuating the droplets with magnetic fields and recording their deformation we probe the local mechanical properties, at any length scale we choose by varying the droplets' diameter. We use the technique to determine the subcellular mechanics of individual blastomeres of zebrafish embryos, and bridge the gap to the tissue scale by measuring the local viscosity and elasticity of zebrafish embryonic tissues. Using this technique, we show that embryonic zebrafish tissues are viscoelastic with a fluid-like behavior at long time scales. This technique will enable mechanobiology and mechano-transduction studies in vivo, including the study of diseases correlated with tissue stiffness, such as cancer.

Micro-/nano-engineered cellular responses for soft tissue engineering and biomedical applications.

PubMed

Tay, Chor Yong; Irvine, Scott Alexander; Boey, Freddy Y C; Tan, Lay Poh; Venkatraman, Subbu

2011-05-23

The development of biomedical devices and reconstruction of functional ex vivo tissues often requires the need to fabricate biomimetic surfaces with features of sub-micrometer precision. This can be achieved with the advancements in micro-/nano-engineering techniques, allowing researchers to manipulate a plethora of cellular behaviors at the cell-biomaterial interface. Systematic studies conducted on these 2D engineered surfaces have unraveled numerous novel findings that can potentially be integrated as part of the design consideration for future 2D and 3D biomaterials and will no doubt greatly benefit tissue engineering. In this review, recent developments detailing the use of micro-/nano-engineering techniques to direct cellular orientation and function pertinent to soft tissue engineering will be highlighted. Particularly, this article aims to provide valuable insights into distinctive cell interactions and reactions to controlled surfaces, which can be exploited to understand the mechanisms of cell growth on micro-/nano-engineered interfaces, and to harness this knowledge to optimize the performance of 3D artificial soft tissue grafts and biomedical applications. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A new cellular automata model of traffic flow with negative exponential weighted look-ahead potential

NASA Astrophysics Data System (ADS)

Ma, Xiao; Zheng, Wei-Fan; Jiang, Bao-Shan; Zhang, Ji-Ye

2016-10-01

With the development of traffic systems, some issues such as traffic jams become more and more serious. Efficient traffic flow theory is needed to guide the overall controlling, organizing and management of traffic systems. On the basis of the cellular automata model and the traffic flow model with look-ahead potential, a new cellular automata traffic flow model with negative exponential weighted look-ahead potential is presented in this paper. By introducing the negative exponential weighting coefficient into the look-ahead potential and endowing the potential of vehicles closer to the driver with a greater coefficient, the modeling process is more suitable for the driver’s random decision-making process which is based on the traffic environment that the driver is facing. The fundamental diagrams for different weighting parameters are obtained by using numerical simulations which show that the negative exponential weighting coefficient has an obvious effect on high density traffic flux. The complex high density non-linear traffic behavior is also reproduced by numerical simulations. Project supported by the National Natural Science Foundation of China (Grant Nos. 11572264, 11172247, 11402214, and 61373009).

A geometrically controlled rigidity transition in a model for confluent 3D tissues

NASA Astrophysics Data System (ADS)

Merkel, Matthias; Manning, M. Lisa

2018-02-01

The origin of rigidity in disordered materials is an outstanding open problem in statistical physics. Previously, a class of 2D cellular models has been shown to undergo a rigidity transition controlled by a mechanical parameter that specifies cell shapes. Here, we generalize this model to 3D and find a rigidity transition that is similarly controlled by the preferred surface area S 0: the model is solid-like below a dimensionless surface area of {s}0\\equiv {S}0/{\\bar{V}}2/3≈ 5.413 with \\bar{V} being the average cell volume, and fluid-like above this value. We demonstrate that, unlike jamming in soft spheres, residual stresses are necessary to create rigidity. These stresses occur precisely when cells are unable to obtain their desired geometry, and we conjecture that there is a well-defined minimal surface area possible for disordered cellular structures. We show that the behavior of this minimal surface induces a linear scaling of the shear modulus with the control parameter at the transition point, which is different from the scaling observed in particulate matter. The existence of such a minimal surface may be relevant for biological tissues and foams, and helps explain why cell shapes are a good structural order parameter for rigidity transitions in biological tissues.

Self-organized perturbations enhance class IV behavior and 1/f power spectrum in elementary cellular automata.

PubMed

Nakajima, Kohei; Haruna, Taichi

2011-09-01

In this paper, we propose a new class of cellular automata based on the modification of its state space. It is introduced to model a computation which is exposed to an environment. We formalized the computation as extension and projection processes of its state space and resulting misidentifications of the state. This is motivated to embed the role of an environment into the system itself, which naturally induces self-organized internal perturbations rather than the usual external perturbations. Implementing this structure into the elementary cellular automata, we characterized its effect by means of input entropy and power spectral analysis. As a result, the cellular automata with this structure showed robust class IV behavior and a 1/f power spectrum in a wide range of rule space comparative to the notion of the edge of chaos. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Numerical simulation of biofilm growth in flow channels using a cellular automaton approach coupled with a macro flow computation.

PubMed

Yamamoto, Takehiro; Ueda, Shuya

2013-01-01

Biofilm is a slime-like complex aggregate of microorganisms and their products, extracellular polymer substances, that grows on a solid surface. The growth phenomenon of biofilm is relevant to the corrosion and clogging of water pipes, the chemical processes in a bioreactor, and bioremediation. In these phenomena, the behavior of the biofilm under flow has an important role. Therefore, controlling the biofilm behavior in each process is important. To provide a computational tool for analyzing biofilm growth, the present study proposes a computational model for the simulation of biofilm growth in flows. This model accounts for the growth, decay, detachment and adhesion of biofilms. The proposed model couples the computation of the surrounding fluid flow, using the finite volume method, with the simulation of biofilm growth, using the cellular automaton approach, a relatively low-computational-cost method. Furthermore, a stochastic approach for considering the adhesion process is proposed. Numerical simulations for the biofilm growth on a planar wall and that in an L-shaped rectangular channel were carried out. A variety of biofilm structures were observed depending on the strength of the flow. Moreover, the importance of the detachment and adhesion processes was confirmed.

Effect of the Addition of a Labile Gelatin Component on the Degradation and Solute Release Kinetics of a Stable PEG Hydrogel

PubMed Central

Waldeck, H.; Kao, W. J.

2013-01-01

Characterization of the degradation mechanisms and resulting products of biodegradable materials is critical in understanding the behavior of the material including solute transport and biological response. Previous mathematical analyses of a semi-interpenetrating network (sIPN) containing both labile gelatin and a stable cross-linked poly(ethylene glycol) (PEG) network found that diffusion-based models alone were unable to explain the release kinetics of solutes from the system. In this study, degradation of the sIPN and its effect on solute release and swelling kinetics were investigated. The kinetics of the primary mode of degradation, gelatin dissolution, was dependent on temperature, preparation methods, PEGdA and gelatin concentration, and the weight ratio between the gelatin and PEG. The gelatin dissolution rate positively correlated with both matrix swelling and the release kinetics of high-molecular-weight model compound, FITC-dextran. Coupled with previous in vitro studies, the kinetics of sIPN degradation provided insights into the time-dependent changes in cellular response including adhesion and protein expression. These results provide a facile guide in material formulation to control the delivery of high-molecular-weight compounds with concomitant modulation of cellular behavior. PMID:21801489

Brain glucose sensing in homeostatic and hedonic regulation.

PubMed

Steinbusch, Laura; Labouèbe, Gwenaël; Thorens, Bernard

2015-09-01

Glucose homeostasis as well as homeostatic and hedonic control of feeding is regulated by hormonal, neuronal, and nutrient-related cues. Glucose, besides its role as a source of metabolic energy, is an important signal controlling hormone secretion and neuronal activity, hence contributing to whole-body metabolic integration in coordination with feeding control. Brain glucose sensing plays a key, but insufficiently explored, role in these metabolic and behavioral controls, which when deregulated may contribute to the development of obesity and diabetes. The recent introduction of innovative transgenic, pharmacogenetic, and optogenetic techniques allows unprecedented analysis of the complexity of central glucose sensing at the molecular, cellular, and neuronal circuit levels, which will lead to a new understanding of the pathogenesis of metabolic diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors

PubMed Central

Nieh, Edward H.; Kim, Sung-Yon; Namburi, Praneeth; Tye, Kay M.

2014-01-01

The neural circuits underlying emotional valence and motivated behaviors are several synapses away from both defined sensory inputs and quantifiable motor outputs. Electrophysiology has provided us with a suitable means for observing neural activity during behavior, but methods for controlling activity for the purpose of studying motivated behaviors have been inadequate: electrical stimulation lacks cellular specificity and pharmacological manipulation lacks temporal resolution. The recent emergence of optogenetic tools provides a new means for establishing causal relationships between neural activity and behavior. Optogenetics, the use of genetically-encodable light-activated proteins, permits the modulation of specific neural circuit elements with millisecond precision. The ability to control individual cell types, and even projections between distal regions, allows us to investigate functional connectivity in a causal manner. The greatest consequence of controlling neural activity with finer precision has been the characterization of individual neural circuits within anatomical brain regions as defined functional units. Within the mesolimbic dopamine system, optogenetics has helped separate subsets of dopamine neurons with distinct functions for reward, aversion and salience processing, elucidated GABA neuronal effects on behavior, and characterized connectivity with forebrain and cortical structures. Within the striatum, optogenetics has confirmed the opposing relationship between direct and indirect pathway medium spiny neurons (MSNs), in addition to characterizing the inhibition of MSNs by cholinergic interneurons. Within the hypothalamus, optogenetics has helped overcome the heterogeneity in neuronal cell-type and revealed distinct circuits mediating aggression and feeding. Within the amygdala, optogenetics has allowed the study of intra-amygdala microcircuitry as well as interconnections with distal regions involved in fear and anxiety. In this review, we will present the body of optogenetic studies that has significantly enhanced our understanding of emotional valence and motivated behaviors. PMID:23142759

Wave failure at strong coupling in intracellular C a2 + signaling system with clustered channels

NASA Astrophysics Data System (ADS)

Li, Xiang; Wu, Yuning; Gao, Xuejuan; Cai, Meichun; Shuai, Jianwei

2018-01-01

As an important intracellular signal, C a2 + ions control diverse cellular functions. In this paper, we discuss the C a2 + signaling with a two-dimensional model in which the inositol 1,4,5-trisphosphate (I P3 ) receptor channels are distributed in clusters on the endoplasmic reticulum membrane. The wave failure at large C a2 + diffusion coupling is discussed in detail in the model. We show that with varying model parameters the wave failure is a robust behavior with either deterministic or stochastic channel dynamics. We suggest that the wave failure should be a general behavior in inhomogeneous diffusing systems with clustered excitable regions and may occur in biological C a2 + signaling systems.

The influence of surface properties of plasma-etched polydimethylsiloxane (PDMS) on cell growth and morphology.

PubMed

Pennisi, Cristian P; Zachar, Vladimir; Gurevich, Leonid; Patriciu, Andrei; Struijk, Johannes J

2010-01-01

Polydimethylsiloxane (PDMS) or silicone rubber is a widely used implant material. Approaches to promote tissue integration to PDMS are desirable to avoid clinical problems associated with sliding and friction between tissue and implant. Plasma-etching is a useful way to control cell behavior on PDMS without additional coatings. In this work, different plasma processing conditions were used to modify the surface properties of PDMS substrates. Surface nanotopography and wettability were measured to study their effect on in vitro growth and morphology of fibroblasts. While fluorinated plasma treatments produced nanorough hydrophobic and superhydrophobic surfaces that had negative or little influences on cellular behavior, water vapor/oxygen plasma produced smooth hydrophillic surfaces that enhanced cell growth.

Photo- and electropatterning of hydrogel-encapsulated living cell arrays.

PubMed

Albrecht, Dirk R; Tsang, Valerie Liu; Sah, Robert L; Bhatia, Sangeeta N

2005-01-01

Living cells have the potential to serve as sensors, naturally integrating the response to stimuli to generate predictions about cell fate (e.g., differentiation, migration, proliferation, apoptosis). Miniaturized arrays of living cells further offer the capability to interrogate many cells in parallel and thereby enable high-throughput and/or combinatorial assays. However, the interface between living cells and synthetic chip platforms is a critical one wherein the cellular phenotype must be preserved to generate useful signals. While some cell types retain tissue-specific features on a flat (2-D) surface, it has become increasingly apparent that a 3-D physical environment will be required for others. In this paper, we present two independent methods for creating living cell arrays that are encapsulated within a poly(ethylene glycol)-based hydrogel to create a local 3-D microenvironment. First, 'photopatterning' selectively crosslinks hydrogel microstructures containing living cells with approximately 100 microm feature size. Second, 'electropatterning' utilizes dielectrophoretic forces to position cells within a prepolymer solution prior to crosslinking, forming cell patterns with micron resolution. We further combine these methods to obtain hierarchical control of cell positioning over length scales ranging from microns to centimeters. This level of microenvironmental control should enable the fabrication of next-generation cellular microarrays in which robust 3-D cultures of cells are presented with appropriate physical and chemical cues and, consequently, report on cellular responses that resemble in vivo behavior.

A pilgrim's progress: Seeking meaning in primordial germ cell migration.

PubMed

Cantú, Andrea V; Laird, Diana J

2017-10-01

Comparative studies of primordial germ cell (PGC) development across organisms in many phyla reveal surprising diversity in the route of migration, timing and underlying molecular mechanisms, suggesting that the process of migration itself is conserved. However, beyond the perfunctory transport of cellular precursors to their later arising home of the gonads, does PGC migration serve a function? Here we propose that the process of migration plays an additional role in quality control, by eliminating PGCs incapable of completing migration as well as through mechanisms that favor PGCs capable of responding appropriately to migration cues. Focusing on PGCs in mice, we explore evidence for a selective capacity of migration, considering the tandem regulation of proliferation and migration, cell-intrinsic and extrinsic control, the potential for tumors derived from failed PGC migrants, the potential mechanisms by which migratory PGCs vary in their cellular behaviors, and corresponding effects on development. We discuss the implications of a selective role of PGC migration for in vitro gametogenesis. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Realistic modeling of neurons and networks: towards brain simulation.

PubMed

D'Angelo, Egidio; Solinas, Sergio; Garrido, Jesus; Casellato, Claudia; Pedrocchi, Alessandra; Mapelli, Jonathan; Gandolfi, Daniela; Prestori, Francesca

2013-01-01

Realistic modeling is a new advanced methodology for investigating brain functions. Realistic modeling is based on a detailed biophysical description of neurons and synapses, which can be integrated into microcircuits. The latter can, in turn, be further integrated to form large-scale brain networks and eventually to reconstruct complex brain systems. Here we provide a review of the realistic simulation strategy and use the cerebellar network as an example. This network has been carefully investigated at molecular and cellular level and has been the object of intense theoretical investigation. The cerebellum is thought to lie at the core of the forward controller operations of the brain and to implement timing and sensory prediction functions. The cerebellum is well described and provides a challenging field in which one of the most advanced realistic microcircuit models has been generated. We illustrate how these models can be elaborated and embedded into robotic control systems to gain insight into how the cellular properties of cerebellar neurons emerge in integrated behaviors. Realistic network modeling opens up new perspectives for the investigation of brain pathologies and for the neurorobotic field.

Realistic modeling of neurons and networks: towards brain simulation

PubMed Central

D’Angelo, Egidio; Solinas, Sergio; Garrido, Jesus; Casellato, Claudia; Pedrocchi, Alessandra; Mapelli, Jonathan; Gandolfi, Daniela; Prestori, Francesca

Summary Realistic modeling is a new advanced methodology for investigating brain functions. Realistic modeling is based on a detailed biophysical description of neurons and synapses, which can be integrated into microcircuits. The latter can, in turn, be further integrated to form large-scale brain networks and eventually to reconstruct complex brain systems. Here we provide a review of the realistic simulation strategy and use the cerebellar network as an example. This network has been carefully investigated at molecular and cellular level and has been the object of intense theoretical investigation. The cerebellum is thought to lie at the core of the forward controller operations of the brain and to implement timing and sensory prediction functions. The cerebellum is well described and provides a challenging field in which one of the most advanced realistic microcircuit models has been generated. We illustrate how these models can be elaborated and embedded into robotic control systems to gain insight into how the cellular properties of cerebellar neurons emerge in integrated behaviors. Realistic network modeling opens up new perspectives for the investigation of brain pathologies and for the neurorobotic field. PMID:24139652

Traffic dynamics around weaving section influenced by accident: Cellular automata approach

NASA Astrophysics Data System (ADS)

Kong, Lin-Peng; Li, Xin-Gang; Lam, William H. K.

2015-07-01

The weaving section, as a typical bottleneck, is one source of vehicle conflicts and an accident-prone area. Traffic accident will block lanes and the road capacity will be reduced. Several models have been established to study the dynamics around traffic bottlenecks. However, little attention has been paid to study the complex traffic dynamics influenced by the combined effects of bottleneck and accident. This paper presents a cellular automaton model to characterize accident-induced traffic behavior around the weaving section. Some effective control measures are proposed and verified for traffic management under accident condition. The total flux as a function of inflow rates, the phase diagrams, the spatial-temporal diagrams, and the density and velocity profiles are presented to analyze the impact of accident. It was shown that the proposed control measures for weaving traffic can improve the capacity of weaving section under both normal and accident conditions; the accidents occurring on median lane in the weaving section are more inclined to cause traffic jam and reduce road capacity; the capacity of weaving section will be greatly reduced when the accident happens downstream the weaving section.

Mapping Thermal Habitat of Ectotherms Based on Behavioral Thermoregulation in a Controlled Thermal Environment

NASA Astrophysics Data System (ADS)

Fei, T.; Skidmore, A.; Liu, Y.

2012-07-01

Thermal environment is especially important to ectotherm because a lot of physiological functions rely on the body temperature such as thermoregulation. The so-called behavioural thermoregulation function made use of the heterogeneity of the thermal properties within an individual's habitat to sustain the animal's physiological processes. This function links the spatial utilization and distribution of individual ectotherm with the thermal properties of habitat (thermal habitat). In this study we modelled the relationship between the two by a spatial explicit model that simulates the movements of a lizard in a controlled environment. The model incorporates a lizard's transient body temperatures with a cellular automaton algorithm as a way to link the physiology knowledge of the animal with the spatial utilization of its microhabitat. On a larger spatial scale, 'thermal roughness' of the habitat was defined and used to predict the habitat occupancy of the target species. The results showed the habitat occupancy can be modelled by the cellular automaton based algorithm at a smaller scale, and can be modelled by the thermal roughness index at a larger scale.

Geometric confinement influences cellular mechanical properties I -- adhesion area dependence.

PubMed

Su, Judith; Jiang, Xingyu; Welsch, Roy; Whitesides, George M; So, Peter T C

2007-06-01

Interactions between the cell and the extracellular matrix regulate a variety of cellular properties and functions, including cellular rheology. In the present study of cellular adhesion, area was controlled by confining NIH 3T3 fibroblast cells to circular micropatterned islands of defined size. The shear moduli of cells adhering to islands of well defined geometry, as measured by magnetic microrheometry, was found to have a significantly lower variance than those of cells allowed to spread on unpatterned surfaces. We observe that the area of cellular adhesion influences shear modulus. Rheological measurements further indicate that cellular shear modulus is a biphasic function of cellular adhesion area with stiffness decreasing to a minimum value for intermediate areas of adhesion, and then increasing for cells on larger patterns. We propose a simple hypothesis: that the area of adhesion affects cellular rheological properties by regulating the structure of the actin cytoskeleton. To test this hypothesis, we quantified the volume fraction of polymerized actin in the cytosol by staining with fluorescent phalloidin and imaging using quantitative 3D microscopy. The polymerized actin volume fraction exhibited a similar biphasic dependence on adhesion area. Within the limits of our simplifying hypothesis, our experimental results permit an evaluation of the ability of established, micromechanical models to predict the cellular shear modulus based on polymerized actin volume fraction. We investigated the "tensegrity", "cellular-solids", and "biopolymer physics" models that have, respectively, a linear, quadratic, and 5/2 dependence on polymerized actin volume fraction. All three models predict that a biphasic trend in polymerized actin volume fraction as a function of adhesion area will result in a biphasic behavior in shear modulus. Our data favors a higher-order dependence on polymerized actin volume fraction. Increasingly better experimental agreement is observed for the tensegrity, the cellular solids, and the biopolymer models respectively. Alternatively if we postulate the existence of a critical actin volume fraction below which the shear modulus vanishes, the experimental data can be equivalently described by a model with an almost linear dependence on polymerized actin volume fraction; this observation supports a tensegrity model with a critical actin volume fraction.

Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats.

PubMed

Zlebnik, Natalie E; Hedges, Valerie L; Carroll, Marilyn E; Meisel, Robert L

2014-03-15

Emerging evidence from human and animal studies suggests that exercise is a highly effective treatment for drug addiction. However, most work has been done in behavioral models, and the effects of exercise on the neurobiological substrates of addiction have not been identified. Specifically, it is unknown whether prior exercise exposure alters neuronal activation of brain reward circuitry in response to drugs of abuse. To investigate this hypothesis, rats were given 21 days of daily access to voluntary wheel running in a locked or unlocked running wheel. Subsequently, they were challenged with a saline or cocaine (15 mg/kg, i.p.) injection and sacrificed for c-Fos immunohistochemistry. The c-Fos transcription factor is a measure of cellular activity and was used to quantify cocaine-induced activation of reward-processing areas of the brain: nucleus accumbens (NAc), caudate putamen (CPu), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). The mean fold change in cocaine-induced c-Fos cell counts relative to saline-induced c-Fos cell counts was significantly higher in exercising compared to control rats in the NAc core, dorsomedial and dorsolateral CPu, the prelimbic area, and the OFC, indicating differential cocaine-specific cellular activation of brain reward circuitry between exercising and control animals. These results suggest neurobiological mechanisms by which voluntary wheel running attenuates cocaine-motivated behaviors and provide support for exercise as a novel treatment for drug addiction. Copyright © 2013 Elsevier B.V. All rights reserved.

Regulation of zebrafish sleep and arousal states: current and prospective approaches

PubMed Central

Chiu, Cindy N.; Prober, David A.

2013-01-01

Every day, we shift among various states of sleep and arousal to meet the many demands of our bodies and environment. A central puzzle in neurobiology is how the brain controls these behavioral states, which are essential to an animal's well-being and survival. Mammalian models have predominated sleep and arousal research, although in the past decade, invertebrate models have made significant contributions to our understanding of the genetic underpinnings of behavioral states. More recently, the zebrafish has emerged as a promising model system for sleep and arousal research. Here we review experimental evidence that the zebrafish, a diurnal vertebrate, exhibits fundamental behavioral and neurochemical characteristics of mammalian sleep and arousal. We also propose how specific advantages of the zebrafish can be harnessed to advance the field. These include tractable genetics to identify and manipulate molecular and cellular regulators of behavioral states, optical transparency to facilitate in vivo observation of neural structure and function, and amenability to high-throughput drug screens to discover novel therapies for neurological disorders. PMID:23576957

A SIMPLE CELLULAR AUTOMATON MODEL FOR HIGH-LEVEL VEGETATION DYNAMICS

EPA Science Inventory

We have produced a simple two-dimensional (ground-plan) cellular automata model of vegetation dynamics specifically to investigate high-level community processes. The model is probabilistic, with individual plant behavior determined by physiologically-based rules derived from a w...

An extended cost potential field cellular automata model considering behavior variation of pedestrian flow

NASA Astrophysics Data System (ADS)

Guo, Fang; Li, Xingli; Kuang, Hua; Bai, Yang; Zhou, Huaguo

2016-11-01

The original cost potential field cellular automata describing normal pedestrian evacuation is extended to study more general evacuation scenarios. Based on the cost potential field function, through considering the psychological characteristics of crowd under emergencies, the quantitative formula of behavior variation is introduced to reflect behavioral changes caused by psychology tension. The numerical simulations are performed to investigate the effects of the magnitude of behavior variation, the different pedestrian proportions with different behavior variation and other factors on the evacuation efficiency and process in a room. The spatiotemporal dynamic characteristic during the evacuation process is also discussed. The results show that compared with the normal evacuation, the behavior variation under an emergency does not necessarily lead to the decrease of the evacuation efficiency. At low density, the increase of the behavior variation can improve the evacuation efficiency, while at high density, the evacuation efficiency drops significantly with the increasing amplitude of the behavior variation. In addition, the larger proportion of pedestrian affected by the behavior variation will prolong the evacuation time.

Neural plasticity and behavior - sixty years of conceptual advances.

PubMed

Sweatt, J David

2016-10-01

This brief review summarizes 60 years of conceptual advances that have demonstrated a role for active changes in neuronal connectivity as a controller of behavior and behavioral change. Seminal studies in the first phase of the six-decade span of this review firmly established the cellular basis of behavior - a concept that we take for granted now, but which was an open question at the time. Hebbian plasticity, including long-term potentiation and long-term depression, was then discovered as being important for local circuit refinement in the context of memory formation and behavioral change and stabilization in the mammalian central nervous system. Direct demonstration of plasticity of neuronal circuit function in vivo, for example, hippocampal neurons forming place cell firing patterns, extended this concept. However, additional neurophysiologic and computational studies demonstrated that circuit development and stabilization additionally relies on non-Hebbian, homoeostatic, forms of plasticity, such as synaptic scaling and control of membrane intrinsic properties. Activity-dependent neurodevelopment was found to be associated with cell-wide adjustments in post-synaptic receptor density, and found to occur in conjunction with synaptic pruning. Pioneering cellular neurophysiologic studies demonstrated the critical roles of transmembrane signal transduction, NMDA receptor regulation, regulation of neural membrane biophysical properties, and back-propagating action potential in critical time-dependent coincidence detection in behavior-modifying circuits. Concerning the molecular mechanisms underlying these processes, regulation of gene transcription was found to serve as a bridge between experience and behavioral change, closing the 'nature versus nurture' divide. Both active DNA (de)methylation and regulation of chromatin structure have been validated as crucial regulators of gene transcription during learning. The discovery of protein synthesis dependence on the acquisition of behavioral change was an influential discovery in the neurochemistry of behavioral modification. Higher order cognitive functions such as decision making and spatial and language learning were also discovered to hinge on neural plasticity mechanisms. The role of disruption of these processes in intellectual disabilities, memory disorders, and drug addiction has recently been clarified based on modern genetic techniques, including in the human. The area of neural plasticity and behavior has seen tremendous advances over the last six decades, with many of those advances being specifically in the neurochemistry domain. This review provides an overview of the progress in the area of neuroplasticity and behavior over the life-span of the Journal of Neurochemistry. To organize the broad literature base, the review collates progress into fifteen broad categories identified as 'conceptual advances', as viewed by the author. The fifteen areas are delineated in the figure above. This article is part of the 60th Anniversary special issue. © 2016 International Society for Neurochemistry.

The association between problematic cellular phone use and risky behaviors and low self-esteem among Taiwanese adolescents.

PubMed

Yang, Yuan-Sheng; Yen, Ju-Yu; Ko, Chih-Hung; Cheng, Chung-Ping; Yen, Cheng-Fang

2010-04-28

Cellular phone use (CPU) is an important part of life for many adolescents. However, problematic CPU may complicate physiological and psychological problems. The aim of our study was to examine the associations between problematic CPU and a series of risky behaviors and low self-esteem in Taiwanese adolescents. A total of 11,111 adolescent students in Southern Taiwan were randomly selected into this study. We used the Problematic Cellular Phone Use Questionnaire to identify the adolescents with problematic CPU. Meanwhile, a series of risky behaviors and self-esteem were evaluated. Multilevel logistic regression analyses were employed to examine the associations between problematic CPU and risky behaviors and low self-esteem regarding gender and age. The results indicated that positive associations were found between problematic CPU and aggression, insomnia, smoking cigarettes, suicidal tendencies, and low self-esteem in all groups with different sexes and ages. However, gender and age differences existed in the associations between problematic CPU and suspension from school, criminal records, tattooing, short nocturnal sleep duration, unprotected sex, illicit drugs use, drinking alcohol and chewing betel nuts. There were positive associations between problematic CPU and a series of risky behaviors and low self-esteem in Taiwanese adolescents. It is worthy for parents and mental health professionals to pay attention to adolescents' problematic CPU.

The role of the interaction network in the emergence of diversity of behavior

PubMed Central

Tabacof, Pedro; Von Zuben, Fernando J.

2017-01-01

How can systems in which individuals’ inner workings are very similar to each other, as neural networks or ant colonies, produce so many qualitatively different behaviors, giving rise to roles and specialization? In this work, we bring new perspectives to this question by focusing on the underlying network that defines how individuals in these systems interact. We applied a genetic algorithm to optimize rules and connections of cellular automata in order to solve the density classification task, a classical problem used to study emergent behaviors in decentralized computational systems. The networks used were all generated by the introduction of shortcuts in an originally regular topology, following the small-world model. Even though all cells follow the exact same rules, we observed the existence of different classes of cells’ behaviors in the best cellular automata found—most cells were responsible for memory and others for integration of information. Through the analysis of structural measures and patterns of connections (motifs) in successful cellular automata, we observed that the distribution of shortcuts between distant regions and the speed in which a cell can gather information from different parts of the system seem to be the main factors for the specialization we observed, demonstrating how heterogeneity in a network can create heterogeneity of behavior. PMID:28234962

Fast encryption of RGB color digital images using a tweakable cellular automaton based schema

NASA Astrophysics Data System (ADS)

Faraoun, Kamel Mohamed

2014-12-01

We propose a new tweakable construction of block-enciphers using second-order reversible cellular automata, and we apply it to encipher RGB-colored images. The proposed construction permits a parallel encryption of the image content by extending the standard definition of a block cipher to take into account a supplementary parameter used as a tweak (nonce) to control the behavior of the cipher from one region of the image to the other, and hence avoid the necessity to use slow sequential encryption's operating modes. The proposed construction defines a flexible pseudorandom permutation that can be used with efficacy to solve the electronic code book problem without the need to a specific sequential mode. Obtained results from various experiments show that the proposed schema achieves high security and execution performances, and enables an interesting mode of selective area decryption due to the parallel character of the approach.

Long-Term Impact of a Cell Phone-Enhanced Parenting Intervention.

PubMed

Lefever, Jennifer E Burke; Bigelow, Kathryn M; Carta, Judith J; Borkowski, John G; Grandfield, Elizabeth; McCune, Luke; Irvin, Dwight W; Warren, Steven F

2017-11-01

Home visiting programs support positive parenting in populations at-risk of child maltreatment, but their impact is often limited by poor retention and engagement. The current study assessed whether a cellular phone-supported version (PCI-C) of the Parent-Child Interactions (PCI) intervention improved long-term parenting practices, maternal depression, and children's aggression. Low-income mothers ( n = 371) of preschool-aged children were assigned to one of the three groups: PCI-C, PCI, and a wait-list control (WLC) group. Parenting improved in both intervention groups between baseline and 12-month follow-up compared to the WLC. Children in the PCI-C group were rated to be more cooperative and less aggressive than children in the WLC. The results offer evidence of the long-term effectiveness of PCI and the additional benefits of cellular phone supports for promoting intervention retention and improving children's behavior.

An Analysis of Pathological Activities of CCN Proteins in Joint Disorders: Mechanical Stretch-Mediated CCN2 Expression in Cultured Meniscus Cells.

PubMed

Furumatsu, Takayuki; Ozaki, Toshifumi

2017-01-01

The multifunctional growth factor CYR61/CTGF/NOV (CCN) 2, also known as connective tissue growth factor, regulates cellular proliferation, differentiation, and tissue regeneration. Recent literatures have described important roles of CCN2 in the meniscus metabolism. However, the mechanical stress-mediated transcriptional regulation of CCN2 in the meniscus remains unclear. The meniscus is a fibrocartilaginous tissue that controls complex biomechanics of the knee joint. Therefore, the injured unstable meniscus has a poor healing potential especially in the avascular inner region. In addition, dysfunction of the meniscus correlates with the progression of degenerative knee joint disorders and joint space narrowing. Here, we describe an experimental approach that investigates the distinct cellular behavior of inner and outer meniscus cells in response to mechanical stretch. Our experimental model can analyze the relationships between stretch-induced CCN2 expression and its functional role in the meniscus homeostasis.

Sporulation in the Budding Yeast Saccharomyces cerevisiae

PubMed Central

Neiman, Aaron M.

2011-01-01

In response to nitrogen starvation in the presence of a poor carbon source, diploid cells of the yeast Saccharomyces cerevisiae undergo meiosis and package the haploid nuclei produced in meiosis into spores. The formation of spores requires an unusual cell division event in which daughter cells are formed within the cytoplasm of the mother cell. This process involves the de novo generation of two different cellular structures: novel membrane compartments within the cell cytoplasm that give rise to the spore plasma membrane and an extensive spore wall that protects the spore from environmental insults. This article summarizes what is known about the molecular mechanisms controlling spore assembly with particular attention to how constitutive cellular functions are modified to create novel behaviors during this developmental process. Key regulatory points on the sporulation pathway are also discussed as well as the possible role of sporulation in the natural ecology of S. cerevisiae. PMID:22084423

Dynamics of Active Microfilaments

NASA Astrophysics Data System (ADS)

Ling, Feng; Guo, Hanliang; Kanso, Eva

2017-11-01

Soft elastic filaments are ubiquitous in natural and artificial systems at various length scales, and their interactions within and between filaments and their environments provide a persistent source of curiosity due to both the complexity of their behaviors and the relative mathematical simplicity of their structures. Specifically, a deeper understanding of the dynamic characteristics of microscopic filaments in viscous fluids is relevant to many biophysical and physiological processes. Here we start with the Cosserat model that allows all six possible modes of deformation for an elastic rod, and focus on the case of inextensible filaments submerged in viscous fluids by ignoring inertial effects and using local resistive force theory for fluid-filament interactions. We verify our simulations against special analytic solutions and present some results on the active internal control of cilia and flagella motion. We conclude by commenting on the utility of this general framework for studying other cellular and sub-cellular physical processes such as systems involving protein filaments.

The behavioral genetics of nonhuman primates: Status and prospects.

PubMed

Rogers, Jeffrey

2018-01-01

The complexity and diversity of primate behavior have long attracted the attention of ethologists, psychologists, behavioral ecologists, and neuroscientists. Recent studies have advanced our understanding of the nature of genetic influences on differences in behavior among individuals within species. A number of analyses have focused on the genetic analysis of behavioral reactions to specific experimental tests, providing estimates of the degree of genetic control over reactivity, and beginning to identify the genes involved. Substantial progress is also being made in identifying genetic factors that influence the structure and function of the primate brain. Most of the published studies on these topics have examined either cercopithecines or chimpanzees, though a few studies have addressed these questions in other primate species. One potentially important line of research is beginning to identify the epigenetic processes that influence primate behavior, thus revealing specific cellular and molecular mechanisms by which environmental experiences can influence gene expression or gene function relevant to behavior. This review summarizes many of these studies of non-human primate behavioral genetics. The primary focus is on analyses that address the nature of the genes and genetic processes that affect differences in behavior among individuals within non-human primate species. Analyses of between species differences and potential avenues for future research are also discussed. © 2018 American Association of Physical Anthropologists.

Utilizing Fibronectin Integrin-Binding Specificity to Control Cellular Responses

PubMed Central

Bachman, Haylee; Nicosia, John; Dysart, Marilyn; Barker, Thomas H.

2015-01-01

Significance: Cells communicate with the extracellular matrix (ECM) protein fibronectin (Fn) through integrin receptors on the cell surface. Controlling integrin–Fn interactions offers a promising approach to directing cell behavior, such as adhesion, migration, and differentiation, as well as coordinated tissue behaviors such as morphogenesis and wound healing. Recent Advances: Several different groups have developed recombinant fragments of Fn that can control epithelial to mesenchymal transition, sequester growth factors, and promote bone and wound healing. It is thought that these physiological responses are, in part, due to specific integrin engagement. Furthermore, it has been postulated that the integrin-binding domain of Fn is a mechanically sensitive switch that drives binding of one integrin heterodimer over another. Critical Issues: Although computational simulations have predicted the mechano-switch hypothesis and recent evidence supports the existence of varying strain states of Fn in vivo, experimental evidence of the Fn integrin switch is still lacking. Future Directions: Evidence of the integrin mechano-switch will enable the development of new Fn-based peptides in tissue engineering and wound healing, as well as deepen our understanding of ECM pathologies, such as fibrosis. PMID:26244106

Convergence of Artificial Protein Polymers and Intrinsically Disordered Proteins.

PubMed

Dzuricky, Michael; Roberts, Stefan; Chilkoti, Ashutosh

2018-05-01

A flurry of research in recent years has revealed the molecular origins of many membraneless organelles to be the liquid phase separation of intrinsically disordered proteins (IDPs). Consequently, protein disorder has emerged as an important driver of intracellular compartmentalization by providing specialized microenvironments chemically distinct from the surrounding medium. Though the importance of protein disorder and its relationship to intracellular phase behavior are clear, a detailed understanding of how such phase behavior can be predicted and controlled remains elusive. While research in IDPs has largely focused on the implications of structural disorder on cellular function and disease, another field, that of artificial protein polymers, has focused on the de novo design of protein polymers with controllable material properties. A subset of these polymers, specifically those derived from structural proteins such as elastin and resilin, are also disordered sequences that undergo liquid-liquid phase separation. This phase separation has been used in a variety of biomedical applications, and researchers studying these polymers have developed methods to precisely characterize and tune their phase behavior. Despite their disparate origins, both fields are complementary as they study the phase behavior of intrinsically disordered polypeptides. This Perspective hopes to stimulate collaborative efforts by highlighting the similarities between these two fields and by providing examples of how such collaboration could be mutually beneficial.

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

PubMed

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.

Mediators of Physical Activity on Neurocognitive Function: A Review at Multiple Levels of Analysis.

PubMed

Stillman, Chelsea M; Cohen, Jamie; Lehman, Morgan E; Erickson, Kirk I

2016-01-01

Physical activity (PA) is known to maintain and improve neurocognitive health. However, there is still a poor understanding of the mechanisms by which PA exerts its effects on the brain and cognition in humans. Many of the most widely discussed mechanisms of PA are molecular and cellular and arise from animal models. While information about basic cellular and molecular mechanisms is an important foundation from which to build our understanding of how PA promotes cognitive health in humans, there are other pathways that could play a role in this relationship. For example, PA-induced changes to cellular and molecular pathways likely initiate changes to macroscopic properties of the brain and/or to behavior that in turn influence cognition. The present review uses a more macroscopic lens to identify potential brain and behavioral/socioemotional mediators of the association between PA and cognitive function. We first summarize what is known regarding cellular and molecular mechanisms, and then devote the remainder of the review to discussing evidence for brain systems and behavioral/socioemotional pathways by which PA influences cognition. It is our hope that discussing mechanisms at multiple levels of analysis will stimulate the field to examine both brain and behavioral mediators. Doing so is important, as it could lead to a more complete characterization of the processes by which PA influences neurocognitive function, as well as a greater variety of targets for modifying neurocognitive function in clinical contexts.

ZnO nanotube waveguide arrays on graphene films for local optical excitation on biological cells

NASA Astrophysics Data System (ADS)

Baek, Hyeonjun; Kwak, Hankyul; Song, Minho S.; Ha, Go Eun; Park, Jongwoo; Tchoe, Youngbin; Hyun, Jerome K.; Park, Hye Yoon; Cheong, Eunji; Yi, Gyu-Chul

2017-04-01

We report on scalable and position-controlled optical nanoprobe arrays using ZnO nanotube waveguides on graphene films for use in local optical excitation. For the waveguide fabrication, position-controlled and well-ordered ZnO nanotube arrays were grown on chemical vapor deposited graphene films with a submicron patterned mask layer and Au prepared between the interspace of nanotubes. Mammalian cells were cultured on the nanotube waveguide arrays and were locally excited by light illuminated through the nanotubes. Fluorescence and optogenetic signals could be excited through the optical nanoprobes. This method offers the ability to investigate cellular behavior with a high spatial resolution that surpasses the current limitation.

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

PubMed Central

Anderson, Eric J; Falls, Thomas D; Sorkin, Adam M; Tate, Melissa L Knothe

2006-01-01

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. PMID:16672051

The plausibility of a role for mercury in the etiology of autism: a cellular perspective

PubMed Central

Garrecht, Matthew; Austin, David W.

2011-01-01

Autism is defined by a behavioral set of stereotypic and repetitious behavioral patterns in combination with social and communication deficits. There is emerging evidence supporting the hypothesis that autism may result from a combination of genetic susceptibility and exposure to environmental toxins at critical moments in development. Mercury (Hg) is recognized as a ubiquitous environmental neurotoxin and there is mounting evidence linking it to neurodevelopmental disorders, including autism. Of course, the evidence is not derived from experimental trials with humans but rather from methods focusing on biomarkers of Hg damage, measurements of Hg exposure, epidemiological data, and animal studies. For ethical reasons, controlled Hg exposure in humans will never be conducted. Therefore, to properly evaluate the Hg-autism etiological hypothesis, it is essential to first establish the biological plausibility of the hypothesis. This review examines the plausibility of Hg as the primary etiological agent driving the cellular mechanisms by which Hg-induced neurotoxicity may result in the physiological attributes of autism. Key areas of focus include: (1) route and cellular mechanisms of Hg exposure in autism; (2) current research and examples of possible genetic variables that are linked to both Hg sensitivity and autism; (3) the role Hg may play as an environmental toxin fueling the oxidative stress found in autism; (4) role of mitochondrial dysfunction; and (5) possible role of Hg in abnormal neuroexcitory and excitotoxity that may play a role in the immune dysregulation found in autism. Future research directions that would assist in addressing the gaps in our knowledge are proposed. PMID:22163375

Anthrax Toxin

DTIC Science & Technology

1984-10-26

focused initially on EF because it seemed possible that this component, like cholera toxin, might cause edema in skin through elevation of cellular cAMP...behavior differed from that seen in cells exposed to cholera toxin, where cellular cAMP levels remain elevated upon toxin removal. Studies in CHO cell...LF, the rat bioassay is not likely to be an appropriate system for studying the cellular and molecular mechanisms of action of LF. Therefore, a survey

Building New Bridges between In Vitro and In Vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology.

PubMed

Pearlstein, Robert A; McKay, Daniel J J; Hornak, Viktor; Dickson, Callum; Golosov, Andrei; Harrison, Tyler; Velez-Vega, Camilo; Duca, José

2017-01-01

Cellular drug targets exist within networked function-generating systems whose constituent molecular species undergo dynamic interdependent non-equilibrium state transitions in response to specific perturbations (i.e.. inputs). Cellular phenotypic behaviors are manifested through the integrated behaviors of such networks. However, in vitro data are frequently measured and/or interpreted with empirical equilibrium or steady state models (e.g. Hill, Michaelis-Menten, Briggs-Haldane) relevant to isolated target populations. We propose that cells act as analog computers, "solving" sets of coupled "molecular differential equations" (i.e. represented by populations of interacting species)via "integration" of the dynamic state probability distributions among those populations. Disconnects between biochemical and functional/phenotypic assays (cellular/in vivo) may arise with targetcontaining systems that operate far from equilibrium, and/or when coupled contributions (including target-cognate partner binding and drug pharmacokinetics) are neglected in the analysis of biochemical results. The transformation of drug discovery from a trial-and-error endeavor to one based on reliable design criteria depends on improved understanding of the dynamic mechanisms powering cellular function/dysfunction at the systems level. Here, we address the general mechanisms of molecular and cellular function and pharmacological modulation thereof. We outline a first principles theory on the mechanisms by which free energy is stored and transduced into biological function, and by which biological function is modulated by drug-target binding. We propose that cellular function depends on dynamic counter-balanced molecular systems necessitated by the exponential behavior of molecular state transitions under non-equilibrium conditions, including positive versus negative mass action kinetics and solute-induced perturbations to the hydrogen bonds of solvating water versus kT. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

THE FUNCTIONAL ARCHITECTURE OF DEHYDRATION-ANOREXIA

PubMed Central

Watts, Alan G.; Boyle, Christina N.

2010-01-01

The anorexia that accompanies the drinking of hypertonic saline (DE-anorexia) is a critical adaptive behavioral mechanism that helps protect the integrity of fluid compartments during extended periods of cellular dehydration. Feeding is rapidly reinstated once drinking water is made available again. The relative simplicity and reproducibility of these behaviors makes DE-anorexia a very useful model for investigating how the various neural networks that control ingestive behaviors first suppress and then reinstate feeding. We show that DE-anorexia develops primarily because the mechanisms that terminate ongoing meals are upregulated in such a way as to significantly reduce meal size. At the same time however, signals generated by the ensuing negative energy balance appropriately activate neural mechanisms that can increase food intake. But as the output from these two competing processes is integrated, the net result is an increasing reduction of nocturnal food intake, despite the fact that spontaneous meals are initiated with the same frequency as in control animals. Furthermore, hypothalamic NPY injections also stimulate feeding in DE-anorexic animals with the same latency as controls, but again meals are prematurely terminated. Comparing Fos expression patterns across the brain following 2-deoxyglucose administration to control and DE-anorexic animals implicates neurons in the descending part of the parvicellular paraventricular nucleus of the hypothalamus and the lateral hypothalamic areas as key components of the networks that control DE-anorexia. Finally, DE-anorexia generates multiple inhibitory processes to suppress feeding. These are differentially disengaged once drinking water is reinstated. PMID:20399797

Carbon Nanotubes Hybrid Hydrogels in Drug Delivery: A Perspective Review

PubMed Central

Hampel, Silke; Spizzirri, Umile Gianfranco; Parisi, Ortensia Ilaria; Picci, Nevio; Iemma, Francesca

2014-01-01

The use of biologics, polymers, silicon materials, carbon materials, and metals has been proposed for the preparation of innovative drug delivery devices. One of the most promising materials in this field are the carbon-nanotubes composites and hybrid materials coupling the advantages of polymers (biocompatibility and biodegradability) with those of carbon nanotubes (cellular uptake, stability, electromagnatic, and magnetic behavior). The applicability of polymer-carbon nanotubes composites in drug delivery, with particular attention to the controlled release by composites hydrogel, is being extensively investigated in the present review. PMID:24587993

The Cellular Basis of a Corollary Discharge

NASA Astrophysics Data System (ADS)

Poulet, James F. A.; Hedwig, Berthold

2006-01-01

How do animals discriminate self-generated from external stimuli during behavior and prevent desensitization of their sensory pathways? A fundamental concept in neuroscience states that neural signals, termed corollary discharges or efference copies, are forwarded from motor to sensory areas. Neurons mediating these signals have proved difficult to identify. We show that a single, multisegmental interneuron is responsible for the pre- and postsynaptic inhibition of auditory neurons in singing crickets (Gryllus bimaculatus). Therefore, this neuron represents a corollary discharge interneuron that provides a neuronal basis for the central control of sensory responses.

Effects of acamprosate on attentional set-shifting and cellular function in the prefrontal cortex of chronic alcohol-exposed mice

NASA Astrophysics Data System (ADS)

Hu, Wei

Background: The medial prefrontal cortex (mPFC) inhibits impulsive and compulsive behaviors that characterize drug abuse and dependence. Acamprosate is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Whether acamprosate can modulate executive functions that are impaired by chronic ethanol exposure is unknown. Here we explored the effects of acamprosate on an attentional set-shifting task, and tested whether these behavioral effects are correlated with modulation of glutamatergic synaptic transmission and intrinsic excitability of mPFC neurons. Methods: We induced alcohol dependence in mice via chronic intermittent ethanol (CIE) exposure in vapor chambers and measured changes in alcohol consumption in a limited access 2-bottle choice paradigm. Impairments of executive function were assessed in an attentional set-shifting task. Acamprosate was applied subchronically for 2 days during withdrawal before the final behavioral test. Alcohol-induced changes in cellular function of layer 5/6 pyramidal neurons, and the potential modulation of these changes by acamprosate, were measured using patch clamp recordings in brain slices. Results: Chronic ethanol exposure impaired cognitive flexibility in the attentional set-shifting task. Acamprosate improved overall performance and reduced perseveration. Recordings of mPFC neurons showed that chronic ethanol exposure increased use-dependent presynaptic transmitter release and enhanced postsynaptic N-methyl-D-aspartate receptor (NMDAR) function. Moreover, CIE-treatment lowered input resistance, and decreased the threshold and the afterhyperpolarization (AHP) of action potentials, suggesting chronic ethanol exposure also impacted membrane excitability of mPFC neurons. However, acamprosate treatment did not reverse these ethanol-induced changes cellular function. Conclusion: Acamprosate improved attentional control of ethanol exposed animals, but did not alter the concurrent changes in synaptic transmission or membrane excitability of mPFC neurons, indicating that these changes are not the pharmacological targets of acamprosate in the recovery of mPFC functions affected by chronic ethanol exposure.

Dopamine and extinction: A convergence of theory with fear and reward circuitry

PubMed Central

Abraham, Antony D.; Neve, Kim A.; Lattal, K. Matthew

2014-01-01

Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine’s function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. PMID:24269353

Dopamine and extinction: a convergence of theory with fear and reward circuitry.

PubMed

Abraham, Antony D; Neve, Kim A; Lattal, K Matthew

2014-02-01

Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. Copyright © 2013 Elsevier Inc. All rights reserved.

Computational systems biology and dose-response modeling in relation to new directions in toxicity testing.

PubMed

Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E; Conolly, Rory B

2010-02-01

The new paradigm envisioned for toxicity testing in the 21st century advocates shifting from the current animal-based testing process to a combination of in vitro cell-based studies, high-throughput techniques, and in silico modeling. A strategic component of the vision is the adoption of the systems biology approach to acquire, analyze, and interpret toxicity pathway data. As key toxicity pathways are identified and their wiring details elucidated using traditional and high-throughput techniques, there is a pressing need to understand their qualitative and quantitative behaviors in response to perturbation by both physiological signals and exogenous stressors. The complexity of these molecular networks makes the task of understanding cellular responses merely by human intuition challenging, if not impossible. This process can be aided by mathematical modeling and computer simulation of the networks and their dynamic behaviors. A number of theoretical frameworks were developed in the last century for understanding dynamical systems in science and engineering disciplines. These frameworks, which include metabolic control analysis, biochemical systems theory, nonlinear dynamics, and control theory, can greatly facilitate the process of organizing, analyzing, and understanding toxicity pathways. Such analysis will require a comprehensive examination of the dynamic properties of "network motifs"--the basic building blocks of molecular circuits. Network motifs like feedback and feedforward loops appear repeatedly in various molecular circuits across cell types and enable vital cellular functions like homeostasis, all-or-none response, memory, and biological rhythm. These functional motifs and associated qualitative and quantitative properties are the predominant source of nonlinearities observed in cellular dose response data. Complex response behaviors can arise from toxicity pathways built upon combinations of network motifs. While the field of computational cell biology has advanced rapidly with increasing availability of new data and powerful simulation techniques, a quantitative orientation is still lacking in life sciences education to make efficient use of these new tools to implement the new toxicity testing paradigm. A revamped undergraduate curriculum in the biological sciences including compulsory courses in mathematics and analysis of dynamical systems is required to address this gap. In parallel, dissemination of computational systems biology techniques and other analytical tools among practicing toxicologists and risk assessment professionals will help accelerate implementation of the new toxicity testing vision.

Simulating the behavior of patients who leave a public hospital emergency department without being seen by a physician: a cellular automaton and agent-based framework.

PubMed

Yousefi, Milad; Yousefi, Moslem; Fogliatto, F S; Ferreira, R P M; Kim, J H

2018-01-11

The objective of this study was to develop an agent based modeling (ABM) framework to simulate the behavior of patients who leave a public hospital emergency department (ED) without being seen (LWBS). In doing so, the study complements computer modeling and cellular automata (CA) techniques to simulate the behavior of patients in an ED. After verifying and validating the model by comparing it with data from a real case study, the significance of four preventive policies including increasing number of triage nurses, fast-track treatment, increasing the waiting room capacity and reducing treatment time were investigated by utilizing ordinary least squares regression. After applying the preventing policies in ED, an average of 42.14% reduction in the number of patients who leave without being seen and 6.05% reduction in the average length of stay (LOS) of patients was reported. This study is the first to apply CA in an ED simulation. Comparing the average LOS before and after applying CA with actual times from emergency department information system showed an 11% improvement. The simulation results indicated that the most effective approach to reduce the rate of LWBS is applying fast-track treatment. The ABM approach represents a flexible tool that can be constructed to reflect any given environment. It is also a support system for decision-makers to assess the relative impact of control strategies.

Simulating the behavior of patients who leave a public hospital emergency department without being seen by a physician: a cellular automaton and agent-based framework

PubMed Central

Yousefi, Milad; Yousefi, Moslem; Fogliatto, F.S.; Ferreira, R.P.M.; Kim, J.H.

2018-01-01

The objective of this study was to develop an agent based modeling (ABM) framework to simulate the behavior of patients who leave a public hospital emergency department (ED) without being seen (LWBS). In doing so, the study complements computer modeling and cellular automata (CA) techniques to simulate the behavior of patients in an ED. After verifying and validating the model by comparing it with data from a real case study, the significance of four preventive policies including increasing number of triage nurses, fast-track treatment, increasing the waiting room capacity and reducing treatment time were investigated by utilizing ordinary least squares regression. After applying the preventing policies in ED, an average of 42.14% reduction in the number of patients who leave without being seen and 6.05% reduction in the average length of stay (LOS) of patients was reported. This study is the first to apply CA in an ED simulation. Comparing the average LOS before and after applying CA with actual times from emergency department information system showed an 11% improvement. The simulation results indicated that the most effective approach to reduce the rate of LWBS is applying fast-track treatment. The ABM approach represents a flexible tool that can be constructed to reflect any given environment. It is also a support system for decision-makers to assess the relative impact of control strategies. PMID:29340526

75 FR 57475 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-21

... personal privacy. Name of Committee: Molecular, Cellular and Developmental Neuroscience Integrated Review Group; Cellular and Molecular Biology of Neurodegeneration Study Section. Date: October 14-15, 2010...; Collaborative: Behavioral Genetics and Epidemiology Linked Applications. Date: October 20-21, 2010. Time: 8:30 a...

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

PubMed

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.

Controlling human corneal stromal stem cell contraction to mediate rapid cell and matrix organization of real architecture for 3-dimensional tissue equivalents.

PubMed

Mukhey, Dev; Phillips, James B; Daniels, Julie T; Kureshi, Alvena K

2018-02-01

The architecture of the human corneal stroma consists of a highly organized extracellular matrix (ECM) interspersed with keratocytes. Their progenitor cells; corneal stromal stem cells (CSSC) are located at the periphery, in the limbal stroma. A highly organized corneal ECM is critical for effective transmission of light but this structure may be compromised during injury or disease, resulting in loss of vision. Re-creating normal organization in engineered tissue equivalents for transplantation often involves lengthy culture times that are inappropriate for clinical use or utilisation of synthetic substrates that bring complications such as corneal melting. CSSC have great therapeutic potential owing to their ability to reorganize a disorganized matrix, restoring transparency in scarred corneas. We examined CSSC contractile behavior to assess whether this property could be exploited to rapidly generate cell and ECM organization in Real Architecture For 3D Tissues (RAFT) tissue equivalents (TE) for transplantation. Free-floating collagen gels were characterized to assess contractile behavior of CSSC and establish optimum cell density and culture times. To mediate cell and collagen organization, tethered collagen gels seeded with CSSC were cultured and subsequently stabilized with the RAFT process. We demonstrated rapid creation of biomimetic RAFT TE with tunable structural properties. These displayed three distinct regions of varying degrees of cellular and collagen organization. Interestingly, increased organization coincided with a dramatic loss of PAX6 expression in CSSC, indicating rapid differentiation into keratocytes. The organized RAFT TE system could be a useful bioengineering tool to rapidly create an organized ECM while simultaneously controlling cell phenotype. For the first time, we have demonstrated that human CSSC exhibit the phenomenon of cellular self-alignment in tethered collagen gels. We found this mediated rapid co-alignment of collagen fibrils and thus subsequently exploited this property in vitro to improve the architecture of engineered RAFT tissue equivalents of the corneal stroma. Existing techniques are extremely lengthy and carry significant risk and cost for GMP manufacture. This rapid and tunable technique takes just 8 h of culture and is therefore ideal for clinical manufacture, creating biomimetic tissue equivalents with both cellular and ECM organization. Thus, cellular self-alignment can be a useful bioengineering tool for the development of organized tissue equivalents in a variety of applications. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Pomegranate Supplementation Improves Affective and Motor Behavior in Mice after Radiation Exposure

PubMed Central

Dulcich, Melissa S.; Hartman, Richard E.

2013-01-01

Currently, NASA has plans for extended space travel, and previous research indicates that space radiation can have negative effects on cognitive skills as well as physical and mental health. With long-term space travel, astronauts will be exposed to greater radiation levels. Research shows that an antioxidant-enriched diet may offer some protection against the cellular effects of radiation and may provide significant neuroprotection from the effects of radiation-induced cognitive and behavioral skill deficits. Ninety-six C57BL/6 mice (48 pomegranate fed and 48 control) were irradiated with proton radiation (2 Gy), and two-month postradiation behaviors were assessed using a battery of behavioral tests to measure cognitive and motor functions. Proton irradiation was associated with depression-like behaviors in the tail suspension test, but this effect was ameliorated by the pomegranate diet. Males, in general, displayed worse coordination and balance than females on the rotarod task, and the pomegranate diet ameliorated this effect. Overall, it appears that proton irradiation, which may be encountered in space, may induce a different pattern of behavioral deficits in males than females and that a pomegranate diet may confer protection against some of those effects. PMID:23662154

Health Benefits of Fasting and Caloric Restriction.

PubMed

Golbidi, Saeid; Daiber, Andreas; Korac, Bato; Li, Huige; Essop, M Faadiel; Laher, Ismail

2017-10-23

Obesity and obesity-related diseases, largely resulting from urbanization and behavioral changes, are now of global importance. Energy restriction, though, is associated with health improvements and increased longevity. We review some important mechanisms related to calorie limitation aimed at controlling of metabolic diseases, particularly diabetes. Calorie restriction triggers a complex series of intricate events, including activation of cellular stress response elements, improved autophagy, modification of apoptosis, and alteration in hormonal balance. Intermittent fasting is not only more acceptable to patients, but it also prevents some of the adverse effects of chronic calorie restriction, especially malnutrition. There are many somatic and potentially psychologic benefits of fasting or intermittent calorie restriction. However, some behavioral modifications related to abstinence of binge eating following a fasting period are crucial in maintaining the desired favorable outcomes.

Challenges in Characterizing and Controlling Complex Cellular Systems

NASA Astrophysics Data System (ADS)

Wikswo, John

2011-03-01

Multicellular dynamic biological processes such as developmental differentiation, wound repair, disease, aging, and even homeostasis can be represented by trajectories through a phase space whose extent reflects the genetic, post-translational, and metabolic complexity of the process - easily extending to tens of thousands of dimensions. Intra- and inter-cellular sensing and regulatory systems and their nested, redundant, and non-linear feed-forward and feed-back controls create high-dimensioned attractors in this phase space. Metabolism provides free energy to drive non-equilibrium processes and dynamically reconfigure attractors. Studies of single molecules and cells provide only minimalist projections onto a small number of axes. It may be difficult to infer larger-scale emergent behavior from linearized experiments that perform only small amplitude perturbations on a limited number of the dimensions. Complete characterization may succeed for bounded component problems, such as an individual cell cycle or signaling cascade, but larger systems problems will require a coarse-grained approach. Hence a new experimental and analytical framework is needed. Possibly one could utilize high-amplitude, multi-variable driving of the system to infer coarse-grained, effective models, which in turn can be tested by their ability to control systems behavior. Navigation at will between attractors in a high-dimensioned dynamical system will provide not only detailed knowledge of the shape of attractor basins, but also measures of underlying stochastic events such as noise in gene expression or receptor binding and how both affect system stability and robustness. Needed for this are wide-bandwidth methods to sense and actuate large numbers of intracellular and extracellular variables and automatically and rapidly infer dynamic control models. The success of this approach may be determined by how broadly the sensors and actuators can span the full dimensionality of the phase space. Supported by the Defense Threat Reduction Agency HDTRA-09-1-0013, NIH National Institute on Drug Abuse RC2DA028981, the National Academies Keck Futures Initiative, and the Vanderbilt Institute for Integrative Biosystems Research and Education.

Design of crashworthy structures with controlled behavior in HCA framework

NASA Astrophysics Data System (ADS)

Bandi, Punit

The field of crashworthiness design is gaining more interest and attention from automakers around the world due to increasing competition and tighter safety norms. In the last two decades, topology and topometry optimization methods from structural optimization have been widely explored to improve existing designs or conceive new designs with better crashworthiness. Although many gradient-based and heuristic methods for topology- and topometry-based crashworthiness design are available these days, most of them result in stiff structures that are suitable only for a set of vehicle components in which maximizing the energy absorption or minimizing the intrusion is the main concern. However, there are some other components in a vehicle structure that should have characteristics of both stiffness and flexibility. Moreover, the load paths within the structure and potential buckle modes also play an important role in efficient functioning of such components. For example, the front bumper, side frame rails, steering column, and occupant protection devices like the knee bolster should all exhibit controlled deformation and collapse behavior. The primary objective of this research is to develop new methodologies to design crashworthy structures with controlled behavior. The well established Hybrid Cellular Automaton (HCA) method is used as the basic framework for the new methodologies, and compliant mechanism-type (sub)structures are the highlight of this research. The ability of compliant mechanisms to efficiently transfer force and/or motion from points of application of input loads to desired points within the structure is used to design solid and tubular components that exhibit controlled deformation and collapse behavior under crash loads. In addition, a new methodology for controlling the behavior of a structure under multiple crash load scenarios by adaptively changing the contributions from individual load cases is developed. Applied to practical design problems, the results demonstrate that the methodologies provide a practical tool to aid the design engineer in generating design concepts for crashworthy structures with controlled behavior. Although developed in the HCA framework, the basic ideas behind these methods are generic and can be easily implemented with other available topology- and topometry-based optimization methods.

Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior.

PubMed

Hashimoto, Kyoichi; Yamada, Yosuke; Semi, Katsunori; Yagi, Masaki; Tanaka, Akito; Itakura, Fumiaki; Aoki, Hitomi; Kunisada, Takahiro; Woltjen, Knut; Haga, Hironori; Sakai, Yoshiharu; Yamamoto, Takuya; Yamada, Yasuhiro

2017-01-24

The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect for genetic aberrations. However, the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated. We reprogrammed colon tumor cells in an Apc Min/+ (adenomatous polyposis coli) mouse model, in which the loss of the Apc gene plays a critical role in tumor development and subsequently, established reprogrammed tumor cells (RTCs) that exhibit pluripotent stem cell (PSC)-like signatures of gene expression. We show that the majority of the genes in RTCs that were affected by Apc mutations did not overlap with the genes affected in the intestine. RTCs lacked pluripotency but exhibited an increased expression of Cdx2 and a differentiation propensity that was biased toward the trophectoderm cell lineage. Genetic rescue of the mutated Apc allele conferred pluripotency on RTCs and enabled their differentiation into various cell types in vivo. The redisruption of Apc in RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine, but the majority of the intestinal lesions remained as pretumoral microadenomas. These results highlight the significant influence of cellular context on gene regulation, cellular plasticity, and cellular behavior in response to the loss of the Apc function. Our results also imply that the transition from microadenomas to macroscopic tumors is reprogrammable, which underscores the importance of epigenetic regulation on tumor promotion.

Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior

PubMed Central

Hashimoto, Kyoichi; Yamada, Yosuke; Semi, Katsunori; Yagi, Masaki; Tanaka, Akito; Itakura, Fumiaki; Aoki, Hitomi; Kunisada, Takahiro; Woltjen, Knut; Haga, Hironori; Sakai, Yoshiharu; Yamamoto, Takuya; Yamada, Yasuhiro

2017-01-01

The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect for genetic aberrations. However, the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated. We reprogrammed colon tumor cells in an ApcMin/+ (adenomatous polyposis coli) mouse model, in which the loss of the Apc gene plays a critical role in tumor development and subsequently, established reprogrammed tumor cells (RTCs) that exhibit pluripotent stem cell (PSC)-like signatures of gene expression. We show that the majority of the genes in RTCs that were affected by Apc mutations did not overlap with the genes affected in the intestine. RTCs lacked pluripotency but exhibited an increased expression of Cdx2 and a differentiation propensity that was biased toward the trophectoderm cell lineage. Genetic rescue of the mutated Apc allele conferred pluripotency on RTCs and enabled their differentiation into various cell types in vivo. The redisruption of Apc in RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine, but the majority of the intestinal lesions remained as pretumoral microadenomas. These results highlight the significant influence of cellular context on gene regulation, cellular plasticity, and cellular behavior in response to the loss of the Apc function. Our results also imply that the transition from microadenomas to macroscopic tumors is reprogrammable, which underscores the importance of epigenetic regulation on tumor promotion. PMID:28057861

Ethanol-Induced Changes in PKCε: From Cell to Behavior.

PubMed

Pakri Mohamed, Rashidi M; Mokhtar, Mohd H; Yap, Ernie; Hanim, Athirah; Abdul Wahab, Norhazlina; Jaffar, Farah H F; Kumar, Jaya

2018-01-01

The long-term binge intake of ethanol causes neuroadaptive changes that lead to drinkers requiring higher amounts of ethanol to experience its effects. This neuroadaptation can be partly attributed to the modulation of numerous neurotransmitter receptors by the various protein kinases C (PKCs). PKCs are enzymes that control cellular activities by regulating other proteins via phosphorylation. Among the various isoforms of PKC, PKCε is the most implicated in ethanol-induced biochemical and behavioral changes. Ethanol exposure causes changes to PKCε expression and localization in various brain regions that mediate addiction-favoring plasticity. Ethanol works in conjunction with numerous upstream kinases and second messenger activators to affect cellular PKCε expression. Chauffeur proteins, such as receptors for activated C kinase (RACKs), cause the translocation of PKCε to aberrant sites and mediate ethanol-induced changes. In this article, we aim to review the following: the general structure and function of PKCε, ethanol-induced changes in PKCε expression, the regulation of ethanol-induced PKCε activities in DAG-dependent and DAG-independent environments, the mechanisms underlying PKCε-RACKε translocation in the presence of ethanol, and the existing literature on the role of PKCε in ethanol-induced neurobehavioral changes, with the goal of creating a working model upon which further research can build.

Childhood Personality, Betrayal Trauma, and Leukocyte Telomere Length in Adulthood: A Lifespan Perspective on Conscientiousness and Betrayal Traumas as Predictors of a Biomarker of Cellular Aging.

PubMed

Edmonds, Grant W; Hampson, Sarah E; Côté, Hélène C F; Hill, Patrick L; Klest, Bridget

2016-01-01

Conscientiousness is associated with longevity. As such, identifying the biological pathways linking personality to mortality is important. This study employs longitudinal data spanning >40 years to test prospective associations with Leukocyte Telomere Length (LTL), a potential marker of cellular aging. Because telomeres shorten over time, and are sensitive to oxidative stress, shorter LTL may reflect cumulative damage associated with negative health behaviors and past stressful events. We investigated childhood conscientiousness as a protective factor, expecting an association with longer LTL in adulthood, possibly reflecting slower LTL shortening. Potential lifespan pathways involving childhood trauma, smoking behaviors, and Body Mass Index (BMI) were explored. Childhood conscientiousness showed a small raw association with LTL ( r = .08, p = .04), although this effect did not persist when controlling for age and sex. Despite this lack of a direct effect on LTL, we detected an indirect effect operating jointly through BMI and smoking. Higher rates of childhood betrayal trauma were associated with shorter LTL. Contrary to our hypothesis that conscientiousness would buffer this effect, we found evidence for an interaction with childhood betrayal traumas where the association between childhood betrayal traumas and LTL was larger for those higher on conscientiousness in childhood.

Childhood Personality, Betrayal Trauma, and Leukocyte Telomere Length in Adulthood: A Lifespan Perspective on Conscientiousness and Betrayal Traumas as Predictors of a Biomarker of Cellular Aging

PubMed Central

Edmonds, Grant W.; Hampson, Sarah E.; Côté, Hélène C. F.; Hill, Patrick L.; Klest, Bridget

2016-01-01

Conscientiousness is associated with longevity. As such, identifying the biological pathways linking personality to mortality is important. This study employs longitudinal data spanning >40 years to test prospective associations with Leukocyte Telomere Length (LTL), a potential marker of cellular aging. Because telomeres shorten over time, and are sensitive to oxidative stress, shorter LTL may reflect cumulative damage associated with negative health behaviors and past stressful events. We investigated childhood conscientiousness as a protective factor, expecting an association with longer LTL in adulthood, possibly reflecting slower LTL shortening. Potential lifespan pathways involving childhood trauma, smoking behaviors, and Body Mass Index (BMI) were explored. Childhood conscientiousness showed a small raw association with LTL (r = .08, p = .04), although this effect did not persist when controlling for age and sex. Despite this lack of a direct effect on LTL, we detected an indirect effect operating jointly through BMI and smoking. Higher rates of childhood betrayal trauma were associated with shorter LTL. Contrary to our hypothesis that conscientiousness would buffer this effect, we found evidence for an interaction with childhood betrayal traumas where the association between childhood betrayal traumas and LTL was larger for those higher on conscientiousness in childhood. PMID:28018048

Diverse activities of viral cis-acting RNA regulatory elements revealed using multicolor, long-term, single-cell imaging

PubMed Central

Pocock, Ginger M.; Zimdars, Laraine L.; Yuan, Ming; Eliceiri, Kevin W.; Ahlquist, Paul; Sherer, Nathan M.

2017-01-01

Cis-acting RNA structural elements govern crucial aspects of viral gene expression. How these structures and other posttranscriptional signals affect RNA trafficking and translation in the context of single cells is poorly understood. Herein we describe a multicolor, long-term (>24 h) imaging strategy for measuring integrated aspects of viral RNA regulatory control in individual cells. We apply this strategy to demonstrate differential mRNA trafficking behaviors governed by RNA elements derived from three retroviruses (HIV-1, murine leukemia virus, and Mason-Pfizer monkey virus), two hepadnaviruses (hepatitis B virus and woodchuck hepatitis virus), and an intron-retaining transcript encoded by the cellular NXF1 gene. Striking behaviors include “burst” RNA nuclear export dynamics regulated by HIV-1’s Rev response element and the viral Rev protein; transient aggregations of RNAs into discrete foci at or near the nuclear membrane triggered by multiple elements; and a novel, pulsiform RNA export activity regulated by the hepadnaviral posttranscriptional regulatory element. We incorporate single-cell tracking and a data-mining algorithm into our approach to obtain RNA element–specific, high-resolution gene expression signatures. Together these imaging assays constitute a tractable, systems-based platform for studying otherwise difficult to access spatiotemporal features of viral and cellular gene regulation. PMID:27903772

Ethanol-Induced Changes in PKCε: From Cell to Behavior

PubMed Central

Pakri Mohamed, Rashidi M.; Mokhtar, Mohd H.; Yap, Ernie; Hanim, Athirah; Abdul Wahab, Norhazlina; Jaffar, Farah H. F.; Kumar, Jaya

2018-01-01

The long-term binge intake of ethanol causes neuroadaptive changes that lead to drinkers requiring higher amounts of ethanol to experience its effects. This neuroadaptation can be partly attributed to the modulation of numerous neurotransmitter receptors by the various protein kinases C (PKCs). PKCs are enzymes that control cellular activities by regulating other proteins via phosphorylation. Among the various isoforms of PKC, PKCε is the most implicated in ethanol-induced biochemical and behavioral changes. Ethanol exposure causes changes to PKCε expression and localization in various brain regions that mediate addiction-favoring plasticity. Ethanol works in conjunction with numerous upstream kinases and second messenger activators to affect cellular PKCε expression. Chauffeur proteins, such as receptors for activated C kinase (RACKs), cause the translocation of PKCε to aberrant sites and mediate ethanol-induced changes. In this article, we aim to review the following: the general structure and function of PKCε, ethanol-induced changes in PKCε expression, the regulation of ethanol-induced PKCε activities in DAG-dependent and DAG-independent environments, the mechanisms underlying PKCε-RACKε translocation in the presence of ethanol, and the existing literature on the role of PKCε in ethanol-induced neurobehavioral changes, with the goal of creating a working model upon which further research can build. PMID:29706864

Exon Microarray Analysis of Human Dorsolateral Prefrontal Cortex in Alcoholism

PubMed Central

Manzardo, Ann M.; Gunewardena, Sumedha; Wang, Kun; Butler, Merlin G.

2014-01-01

Background Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein and nucleic acid synthesis, brain development, function and behavioral responses. To further characterize the genetic influences in alcoholism and the effects of alcohol consumption on gene expression, we used a highly sensitive exon microarray to examine mRNA expression in human frontal cortex of alcoholics and control males. Methods Messenger RNA was isolated from the dorsolateral prefrontal cortex (dlPFC, Brodmann area 9) of 7 adult Alcoholic (6 males, 1 female, mean age 48 years) and 7 matched controls. Affymetrix Human Exon 1.0 ST Array was performed according to standard procedures and the results analyzed at the gene level. Microarray findings were validated using qRT-PCR, and the ontology of disturbed genes characterized using Ingenuity Pathway Analysis (IPA). Results Decreased mRNA expression was observed for genes involved in cellular adhesion (e.g., CTNNA3, ITGA2), transport (e.g., TF, ABCA8), nervous system development (e.g., LRP2, UGT8, GLDN) and signaling (e.g., RASGRP, LGR5) with influence over lipid and myelin synthesis (e.g., ASPA, ENPP2, KLK6). IPA identified disturbances in network functions associated with neurological disease, and development including cellular assembly and organization impacting on psychological disorders. Conclusions Our data in alcoholism support a reduction in expression of dlPFC mRNA for genes involved with neuronal growth, differentiation and signaling that targets white matter of the brain. PMID:24890784

Exon microarray analysis of human dorsolateral prefrontal cortex in alcoholism.

PubMed

Manzardo, Ann M; Gunewardena, Sumedha; Wang, Kun; Butler, Merlin G

2014-06-01

Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein and nucleic acid synthesis, brain development, function, and behavioral responses. To further characterize the genetic influences in alcoholism and the effects of alcohol consumption on gene expression, we used a highly sensitive exon microarray to examine mRNA expression in human frontal cortex of alcoholics and control males. Messenger RNA was isolated from the dorsolateral prefrontal cortex (dlPFC; Brodmann area 9) of 7 adult alcoholic (6 males, 1 female, mean age 49 years) and 7 matched controls. Affymetrix Human Exon 1.0 ST array was performed according to standard procedures and the results analyzed at the gene level. Microarray findings were validated using quantitative reverse transcription polymerase chain reaction, and the ontology of disturbed genes characterized using Ingenuity Pathway Analysis (IPA). Decreased mRNA expression was observed for genes involved in cellular adhesion (e.g., CTNNA3, ITGA2), transport (e.g., TF, ABCA8), nervous system development (e.g., LRP2, UGT8, GLDN), and signaling (e.g., RASGRP3, LGR5) with influence over lipid and myelin synthesis (e.g., ASPA, ENPP2, KLK6). IPA identified disturbances in network functions associated with neurological disease and development including cellular assembly and organization impacting on psychological disorders. Our data in alcoholism support a reduction in expression of dlPFC mRNA for genes involved with neuronal growth, differentiation, and signaling that targets white matter of the brain. Copyright © 2014 by the Research Society on Alcoholism.

The association between problematic cellular phone use and risky behaviors and low self-esteem among Taiwanese adolescents

PubMed Central

2010-01-01

Background Cellular phone use (CPU) is an important part of life for many adolescents. However, problematic CPU may complicate physiological and psychological problems. The aim of our study was to examine the associations between problematic CPU and a series of risky behaviors and low self-esteem in Taiwanese adolescents. Methods A total of 11,111 adolescent students in Southern Taiwan were randomly selected into this study. We used the Problematic Cellular Phone Use Questionnaire to identify the adolescents with problematic CPU. Meanwhile, a series of risky behaviors and self-esteem were evaluated. Multilevel logistic regression analyses were employed to examine the associations between problematic CPU and risky behaviors and low self-esteem regarding gender and age. Results The results indicated that positive associations were found between problematic CPU and aggression, insomnia, smoking cigarettes, suicidal tendencies, and low self-esteem in all groups with different sexes and ages. However, gender and age differences existed in the associations between problematic CPU and suspension from school, criminal records, tattooing, short nocturnal sleep duration, unprotected sex, illicit drugs use, drinking alcohol and chewing betel nuts. Conclusions There were positive associations between problematic CPU and a series of risky behaviors and low self-esteem in Taiwanese adolescents. It is worthy for parents and mental health professionals to pay attention to adolescents' problematic CPU. PMID:20426807

Blast induces oxidative stress, inflammation, neuronal loss and subsequent short-term memory impairment in rats.

PubMed

Cho, H J; Sajja, V S S S; Vandevord, P J; Lee, Y W

2013-12-03

Molecular and cellular mechanisms of brain injury after exposure to blast overpressure (BOP) are not clearly known. The present study hypothesizes that pro-oxidative and pro-inflammatory pathways in the brain may be responsible for neuronal loss and behavioral deficits following BOP exposure. Male Sprague-Dawley rats were anesthetized and exposed to calibrated BOP of 129.23±3.01kPa while controls received only anesthesia. In situ dihydroethidium fluorescence staining revealed that BOP significantly increased the production of reactive oxygen species in the brain. In addition, real-time reverse transcriptase-polymerase chain reaction, immunofluorescence staining and enzyme-linked immunosorbent assay demonstrated a significant up-regulation of mRNA and protein expressions of pro-inflammatory mediators, such as interferon-γ and monocyte chemoattractant protein-1, in brains collected from BOP-exposed animals compared with the controls. Furthermore, immunoreactivity of neuronal nuclei in brains indicated that fewer neurons were present following BOP exposure. Moreover, novel object recognition paradigm showed a significant impairment in the short-term memory at 2weeks following BOP exposure. These results suggest that pro-oxidative and pro-inflammatory environments in the brain could play a potential role in BOP-induced neuronal loss and behavioral deficits. It may provide a foundation for defining a molecular and cellular basis of the pathophysiology of blast-induced neurotrauma (BINT). It will also contribute to the development of new therapeutic approaches selectively targeting these pathways, which have great potential in the diagnosis and therapy of BINT. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Integration of miRNA and Protein Profiling Reveals Coordinated Neuroadaptations in the Alcohol-Dependent Mouse Brain

PubMed Central

Gorini, Giorgio; Nunez, Yury O.; Mayfield, R. Dayne

2013-01-01

The molecular mechanisms underlying alcohol dependence involve different neurochemical systems and are brain region-dependent. Chronic Intermittent Ethanol (CIE) procedure, combined with a Two-Bottle Choice voluntary drinking paradigm, represents one of the best available animal models for alcohol dependence and relapse drinking. MicroRNAs, master regulators of the cellular transcriptome and proteome, can regulate their targets in a cooperative, combinatorial fashion, ensuring fine tuning and control over a large number of cellular functions. We analyzed cortex and midbrain microRNA expression levels using an integrative approach to combine and relate data to previous protein profiling from the same CIE-subjected samples, and examined the significance of the data in terms of relative contribution to alcohol consumption and dependence. MicroRNA levels were significantly altered in CIE-exposed dependent mice compared with their non-dependent controls. More importantly, our integrative analysis identified modules of coexpressed microRNAs that were highly correlated with CIE effects and predicted target genes encoding differentially expressed proteins. Coexpressed CIE-relevant proteins, in turn, were often negatively correlated with specific microRNA modules. Our results provide evidence that microRNA-orchestrated translational imbalances are driving the behavioral transition from alcohol consumption to dependence. This study represents the first attempt to combine ex vivo microRNA and protein expression on a global scale from the same mammalian brain samples. The integrative systems approach used here will improve our understanding of brain adaptive changes in response to drug abuse and suggests the potential therapeutic use of microRNAs as tools to prevent or compensate multiple neuroadaptations underlying addictive behavior. PMID:24358208

Asynchronous adaptive time step in quantitative cellular automata modeling

PubMed Central

Zhu, Hao; Pang, Peter YH; Sun, Yan; Dhar, Pawan

2004-01-01

Background The behaviors of cells in metazoans are context dependent, thus large-scale multi-cellular modeling is often necessary, for which cellular automata are natural candidates. Two related issues are involved in cellular automata based multi-cellular modeling: how to introduce differential equation based quantitative computing to precisely describe cellular activity, and upon it, how to solve the heavy time consumption issue in simulation. Results Based on a modified, language based cellular automata system we extended that allows ordinary differential equations in models, we introduce a method implementing asynchronous adaptive time step in simulation that can considerably improve efficiency yet without a significant sacrifice of accuracy. An average speedup rate of 4–5 is achieved in the given example. Conclusions Strategies for reducing time consumption in simulation are indispensable for large-scale, quantitative multi-cellular models, because even a small 100 × 100 × 100 tissue slab contains one million cells. Distributed and adaptive time step is a practical solution in cellular automata environment. PMID:15222901

Dynamics of cellular level function and regulation derived from murine expression array data.

PubMed

de Bivort, Benjamin; Huang, Sui; Bar-Yam, Yaneer

2004-12-21

A major open question of systems biology is how genetic and molecular components interact to create phenotypes at the cellular level. Although much recent effort has been dedicated to inferring effective regulatory influences within small networks of genes, the power of microarray bioinformatics has yet to be used to determine functional influences at the cellular level. In all cases of data-driven parameter estimation, the number of model parameters estimable from a set of data is strictly limited by the size of that set. Rather than infer parameters describing the detailed interactions of just a few genes, we chose a larger-scale investigation so that the cumulative effects of all gene interactions could be analyzed to identify the dynamics of cellular-level function. By aggregating genes into large groups with related behaviors (megamodules), we were able to determine the effective aggregate regulatory influences among 12 major gene groups in murine B lymphocytes over a variety of time steps. Intriguing observations about the behavior of cells at this high level of abstraction include: (i) a medium-term critical global transcriptional dependence on ATP-generating genes in the mitochondria, (ii) a longer-term dependence on glycolytic genes, (iii) the dual role of chromatin-reorganizing genes in transcriptional activation and repression, (iv) homeostasis-favoring influences, (v) the indication that, as a group, G protein-mediated signals are not concentration-dependent in their influence on target gene expression, and (vi) short-term-activating/long-term-repressing behavior of the cell-cycle system that reflects its oscillatory behavior.

Landslides, forest fires, and earthquakes: examples of self-organized critical behavior

NASA Astrophysics Data System (ADS)

Turcotte, Donald L.; Malamud, Bruce D.

2004-09-01

Per Bak conceived self-organized criticality as an explanation for the behavior of the sandpile model. Subsequently, many cellular automata models were found to exhibit similar behavior. Two examples are the forest-fire and slider-block models. Each of these models can be associated with a serious natural hazard: the sandpile model with landslides, the forest-fire model with actual forest fires, and the slider-block model with earthquakes. We examine the noncumulative frequency-area statistics for each natural hazard, and show that each has a robust power-law (fractal) distribution. We propose an inverse-cascade model as a general explanation for the power-law frequency-area statistics of the three cellular-automata models and their ‘associated’ natural hazards.

The mammary cellular hierarchy and breast cancer.

PubMed

Oakes, Samantha R; Gallego-Ortega, David; Ormandy, Christopher J

2014-11-01

Advances in the study of hematopoietic cell maturation have paved the way to a deeper understanding the stem and progenitor cellular hierarchy in the mammary gland. The mammary epithelium, unlike the hematopoietic cellular hierarchy, sits in a complex niche where communication between epithelial cells and signals from the systemic hormonal milieu, as well as from extra-cellular matrix, influence cell fate decisions and contribute to tissue homeostasis. We review the discovery, definition and regulation of the mammary cellular hierarchy and we describe the development of the concepts that have guided our investigations. We outline recent advances in in vivo lineage tracing that is now challenging many of our assumptions regarding the behavior of mammary stem cells, and we show how understanding these cellular lineages has altered our view of breast cancer.

Hippocampal expression of a virus-derived protein impairs memory in mice.

PubMed

Bétourné, Alexandre; Szelechowski, Marion; Thouard, Anne; Abrial, Erika; Jean, Arnaud; Zaidi, Falek; Foret, Charlotte; Bonnaud, Emilie M; Charlier, Caroline M; Suberbielle, Elsa; Malnou, Cécile E; Granon, Sylvie; Rampon, Claire; Gonzalez-Dunia, Daniel

2018-02-13

The analysis of the biology of neurotropic viruses, notably of their interference with cellular signaling, provides a useful tool to get further insight into the role of specific pathways in the control of behavioral functions. Here, we exploited the natural property of a viral protein identified as a major effector of behavioral disorders during infection. We used the phosphoprotein (P) of Borna disease virus, which acts as a decoy substrate for protein kinase C (PKC) when expressed in neurons and disrupts synaptic plasticity. By a lentiviral-based strategy, we directed the singled-out expression of P in the dentate gyrus of the hippocampus and we examined its impact on mouse behavior. Mice expressing the P protein displayed increased anxiety and impaired long-term memory in contextual and spatial memory tasks. Interestingly, these effects were dependent on P protein phosphorylation by PKC, as expression of a mutant form of P devoid of its PKC phosphorylation sites had no effect on these behaviors. We also revealed features of behavioral impairment induced by P protein expression but that were independent of its phosphorylation by PKC. Altogether, our findings provide insight into the behavioral correlates of viral infection, as well as into the impact of virus-mediated alterations of the PKC pathway on behavioral functions.

Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses

PubMed Central

Bhattacharya, Sudin; Conolly, Rory B.; Clewell, Harvey J.; Kaminski, Norbert E.; Andersen, Melvin E.

2014-01-01

Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations. Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data. Methods: Here we have examined dose–response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures. Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays. Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell HJ III, Kaminski NE, Andersen ME. 2014. Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses. Environ Health Perspect 122:1261–1270; http://dx.doi.org/10.1289/ehp.1408244 PMID:25117432

The Temperature Effect on the Compressive Behavior of Closed-Cell Aluminum-Alloy Foams

NASA Astrophysics Data System (ADS)

Movahedi, Nima; Linul, Emanoil; Marsavina, Liviu

2018-01-01

In this research, the mechanical behavior of closed-cell aluminum (Al)-alloy foams was investigated at different temperatures in the range of 25-450 °C. The main mechanical properties of porous Al-alloy foams are affected by the testing temperature, and they decrease with the increase in the temperature during uniaxial compression. From both the constant/serrated character of stress-strain curves and macro/microstructural morphology of deformed cellular structure, it was found that Al foams present a transition temperature from brittle to ductile behavior around 192 °C. Due to the softening of the cellular structure at higher temperatures, linear correlations of the stress amplitude and that of the absorbed energy with the temperature were proposed. Also, it was observed that the presence of inherent defects like micropores in the foam cell walls induced further local stress concentration which weakens the cellular structure's strength and crack propagation and cell-wall plastic deformation are the dominant collapse mechanisms. Finally, an energy absorption study was performed and an optimum temperature was proposed.

Locus ceruleus control of state-dependent gene expression.

PubMed

Cirelli, Chiara; Tononi, Giulio

2004-06-09

Wakefulness and sleep are accompanied by changes in behavior and neural activity, as well as by the upregulation of different functional categories of genes. However, the mechanisms responsible for such state-dependent changes in gene expression are unknown. Here we investigate to what extent state-dependent changes in gene expression depend on the central noradrenergic (NA) system, which is active in wakefulness and reduces its firing during sleep. We measured the levels of approximately 5000 transcripts expressed in the cerebral cortex of control rats and in rats pretreated with DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a neurotoxin that removes the noradrenergic innervation of the cortex. We found that NA depletion reduces the expression of approximately 20% of known wakefulness-related transcripts. Most of these transcripts are involved in synaptic plasticity and in the cellular response to stress. In contrast, NA depletion increased the expression of the sleep-related gene encoding the translation elongation factor 2. These results indicate that the activity of the central NA system during wakefulness modulates neuronal transcription to favor synaptic potentiation and counteract cellular stress, whereas its inactivity during sleep may play a permissive role to enhance brain protein synthesis.

The Cellular Building Blocks of Breathing

PubMed Central

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

2013-01-01

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

Enzyme localization, crowding, and buffers collectively modulate diffusion-influenced signal transduction: Insights from continuum diffusion modeling

PubMed Central

Kekenes-Huskey, Peter M.; Eun, Changsun; McCammon, J. A.

2015-01-01

Biochemical reaction networks consisting of coupled enzymes connect substrate signaling events with biological function. Substrates involved in these reactions can be strongly influenced by diffusion “barriers” arising from impenetrable cellular structures and macromolecules, as well as interactions with biomolecules, especially within crowded environments. For diffusion-influenced reactions, the spatial organization of diffusion barriers arising from intracellular structures, non-specific crowders, and specific-binders (buffers) strongly controls the temporal and spatial reaction kinetics. In this study, we use two prototypical biochemical reactions, a Goodwin oscillator, and a reaction with a periodic source/sink term to examine how a diffusion barrier that partitions substrates controls reaction behavior. Namely, we examine how conditions representative of a densely packed cytosol, including reduced accessible volume fraction, non-specific interactions, and buffers, impede diffusion over nanometer length-scales. We find that diffusion barriers can modulate the frequencies and amplitudes of coupled diffusion-influenced reaction networks, as well as give rise to “compartments” of decoupled reactant populations. These effects appear to be intensified in the presence of buffers localized to the diffusion barrier. These findings have strong implications for the role of the cellular environment in tuning the dynamics of signaling pathways. PMID:26342355

Behavioral toxicology: Stimulating challenges for a growing discipline

USGS Publications Warehouse

Little, Edward E.

1990-01-01

Since the early 1970s, contaminants have been shown to affect virtually every aspect of behavior in terrestrial and aquatic organisms. Behavior inte- grates many cellular processes and is essential to the viability of the organism, the population and the community. Therefore, observations of behavior provide a unique toxicological perspective - one that links the biochemical and ecological conse- quences of environmental contamination.

An Observation-Driven Agent-Based Modeling and Analysis Framework for C. elegans Embryogenesis.

PubMed

Wang, Zi; Ramsey, Benjamin J; Wang, Dali; Wong, Kwai; Li, Husheng; Wang, Eric; Bao, Zhirong

2016-01-01

With cutting-edge live microscopy and image analysis, biologists can now systematically track individual cells in complex tissues and quantify cellular behavior over extended time windows. Computational approaches that utilize the systematic and quantitative data are needed to understand how cells interact in vivo to give rise to the different cell types and 3D morphology of tissues. An agent-based, minimum descriptive modeling and analysis framework is presented in this paper to study C. elegans embryogenesis. The framework is designed to incorporate the large amounts of experimental observations on cellular behavior and reserve data structures/interfaces that allow regulatory mechanisms to be added as more insights are gained. Observed cellular behaviors are organized into lineage identity, timing and direction of cell division, and path of cell movement. The framework also includes global parameters such as the eggshell and a clock. Division and movement behaviors are driven by statistical models of the observations. Data structures/interfaces are reserved for gene list, cell-cell interaction, cell fate and landscape, and other global parameters until the descriptive model is replaced by a regulatory mechanism. This approach provides a framework to handle the ongoing experiments of single-cell analysis of complex tissues where mechanistic insights lag data collection and need to be validated on complex observations.

Hierarchy of cellular decisions in collective behavior: Implications for wound healing.

PubMed

Wickert, Lisa E; Pomerenke, Shaun; Mitchell, Isaiah; Masters, Kristyn S; Kreeger, Pamela K

2016-02-02

Collective processes such as wound re-epithelialization result from the integration of individual cellular decisions. To determine which individual cell behaviors represent the most promising targets to engineer re-epithelialization, we examined collective and individual responses of HaCaT keratinocytes seeded upon polyacrylamide gels of three stiffnesses (1, 30, and 100 kPa) and treated with a range of epidermal growth factor (EGF) doses. Wound closure was found to increase with substrate stiffness, but was responsive to EGF treatment only above a stiffness threshold. Individual cell behaviors were used to create a partial least squares regression model to predict the hierarchy of factors driving wound closure. Unexpectedly, cell area and persistence were found to have the strongest correlation to the observed differences in wound closure. Meanwhile, the model predicted a relatively weak correlation between wound closure with proliferation, and the unexpectedly minor input from proliferation was successfully tested with inhibition by aphidicolin. Combined, these results suggest that the poor clinical results for growth factor-based therapies for chronic wounds may result from a disconnect between the individual cellular behaviors targeted in these approaches and the resulting collective response. Additionally, the stiffness-dependency of EGF sensitivity suggests that therapies matched to microenvironmental characteristics will be more efficacious.

Atg5- and Atg7-dependent autophagy in dopaminergic neurons regulates cellular and behavioral responses to morphine.

PubMed

Su, Ling-Yan; Luo, Rongcan; Liu, Qianjin; Su, Jing-Ran; Yang, Lu-Xiu; Ding, Yu-Qiang; Xu, Lin; Yao, Yong-Gang

2017-09-02

The molecular basis of chronic morphine exposure remains unknown. In this study, we hypothesized that macroautophagy/autophagy of dopaminergic neurons would mediate the alterations of neuronal dendritic morphology and behavioral responses induced by morphine. Chronic morphine exposure caused Atg5 (autophagy-related 5)- and Atg7 (autophagy-related 7)-dependent and dopaminergic neuron-specific autophagy resulting in decreased neuron dendritic spines and the onset of addictive behaviors. In cultured primary midbrain neurons, morphine treatment significantly reduced total dendritic length and complexity, and this effect could be reversed by knockdown of Atg5 or Atg7. Mice deficient for Atg5 or Atg7 specifically in the dopaminergic neurons were less sensitive to developing a morphine reward response, behavioral sensitization, analgesic tolerance and physical dependence compared to wild-type mice. Taken together, our findings suggested that the Atg5- and Atg7-dependent autophagy of dopaminergic neurons contributed to cellular and behavioral responses to morphine and may have implications for the future treatment of drug addiction.

Multi-Scale Modeling in Morphogenesis: A Critical Analysis of the Cellular Potts Model

PubMed Central

Voss-Böhme, Anja

2012-01-01

Cellular Potts models (CPMs) are used as a modeling framework to elucidate mechanisms of biological development. They allow a spatial resolution below the cellular scale and are applied particularly when problems are studied where multiple spatial and temporal scales are involved. Despite the increasing usage of CPMs in theoretical biology, this model class has received little attention from mathematical theory. To narrow this gap, the CPMs are subjected to a theoretical study here. It is asked to which extent the updating rules establish an appropriate dynamical model of intercellular interactions and what the principal behavior at different time scales characterizes. It is shown that the longtime behavior of a CPM is degenerate in the sense that the cells consecutively die out, independent of the specific interdependence structure that characterizes the model. While CPMs are naturally defined on finite, spatially bounded lattices, possible extensions to spatially unbounded systems are explored to assess to which extent spatio-temporal limit procedures can be applied to describe the emergent behavior at the tissue scale. To elucidate the mechanistic structure of CPMs, the model class is integrated into a general multiscale framework. It is shown that the central role of the surface fluctuations, which subsume several cellular and intercellular factors, entails substantial limitations for a CPM's exploitation both as a mechanistic and as a phenomenological model. PMID:22984409

Neuroprotective mechanism of losartan and its interaction with nimesulide against chronic fatigue stress.

PubMed

Kumar, Anil; Singh, Barinder; Mishra, Jitendriya; Sah, Sangeeta Pilkhwal; Pottabathini, Raghavender

2015-12-01

Potential role of angiotensin-II and cyclooxygenase have been suggested in the pathophysiology of chronic fatigue stress. The present study has been designed to evaluate the neuroprotective effect of losartan and its interaction with nimesulide against chronic fatigue stress and related complications in mice. In the present study, male Laca mice (20-30 g) were subjected to running wheel activity test session (RWATS) for 6 min daily for 21 days. Losartan, nimesulide and their combinations were administered daily for 21 days, 45 min before being subjected to RWATS. Various behavioral and biochemical and neuroinflammatory mediators were assessed subsequently. 21 days RWATS treatment significantly decreased number of wheel rotations/6 min indicating fatigue stress like behaviors as compared to naive group. 21 days treatment with losartan (10 and 20 mg/kg, ip), nimesulide (5 and 10 mg/kg, po) and their combinations significantly improved behavior [increased number of wheel rotations, reversal of post-exercise fatigue, locomotor activity, antianxiety-like behavior (number of entries, latency to enter and time spent in mirror chamber), and memory performance (transfer latency in plus-maze performance task)], biochemical parameters (reduced serum corticosterone, brain lipid peroxidation, nitrite concentration, acetylcholinesterase activity, restored reduced glutathione levels and catalase activity) as compared to RWATS control. Besides, TNF-α, CRP levels were significantly attenuated by these drugs and their combinations as compared to control. The present study highlights the role of cyclooxygenase modulation in the neuroprotective effect of losartan against chronic fatigue stress-induced behavioral, biochemical and cellular alterations in mice.

Analysis of high-throughput screening reveals the effect of surface topographies on cellular morphology.

PubMed

Hulsman, Marc; Hulshof, Frits; Unadkat, Hemant; Papenburg, Bernke J; Stamatialis, Dimitrios F; Truckenmüller, Roman; van Blitterswijk, Clemens; de Boer, Jan; Reinders, Marcel J T

2015-03-01

Surface topographies of materials considerably impact cellular behavior as they have been shown to affect cell growth, provide cell guidance, and even induce cell differentiation. Consequently, for successful application in tissue engineering, the contact interface of biomaterials needs to be optimized to induce the required cell behavior. However, a rational design of biomaterial surfaces is severely hampered because knowledge is lacking on the underlying biological mechanisms. Therefore, we previously developed a high-throughput screening device (TopoChip) that measures cell responses to large libraries of parameterized topographical material surfaces. Here, we introduce a computational analysis of high-throughput materiome data to capture the relationship between the surface topographies of materials and cellular morphology. We apply robust statistical techniques to find surface topographies that best promote a certain specified cellular response. By augmenting surface screening with data-driven modeling, we determine which properties of the surface topographies influence the morphological properties of the cells. With this information, we build models that predict the cellular response to surface topographies that have not yet been measured. We analyze cellular morphology on 2176 surfaces, and find that the surface topography significantly affects various cellular properties, including the roundness and size of the nucleus, as well as the perimeter and orientation of the cells. Our learned models capture and accurately predict these relationships and reveal a spectrum of topographies that induce various levels of cellular morphologies. Taken together, this novel approach of high-throughput screening of materials and subsequent analysis opens up possibilities for a rational design of biomaterial surfaces. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Dopamine D2 receptors in striatal output neurons enable the psychomotor effects of cocaine.

PubMed

Kharkwal, Geetika; Radl, Daniela; Lewis, Robert; Borrelli, Emiliana

2016-10-11

The psychomotor effects of cocaine are mediated by dopamine (DA) through stimulation of striatal circuits. Gabaergic striatal medium spiny neurons (MSNs) are the only output of this pivotal structure in the control of movements. The majority of MSNs express either the DA D1 or D2 receptors (D1R, D2R). Studies have shown that the motor effect of cocaine depends on the DA-mediated stimulation of D1R-expressing MSNs (dMSNs), which is mirrored at the cellular level by stimulation of signaling pathways leading to phosphorylation of ERKs and induction of c-fos Nevertheless, activation of dMSNs by cocaine is necessary but not sufficient, and D2R signaling is required for the behavioral and cellular effects of cocaine. Indeed, cocaine motor effects and activation of signaling in dMSNs are blunted in mice with the constitutive knockout of D2R (D2RKO). Using mouse lines with a cell-specific knockout of D2R either in MSNs (MSN-D2RKO) or in dopaminergic neurons (DA-D2RKO), we show that D2R signaling in MSNs is required and permissive for the motor stimulant effects of cocaine and the activation of signaling in dMSNs. MSN-D2RKO mice show the same phenotype as constitutive D2RKO mice both at the behavioral and cellular levels. Importantly, activation of signaling in dMSNs by cocaine is rescued by intrastriatal injection of the GABA antagonist, bicuculline. These results are in support of intrastriatal connections of D2R + -MSNs (iMSNs) with dMSNs and indicate that D2R signaling in MSNs is critical for the function of intrastriatal circuits.

Dopamine D2 receptors in striatal output neurons enable the psychomotor effects of cocaine

PubMed Central

Kharkwal, Geetika; Radl, Daniela; Lewis, Robert; Borrelli, Emiliana

2016-01-01

The psychomotor effects of cocaine are mediated by dopamine (DA) through stimulation of striatal circuits. Gabaergic striatal medium spiny neurons (MSNs) are the only output of this pivotal structure in the control of movements. The majority of MSNs express either the DA D1 or D2 receptors (D1R, D2R). Studies have shown that the motor effect of cocaine depends on the DA-mediated stimulation of D1R-expressing MSNs (dMSNs), which is mirrored at the cellular level by stimulation of signaling pathways leading to phosphorylation of ERKs and induction of c-fos. Nevertheless, activation of dMSNs by cocaine is necessary but not sufficient, and D2R signaling is required for the behavioral and cellular effects of cocaine. Indeed, cocaine motor effects and activation of signaling in dMSNs are blunted in mice with the constitutive knockout of D2R (D2RKO). Using mouse lines with a cell-specific knockout of D2R either in MSNs (MSN-D2RKO) or in dopaminergic neurons (DA-D2RKO), we show that D2R signaling in MSNs is required and permissive for the motor stimulant effects of cocaine and the activation of signaling in dMSNs. MSN-D2RKO mice show the same phenotype as constitutive D2RKO mice both at the behavioral and cellular levels. Importantly, activation of signaling in dMSNs by cocaine is rescued by intrastriatal injection of the GABA antagonist, bicuculline. These results are in support of intrastriatal connections of D2R+-MSNs (iMSNs) with dMSNs and indicate that D2R signaling in MSNs is critical for the function of intrastriatal circuits. PMID:27671625

The effects of media on sleep.

PubMed

Van den Bulck, Jan

2010-12-01

The media are an important part of young people's lives, but television, computer games, Internet use, cellular phone use, and even book reading threaten healthy sleep. Adults do not fully comprehend the ways in which young people use various media. Media use is a type of behavior that may displace sleep time or shorten it. Media content may lead to overexcitement or cause recurring nightmares. The cellular telephone is a particular threat. Parents may also use media excessively, establishing an unhealthy environment that may lead to sleep dysfunction in children and adolescents. Therefore, anticipatory guidance for healthy behavioral changes should be focused on the family.

Sequential neuromodulation of Hebbian plasticity offers mechanism for effective reward-based navigation

PubMed Central

Brzosko, Zuzanna; Zannone, Sara; Schultz, Wolfram

2017-01-01

Spike timing-dependent plasticity (STDP) is under neuromodulatory control, which is correlated with distinct behavioral states. Previously, we reported that dopamine, a reward signal, broadens the time window for synaptic potentiation and modulates the outcome of hippocampal STDP even when applied after the plasticity induction protocol (Brzosko et al., 2015). Here, we demonstrate that sequential neuromodulation of STDP by acetylcholine and dopamine offers an efficacious model of reward-based navigation. Specifically, our experimental data in mouse hippocampal slices show that acetylcholine biases STDP toward synaptic depression, whilst subsequent application of dopamine converts this depression into potentiation. Incorporating this bidirectional neuromodulation-enabled correlational synaptic learning rule into a computational model yields effective navigation toward changing reward locations, as in natural foraging behavior. Thus, temporally sequenced neuromodulation of STDP enables associations to be made between actions and outcomes and also provides a possible mechanism for aligning the time scales of cellular and behavioral learning. DOI: http://dx.doi.org/10.7554/eLife.27756.001 PMID:28691903

Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit

PubMed Central

Anthony, Todd E.; Dee, Nick; Bernard, Amy; Lerchner, Walter; Heintz, Nathaniel; Anderson, David J.

2014-01-01

The extended amygdala has dominated research on the neural circuitry of fear and anxiety, but the septo-hippocampal axis plays an important role as well. The lateral septum (LS) is thought to suppress fear and anxiety, through its outputs to the hypothalamus. However, this structure has not yet been dissected using modern tools. The type 2 CRF receptor (Crfr2) marks a subset of LS neurons, whose functional connectivity we have investigated using optogenetics. Crfr2+ cells include GABAergic projection neurons that connect with the anterior hypothalamus. Surprisingly, we find that these LS outputs enhance stress-induced behavioral measures of anxiety. Furthermore, transient activation of Crfr2+ neurons promotes, while inhibition suppresses, persistent anxious behaviors. LS Crfr2+ outputs also positively regulate circulating corticosteroid levels. These data identify a subset of LS projection neurons that promote, rather than suppress, stress-induced behavioral and endocrinological dimensions of persistent anxiety states, and provide a cellular point-of-entry to LS circuitry. PMID:24485458

Size-tunable silicon/iron oxide hybrid nanoparticles with fluorescence, superparamagnetism, and biocompatibility.

PubMed

Sato, Keisuke; Yokosuka, Shinobu; Takigami, Yasunori; Hirakuri, Kenji; Fujioka, Kouki; Manome, Yoshinobu; Sukegawa, Hiroaki; Iwai, Hideo; Fukata, Naoki

2011-11-23

Magnetic/fluorescent composite materials have become one of the most important tools in the imaging modality in vivo using magnetic resonance imaging (MRI) monitoring and fluorescence optical imaging. We report herein on a simplified procedure to synthesize hybrid nanoparticles (HNPs) that combine silicon and magnetic iron oxides consisting of magnetite (Fe(3)O(4)) and maghemite (γ-Fe(2)O(3)). Intriguingly, our unique synthetic approach can control magnetic and optical behaviors by reducing the particle size, demonstrating that the HNPs with the mean diameter of 3.0 nm exhibit superparamagnetic behavior and green fluorescence in an aqueous solution, ambient air, and a cellular environment, whereas the HNPs with the mean diameter more than 5.0 nm indicate ferromagnetic behavior without fluorescence. Additionally, both HNPs with different diameters possess excellent magnetic responsivity for external applied magnetic field and good biocompatibility due to the low cytotoxicity. Our biocompatible HNPs with the superparamagnetism can provide an attractive approach for diagnostic imaging system in vivo.

Auditory experience controls the maturation of song discrimination and sexual response in Drosophila

PubMed Central

Li, Xiaodong; Ishimoto, Hiroshi

2018-01-01

In birds and higher mammals, auditory experience during development is critical to discriminate sound patterns in adulthood. However, the neural and molecular nature of this acquired ability remains elusive. In fruit flies, acoustic perception has been thought to be innate. Here we report, surprisingly, that auditory experience of a species-specific courtship song in developing Drosophila shapes adult song perception and resultant sexual behavior. Preferences in the song-response behaviors of both males and females were tuned by social acoustic exposure during development. We examined the molecular and cellular determinants of this social acoustic learning and found that GABA signaling acting on the GABAA receptor Rdl in the pC1 neurons, the integration node for courtship stimuli, regulated auditory tuning and sexual behavior. These findings demonstrate that maturation of auditory perception in flies is unexpectedly plastic and is acquired socially, providing a model to investigate how song learning regulates mating preference in insects. PMID:29555017

Optogenetic Control of Cells and Circuits

PubMed Central

Miesenböck, Gero

2013-01-01

The absorption of light by bound or diffusible chromophores causes conformational rearrangements in natural and artificial photoreceptor proteins. These rearrangements are coupled to the opening or closing of ion transport pathways, the association or dissociation of binding partners, the enhancement or suppression of catalytic activity, or the transcription or repression of genetic information. Illumination of cells, tissues, or organisms engineered genetically to express photoreceptor proteins can thus be used to perturb biochemical and electrical signaling with exquisite cellular and molecular specificity. First demonstrated in 2002, this principle of optogenetic control has had a profound impact on neuroscience, where it provides a direct and stringent means of probing the organization of neural circuits and of identifying the neural substrates of behavior. The impact of optogenetic control is also beginning to be felt in other areas of cell and organismal biology. PMID:21819234

Feeding Behavior of Aplysia: A Model System for Comparing Cellular Mechanisms of Classical and Operant Conditioning

ERIC Educational Resources Information Center

Baxter, Douglas A.; Byrne, John H.

2006-01-01

Feeding behavior of Aplysia provides an excellent model system for analyzing and comparing mechanisms underlying appetitive classical conditioning and reward operant conditioning. Behavioral protocols have been developed for both forms of associative learning, both of which increase the occurrence of biting following training. Because the neural…

Further evidence for Clock△19 mice as a model for bipolar disorder mania using cross-species tests of exploration and sensorimotor gating

PubMed Central

van Enkhuizen, Jordy; Minassian, Arpi; Young, Jared W.

2013-01-01

Bipolar disorder (BD) is a pervasive neuropsychiatric disorder characterized by episodes of mania and depression. The switch between mania and depression may reflect seasonal changes and certainly can be affected by alterations in sleep and circadian control. The circadian locomotor output cycles kaput (CLOCK) protein is a key component of the cellular circadian clock. Mutation of the Clock gene encoding this protein in Clock△19 mutant mice leads to behavioral abnormalities reminiscent of BD mania. To date, however, these mice have not been assessed in behavioral paradigms that have cross-species translational validity. In the present studies of Clock△19 and wildtype (WT) littermate mice, we quantified exploratory behavior and sensorimotor gating, which are abnormal in BD manic patients. We also examined the saccharin preference of these mice and their circadian control in different photoperiods. Clock△19 mice exhibited behavioral alterations that are consistent with BD manic patients tested in comparable tasks, including hyperactivity, increased specific exploration, and reduced sensorimotor gating. Moreover, compared to WT mice, Clock△19 mice exhibited a greater preference for sweetened solutions and greater sensitivity to altered photoperiod. In contrast with BD manic patients however, Clock△19 mice exhibited more circumscribed movements during exploration. Future studies will extend the characterization of these mice in measures with cross-species translational relevance to human testing. PMID:23623885

Design and Analysis of Temperature Preference Behavior and its Circadian Rhythm in Drosophila

PubMed Central

Goda, Tadahiro; Leslie, Jennifer R.; Hamada, Fumika N.

2014-01-01

The circadian clock regulates many aspects of life, including sleep, locomotor activity, and body temperature (BTR) rhythms1,2. We recently identified a novel Drosophila circadian output, called the temperature preference rhythm (TPR), in which the preferred temperature in flies rises during the day and falls during the night 3. Surprisingly, the TPR and locomotor activity are controlled through distinct circadian neurons3. Drosophila locomotor activity is a well known circadian behavioral output and has provided strong contributions to the discovery of many conserved mammalian circadian clock genes and mechanisms4. Therefore, understanding TPR will lead to the identification of hitherto unknown molecular and cellular circadian mechanisms. Here, we describe how to perform and analyze the TPR assay. This technique not only allows for dissecting the molecular and neural mechanisms of TPR, but also provides new insights into the fundamental mechanisms of the brain functions that integrate different environmental signals and regulate animal behaviors. Furthermore, our recently published data suggest that the fly TPR shares features with the mammalian BTR3. Drosophila are ectotherms, in which the body temperature is typically behaviorally regulated. Therefore, TPR is a strategy used to generate a rhythmic body temperature in these flies5-8. We believe that further exploration of Drosophila TPR will facilitate the characterization of the mechanisms underlying body temperature control in animals. PMID:24457268

The Belief and Attitude of the Drivers Toward the Usage of Cellphone while Driving; A Population-Based Survey

PubMed Central

Sedaghati Shokri, Batoul; Davoodi, Seyed Rasoul; Azimmohseni, Majid; Khoshfar, Gholamreza

2017-01-01

Objective: To presents a survey investigating differences between drivers' beliefs regarding utilizing cellphone when driving. Methods: In this population-based survey, the participants who were studied in the North of Iran, Gorgan, were categorized as main urban and rural areas. A sample of 400 drivers, 92 women and 308 men, filled out the four sections questionnaire which was based on the Theory of Planned Behavior (TPB) used for measuring the differences between the drivers' opinions (attitudinal beliefs, normative beliefs, and perceived control behavioral beliefs) about utilizing a cell phone when driving along with their age and driving purpose. Data were collected by distributing the 68- query questionnaire between the drivers. Results: The MANOVA analysis showed that important discrepancies were found between the normative, control and behavioral beliefs of cellular phone users while driving. As expected, frequent business and younger users with sturdy intention expressed more benefits of further concentration on family members and fewer obstacles that would prevent them from utilizing cellphone when driving than older and frequently personal users. Conclusion: These results indicated that the benefits of utilizing cellphone while driving are greater than its dangers. To reduce cellphone utilization when driving and increase road safety, more effort is required to lower the perceived advantages of the behavior and to outstand the risks of this hazardous driving act. PMID:29177176

Delivery of Nano-Tethered Therapies to Brain Metastases of Primary Breast Cancer Using a Cellular Trojan Horse

DTIC Science & Technology

2014-10-01

Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse. Cancer Nanotechnol. 3, 47–54 (2012). 2. C. Qiao et...nn5002886. 8. H. Gao et al., Behavior and anti-glioma effect of lapatinib-incorporated lipoprotein-like nanoparticles . Nanotechnology . 23, 435101 (2012...948. [2] Mi-Ran Choi, et al., “Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse”, Cancer Nano, 2012; 3

Piezoelectricity and ferroelectricity of cellular polypropylene electrets films characterized by piezoresponse force microscopy

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

Miao, Hongchen; Sun, Yao; Zhou, Xilong

Cellular electrets polymer is a new ferroelectret material exhibiting large piezoelectricity and has attracted considerable attentions in researches and industries. Property characterization is very important for this material and current investigations are mostly on macroscopic properties. In this work, we conduct nanoscale piezoelectric and ferroelectric characterizations of cellular polypropylene (PP) films using piezoresponse force microscopy (PFM). First, both the single-frequency PFM and dual-frequency resonance-tracking PFM testings were conducted on the cellular PP film. The localized piezoelectric constant d{sub 33} is estimated to be 7–11pC/N by correcting the resonance magnification with quality factor and it is about one order lower thanmore » the macroscopic value. Next, using the switching spectroscopy PFM (SS-PFM), we studied polarization switching behavior of the cellular PP films. Results show that it exhibits the typical ferroelectric-like phase hysteresis loops and butterfly-shaped amplitude loops, which is similar to that of a poly(vinylidene fluoride) (PVDF) ferroelectric polymer film. However, both the phase and amplitude loops of the PP film are intensively asymmetric, which is thought to be caused by the nonzero remnant polarization after poling. Then, the D-E hysteresis loops of both the cellular PP film and PVDF film were measured by using the same wave form as that used in the SS-PFM, and the results show significant differences. Finally, we suggest that the ferroelectric-like behavior of cellular electrets films should be distinguished from that of typical ferroelectrics, both macroscopically and microscopically.« less

Cellular Strategies of Protein Quality Control

PubMed Central

Chen, Bryan; Retzlaff, Marco; Roos, Thomas; Frydman, Judith

2011-01-01

Eukaryotic cells must contend with a continuous stream of misfolded proteins that compromise the cellular protein homeostasis balance and jeopardize cell viability. An elaborate network of molecular chaperones and protein degradation factors continually monitor and maintain the integrity of the proteome. Cellular protein quality control relies on three distinct yet interconnected strategies whereby misfolded proteins can either be refolded, degraded, or delivered to distinct quality control compartments that sequester potentially harmful misfolded species. Molecular chaperones play a critical role in determining the fate of misfolded proteins in the cell. Here, we discuss the spatial and temporal organization of cellular quality control strategies and their implications for human diseases linked to protein misfolding and aggregation. PMID:21746797

Feasibility of including cellular telephone numbers in random digit dialing for epidemiologic case-control studies.

PubMed

Voigt, Lynda F; Schwartz, Stephen M; Doody, David R; Lee, Spencer C; Li, Christopher I

2011-01-01

The usefulness of landline random digit dialing (RDD) in epidemiologic studies is threatened by the rapid increase in households with only cellular telephone service. This study assessed the feasibility of including cellular telephone numbers in RDD and differences between young adults with landline telephones and those with only cellular telephones. Between 2008 and 2009, a total of 9,023 cellular telephone numbers were called and 43.8% were successfully screened; 248 men and 249 women who resided in 3 Washington State counties, were 20-44 years of age, and used only cellular telephones were interviewed. They were compared with 332 men and 526 women with landline telephones interviewed as controls for 2 case-control studies conducted in parallel with cellular telephone interviewing. Cellular-only users were more likely to be college educated and less likely to have fathered/birthed a child than were their landline counterparts. Male cellular-only users were less likely to be obese and more likely to exercise, to be Hispanic, and to have lower incomes, while female cellular-only users were more likely to be single than landline respondents. Including cellular telephone numbers in RDD is feasible and should be incorporated into epidemiologic studies that rely on this method to ascertain subjects, although low screening rates could hamper the representativeness of such a sample.

A Cellular Automata-based Model for Simulating Restitution Property in a Single Heart Cell.

PubMed

Sabzpoushan, Seyed Hojjat; Pourhasanzade, Fateme

2011-01-01

Ventricular fibrillation is the cause of the most sudden mortalities. Restitution is one of the specific properties of ventricular cell. The recent findings have clearly proved the correlation between the slope of restitution curve with ventricular fibrillation. This; therefore, mandates the modeling of cellular restitution to gain high importance. A cellular automaton is a powerful tool for simulating complex phenomena in a simple language. A cellular automaton is a lattice of cells where the behavior of each cell is determined by the behavior of its neighboring cells as well as the automata rule. In this paper, a simple model is depicted for the simulation of the property of restitution in a single cardiac cell using cellular automata. At first, two state variables; action potential and recovery are introduced in the automata model. In second, automata rule is determined and then recovery variable is defined in such a way so that the restitution is developed. In order to evaluate the proposed model, the generated restitution curve in our study is compared with the restitution curves from the experimental findings of valid sources. Our findings indicate that the presented model is not only capable of simulating restitution in cardiac cell, but also possesses the capability of regulating the restitution curve.

Novel Polyurethane Matrix Systems Reveal a Particular Sustained Release Behavior Studied by Imaging and Computational Modeling.

PubMed

Campiñez, María Dolores; Caraballo, Isidoro; Puchkov, Maxim; Kuentz, Martin

2017-07-01

The aim of the present work was to better understand the drug-release mechanism from sustained release matrices prepared with two new polyurethanes, using a novel in silico formulation tool based on 3-dimensional cellular automata. For this purpose, two polymers and theophylline as model drug were used to prepare binary matrix tablets. Each formulation was simulated in silico, and its release behavior was compared to the experimental drug release profiles. Furthermore, the polymer distributions in the tablets were imaged by scanning electron microscopy (SEM) and the changes produced by the tortuosity were quantified and verified using experimental data. The obtained results showed that the polymers exhibited a surprisingly high ability for controlling drug release at low excipient concentrations (only 10% w/w of excipient controlled the release of drug during almost 8 h). The mesoscopic in silico model helped to reveal how the novel biopolymers were controlling drug release. The mechanism was found to be a special geometrical arrangement of the excipient particles, creating an almost continuous barrier surrounding the drug in a very effective way, comparable to lipid or waxy excipients but with the advantages of a much higher compactability, stability, and absence of excipient polymorphism.

Acamprosate rescues neuronal defects in the Drosophila model of Fragile X Syndrome.

PubMed

Hutson, Russell L; Thompson, Rachel L; Bantel, Andrew P; Tessier, Charles R

2018-02-15

Several off-label studies have shown that acamprosate can provide some clinical benefits in youth with Fragile X Syndrome (FXS), an autism spectrum disorder caused by loss of function of the highly conserved FMR1 gene. This study investigated the ability of acamprosate to rescue cellular, molecular and behavioral defects in the Drosophila model of FXS. A high (100μM) and low (10μM) dose of acamprosate was fed to Drosophila FXS (dfmr1 null) or genetic control (w 1118 ) larvae and then analyzed in multiple paradigms. A larval crawling assay was used to monitor aberrant FXS behavior, overgrowth of the neuromuscular junction (NMJ) was quantified to assess neuronal development, and quantitative RT-PCR was used to evaluate expression of deregulated cbp53E mRNA. Acamprosate treatment partially or completely rescued all of the FXS phenotypes analyzed, according to dose. High doses rescued cellular overgrowth and dysregulated cbp53E mRNA expression, but aberrant crawling behavior was not affected. Low doses of acamprosate, however, did not affect synapse number at the NMJ, but could rescue NMJ overgrowth, locomotor defects, and cbp53E mRNA expression. This dual nature of acamprosate suggests multiple molecular mechanisms may be involved in acamprosate function depending on the dosage used. Acamprosate may be a useful therapy for FXS and potentially other autism spectrum disorders. However, understanding the molecular mechanisms involved with different doses of this drug will likely be necessary to obtain optimal results. Copyright © 2018 Elsevier Inc. All rights reserved.

Gradient Material Strategies for Hydrogel Optimization in Tissue Engineering Applications

PubMed Central

2018-01-01

Although a number of combinatorial/high-throughput approaches have been developed for biomaterial hydrogel optimization, a gradient sample approach is particularly well suited to identify hydrogel property thresholds that alter cellular behavior in response to interacting with the hydrogel due to reduced variation in material preparation and the ability to screen biological response over a range instead of discrete samples each containing only one condition. This review highlights recent work on cell–hydrogel interactions using a gradient material sample approach. Fabrication strategies for composition, material and mechanical property, and bioactive signaling gradient hydrogels that can be used to examine cell–hydrogel interactions will be discussed. The effects of gradients in hydrogel samples on cellular adhesion, migration, proliferation, and differentiation will then be examined, providing an assessment of the current state of the field and the potential of wider use of the gradient sample approach to accelerate our understanding of matrices on cellular behavior. PMID:29485612

Two-dimensional fluid-filled closed-cell cellular solid as an acoustic metamaterial with negative index

NASA Astrophysics Data System (ADS)

Dorodnitsyn, V.; Van Damme, B.

2016-04-01

A concept for acoustic metamaterials consisting of a cellular medium with fluid-filled cells is fabricated and studied experimentally. In such a system, the fluid and solid structure explicitly interact, and elastic wave propagation is coupled to both phases. Focusing here on shear wave behavior, we confirm previous numerical studies in three steps. We first measure the material deformations pertaining to three qualitatively different shear wave modes in the frequency range below 3.5 kHz. We then measure the group velocity and demonstrate that, within a certain frequency interval, the group and phase velocity have opposite signs. This shows that the system acts as a negative-index metamaterial. Finally, we confirm the presence of band gaps due to the locally resonant behavior of the cell walls. The demonstrated concept of a closed, fluid-filled cellular material as an acoustic metamaterial opens a wide space for applications.

Blue light-mediated transcriptional activation and repression of gene expression in bacteria

PubMed Central

Jayaraman, Premkumar; Devarajan, Kavya; Chua, Tze Kwang; Zhang, Hanzhong; Gunawan, Erry; Poh, Chueh Loo

2016-01-01

Light-regulated modules offer unprecedented new ways to control cellular behavior in precise spatial and temporal resolution. The availability of such tools may dramatically accelerate the progression of synthetic biology applications. Nonetheless, current optogenetic toolbox of prokaryotes has potential issues such as lack of rapid and switchable control, less portable, low dynamic expression and limited parts. To address these shortcomings, we have engineered a novel bidirectional promoter system for Escherichia coli that can be induced or repressed rapidly and reversibly using the blue light dependent DNA-binding protein EL222. We demonstrated that by modulating the dosage of light pulses or intensity we could control the level of gene expression precisely. We show that both light-inducible and repressible system can function in parallel with high spatial precision in a single cell and can be switched stably between ON- and OFF-states by repetitive pulses of blue light. In addition, the light-inducible and repressible expression kinetics were quantitatively analysed using a mathematical model. We further apply the system, for the first time, to optogenetically synchronize two receiver cells performing different logic behaviors over time using blue light as a molecular clock signal. Overall, our modular approach layers a transformative platform for next-generation light-controllable synthetic biology systems in prokaryotes. PMID:27353329

Rule-Based Simulation of Multi-Cellular Biological Systems—A Review of Modeling Techniques

PubMed Central

Hwang, Minki; Garbey, Marc; Berceli, Scott A.; Tran-Son-Tay, Roger

2011-01-01

Emergent behaviors of multi-cellular biological systems (MCBS) result from the behaviors of each individual cells and their interactions with other cells and with the environment. Modeling MCBS requires incorporating these complex interactions among the individual cells and the environment. Modeling approaches for MCBS can be grouped into two categories: continuum models and cell-based models. Continuum models usually take the form of partial differential equations, and the model equations provide insight into the relationship among the components in the system. Cell-based models simulate each individual cell behavior and interactions among them enabling the observation of the emergent system behavior. This review focuses on the cell-based models of MCBS, and especially, the technical aspect of the rule-based simulation method for MCBS is reviewed. How to implement the cell behaviors and the interactions with other cells and with the environment into the computational domain is discussed. The cell behaviors reviewed in this paper are division, migration, apoptosis/necrosis, and differentiation. The environmental factors such as extracellular matrix, chemicals, microvasculature, and forces are also discussed. Application examples of these cell behaviors and interactions are presented. PMID:21369345

Manipulating the Cellular Circadian Period of Arginine Vasopressin Neurons Alters the Behavioral Circadian Period.

PubMed

Mieda, Michihiro; Okamoto, Hitoshi; Sakurai, Takeshi

2016-09-26

As the central pacemaker in mammals, the circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is a heterogeneous structure consisting of multiple types of GABAergic neurons with distinct chemical identities [1, 2]. Although individual cells have a cellular clock driven by autoregulatory transcriptional/translational feedback loops of clock genes, interneuronal communication among SCN clock neurons is likely essential for the SCN to generate a highly robust, coherent circadian rhythm [1]. However, neuronal mechanisms that determine circadian period length remain unclear. The SCN is composed of two subdivisions: a ventral core region containing vasoactive intestinal peptide (VIP)-producing neurons and a dorsal shell region characterized by arginine vasopressin (AVP)-producing neurons. Here we examined whether AVP neurons act as pacemaker cells that regulate the circadian period of behavior rhythm in mice. The deletion of casein kinase 1 delta (CK1δ) specific to AVP neurons, which was expected to lengthen the period of cellular clocks [3-6], lengthened the free-running period of circadian behavior as well. Conversely, the overexpression of CK1δ specific to SCN AVP neurons shortened the free-running period. PER2::LUC imaging in slices confirmed that cellular circadian periods of the SCN shell were lengthened in mice without CK1δ in AVP neurons. Thus, AVP neurons may be an essential component of circadian pacemaker cells in the SCN. Remarkably, the alteration of the shell-core phase relationship in the SCN of these mice did not impair the generation per se of circadian behavior rhythm, thereby underscoring the robustness of the SCN network. Copyright © 2016 Elsevier Ltd. All rights reserved.

ON THE BIOMECHANICS OF HEART VALVE FUNCTION

PubMed Central

Sacks, Michael S.; Merryman, W. David; Schmidt, David E.

2009-01-01

Heart valves (HVs) are fluidic control components of the heart that ensure unidirectional blood flow during the cardiac cycle. However, this description does not adequately describe the biomechanical ramifications of their function in that their mechanics are multi-modal. Moreover, they must replicate their cyclic function over an entire lifetime, with an estimated total functional demand of least 3×109 cycles. The focus of the present review is on the functional biomechanics of heart valves. Thus, the focus of the present review is on functional biomechanics, referring primarily to biosolid as well as several key biofluid mechanical aspects underlying heart valve physiological function. Specifically, we refer to the mechanical behaviors of the extra-cellular matrix structural proteins, underlying cellular function, and their integrated relation to the major aspects of valvular hemodynamic function. While we focus on the work from the author’s laboratories, relevant works of other investigators have been included whenever appropriate. We conclude with a summary of important future trends. PMID:19540499

Triggering signaling pathways using F-actin self-organization.

PubMed

Colin, A; Bonnemay, L; Gayrard, C; Gautier, J; Gueroui, Z

2016-10-04

The spatiotemporal organization of proteins within cells is essential for cell fate behavior. Although it is known that the cytoskeleton is vital for numerous cellular functions, it remains unclear how cytoskeletal activity can shape and control signaling pathways in space and time throughout the cell cytoplasm. Here we show that F-actin self-organization can trigger signaling pathways by engineering two novel properties of the microfilament self-organization: (1) the confinement of signaling proteins and (2) their scaffolding along actin polymers. Using in vitro reconstitutions of cellular functions, we found that both the confinement of nanoparticle-based signaling platforms powered by F-actin contractility and the scaffolding of engineered signaling proteins along actin microfilaments can drive a signaling switch. Using Ran-dependent microtubule nucleation, we found that F-actin dynamics promotes the robust assembly of microtubules. Our in vitro assay is a first step towards the development of novel bottom-up strategies to decipher the interplay between cytoskeleton spatial organization and signaling pathway activity.

Triggering signaling pathways using F-actin self-organization

PubMed Central

Colin, A.; Bonnemay, L.; Gayrard, C.; Gautier, J.; Gueroui, Z.

2016-01-01

The spatiotemporal organization of proteins within cells is essential for cell fate behavior. Although it is known that the cytoskeleton is vital for numerous cellular functions, it remains unclear how cytoskeletal activity can shape and control signaling pathways in space and time throughout the cell cytoplasm. Here we show that F-actin self-organization can trigger signaling pathways by engineering two novel properties of the microfilament self-organization: (1) the confinement of signaling proteins and (2) their scaffolding along actin polymers. Using in vitro reconstitutions of cellular functions, we found that both the confinement of nanoparticle-based signaling platforms powered by F-actin contractility and the scaffolding of engineered signaling proteins along actin microfilaments can drive a signaling switch. Using Ran-dependent microtubule nucleation, we found that F-actin dynamics promotes the robust assembly of microtubules. Our in vitro assay is a first step towards the development of novel bottom-up strategies to decipher the interplay between cytoskeleton spatial organization and signaling pathway activity. PMID:27698406

Dissection of neuronal gap junction circuits that regulate social behavior in Caenorhabditis elegans.

PubMed

Jang, Heeun; Levy, Sagi; Flavell, Steven W; Mende, Fanny; Latham, Richard; Zimmer, Manuel; Bargmann, Cornelia I

2017-02-14

A hub-and-spoke circuit of neurons connected by gap junctions controls aggregation behavior and related behavioral responses to oxygen, pheromones, and food in Caenorhabditis elegans The molecular composition of the gap junctions connecting RMG hub neurons with sensory spoke neurons is unknown. We show here that the innexin gene unc-9 is required in RMG hub neurons to drive aggregation and related behaviors, indicating that UNC-9-containing gap junctions mediate RMG signaling. To dissect the circuit in detail, we developed methods to inhibit unc-9 -based gap junctions with dominant-negative unc-1 transgenes. unc-1(dn) alters a stomatin-like protein that regulates unc-9 electrical signaling; its disruptive effects can be rescued by a constitutively active UNC-9::GFP protein, demonstrating specificity. Expression of unc-1(dn) in RMG hub neurons, ADL or ASK pheromone-sensing neurons, or URX oxygen-sensing neurons disrupts specific elements of aggregation-related behaviors. In ADL, unc-1(dn) has effects opposite to those of tetanus toxin light chain, separating the roles of ADL electrical and chemical synapses. These results reveal roles of gap junctions in a complex behavior at cellular resolution and provide a tool for similar exploration of other gap junction circuits.

Dissection of neuronal gap junction circuits that regulate social behavior in Caenorhabditis elegans

PubMed Central

Jang, Heeun; Levy, Sagi; Flavell, Steven W.; Mende, Fanny; Latham, Richard; Zimmer, Manuel; Bargmann, Cornelia I.

2017-01-01

A hub-and-spoke circuit of neurons connected by gap junctions controls aggregation behavior and related behavioral responses to oxygen, pheromones, and food in Caenorhabditis elegans. The molecular composition of the gap junctions connecting RMG hub neurons with sensory spoke neurons is unknown. We show here that the innexin gene unc-9 is required in RMG hub neurons to drive aggregation and related behaviors, indicating that UNC-9–containing gap junctions mediate RMG signaling. To dissect the circuit in detail, we developed methods to inhibit unc-9–based gap junctions with dominant-negative unc-1 transgenes. unc-1(dn) alters a stomatin-like protein that regulates unc-9 electrical signaling; its disruptive effects can be rescued by a constitutively active UNC-9::GFP protein, demonstrating specificity. Expression of unc-1(dn) in RMG hub neurons, ADL or ASK pheromone-sensing neurons, or URX oxygen-sensing neurons disrupts specific elements of aggregation-related behaviors. In ADL, unc-1(dn) has effects opposite to those of tetanus toxin light chain, separating the roles of ADL electrical and chemical synapses. These results reveal roles of gap junctions in a complex behavior at cellular resolution and provide a tool for similar exploration of other gap junction circuits. PMID:28143932

Development And Use Of Advanced Microfabricated Traction Force Sensing Substrates To Study The Effect of Nanosilver On Human Macrophages

NASA Astrophysics Data System (ADS)

Stark, Daniel Thomas

While nanoparticles are a natural byproduct of combustion and a number of natural processes, engineered nanoparticles have only recently entered the consumer market. This motivates the development of methods for studying their effects on human cells, thereby indicating how larger models such as animals and humans might react to them. This research develops a method to mechanically characterize cellular traction forces as a measure of exposure to nanoparticles. To do this, 1microm micropillar molds were fabricated in silicon wafers using smooth sidewall reactive ion plasma etching technologies. Polydimethylsiloxane (PDMS), was cured inside the silicon molds, subsequently treated for cell culture and used to measure cellular traction forces over time in live cell time-lapse experiments. For the first time, transmitted light was used to visualize the PDMS micropillars; a force resolution of 5.6 +/-2.1nN was achieved across all experiments using a standard Olympus IX81 confocal microscope affixed with a 60x NA2.1 objective. To initiate cellular movement, monocyte chemoattractant protein (MCP-1) was conjugated to 1microm latex beads. The effects of 40nm silver nanoparticle exposures were quantified using the micropillar array. Changes in cellular behavior between the control group and cells exposed to nanosilver were not significant, although a comparison between the 5microg/ml and 10microg/ml nanosilver concentrations yielded strong significance using a 2 sided Students t test.

Mechanical perturbation control of cardiac alternans

NASA Astrophysics Data System (ADS)

Hazim, Azzam; Belhamadia, Youssef; Dubljevic, Stevan

2018-05-01

Cardiac alternans is a disturbance in heart rhythm that is linked to the onset of lethal cardiac arrhythmias. Mechanical perturbation control has been recently used to suppress alternans in cardiac tissue of relevant size. In this control strategy, cardiac tissue mechanics are perturbed via active tension generated by the heart's electrical activity, which alters the tissue's electric wave profile through mechanoelectric coupling. We analyze the effects of mechanical perturbation on the dynamics of a map model that couples the membrane voltage and active tension systems at the cellular level. Therefore, a two-dimensional iterative map of the heart beat-to-beat dynamics is introduced, and a stability analysis of the system of coupled maps is performed in the presence of a mechanical perturbation algorithm. To this end, a bidirectional coupling between the membrane voltage and active tension systems in a single cardiac cell is provided, and a discrete form of the proposed control algorithm, that can be incorporated in the coupled maps, is derived. In addition, a realistic electromechanical model of cardiac tissue is employed to explore the feasibility of suppressing alternans at cellular and tissue levels. Electrical activity is represented in two detailed ionic models, the Luo-Rudy 1 and the Fox models, while two active contractile tension models, namely a smooth variant of the Nash-Panfilov model and the Niederer-Hunter-Smith model, are used to represent mechanical activity in the heart. The Mooney-Rivlin passive elasticity model is employed to describe passive mechanical behavior of the myocardium.

Computerized microfluidic cell culture using elastomeric channels and Braille displays.

PubMed

Gu, Wei; Zhu, Xiaoyue; Futai, Nobuyuki; Cho, Brenda S; Takayama, Shuichi

2004-11-09

Computer-controlled microfluidics would advance many types of cellular assays and microscale tissue engineering studies wherever spatiotemporal changes in fluidics need to be defined. However, this goal has been elusive because of the limited availability of integrated, programmable pumps and valves. This paper demonstrates how a refreshable Braille display, with its grid of 320 vertically moving pins, can power integrated pumps and valves through localized deformations of channel networks within elastic silicone rubber. The resulting computerized fluidic control is able to switch among: (i) rapid and efficient mixing between streams, (ii) multiple laminar flows with minimal mixing between streams, and (iii) segmented plug-flow of immiscible fluids within the same channel architecture. The same control method is used to precisely seed cells, compartmentalize them into distinct subpopulations through channel reconfiguration, and culture each cell subpopulation for up to 3 weeks under perfusion. These reliable microscale cell cultures showed gradients of cellular behavior from C2C12 myoblasts along channel lengths, as well as differences in cell density of undifferentiated myoblasts and differentiation patterns, both programmable through different flow rates of serum-containing media. This technology will allow future microscale tissue or cell studies to be more accessible, especially for high-throughput, complex, and long-term experiments. The microfluidic actuation method described is versatile and computer programmable, yet simple, well packaged, and portable enough for personal use.

Computerized microfluidic cell culture using elastomeric channels and Braille displays

PubMed Central

Gu, Wei; Zhu, Xiaoyue; Futai, Nobuyuki; Cho, Brenda S.; Takayama, Shuichi

2004-01-01

Computer-controlled microfluidics would advance many types of cellular assays and microscale tissue engineering studies wherever spatiotemporal changes in fluidics need to be defined. However, this goal has been elusive because of the limited availability of integrated, programmable pumps and valves. This paper demonstrates how a refreshable Braille display, with its grid of 320 vertically moving pins, can power integrated pumps and valves through localized deformations of channel networks within elastic silicone rubber. The resulting computerized fluidic control is able to switch among: (i) rapid and efficient mixing between streams, (ii) multiple laminar flows with minimal mixing between streams, and (iii) segmented plug-flow of immiscible fluids within the same channel architecture. The same control method is used to precisely seed cells, compartmentalize them into distinct subpopulations through channel reconfiguration, and culture each cell subpopulation for up to 3 weeks under perfusion. These reliable microscale cell cultures showed gradients of cellular behavior from C2C12 myoblasts along channel lengths, as well as differences in cell density of undifferentiated myoblasts and differentiation patterns, both programmable through different flow rates of serum-containing media. This technology will allow future microscale tissue or cell studies to be more accessible, especially for high-throughput, complex, and long-term experiments. The microfluidic actuation method described is versatile and computer programmable, yet simple, well packaged, and portable enough for personal use. PMID:15514025

A cellular automaton model of wildfire propagation and extinction

Treesearch

Keith C. Clarke; James A. Brass; Phillip J. Riggan

1994-01-01

We propose a new model to predict the spatial and temporal behavior of wildfires. Fire spread and intensity were simulated using a cellular automaton model. Monte Carlo techniques were used to provide fire risk probabilities for areas where fuel loadings and topography are known. The model assumes predetermined or measurable environmental variables such as wind...

Heat shock factor-1 intertwines insulin/IGF-1, TGF-β and cGMP signaling to control development and aging.

PubMed

Barna, János; Princz, Andrea; Kosztelnik, Mónika; Hargitai, Balázs; Takács-Vellai, Krisztina; Vellai, Tibor

2012-11-01

Temperature affects virtually all cellular processes. A quick increase in temperature challenges the cells to undergo a heat shock response to maintain cellular homeostasis. Heat shock factor-1 (HSF-1) functions as a major player in this response as it activates the transcription of genes coding for molecular chaperones (also called heat shock proteins) that maintain structural integrity of proteins. However, the mechanisms by which HSF-1 adjusts fundamental cellular processes such as growth, proliferation, differentiation and aging to the ambient temperature remain largely unknown. We demonstrate here that in Caenorhabditis elegans HSF-1 represses the expression of daf-7 encoding a TGF-β (transforming growth factor-beta) ligand, to induce young larvae to enter the dauer stage, a developmentally arrested, non-feeding, highly stress-resistant, long-lived larval form triggered by crowding and starvation. Under favorable conditions, HSF-1 is inhibited by crowding pheromone-sensitive guanylate cyclase/cGMP (cyclic guanosine monophosphate) and systemic nutrient-sensing insulin/IGF-1 (insulin-like growth factor-1) signaling; loss of HSF-1 activity allows DAF-7 to promote reproductive growth. Thus, HSF-1 interconnects the insulin/IGF-1, TGF-β and cGMP neuroendocrine systems to control development and longevity in response to diverse environmental stimuli. Furthermore, HSF-1 upregulates another TGF-β pathway-interacting gene, daf-9/cytochrome P450, thereby fine-tuning the decision between normal growth and dauer formation. Together, these results provide mechanistic insight into how temperature, nutrient availability and population density coordinately influence development, lifespan, behavior and stress response through HSF-1.

Fitness landscape transformation through a single amino acid change in the rho terminator.

PubMed

Freddolino, Peter L; Goodarzi, Hani; Tavazoie, Saeed

2012-05-01

Regulatory networks allow organisms to match adaptive behavior to the complex and dynamic contingencies of their native habitats. Upon a sudden transition to a novel environment, the mismatch between the native behavior and the new niche provides selective pressure for adaptive evolution through mutations in elements that control gene expression. In the case of core components of cellular regulation and metabolism, with broad control over diverse biological processes, such mutations may have substantial pleiotropic consequences. Through extensive phenotypic analyses, we have characterized the systems-level consequences of one such mutation (rho*) in the global transcriptional terminator Rho of Escherichia coli. We find that a single amino acid change in Rho results in a massive change in the fitness landscape of the cell, with widely discrepant fitness consequences of identical single locus perturbations in rho* versus rho(WT) backgrounds. Our observations reveal the extent to which a single regulatory mutation can transform the entire fitness landscape of the cell, causing a massive change in the interpretation of individual mutations and altering the evolutionary trajectories which may be accessible to a bacterial population.

Transparent metal model study of the use of a cellular growth front to form aligned monotectic composite materials

NASA Technical Reports Server (NTRS)

Kaukler, William F.

1988-01-01

The purpose of this work was to resolve a scientific controversy in the understanding of how second phase particles become aligned during unidirectional growth of a monotectic alloy. A second aspect was to make the first systematic observations of the solidification behavior of a monotectic alloy during cellular growth in-situ. This research provides the first systematic transparent model study of cellular solidification. An interface stability diagram was developed for the planar to cellular transition of the succinonitrile glycerol (SNG) system. A method was developed utilizing Fourier Transform Infrared Spectroscopy which allows quantitative compositional analysis of directionally solidified SNG along the growth axis. To determine the influence of cellular growth front on alignment for directionally solidified monotectic alloys, the planar and cellular growth morphology was observed in-situ for SNG between 8 and 17 percent glycerol and for a range of over two orders of magnitude G/R.

Modeling the mechanics of cancer: effect of changes in cellular and extra-cellular mechanical properties.

PubMed

Katira, Parag; Bonnecaze, Roger T; Zaman, Muhammad H

2013-01-01

Malignant transformation, though primarily driven by genetic mutations in cells, is also accompanied by specific changes in cellular and extra-cellular mechanical properties such as stiffness and adhesivity. As the transformed cells grow into tumors, they interact with their surroundings via physical contacts and the application of forces. These forces can lead to changes in the mechanical regulation of cell fate based on the mechanical properties of the cells and their surrounding environment. A comprehensive understanding of cancer progression requires the study of how specific changes in mechanical properties influences collective cell behavior during tumor growth and metastasis. Here we review some key results from computational models describing the effect of changes in cellular and extra-cellular mechanical properties and identify mechanistic pathways for cancer progression that can be targeted for the prediction, treatment, and prevention of cancer.

Origami interleaved tube cellular materials

NASA Astrophysics Data System (ADS)

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.

In vitro labeling strategies for in cellulo fluorescence microscopy of single ribonucleoprotein machines.

PubMed

Custer, Thomas C; Walter, Nils G

2017-07-01

RNA plays a fundamental, ubiquitous role as either substrate or functional component of many large cellular complexes-"molecular machines"-used to maintain and control the readout of genetic information, a functional landscape that we are only beginning to understand. The cellular mechanisms for the spatiotemporal organization of the plethora of RNAs involved in gene expression are particularly poorly understood. Intracellular single-molecule fluorescence microscopy provides a powerful emerging tool for probing the pertinent mechanistic parameters that govern cellular RNA functions, including those of protein coding messenger RNAs (mRNAs). Progress has been hampered, however, by the scarcity of efficient high-yield methods to fluorescently label RNA molecules without the need to drastically increase their molecular weight through artificial appendages that may result in altered behavior. Herein, we employ T7 RNA polymerase to body label an RNA with a cyanine dye, as well as yeast poly(A) polymerase to strategically place multiple 2'-azido-modifications for subsequent fluorophore labeling either between the body and tail or randomly throughout the tail. Using a combination of biochemical and single-molecule fluorescence microscopy approaches, we demonstrate that both yeast poly(A) polymerase labeling strategies result in fully functional mRNA, whereas protein coding is severely diminished in the case of body labeling. © 2016 The Protein Society.

Agent-based models of cellular systems.

PubMed

Cannata, Nicola; Corradini, Flavio; Merelli, Emanuela; Tesei, Luca

2013-01-01

Software agents are particularly suitable for engineering models and simulations of cellular systems. In a very natural and intuitive manner, individual software components are therein delegated to reproduce "in silico" the behavior of individual components of alive systems at a given level of resolution. Individuals' actions and interactions among individuals allow complex collective behavior to emerge. In this chapter we first introduce the readers to software agents and multi-agent systems, reviewing the evolution of agent-based modeling of biomolecular systems in the last decade. We then describe the main tools, platforms, and methodologies available for programming societies of agents, possibly profiting also of toolkits that do not require advanced programming skills.

Osteogenesis potential of different titania nanotubes in oxidative stress microenvironment.

PubMed

Yu, Yonglin; Shen, Xinkun; Luo, Zhong; Hu, Yan; Li, Menghuan; Ma, Pingping; Ran, Qichun; Dai, Liangliang; He, Ye; Cai, Kaiyong

2018-06-01

Oxidative stress is commonly existed in bone degenerative disease (osteoarthritis, osteoporosis etc.) and some antioxidants had great potential to enhance osteogenesis. In this study, we aim to investigate the anti-oxidative properties of various TiO 2 nanotubes (TNTs) so to screen the desirable size for improved osteogenesis and reveal the underlying molecular mechanism in vitro. Comparing cellular behaviors under normal and oxidative stress conditions, an interesting conclusion was obtained. In normal microenvironment, small TNTs were beneficial for adhesion and proliferation of osteoblasts, but large TNTs greatly increased osteogenic differentiation. However, after H 2 O 2 (300 μM) treatment (mimicking oxidative stress), only large TNTs samples demonstrated superior cellular behaviors of increased osteoblasts' adhesion, survival and differentiation when comparing with those of native titanium (control). Molecular results revealed that oxidative stress resistance of large nanotubes was closely related to the high expression of integrin α5β1 (ITG α5β1), which further up-regulated the production of anti-apoptotic proteins (p-FAK, p-Akt, p-FoxO3a and Bcl2) and down-regulated the expression of pro-apoptotic protein (Bax). Moreover, we found that Wnt signals (Wnt3a, Wnt5a, Lrp5, Lrp6 and β-catenin) played an important role in promoting osteogenic differentiation of osteoblasts under oxidative condition. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cell-based therapeutics: the next pillar of medicine.

PubMed

Fischbach, Michael A; Bluestone, Jeffrey A; Lim, Wendell A

2013-04-03

Two decades ago, the pharmaceutical industry-long dominated by small-molecule drugs-was revolutionized by the the advent of biologics. Today, biomedicine sits on the cusp of a new revolution: the use of microbial and human cells as versatile therapeutic engines. Here, we discuss the promise of this "third pillar" of therapeutics in the context of current scientific, regulatory, economic, and perceptual challenges. History suggests that the advent of cellular medicines will require the development of a foundational cellular engineering science that provides a systematic framework for safely and predictably altering and regulating cellular behaviors.

Sexual Experience in Female Rodents: Cellular Mechanisms and Functional Consequences

PubMed Central

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

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

PubMed Central

Aguilar-Arnal, Lorena; Sassone-Corsi, Paolo

2015-01-01

Circadian rhythms drive the temporal organization of a wide variety of physiological and behavioral functions in ∼24-h cycles. This control is achieved through a complex program of gene expression. In mammals, the molecular clock machinery consists of interconnected transcriptional–translational feedback loops that ultimately ensure the proper oscillation of thousands of genes in a tissue-specific manner. To achieve circadian transcriptional control, chromatin remodelers serve the clock machinery by providing appropriate oscillations to the epigenome. Recent findings have revealed the presence of circadian interactomes, nuclear “hubs” of genome topology where coordinately expressed circadian genes physically interact in a spatial and temporal-specific manner. Thus, a circadian nuclear landscape seems to exist, whose interplay with metabolic pathways and clock regulators translates into specific transcriptional programs. Deciphering the molecular mechanisms that connect the circadian clock machinery with the nuclear landscape will reveal yet unexplored pathways that link cellular metabolism to epigenetic control. PMID:25378702

Gelatin device for the delivery of growth factors involved in endochondral ossification.

PubMed

Ahrens, Lucas A J; Vonwil, Daniel; Christensen, Jon; Shastri, V Prasad

2017-01-01

Controlled release drug delivery systems are well established as oral and implantable dosage forms. However, the controlled release paradigm can also be used to present complex soluble signals responsible for cellular organization during development. Endochondral ossification (EO), the developmental process of bone formation from a cartilage matrix is controlled by several soluble signals with distinct functions that vary in structure, molecular weight and stability. This makes delivering them from a single vehicle rather challenging. Herein, a gelatin-based delivery system suitable for the delivery of small molecules as well as recombinant human (rh) proteins (rhWNT3A, rhFGF2, rhVEGF, rhBMP4) is reported. The release behavior and biological activity of the released molecules was validated using analytical and biological assays, including cell reporter systems. The simplicity of fabrication of the gelatin device should foster its adaptation by the diverse scientific community interested in interrogating developmental processes, in vivo.

Gelatin device for the delivery of growth factors involved in endochondral ossification

PubMed Central

Ahrens, Lucas A. J.; Vonwil, Daniel; Christensen, Jon

2017-01-01

Controlled release drug delivery systems are well established as oral and implantable dosage forms. However, the controlled release paradigm can also be used to present complex soluble signals responsible for cellular organization during development. Endochondral ossification (EO), the developmental process of bone formation from a cartilage matrix is controlled by several soluble signals with distinct functions that vary in structure, molecular weight and stability. This makes delivering them from a single vehicle rather challenging. Herein, a gelatin-based delivery system suitable for the delivery of small molecules as well as recombinant human (rh) proteins (rhWNT3A, rhFGF2, rhVEGF, rhBMP4) is reported. The release behavior and biological activity of the released molecules was validated using analytical and biological assays, including cell reporter systems. The simplicity of fabrication of the gelatin device should foster its adaptation by the diverse scientific community interested in interrogating developmental processes, in vivo. PMID:28380024

Maintenance of Mitochondrial Oxygen Homeostasis by Cosubstrate Compensation

PubMed Central

Kueh, Hao Yuan; Niethammer, Philipp; Mitchison, Timothy J.

2013-01-01

Mitochondria maintain a constant rate of aerobic respiration over a wide range of oxygen levels. However, the control strategies underlying oxygen homeostasis are still unclear. Using mathematical modeling, we found that the mitochondrial electron transport chain (ETC) responds to oxygen level changes by undergoing compensatory changes in reduced electron carrier levels. This emergent behavior, which we named cosubstrate compensation (CSC), enables the ETC to maintain homeostasis over a wide of oxygen levels. When performing CSC, our ETC models recapitulated a classic scaling relationship discovered by Chance [Chance B (1965) J. Gen. Physiol. 49:163-165] relating the extent of oxygen homeostasis to the kinetics of mitochondrial electron transport. Analysis of an in silico mitochondrial respiratory system further showed evidence that CSC constitutes the dominant control strategy for mitochondrial oxygen homeostasis during active respiration. Our findings indicate that CSC constitutes a robust control strategy for homeostasis and adaptation in cellular biochemical networks. PMID:23528093

Early life experience alters behavior during social defeat: focus on serotonergic systems.

PubMed

Gardner, K L; Thrivikraman, K V; Lightman, S L; Plotsky, P M; Lowry, C A

2005-01-01

Early life experience can have prolonged effects on neuroendocrine, autonomic, and behavioral responses to stress. The objective of this study was to investigate the effects of early life experience on behavior during social defeat, as well as on associated functional cellular responses in serotonergic and non-serotonergic neurons within the dorsal raphe nucleus, a structure which plays an important role in modulation of stress-related physiology and behavior. Male Long Evans rat pups were exposed to either normal animal facility rearing or 15 min or 180 min of maternal separation from postnatal days 2-14. As adults, these rats were exposed to a social defeat protocol. Differences in behavior were seen among the early life treatment groups during social defeat; rats exposed to 180 min of maternal separation from postnatal days 2-14 displayed more passive-submissive behaviors and less proactive coping behaviors. Analysis of the distribution of tryptophan hydroxylase and c-Fos-like immunoreactivity in control rats exposed to a novel cage and rats exposed to social defeat revealed that, independent of the early life experience, rats exposed to social defeat showed an increase in the number of c-Fos-like immunoreactive nuclei in serotonergic neurons in the middle and caudal parts of the dorsal dorsal raphe nucleus and caudal part of the ventral dorsal raphe nucleus, regions known to contain serotonergic neurons projecting to central autonomic and emotional motor control systems. This is the first study to show that the dorsomedial part of the mid-rostrocaudal dorsal raphe nucleus is engaged by a naturalistic stressor and supports the hypothesis that early life experience alters behavioral coping strategies during social conflict; furthermore, this study is consistent with the hypothesis that topographically organized subpopulations of serotonergic neurons principally within the mid-rostrocaudal and caudal part of the dorsal dorsal raphe nucleus modulate stress-related physiological and behavioral responses.

Effect of surface modification by nitrogen ion implantation on the electrochemical and cellular behaviors of super-elastic NiTi shape memory alloy.

PubMed

Maleki-Ghaleh, H; Khalil-Allafi, J; Sadeghpour-Motlagh, M; Shakeri, M S; Masoudfar, S; Farrokhi, A; Beygi Khosrowshahi, Y; Nadernezhad, A; Siadati, M H; Javidi, M; Shakiba, M; Aghaie, E

2014-12-01

The aim of this investigation was to enhance the biological behavior of NiTi shape memory alloy while preserving its super-elastic behavior in order to facilitate its compatibility for application in human body. The surfaces of NiTi samples were bombarded by three different nitrogen doses. Small-angle X-ray diffraction was employed for evaluating the generated phases on the bombarded surfaces. The electrochemical behaviors of the bare and surface-modified NiTi samples were studied in simulated body fluid (SBF) using electrochemical impedance and potentio-dynamic polarization tests. Ni ion release during a 2-month period of service in the SBF environment was evaluated using atomic absorption spectrometry. The cellular behavior of nitrogen-modified samples was studied using fibroblast cells. Furthermore, the effect of surface modification on super-elasticity was investigated by tensile test. The results showed the improvement of both corrosion and biological behaviors of the modified NiTi samples. However, no significant change in the super-elasticity was observed. Samples modified at 1.4E18 ion cm(-2) showed the highest corrosion resistance and the lowest Ni ion release.

The biophysical bases of will-less behaviors

PubMed Central

Perez Velazquez, José L.

2012-01-01

Are there distinctions at the neurophysiological level that correlate with voluntary and involuntary actions? Whereas the wide variety of involuntary behaviors (and here mostly the deviant or pathological ones will be considered) will necessarily be represented at some biophysical level in nervous system activity–for after all those cellular activity patterns manifest themselves as behaviors and thus there will be a multiplicity of them–there could be some general tendencies to be discerned amongst that assortment. Collecting observations derived from neurophysiological activity associated with several pathological conditions characterized by presenting will-less actions such as Parkinson's disease, seizures, alien hand syndrome and tics, it is proposed that a general neurophysiologic tendency of brain activity that correlates with involuntary actions is higher than normal synchrony in specific brain cell networks, depending upon the behavior in question. Wilful, considered normal behavior, depends on precise coordination of the collective activity in cell ensembles that may be lost, or diminished, when there are tendencies toward more than normal or aberrant synchronization of cellular activity. Hence, rapid fluctuations in synchrony is associated with normal actions and cognition while less variability in brain recordings particularly with regards to synchronization could be a signature of unconscious and deviant behaviors in general. PMID:23109920

A receptor and neuron that activate a circuit limiting sucrose consumption.

PubMed

Joseph, Ryan M; Sun, Jennifer S; Tam, Edric; Carlson, John R

2017-03-23

The neural control of sugar consumption is critical for normal metabolism. In contrast to sugar-sensing taste neurons that promote consumption, we identify a taste neuron that limits sucrose consumption in Drosophila . Silencing of the neuron increases sucrose feeding; optogenetic activation decreases it. The feeding inhibition depends on the IR60b receptor, as shown by behavioral analysis and Ca 2+ imaging of an IR60b mutant. The IR60b phenotype shows a high degree of chemical specificity when tested with a broad panel of tastants. An automated analysis of feeding behavior in freely moving flies shows that IR60b limits the duration of individual feeding bouts. This receptor and neuron provide the molecular and cellular underpinnings of a new element in the circuit logic of feeding regulation. We propose a dynamic model in which sucrose acts via IR60b to activate a circuit that inhibits feeding and prevents overconsumption.

a Discrete Mathematical Model to Simulate Malware Spreading

NASA Astrophysics Data System (ADS)

Del Rey, A. Martin; Sánchez, G. Rodriguez

2012-10-01

With the advent and worldwide development of Internet, the study and control of malware spreading has become very important. In this sense, some mathematical models to simulate malware propagation have been proposed in the scientific literature, and usually they are based on differential equations exploiting the similarities with mathematical epidemiology. The great majority of these models study the behavior of a particular type of malware called computer worms; indeed, to the best of our knowledge, no model has been proposed to simulate the spreading of a computer virus (the traditional type of malware which differs from computer worms in several aspects). In this sense, the purpose of this work is to introduce a new mathematical model not based on continuous mathematics tools but on discrete ones, to analyze and study the epidemic behavior of computer virus. Specifically, cellular automata are used in order to design such model.

Interaction of polymer-coated silicon nanocrystals with lipid bilayers and surfactant interfaces

NASA Astrophysics Data System (ADS)

Elbaradei, Ahmed; Brown, Samuel L.; Miller, Joseph B.; May, Sylvio; Hobbie, Erik K.

2016-10-01

We use photoluminescence (PL) microscopy to measure the interaction between polyethylene-glycol-coated (PEGylated) silicon nanocrystals (SiNCs) and two model surfaces: lipid bilayers and surfactant interfaces. By characterizing the photostability, transport, and size-dependent emission of the PEGylated nanocrystal clusters, we demonstrate the retention of red PL suitable for detection and tracking with minimal blueshift after a year in an aqueous environment. The predominant interaction measured for both interfaces is short-range repulsion, consistent with the ideal behavior anticipated for PEGylated phospholipid coatings. However, we also observe unanticipated attractive behavior in a small number of scenarios for both interfaces. We attribute this anomaly to defective PEG coverage on a subset of the clusters, suggesting a possible strategy for enhancing cellular uptake by controlling the homogeneity of the PEG corona. In both scenarios, the shape of the apparent potential is modeled through the free or bound diffusion of the clusters near the confining interface.

Using glutamate homeostasis as a target for treating addictive disorders

PubMed Central

Reissner, Kathryn J.; Kalivas, Peter W.

2010-01-01

Well-developed cellular mechanisms exist to preserve glutamate homeostasis and regulate extrasynaptic glutamate levels. Accumulating evidence indicates that disruptions in glutamate homeostasis are associated with addictive disorders. The disruptions in glutamate concentrations observed following prolonged exposure to drugs of abuse are associated with changes in the function and activity of several key components within the homeostatic control mechanism, including the cystine/glutamate exchanger xc− and the glial glutamate transporter EAAT2/GLT-1. Changes in the balance between synaptic and extrasynaptic glutamate levels in turn influence signaling through pre- and postsynaptic glutamate receptors, and thus affect synaptic plasticity and circuit-level activity. In this review we describe the evidence for impaired glutamate homestasis as a critical mediator of long-term drug-seeking behaviors, how chronic neuroadaptations in xc− and GLT-1 mediate a disruption in glutamate homeostasis, and how targeting these components restores glutamate levels and inhibits drug-seeking behaviors. PMID:20634691

The auxetic behavior of an expanded periodic cellular structure

NASA Astrophysics Data System (ADS)

Ciolan, Mihaela A.; Lache, Simona; Velea, Marian N.

2018-02-01

Within nowadays research, when it comes to lightweight sandwich panels, periodic cellular structures are considered real trendsetters. One of the most used type of core in producing sandwich panels is the honeycomb. However, due to its relatively high manufacturing cost, this structure has limited applications; therefore, research has been carried out in order to develop alternative solutions. An example in this sense is the ExpaAsym cellular structure, developed at the Transilvania University of Braşov; it represents a periodic cellular structure manufactured through a mechanically expansion process of a previously cut and perforated sheet material. The relative density of the structure was proven to be significantly lower than the one of the honeycomb. This gives a great advantage to the structure, due to the fact that when the internal angle A of the unit cell is 60°, after the mechanical expansion it results a hexagonal structure. The main objective of this paper is to estimate the in-plane Poisson ratios of the structure, in terms of its geometrical parameters. It is therefore analytically shown that for certain values of the geometric parameters, the in-plane Poisson ratios have negative values when the internal angle exceeds 90°, which determines its auxetic behavior.

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

PubMed

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.

Coupled pulsating and cellular structure in the propagation of globally planar detonations in free space

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

Han, Wenhu; Key Laboratory for Thermal Science and Power Engineering of Ministry of Education, Department of Thermal Engineering, Tsinghua University, Beijing 100084; Gao, Yang, E-mail: gaoyang-00@mails.tsinghua.edu.cn

The globally planar detonation in free space is numerically simulated, with particular interest to understand and quantify the emergence and evolution of the one-dimensional pulsating instability and the two-dimensional cellular structure which is inherently also affected by pulsating instability. It is found that the pulsation includes three stages: rapid decay of the overdrive, approach to the Chapman-Jouguet state and emergence of weak pulsations, and the formation of strong pulsations; while evolution of the cellular structure also exhibits distinct behavior at these three stages: no cell formation, formation of small-scale, irregular cells, and formation of regular cells of a larger scale.more » Furthermore, the average shock pressure in the detonation front consists of fine-scale oscillations reflecting the collision dynamics of the triple-shock structure and large-scale oscillations affected by the global pulsation. The common stages of evolution between the cellular structure and the pulsating behavior, as well as the existence of shock-front pressure oscillation, suggest highly correlated mechanisms between them. Detonations with period doubling, period quadrupling, and chaotic amplitudes were also observed and studied for progressively increasing activation energies.« less

A Mathematical Model to study the Dynamics of Epithelial Cellular Networks

PubMed Central

Abate, Alessandro; Vincent, Stéphane; Dobbe, Roel; Silletti, Alberto; Master, Neal; Axelrod, Jeffrey D.; Tomlin, Claire J.

2013-01-01

Epithelia are sheets of connected cells that are essential across the animal kingdom. Experimental observations suggest that the dynamical behavior of many single-layered epithelial tissues has strong analogies with that of specific mechanical systems, namely large networks consisting of point masses connected through spring-damper elements and undergoing the influence of active and dissipating forces. Based on this analogy, this work develops a modeling framework to enable the study of the mechanical properties and of the dynamic behavior of large epithelial cellular networks. The model is built first by creating a network topology that is extracted from the actual cellular geometry as obtained from experiments, then by associating a mechanical structure and dynamics to the network via spring-damper elements. This scalable approach enables running simulations of large network dynamics: the derived modeling framework in particular is predisposed to be tailored to study general dynamics (for example, morphogenesis) of various classes of single-layered epithelial cellular networks. In this contribution we test the model on a case study of the dorsal epithelium of the Drosophila melanogaster embryo during early dorsal closure (and, less conspicuously, germband retraction). PMID:23221083

Control of fluxes in metabolic networks

PubMed Central

Basler, Georg; Nikoloski, Zoran; Larhlimi, Abdelhalim; Barabási, Albert-László; Liu, Yang-Yu

2016-01-01

Understanding the control of large-scale metabolic networks is central to biology and medicine. However, existing approaches either require specifying a cellular objective or can only be used for small networks. We introduce new coupling types describing the relations between reaction activities, and develop an efficient computational framework, which does not require any cellular objective for systematic studies of large-scale metabolism. We identify the driver reactions facilitating control of 23 metabolic networks from all kingdoms of life. We find that unicellular organisms require a smaller degree of control than multicellular organisms. Driver reactions are under complex cellular regulation in Escherichia coli, indicating their preeminent role in facilitating cellular control. In human cancer cells, driver reactions play pivotal roles in malignancy and represent potential therapeutic targets. The developed framework helps us gain insights into regulatory principles of diseases and facilitates design of engineering strategies at the interface of gene regulation, signaling, and metabolism. PMID:27197218

Analysis of cellular adhesion on superhydrophobic and superhydrophilic vertically aligned carbon nanotube scaffolds.

PubMed

Machado, M M; Lobo, A O; Marciano, F R; Corat, E J; Corat, M A F

2015-03-01

We analyzed GFP cells after 24h cultivated on superhydrophilic vertically aligned carbon nanotube scaffolds. We produced two different densities of VACNT scaffolds on Ti using Ni or Fe catalysts. A simple and fast oxygen plasma treatment promoted the superhydrophilicity of them. We used five different substrates, such as: as-grown VACNT produced using Ni as catalyst (Ni), as-grown VACNT produced using Fe as catalyst (Fe), VACNT-O produced using Ni as catalyst (NiO), VACNT-O produced using Fe as catalyst (FeO) and Ti (control). The 4',6-diamidino-2-phenylindole reagent nuclei stained the adherent cells cultivated on five different analyzed scaffolds. We used fluorescence microscopy for image collect, ImageJ® to count adhered cell and GraphPad Prism 5® for statistical analysis. We demonstrated in crescent order: Fe, Ni, NiO, FeO and Ti scaffolds that had an improved cellular adhesion. Oxygen treatment associated to high VACNT density (group FeO) presented significantly superior cell adhesion up to 24h. However, they do not show significant differences compared with Ti substrates (control). We demonstrated that all the analyzed substrates were nontoxic. Also, we proposed that the density and hydrophilicity influenced the cell adhesion behavior. Copyright © 2014 Elsevier B.V. All rights reserved.

Alternating Magnetic Field Controlled, Multifunctional Nano-Reservoirs: Intracellular Uptake and Improved Biocompatibility

NASA Astrophysics Data System (ADS)

Ghosh, Santaneel; Ghoshmitra, Somesree; Cai, Tong; Diercks, David R.; Mills, Nathaniel C.; Hynds, Dianna L.

2010-01-01

Biocompatible magnetic nanoparticles hold great therapeutic potential, but conventional particles can be toxic. Here, we report the synthesis and alternating magnetic field dependent actuation of a remotely controllable, multifunctional nano-scale system and its marked biocompatibility with mammalian cells. Monodisperse, magnetic nanospheres based on thermo-sensitive polymer network poly(ethylene glycol) ethyl ether methacrylate- co-poly(ethylene glycol) methyl ether methacrylate were synthesized using free radical polymerization. Synthesized nanospheres have oscillating magnetic field induced thermo-reversible behavior; exhibiting desirable characteristics comparable to the widely used poly- N-isopropylacrylamide-based systems in shrinkage plus a broader volumetric transition range. Remote heating and model drug release were characterized for different field strengths. Nanospheres containing nanoparticles up to an iron concentration of 6 mM were readily taken up by neuron-like PC12 pheochromocytoma cells and had reduced toxicity compared to other surface modified magnetic nanocarriers. Furthermore, nanosphere exposure did not inhibit the extension of cellular processes (neurite outgrowth) even at high iron concentrations (6 mM), indicating minimal negative effects in cellular systems. Excellent intracellular uptake and enhanced biocompatibility coupled with the lack of deleterious effects on neurite outgrowth and prior Food and Drug Administration (FDA) approval of PEG-based carriers suggest increased therapeutic potential of this system for manipulating axon regeneration following nervous system injury.

Local cellular neighborhood controls proliferation in cell competition

PubMed Central

Bove, Anna; Gradeci, Daniel; Fujita, Yasuyuki; Banerjee, Shiladitya; Charras, Guillaume; Lowe, Alan R.

2017-01-01

Cell competition is a quality-control mechanism through which tissues eliminate unfit cells. Cell competition can result from short-range biochemical inductions or long-range mechanical cues. However, little is known about how cell-scale interactions give rise to population shifts in tissues, due to the lack of experimental and computational tools to efficiently characterize interactions at the single-cell level. Here, we address these challenges by combining long-term automated microscopy with deep-learning image analysis to decipher how single-cell behavior determines tissue makeup during competition. Using our high-throughput analysis pipeline, we show that competitive interactions between MDCK wild-type cells and cells depleted of the polarity protein scribble are governed by differential sensitivity to local density and the cell type of each cell’s neighbors. We find that local density has a dramatic effect on the rate of division and apoptosis under competitive conditions. Strikingly, our analysis reveals that proliferation of the winner cells is up-regulated in neighborhoods mostly populated by loser cells. These data suggest that tissue-scale population shifts are strongly affected by cellular-scale tissue organization. We present a quantitative mathematical model that demonstrates the effect of neighbor cell–type dependence of apoptosis and division in determining the fitness of competing cell lines. PMID:28931601

RRM2 induces NF-{kappa}B-dependent MMP-9 activation and enhances cellular invasiveness

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

Duxbury, Mark S.; Whang, Edward E.

2007-03-02

Ribonucleotide reductase is a dimeric enzyme that catalyzes conversion of ribonucleotide 5'-diphosphates to their 2'-deoxynucleotide forms, a rate-limiting step in the production of 2'-deoxyribonucleoside 5'-triphosphates required for DNA synthesis. The ribonucleotide reductase M2 subunit (RRM2) is a determinant of malignant cellular behavior in a range of human cancers. We examined the effect of RRM2 overexpression on pancreatic adenocarcinoma cellular invasiveness and nuclear factor-{kappa}B (NF-{kappa}B) transcription factor activity. RRM2 overexpression increases pancreatic adenocarcinoma cellular invasiveness and MMP-9 expression in a NF-{kappa}B-dependent manner. RNA interference (RNAi)-mediated silencing of RRM2 expression attenuates cellular invasiveness and NF-{kappa}B activity. NF-{kappa}B is a key mediator ofmore » the invasive phenotypic changes induced by RRM2 overexpression.« less

Peptide-based Fluorescent Sensors of Protein Kinase Activity: Design and Applications

PubMed Central

Sharma, Vyas; Wang, Qunzhao; Lawrence, David S.

2009-01-01

Protein kinases control the flow of information through cell-signaling pathways. A detailed analysis of their behavior enhances our ability to understand normal cellular states and to devise therapeutic interventions for diseases. The design and application of “Environmentally-Sensitive”, “Deep-Quench” and “Self-Reporting” sensor systems for studying protein kinase activity are described. These sensors allow real-time activity measurements in a continuous manner for a wide variety of kinases. As these sensors can be adapted from an in vitro screen to imaging kinase activity in living cells, they support both preliminary and later stages of drug discovery. PMID:17881302

Interactions between semiconductor nanowires and living cells.

PubMed

Prinz, Christelle N

2015-06-17

Semiconductor nanowires are increasingly used for biological applications and their small dimensions make them a promising tool for sensing and manipulating cells with minimal perturbation. In order to interface cells with nanowires in a controlled fashion, it is essential to understand the interactions between nanowires and living cells. The present paper reviews current progress in the understanding of these interactions, with knowledge gathered from studies where living cells were interfaced with vertical nanowire arrays. The effect of nanowires on cells is reported in terms of viability, cell-nanowire interface morphology, cell behavior, changes in gene expression as well as cellular stress markers. Unexplored issues and unanswered questions are discussed.

[Neuronal and synaptic properties: fundamentals of network plasticity].

PubMed

Le Masson, G

2000-02-01

Neurons, within the nervous system, are organized in different neural networks through synaptic connections. Two fundamental components are dynamically interacting in these functional units. The first one are the neurons themselves, and far from being simple action potential generators, they are capable of complex electrical integrative properties due to various types, number, distribution and modulation of voltage-gated ionic channels. The second elements are the synapses where a similar complexity and plasticity is found. Identifying both cellular and synaptic intrinsic properties is necessary to understand the links between neural networks behavior and physiological function, and is a useful step towards a better control of neurological diseases.

Effect of Withaferin A on A549 cellular proliferation and apoptosis in non-small cell lung cancer.

PubMed

Cai, Yong; Sheng, Zhao-Ying; Chen, Yun; Bai, Chong

2014-01-01

To explore the effect of Withaferin A on A549 cellular proliferation and apoptosis in non-small cell lung cancer (NSCLC). NSCNC cell line A549 was selected to explore the effect of Withaferin A on A549 cellular proliferation, apoptosis and the PI3K/Akt signal pathway capable of regulating tumor biological behavior by assessment of cellular proliferation, cellular apoptotic rates and cellular cycling as well as by immuno-blotting. Withaferin A could inhibit A549 cellular proliferation and the control rate was dosage-dependent (P<0.05), which also increased time-dependently with the same dosage of Withaferin A (P<0.05). The apoptotic indexes in A549 cells treated with 0, 2.5, 5.0, 10.0 and 20.0 μmol·L-1 Withaferin A for 48 h were significantly different (P<0.05). In addition, the apoptotic rates of each group in both early and advanced stages were higher than those in 0 μmol·L-1 (P<0.05), which were evidently higher after 48 h than those after 24 h (P<0.05). A549 cells treated by Withaferin A for 48 h were markedly lower in Bcl-2 level and obviously higher in Bax and cleaved caspase-3 levels than those treated by 0 μmol·L-1 Withaferin A (P<0.05), and there were significant differences among 5, 10 and 20 μmol·L-1 Withaferin A (P<0.05). The ratios of A549 cells treated by Withaferin A for 48 h in G0/G1 stage were higher than those in 0 μmol·L-1 , while those in S and G2/M stages were obviously lower than those in G2/M stage, and there were significant differences in 5.0, 10.0 and 20.0 μmol·L-1 Withaferin A (P<0.05). Additionally, p-Akt/Akt values were in reverse association with dosage, and the differences were significant (P<0.05). Withaferin A can inhibit the proliferation and apoptosis of A549 cells by suppressing activation of the PI3K/Akt pathways.

Tyramine Actions on Drosophila Flight Behavior Are Affected by a Glial Dehydrogenase/Reductase.

PubMed

Ryglewski, Stefanie; Duch, Carsten; Altenhein, Benjamin

2017-01-01

The biogenic amines octopamine (OA) and tyramine (TA) modulate insect motor behavior in an antagonistic manner. OA generally enhances locomotor behaviors such as Drosophila larval crawling and flight, whereas TA decreases locomotor activity. However, the mechanisms and cellular targets of TA modulation of locomotor activity are incompletely understood. This study combines immunocytochemistry, genetics and flight behavioral assays in the Drosophila model system to test the role of a candidate enzyme for TA catabolism, named Nazgul (Naz), in flight motor behavioral control. We hypothesize that the dehydrogenase/reductase Naz represents a critical step in TA catabolism. Immunocytochemistry reveals that Naz is localized to a subset of Repo positive glial cells with cell bodies along the motor neuropil borders and numerous positive Naz arborizations extending into the synaptic flight motor neuropil. RNAi knock down of Naz in Repo positive glial cells reduces Naz protein level below detection level by Western blotting. The resulting consequence is a reduction in flight durations, thus mimicking known motor behavioral phenotypes as resulting from increased TA levels. In accord with the interpretation that reduced TA degradation by Naz results in increased TA levels in the flight motor neuropil, the motor behavioral phenotype can be rescued by blocking TA receptors. Our findings indicate that TA modulates flight motor behavior by acting on central circuitry and that TA is normally taken up from the central motor neuropil by Repo-positive glial cells, desaminated and further degraded by Naz.

Tyramine Actions on Drosophila Flight Behavior Are Affected by a Glial Dehydrogenase/Reductase

PubMed Central

Ryglewski, Stefanie; Duch, Carsten; Altenhein, Benjamin

2017-01-01

The biogenic amines octopamine (OA) and tyramine (TA) modulate insect motor behavior in an antagonistic manner. OA generally enhances locomotor behaviors such as Drosophila larval crawling and flight, whereas TA decreases locomotor activity. However, the mechanisms and cellular targets of TA modulation of locomotor activity are incompletely understood. This study combines immunocytochemistry, genetics and flight behavioral assays in the Drosophila model system to test the role of a candidate enzyme for TA catabolism, named Nazgul (Naz), in flight motor behavioral control. We hypothesize that the dehydrogenase/reductase Naz represents a critical step in TA catabolism. Immunocytochemistry reveals that Naz is localized to a subset of Repo positive glial cells with cell bodies along the motor neuropil borders and numerous positive Naz arborizations extending into the synaptic flight motor neuropil. RNAi knock down of Naz in Repo positive glial cells reduces Naz protein level below detection level by Western blotting. The resulting consequence is a reduction in flight durations, thus mimicking known motor behavioral phenotypes as resulting from increased TA levels. In accord with the interpretation that reduced TA degradation by Naz results in increased TA levels in the flight motor neuropil, the motor behavioral phenotype can be rescued by blocking TA receptors. Our findings indicate that TA modulates flight motor behavior by acting on central circuitry and that TA is normally taken up from the central motor neuropil by Repo-positive glial cells, desaminated and further degraded by Naz. PMID:29021745

Cellular, Molecular, and Genetic Substrates Underlying the Impact of Nicotine on Learning

PubMed Central

Gould, Thomas J.; Leach, Prescott T.

2013-01-01

Addiction is a chronic disorder marked by long-lasting maladaptive changes in behavior and in reward system function. However, the factors that contribute to the behavioral and biological changes that occur with addiction are complex and go beyond reward. Addiction involves changes in cognitive control and the development of disruptive drug-stimuli associations that can drive behavior. A reason for the strong influence drugs of abuse can exert on cognition may be the striking overlap between the neurobiological substrates of addiction and of learning and memory, especially areas involved in declarative memory. Declarative memories are critically involved in the formation of autobiographical memories, and the ability of drugs of abuse to alter these memories could be particularly detrimental. A key structure in this memory system is the hippocampus, which is critically involved in binding multimodal stimuli together to form complex long-term memories. While all drugs of abuse can alter hippocampal function, this review focuses on nicotine. Addiction to tobacco products is insidious, with the majority of smokers wanting to quit; yet the majority of those that attempt to quit fail. Nicotine addiction is associated with the presence of drug-context and drug-cue associations that trigger drug seeking behavior and altered cognition during periods of abstinence, which contributes to relapse. This suggests that understanding the effects of nicotine on learning and memory will advance understanding and potentially facilitate treating nicotine addiction. The following sections examine: 1) how the effects of nicotine on hippocampus-dependent learning change as nicotine administration transitions from acute to chronic and then to withdrawal from chronic treatment and the potential impact of these changes on addiction, 2) how nicotine usurps the cellular mechanisms of synaptic plasticity, 3) the physiological changes in the hippocampus that may contribute to nicotine withdrawal deficits in learning, and 4) the role of genetics and developmental stage (i.e., adolescence) in these effects. PMID:23973448

Theoretical aspects of cellular decision-making and information-processing.

PubMed

Kobayashi, Tetsuya J; Kamimura, Atsushi

2012-01-01

Microscopic biological processes have extraordinary complexity and variety at the sub-cellular, intra-cellular, and multi-cellular levels. In dealing with such complex phenomena, conceptual and theoretical frameworks are crucial, which enable us to understand seemingly different intra- and inter-cellular phenomena from unified viewpoints. Decision-making is one such concept that has attracted much attention recently. Since a number of cellular behavior can be regarded as processes to make specific actions in response to external stimuli, decision-making can cover and has been used to explain a broad range of different cellular phenomena [Balázsi et al. (Cell 144(6):910, 2011), Zeng et al. (Cell 141(4):682, 2010)]. Decision-making is also closely related to cellular information-processing because appropriate decisions cannot be made without exploiting the information that the external stimuli contain. Efficiency of information transduction and processing by intra-cellular networks determines the amount of information obtained, which in turn limits the efficiency of subsequent decision-making. Furthermore, information-processing itself can serve as another concept that is crucial for understanding of other biological processes than decision-making. In this work, we review recent theoretical developments on cellular decision-making and information-processing by focusing on the relation between these two concepts.

Molecular basis of alcoholism.

PubMed

Most, Dana; Ferguson, Laura; Harris, R Adron

2014-01-01

Acute alcohol intoxication causes cellular changes in the brain that last for hours, while chronic alcohol use induces widespread neuroadaptations in the nervous system that can last a lifetime. Chronic alcohol use and the progression into dependence involve the remodeling of synapses caused by changes in gene expression produced by alcohol. The progression of alcohol use, abuse, and dependence can be divided into stages, which include intoxication, withdrawal, and craving. Each stage is associated with specific changes in gene expression, cellular function, brain circuits, and ultimately behavior. What are the molecular mechanisms underlying the transition from recreational use (acute) to dependence (chronic)? What cellular adaptations result in drug memory retention, leading to the persistence of addictive behaviors, even after prolonged drug abstinence? Research into the neurobiology of alcoholism aims to answer these questions. This chapter will describe the molecular adaptations caused by alcohol use and dependence, and will outline key neurochemical participants in alcoholism at the molecular level, which are also potential targets for therapy. © 2014 Elsevier B.V. All rights reserved.

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

PubMed Central

Denning, Denise; Roos, Wouter H.

2016-01-01

ABSTRACT 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 defined microenvironment has also garnered deep insight into the engineering mechanisms existing within the cell. This review presents recent experimental findings on the influence of several parameters of the extracellular environment on cell behavior and fate, such as substrate topography, stiffness, chemistry and charge. In addition, the use of synthetic environments to measure physical properties of the reconstituted cytoskeleton and their interaction with intracellular proteins such as molecular motors is discussed, which is relevant for understanding cell migration, division and structural integrity, as well as intracellular transport. Insight is provided regarding the next steps to be taken in this interdisciplinary field, in order to achieve the global aim of artificially directing cellular response. PMID:27266767

Composite nanowire networks for biological sensor platforms

NASA Astrophysics Data System (ADS)

Jabal, Jamie Marie Francisco

The main goal of this research is to design, fabricate, and test a nanomaterial-based platform adequate for the measurement of physiological changes in living cells. The two primary objectives toward this end are (1) the synthesis and selection of a suitable nanomaterial and (2) the demonstration of cellular response to a direct stimulus. Determining a useful nanomaterial morphology and behavior within a sensor configuration presented challenges based on cellular integration and access to electrochemical characterization. The prospect for feasible optimization and eventual scale-up in technology were also significant. Constraining criteria are that the nanomaterial detector must (a) be cheap and relatively easy to fabricate controllably, (b) encourage cell attachment, (c) exhibit consistent wettability over time, and (d) facilitate electrochemical processes. The ultimate goal would be to transfer a proof-of-principle and proof-of-design for a whole-cell sensor technology that is cost effective and has a potential for hand-held packaging. Initial tasks were to determine an effective and highly-functional nanomaterial for biosensors by assessing wettability, morphology and conductivity behavior of several candidate materials: gallium nitride nanowires, silicon dioxide nanosprings and nanowires, and titania nanofibers. Electrospinning poly(vinyl pyrrolidone)-coated titania nano- and microfibers (O20 nm--2 microm) into a pseudo-random network is controllable to a uniformity of 1--2° in contact angle. The final electrode can be prepared with a precise wettability ranging from partial wetting to ultrahydrophobic (170°) on a variety of substrates: glass, indium tin oxide, silicon, and aluminum. Fiber mats exhibit excellent mechanical stability against rinsing, and support the incubation of epithelial (skin) and pancreatic cells. Impedance spectroscopy on the whole-cell sensor shows resistive changes attributed to cell growth as well as complex frequency-dependent behavior that can be interpreted as simple RCL circuit behavior with changing component parameters. Upon addition of lactic acid, some cell death is evident but complex impedance measurements indicate competing cell growth with adjustment to media pH. The surface impedance of the PVP-titania fiber-ITO electrode has been used in a novel measurement method to reveal significant qualitative and quantitative materials response characteristics associated with changes in solution environment, fiber mat morphology, and the state of the cells' attachment, proliferation and death.

Maternal ingestion of Ipomoea carnea: Effects on goat-kid bonding and behavior

USDA-ARS?s Scientific Manuscript database

Ipomoea carnea is a toxic plant found in Brazil and other tropical and subtropical countries and often causes poisoning of livestock. The plant contains the alkaloids swainsonine and calystegines, which inhibit key cellular enzymes and cause systematic cell death. This study evaluated the behavioral...

Neonate behavior in goats is affected by maternal ingestion of Ipomoea carnea

USDA-ARS?s Scientific Manuscript database

Ipomoea carnea is a toxic plant that grows in tropical areas, and is readily consumed by grazing goats. The plant contains the alkaloids swainsonine and calystegines, which inhibit cellular enzymes and cause systematic cell death. This study evaluated the behavioral effects on dams and kids of prena...

The nociception genes painless and Piezo are required for the cellular immune response of Drosophila larvae to wasp parasitization.

PubMed

Tokusumi, Yumiko; Tokusumi, Tsuyoshi; Schulz, Robert A

2017-05-13

In vertebrates, interaction between the nervous system and immune system is important to protect a challenged host from stress inputs from external sources. In this study, we demonstrate that sensory neurons are involved in the cellular immune response elicited by wasp infestation of Drosophila larvae. Multidendritic class IV neurons sense contacts from external stimuli and induce avoidance behaviors for host defense. Our findings show that inactivation of these sensory neurons impairs the cellular response against wasp parasitization. We also demonstrate that the nociception genes encoding the mechanosensory receptors Painless and Piezo, both expressed in class IV neurons, are essential for the normal cellular immune response to parasite challenge. Copyright © 2017. Published by Elsevier Inc.

Lempel-Ziv complexity analysis of one dimensional cellular automata.

PubMed

Estevez-Rams, E; Lora-Serrano, R; Nunes, C A J; Aragón-Fernández, B

2015-12-01

Lempel-Ziv complexity measure has been used to estimate the entropy density of a string. It is defined as the number of factors in a production factorization of a string. In this contribution, we show that its use can be extended, by using the normalized information distance, to study the spatiotemporal evolution of random initial configurations under cellular automata rules. In particular, the transfer information from time consecutive configurations is studied, as well as the sensitivity to perturbed initial conditions. The behavior of the cellular automata rules can be grouped in different classes, but no single grouping captures the whole nature of the involved rules. The analysis carried out is particularly appropriate for studying the computational processing capabilities of cellular automata rules.

Phase transitions in coupled map lattices and in associated probabilistic cellular automata.

PubMed

Just, Wolfram

2006-10-01

Analytical tools are applied to investigate piecewise linear coupled map lattices in terms of probabilistic cellular automata. The so-called disorder condition of probabilistic cellular automata is closely related with attracting sets in coupled map lattices. The importance of this condition for the suppression of phase transitions is illustrated by spatially one-dimensional systems. Invariant densities and temporal correlations are calculated explicitly. Ising type phase transitions are found for one-dimensional coupled map lattices acting on repelling sets and for a spatially two-dimensional Miller-Huse-like system with stable long time dynamics. Critical exponents are calculated within a finite size scaling approach. The relevance of detailed balance of the resulting probabilistic cellular automaton for the critical behavior is pointed out.

Lempel-Ziv complexity analysis of one dimensional cellular automata

NASA Astrophysics Data System (ADS)

Estevez-Rams, E.; Lora-Serrano, R.; Nunes, C. A. J.; Aragón-Fernández, B.

2015-12-01

Lempel-Ziv complexity measure has been used to estimate the entropy density of a string. It is defined as the number of factors in a production factorization of a string. In this contribution, we show that its use can be extended, by using the normalized information distance, to study the spatiotemporal evolution of random initial configurations under cellular automata rules. In particular, the transfer information from time consecutive configurations is studied, as well as the sensitivity to perturbed initial conditions. The behavior of the cellular automata rules can be grouped in different classes, but no single grouping captures the whole nature of the involved rules. The analysis carried out is particularly appropriate for studying the computational processing capabilities of cellular automata rules.

Assessing the Molecular Genetics of the Development of Executive Attention in Children: Focus on Genetic Pathways Related to the Anterior Cingulate Cortex and Dopamine

PubMed Central

Brocki, Karin; Clerkin, Suzanne M.; Guise, Kevin G.; Fan, Jin; Fossella, John A.

2009-01-01

It is well-known that children show gradual and protracted improvement in an array of behaviors involved in the conscious control of thought and emotion. Non-invasive neuroimaging in developing populations has revealed many neural correlates of behavior, particularly in the developing cingulate cortex and fronto-striatal circuits. These brain regions, themselves, undergo protracted molecular and cellular change in the first two decades of human development and, as such, are ideal regions of interest for cognitive- and imaging-genetic studies that seek to link processes at the biochemical and synaptic levels to brain activity and behavior. We review our research to-date that employs both adult and child-friendly versions of the Attention Network Task (ANT) in an effort to begin to describe the role of specific genes in the assembly of a functional attention system. Presently, we constrain our predictions for genetic association studies by focusing on the role of the anterior cingulate cortex (ACC) and of dopamine in the development of executive attention. PMID:19344637

The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders

PubMed Central

Mosconi, Matthew W.; Wang, Zheng; Schmitt, Lauren M.; Tsai, Peter; Sweeney, John A.

2015-01-01

The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching, and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD. PMID:26388713

Collective interaction of microscale matters in natural analogy: human cancer cells vs. microspheres

NASA Astrophysics Data System (ADS)

Ahn, Sungsook; Lee, Sang Joon; Postech Team

2014-11-01

Collective behaviors have been considered both in living and lifeless things as a natural phenomenon. During the ordering process, a sudden and spontaneous transition is typically generated between an order and a disorder according to the population density of interacting elements. In a cellular level collective behavior, the cells are distributed in the characteristic patterns according to the population density and the mutual interaction of the individual cells undergo density-dependent diffusive motion. On the other hand, density-controlled surface-modified hollow microsphere suspension induces an overpopulation via buoyancy which provides a driving force to induce an assembly. The collective behaviors of the cells and microspheres in a designed liquid medium are explained in terms of the deviation from the interparticle distance distribution and the induced strength to organize the particle position in a specific distance range. as a result, microscale particulate matters exhibit high resemblance in their pair correlation and dynamical heterogeneity in the intermediate range between a single individual and an agglomerate. Therefore, it is suggested that biological systems are analogically explained to be dominated by physically interactive aspects.

Process-Structure-Property Relationships for 316L Stainless Steel Fabricated by Additive Manufacturing and Its Implication for Component Engineering

NASA Astrophysics Data System (ADS)

Yang, Nancy; Yee, J.; Zheng, B.; Gaiser, K.; Reynolds, T.; Clemon, L.; Lu, W. Y.; Schoenung, J. M.; Lavernia, E. J.

2017-04-01

We investigate the process-structure-property relationships for 316L stainless steel prototyping utilizing 3-D laser engineered net shaping (LENS), a commercial direct energy deposition additive manufacturing process. The study concluded that the resultant physical metallurgy of 3-D LENS 316L prototypes is dictated by the interactive metallurgical reactions, during instantaneous powder feeding/melting, molten metal flow and liquid metal solidification. The study also showed 3-D LENS manufacturing is capable of building high strength and ductile 316L prototypes due to its fine cellular spacing from fast solidification cooling, and the well-fused epitaxial interfaces at metal flow trails and interpass boundaries. However, without further LENS process control and optimization, the deposits are vulnerable to localized hardness variation attributed to heterogeneous microstructure, i.e., the interpass heat-affected zone (HAZ) from repetitive thermal heating during successive layer depositions. Most significantly, the current deposits exhibit anisotropic tensile behavior, i.e., lower strain and/or premature interpass delamination parallel to build direction (axial). This anisotropic behavior is attributed to the presence of interpass HAZ, which coexists with flying feedstock inclusions and porosity from incomplete molten metal fusion. The current observations and findings contribute to the scientific basis for future process control and optimization necessary for material property control and defect mitigation.

Extrinsic Embryonic Sensory Stimulation Alters Multimodal Behavior and Cellular Activation

PubMed Central

Markham, Rebecca G.; Shimizu, Toru; Lickliter, Robert

2009-01-01

Embryonic vision is generated and maintained by spontaneous neuronal activation patterns, yet extrinsic stimulation also sculpts sensory development. Because the sensory and motor systems are interconnected in embryogenesis, how extrinsic sensory activation guides multimodal differentiation is an important topic. Further, it is unknown whether extrinsic stimulation experienced near sensory sensitivity onset contributes to persistent brain changes, ultimately affecting postnatal behavior. To determine the effects of extrinsic stimulation on multimodal development, we delivered auditory stimulation to bobwhite quail groups during early, middle, or late embryogenesis, and then tested postnatal behavioral responsiveness to auditory or visual cues. Auditory preference tendencies were more consistently toward the conspecific stimulus for animals stimulated during late embryogenesis. Groups stimulated during middle or late embryogenesis showed altered postnatal species-typical visual responsiveness, demonstrating a persistent multimodal effect. We also examined whether auditory-related brain regions are receptive to extrinsic input during middle embryogenesis by measuring postnatal cellular activation. Stimulated birds showed a greater number of ZENK-immunopositive cells per unit volume of brain tissue in deep optic tectum, a midbrain region strongly implicated in multimodal function. We observed similar results in the medial and caudomedial nidopallia in the telencephalon. There were no ZENK differences between groups in inferior colliculus or in caudolateral nidopallium, avian analog to prefrontal cortex. To our knowledge, these are the first results linking extrinsic stimulation delivered so early in embryogenesis to changes in postnatal multimodal behavior and cellular activation. The potential role of competitive interactions between the sensory and motor systems is discussed. PMID:18777564

Cell-Based Therapeutics: The Next Pillar of Medicine

PubMed Central

Fischbach, Michael A.; Bluestone, Jeffrey A.; Lim, Wendell A.

2013-01-01

Two decades ago, the pharmaceutical industry—long dominated by small-molecule drugs—was revolutionized by the the advent of biologics. Today, biomedicine sits on the cusp of a new revolution: the use of microbial and human cells as versatile therapeutic engines. Here, we discuss the promise of this “third pillar” of therapeutics in the context of current scientific, regulatory, economic, and perceptual challenges. History suggests that the advent of cellular medicines will require the development of a foundational cellular engineering science that provides a systematic framework for safely and predictably altering and regulating cellular behaviors. PMID:23552369

Ultraminiaturized photovoltaic and radio frequency powered optoelectronic systems for wireless optogenetics.

PubMed

Park, Sung Il; Shin, Gunchul; Banks, Anthony; McCall, Jordan G; Siuda, Edward R; Schmidt, Martin J; Chung, Ha Uk; Noh, Kyung Nim; Mun, Jonathan Guo-Han; Rhodes, Justin; Bruchas, Michael R; Rogers, John A

2015-10-01

Wireless control and power harvesting systems that operate injectable, cellular-scale optoelectronic components provide important demonstrated capabilities in neuromodulatory techniques such as optogenetics. Here, we report a radio frequency (RF) control/harvesting device that offers dramatically reduced size, decreased weight and improved efficiency compared to previously reported technologies. Combined use of this platform with ultrathin, multijunction, high efficiency solar cells allows for hundred-fold reduction of transmitted RF power, which greatly enhances the wireless coverage. Fabrication involves separate construction of the harvester and the injectable µ-ILEDs. To test whether the presence of the implantable device alters behavior, we implanted one group of wild type mice and compared sociability behavior to unaltered controls. Social interaction experiments followed protocols defined by Silverman et al. with minor modifications. The results presented here demonstrate that miniaturized RF harvesters, and RF control strategies with photovoltaic harvesters can, when combined with injectable µ-ILEDs, offer versatile capabilities in optogenetics. Experimental and modeling studies establish a range of effective operating conditions for these two approaches. Optogenetics studies with social groups of mice demonstrate the utility of these systems. The addition of miniaturized, high performance photovoltaic cells significantly expands the operating range and reduces the required RF power. The platform can offer capabilities to modulate signaling path in the brain region of freely-behaving animals. These suggest its potential for widespread use in neuroscience.

Domain 4 (D4) of Perfringolysin O to Visualize Cholesterol in Cellular Membranes-The Update.

PubMed

Maekawa, Masashi

2017-03-03

The cellular membrane of eukaryotes consists of phospholipids, sphingolipids, cholesterol and membrane proteins. Among them, cholesterol is crucial for various cellular events (e.g., signaling, viral/bacterial infection, and membrane trafficking) in addition to its essential role as an ingredient of steroid hormones, vitamin D, and bile acids. From a micro-perspective, at the plasma membrane, recent emerging evidence strongly suggests the existence of lipid nanodomains formed with cholesterol and phospholipids (e.g., sphingomyelin, phosphatidylserine). Thus, it is important to elucidate how cholesterol behaves in membranes and how the behavior of cholesterol is regulated at the molecular level. To elucidate the complexed characteristics of cholesterol in cellular membranes, a couple of useful biosensors that enable us to visualize cholesterol in cellular membranes have been recently developed by utilizing domain 4 (D4) of Perfringolysin O (PFO, theta toxin), a cholesterol-binding toxin. This review highlights the current progress on development of novel cholesterol biosensors that uncover new insights of cholesterol in cellular membranes.

Massive cellular disruption occurs during early imbibition of Cuphea seeds containing crystallized triacylglycerols.

PubMed

Volk, Gayle M; Crane, Jennifer; Caspersen, Ann M; Hill, Lisa M; Gardner, Candice; Walters, Christina

2006-11-01

The transition from anhydrobiotic to hydrated state occurs during early imbibition of seeds and is lethal if lipid reserves in seeds are crystalline. Low temperatures crystallize lipids during seed storage. We examine the nature of cellular damage observed in seeds of Cuphea wrightii and C. lanceolata that differ in triacylglycerol composition and phase behavior. Intracellular structure, observed using transmission electron microscopy, is profoundly and irreversibly perturbed if seeds with crystalline triacylglycerols are imbibed briefly. A brief heat treatment that melts triacylglycerols before imbibition prevents the loss of cell integrity; however, residual effects of cold treatments in C. wrightii cells are reflected by the apparent coalescence of protein and oil bodies. The timing and temperature dependence of cellular changes suggest that damage arises via a physical mechanism, perhaps as a result of shifts in hydrophobic and hydrophilic interactions when triacylglycerols undergo phase changes. Stabilizers of oil body structure such as oleosins that rely on a balance of physical forces may become ineffective when triacylglycerols crystallize. Recent observations linking poor oil body stability and poor seed storage behavior are potentially explained by the phase behavior of the storage lipids. These findings directly impact the feasibility of preserving genetic resources from some tropical and subtropical species.

In search of the Golden Fleece: Unraveling principles of morphogenesis by studying the integrative biology of skin appendages

PubMed Central

Hughes, Michael W.; Wu, Ping; Jiang, Ting-Xin; Lin, Sung-Jan; Dong, Chen-Yuan; Li, Ang; Hsieh, Fon-Jou; Widelitz, Randall B.; Choung, Cheng Ming

2013-01-01

Summary The mythological story of the Golden Fleece symbolizes the magical regenerative power of skin appendages. Similar to the adventurous pursuit of the Golden Fleece by the multi-talented Argonauts, today we also need an integrated multi-disciplined approach to understand the cellular and molecular processes during development, regeneration and evolution of skin appendages. To this end, we have explored several aspects of skin appendage biology that contribute to the Turing activator / inhibitor model in feather pattern formation, the topo-biological arrangement of stem cells in organ shape determination, the macro-environmental regulation of stem cells in regenerative hair waves, and potential novel molecular pathways in the morphological evolution of feathers. Here we show our current integrative biology efforts to unravel the complex cellular behavior in patterning stem cells and the control of regional specificity in skin appendages. We use feather / scale tissue recombination to demonstrate the timing control of competence and inducibility. Feathers from different body regions are used to study skin regional specificity. Bioinformatic analyses of transcriptome microarrays show the potential involvement of candidate molecular pathways. We further show Hox genes exhibit some region specific expression patterns. To visualize real time events, we applied time-lapse movies, confocal microscopy and multiphoton microscopy to analyze the morphogenesis of cultured embryonic chicken skin explants. These modern imaging technologies reveal unexpectedly complex cellular flow and organization of extracellular matrix molecules in three dimensions. While these approaches are in preliminary stages, this perspective highlights the challenges we face and new integrative tools we will use. Future work will follow these leads to develop a systems biology view and understanding in the morphogenetic principles that govern the development and regeneration of ectodermal organs. PMID:21437328

Effects of antioxidant, OPC-14117, on secondary cellular damage and behavioral deficits following cortical contusion in the rat.

PubMed

Aoyama, Naoki; Katayama, Yoichi; Kawamata, Tatsuro; Maeda, Takeshi; Mori, Tatsuro; Yamamoto, Takamitsu; Kikuchi, Tetsuro; Uwahodo, Yasuhumi

2002-05-03

In the present study, we examined the effects of OPC-14117, a superoxide radical scavenger, on the secondary cellular damage and cognitive dysfunction occurring in a rat model of cerebral contusion induced by a controlled cortical impact (CCI). Histological examinations revealed that the contusion necrosis volume reached 13.6+/-5.3 mm(3) in non-treated animals and declined to 1.9+/-0.6 mm(3) in OPC-14117-treated animals (P<0.01). The cell number of the CA3 region was 120.0+/-12.4 cells/mm in the normal controls, 73.6+/-9.9 cells/mm in the non-treated animals, and 111.2+/-10.2 cells/mm in the OPC-14117-treated animals, indicating that CCI-induced selective neuronal cell death in the CA3 region was attenuated by the OPC-14117 administration (P<0.01). The tissue osmolality, as determined with a vapor pressure osmometer, was 314.5+/-15.4 mmol/kg in the normal brain and increased to 426.0+/-20.1 mmol/kg at 12 h following CCI. The increase in tissue osmolality was significantly attenuated by OPC-14117 administration (P<0.01). The OPC-14117 administration also attenuated the CCI-induced cognitive deficits. The OPC-14117-treated animals showed a tendency to improve on the Morris water maze performance test. The impairment of the habituation of exploratory activity elicited by CCI was significantly attenuated by OPC-14117 administration (P<0.05). In conclusion, OPC-14117 may have a potential for decreasing secondary cellular damage due to traumatic brain injury since it is as efficacious as any other compound tested in this model.

Engineering a light-activated caspase-3 for precise ablation of neurons in vivo.

PubMed

Smart, Ashley D; Pache, Roland A; Thomsen, Nathan D; Kortemme, Tanja; Davis, Graeme W; Wells, James A

2017-09-26

The circuitry of the brain is characterized by cell heterogeneity, sprawling cellular anatomy, and astonishingly complex patterns of connectivity. Determining how complex neural circuits control behavior is a major challenge that is often approached using surgical, chemical, or transgenic approaches to ablate neurons. However, all these approaches suffer from a lack of precise spatial and temporal control. This drawback would be overcome if cellular ablation could be controlled with light. Cells are naturally and cleanly ablated through apoptosis due to the terminal activation of caspases. Here, we describe the engineering of a light-activated human caspase-3 (Caspase-LOV) by exploiting its natural spring-loaded activation mechanism through rational insertion of the light-sensitive LOV2 domain that expands upon illumination. We apply the light-activated caspase (Caspase-LOV) to study neurodegeneration in larval and adult Drosophila Using the tissue-specific expression system (UAS)-GAL4, we express Caspase-LOV specifically in three neuronal cell types: retinal, sensory, and motor neurons. Illumination of whole flies or specific tissues containing Caspase-LOV-induced cell death and allowed us to follow the time course and sequence of neurodegenerative events. For example, we find that global synchronous activation of caspase-3 drives degeneration with a different time-course and extent in sensory versus motor neurons. We believe the Caspase-LOV tool we engineered will have many other uses for neurobiologists and others for specific temporal and spatial ablation of cells in complex organisms.

Engineering a light-activated caspase-3 for precise ablation of neurons in vivo

PubMed Central

Smart, Ashley D.; Pache, Roland A.; Thomsen, Nathan D.; Kortemme, Tanja; Davis, Graeme W.; Wells, James A.

2017-01-01

The circuitry of the brain is characterized by cell heterogeneity, sprawling cellular anatomy, and astonishingly complex patterns of connectivity. Determining how complex neural circuits control behavior is a major challenge that is often approached using surgical, chemical, or transgenic approaches to ablate neurons. However, all these approaches suffer from a lack of precise spatial and temporal control. This drawback would be overcome if cellular ablation could be controlled with light. Cells are naturally and cleanly ablated through apoptosis due to the terminal activation of caspases. Here, we describe the engineering of a light-activated human caspase-3 (Caspase-LOV) by exploiting its natural spring-loaded activation mechanism through rational insertion of the light-sensitive LOV2 domain that expands upon illumination. We apply the light-activated caspase (Caspase-LOV) to study neurodegeneration in larval and adult Drosophila. Using the tissue-specific expression system (UAS)-GAL4, we express Caspase-LOV specifically in three neuronal cell types: retinal, sensory, and motor neurons. Illumination of whole flies or specific tissues containing Caspase-LOV–induced cell death and allowed us to follow the time course and sequence of neurodegenerative events. For example, we find that global synchronous activation of caspase-3 drives degeneration with a different time-course and extent in sensory versus motor neurons. We believe the Caspase-LOV tool we engineered will have many other uses for neurobiologists and others for specific temporal and spatial ablation of cells in complex organisms. PMID:28893998

Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism?

PubMed

Whitaker-Azmitia, Patricia M

2005-02-01

The hypothesis explored in this review is that the high levels of serotonin in the blood seen in some autistic children (the so-called hyperserotonemia of autism) may lead to some of the behavioral and cellular changes also observed in the disorder. At early stages of development, when the blood-brain Barrier is not yet fully formed, the high levels of serotonin in the blood can enter the brain of a developing fetus and cause loss of serotonin terminals through a known negative feedback function of serotonin during development. The loss of serotonin innervation persists throughout subsequent development and the symptoms of autism appear. A review of the basic scientific literature on prenatal treatments affecting serotonin is given, in support of this hypothesis, with an emphasis on studies using the serotonin agonist, 5-methoxytryptamine (5-MT). In work using 5-MT to mimic hyperserotonemia, Sprague-Dawley rats are treated from gestational day 12 until postnatal 20. In published reports, these animals have been found to have a significant loss of serotonin terminals, decreased metabolic activity in cortex, changes in columnar development in cortex, changes in serotonin receptors, and "autistic-like" behaviors. In preliminary cellular findings given in this review, the animals have also been found to have cellular changes in two relevant brain regions: 1. Central nucleus of the amygdala, a brain region involved in fear-responding, where an increase in calcitonin gene related peptide (CGRP) was found 2. Paraventricular nucleus of the hypothalamus, a brain region involved in social memory and bonding, where a decrease in oxytocin was found. Both of these cellular changes could result from loss of serotonin innervation, possibly due to loss of terminal outgrowth from the same cells of the raphe nuclei. Thus, increased serotonergic activity during development could damage neurocircuitry involved in emotional responding to social stressors and may have relevance to the symptoms of autism.

Inter-Cellular Forces Orchestrate Contact Inhibition of Locomotion

PubMed Central

Davis, John R.; Luchici, Andrei; Mosis, Fuad; Thackery, James; Salazar, Jesus A.; Mao, Yanlan; Dunn, Graham A.; Betz, Timo; Miodownik, Mark; Stramer, Brian M.

2015-01-01

Summary Contact inhibition of locomotion (CIL) is a multifaceted process that causes many cell types to repel each other upon collision. During development, this seemingly uncoordinated reaction is a critical driver of cellular dispersion within embryonic tissues. Here, we show that Drosophila hemocytes require a precisely orchestrated CIL response for their developmental dispersal. Hemocyte collision and subsequent repulsion involves a stereotyped sequence of kinematic stages that are modulated by global changes in cytoskeletal dynamics. Tracking actin retrograde flow within hemocytes in vivo reveals synchronous reorganization of colliding actin networks through engagement of an inter-cellular adhesion. This inter-cellular actin-clutch leads to a subsequent build-up in lamellar tension, triggering the development of a transient stress fiber, which orchestrates cellular repulsion. Our findings reveal that the physical coupling of the flowing actin networks during CIL acts as a mechanotransducer, allowing cells to haptically sense each other and coordinate their behaviors. PMID:25799385

Derivation of large-scale cellular regulatory networks from biological time series data.

PubMed

de Bivort, Benjamin L

2010-01-01

Pharmacological agents and other perturbants of cellular homeostasis appear to nearly universally affect the activity of many genes, proteins, and signaling pathways. While this is due in part to nonspecificity of action of the drug or cellular stress, the large-scale self-regulatory behavior of the cell may also be responsible, as this typically means that when a cell switches states, dozens or hundreds of genes will respond in concert. If many genes act collectively in the cell during state transitions, rather than every gene acting independently, models of the cell can be created that are comprehensive of the action of all genes, using existing data, provided that the functional units in the model are collections of genes. Techniques to develop these large-scale cellular-level models are provided in detail, along with methods of analyzing them, and a brief summary of major conclusions about large-scale cellular networks to date.

β-Catenin activation regulates tissue growth non-cell autonomously in the hair stem cell niche.

PubMed

Deschene, Elizabeth R; Myung, Peggy; Rompolas, Panteleimon; Zito, Giovanni; Sun, Thomas Yang; Taketo, Makoto M; Saotome, Ichiko; Greco, Valentina

2014-03-21

Wnt/β-catenin signaling is critical for tissue regeneration. However, it is unclear how β-catenin controls stem cell behaviors to coordinate organized growth. Using live imaging, we show that activation of β-catenin specifically within mouse hair follicle stem cells generates new hair growth through oriented cell divisions and cellular displacement. β-Catenin activation is sufficient to induce hair growth independently of mesenchymal dermal papilla niche signals normally required for hair regeneration. Wild-type cells are co-opted into new hair growths by β-catenin mutant cells, which non-cell autonomously activate Wnt signaling within the neighboring wild-type cells via Wnt ligands. This study demonstrates a mechanism by which Wnt/β-catenin signaling controls stem cell-dependent tissue growth non-cell autonomously and advances our understanding of the mechanisms that drive coordinated regeneration.

AzoCholine Enables Optical Control of Alpha 7 Nicotinic Acetylcholine Receptors in Neural Networks.

PubMed

Damijonaitis, Arunas; Broichhagen, Johannes; Urushima, Tatsuya; Hüll, Katharina; Nagpal, Jatin; Laprell, Laura; Schönberger, Matthias; Woodmansee, David H; Rafiq, Amir; Sumser, Martin P; Kummer, Wolfgang; Gottschalk, Alexander; Trauner, Dirk

2015-05-20

Nicotinic acetylcholine receptors (nAChRs) are essential for cellular communication in higher organisms. Even though a vast pharmacological toolset to study cholinergic systems has been developed, control of endogenous neuronal nAChRs with high spatiotemporal precision has been lacking. To address this issue, we have generated photoswitchable nAChR agonists and re-evaluated the known photochromic ligand, BisQ. Using electrophysiology, we found that one of our new compounds, AzoCholine, is an excellent photoswitchable agonist for neuronal α7 nAChRs, whereas BisQ was confirmed to be an agonist for the muscle-type nAChR. AzoCholine could be used to modulate cholinergic activity in a brain slice and in dorsal root ganglion neurons. In addition, we demonstrate light-dependent perturbation of behavior in the nematode, Caenorhabditis elegans.

Cellular phone use and brain tumor: a meta-analysis.

PubMed

Kan, Peter; Simonsen, Sara E; Lyon, Joseph L; Kestle, John R W

2008-01-01

The dramatic increase in the use of cellular phones has generated concerns about potential adverse effects, especially the development of brain tumors. We conducted a meta-analysis to examine the effect of cellular phone use on the risk of brain tumor development. We searched the literature using MEDLINE to locate case-control studies on cellular phone use and brain tumors. Odds ratios (ORs) for overall effect and stratified ORs associated with specific brain tumors, long-term use, and analog/digital phones were calculated for each study using its original data. A pooled estimator of each OR was then calculated using a random-effects model. Nine case-control studies containing 5,259 cases of primary brain tumors and 12,074 controls were included. All studies reported ORs according to brain tumor subtypes, and five provided ORs on patients with > or =10 years of follow up. Pooled analysis showed an overall OR of 0.90 (95% confidence interval [CI] 0.81-0.99) for cellular phone use and brain tumor development. The pooled OR for long-term users of > or =10 years (5 studies) was 1.25 (95% CI 1.01-1.54). No increased risk was observed in analog or digital cellular phone users. We found no overall increased risk of brain tumors among cellular phone users. The potential elevated risk of brain tumors after long-term cellular phone use awaits confirmation by future studies.

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei.

PubMed

Prosser, Haydn M; Bradley, Allan; Chesham, Johanna E; Ebling, Francis J P; Hastings, Michael H; Maywood, Elizabeth S

2007-01-09

The suprachiasmatic nucleus (SCN), the brain's principal circadian pacemaker, coordinates adaptive daily cycles of behavior and physiology, including the rhythm of sleep and wakefulness. The cellular mechanism sustaining SCN circadian timing is well characterized, but the neurochemical pathways by which SCN neurons coordinate circadian behaviors remain unknown. SCN transplant studies suggest a role for (unidentified) secreted factors, and one potential candidate is the SCN neuropeptide prokineticin 2 (Prok2). Prok2 and its cognate prokineticin receptor 2 (Prokr2/Gpcr73l1) are widely expressed in both the SCN and its neural targets, and Prok2 is light-regulated. Hence, they may contribute to cellular timing within the SCN, entrainment of the clock, and/or they may mediate circadian output. We show that a targeted null mutation of Prokr2 disrupts circadian coordination of the activity cycle and thermoregulation. Specifically, mice lacking Prokr2 lost precision in timing the onset of nocturnal locomotor activity; and under both a light/dark cycle and continuous darkness, there was a pronounced temporal redistribution of activity away from early to late circadian night. Moreover, the coherence of circadian behavior was significantly reduced, and nocturnal body temperature was depressed. Entrainment by light is not, however, dependent on Prokr2, and bioluminescence real-time imaging of organotypical SCN slices showed that the mutant SCN is fully competent as a circadian oscillator. We conclude that Prokr2 is not necessary for SCN cellular timekeeping or entrainment, but it is an essential link for coordination of circadian behavior and physiology by the SCN, especially in defining the onset and maintenance of circadian night.

Control of fluxes in metabolic networks.

PubMed

Basler, Georg; Nikoloski, Zoran; Larhlimi, Abdelhalim; Barabási, Albert-László; Liu, Yang-Yu

2016-07-01

Understanding the control of large-scale metabolic networks is central to biology and medicine. However, existing approaches either require specifying a cellular objective or can only be used for small networks. We introduce new coupling types describing the relations between reaction activities, and develop an efficient computational framework, which does not require any cellular objective for systematic studies of large-scale metabolism. We identify the driver reactions facilitating control of 23 metabolic networks from all kingdoms of life. We find that unicellular organisms require a smaller degree of control than multicellular organisms. Driver reactions are under complex cellular regulation in Escherichia coli, indicating their preeminent role in facilitating cellular control. In human cancer cells, driver reactions play pivotal roles in malignancy and represent potential therapeutic targets. The developed framework helps us gain insights into regulatory principles of diseases and facilitates design of engineering strategies at the interface of gene regulation, signaling, and metabolism. © 2016 Basler et al.; Published by Cold Spring Harbor Laboratory Press.

Role of cellular oxalate in oxalate clearance of patients with calcium oxalate monohydrate stone formation and normal controls.

PubMed

Oehlschläger, Sven; Fuessel, Susanne; Meye, Axel; Herrmann, Jana; Froehner, Michael; Albrecht, Steffen; Wirth, Manfred P

2009-03-01

To examine the cellular, plasma, and urinary oxalate and erythrocyte oxalate flux in patients with calcium oxalate monohydrate (COM) stone formation vs normal controls. Pathologic oxalate clearance in humans is mostly integrated in calcium oxalate stone formation. An underlying cause of deficient oxalate clearance could be defective transmembrane oxalate transport, which, in many tissues, is regulated by an anion exchanger (SLC26). We studied 2 groups: 40 normal controls and 41 patients with COM stone formation. Red blood cells were divided for cellular oxalate measurement and for resuspension in a buffered solution (pH 7.40); 0.1 mmol/L oxalate was added. The supernatant was measured for oxalate immediately and 1 hour after incubation. The plasma and urinary oxalate were analyzed in parallel. The mean cellular oxalate concentrations were significantly greater in the normal controls (5.25 +/- 0.47 micromol/L) than in those with COM stone formation (2.36 +/- 0.28 micromol/L; P < .01). The mean urinary oxalate concentrations were significantly greater in those with COM stone formation (0.31 +/- 0.02 mmol/L) than in the controls (0.24 +/- 0.02 mmol/L; P < .01). The cellular oxalate concentrations correlated significantly with the plasma (r = 0.49-0.63; P < .01) and urinary oxalate (r = -0.29-0.41; P < .03) concentrations in both groups. The plasma oxalate concentrations correlated significantly with the urinary oxalate concentrations (r = -0.30; P < .03) in the controls and with the erythrocyte oxalate flux (r = 0.25; P < .05) in those with COM stone formation. Our data implicate the presence of a cellular oxalate buffer to stabilize plasma and urinary oxalate concentrations in normal controls.

A Cellular Automaton Framework for Infectious Disease Spread Simulation

PubMed Central

Pfeifer, Bernhard; Kugler, Karl; Tejada, Maria M; Baumgartner, Christian; Seger, Michael; Osl, Melanie; Netzer, Michael; Handler, Michael; Dander, Andreas; Wurz, Manfred; Graber, Armin; Tilg, Bernhard

2008-01-01

In this paper, a cellular automaton framework for processing the spatiotemporal spread of infectious diseases is presented. The developed environment simulates and visualizes how infectious diseases might spread, and hence provides a powerful instrument for health care organizations to generate disease prevention and contingency plans. In this study, the outbreak of an avian flu like virus was modeled in the state of Tyrol, and various scenarios such as quarantine, effect of different medications on viral spread and changes of social behavior were simulated. The proposed framework is implemented using the programming language Java. The set up of the simulation environment requires specification of the disease parameters and the geographical information using a population density colored map, enriched with demographic data. The results of the numerical simulations and the analysis of the computed parameters will be used to get a deeper understanding of how the disease spreading mechanisms work, and how to protect the population from contracting the disease. Strategies for optimization of medical treatment and vaccination regimens will also be investigated using our cellular automaton framework. In this study, six different scenarios were simulated. It showed that geographical barriers may help to slow down the spread of an infectious disease, however, when an aggressive and deadly communicable disease spreads, only quarantine and controlled medical treatment are able to stop the outbreak, if at all. PMID:19415136

Activation of Actuating Hydrogels with WS2 Nanosheets for Biomimetic Cellular Structures and Steerable Prompt Deformation.

PubMed

Zong, Lu; Li, Xiankai; Han, Xiangsheng; Lv, Lili; Li, Mingjie; You, Jun; Wu, Xiaochen; Li, Chaoxu

2017-09-20

Macroscopic soft actuation is intrinsic to living organisms in nature, including slow deformation (e.g., contraction, bending, twisting, and curling) of plants motivated by microscopic swelling and shrinking of cells, and rapid motion of animals (e.g., deformation of jellyfish) motivated by cooperative nanoscale movement of motor proteins. These actuation behaviors, with an exceptional combination of tunable speed and programmable deformation direction, inspire us to design artificial soft actuators for broad applications in artificial muscles, nanofabrication, chemical valves, microlenses, soft robotics, etc. However, so far artificial soft actuators have been typically produced on the basis of poly(N-isopropylacrylamide) (PNiPAM), whose deformation is motived by volumetric shrinkage and swelling in analogue to plant cells, and exhibits sluggish actuation kinetics. In this study, alginate-exfoliated WS 2 nanosheets were incorporated into ice-template-polymerized PNiPAM hydrogels with the cellular microstructures which mimic plant cells, yet the prompt steerable actuation of animals. Because of the nanosheet-reinforced pore walls formed in situ in freezing polymerization and reasonable hierarchical water channels, this cellular hybrid hydrogel achieves super deformation speed (on the order of magnitude of 10° s), controllable deformation direction, and high near-infrared light responsiveness, offering an unprecedented platform of artificial muscles for various soft robotics and devices (e.g., rotator, microvalve, aquatic swimmer, and water-lifting filter).

Collective Cellular Decision-Making Gives Developmental Plasticity: A Model of Signaling in Branching Roots

NASA Astrophysics Data System (ADS)

McCleery, W. Tyler; Mohd-Radzman, Nadiatul A.; Grieneisen, Veronica A.

Cells within tissues can be regarded as autonomous entities that respond to their local environment and signaling from neighbors. Cell coordination is particularly important in plants, where root architecture must strategically invest resources for growth to optimize nutrient acquisition. Thus, root cells are constantly adapting to environmental cues and neighbor communication in a non-linear manner. To explain such plasticity, we view the root as a swarm of coupled multi-cellular structures, ''metamers'', rather than as a continuum of identical cells. These metamers are individually programmed to achieve a local objective - developing a lateral root primordia, which aids in local foraging of nutrients. Collectively, such individual attempts may be halted, structuring root architecture as an emergent behavior. Each metamer's decision to branch is coordinated locally and globally through hormone signaling, including processes of controlled diffusion, active polar transport, and dynamic feedback. We present a physical model of the signaling mechanism that coordinates branching decisions in response to the environment. This work was funded by the European Commission 7th Framework Program, Project No. 601062, SWARM-ORGAN.

Phase change cellular automata modeling of GeTe, GaSb and SnSe stacked chalcogenide films

NASA Astrophysics Data System (ADS)

Mihai, C.; Velea, A.

2018-06-01

Data storage needs are increasing at a rapid pace across all economic sectors, so the need for new memory technologies with adequate capabilities is also high. Phase change memories (PCMs) are a leading contender in the emerging race for non-volatile memories due to their fast operation speed, high scalability, good reliability and low power consumption. However, in order to meet the present and future storage demands, PCM technologies must further increase the storage density. Here, we employ a probabilistic cellular automata approach to explore the multi-step threshold switching from the reset (off) to the set (on) state in chalcogenide stacked structures. Simulations have shown that in order to obtain multi-step switching with high contrast among different resistance states, the stacked structure needs to contain materials with a large difference among their crystallization temperatures and careful tuning of strata thicknesses. The crystallization dynamics can be controlled through the external energy pulses applied to the system, in such a way that a balance between nucleation and growth in phase change behavior can be achieved, optimized for PCMs.

microRNA and Autism.

PubMed

Anitha, Ayyappan; Thanseem, Ismail

2015-01-01

Autism is a complex neurodevelopmental disorder characterized by deficiencies in social interaction and communication, and by repetitive and stereotyped behaviors. According to a recent report, the prevalence of this pervasive developmental disorder has risen to 1 in 88. This will have enormous public health implications in the future, and has necessitated the need to discover predictive biomarkers that could index for autism before the onset of symptoms. microRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression at the posttranscriptional level. They have recently emerged as prominent epigenetic regulators of various cellular processes including neurodevelopment. They are abundantly present in the brain, and their dysfunction has been implicated in an array of neuropathological conditions including autism. miRNAs, previously known to be expressed only in cells and tissues, have also been detected in extracellular body fluids such as serum, plasma, saliva, and urine. Altered expression of cellular and circulating miRNAs have been observed in autistic individuals compared to healthy controls. miRNAs are now being considered as potential targets for the development of novel therapeutic strategies for autism.

Impact of time delay on the dynamics of SEIR epidemic model using cellular automata

NASA Astrophysics Data System (ADS)

Sharma, Natasha; Gupta, Arvind Kumar

2017-04-01

The delay of an infectious disease is significant when aiming to predict its strength and spreading patterns. In this paper the SEIR ​(susceptible-exposed-infected-recovered) epidemic spread with time delay is analyzed through a two-dimensional cellular automata model. The time delay corresponding to the infectious span, predominantly, includes death during the latency period in due course of infection. The advancement of whole system is described by SEIR transition function complemented with crucial factors like inhomogeneous population distribution, birth and disease independent mortality. Moreover, to reflect more realistic population dynamics some stochastic parameters like population movement and connections at local level are also considered. The existence and stability of disease free equilibrium is investigated. Two prime behavioral patterns of disease dynamics is found depending on delay. The critical value of delay, beyond which there are notable variations in spread patterns, is computed. The influence of important parameters affecting the disease dynamics on basic reproduction number is also examined. The results obtained show that delay plays an affirmative role to control disease progression in an infected host.

Manufacturing and Characterization of 18Ni Marage 300 Lattice Components by Selective Laser Melting.

PubMed

Contuzzi, Nicola; Campanelli, Sabina L; Casavola, Caterina; Lamberti, Luciano

2013-08-13

The spreading use of cellular structures brings the need to speed up manufacturing processes without deteriorating mechanical properties. By using Selective Laser Melting (SLM) to produce cellular structures, the designer has total freedom in defining part geometry and manufacturing is simplified. The paper investigates the suitability of Selective Laser Melting for manufacturing steel cellular lattice structures with characteristic dimensions in the micrometer range. Alternative lattice topologies including reinforcing bars in the vertical direction also are considered. The selected lattice structure topology is shown to be superior over other lattice structure designs considered in literature. Compression tests are carried out in order to evaluate mechanical strength of lattice strut specimens made via SLM. Compressive behavior of samples also is simulated by finite element analysis and numerical results are compared with experimental data in order to assess the constitutive behavior of the lattice structure designs considered in this study. Experimental data show that it is possible to build samples of relative density in the 0.2456-0.4367 range. Compressive strength changes almost linearly with respect to relative density, which in turns depends linearly on the number of vertical reinforces. Specific strength increases with cell and strut edge size. Numerical simulations confirm the plastic nature of the instability phenomena that leads the cellular structures to collapse under compression loading.

Altered cellular and humoral immunity to varicella-zoster virus in patients with autoimmune diseases.

PubMed

Rondaan, Christien; de Haan, Aalzen; Horst, Gerda; Hempel, J Cordelia; van Leer, Coretta; Bos, Nicolaas A; van Assen, Sander; Bijl, Marc; Westra, Johanna

2014-11-01

Patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and granulomatosis with polyangiitis (Wegener's) (GPA) have a 3-20-fold increased risk of herpes zoster compared to the general population. The aim of this study was to evaluate if susceptibility is due to decreased levels of cellular and/or humoral immunity to the varicella-zoster virus (VZV). A cross-sectional study of VZV-specific immunity was performed in 38 SLE patients, 33 GPA patients, and 51 healthy controls. Levels of IgG and IgM antibodies to VZV were measured using an in-house glycoprotein enzyme-linked immunosorbent assay (ELISA). Cellular responses to VZV were determined by interferon-γ (IFNγ) enzyme-linked immunospot (ELISpot) assay and carboxyfluorescein succinimidyl ester (CFSE) dye dilution proliferation assay. Levels of IgG antibodies to VZV were increased in SLE patients as compared to healthy controls, but levels of IgM antibodies to VZV were not. Antibody levels in GPA patients did not differ significantly from levels in healthy controls. In response to stimulation with VZV, decreased numbers of IFNγ spot-forming cells were found among SLE patients (although not GPA patients) as compared to healthy controls. Proliferation of CD4+ T cells in response to stimulation with VZV was decreased in SLE patients but not GPA patients. SLE patients have increased levels of IgG antibodies against VZV, while cellular immunity is decreased. In GPA patients, antibody levels as well as cellular responses to VZV were comparable to those in healthy controls. These data suggest that increased prevalence of herpes zoster in SLE patients is due to a poor cellular response. Vaccination strategies should aim to boost cellular immunity against VZV. Copyright © 2014 by the American College of Rheumatology.

Cellular and nerve regeneration within a biosynthetic extracellular matrix for corneal transplantation

NASA Astrophysics Data System (ADS)

Li, Fengfu; Carlsson, David; Lohmann, Chris; Suuronen, Erik; Vascotto, Sandy; Kobuch, Karin; Sheardown, Heather; Munger, Rejean; Nakamura, Masatsugu; Griffith, May

2003-12-01

Our objective was to determine whether key properties of extracellular matrix (ECM) macromolecules can be replicated within tissue-engineered biosynthetic matrices to influence cellular properties and behavior. To achieve this, hydrated collagen and N-isopropylacrylamide copolymer-based ECMs were fabricated and tested on a corneal model. The structural and immunological simplicity of the cornea and importance of its extensive innervation for optimal functioning makes it an ideal test model. In addition, corneal failure is a clinically significant problem. Matrices were therefore designed to have the optical clarity and the proper dimensions, curvature, and biomechanical properties for use as corneal tissue replacements in transplantation. In vitro studies demonstrated that grafting of the laminin adhesion pentapeptide motif, YIGSR, to the hydrogels promoted epithelial stratification and neurite in-growth. Implants into pigs' corneas demonstrated successful in vivo regeneration of host corneal epithelium, stroma, and nerves. In particular, functional nerves were observed to rapidly regenerate in implants. By comparison, nerve regeneration in allograft controls was too slow to be observed during the experimental period, consistent with the behavior of human cornea transplants. Other corneal substitutes have been produced and tested, but here we report an implantable matrix that performs as a physiologically functional tissue substitute and not simply as a prosthetic device. These biosynthetic ECM replacements should have applicability to many areas of tissue engineering and regenerative medicine, especially where nerve function is required. regenerative medicine | tissue engineering | cornea | implantation | innervation

Effects of prepartum ingestion of Ipomoea carnea on postpartum maternal and neonate behavior in goats

USDA-ARS?s Scientific Manuscript database

Ipomoea carnea (I. carnea) is a toxic plant that grows in tropical areas, and is readily consumed by grazing goats. The plant contains the alkaloids swainsonine and calystegines, which inhibit cellular enzymes and cause systematic cell death. This study evaluated the behavioral effects on dams and k...

Cellular mechanisms underlying behavioral state-dependent bidirectional modulation of motor cortex output.

PubMed

Schiemann, Julia; Puggioni, Paolo; Dacre, Joshua; Pelko, Miha; Domanski, Aleksander; van Rossum, Mark C W; Duguid, Ian

2015-05-26

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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Visualization of cortical, subcortical, and deep brain neural circuit dynamics during naturalistic mammalian behavior with head-mounted microscopes and chronically implanted lenses

PubMed Central

Resendez, Shanna L.; Jennings, Josh H.; Ung, Randall L.; Namboodiri, Vijay Mohan K.; Zhou, Zhe Charles; Otis, James M.; Nomura, Hiroshi; McHenry, Jenna A.; Kosyk, Oksana; Stuber, Garret D.

2016-01-01

Genetically encoded calcium indicators for visualizing dynamic cellular activity have greatly expanded our understanding of the brain. However, due to light scattering properties of the brain as well as the size and rigidity of traditional imaging technology, in vivo calcium imaging has been limited to superficial brain structures during head fixed behavioral tasks. This limitation can now be circumvented by utilizing miniature, integrated microscopes in conjunction with an implantable microendoscopic lens to guide light into and out of the brain, thus permitting optical access to deep brain (or superficial) neural ensembles during naturalistic behaviors. Here, we describe procedural steps to conduct such imaging studies using mice. However, we anticipate the protocol can be easily adapted for use in other small vertebrates. Successful completion of this protocol will permit cellular imaging of neuronal activity and the generation of data sets with sufficient statistical power to correlate neural activity with stimulus presentation, physiological state, and other aspects of complex behavioral tasks. This protocol takes 6–11 weeks to complete. PMID:26914316

Neurobiological Mechanisms for the Regulation of Mammalian Sleep-Wake Behavior: Reinterpretation of Historical Evidence and Inclusion of Contemporary Cellular and Molecular Evidence

PubMed Central

Datta, Subimal; MacLean, Robert Ross

2007-01-01

At its most basic level, the function of mammalian sleep can be described as a restorative process of the brain and body; recently, however, progressive research has revealed a host of vital functions to which sleep is essential. Although many excellent reviews on sleep behavior have been published, none have incorporated contemporary studies examining the molecular mechanisms that govern the various stages of sleep. Utilizing a holistic approach, this review is focused on the basic mechanisms involved in the transition from wakefulness, initiation of sleep and the subsequent generation of slow-wave sleep and rapid eye movement (REM) sleep. Additionally, using recent molecular studies and experimental evidence that provides a direct link to sleep as a behavior, we have developed a new model, the Cellular-Molecular-Network model, explaining the mechanisms responsible for regulating REM sleep. By analyzing the fundamental neurobiological mechanisms responsible for the generation and maintenance of sleep-wake behavior in mammals, we intend to provide a broader understanding of our present knowledge in the field of sleep research. PMID:17445891

Watching cellular machinery in action, one molecule at a time.

PubMed

Monachino, Enrico; Spenkelink, Lisanne M; van Oijen, Antoine M

2017-01-02

Single-molecule manipulation and imaging techniques have become important elements of the biologist's toolkit to gain mechanistic insights into cellular processes. By removing ensemble averaging, single-molecule methods provide unique access to the dynamic behavior of biomolecules. Recently, the use of these approaches has expanded to the study of complex multiprotein systems and has enabled detailed characterization of the behavior of individual molecules inside living cells. In this review, we provide an overview of the various force- and fluorescence-based single-molecule methods with applications both in vitro and in vivo, highlighting these advances by describing their applications in studies on cytoskeletal motors and DNA replication. We also discuss how single-molecule approaches have increased our understanding of the dynamic behavior of complex multiprotein systems. These methods have shown that the behavior of multicomponent protein complexes is highly stochastic and less linear and deterministic than previously thought. Further development of single-molecule tools will help to elucidate the molecular dynamics of these complex systems both inside the cell and in solutions with purified components. © 2017 Monachino et al.

Adsorption of enamel matrix proteins to a bovine-derived bone grafting material and its regulation of cell adhesion, proliferation, and differentiation.

PubMed

Miron, Richard J; Bosshardt, Dieter D; Hedbom, Erik; Zhang, Yufeng; Haenni, Beat; Buser, Daniel; Sculean, Anton

2012-07-01

The use of various combinations of enamel matrix derivative (EMD) and grafting materials has been shown to promote periodontal wound healing/regeneration. However, the downstream cellular behavior of periodontal ligament (PDL) cells and osteoblasts has not yet been studied. Furthermore, it is unknown to what extent the bleeding during regenerative surgery may influence the adsorption of exogenous proteins to the surface of bone grafting materials and the subsequent cellular behavior. In the present study, the aim is to test EMD adsorption to the surface of natural bone mineral (NBM) particles in the presence of blood and determine the effect of EMD coating to NBM particles on downstream cellular pathways, such as adhesion, proliferation, and differentiation of primary human osteoblasts and PDL cells. NBM particles were precoated in various settings with EMD or human blood and analyzed for protein adsorption patterns via fluorescent imaging and high-resolution immunocytochemistry with an anti-EMD antibody. Cell attachment and cell proliferation were quantified using fluorescent double-stranded DNA-binding dye. Cell differentiation was analyzed using real-time polymerase chain reaction for genes encoding runt-related transcription factor 2, alkaline phosphatase (ALP), osteocalcin (OC), and collagen1α1 (COL1A1), and mineralization was assessed using red dye staining. Analysis of cell attachment and cell proliferation revealed significantly higher osteoblast and PDL cell attachment on EMD-coated surfaces when compared with control and blood-coated surfaces. EMD also stimulated release of growth factors and cytokines, including bone morphogenetic protein 2 and transforming growth factor β1. Moreover, there were significantly higher mRNA levels of osteoblast differentiation markers, including COL1A1, ALP, and OC, in osteoblasts and PDL cells cultured on EMD-coated NBM particles. The present results suggest that 1) EMD enhances osteoblast and PDL cell attachment, proliferation, and differentiation on NBM particles, and 2) blood contamination of the grafting material before mixing with EMD may inhibit EMD adsorption.

Intracellular redox status controls membrane localization of pro- and anti-migratory signaling molecules.

PubMed

Hempel, Nadine; Melendez, J Andres

2014-01-01

Shifts in intracellular Reactive Oxygen Species (ROS) have been shown to contribute to carcinogenesis and to tumor progression. In addition to DNA and cell damage by surges in ROS, sub-lethal increases in ROS are implicated in regulating cellular signaling that enhances pro-metastatic behavior. We previously showed that subtle increases in endogenous H2O2 regulate migratory and invasive behavior of metastatic bladder cancer cells through phosphatase inhibition and consequential phosphorylation of p130cas, an adapter of the FAK signaling pathway. We further showed that enhanced redox status contributed to enhanced localization of p130cas to the membrane of metastatic cells. Here we show that this signaling complex can similarly be induced in a redox-engineered cell culture model that enables regulation of intracellular steady state H2O2 level by enforced expression of superoxide dismutase 2 (Sod2) and catalase. Expression of Sod2 leads to enhanced p130cas phosphorylation in HT-1080 fibrosarcoma and UM-UC-6 bladder cancer cells. These changes are mediated by H2O2, as co-expression of Catalase abrogates p130cas phosphorylation and its interaction with the adapter protein Crk. Importantly, we establish that the redox environment influence the localization of the tumor suppressor and phosphatase PTEN, in both redox-engineered and metastatic bladder cancer cells that display endogenous increases in H2O2. Importantly, PTEN oxidation leads to its dissociation from the plasma membrane. This indicates that oxidation of PTEN not only influences its activity, but also regulates its cellular localization, effectively removing it from its primary site of lipid phosphatase activity. These data introduce hitherto unappreciated paradigms whereby ROS can reciprocally regulate the cellular localization of pro- and anti-migratory signaling molecules, p130cas and PTEN, respectively. These data further confirm that altering antioxidant status and the intracellular ROS environment can have profound effects on pro-metastatic signaling pathways.

The use of mobile apps to improve nutrition outcomes: A systematic literature review.

PubMed

DiFilippo, Kristen N; Huang, Wen-Hao; Andrade, Juan E; Chapman-Novakofski, Karen M

2015-07-01

We conducted a systematic review to determine if the use of nutrition apps resulted in improved outcomes, including knowledge and behavior, among healthy adults. Using app(s), cellular phone, iPads, mobile phone, mobile telephone, smart phone, mobile and mHealth as search terms with diet, food and nutrition as qualifiers we searched PubMed, CINAHL (January 2008-October 2013) and Web of Science (January 2008-January 2014). Inclusion criteria were peer-reviewed randomized controlled trials, non-controlled trials, and cohort studies published in English that used apps to increase nutrition knowledge or improve behavior related to nutrition. Studies that were descriptive, did not include apps, focused on app development, app satisfaction app feasibility, text messaging, or digital photography were excluded. We evaluated article quality using the Academy of Nutrition and Dietetics Evidence Analysis Manual. Data was extracted for knowledge, behavior and weight change. Our initial search identified 12,010 titles from PubMed, 260 from CINAHL and 4762 from Web of Science; of these, only four articles met all search criteria. Positive quality ratings were given to three articles; only one reported knowledge outcomes (non-significant). All four articles evaluated weight loss and suggested an advantage to using nutrition apps. Behavioral changes in reviewed studies included increased adherence to diet monitoring (p < 0.001) and decreased effort to continue diet without app (p = 0.024). Few studies, however, have explored the use of nutrition apps as supportive educational interventions. Most apps focus on weight loss with inconsistent outcomes. We conclude that using apps for education needs additional research which includes behavior theory within the app and improved study design. © The Author(s) 2015.

Using cell deformation and motion to predict forces and collective behavior in morphogenesis.

PubMed

Merkel, Matthias; Manning, M Lisa

2017-07-01

In multi-cellular organisms, morphogenesis translates processes at the cellular scale into tissue deformation at the scale of organs and organisms. To understand how biochemical signaling regulates tissue form and function, we must understand the mechanical forces that shape cells and tissues. Recent progress in developing mechanical models for tissues has led to quantitative predictions for how cell shape changes and polarized cell motility generate forces and collective behavior on the tissue scale. In particular, much insight has been gained by thinking about biological tissues as physical materials composed of cells. Here we review these advances and discuss how they might help shape future experiments in developmental biology. Copyright © 2016 Elsevier Ltd. All rights reserved.

Characterizing emergent properties of immunological systems with multi-cellular rule-based computational modeling.

PubMed

Chavali, Arvind K; Gianchandani, Erwin P; Tung, Kenneth S; Lawrence, Michael B; Peirce, Shayn M; Papin, Jason A

2008-12-01

The immune system is comprised of numerous components that interact with one another to give rise to phenotypic behaviors that are sometimes unexpected. Agent-based modeling (ABM) and cellular automata (CA) belong to a class of discrete mathematical approaches in which autonomous entities detect local information and act over time according to logical rules. The power of this approach lies in the emergence of behavior that arises from interactions between agents, which would otherwise be impossible to know a priori. Recent work exploring the immune system with ABM and CA has revealed novel insights into immunological processes. Here, we summarize these applications to immunology and, particularly, how ABM can help formulate hypotheses that might drive further experimental investigations of disease mechanisms.

Spatial Dynamics of Multilayer Cellular Neural Networks

NASA Astrophysics Data System (ADS)

Wu, Shi-Liang; Hsu, Cheng-Hsiung

2018-02-01

The purpose of this work is to study the spatial dynamics of one-dimensional multilayer cellular neural networks. We first establish the existence of rightward and leftward spreading speeds of the model. Then we show that the spreading speeds coincide with the minimum wave speeds of the traveling wave fronts in the right and left directions. Moreover, we obtain the asymptotic behavior of the traveling wave fronts when the wave speeds are positive and greater than the spreading speeds. According to the asymptotic behavior and using various kinds of comparison theorems, some front-like entire solutions are constructed by combining the rightward and leftward traveling wave fronts with different speeds and a spatially homogeneous solution of the model. Finally, various qualitative features of such entire solutions are investigated.

Cellular-based modeling of oscillatory dynamics in brain networks.

PubMed

Skinner, Frances K

2012-08-01

Oscillatory, population activities have long been known to occur in our brains during different behavioral states. We know that many different cell types exist and that they contribute in distinct ways to the generation of these activities. I review recent papers that involve cellular-based models of brain networks, most of which include theta, gamma and sharp wave-ripple activities. To help organize the modeling work, I present it from a perspective of three different types of cellular-based modeling: 'Generic', 'Biophysical' and 'Linking'. Cellular-based modeling is taken to encompass the four features of experiment, model development, theory/analyses, and model usage/computation. The three modeling types are shown to include these features and interactions in different ways. Copyright © 2012 Elsevier Ltd. All rights reserved.

Intracellular Localization and Cellular Factors Interaction of HTLV-1 and HTLV-2 Tax Proteins: Similarities and Functional Differences

PubMed Central

Bertazzoni, Umberto; Turci, Marco; Avesani, Francesca; Di Gennaro, Gianfranco; Bidoia, Carlo; Romanelli, Maria Grazia

2011-01-01

Human T-lymphotropic viruses type 1 (HTLV-1) and type 2 (HTLV-2) present very similar genomic structures but HTLV-1 is more pathogenic than HTLV-2. Is this difference due to their transactivating Tax proteins, Tax-1 and Tax-2, which are responsible for viral and cellular gene activation? Do Tax-1 and Tax-2 differ in their cellular localization and in their interaction pattern with cellular factors? In this review, we summarize Tax-1 and Tax-2 structural and phenotypic properties, their interaction with factors involved in signal transduction and their localization-related behavior within the cell. Special attention will be given to the distinctions between Tax-1 and Tax-2 that likely play an important role in their transactivation activity. PMID:21994745

From cells to tissue: A continuum model of epithelial mechanics

NASA Astrophysics Data System (ADS)

Ishihara, Shuji; Marcq, Philippe; Sugimura, Kaoru

2017-08-01

A two-dimensional continuum model of epithelial tissue mechanics was formulated using cellular-level mechanical ingredients and cell morphogenetic processes, including cellular shape changes and cellular rearrangements. This model incorporates stress and deformation tensors, which can be compared with experimental data. Focusing on the interplay between cell shape changes and cell rearrangements, we elucidated dynamical behavior underlying passive relaxation, active contraction-elongation, and tissue shear flow, including a mechanism for contraction-elongation, whereby tissue flows perpendicularly to the axis of cell elongation. This study provides an integrated scheme for the understanding of the orchestration of morphogenetic processes in individual cells to achieve epithelial tissue morphogenesis.

A Multi-Paradigm Modeling Framework to Simulate Dynamic Reciprocity in a Bioreactor

PubMed Central

Kaul, Himanshu; Cui, Zhanfeng; Ventikos, Yiannis

2013-01-01

Despite numerous technology advances, bioreactors are still mostly utilized as functional black-boxes where trial and error eventually leads to the desirable cellular outcome. Investigators have applied various computational approaches to understand the impact the internal dynamics of such devices has on overall cell growth, but such models cannot provide a comprehensive perspective regarding the system dynamics, due to limitations inherent to the underlying approaches. In this study, a novel multi-paradigm modeling platform capable of simulating the dynamic bidirectional relationship between cells and their microenvironment is presented. Designing the modeling platform entailed combining and coupling fully an agent-based modeling platform with a transport phenomena computational modeling framework. To demonstrate capability, the platform was used to study the impact of bioreactor parameters on the overall cell population behavior and vice versa. In order to achieve this, virtual bioreactors were constructed and seeded. The virtual cells, guided by a set of rules involving the simulated mass transport inside the bioreactor, as well as cell-related probabilistic parameters, were capable of displaying an array of behaviors such as proliferation, migration, chemotaxis and apoptosis. In this way the platform was shown to capture not only the impact of bioreactor transport processes on cellular behavior but also the influence that cellular activity wields on that very same local mass transport, thereby influencing overall cell growth. The platform was validated by simulating cellular chemotaxis in a virtual direct visualization chamber and comparing the simulation with its experimental analogue. The results presented in this paper are in agreement with published models of similar flavor. The modeling platform can be used as a concept selection tool to optimize bioreactor design specifications. PMID:23555740

Diurnal Regulation of Cellular Processes in the Cyanobacterium Synechocystis sp. Strain PCC 6803: Insights from Transcriptomic, Fluxomic, and Physiological Analyses

PubMed Central

Saha, Rajib; Liu, Deng; Hoynes-O’Connor, Allison; Liberton, Michelle; Yu, Jingjie; Bhattacharyya-Pakrasi, Maitrayee; Balassy, Andrea; Zhang, Fuzhong; Maranas, Costas D.

2016-01-01

ABSTRACT Synechocystis sp. strain PCC 6803 is the most widely studied model cyanobacterium, with a well-developed omics level knowledgebase. Like the lifestyles of other cyanobacteria, that of Synechocystis PCC 6803 is tuned to diurnal changes in light intensity. In this study, we analyzed the expression patterns of all of the genes of this cyanobacterium over two consecutive diurnal periods. Using stringent criteria, we determined that the transcript levels of nearly 40% of the genes in Synechocystis PCC 6803 show robust diurnal oscillating behavior, with a majority of the transcripts being upregulated during the early light period. Such transcripts corresponded to a wide array of cellular processes, such as light harvesting, photosynthetic light and dark reactions, and central carbon metabolism. In contrast, transcripts of membrane transporters for transition metals involved in the photosynthetic electron transport chain (e.g., iron, manganese, and copper) were significantly upregulated during the late dark period. Thus, the pattern of global gene expression led to the development of two distinct transcriptional networks of coregulated oscillatory genes. These networks help describe how Synechocystis PCC 6803 regulates its metabolism toward the end of the dark period in anticipation of efficient photosynthesis during the early light period. Furthermore, in silico flux prediction of important cellular processes and experimental measurements of cellular ATP, NADP(H), and glycogen levels showed how this diurnal behavior influences its metabolic characteristics. In particular, NADPH/NADP+ showed a strong correlation with the majority of the genes whose expression peaks in the light. We conclude that this ratio is a key endogenous determinant of the diurnal behavior of this cyanobacterium. PMID:27143387

Biomimetic engineering of a generic cell-on-membrane architecture by microfluidic engraving for on-chip bioassays.

PubMed

Lee, Sang-Wook; Noh, Ji-Yoon; Park, Seung Chul; Chung, Jin-Ho; Lee, Byoungho; Lee, Sin-Doo

2012-05-22

We develop a biomimetic cell-on-membrane architecture in close-volume format which allows the interfacial biocompatibility and the reagent delivery capability for on-chip bioassays. The key concept lies in the microfluidic engraving of lipid membranes together with biological cells on a supported substrate with topographic patterns. The simultaneous engraving process of a different class of fluids is promoted by the front propagation of an air-water interface inside a flow-cell. This highly parallel, microfluidic cell-on-membrane approach opens a door to the natural biocompatibility in mimicking cellular stimuli-response behavior essential for diverse on-chip bioassays that can be precisely controlled in the spatial and temporal manner.

OPTOGENETICS, SEX AND VIOLENCE IN THE BRAIN: IMPLICATIONS FOR PSYCHIATRY

PubMed Central

Anderson, David J.

2012-01-01

Pathological aggression, and the inability to control aggressive impulses, takes a tremendous toll on society. Yet aggression is a normal component of the innate behavior repertoire of most vertebrate animal species, as well as of many invertebrates. Progress in understanding the etiology of disorders of aggressive behavior, whether genetic or environmental in nature, therefore requires an understanding of the brain circuitry that controls normal aggression. Efforts to understand this circuitry at the level of specific neuronal populations have been constrained by the limited resolution of classical methodologies, such as electrical stimulation and electrolytic lesion. The availability of new, genetically based tools for mapping and manipulating neural circuits at the level of specific, genetically defined neuronal subtypes provides an opportunity to investigate the functional organization of aggression circuitry with cellular resolution. However these technologies are optimally applied in the mouse, where there has been surprisingly little traditional work on the functional neuroanatomy of aggression. Here we discuss recent, initial efforts to apply optogenetics and other state-of-the-art methods to the dissection of aggression circuitry in the mouse. We find, surprisingly, that neurons necessary and sufficient for inter-male aggression are located within the ventrolateral subdivision of the ventromedial hypothalamic nucleus (VMHvl), a structure traditionally associated with reproductive behavior. These neurons are intermingled with neurons activated during male-female mating, with ~20% overlap between the populations. We discuss the significance of these findings with respect to neuroethological and neuroanatomical perspectives on the functional organization of innate behaviors, and their potential implications for psychiatry. PMID:22209636

Binge alcohol drinking elicits persistent negative affect in mice.

PubMed

Lee, Kaziya M; Coehlo, Michal; McGregor, Hadley A; Waltermire, Ryan S; Szumlinski, Karen K

2015-09-15

Cessation from chronic alcohol abuse often produces a dysphoric state that can persist into protracted withdrawal. This dysphoric state is theorized to function as a negative reinforcer that maintains excessive alcohol consumption and/or precipitates relapse in those struggling to abstain from alcohol. However, we know relatively little regarding the impact of cessation from binge drinking on behavioral measures of negative affect and related neurobiology. Male C57BL/6J mice were given access to unsweetened 20% alcohol for 6 weeks under modified Drinking-in-the-dark procedures, followed by behavioral testing beginning either 1 or 21 days into withdrawal. Mice were administered a behavioral test battery consisting of: the elevated plus maze, light/dark box, novel object test, marble burying test, Porsolt forced swim test and sucrose preference test to assess anxiogenic and depressive signs. Egr1 immunostaining was used to quantify cellular activity within the central nucleus of the amygdala (CEA), basolateral amygdala (BLA), bed nucleus of the stria terminalis (BNST), and the nucleus accumbens (Acb) shell (AcbSh) and core (AcbC). Compared to water controls, alcohol-drinking mice exhibited higher indices of emotionality in the majority of behavioral assays. The hyper-emotionality exhibited by binge drinking mice was apparent at both withdrawal time-points and correlated with higher Egr1+ cell counts in the CEA and BNST, compared to controls. These data show that affective symptoms emerge very early after cessation of binge drinking and persist into protracted withdrawal. A history of binge drinking is capable of producing enduring neuroadaptations within brain circuits mediating emotional arousal. Copyright © 2015 Elsevier B.V. All rights reserved.

MicroRNA-133 Inhibits Behavioral Aggregation by Controlling Dopamine Synthesis in Locusts

PubMed Central

Wang, Yanli; Guo, Xiaojiao; He, Jing; Kang, Le

2014-01-01

Phenotypic plasticity is ubiquitous and primarily controlled by interactions between environmental and genetic factors. The migratory locust, a worldwide pest, exhibits pronounced phenotypic plasticity, which is a population density-dependent transition that occurs between the gregarious and solitary phases. Genes involved in dopamine synthesis have been shown to regulate the phase transition of locusts. However, the function of microRNAs in this process remains unknown. In this study, we report the participation of miR-133 in dopamine production and the behavioral transition by negatively regulating two critical genes, henna and pale, in the dopamine pathway. miR-133 participated in the post-transcriptional regulation of henna and pale by binding to their coding region and 3′ untranslated region, respectively. miR-133 displayed cellular co-localization with henna/pale in the protocerebrum, and its expression in the protocerebrum was negatively correlated with henna and pale expression. Moreover, miR-133 agomir delivery suppressed henna and pale expression, which consequently decreased dopamine production, thus resulting in the behavioral shift of the locusts from the gregarious phase to the solitary phase. Increasing the dopamine content could rescue the solitary phenotype, which was induced by miR-133 agomir delivery. Conversely, miR-133 inhibition increased the expression of henna and pale, resulting in the gregarious-like behavior of solitary locusts; this gregarious phenotype could be rescued by RNA interference of henna and pale. This study shows the novel function and modulation pattern of a miRNA in phenotypic plasticity and provides insight into the underlying molecular mechanisms of the phase transition of locusts. PMID:24586212

MicroRNA-133 inhibits behavioral aggregation by controlling dopamine synthesis in locusts.

PubMed

Yang, Meiling; Wei, Yuanyuan; Jiang, Feng; Wang, Yanli; Guo, Xiaojiao; He, Jing; Kang, Le

2014-02-01

Phenotypic plasticity is ubiquitous and primarily controlled by interactions between environmental and genetic factors. The migratory locust, a worldwide pest, exhibits pronounced phenotypic plasticity, which is a population density-dependent transition that occurs between the gregarious and solitary phases. Genes involved in dopamine synthesis have been shown to regulate the phase transition of locusts. However, the function of microRNAs in this process remains unknown. In this study, we report the participation of miR-133 in dopamine production and the behavioral transition by negatively regulating two critical genes, henna and pale, in the dopamine pathway. miR-133 participated in the post-transcriptional regulation of henna and pale by binding to their coding region and 3' untranslated region, respectively. miR-133 displayed cellular co-localization with henna/pale in the protocerebrum, and its expression in the protocerebrum was negatively correlated with henna and pale expression. Moreover, miR-133 agomir delivery suppressed henna and pale expression, which consequently decreased dopamine production, thus resulting in the behavioral shift of the locusts from the gregarious phase to the solitary phase. Increasing the dopamine content could rescue the solitary phenotype, which was induced by miR-133 agomir delivery. Conversely, miR-133 inhibition increased the expression of henna and pale, resulting in the gregarious-like behavior of solitary locusts; this gregarious phenotype could be rescued by RNA interference of henna and pale. This study shows the novel function and modulation pattern of a miRNA in phenotypic plasticity and provides insight into the underlying molecular mechanisms of the phase transition of locusts.

To Be or Not to Be: Controlling Cellular Suicide | Center for Cancer Research

Cancer.gov

When a cell is damaged and can no longer function properly, a complex series of molecular steps is triggered that allows it to die in a controlled manner. This cellular suicide is called programmed cell death, or apoptosis.

Discovery of a New Cellular Motion and Its Relevance to Breast Cancer and Involution

DTIC Science & Technology

2014-02-01

motion (CAMo), live cell imaging , confocal microscopy Overall Project Summary: During this first year of funding we have concentrated our work to...cell types in 3D cultures and in vivo. Subtask 1.1a: Real time live cell imaging using confocal microscopy will be used to image cellular movement...exciting as they are important steps in understanding behavior of normal myoepithelial cells using live cell imaging in physiologically

Cellular interactions with tissue-engineered microenvironments and nanoparticles

NASA Astrophysics Data System (ADS)

Pan, Zhi

Tissue-engineered hydrogels composed of intermolecularlly crosslinked hyaluronan (HA-DTPH) and fibronectin functional domains (FNfds) were applied as a physiological relevant ECM mimic with controlled mechanical and biochemical properties. Cellular interactions with this tissue-engineered environment, especially physical interactions (cellular traction forces), were quantitatively measured by using the digital image speckle correlation (DISC) technique and finite element method (FEM). By correlating with other cell functions such as cell morphology and migration, a comprehensive structure-function relationship between cells and their environments was identified. Furthermore, spatiotemporal redistribution of cellular traction stresses was time-lapse measured during cell migration to better understand the dynamics of cell mobility. The results suggest that the reinforcement of the traction stresses around the nucleus, as well as the relaxation of nuclear deformation, are critical steps during cell migration, serving as a speed regulator, which must be considered in any dynamic molecular reconstruction model of tissue cell migration. Besides single cell migration, en masse cell migration was studied by using agarose droplet migration assay. Cell density was demonstrated to be another important parameter to influence cell behaviors besides substrate properties. Findings from these studies will provide fundamental design criteria to develop novel and effective tissue-engineered constructs. Cellular interactions with rutile and anatase TiO2 nanoparticles were also studied. These particles can penetrate easily through the cell membrane and impair cell function, with the latter being more damaging. The exposure to nanoparticles was found to decrease cell area, cell proliferation, motility, and contractility. To prevent this, a dense grafted polymer brush coating was applied onto the nanoparticle surface. These modified nanoparticles failed to adhere to and penetrate through the cell membrane. As a consequence, the coating effectively decreased reactive oxygen species (ROS) formation and protected the cells. Considering the broad applications of these nanoparticles in personal health care products, the functionalized polymer coating will likely play an important role in protecting cells and tissue from damage.

Comprehensive finite element modeling of Ti-6Al-4V cellular solids fabricated by electron beam melting

NASA Astrophysics Data System (ADS)

Arrieta, Edel

Additive manufacturing permits the fabrication of cellular metals which are materials that can be highly customizable and possess multiple and extraordinary properties such as damage tolerance, metamorphic and auxetic behaviors, and high specific stiffness. This makes them the subject of interest for innovative applications. With interest in these materials for energy absorption applications, this work presents the development of nonlinear finite element models in commercial software platforms (MSC Patran/Nastran) that permit the analysis of the deformation mechanisms of these materials under compressive loads. In the development of these models, a detailed multiscale study on the different factors affecting the response of cellular metals was conducted with the objective to understanding the physics with the objective of selecting the most appropriate experiments. In that manner, a series of experiments were conducted on Ti-6Al-4V specimens fabricated by electron beam melting at different manufacturing orientations. Digital image correlation was presented as a vital tool for the measurement of strains in specimens with complex shapes; the experiments contemplated compression and tension tests of Ti-6Al-4V solid components, as well as compression tests on cellular lattices of the same alloy. FEMs were developed from the same CAD file utilized for the fabrication of the lattices; in addition, different meshing approaches and mesh convergence analysis were discussed. The mesh density showed convergence in models with over 70,000 elements, permitting the evaluation of the stress/strain-distribution mechanisms in the lattices. However, because of the considerable variability of the experimental material properties, some numerical results showed significant errors in predicting the compressive force applied to the lattices during the experiments; thus suggesting the need to improve the quality control in the manufacturing process and develop better technologies in computational mechanics for the modeling of cellular metals.

The Circadian Clock in Cancer Development and Therapy

PubMed Central

Fu, Loning; Kettner, Nicole M.

2014-01-01

Most aspects of mammalian function display circadian rhythms driven by an endogenous clock. The circadian clock is operated by genes and comprises a central clock in the brain that responds to environmental cues and controls subordinate clocks in peripheral tissues via circadian output pathways. The central and peripheral clocks coordinately generate rhythmic gene expression in a tissue-specific manner in vivo to couple diverse physiological and behavioral processes to periodic changes in the environment. However, as the world industrialized, activities that disrupt endogenous homeostasis with external circadian cues have increased. This change in lifestyle has been linked to increased risk of diseases in all aspects of human health, including cancer. Studies in humans and animal models have revealed that cancer development in vivo is closely associated with the loss of circadian homeostasis in energy balance, immune function and aging that are supported by cellular functions important for tumor suppression including cell proliferation, senescence, metabolism and DNA damage response. The clock controls these cellular functions both locally in cells of peripheral tissues and at the organismal level via extracellular signaling. Thus, the hierarchical mammalian circadian clock provides a unique system to study carcinogenesis as a deregulated physiological process in vivo. The asynchrony between host and malignant tissues in cell proliferation and metabolism also provides new and exciting options for novel anti-cancer therapies. PMID:23899600

Combinatorial approaches to evaluate nanodiamond uptake and induced cellular fate

NASA Astrophysics Data System (ADS)

Eldawud, Reem; Reitzig, Manuela; Opitz, Jörg; Rojansakul, Yon; Jiang, Wenjuan; Nangia, Shikha; Zoica Dinu, Cerasela

2016-02-01

Nanodiamonds (NDs) are an emerging class of engineered nanomaterials that hold great promise for the next generation of bionanotechnological products to be used for drug and gene delivery, or for bio-imaging and biosensing. Previous studies have shown that upon their cellular uptake, NDs exhibit high biocompatibility in various in vitro and in vivo set-ups. Herein we hypothesized that the increased NDs biocompatibility is a result of minimum membrane perturbations and their reduced ability to induce disruption or damage during cellular translocation. Using multi-scale combinatorial approaches that simulate ND-membrane interactions, we correlated NDs real-time cellular uptake and kinetics with the ND-induced membrane fluctuations to derive energy requirements for the uptake to occur. Our discrete and real-time analyses showed that the majority of NDs internalization occurs within 2 h of cellular exposure, however, with no effects on cellular viability, proliferation or cellular behavior. Furthermore, our simulation analyses using coarse-grained models identified key changes in the energy profile, membrane deformation and recovery time, all functions of the average ND or ND-based agglomerate size. Understanding the mechanisms responsible for ND-cell membrane interactions could possibly advance their implementation in various biomedical applications.

Combinatorial approaches to evaluate nanodiamond uptake and induced cellular fate

PubMed Central

Eldawud, Reem; Reitzig, Manuela; Opitz, Jörg; Rojansakul, Yon; Jiang, Wenjuan; Nangia, Shikha; Dinu, Cerasela Zoica

2016-01-01

Nanodiamonds (NDs) are an emerging class of engineered nanomaterials that hold great promise for the next generation of bionanotechnological products to be used for drug and gene delivery, or for bio-imaging and biosensing. Previous studies have shown that upon their cellular uptake, NDs exhibit high biocompatibility in various in vitro and in vivo set-ups. Herein we hypothesized that the increased NDs biocompatibility is a result of minimum membrane perturbations and their reduced ability to induce disruption or damage during cellular translocation. Using multi-scale combinatorial approaches that simulate ND-membrane interactions, we correlated NDs real-time cellular uptake and kinetics with the ND-induced membrane fluctuations to derive energy requirements for the uptake to occur. Our discrete and real-time analyses showed that the majority of NDs internalization occurs within 2 h of cellular exposure, however, with no effects on cellular viability, proliferation or cellular behavior. Furthermore, our simulation analyses using coarse-grained models identified key changes in the energy profile, membrane deformation and recovery time, all functions of the average ND or ND-based agglomerate size. Understanding the mechanisms responsible for ND-cell membrane interactions could possibly advance their implementation in various biomedical applications. PMID:26820775

Maternal Ingestion of Ipomoea carnea: Effects on Goat-Kid Bonding and Behavior

PubMed Central

Gotardo, André T.; Pfister, James A.; Raspantini, Paulo C. F.; Górniak, Silvana L.

2016-01-01

Ipomoea carnea is a toxic plant found in Brazil and other tropical and subtropical countries and often causes poisoning of livestock. The plant contains the alkaloids swainsonine and calystegines, which inhibit key cellular enzymes and cause systematic cell death. This study evaluated the behavioral effects of prenatal ingestion of this plant on dams and their kids. Twenty-four pregnant goats were randomly allocated into four treatment groups and received the following doses (g/kg BW) of fresh I. carnea: 0 (control group), 1.0 (IC1), 3.0 (IC3), and 5.0 (IC5) from day 27 of gestation until parturition. Dam and kid bonding and behavior were evaluated by several tests, immediately after birth until six weeks of age. Dams from IC3 and IC5 groups spent less time paying attention to the newborn. There was a lack of maternal-infant bonding due to I. carnea intoxication. Kids from treated dams had difficulty in standing, suckling, and in recognizing their mother hours after birth. I. carnea can also compromise the kids’ ability to learn and to retain spatial memory. We suggest that kids from pregnant goats given I. carnea during gestation have significant behavioral alterations and developmental delays that may compromise their survival. PMID:26999204

Light Activated Escape Circuits: A Behavior and Neurophysiology Lab Module using Drosophila Optogenetics

PubMed Central

Titlow, Josh S.; Johnson, Bruce R.; Pulver, Stefan R.

2015-01-01

The neural networks that control escape from predators often show very clear relationships between defined sensory inputs and stereotyped motor outputs. This feature provides unique opportunities for researchers, but it also provides novel opportunities for neuroscience educators. Here we introduce new teaching modules using adult Drosophila that have been engineered to express csChrimson, a red-light sensitive channelrhodopsin, in specific sets of neurons and muscles mediating visually guided escape behaviors. This lab module consists of both behavior and electrophysiology experiments that explore the neural basis of flight escape. Three preparations are described that demonstrate photo-activation of the giant fiber circuit and how to quantify these behaviors. One of the preparations is then used to acquire intracellular electrophysiology recordings from different flight muscles. The diversity of action potential waveforms and firing frequencies observed in the flight muscles make this a rich preparation to study the ionic basic of cellular excitability. By activating different cells within the giant fiber pathway we also demonstrate principles of synaptic transmission and neural circuits. Beyond conveying core neurobiological concepts it is also expected that using these cutting edge techniques will enhance student motivation and attitudes towards biological research. Data collected from students and educators who have been involved in development of the module are presented to support this notion. PMID:26240526

Maternal Ingestion of Ipomoea carnea: Effects on Goat-Kid Bonding and Behavior.

PubMed

Gotardo, André T; Pfister, James A; Raspantini, Paulo C F; Górniak, Silvana L

2016-03-16

Ipomoea carnea is a toxic plant found in Brazil and other tropical and subtropical countries and often causes poisoning of livestock. The plant contains the alkaloids swainsonine and calystegines, which inhibit key cellular enzymes and cause systematic cell death. This study evaluated the behavioral effects of prenatal ingestion of this plant on dams and their kids. Twenty-four pregnant goats were randomly allocated into four treatment groups and received the following doses (g/kg BW) of fresh I. carnea: 0 (control group), 1.0 (IC1), 3.0 (IC3), and 5.0 (IC5) from day 27 of gestation until parturition. Dam and kid bonding and behavior were evaluated by several tests, immediately after birth until six weeks of age. Dams from IC3 and IC5 groups spent less time paying attention to the newborn. There was a lack of maternal-infant bonding due to I. carnea intoxication. Kids from treated dams had difficulty in standing, suckling, and in recognizing their mother hours after birth. I. carnea can also compromise the kids' ability to learn and to retain spatial memory. We suggest that kids from pregnant goats given I. carnea during gestation have significant behavioral alterations and developmental delays that may compromise their survival.

Mechanical behavior of regular open-cell porous biomaterials made of diamond lattice unit cells.

PubMed

Ahmadi, S M; Campoli, G; Amin Yavari, S; Sajadi, B; Wauthle, R; Schrooten, J; Weinans, H; Zadpoor, A A

2014-06-01

Cellular structures with highly controlled micro-architectures are promising materials for orthopedic applications that require bone-substituting biomaterials or implants. The availability of additive manufacturing techniques has enabled manufacturing of biomaterials made of one or multiple types of unit cells. The diamond lattice unit cell is one of the relatively new types of unit cells that are used in manufacturing of regular porous biomaterials. As opposed to many other types of unit cells, there is currently no analytical solution that could be used for prediction of the mechanical properties of cellular structures made of the diamond lattice unit cells. In this paper, we present new analytical solutions and closed-form relationships for predicting the elastic modulus, Poisson׳s ratio, critical buckling load, and yield (plateau) stress of cellular structures made of the diamond lattice unit cell. The mechanical properties predicted using the analytical solutions are compared with those obtained using finite element models. A number of solid and porous titanium (Ti6Al4V) specimens were manufactured using selective laser melting. A series of experiments were then performed to determine the mechanical properties of the matrix material and cellular structures. The experimentally measured mechanical properties were compared with those obtained using analytical solutions and finite element (FE) models. It has been shown that, for small apparent density values, the mechanical properties obtained using analytical and numerical solutions are in agreement with each other and with experimental observations. The properties estimated using an analytical solution based on the Euler-Bernoulli theory markedly deviated from experimental results for large apparent density values. The mechanical properties estimated using FE models and another analytical solution based on the Timoshenko beam theory better matched the experimental observations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sleep, Plasticity and Memory from Molecules to Whole-Brain Networks

PubMed Central

Abel, Ted; Havekes, Robbert; Saletin, Jared M.; Walker, Matthew P.

2014-01-01

Despite the ubiquity of sleep across phylogeny, its function remains elusive. In this review, we consider one compelling candidate: brain plasticity associated with memory processing. Focusing largely on hippocampus-dependent memory in rodents and humans, we describe molecular, cellular, network, whole-brain and behavioral evidence establishing a role for sleep both in preparation for initial memory encoding, and in the subsequent offline consolidation ofmemory. Sleep and sleep deprivation bidirectionally alter molecular signaling pathways that regulate synaptic strength and control plasticity-related gene transcription and protein translation. At the cellular level, sleep deprivation impairs cellular excitability necessary for inducing synaptic potentiation and accelerates the decay of long-lasting forms of synaptic plasticity. In contrast, NREM and REM sleep enhance previously induced synaptic potentiation, although synaptic de-potentiation during sleep has also been observed. Beyond single cell dynamics, large-scale cell ensembles express coordinated replay of prior learning-related firing patterns during subsequent sleep. This occurs in the hippocampus, in the cortex, and between the hippocampus and cortex, commonly in association with specific NREM sleep oscillations. At the whole-brain level, somewhat analogous learning-associated hippocampal (re)activation during NREM sleep has been reported in humans. Moreover, the same cortical NREM oscillations associated with replay in rodents also promote human hippocampal memory consolidation, and this process can be manipulated using exogenous reactivation cues during sleep. Mirroring molecular findings in rodents, specific NREM sleep oscillations before encoding refresh human hippocampal learning capacity, while deprivation of sleep conversely impairs subsequent hippocampal activity and associated encoding. Together, these cross-descriptive level findings demonstrate that the unique neurobiology of sleep exert powerful effects on molecular, cellular and network mechanism of plasticity that govern both initial learning and subsequent long-term memory consolidation. PMID:24028961

Cortactin promotes exosome secretion by controlling branched actin dynamics

PubMed Central

Sinha, Seema; Hoshino, Daisuke; Hong, Nan Hyung; Seiki, Motoharu; Tyska, Matthew J.

2016-01-01

Exosomes are extracellular vesicles that influence cellular behavior and enhance cancer aggressiveness by carrying bioactive molecules. The mechanisms that regulate exosome secretion are poorly understood. Here, we show that the actin cytoskeletal regulatory protein cortactin promotes exosome secretion. Knockdown or overexpression of cortactin in cancer cells leads to a respective decrease or increase in exosome secretion, without altering exosome cargo content. Live-cell imaging revealed that cortactin controls both trafficking and plasma membrane docking of multivesicular late endosomes (MVEs). Regulation of exosome secretion by cortactin requires binding to the branched actin nucleating Arp2/3 complex and to actin filaments. Furthermore, cortactin, Rab27a, and coronin 1b coordinately control stability of cortical actin MVE docking sites and exosome secretion. Functionally, the addition of purified exosomes to cortactin-knockdown cells rescued defects of those cells in serum-independent growth and invasion. These data suggest a model in which cortactin promotes exosome secretion by stabilizing cortical actin-rich MVE docking sites. PMID:27402952

Cortactin promotes exosome secretion by controlling branched actin dynamics.

PubMed

Sinha, Seema; Hoshino, Daisuke; Hong, Nan Hyung; Kirkbride, Kellye C; Grega-Larson, Nathan E; Seiki, Motoharu; Tyska, Matthew J; Weaver, Alissa M

2016-07-18

Exosomes are extracellular vesicles that influence cellular behavior and enhance cancer aggressiveness by carrying bioactive molecules. The mechanisms that regulate exosome secretion are poorly understood. Here, we show that the actin cytoskeletal regulatory protein cortactin promotes exosome secretion. Knockdown or overexpression of cortactin in cancer cells leads to a respective decrease or increase in exosome secretion, without altering exosome cargo content. Live-cell imaging revealed that cortactin controls both trafficking and plasma membrane docking of multivesicular late endosomes (MVEs). Regulation of exosome secretion by cortactin requires binding to the branched actin nucleating Arp2/3 complex and to actin filaments. Furthermore, cortactin, Rab27a, and coronin 1b coordinately control stability of cortical actin MVE docking sites and exosome secretion. Functionally, the addition of purified exosomes to cortactin-knockdown cells rescued defects of those cells in serum-independent growth and invasion. These data suggest a model in which cortactin promotes exosome secretion by stabilizing cortical actin-rich MVE docking sites. © 2016 Sinha et al.

The effects of perception of risk and importance of answering and initiating a cellular phone call while driving.

PubMed

Nelson, Erik; Atchley, Paul; Little, Todd D

2009-05-01

Recent data suggest that laws banning cellular phone use while driving may not change use patterns, especially among young drivers with high rates of mobile phone adoption. We examined reasons younger drivers choose or do not choose to talk on a phone while driving among a sample of young drivers (n=276) with very high ownership of cellular phones (over 99%) and a very high use of cellular phones while driving (100% for those that were primary operators of an automobile). Respondents were surveyed for patterns of use, types of call, perceived risk, and motivations for use. The data were analyzed using structural equation modeling (SEM) to explore the relationships between perceived risk of the behavior, emotionality of the call, perceived importance of the call, and how often calls were initiated versus answered. The model suggests that even though people believe that talking on a cellular phone while driving is dangerous, they will tend to initiate a cellular conversation if they believe that the call is important.

Cellular phones, cordless phones, and the risks of glioma and meningioma (Interphone Study Group, Germany).

PubMed

Schüz, Joachim; Böhler, Eva; Berg, Gabriele; Schlehofer, Brigitte; Hettinger, Iris; Schlaefer, Klaus; Wahrendorf, Jürgen; Kunna-Grass, Katharina; Blettner, Maria

2006-03-15

The widespread use of cellular telephones has generated concern about possible adverse health effects, particularly brain tumors. In this population-based case-control study carried out in three regions of Germany, all incident cases of glioma and meningioma among patients aged 30-69 years were ascertained during 2000-2003. Controls matched on age, gender, and region were randomly drawn from population registries. In total, 366 glioma cases, 381 meningioma cases, and 1,494 controls were interviewed. Overall use of a cellular phone was not associated with brain tumor risk; the respective odds ratios were 0.98 (95% confidence interval (CI): 0.74, 1.29) for glioma and 0.84 (95% CI: 0.62, 1.13) for meningioma. Among persons who had used cellular phones for 10 or more years, increased risk was found for glioma (odds ratio = 2.20, 95% CI: 0.94, 5.11) but not for meningioma (odds ratio = 1.09, 95% CI: 0.35, 3.37). No excess of temporal glioma (p = 0.41) or meningioma (p = 0.43) was observed in cellular phone users as compared with nonusers. Cordless phone use was not related to either glioma risk or meningioma risk. In conclusion, no overall increased risk of glioma or meningioma was observed among these cellular phone users; however, for long-term cellular phone users, results need to be confirmed before firm conclusions can be drawn.

Calcium dynamics regulating the timing of decision-making in C. elegans.

PubMed

Tanimoto, Yuki; Yamazoe-Umemoto, Akiko; Fujita, Kosuke; Kawazoe, Yuya; Miyanishi, Yosuke; Yamazaki, Shuhei J; Fei, Xianfeng; Busch, Karl Emanuel; Gengyo-Ando, Keiko; Nakai, Junichi; Iino, Yuichi; Iwasaki, Yuishi; Hashimoto, Koichi; Kimura, Koutarou D

2017-05-23

Brains regulate behavioral responses with distinct timings. Here we investigate the cellular and molecular mechanisms underlying the timing of decision-making during olfactory navigation in Caenorhabditis elegans . We find that, based on subtle changes in odor concentrations, the animals appear to choose the appropriate migratory direction from multiple trials as a form of behavioral decision-making. Through optophysiological, mathematical and genetic analyses of neural activity under virtual odor gradients, we further find that odor concentration information is temporally integrated for a decision by a gradual increase in intracellular calcium concentration ([Ca 2+ ] i ), which occurs via L-type voltage-gated calcium channels in a pair of olfactory neurons. In contrast, for a reflex-like behavioral response, [Ca 2+ ] i rapidly increases via multiple types of calcium channels in a pair of nociceptive neurons. Thus, the timing of neuronal responses is determined by cell type-dependent involvement of calcium channels, which may serve as a cellular basis for decision-making.

Ultrasensitive dual phosphorylation dephosphorylation cycle kinetics exhibits canonical competition behavior

NASA Astrophysics Data System (ADS)

Huang, Qingdao; Qian, Hong

2009-09-01

We establish a mathematical model for a cellular biochemical signaling module in terms of a planar differential equation system. The signaling process is carried out by two phosphorylation-dephosphorylation reaction steps that share common kinase and phosphatase with saturated enzyme kinetics. The pair of equations is particularly simple in the present mathematical formulation, but they are singular. A complete mathematical analysis is developed based on an elementary perturbation theory. The dynamics exhibits the canonical competition behavior in addition to bistability. Although widely understood in ecological context, we are not aware of a full range of biochemical competition in a simple signaling network. The competition dynamics has broad implications to cellular processes such as cell differentiation and cancer immunoediting. The concepts of homogeneous and heterogeneous multisite phosphorylation are introduced and their corresponding dynamics are compared: there is no bistability in a heterogeneous dual phosphorylation system. A stochastic interpretation is also provided that further gives intuitive understanding of the bistable behavior inside the cells.

Luminal mitosis drives epithelial cell dispersal within the branching ureteric bud

PubMed Central

Packard, Adam; Georgas, Kylie; Michos, Odyssé; Riccio, Paul; Cebrian, Cristina; Combes, Alexander N.; Ju, Adler; Ferrer-Vaquer, Anna; Hadjantonakis, Anna-Katerina; Zong, Hui; Little, Melissa H.; Costantini, Frank

2013-01-01

Summary The ureteric bud is an epithelial tube that undergoes branching morphogenesis to form the renal collecting system. Though development of a normal kidney depends on proper ureteric bud morphogenesis, the cellular events underlying this process remain obscure. Here, we used time-lapse microscopy together with several genetic labeling methods to observe ureteric bud cell behaviors in developing mouse kidneys. We observed an unexpected cell behavior in the branching tips of the ureteric bud, which we term “mitosis-associated cell dispersal”. Pre-mitotic ureteric tip cells delaminate from the epithelium and divide within the lumen; while one daughter cell retains a basal process, allowing it to reinsert into the epithelium at the site of origin, the other daughter cell reinserts at a position one to three cell diameters away. Given the high rate of cell division in ureteric tips, this cellular behavior causes extensive epithelial cell rearrangements that may contribute to renal branching morphogenesis. PMID:24183650

Calcium dynamics regulating the timing of decision-making in C. elegans

PubMed Central

Tanimoto, Yuki; Yamazoe-Umemoto, Akiko; Fujita, Kosuke; Kawazoe, Yuya; Miyanishi, Yosuke; Yamazaki, Shuhei J; Fei, Xianfeng; Busch, Karl Emanuel; Gengyo-Ando, Keiko; Nakai, Junichi; Iino, Yuichi; Iwasaki, Yuishi; Hashimoto, Koichi; Kimura, Koutarou D

2017-01-01

Brains regulate behavioral responses with distinct timings. Here we investigate the cellular and molecular mechanisms underlying the timing of decision-making during olfactory navigation in Caenorhabditis elegans. We find that, based on subtle changes in odor concentrations, the animals appear to choose the appropriate migratory direction from multiple trials as a form of behavioral decision-making. Through optophysiological, mathematical and genetic analyses of neural activity under virtual odor gradients, we further find that odor concentration information is temporally integrated for a decision by a gradual increase in intracellular calcium concentration ([Ca2+]i), which occurs via L-type voltage-gated calcium channels in a pair of olfactory neurons. In contrast, for a reflex-like behavioral response, [Ca2+]i rapidly increases via multiple types of calcium channels in a pair of nociceptive neurons. Thus, the timing of neuronal responses is determined by cell type-dependent involvement of calcium channels, which may serve as a cellular basis for decision-making. DOI: http://dx.doi.org/10.7554/eLife.21629.001 PMID:28532547

Functional imaging of hippocampal place cells at cellular resolution during virtual navigation

PubMed Central

Dombeck, Daniel A.; Harvey, Christopher D.; Tian, Lin; Looger, Loren L.; Tank, David W.

2010-01-01

Spatial navigation is a widely employed behavior in rodent studies of neuronal circuits underlying cognition, learning and memory. In vivo microscopy combined with genetically-encoded indicators provides important new tools to study neuronal circuits, but has been technically difficult to apply during navigation. We describe methods to image the activity of hippocampal CA1 neurons with sub-cellular resolution in behaving mice. Neurons expressing the genetically encoded calcium indicator GCaMP3 were imaged through a chronic hippocampal window. Head-fixed mice performed spatial behaviors within a setup combining a virtual reality system and a custom built two-photon microscope. Populations of place cells were optically identified, and the correlation between the location of their place fields in the virtual environment and their anatomical location in the local circuit was measured. The combination of virtual reality and high-resolution functional imaging should allow for a new generation of studies to probe neuronal circuit dynamics during behavior. PMID:20890294

Behavioral epigenetics

PubMed Central

Lester, Barry M.; Tronick, Edward; Nestler, Eric; Abel, Ted; Kosofsky, Barry; Kuzawa, Christopher W.; Marsit, Carmen J.; Maze, Ian; Meaney, Michael J.; Monteggia, Lisa M.; Reul, Johannes M. H. M.; Skuse, David H.; Sweatt, J. David; Wood, Marcelo A.

2013-01-01

Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the University of Massachusetts Boston, “Behavioral Epigenetics” was held on October 29–30, 2010 at the University of Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epigenetic modulation of normative development, developmental disorders, and psychopathology. This report provides an overview of the research presented by leading scientists and lively discussion about the future of investigation at the behavioral epigenetic level. PMID:21615751

Translational Control in Cancer Etiology

PubMed Central

Ruggero, Davide

2013-01-01

The link between perturbations in translational control and cancer etiology is becoming a primary focus in cancer research. It has now been established that genetic alterations in several components of the translational apparatus underlie spontaneous cancers as well as an entire class of inherited syndromes known as “ribosomopathies” associated with increased cancer susceptibility. These discoveries have illuminated the importance of deregulations in translational control to very specific cellular processes that contribute to cancer etiology. In addition, a growing body of evidence supports the view that deregulation of translational control is a common mechanism by which diverse oncogenic pathways promote cellular transformation and tumor development. Indeed, activation of these key oncogenic pathways induces rapid and dramatic translational reprogramming both by increasing overall protein synthesis and by modulating specific mRNA networks. These translational changes promote cellular transformation, impacting almost every phase of tumor development. This paradigm represents a new frontier in the multihit model of cancer formation and offers significant promise for innovative cancer therapies. Current research, in conjunction with cutting edge technologies, will further enable us to explore novel mechanisms of translational control, functionally identify translationally controlled mRNA groups, and unravel their impact on cellular transformation and tumorigenesis. PMID:22767671

Brain tumor modeling: glioma growth and interaction with chemotherapy

NASA Astrophysics Data System (ADS)

Banaem, Hossein Y.; Ahmadian, Alireza; Saberi, Hooshangh; Daneshmehr, Alireza; Khodadad, Davood

2011-10-01

In last decade increasingly mathematical models of tumor growths have been studied, particularly on solid tumors which growth mainly caused by cellular proliferation. In this paper we propose a modified model to simulate the growth of gliomas in different stages. Glioma growth is modeled by a reaction-advection-diffusion. We begin with a model of untreated gliomas and continue with models of polyclonal glioma following chemotherapy. From relatively simple assumptions involving homogeneous brain tissue bounded by a few gross anatomical landmarks (ventricles and skull) the models have been expanded to include heterogeneous brain tissue with different motilities of glioma cells in grey and white matter. Tumor growth is characterized by a dangerous change in the control mechanisms, which normally maintain a balance between the rate of proliferation and the rate of apoptosis (controlled cell death). Result shows that this model closes to clinical finding and can simulate brain tumor behavior properly.

TOPICAL REVIEW: Artificial extracellular matrix for embryonic stem cell cultures: a new frontier of nanobiomaterials

NASA Astrophysics Data System (ADS)

Amranul Haque, Md; Nagaoka, Masato; Hexig, Bayar; Akaike, Toshihiro

2010-02-01

Nanobiomaterials can play a central role in regenerative medicine and tissue engineering by facilitating cellular behavior and function, such as those where extracellular matrices (ECMs) direct embryonic stem (ES) cell morphogenesis, proliferation, differentiation and apoptosis. However, controlling ES cell proliferation and differentiation using matrices from natural sources is still challenging due to complex and heterogeneous culture conditions. Moreover, the systemic investigation of the regulation of self-renewal and differentiation to lineage specific cells depends on the use of defined and stress-free culture conditions. Both goals can be achieved by the development of biomaterial design targeting ECM or growth factors for ES cell culture. This targeted application will benefit from expansion of ES cells for transplantation, as well as the production of a specific differentiated cell type either by controlling the differentiation in a very specific pathway or by elimination of undesirable cell types.

New approaches to thyroid hormones and purinergic signaling.

PubMed

Silveira, Gabriel Fernandes; Buffon, Andréia; Bruno, Alessandra Nejar

2013-01-01

It is known that thyroid hormones influence a wide variety of events at the molecular, cellular, and functional levels. Thyroid hormones (TH) play pivotal roles in growth, cell proliferation, differentiation, apoptosis, development, and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. Most of these effects result in pathological and physiological events and are already well described in the literature. Even so, many recent studies have been devoted to bringing new information on problems in controlling the synthesis and release of these hormones and to elucidating mechanisms of the action of these hormones unconventionally. The purinergic system was recently linked to thyroid diseases, including enzymes, receptors, and enzyme products related to neurotransmitter release, nociception, behavior, and other vascular systems. Thus, throughout this text we intend to relate the relationship between the TH in physiological and pathological situations with the purinergic signaling.

New Approaches to Thyroid Hormones and Purinergic Signaling

PubMed Central

Silveira, Gabriel Fernandes; Buffon, Andréia; Bruno, Alessandra Nejar

2013-01-01

It is known that thyroid hormones influence a wide variety of events at the molecular, cellular, and functional levels. Thyroid hormones (TH) play pivotal roles in growth, cell proliferation, differentiation, apoptosis, development, and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. Most of these effects result in pathological and physiological events and are already well described in the literature. Even so, many recent studies have been devoted to bringing new information on problems in controlling the synthesis and release of these hormones and to elucidating mechanisms of the action of these hormones unconventionally. The purinergic system was recently linked to thyroid diseases, including enzymes, receptors, and enzyme products related to neurotransmitter release, nociception, behavior, and other vascular systems. Thus, throughout this text we intend to relate the relationship between the TH in physiological and pathological situations with the purinergic signaling. PMID:23956925

Modeling infectious disease dynamics in the complex landscape of global health

PubMed Central

Heesterbeek, Hans; Anderson, Roy; Andreasen, Viggo; Bansal, Shweta; De Angelis, Daniela; Dye, Chris; Eames, Ken; Edmunds, John; Frost, Simon; Funk, Sebastian; Hollingsworth, Deirdre; House, Thomas; Isham, Valerie; Klepac, Petra; Lessler, Justin; Lloyd-Smith, James; Metcalf, Jessica; Mollison, Denis; Pellis, Lorenzo; Pulliam, Juliet; Roberts, Mick; Viboud, Cecile

2015-01-01

Despite some notable successes in the control of infectious diseases, transmissible pathogens still pose an enormous threat to human and animal health. The ecological and evolutionary dynamics of infections play out on a wide range of interconnected temporal, organizational and spatial scales, which even within a single pathogen often span hours to months, cellular to ecosystem levels, and local to pandemic spread. Some pathogens are directly transmitted between individuals of a single species, while others circulate among multiple hosts, need arthropod vectors, or can survive in environmental reservoirs. Many factors, including increasing antimicrobial resistance, increased human connectivity, and dynamic human behavior, raise prevention and control from formerly national to international issues. In the face of this complexity, mathematical models offer essential tools for synthesizing information to understand epidemiological patterns, and for developing the quantitative evidence base for decision-making in global health. PMID:25766240

Optically triggering spatiotemporally confined GPCR activity in a cell and programming neurite initiation and extension

PubMed Central

Karunarathne, W. K. Ajith; Giri, Lopamudra; Kalyanaraman, Vani; Gautam, N.

2013-01-01

G-protein–coupled receptor (GPCR) activity gradients evoke important cell behavior but there is a dearth of methods to induce such asymmetric signaling in a cell. Here we achieved reversible, rapidly switchable patterns of spatiotemporally restricted GPCR activity in a single cell. We recruited properties of nonrhodopsin opsins—rapid deactivation, distinct spectral tuning, and resistance to bleaching—to activate native Gi, Gq, or Gs signaling in selected regions of a cell. Optical inputs were designed to spatiotemporally control levels of second messengers, IP3, phosphatidylinositol (3,4,5)-triphosphate, and cAMP in a cell. Spectrally selective imaging was accomplished to simultaneously monitor optically evoked molecular and cellular response dynamics. We show that localized optical activation of an opsin-based trigger can induce neurite initiation, phosphatidylinositol (3,4,5)-triphosphate increase, and actin remodeling. Serial optical inputs to neurite tips can refashion early neuron differentiation. Methods here can be widely applied to program GPCR-mediated cell behaviors. PMID:23479634

Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice.

PubMed

Spoida, Katharina; Masseck, Olivia A; Deneris, Evan S; Herlitze, Stefan

2014-04-29

Serotonin 2c receptors (5-HT2c-Rs) are drug targets for certain mental disorders, including schizophrenia, depression, and anxiety. 5-HT2c-Rs are expressed throughout the brain, making it difficult to link behavioral changes to circuit specific receptor expression. Various 5-HT-Rs, including 5-HT2c-Rs, are found in the dorsal raphe nucleus (DRN); however, the function of 5-HT2c-Rs and their influence on the serotonergic signals mediating mood disorders remain unclear. To investigate the role of 5-HT2c-Rs in the DRN in mice, we developed a melanopsin-based optogenetic probe for activation of Gq signals in cellular domains, where 5-HT2c-Rs are localized. Our results demonstrate that precise temporal control of Gq signals in 5-HT2c-R domains in GABAergic neurons upstream of 5-HT neurons provides negative feedback regulation of serotonergic firing to modulate anxiety-like behavior in mice.

Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice

PubMed Central

Spoida, Katharina; Masseck, Olivia A.; Deneris, Evan S.; Herlitze, Stefan

2014-01-01

Serotonin 2c receptors (5-HT2c-Rs) are drug targets for certain mental disorders, including schizophrenia, depression, and anxiety. 5-HT2c-Rs are expressed throughout the brain, making it difficult to link behavioral changes to circuit specific receptor expression. Various 5-HT-Rs, including 5-HT2c-Rs, are found in the dorsal raphe nucleus (DRN); however, the function of 5-HT2c-Rs and their influence on the serotonergic signals mediating mood disorders remain unclear. To investigate the role of 5-HT2c-Rs in the DRN in mice, we developed a melanopsin-based optogenetic probe for activation of Gq signals in cellular domains, where 5-HT2c-Rs are localized. Our results demonstrate that precise temporal control of Gq signals in 5-HT2c-R domains in GABAergic neurons upstream of 5-HT neurons provides negative feedback regulation of serotonergic firing to modulate anxiety-like behavior in mice. PMID:24733892

Cerebellar Plasticity and Motor Learning Deficits in a Copy Number Variation Mouse Model of Autism

PubMed Central

Piochon, Claire; Kloth, Alexander D; Grasselli, Giorgio; Titley, Heather K; Nakayama, Hisako; Hashimoto, Kouichi; Wan, Vivian; Simmons, Dana H; Eissa, Tahra; Nakatani, Jin; Cherskov, Adriana; Miyazaki, Taisuke; Watanabe, Masahiko; Takumi, Toru; Kano, Masanobu; Wang, Samuel S-H; Hansel, Christian

2014-01-01

A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, occurring in a majority of children with autism, consistent with perturbation in cerebellar function. Here we report alterations in motor behavior and cerebellar synaptic plasticity in a mouse model (patDp/+) for the human 15q11-13 duplication, one of the most frequently observed genetic aberrations in autism. These mice show ASD-resembling social behavior deficits. We find that in patDp/+ mice delay eyeblink conditioning—a form of cerebellum-dependent motor learning—is impaired, and observe deregulation of a putative cellular mechanism for motor learning, long-term depression (LTD) at parallel fiber-Purkinje cell synapses. Moreover, developmental elimination of surplus climbing fibers—a model for activity-dependent synaptic pruning—is impaired. These findings point to deficits in synaptic plasticity and pruning as potential causes for motor problems and abnormal circuit development in autism. PMID:25418414

Design Considerations for Developing Biodegradable Magnesium Implants

NASA Astrophysics Data System (ADS)

Brar, Harpreet S.; Keselowsky, Benjamin G.; Sarntinoranont, Malisa; Manuel, Michele V.

The integration of biodegradable and bioabsorbable magnesium implants into the human body is a complex undertaking that faces major challenges. The complexity arises from the fact that biomaterials must meet both engineering and physiological requirements to ensure the desired properties. Historically, efforts have been focused on the behavior of commercial magnesium alloys in biological environments and their resultant effect on cell-mediated processes. Developing causal relationships between alloy chemistry and micro structure, and its effect on cellular behavior can be a difficult and time intensive process. A systems design approach driven by thermodynamics has the power to provide significant contributions in developing the next generation of magnesium alloy implants with controlled degradability, biocompatibility, and optimized mechanical properties, at reduced time and cost. This approach couples experimental research with theory and mechanistic modeling for the accelerated development of materials. The aim of this article is to enumerate this strategy, design considerations and hurdles for developing new magnesium alloys for use as biodegradable implant materials [1].

Single-Cell Memory Regulates a Neural Circuit for Sensory Behavior.

PubMed

Kobayashi, Kyogo; Nakano, Shunji; Amano, Mutsuki; Tsuboi, Daisuke; Nishioka, Tomoki; Ikeda, Shingo; Yokoyama, Genta; Kaibuchi, Kozo; Mori, Ikue

2016-01-05

Unveiling the molecular and cellular mechanisms underlying memory has been a challenge for the past few decades. Although synaptic plasticity is proven to be essential for memory formation, the significance of "single-cell memory" still remains elusive. Here, we exploited a primary culture system for the analysis of C. elegans neurons and show that a single thermosensory neuron has an ability to form, retain, and reset a temperature memory. Genetic and proteomic analyses found that the expression of the single-cell memory exhibits inter-individual variability, which is controlled by the evolutionarily conserved CaMKI/IV and Raf pathway. The variable responses of a sensory neuron influenced the neural activity of downstream interneurons, suggesting that modulation of the sensory neurons ultimately determines the behavioral output in C. elegans. Our results provide proof of single-cell memory and suggest that the individual differences in neural responses at the single-cell level can confer individuality. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Inhibition of oxidative stress in cholinergic projection neurons fully rescues aging-associated olfactory circuit degeneration in Drosophila

PubMed Central

Loschek, Laura F; La Fortezza, Marco; Friedrich, Anja B; Blais, Catherine-Marie; Üçpunar, Habibe K; Yépez, Vicente A; Lehmann, Martin; Gompel, Nicolas; Gagneur, Julien; Sigrist, Stephan J

2018-01-01

Loss of the sense of smell is among the first signs of natural aging and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Cellular and molecular mechanisms promoting this smell loss are not understood. Here, we show that Drosophila melanogaster also loses olfaction before vision with age. Within the olfactory circuit, cholinergic projection neurons show a reduced odor response accompanied by a defect in axonal integrity and reduction in synaptic marker proteins. Using behavioral functional screening, we pinpoint that expression of the mitochondrial reactive oxygen scavenger SOD2 in cholinergic projection neurons is necessary and sufficient to prevent smell degeneration in aging flies. Together, our data suggest that oxidative stress induced axonal degeneration in a single class of neurons drives the functional decline of an entire neural network and the behavior it controls. Given the important role of the cholinergic system in neurodegeneration, the fly olfactory system could be a useful model for the identification of drug targets. PMID:29345616

Evolutionarily Conserved, Multitasking TRP Channels: Lessons from Worms and Flies

PubMed Central

Venkatachalam, Kartik; Luo, Junjie; Montell, Craig

2015-01-01

The Transient Receptor Potential (TRP) channel family is comprised of a large group of cation-permeable channels, which display an extraordinary diversity of roles in sensory signaling. TRPs allow animals to detect chemicals, mechanical force, light, and changes in temperature. Consequently, these channels control a plethora of animal behaviors. Moreover, their functions are not limited to the classical senses, as they are cellular sensors, which are critical for ionic homeostasis and metabolism. Two genetically tractable invertebrate model organisms, Caenorhabditis elegans and Drosophila melanogaster, have led the way in revealing a wide array of sensory roles and behaviors that depend on TRP channels. Two overriding themes have emerged from these studies. First, TRPs are multitasking proteins, and second, many functions and modes of activation of these channels are evolutionarily conserved, including some that were formerly thought to be unique to invertebrates, such as phototransduction. Thus, worms and flies offer the potential to decipher roles for mammalian TRPs, which would otherwise not be suspected. PMID:24961975

Circadian Rhythms in Fear Conditioning: An Overview of Behavioral, Brain System, and Molecular Interactions

PubMed Central

Stork, Oliver

2017-01-01

The formation of fear memories is a powerful and highly evolutionary conserved mechanism that serves the behavioral adaptation to environmental threats. Accordingly, classical fear conditioning paradigms have been employed to investigate fundamental molecular processes of memory formation. Evidence suggests that a circadian regulation mechanism allows for a timestamping of such fear memories and controlling memory salience during both their acquisition and their modification after retrieval. These mechanisms include an expression of molecular clocks in neurons of the amygdala, hippocampus, and medial prefrontal cortex and their tight interaction with the intracellular signaling pathways that mediate neural plasticity and information storage. The cellular activities are coordinated across different brain regions and neural circuits through the release of glucocorticoids and neuromodulators such as acetylcholine, which integrate circadian and memory-related activation. Disturbance of this interplay by circadian phase shifts or traumatic experience appears to be an important factor in the development of stress-related psychopathology, considering these circadian components are of critical importance for optimizing therapeutic approaches to these disorders. PMID:28698810

Neural circuits. Labeling of active neural circuits in vivo with designed calcium integrators.

PubMed

Fosque, Benjamin F; Sun, Yi; Dana, Hod; Yang, Chao-Tsung; Ohyama, Tomoko; Tadross, Michael R; Patel, Ronak; Zlatic, Marta; Kim, Douglas S; Ahrens, Misha B; Jayaraman, Vivek; Looger, Loren L; Schreiter, Eric R

2015-02-13

The identification of active neurons and circuits in vivo is a fundamental challenge in understanding the neural basis of behavior. Genetically encoded calcium (Ca(2+)) indicators (GECIs) enable quantitative monitoring of cellular-resolution activity during behavior. However, such indicators require online monitoring within a limited field of view. Alternatively, post hoc staining of immediate early genes (IEGs) indicates highly active cells within the entire brain, albeit with poor temporal resolution. We designed a fluorescent sensor, CaMPARI, that combines the genetic targetability and quantitative link to neural activity of GECIs with the permanent, large-scale labeling of IEGs, allowing a temporally precise "activity snapshot" of a large tissue volume. CaMPARI undergoes efficient and irreversible green-to-red conversion only when elevated intracellular Ca(2+) and experimenter-controlled illumination coincide. We demonstrate the utility of CaMPARI in freely moving larvae of zebrafish and flies, and in head-fixed mice and adult flies. Copyright © 2015, American Association for the Advancement of Science.

A biotic video game smart phone kit for formal and informal biophysics education

NASA Astrophysics Data System (ADS)

Kim, Honesty; Lee, Seung Ah; Riedel-Kruse, Ingmar

2015-03-01

Novel ways for formal and informal biophysics education are important. We present a low-cost biotic game design kit that incorporates microbial organisms into an interactive gaming experience: A 3D-printable microscope containing four LEDs controlled by a joystick enable human players to provide directional light stimuli to the motile single-celled organism Euglena gracilis. These cellular behaviors are displayed on the integrated smart phone. Real time cell-tracking couples these cells into interactive biotic video game play, i.e., the human player steers Euglena to play soccer with virtual balls and goals. The player's learning curve in mastering this fun game is intrinsically coupled to develop a deeper knowledge about Euglena's cell morphology and the biophysics of its phototactic behavior. This kit is dual educational - via construction and via play - and it provides an engaging theme for a formal biophysics devices class as well as to be presented in informal outreach activities; its low cost and open soft- and hardware should enable wide adoption.

Differential growth of wrinkled biofilms

NASA Astrophysics Data System (ADS)

Espeso, D. R.; Carpio, A.; Einarsson, B.

2015-02-01

Biofilms are antibiotic-resistant bacterial aggregates that grow on moist surfaces and can trigger hospital-acquired infections. They provide a classical example in biology where the dynamics of cellular communities may be observed and studied. Gene expression regulates cell division and differentiation, which affect the biofilm architecture. Mechanical and chemical processes shape the resulting structure. We gain insight into the interplay between cellular and mechanical processes during biofilm development on air-agar interfaces by means of a hybrid model. Cellular behavior is governed by stochastic rules informed by a cascade of concentration fields for nutrients, waste, and autoinducers. Cellular differentiation and death alter the structure and the mechanical properties of the biofilm, which is deformed according to Föppl-Von Kármán equations informed by cellular processes and the interaction with the substratum. Stiffness gradients due to growth and swelling produce wrinkle branching. We are able to reproduce wrinkled structures often formed by biofilms on air-agar interfaces, as well as spatial distributions of differentiated cells commonly observed with B. subtilis.

Inter-cellular forces orchestrate contact inhibition of locomotion.

PubMed

Davis, John R; Luchici, Andrei; Mosis, Fuad; Thackery, James; Salazar, Jesus A; Mao, Yanlan; Dunn, Graham A; Betz, Timo; Miodownik, Mark; Stramer, Brian M

2015-04-09

Contact inhibition of locomotion (CIL) is a multifaceted process that causes many cell types to repel each other upon collision. During development, this seemingly uncoordinated reaction is a critical driver of cellular dispersion within embryonic tissues. Here, we show that Drosophila hemocytes require a precisely orchestrated CIL response for their developmental dispersal. Hemocyte collision and subsequent repulsion involves a stereotyped sequence of kinematic stages that are modulated by global changes in cytoskeletal dynamics. Tracking actin retrograde flow within hemocytes in vivo reveals synchronous reorganization of colliding actin networks through engagement of an inter-cellular adhesion. This inter-cellular actin-clutch leads to a subsequent build-up in lamellar tension, triggering the development of a transient stress fiber, which orchestrates cellular repulsion. Our findings reveal that the physical coupling of the flowing actin networks during CIL acts as a mechanotransducer, allowing cells to haptically sense each other and coordinate their behaviors. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Super-Resolution Microscopy: Shedding Light on the Cellular Plasma Membrane.

PubMed

Stone, Matthew B; Shelby, Sarah A; Veatch, Sarah L

2017-06-14

Lipids and the membranes they form are fundamental building blocks of cellular life, and their geometry and chemical properties distinguish membranes from other cellular environments. Collective processes occurring within membranes strongly impact cellular behavior and biochemistry, and understanding these processes presents unique challenges due to the often complex and myriad interactions between membrane components. Super-resolution microscopy offers a significant gain in resolution over traditional optical microscopy, enabling the localization of individual molecules even in densely labeled samples and in cellular and tissue environments. These microscopy techniques have been used to examine the organization and dynamics of plasma membrane components, providing insight into the fundamental interactions that determine membrane functions. Here, we broadly introduce the structure and organization of the mammalian plasma membrane and review recent applications of super-resolution microscopy to the study of membranes. We then highlight some inherent challenges faced when using super-resolution microscopy to study membranes, and we discuss recent technical advancements that promise further improvements to super-resolution microscopy and its application to the plasma membrane.

Simulation of the Burridge-Knopoff model of earthquakes with variable range stress transfer.

PubMed

Xia, Junchao; Gould, Harvey; Klein, W; Rundle, J B

2005-12-09

Simple models of earthquake faults are important for understanding the mechanisms for their observed behavior, such as Gutenberg-Richter scaling and the relation between large and small events, which is the basis for various forecasting methods. Although cellular automaton models have been studied extensively in the long-range stress transfer limit, this limit has not been studied for the Burridge-Knopoff model, which includes more realistic friction forces and inertia. We find that the latter model with long-range stress transfer exhibits qualitatively different behavior than both the long-range cellular automaton models and the usual Burridge-Knopoff model with nearest-neighbor springs, depending on the nature of the velocity-weakening friction force. These results have important implications for our understanding of earthquakes and other driven dissipative systems.

Tissue morphodynamics shaping the early mouse embryo.

PubMed

Sutherland, Ann E

2016-07-01

Generation of the elongated vertebrate body plan from the initially radially symmetrical embryo requires comprehensive changes to tissue form. These shape changes are generated by specific underlying cell behaviors, coordinated in time and space. Major principles and also specifics are emerging, from studies in many model systems, of the cell and physical biology of how region-specific cell behaviors produce regional tissue morphogenesis, and how these, in turn, are integrated at the level of the embryo. New technical approaches have made it possible more recently, to examine the morphogenesis of the mouse embryo in depth, and to elucidate the underlying cellular mechanisms. This review focuses on recent advances in understanding the cellular basis for the early fundamental events that establish the basic form of the embryo. Copyright © 2016 Elsevier Ltd. All rights reserved.

Metabolism and function of phenazines in bacteria: impacts on the behavior of bacteria in the environment and biotechnological processes

PubMed Central

Pierson, Elizabeth A.

2010-01-01

Phenazines constitute a large group of nitrogen-containing heterocyclic compounds produced by a diverse range of bacteria. Both natural and synthetic phenazine derivatives are studied due their impacts on bacterial interactions and biotechnological processes. Phenazines serve as electron shuttles to alternate terminal acceptors, modify cellular redox states, act as cell signals that regulate patterns of gene expression, contribute to biofilm formation and architecture, and enhance bacterial survival. Phenazines have diverse effects on eukaryotic hosts and host tissues, including the modification of multiple host cellular responses. In plants, phenazines also may influence growth and elicit induced systemic resistance. Here, we discuss emerging evidence that phenazines play multiple roles for the producing organism and contribute to their behavior and ecological fitness. PMID:20352425

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

Hofstetter, Markus; Howgate, John; Schmid, Martin

Highlights: Black-Right-Pointing-Pointer Gallium nitride based sensors show promising characteristics to monitor cellular parameters. Black-Right-Pointing-Pointer Cell growth experiments reveal excellent biocompatibiltiy of the host GaN material. Black-Right-Pointing-Pointer We present a biofunctionality assay using ionizing radiation. Black-Right-Pointing-Pointer DNA repair is utilized to evaluate material induced alterations in the cellular behavior. Black-Right-Pointing-Pointer GaN shows no bio-functional influence on the cellular environment. -- Abstract: There is an increasing interest in the integration of hybrid bio-semiconductor systems for the non-invasive evaluation of physiological parameters. High quality gallium nitride and its alloys show promising characteristics to monitor cellular parameters. Nevertheless, such applications not only request appropriatemore » sensing capabilities but also the biocompatibility and especially the biofunctionality of materials. Here we show extensive biocompatibility studies of gallium nitride and, for the first time, a biofunctionality assay using ionizing radiation. Analytical sensor devices are used in medical settings, as well as for cell- and tissue engineering. Within these fields, semiconductor devices have increasingly been applied for online biosensing on a cellular and tissue level. Integration of advanced materials such as gallium nitride into these systems has the potential to increase the range of applicability for a multitude of test devices and greatly enhance sensitivity and functionality. However, for such applications it is necessary to optimize cell-surface interactions and to verify the biocompatibility of the semiconductor. In this work, we present studies of mouse fibroblast cell activity grown on gallium nitride surfaces after applying external noxa. Cell-semiconductor hybrids were irradiated with X-rays at air kerma doses up to 250 mGy and the DNA repair dynamics, cell proliferation, and cell growth dynamics of adherent cells were compared to control samples. The impact of ionizing radiation on DNA, along with the associated cellular repair mechanisms, is well characterized and serves as a reference tool for evaluation of substrate effects. The results indicate that gallium nitride does not require specific surface treatments to ensure biocompatibility and suggest that cell signaling is not affected by micro-environmental alterations arising from gallium nitride-cell interactions. The observation that gallium nitride provides no bio-functional influence on the cellular environment confirms that this material is well suited for future biosensing applications without the need for additional chemical surface modification.« less

Process-Structure-Property Relationships for 316L Stainless Steel Fabricated by Additive Manufacturing and Its Implication for Component Engineering

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

Yang, Nancy; Yee, J.; Zheng, B.

We investigate the process-structure-property relationships for 316L stainless steel prototyping utilizing 3-D laser engineered net shaping (LENS), a commercial direct energy deposition additive manufacturing process. Our study concluded that the resultant physical metallurgy of 3-D LENS 316L prototypes is dictated by the interactive metallurgical reactions, during instantaneous powder feeding/melting, molten metal flow and liquid metal solidification. This study also showed 3-D LENS manufacturing is capable of building high strength and ductile 316L prototypes due to its fine cellular spacing from fast solidification cooling, and the well-fused epitaxial interfaces at metal flow trails and interpass boundaries. However, without further LENS processmore » control and optimization, the deposits are vulnerable to localized hardness variation attributed to heterogeneous microstructure, i.e., the interpass heat-affected zone (HAZ) from repetitive thermal heating during successive layer depositions. Most significantly, the current deposits exhibit anisotropic tensile behavior, i.e., lower strain and/or premature interpass delamination parallel to build direction (axial). This anisotropic behavior is attributed to the presence of interpass HAZ, which coexists with flying feedstock inclusions and porosity from incomplete molten metal fusion. Our current observations and findings contribute to the scientific basis for future process control and optimization necessary for material property control and defect mitigation.« less

Process-Structure-Property Relationships for 316L Stainless Steel Fabricated by Additive Manufacturing and Its Implication for Component Engineering

DOE PAGES

Yang, Nancy; Yee, J.; Zheng, B.; ...

2016-12-08

We investigate the process-structure-property relationships for 316L stainless steel prototyping utilizing 3-D laser engineered net shaping (LENS), a commercial direct energy deposition additive manufacturing process. Our study concluded that the resultant physical metallurgy of 3-D LENS 316L prototypes is dictated by the interactive metallurgical reactions, during instantaneous powder feeding/melting, molten metal flow and liquid metal solidification. This study also showed 3-D LENS manufacturing is capable of building high strength and ductile 316L prototypes due to its fine cellular spacing from fast solidification cooling, and the well-fused epitaxial interfaces at metal flow trails and interpass boundaries. However, without further LENS processmore » control and optimization, the deposits are vulnerable to localized hardness variation attributed to heterogeneous microstructure, i.e., the interpass heat-affected zone (HAZ) from repetitive thermal heating during successive layer depositions. Most significantly, the current deposits exhibit anisotropic tensile behavior, i.e., lower strain and/or premature interpass delamination parallel to build direction (axial). This anisotropic behavior is attributed to the presence of interpass HAZ, which coexists with flying feedstock inclusions and porosity from incomplete molten metal fusion. Our current observations and findings contribute to the scientific basis for future process control and optimization necessary for material property control and defect mitigation.« less

Manufacturing and Characterization of 18Ni Marage 300 Lattice Components by Selective Laser Melting

PubMed Central

Contuzzi, Nicola; Campanelli, Sabina L.; Casavola, Caterina; Lamberti, Luciano

2013-01-01

The spreading use of cellular structures brings the need to speed up manufacturing processes without deteriorating mechanical properties. By using Selective Laser Melting (SLM) to produce cellular structures, the designer has total freedom in defining part geometry and manufacturing is simplified. The paper investigates the suitability of Selective Laser Melting for manufacturing steel cellular lattice structures with characteristic dimensions in the micrometer range. Alternative lattice topologies including reinforcing bars in the vertical direction also are considered. The selected lattice structure topology is shown to be superior over other lattice structure designs considered in literature. Compression tests are carried out in order to evaluate mechanical strength of lattice strut specimens made via SLM. Compressive behavior of samples also is simulated by finite element analysis and numerical results are compared with experimental data in order to assess the constitutive behavior of the lattice structure designs considered in this study. Experimental data show that it is possible to build samples of relative density in the 0.2456–0.4367 range. Compressive strength changes almost linearly with respect to relative density, which in turns depends linearly on the number of vertical reinforces. Specific strength increases with cell and strut edge size. Numerical simulations confirm the plastic nature of the instability phenomena that leads the cellular structures to collapse under compression loading. PMID:28811445

In vitro and in vivo analysis and characterization of engineered spinal neural implants (Conference Presentation)

NASA Astrophysics Data System (ADS)

Shor, Erez; Shoham, Shy; Levenberg, Shulamit

2016-03-01

Spinal cord injury is a devastating medical condition. Recent developments in pre-clinical and clinical research have started to yield neural implants inducing functional recovery after spinal cord transection injury. However, the functional performance of the transplants was assessed using histology and behavioral experiments which are unable to study cell dynamics and the therapeutic response. Here, we use neurophotonic tools and optogenetic probes to investigate cellular level morphology and activity characteristics of neural implants over time at the cellular level. These methods were used in-vitro and in-vivo, in a mouse spinal cord injury implant model. Following previous attempts to induce recovery after spinal cord injury, we engineered a pre-vascularized implant to obtain better functional performance. To image network activity of a construct implanted in a mouse spinal cord, we transfected the implant to express GCaMP6 calcium activity indicators and implanted these constructs under a spinal cord chamber enabling 2-photon chronic in vivo neural activity imaging. Activity and morphology analysis image processing software was developed to automatically quantify the behavior of the neural and vascular networks. Our experimental results and analyses demonstrate that vascularized and non-vascularized constructs exhibit very different morphologic and activity patterns at the cellular level. This work enables further optimization of neural implants and also provides valuable tools for continuous cellular level monitoring and evaluation of transplants designed for various neurodegenerative disease models.

Smooth muscle-like tissue constructs with circumferentially oriented cells formed by the cell fiber technology.

PubMed

Hsiao, Amy Y; Okitsu, Teru; Onoe, Hiroaki; Kiyosawa, Mahiro; Teramae, Hiroki; Iwanaga, Shintaroh; Kazama, Tomohiko; Matsumoto, Taro; Takeuchi, Shoji

2015-01-01

The proper functioning of many organs and tissues containing smooth muscles greatly depends on the intricate organization of the smooth muscle cells oriented in appropriate directions. Consequently controlling the cellular orientation in three-dimensional (3D) cellular constructs is an important issue in engineering tissues of smooth muscles. However, the ability to precisely control the cellular orientation at the microscale cannot be achieved by various commonly used 3D tissue engineering building blocks such as spheroids. This paper presents the formation of coiled spring-shaped 3D cellular constructs containing circumferentially oriented smooth muscle-like cells differentiated from dedifferentiated fat (DFAT) cells. By using the cell fiber technology, DFAT cells suspended in a mixture of extracellular proteins possessing an optimized stiffness were encapsulated in the core region of alginate shell microfibers and uniformly aligned to the longitudinal direction. Upon differentiation induction to the smooth muscle lineage, DFAT cell fibers self-assembled to coiled spring structures where the cells became circumferentially oriented. By changing the initial core-shell microfiber diameter, we demonstrated that the spring pitch and diameter could be controlled. 21 days after differentiation induction, the cell fibers contained high percentages of ASMA-positive and calponin-positive cells. Our technology to create these smooth muscle-like spring constructs enabled precise control of cellular alignment and orientation in 3D. These constructs can further serve as tissue engineering building blocks for larger organs and cellular implants used in clinical treatments.

Smooth Muscle-Like Tissue Constructs with Circumferentially Oriented Cells Formed by the Cell Fiber Technology

PubMed Central

Hsiao, Amy Y.; Okitsu, Teru; Onoe, Hiroaki; Kiyosawa, Mahiro; Teramae, Hiroki; Iwanaga, Shintaroh; Kazama, Tomohiko; Matsumoto, Taro; Takeuchi, Shoji

2015-01-01

The proper functioning of many organs and tissues containing smooth muscles greatly depends on the intricate organization of the smooth muscle cells oriented in appropriate directions. Consequently controlling the cellular orientation in three-dimensional (3D) cellular constructs is an important issue in engineering tissues of smooth muscles. However, the ability to precisely control the cellular orientation at the microscale cannot be achieved by various commonly used 3D tissue engineering building blocks such as spheroids. This paper presents the formation of coiled spring-shaped 3D cellular constructs containing circumferentially oriented smooth muscle-like cells differentiated from dedifferentiated fat (DFAT) cells. By using the cell fiber technology, DFAT cells suspended in a mixture of extracellular proteins possessing an optimized stiffness were encapsulated in the core region of alginate shell microfibers and uniformly aligned to the longitudinal direction. Upon differentiation induction to the smooth muscle lineage, DFAT cell fibers self-assembled to coiled spring structures where the cells became circumferentially oriented. By changing the initial core-shell microfiber diameter, we demonstrated that the spring pitch and diameter could be controlled. 21 days after differentiation induction, the cell fibers contained high percentages of ASMA-positive and calponin-positive cells. Our technology to create these smooth muscle-like spring constructs enabled precise control of cellular alignment and orientation in 3D. These constructs can further serve as tissue engineering building blocks for larger organs and cellular implants used in clinical treatments. PMID:25734774

ELECTRICAL SIGNALING IN CONTROL OF OCULAR CELL BEHAVIORS

PubMed Central

Zhao, Min; Chalmers, Laura; Cao, Lin; Viera, Ana C.; Mannis, Mark; Reid, Brian

2011-01-01

Epithelia of the cornea, lens and retina contain a vast array of ion channels and pumps. Together they produce a polarized flow of ions in and out of cells, as well as across the epithelia. These naturally occurring ion fluxes are essential to the hydration and metabolism of the ocular tissues, especially for the avascular cornea and lens. The directional transport of ions generates electric fields and currents in those tissues. Applied electric fields affect migration, division and proliferation of ocular cells which are important in homeostasis and healing of the ocular tissues. Abnormalities in any of those aspects may underlie many ocular diseases, for example chronic corneal ulcers, posterior capsule opacity after cataract surgery, and retinopathies. Electric field-inducing cellular responses, termed electrical signaling here, therefore may be an unexpected yet powerful mechanism in regulating ocular cell behavior. Both endogenous electric fields and applied electric fields could be exploited to regulate ocular cells. We aim to briefly describe the physiology of the naturally occurring electrical activities in the corneal, lens, and retinal epithelia, to provide experimental evidence of the effects of electric fields on ocular cell behaviors, and to suggest possible clinical implications. PMID:22020127

Mechanically dynamic PDMS substrates to investigate changing cell environments

PubMed Central

Yeh, Yi-Cheun; Corbin, Elise A.; Caliari, Steven R.; Ouyang, Liu; Vega, Sebastián L.; Truitt, Rachel; Han, Lin; Margulies, Kenneth B.; Burdick, Jason A.

2018-01-01

Mechanics of the extracellular matrix (ECM) play a pivotal role in governing cell behavior, such as cell spreading and differentiation. ECM mechanics have been recapitulated primarily in elastic hydrogels, including with dynamic properties to mimic complex behaviors (e.g., fibrosis); however, these dynamic hydrogels fail to introduce the viscoelastic nature of many tissues. Here, we developed a two-step crosslinking strategy to first form (via platinum-catalyzed crosslinking) networks of polydimethylsiloxane (PDMS) and then to increase PDMS crosslinking (via thiol-ene click reaction) in a temporally-controlled manner. This photoinitiated reaction increased the compressive modulus of PDMS up to 10-fold within minutes and was conducted under cytocompatible conditions. With stiffening, cells displayed increased spreading, changing from ~1300 to 1900 μm2 and from ~2700 to 4600 μm2 for fibroblasts and mesenchymal stem cells, respectively. In addition, higher myofibroblast activation (from ~2 to 20%) for cardiac fibroblasts was observed with increasing PDMS substrate stiffness. These results indicate a cellular response to changes in PDMS substrate mechanics, along with a demonstration of a mechanically dynamic and photoresponsive PDMS substrate platform to model the dynamic behavior of ECM. PMID:28843064

Mechanically dynamic PDMS substrates to investigate changing cell environments.

PubMed

Yeh, Yi-Cheun; Corbin, Elise A; Caliari, Steven R; Ouyang, Liu; Vega, Sebastián L; Truitt, Rachel; Han, Lin; Margulies, Kenneth B; Burdick, Jason A

2017-11-01

Mechanics of the extracellular matrix (ECM) play a pivotal role in governing cell behavior, such as cell spreading and differentiation. ECM mechanics have been recapitulated primarily in elastic hydrogels, including with dynamic properties to mimic complex behaviors (e.g., fibrosis); however, these dynamic hydrogels fail to introduce the viscoelastic nature of many tissues. Here, we developed a two-step crosslinking strategy to first form (via platinum-catalyzed crosslinking) networks of polydimethylsiloxane (PDMS) and then to increase PDMS crosslinking (via thiol-ene click reaction) in a temporally-controlled manner. This photoinitiated reaction increased the compressive modulus of PDMS up to 10-fold within minutes and was conducted under cytocompatible conditions. With stiffening, cells displayed increased spreading, changing from ∼1300 to 1900 μm 2 and from ∼2700 to 4600 μm 2 for fibroblasts and mesenchymal stem cells, respectively. In addition, higher myofibroblast activation (from ∼2 to 20%) for cardiac fibroblasts was observed with increasing PDMS substrate stiffness. These results indicate a cellular response to changes in PDMS substrate mechanics, along with a demonstration of a mechanically dynamic and photoresponsive PDMS substrate platform to model the dynamic behavior of ECM. Copyright © 2017 Elsevier Ltd. All rights reserved.

Running wheel training does not change neurogenesis levels or alter working memory tasks in adult rats

PubMed Central

Rojas, Manuel J.; Cardenas P., Fernando

2017-01-01

Background Exercise can change cellular structure and connectivity (neurogenesis or synaptogenesis), causing alterations in both behavior and working memory. The aim of this study was to evaluate the effect of exercise on working memory and hippocampal neurogenesis in adult male Wistar rats using a T-maze test. Methods An experimental design with two groups was developed: the experimental group (n = 12) was subject to a forced exercise program for five days, whereas the control group (n = 9) stayed in the home cage. Six to eight weeks after training, the rats’ working memory was evaluated in a T-maze test and four choice days were analyzed, taking into account alternation as a working memory indicator. Hippocampal neurogenesis was evaluated by means of immunohistochemistry of BrdU positive cells. Results No differences between groups were found in the behavioral variables (alternation, preference index, time of response, time of trial or feeding), or in the levels of BrdU positive cells. Discussion Results suggest that although exercise may have effects on brain structure, a construct such as working memory may require more complex changes in networks or connections to demonstrate a change at behavioral level. PMID:28503368

Synaptic potentiation onto habenula neurons in learned helplessness model of depression

PubMed Central

Li, Bo; Piriz, Joaquin; Mirrione, Martine; Chung, ChiHye; Proulx, Christophe D.; Schulz, Daniela; Henn, Fritz; Malinow, Roberto

2010-01-01

The cellular basis of depressive disorders is poorly understood1. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (i.e. disappointment or anticipation of a negative outcome)2, 3, 4. LHb neurons project to and modulate dopamine-rich regions such as the ventral-tegmental area (VTA)2, 5 that control reward-seeking behavior6 and participate in depressive disorders7. Here we show in two learned helplessness models of depression that excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal’s helplessness behavior and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective on depressed patients8, 9, dramatically suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behavior in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression. PMID:21350486

Delay and Trace Fear Conditioning in C57BL/6 and DBA/2 Mice: Issues of Measurement and Performance

ERIC Educational Resources Information Center

Tipps, Megan E.; Raybuck, Jonathan D.; Buck, Kari J.; Lattal, K. Matthew

2014-01-01

Strain comparison studies have been critical to the identification of novel genetic and molecular mechanisms in learning and memory. However, even within a single learning paradigm, the behavioral data for the same strain can vary greatly, making it difficult to form meaningful conclusions at both the behavioral and cellular level. In fear…

Immune Abnormalities in Autism Spectrum Disorder-Could They Hold Promise for Causative Treatment?

PubMed

Gładysz, Dominika; Krzywdzińska, Amanda; Hozyasz, Kamil K

2018-01-06

Autism spectrum disorders (ASD) are characterized by impairments in language and communication development, social behavior, and the occurrence of stereotypic patterns of behavior and interests. Despite substantial speculation about causes of ASD, its exact etiology remains unknown. Recent studies highlight a link between immune dysfunction and behavioral traits. Various immune anomalies, including humoral and cellular immunity along with abnormalities at the molecular level, have been reported. There is evidence of altered immune function both in cerebrospinal fluid and peripheral blood. Several studies hypothesize a role for neuroinflammation in ASD and are supported by brain tissue and cerebrospinal fluid analysis, as well as evidence of microglial activation. It has been shown that immune abnormalities occur in a substantial number of individuals with ASD. Identifying subgroups with immune system dysregulation and linking specific cellular immunophenotypes to different symptoms would be key to defining a group of patients with immune abnormalities as a major etiology underlying behavioral symptoms. These determinations would provide the opportunity to investigate causative treatments for a defined patient group that may specifically benefit from such an approach. This review summarizes recent insights into immune system dysfunction in individuals with ASD and discusses the potential implications for future therapies.

Deep brain optical measurements of cell type-specific neural activity in behaving mice.

PubMed

Cui, Guohong; Jun, Sang Beom; Jin, Xin; Luo, Guoxiang; Pham, Michael D; Lovinger, David M; Vogel, Steven S; Costa, Rui M

2014-01-01

Recent advances in genetically encoded fluorescent sensors enable the monitoring of cellular events from genetically defined groups of neurons in vivo. In this protocol, we describe how to use a time-correlated single-photon counting (TCSPC)-based fiber optics system to measure the intensity, emission spectra and lifetime of fluorescent biosensors expressed in deep brain structures in freely moving mice. When combined with Cre-dependent selective expression of genetically encoded Ca(2+) indicators (GECIs), this system can be used to measure the average neural activity from a specific population of cells in mice performing complex behavioral tasks. As an example, we used viral expression of GCaMPs in striatal projection neurons (SPNs) and recorded the fluorescence changes associated with calcium spikes from mice performing a lever-pressing operant task. The whole procedure, consisting of virus injection, behavior training and optical recording, takes 3-4 weeks to complete. With minor adaptations, this protocol can also be applied to recording cellular events from other cell types in deep brain regions, such as dopaminergic neurons in the ventral tegmental area. The simultaneously recorded fluorescence signals and behavior events can be used to explore the relationship between the neural activity of specific brain circuits and behavior.

Integrating Computer/Multimedia Technology in a High School Biology Curriculum.

ERIC Educational Resources Information Center

Matray, Paul; Proulx, Steve

1995-01-01

Discusses hardware and software used to teach scientific method, ecology, evolution, mitosis and meiosis, photosynthesis, cellular respiration, circulatory and respiratory systems, reproduction and drugs, behavior, and genetics. (MKR)

Astrocytes Regulate GLP-1 Receptor-Mediated Effects on Energy Balance

PubMed Central

Reiner, David J.; Mietlicki-Baase, Elizabeth G.; McGrath, Lauren E.; Zimmer, Derek J.; Bence, Kendra K.; Sousa, Gregory L.; Konanur, Vaibhav R.; Krawczyk, Joanna; Burk, David H.; Kanoski, Scott E.; Hermann, Gerlinda E.; Rogers, Richard C.

2016-01-01

Astrocytes are well established modulators of extracellular glutamate, but their direct influence on energy balance-relevant behaviors is largely understudied. As the anorectic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists are partly mediated by central modulation of glutamatergic signaling, we tested the hypothesis that astrocytic GLP-1R signaling regulates energy balance in rats. Central or peripheral administration of a fluorophore-labeled GLP-1R agonist, exendin-4, localizes within astrocytes and neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus critical for energy balance control. This effect is mediated by GLP-1R, as the uptake of systemically administered fluorophore-tagged exendin-4 was blocked by central pretreatment with the competitive GLP-1R antagonist exendin-(9–39). Ex vivo analyses show prolonged exendin-4-induced activation (live cell calcium signaling) of NTS astrocytes and neurons; these effects are also attenuated by exendin-(9–39), indicating mediation by the GLP-1R. In vitro analyses show that the application of GLP-1R agonists increases cAMP levels in astrocytes. Immunohistochemical analyses reveal that endogenous GLP-1 axons form close synaptic apposition with NTS astrocytes. Finally, pharmacological inhibition of NTS astrocytes attenuates the anorectic and body weight-suppressive effects of intra-NTS GLP-1R activation. Collectively, data demonstrate a role for NTS astrocytic GLP-1R signaling in energy balance control. SIGNIFICANCE STATEMENT Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are approved by the Food and Drug Administration for the treatment of obesity, but the cellular mechanisms underlying the anorectic effects of GLP-1 require further investigation. Astrocytes represent a major cellular population in the CNS that regulates neurotransmission, yet the role of astrocytes in mediating energy balance is largely unstudied. The current data provide novel evidence that astrocytes within the NTS are relevant for energy balance control by GLP-1 signaling. Here, we report that GLP-1R agonists activate and internalize within NTS astrocytes, while behavioral data suggest the pharmacological relevance of NTS astrocytic GLP-1R activation for food intake and body weight. These findings support a previously unknown role for CNS astrocytes in energy balance control by GLP-1 signaling. PMID:27013681

Microfluidic engineering of neural stem cell niches for fate determination

PubMed Central

Ma, Jingyun; Li, Na; Wang, Liang; Shen, Liming; Sun, Yu; Wang, Yajun; Zhao, Jingyuan; Wei, Wenjuan; Ren, Yan; Liu, Jing

2017-01-01

Neural stem cell (NSC) transplantation has great therapeutic potential for neurodegenerative diseases and central nervous system injuries. Successful NSC replacement therapy requires precise control over the cellular behaviors. However, the regulation of NSC fate is largely unclear, which severely restricts the potential clinical applications. To develop an effective model, we designed an assembled microfluidic system to engineer NSC niches and assessed the effects of various culture conditions on NSC fate determination. Five types of NSC microenvironments, including two-dimensional (2D) cellular monolayer culture, 2D cellular monolayer culture on the extracellular matrix (ECM), dispersed cells in the ECM, three-dimensional (3D) spheroid aggregates, and 3D spheroids cultured in the ECM, were constructed within an integrated microfluidic chip simultaneously. In addition, we evaluated the influence of static and perfusion culture on NSCs. The efficiency of this approach was evaluated comprehensively by characterization of NSC viability, self-renewal, proliferation, and differentiation into neurons, astrocytes, or oligodendrocytes. Differences in the status and fate of NSCs governed by the culture modes and micro-niches were analyzed. NSCs in the microfluidic device demonstrated good viability, the 3D culture in the ECM facilitated NSC self-renewal and proliferation, and 2D culture in the static state and spheroid culture under perfusion conditions benefited NSC differentiation. Regulation of NSC self-renewal and differentiation on this microfluidic device could provide NSC-based medicinal products and references for distinct nerve disease therapy. PMID:28798841

Controlling nuclear RNA levels.

PubMed

Schmid, Manfred; Jensen, Torben Heick

2018-05-10

RNA turnover is an integral part of cellular RNA homeostasis and gene expression regulation. Whereas the cytoplasmic control of protein-coding mRNA is often the focus of study, we discuss here the less appreciated role of nuclear RNA decay systems in controlling RNA polymerase II (RNAPII)-derived transcripts. Historically, nuclear RNA degradation was found to be essential for the functionalization of transcripts through their proper maturation. Later, it was discovered to also be an important caretaker of nuclear hygiene by removing aberrant and unwanted transcripts. Recent years have now seen a set of new protein complexes handling a variety of new substrates, revealing functions beyond RNA processing and the decay of non-functional transcripts. This includes an active contribution of nuclear RNA metabolism to the overall cellular control of RNA levels, with mechanistic implications during cellular transitions.

[Neurotransmitter mechanisms of context-dependent behavior].

PubMed

D'iakonova, V E

2012-01-01

The influence of context on behavioral choice is well known. Context can refer to behavioral state of an animal and to external factors such as season, presence of other individuals or food availability. How external and internal factors influencing decision-making are translated at the cellular level? I review the recent neuroethological data that strongly suggest that context reflects in content of neuroactive substances (neurotransmitters, modulators, hormones) that present in the extraneuronal milieu, while heterochemical neuronal microenvironment in its turn impacts motor program selection.

Diverse activities of viral cis-acting RNA regulatory elements revealed using multicolor, long-term, single-cell imaging.

PubMed

Pocock, Ginger M; Zimdars, Laraine L; Yuan, Ming; Eliceiri, Kevin W; Ahlquist, Paul; Sherer, Nathan M

2017-02-01

Cis-acting RNA structural elements govern crucial aspects of viral gene expression. How these structures and other posttranscriptional signals affect RNA trafficking and translation in the context of single cells is poorly understood. Herein we describe a multicolor, long-term (>24 h) imaging strategy for measuring integrated aspects of viral RNA regulatory control in individual cells. We apply this strategy to demonstrate differential mRNA trafficking behaviors governed by RNA elements derived from three retroviruses (HIV-1, murine leukemia virus, and Mason-Pfizer monkey virus), two hepadnaviruses (hepatitis B virus and woodchuck hepatitis virus), and an intron-retaining transcript encoded by the cellular NXF1 gene. Striking behaviors include "burst" RNA nuclear export dynamics regulated by HIV-1's Rev response element and the viral Rev protein; transient aggregations of RNAs into discrete foci at or near the nuclear membrane triggered by multiple elements; and a novel, pulsiform RNA export activity regulated by the hepadnaviral posttranscriptional regulatory element. We incorporate single-cell tracking and a data-mining algorithm into our approach to obtain RNA element-specific, high-resolution gene expression signatures. Together these imaging assays constitute a tractable, systems-based platform for studying otherwise difficult to access spatiotemporal features of viral and cellular gene regulation. © 2017 Pocock et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Oleic Acid in the Ventral Tegmental Area Inhibits Feeding, Food Reward, and Dopamine Tone.

PubMed

Hryhorczuk, Cecile; Sheng, Zhenyu; Décarie-Spain, Léa; Giguère, Nicolas; Ducrot, Charles; Trudeau, Louis-Éric; Routh, Vanessa H; Alquier, Thierry; Fulton, Stephanie

2018-02-01

Long-chain fatty acids (FAs) act centrally to decrease food intake and hepatic glucose production and alter hypothalamic neuronal activity in a manner that depends on FA type and cellular transport proteins. However, it is not known whether FAs are sensed by ventral tegmental area (VTA) dopamine (DA) neurons to control food-motivated behavior and DA neurotransmission. We investigated the impact of the monounsaturated FA oleate in the VTA on feeding, locomotion, food reward, and DA neuronal activity and DA neuron expression of FA-handling proteins and FA uptake. A single intra-VTA injection of oleate, but not of the saturated FA palmitate, decreased food intake and increased locomotor activity. Furthermore, intra-VTA oleate blunted the rewarding effects of high-fat/sugar food in an operant task and inhibited DA neuronal firing. Using sorted DA neuron preparations from TH-eGFP mice we found that DA neurons express FA transporter and binding proteins, and are capable of intracellular transport of long-chain FA. Finally, we demonstrate that a transporter blocker attenuates FA uptake into DA neurons and blocks the effects of intra-VTA oleate to decrease food-seeking and DA neuronal activity. Together, these results suggest that DA neurons detect FA and that oleate has actions in the VTA to suppress DA neuronal activity and food seeking following cellular incorporation. These findings highlight the capacity of DA neurons to act as metabolic sensors by responding not only to hormones but also to FA nutrient signals to modulate food-directed behavior.

The Vertebrate Brain, Evidence of Its Modular Organization and Operating System: Insights into the Brain's Basic Units of Structure, Function, and Operation and How They Influence Neuronal Signaling and Behavior.

PubMed

Baslow, Morris H

2011-01-01

The human brain is a complex organ made up of neurons and several other cell types, and whose role is processing information for use in eliciting behaviors. However, the composition of its repeating cellular units for both structure and function are unresolved. Based on recent descriptions of the brain's physiological "operating system", a function of the tri-cellular metabolism of N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) for supply of energy, and on the nature of "neuronal words and languages" for intercellular communication, insights into the brain's modular structural and functional units have been gained. In this article, it is proposed that the basic structural unit in brain is defined by its physiological operating system, and that it consists of a single neuron, and one or more astrocytes, oligodendrocytes, and vascular system endothelial cells. It is also proposed that the basic functional unit in the brain is defined by how neurons communicate, and consists of two neurons and their interconnecting dendritic-synaptic-dendritic field. Since a functional unit is composed of two neurons, it requires two structural units to form a functional unit. Thus, the brain can be envisioned as being made up of the three-dimensional stacking and intertwining of myriad structural units which results not only in its gross structure, but also in producing a uniform distribution of binary functional units. Since the physiological NAA-NAAG operating system for supply of energy is repeated in every structural unit, it is positioned to control global brain function.

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

Szymańska, Paulina; Martin, Katie R.; MacKeigan, Jeffrey P.

We constructed a mechanistic, computational model for regulation of (macro)autophagy and protein synthesis (at the level of translation). The model was formulated to study the system-level consequences of interactions among the following proteins: two key components of MTOR complex 1 (MTORC1), namely the protein kinase MTOR (mechanistic target of rapamycin) and the scaffold protein RPTOR; the autophagy-initiating protein kinase ULK1; and the multimeric energy-sensing AMP-activated protein kinase (AMPK). Inputs of the model include intrinsic AMPK kinase activity, which is taken as an adjustable surrogate parameter for cellular energy level or AMP:ATP ratio, and rapamycin dose, which controls MTORC1 activity. Outputsmore » of the model include the phosphorylation level of the translational repressor EIF4EBP1, a substrate of MTORC1, and the phosphorylation level of AMBRA1 (activating molecule in BECN1-regulated autophagy), a substrate of ULK1 critical for autophagosome formation. The model incorporates reciprocal regulation of mTORC1 and ULK1 by AMPK, mutual inhibition of MTORC1 and ULK1, and ULK1-mediated negative feedback regulation of AMPK. Through analysis of the model, we find that these processes may be responsible, depending on conditions, for graded responses to stress inputs, for bistable switching between autophagy and protein synthesis, or relaxation oscillations, comprising alternating periods of autophagy and protein synthesis. A sensitivity analysis indicates that the prediction of oscillatory behavior is robust to changes of the parameter values of the model. The model provides testable predictions about the behavior of the AMPK-MTORC1-ULK1 network, which plays a central role in maintaining cellular energy and nutrient homeostasis.« less

A novel image encryption algorithm using chaos and reversible cellular automata

NASA Astrophysics Data System (ADS)

Wang, Xingyuan; Luan, Dapeng

2013-11-01

In this paper, a novel image encryption scheme is proposed based on reversible cellular automata (RCA) combining chaos. In this algorithm, an intertwining logistic map with complex behavior and periodic boundary reversible cellular automata are used. We split each pixel of image into units of 4 bits, then adopt pseudorandom key stream generated by the intertwining logistic map to permute these units in confusion stage. And in diffusion stage, two-dimensional reversible cellular automata which are discrete dynamical systems are applied to iterate many rounds to achieve diffusion on bit-level, in which we only consider the higher 4 bits in a pixel because the higher 4 bits carry almost the information of an image. Theoretical analysis and experimental results demonstrate the proposed algorithm achieves a high security level and processes good performance against common attacks like differential attack and statistical attack. This algorithm belongs to the class of symmetric systems.

Spatial reconstruction of single-cell gene expression

PubMed Central

Satija, Rahul; Farrell, Jeffrey A.; Gennert, David; Schier, Alexander F.; Regev, Aviv

2015-01-01

Spatial localization is a key determinant of cellular fate and behavior, but spatial RNA assays traditionally rely on staining for a limited number of RNA species. In contrast, single-cell RNA-seq allows for deep profiling of cellular gene expression, but established methods separate cells from their native spatial context. Here we present Seurat, a computational strategy to infer cellular localization by integrating single-cell RNA-seq data with in situ RNA patterns. We applied Seurat to spatially map 851 single cells from dissociated zebrafish (Danio rerio) embryos, inferring a transcriptome-wide map of spatial patterning. We confirmed Seurat’s accuracy using several experimental approaches, and used it to identify a set of archetypal expression patterns and spatial markers. Additionally, Seurat correctly localizes rare subpopulations, accurately mapping both spatially restricted and scattered groups. Seurat will be applicable to mapping cellular localization within complex patterned tissues in diverse systems. PMID:25867923

Cellular complexity captured in durable silica biocomposites

PubMed Central

Kaehr, Bryan; Townson, Jason L.; Kalinich, Robin M.; Awad, Yasmine H.; Swartzentruber, B. S.; Dunphy, Darren R.; Brinker, C. Jeffrey

2012-01-01

Tissue-derived cultured cells exhibit a remarkable range of morphological features in vitro, depending on phenotypic expression and environmental interactions. Translation of these cellular architectures into inorganic materials would provide routes to generate hierarchical nanomaterials with stabilized structures and functions. Here, we describe the fabrication of cell/silica composites (CSCs) and their conversion to silica replicas using mammalian cells as scaffolds to direct complex structure formation. Under mildly acidic solution conditions, silica deposition is restricted to the molecularly crowded cellular template. Inter- and intracellular heterogeneity from the nano- to macroscale is captured and dimensionally preserved in CSCs following drying and subjection to extreme temperatures allowing, for instance, size and shape preserving pyrolysis of cellular architectures to form conductive carbon replicas. The structural and behavioral malleability of the starting material (cultured cells) provides opportunities to develop robust and economical biocomposites with programmed structures and functions. PMID:23045634

Evolution of Cellular Automata toward a LIFE-Like Rule Guided by 1/ƒ Noise

NASA Astrophysics Data System (ADS)

Ninagawa, Shigeru

There is evidence in favor of a relationship between the presence of 1/ƒ noise and computational universality in cellular automata. To confirm the relationship, we search for two-dimensional cellular automata with a 1/ƒ power spectrum by means of genetic algorithms. The power spectrum is calculated from the evolution of the state of the cell, starting from a random initial configuration. The fitness is estimated by the power spectrum with consideration of the spectral similarity to the 1/ƒ spectrum. The result shows that the rule with the highest fitness over the most runs exhibits a 1/ƒ type spectrum and its transition function and behavior are quite similar to those of the Game of Life, which is known to be a computationally universal cellular automaton. These results support the relationship between the presence of 1/ƒ noise and computational universality.

Atomic force microscopy studies on cellular elastic and viscoelastic properties.

PubMed

Li, Mi; Liu, Lianqing; Xi, Ning; Wang, Yuechao

2018-01-01

In this work, a method based on atomic force microscopy (AFM) approach-reside-retract experiments was established to simultaneously quantify the elastic and viscoelastic properties of single cells. First, the elastic and viscoelastic properties of normal breast cells and cancerous breast cells were measured, showing significant differences in Young's modulus and relaxation times between normal and cancerous breast cells. Remarkable differences in cellular topography between normal and cancerous breast cells were also revealed by AFM imaging. Next, the elastic and viscoelasitc properties of three other types of cell lines and primary normal B lymphocytes were measured; results demonstrated the potential of cellular viscoelastic properties in complementing cellular Young's modulus for discerning different states of cells. This research provides a novel way to quantify the mechanical properties of cells by AFM, which allows investigation of the biomechanical behaviors of single cells from multiple aspects.

Functional Assays for Neurotoxicity Testing

EPA Science Inventory

Neurobehavioral and pathological evaluations of the nervous system are complementary components of basic research and toxicity testing of pharmaceutical and environmental chemicals. While neuropathological assessments provide insight as to cellular changes in neurons, behavioral ...

Functional Assays for Neurotoxicity Testing*

EPA Science Inventory

Neurobehavioral and pathological evaluations of the nervous system are complementary components of basic research and toxicity testing of pharmaceutical and environmental chemicals. While neuropathological assessments provide insight as to cellular changes in neurons, behavioral ...

Endoplasmic Reticulum-Plasma Membrane Contacts Regulate Cellular Excitability.

PubMed

Dickson, Eamonn J

2017-01-01

Cells that have intrinsic electrical excitability utilize changes in membrane potential to communicate with neighboring cells and initiate cellular cascades. Excitable cells like neurons and myocytes have evolved highly specialized subcellular architectures to translate these electrical signals into cellular events. One such structural specialization is sarco-/endoplasmic reticulum-plasma membrane contact sites. These membrane contact sites are positioned by specific membrane-membrane tethering proteins and contain an ever-expanding list of additional proteins that organize information transfer across the junctional space (~ 15-25 nm distance) to shape membrane identity and control cellular excitability. In this chapter we discuss how contacts between the sarco-/endoplasmic reticulum and plasma membrane are essential for regulated excitation-contraction coupling in striated muscle and control of lipid-dependent ion channels.

Fire and Heat Spreading Model Based on Cellular Automata Theory

NASA Astrophysics Data System (ADS)

Samartsev, A. A.; Rezchikov, A. F.; Kushnikov, V. A.; Ivashchenko, V. A.; Bogomolov, A. S.; Filimonyuk, L. Yu; Dolinina, O. N.; Kushnikov, O. V.; Shulga, T. E.; Tverdokhlebov, V. A.; Fominykh, D. S.

2018-05-01

The distinctive feature of the proposed fire and heat spreading model in premises is the reduction of the computational complexity due to the use of the theory of cellular automata with probability rules of behavior. The possibilities and prospects of using this model in practice are noted. The proposed model has a simple mechanism of integration with agent-based evacuation models. The joint use of these models could improve floor plans and reduce the time of evacuation from premises during fires.

Reinforcement Learning of Two-Joint Virtual Arm Reaching in a Computer Model of Sensorimotor Cortex

PubMed Central

Neymotin, Samuel A.; Chadderdon, George L.; Kerr, Cliff C.; Francis, Joseph T.; Lytton, William W.

2014-01-01

Neocortical mechanisms of learning sensorimotor control involve a complex series of interactions at multiple levels, from synaptic mechanisms to cellular dynamics to network connectomics. We developed a model of sensory and motor neocortex consisting of 704 spiking model neurons. Sensory and motor populations included excitatory cells and two types of interneurons. Neurons were interconnected with AMPA/NMDA and GABAA synapses. We trained our model using spike-timing-dependent reinforcement learning to control a two-joint virtual arm to reach to a fixed target. For each of 125 trained networks, we used 200 training sessions, each involving 15 s reaches to the target from 16 starting positions. Learning altered network dynamics, with enhancements to neuronal synchrony and behaviorally relevant information flow between neurons. After learning, networks demonstrated retention of behaviorally relevant memories by using proprioceptive information to perform reach-to-target from multiple starting positions. Networks dynamically controlled which joint rotations to use to reach a target, depending on current arm position. Learning-dependent network reorganization was evident in both sensory and motor populations: learned synaptic weights showed target-specific patterning optimized for particular reach movements. Our model embodies an integrative hypothesis of sensorimotor cortical learning that could be used to interpret future electrophysiological data recorded in vivo from sensorimotor learning experiments. We used our model to make the following predictions: learning enhances synchrony in neuronal populations and behaviorally relevant information flow across neuronal populations, enhanced sensory processing aids task-relevant motor performance and the relative ease of a particular movement in vivo depends on the amount of sensory information required to complete the movement. PMID:24047323

A model of the regulatory network involved in the control of the cell cycle and cell differentiation in the Caenorhabditis elegans vulva.

PubMed

Weinstein, Nathan; Ortiz-Gutiérrez, Elizabeth; Muñoz, Stalin; Rosenblueth, David A; Álvarez-Buylla, Elena R; Mendoza, Luis

2015-03-13

There are recent experimental reports on the cross-regulation between molecules involved in the control of the cell cycle and the differentiation of the vulval precursor cells (VPCs) of Caenorhabditis elegans. Such discoveries provide novel clues on how the molecular mechanisms involved in the cell cycle and cell differentiation processes are coordinated during vulval development. Dynamic computational models are helpful to understand the integrated regulatory mechanisms affecting these cellular processes. Here we propose a simplified model of the regulatory network that includes sufficient molecules involved in the control of both the cell cycle and cell differentiation in the C. elegans vulva to recover their dynamic behavior. We first infer both the topology and the update rules of the cell cycle module from an expected time series. Next, we use a symbolic algorithmic approach to find which interactions must be included in the regulatory network. Finally, we use a continuous-time version of the update rules for the cell cycle module to validate the cyclic behavior of the network, as well as to rule out the presence of potential artifacts due to the synchronous updating of the discrete model. We analyze the dynamical behavior of the model for the wild type and several mutants, finding that most of the results are consistent with published experimental results. Our model shows that the regulation of Notch signaling by the cell cycle preserves the potential of the VPCs and the three vulval fates to differentiate and de-differentiate, allowing them to remain completely responsive to the concentration of LIN-3 and lateral signal in the extracellular microenvironment.

Glucose supplement reverses the fasting-induced suppression of cellular immunity in Mongolian gerbils (Meriones unguiculatus).

PubMed

Xu, De-Li; Wang, De-Hua

2011-10-01

Glucose plays an important role in immunity. Three day fasting will decrease cellular immunity and blood glucose levels in Mongolian gerbils (Meriones unguiculatus). In the present study, we tested the hypothesis that glucose supplement can reverse the fasting-induced suppression in cellular immunity in gerbils. Twenty-eight male gerbils were selected and randomly divided into fed and fasting groups. Half of the gerbils in each group were then provided with either 10% glucose water or pure water. After 66 h, each gerbil was injected with phytohaemagglutinin (PHA) solution to challenge cellular immunity. Results showed that glucose supplement restored blood glucose levels in fasted gerbils to those of the fed controls. It also recovered cellular immunity, body fat mass and serum leptin levels in fasted gerbils to the values of the fed controls. Blood glucose levels were positively correlated with body fat mass, leptin levels and cellular immune responses. Thymus and spleen masses, and white blood cells in fasted gerbils were not affected by glucose supplement. In general, our data demonstrate that glucose supplement could reverse fasting-induced suppression of cellular immunity in Mongolian gerbils. Copyright © 2011 Elsevier GmbH. All rights reserved.

Opposing Effects of Acute versus Chronic Blockade of Frontal Cortex Somatostatin-Positive Inhibitory Neurons on Behavioral Emotionality in Mice

PubMed Central

Soumier, Amelie; Sibille, Etienne

2014-01-01

Reduced expression of somatostatin (SST) is reported across chronic brain conditions including major depression and normal aging. SST is a signaling neuropeptide and marker of gamma-amino butyric acid (GABA) neurons, which specifically inhibit pyramidal neuron dendrites. Studies in auditory cortex suggest that chronic reduction in dendritic inhibition induces compensatory homeostatic adaptations that oppose the effects of acute inhibition. Whether such mechanisms occur in frontal cortex (FC) and affect behavioral outcome is not known. Here, we used two complementary viral vector strategies to examine the effects of acute vs chronic inhibition of SST-positive neurons on behavioral emotionality in adult mice. SST-IRES-Cre mice were injected in FC (prelimbic/precingulate) with CRE-dependent adeno-associated viral (AAV) vector encoding the engineered Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug (DREADD-hM4Di) or a control reporter (AAV-DIO-mCherry) for acute or chronic cellular inhibition. A separate cohort was injected with CRE-dependent AAV vectors expressing diphtheria toxin (DTA) to selectively ablate FC SST neurons. Mice were assessed for anxiety- and depressive-like behaviors (defined as emotionality). Results indicate that acute inhibition of FC SST neurons increased behavioral emotionality, whereas chronic inhibition decreased behavioral emotionality. Furthermore, ablation of FC SST neurons also decreased behavioral emotionality under baseline condition and after chronic stress. Together, our results reveal opposite effects of acute and chronic inhibition of FC SST neurons on behavioral emotionality and suggest the recruitment of homeostatic plasticity mechanisms that have implications for understanding the neurobiology of chronic brain conditions affecting dendritic-targeting inhibitory neurons. PMID:24690741

Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice.

PubMed

Soumier, Amelie; Sibille, Etienne

2014-08-01

Reduced expression of somatostatin (SST) is reported across chronic brain conditions including major depression and normal aging. SST is a signaling neuropeptide and marker of gamma-amino butyric acid (GABA) neurons, which specifically inhibit pyramidal neuron dendrites. Studies in auditory cortex suggest that chronic reduction in dendritic inhibition induces compensatory homeostatic adaptations that oppose the effects of acute inhibition. Whether such mechanisms occur in frontal cortex (FC) and affect behavioral outcome is not known. Here, we used two complementary viral vector strategies to examine the effects of acute vs chronic inhibition of SST-positive neurons on behavioral emotionality in adult mice. SST-IRES-Cre mice were injected in FC (prelimbic/precingulate) with CRE-dependent adeno-associated viral (AAV) vector encoding the engineered Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug (DREADD-hM4Di) or a control reporter (AAV-DIO-mCherry) for acute or chronic cellular inhibition. A separate cohort was injected with CRE-dependent AAV vectors expressing diphtheria toxin (DTA) to selectively ablate FC SST neurons. Mice were assessed for anxiety- and depressive-like behaviors (defined as emotionality). Results indicate that acute inhibition of FC SST neurons increased behavioral emotionality, whereas chronic inhibition decreased behavioral emotionality. Furthermore, ablation of FC SST neurons also decreased behavioral emotionality under baseline condition and after chronic stress. Together, our results reveal opposite effects of acute and chronic inhibition of FC SST neurons on behavioral emotionality and suggest the recruitment of homeostatic plasticity mechanisms that have implications for understanding the neurobiology of chronic brain conditions affecting dendritic-targeting inhibitory neurons.

Integrated optimisation technique based on computer-aided capacity and safety evaluation for managing downstream lane-drop merging area of signalised junctions

NASA Astrophysics Data System (ADS)

Chen, CHAI; Yiik Diew, WONG

2017-02-01

This study provides an integrated strategy, encompassing microscopic simulation, safety assessment, and multi-attribute decision-making, to optimize traffic performance at downstream merging area of signalized intersections. A Fuzzy Cellular Automata (FCA) model is developed to replicate microscopic movement and merging behavior. Based on simulation experiment, the proposed FCA approach is able to provide capacity and safety evaluation of different traffic scenarios. The results are then evaluated through data envelopment analysis (DEA) and analytic hierarchy process (AHP). Optimized geometric layout and control strategies are then suggested for various traffic conditions. An optimal lane-drop distance that is dependent on traffic volume and speed limit can thus be established at the downstream merging area.

Self-assembling enzymes and the origins of the cytoskeleton

PubMed Central

Barry, Rachael; Gitai, Zemer

2011-01-01

The bacterial cytoskeleton is composed of a complex and diverse group of proteins that self-assemble into linear filaments. These filaments support and organize cellular architecture and provide a dynamic network controlling transport and localization within the cell. Here, we review recent discoveries related to a newly appreciated class of self-assembling proteins that expand our view of the bacterial cytoskeleton and provide potential explanations for its evolutionary origins. Specifically, several types of metabolic enzymes can form structures similar to established cytoskeletal filaments and, in some cases, these structures have been repurposed for structural uses independent of their normal role. The behaviors of these enzymes suggest that some modern cytoskeletal proteins may have evolved from dual-role proteins with catalytic and structural functions. PMID:22014508