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Sample records for regulate cell behavior

  1. Glial Cell Regulation of Rhythmic Behavior

    PubMed Central

    Jackson, F. Rob; Ng, Fanny S.; Sengupta, Sukanya; You, Samantha; Huang, Yanmei

    2015-01-01

    Brain glial cells, in particular astrocytes and microglia, secrete signaling molecules that regulate glia–glia or glia–neuron communication and synaptic activity. While much is known about roles of glial cells in nervous system development, we are only beginning to understand the physiological functions of such cells in the adult brain. Studies in vertebrate and invertebrate models, in particular mice and Drosophila, have revealed roles of glia–neuron communication in the modulation of complex behavior. This chapter emphasizes recent evidence from studies of rodents and Drosophila that highlight the importance of glial cells and similarities or differences in the neural circuits regulating circadian rhythms and sleep in the two models. The chapter discusses cellular, molecular, and genetic approaches that have been useful in these models for understanding how glia–neuron communication contributes to the regulation of rhythmic behavior. PMID:25707272

  2. HOW MATRIX METALLOPROTEINASES REGULATE CELL BEHAVIOR

    PubMed Central

    Sternlicht, Mark D.; Werb, Zena

    2009-01-01

    The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor–binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease. PMID:11687497

  3. Nanotechnology in the regulation of stem cell behavior

    NASA Astrophysics Data System (ADS)

    Wu, King-Chuen; Tseng, Ching-Li; Wu, Chi-Chang; Kao, Feng-Chen; Tu, Yuan-Kun; So, Edmund C.; Wang, Yang-Kao

    2013-10-01

    Stem cells are known for their potential to repair damaged tissues. The adhesion, growth and differentiation of stem cells are likely controlled by the surrounding microenvironment which contains both chemical and physical cues. Physical cues in the microenvironment, for example, nanotopography, were shown to play important roles in stem cell fate decisions. Thus, controlling stem cell behavior by nanoscale topography has become an important issue in stem cell biology. Nanotechnology has emerged as a new exciting field and research from this field has greatly advanced. Nanotechnology allows the manipulation of sophisticated surfaces/scaffolds which can mimic the cellular environment for regulating cellular behaviors. Thus, we summarize recent studies on nanotechnology with applications to stem cell biology, including the regulation of stem cell adhesion, growth, differentiation, tracking and imaging. Understanding the interactions of nanomaterials with stem cells may provide the knowledge to apply to cell-scaffold combinations in tissue engineering and regenerative medicine.

  4. Biophysical regulation of stem cell behavior within the niche

    PubMed Central

    2012-01-01

    Stem cells reside within most tissues throughout the lifetimes of mammalian organisms. To maintain their capacities for division and differentiation and thereby build, maintain, and regenerate organ structure and function, these cells require extensive and precise regulation, and a critical facet of this control is the local environment or niche surrounding the cell. It is well known that soluble biochemical signals play important roles within such niches, and a number of biophysical aspects of the microenvironment, including mechanical cues and spatiotemporally varying biochemical signals, have also been increasingly recognized to contribute to the repertoire of stimuli that regulate various stem cells in various tissues of both vertebrates and invertebrates. For example, biochemical factors immobilized to the extracellular matrix or the surface of neighboring cells can be spatially organized in their placement. Furthermore, the extracellular matrix provides mechanical support and regulatory information, such as its elastic modulus and interfacial topography, which modulate key aspects of stem cell behavior. Numerous examples of each of these modes of regulation indicate that biophysical aspects of the niche must be appreciated and studied in conjunction with its biochemical properties. PMID:23241436

  5. Electrical stimulation as a biomimicry tool for regulating muscle cell behavior.

    PubMed

    Ahadian, Samad; Ostrovidov, Serge; Hosseini, Vahid; Kaji, Hirokazu; Ramalingam, Murugan; Bae, Hojae; Khademhosseini, Ali

    2013-01-01

    There is a growing need to understand muscle cell behaviors and to engineer muscle tissues to replace defective tissues in the body. Despite a long history of the clinical use of electric fields for muscle tissues in vivo, electrical stimulation (ES) has recently gained significant attention as a powerful tool for regulating muscle cell behaviors in vitro. ES aims to mimic the electrical environment of electroactive muscle cells (e.g., cardiac or skeletal muscle cells) by helping to regulate cell-cell and cell-extracellular matrix (ECM) interactions. As a result, it can be used to enhance the alignment and differentiation of skeletal or cardiac muscle cells and to aid in engineering of functional muscle tissues. Additionally, ES can be used to control and monitor force generation and electrophysiological activity of muscle tissues for bio-actuation and drug-screening applications in a simple, high-throughput, and reproducible manner. In this review paper, we briefly describe the importance of ES in regulating muscle cell behaviors in vitro, as well as the major challenges and prospective potential associated with ES in the context of muscle tissue engineering. PMID:23823664

  6. Electrical stimulation as a biomimicry tool for regulating muscle cell behavior

    PubMed Central

    Ahadian, Samad; Ostrovidov, Serge; Hosseini, Vahid; Kaji, Hirokazu; Ramalingam, Murugan; Bae, Hojae; Khademhosseini, Ali

    2013-01-01

    There is a growing need to understand muscle cell behaviors and to engineer muscle tissues to replace defective tissues in the body. Despite a long history of the clinical use of electric fields for muscle tissues in vivo, electrical stimulation (ES) has recently gained significant attention as a powerful tool for regulating muscle cell behaviors in vitro. ES aims to mimic the electrical environment of electroactive muscle cells (e.g., cardiac or skeletal muscle cells) by helping to regulate cell-cell and cell-extracellular matrix (ECM) interactions. As a result, it can be used to enhance the alignment and differentiation of skeletal or cardiac muscle cells and to aid in engineering of functional muscle tissues. Additionally, ES can be used to control and monitor force generation and electrophysiological activity of muscle tissues for bio-actuation and drug-screening applications in a simple, high-throughput, and reproducible manner. In this review paper, we briefly describe the importance of ES in regulating muscle cell behaviors in vitro, as well as the major challenges and prospective potential associated with ES in the context of muscle tissue engineering. PMID:23823664

  7. Molecular bioelectricity: how endogenous voltage potentials control cell behavior and instruct pattern regulation in vivo

    PubMed Central

    Levin, Michael

    2014-01-01

    In addition to biochemical gradients and transcriptional networks, cell behavior is regulated by endogenous bioelectrical cues originating in the activity of ion channels and pumps, operating in a wide variety of cell types. Instructive signals mediated by changes in resting potential control proliferation, differentiation, cell shape, and apoptosis of stem, progenitor, and somatic cells. Of importance, however, cells are regulated not only by their own Vmem but also by the Vmem of their neighbors, forming networks via electrical synapses known as gap junctions. Spatiotemporal changes in Vmem distribution among nonneural somatic tissues regulate pattern formation and serve as signals that trigger limb regeneration, induce eye formation, set polarity of whole-body anatomical axes, and orchestrate craniofacial patterning. New tools for tracking and functionally altering Vmem gradients in vivo have identified novel roles for bioelectrical signaling and revealed the molecular pathways by which Vmem changes are transduced into cascades of downstream gene expression. Because channels and gap junctions are gated posttranslationally, bioelectrical networks have their own characteristic dynamics that do not reduce to molecular profiling of channel expression (although they couple functionally to transcriptional networks). The recent data provide an exciting opportunity to crack the bioelectric code, and learn to program cellular activity at the level of organs, not only cell types. The understanding of how patterning information is encoded in bioelectrical networks, which may require concepts from computational neuroscience, will have transformative implications for embryogenesis, regeneration, cancer, and synthetic bioengineering. PMID:25425556

  8. Protein kinase C regulates mood-related behaviors and adult hippocampal cell proliferation in rats.

    PubMed

    Abrial, Erika; Etievant, Adeline; Bétry, Cécile; Scarna, Hélène; Lucas, Guillaume; Haddjeri, Nasser; Lambás-Señas, Laura

    2013-06-01

    The neurobiological mechanisms underlying the pathophysiology and therapeutics of bipolar disorder are still unknown. In recent years, protein kinase C (PKC) has emerged as a potential key player in mania. To further investigate the role of this signaling system in mood regulation, we examined the effects of PKC modulators in behavioral tests modeling several facets of bipolar disorder and in adult hippocampal cell proliferation in rats. Our results showed that a single injection of the PKC inhibitors tamoxifen (80 mg/kg, i.p.) and chelerythrine (3 mg/kg, s.c.) attenuated amphetamine-induced hyperlocomotion and decreased risk-taking behavior, supporting the efficacy of PKC blockade in acute mania. Moreover, chronic exposure to tamoxifen (10 mg/kg/day, i.p., for 14 days) or chelerythrine (0.3 mg/kg/day, s.c., for 14 days) caused depressive-like behavior in the forced swim test, and resulted in a reduction of cell proliferation in the dentate gyrus of the hippocampus. Finally, we showed that, contrary to the PKC inhibitors, the PKC activator phorbol 12-myristate 13-acetate (PMA) enhanced risk-taking behavior and induced an antidepressant-like effect. Taken together, these findings support the involvement of PKC in regulating opposite facets of bipolar disorder, and emphasize a major role for PKC in this disease. PMID:23228462

  9. Regulation and evolution of cardiopharyngeal cell identity and behavior: insights from simple chordates.

    PubMed

    Kaplan, Nicole; Razy-Krajka, Florian; Christiaen, Lionel

    2015-06-01

    The vertebrate heart arises from distinct first and second heart fields. The latter also share a common origin with branchiomeric muscles in the pharyngeal mesoderm and transcription regulators, such as Nkx2-5, Tbx1 and Islet1. Despite significant progress, the complexity of vertebrate embryos has hindered the identification of multipotent cardiopharyngeal progenitors. Here, we summarize recent insights in cardiopharyngeal development gained from ascidian models, among the closest relatives to vertebrates. In a simplified cellular context, progressive fate specification of the ascidian cardiopharyngeal precursors presents striking similarities with their vertebrate counterparts. Multipotent cardiopharyngeal progenitors are primed to activate both the early cardiac and pharyngeal muscles programs, which segregate following asymmetric cells divisions as a result of regulatory cross-antagonisms involving Tbx1 and Nkx2-5 homologs. Activation of Ebf in pharyngeal muscle founder cells triggers both Myogenic Regulatory Factor-associated differentiation and Notch-mediated maintenance of an undifferentiated state in distinct precursors. Cross-species comparisons revealed the deep conservation of the cardiopharyngeal developmental sequence in spite of extreme genome sequence divergence, gene network rewiring and specific morphogenetic differences. Finally, analyses are beginning to uncover the influence of surrounding tissues in determining cardiopharyngeal cell identity and behavior. Thus, ascidian embryos offer a unique opportunity to study gene regulation and cell behaviors at the cellular level throughout cardiopharyngeal morphogenesis and evolution. PMID:25819888

  10. Nitric oxide regulates cell behavior on an interactive cell-derived extracellular matrix scaffold.

    PubMed

    Xing, Qi; Zhang, Lijun; Redman, Travis; Qi, Shaohai; Zhao, Feng

    2015-12-01

    During tissue injury and wound healing process, there are dynamic reciprocal interactions among cells, extracellular matrix (ECM), and mediating molecules which are crucial for functional tissue repair. Nitric oxide (NO) is one of the key mediating molecules that can positively regulate various biological activities involved in wound healing. Various ECM components serve as binding sites for cells and mediating molecules, and the interactions further stimulate cellular activities. Human mesenchymal stem cells (hMSCs) can migrate to the wound site and contribute to tissue regeneration through differentiation and paracrine signaling. The objective of this work was to investigate the regulatory effect of NO on hMSCs in an interactive ECM-rich microenvironment. In order to mimic the in vivo stromal environment in wound site, a cell-derived ECM scaffold that was able to release NO within the range of in vivo wound fluid NO level was fabricated. Results showed that the micro-molar level of NO released from the ECM scaffold had an inhibitory effect on cellular activities of hMSCs. The NO impaired cell growth, altered cell morphology, disrupted the F-actin organization, also decreased the expression of focal adhesion related molecules integrin α5 and paxillin. These results may contribute to the elucidation of how NO acts on hMSCs in wound healing process. PMID:26074441

  11. Rapid coating of surfaces with functionalized nanoparticles for regulation of cell behavior.

    PubMed

    Tang, Rui; Moyano, Daniel F; Subramani, Chandramouleeswaran; Yan, Bo; Jeoung, Eunhee; Tonga, Gülen Yesilbag; Duncan, Bradley; Yeh, Yi-Cheun; Jiang, Ziwen; Kim, Chaekyu; Rotello, Vincent M

    2014-05-28

    A robust monolayer of nanoparticles is formed via dip-coating of cell culture plates. These surfaces provide cell type-specific modulation of growth behavior without the uptake of nanoparticles. PMID:24677290

  12. Oxygen, a Key Factor Regulating Cell Behavior during Neurogenesis and Cerebral Diseases

    PubMed Central

    Zhang, Kuan; Zhu, Lingling; Fan, Ming

    2011-01-01

    Oxygen is vital to maintain the normal functions of almost all the organs, especially for brain which is one of the heaviest oxygen consumers in the body. The important roles of oxygen on the brain are not only reflected in the development, but also showed in the pathological processes of many cerebral diseases. In the current review, we summarized the oxygen levels in brain tissues tested by real-time measurements during the embryonic and adult neurogenesis, the cerebral diseases, or in the hyperbaric/hypobaric oxygen environment. Oxygen concentration is low in fetal brain (0.076–7.6 mmHg) and in adult brain (11.4–53.2 mmHg), decreased during stroke, and increased in hyperbaric oxygen environment. In addition, we reviewed the effects of oxygen tensions on the behaviors of neural stem cells (NSCs) in vitro cultures at different oxygen concentration (15.2–152 mmHg) and in vivo niche during different pathological states and in hyperbaric/hypobaric oxygen environment. Moderate hypoxia (22.8–76 mmHg) can promote the proliferation of NSCs and enhance the differentiation of NSCs into the TH-positive neurons. Next, we briefly presented the oxygen-sensitive molecular mechanisms regulating NSCs proliferation and differentiation recently found including the Notch, Bone morphogenetic protein and Wnt pathways. Finally, the future perspectives about the roles of oxygen on brain and NSCs were given. PMID:21503147

  13. Regulation of Cancer Cell Behavior by the Small GTPase Rab13.

    PubMed

    Ioannou, Maria S; McPherson, Peter S

    2016-05-01

    The members of the Rab family of GTPases are master regulators of cellular membrane trafficking. With ∼70 members in humans, Rabs have been implicated in all steps of membrane trafficking ranging from vesicle formation and transport to vesicle docking/tethering and fusion. Vesicle trafficking controls the localization and levels of a myriad of proteins, thus regulating cellular functions including proliferation, metabolism, cell-cell adhesion, and cell migration. It is therefore not surprising that impairment of Rab pathways is associated with diseases including cancer. In this review, we highlight evidence supporting the role of Rab13 as a potent driver of cancer progression. PMID:27044746

  14. Co-regulation of cell behavior by electromagnetic stimulus and extracellular environment

    NASA Astrophysics Data System (ADS)

    Taghian, Toloo; Sheikh, Abdul; Narmoneva, Daria; Kogan, Andrei

    2014-03-01

    Chronic wounds do not effectively respond to pharmacological treatments because of insufficient blood supply (Impaired angiogenesis) in the wound. Developing non-pharmacological treatments requires application of advanced technology to control natural cell signals to trigger desired cell responses. Application of external electric field (EF) has been shown to enhance angiogenesis through manipulation of naturally-generated EF in the ionic environment surrounding cells and across the cell membrane; however biophysical mechanisms of cell responses to EF remain unknown. EF-cell interactions may be affected by both the distribution of the induced EF within the cell and the properties of the extracellular matrix (ECM), which is known to regulate cell response to the external stimuli. We have developed a combined theoretical-experimental approach to study EF-cell interactions. Our theoretical 3D interaction model provides spatial distribution of the induced EF in cell and extracellular space and predicts a frequency specific cell response to EF. Experimentally measured responses of cells to EF including growth factor expression and capillary morphogenesis confirm this prediction. We show that natural versus synthetic ECM can differentially mediate cell response to EF. The authors acknowledge the financial support from the NSF (DMR-1206784 & DMR-0804199 to AK); the NIH (1R21 DK078814-01A1 to DN) and the University of Cincinnati (Interdisciplinary Faculty Research Support Grant to DN and AK).

  15. The neural stem cell fate determinant TRIM32 regulates complex behavioral traits

    PubMed Central

    Hillje, Anna-Lena; Beckmann, Elisabeth; Pavlou, Maria A. S.; Jaeger, Christian; Pacheco, Maria P.; Sauter, Thomas; Schwamborn, Jens C.; Lewejohann, Lars

    2015-01-01

    In mammals, new neurons are generated throughout the entire lifespan in two restricted areas of the brain, the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ)—olfactory bulb (OB) system. In both regions newborn neurons display unique properties that clearly distinguish them from mature neurons. Enhanced excitability and increased synaptic plasticity enables them to add specific properties to information processing by modulating the existing local circuitry of already established mature neurons. Hippocampal neurogenesis has been suggested to play a role in spatial-navigation learning, spatial memory, and spatial pattern separation. Cumulative evidences implicate that adult-born OB neurons contribute to learning processes and odor memory. We recently demonstrated that the cell fate determinant TRIM32 is upregulated in differentiating neuroblasts of the SVZ-OB system in the adult mouse brain. The absence of TRIM32 leads to increased progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated OB neurons. Here, we present novel data from behavioral studies showing that such an enhancement of OB neurogenesis not necessarily leads to increased olfactory performance but in contrast even results in impaired olfactory capabilities. In addition, we show at the cellular level that TRIM32 protein levels increase during differentiation of neural stem cells (NSCs). At the molecular level, several metabolic intermediates that are connected to glycolysis, glycine, or cysteine metabolism are deregulated in TRIM32 knockout mice brain tissue. These metabolomics pathways are directly or indirectly linked to anxiety or depression like behavior. In summary, our study provides comprehensive data on how the impairment of neurogenesis caused by the loss of the cell fate determinant TRIM32 causes a decrease of olfactory performance as well as a deregulation of metabolomic pathways that are linked to mood

  16. The neural stem cell fate determinant TRIM32 regulates complex behavioral traits.

    PubMed

    Hillje, Anna-Lena; Beckmann, Elisabeth; Pavlou, Maria A S; Jaeger, Christian; Pacheco, Maria P; Sauter, Thomas; Schwamborn, Jens C; Lewejohann, Lars

    2015-01-01

    In mammals, new neurons are generated throughout the entire lifespan in two restricted areas of the brain, the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ)-olfactory bulb (OB) system. In both regions newborn neurons display unique properties that clearly distinguish them from mature neurons. Enhanced excitability and increased synaptic plasticity enables them to add specific properties to information processing by modulating the existing local circuitry of already established mature neurons. Hippocampal neurogenesis has been suggested to play a role in spatial-navigation learning, spatial memory, and spatial pattern separation. Cumulative evidences implicate that adult-born OB neurons contribute to learning processes and odor memory. We recently demonstrated that the cell fate determinant TRIM32 is upregulated in differentiating neuroblasts of the SVZ-OB system in the adult mouse brain. The absence of TRIM32 leads to increased progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated OB neurons. Here, we present novel data from behavioral studies showing that such an enhancement of OB neurogenesis not necessarily leads to increased olfactory performance but in contrast even results in impaired olfactory capabilities. In addition, we show at the cellular level that TRIM32 protein levels increase during differentiation of neural stem cells (NSCs). At the molecular level, several metabolic intermediates that are connected to glycolysis, glycine, or cysteine metabolism are deregulated in TRIM32 knockout mice brain tissue. These metabolomics pathways are directly or indirectly linked to anxiety or depression like behavior. In summary, our study provides comprehensive data on how the impairment of neurogenesis caused by the loss of the cell fate determinant TRIM32 causes a decrease of olfactory performance as well as a deregulation of metabolomic pathways that are linked to mood disorders

  17. Regulation of shear stress on rolling behaviors of HL-60 cells on P-selectin

    NASA Astrophysics Data System (ADS)

    Ling, YingChen; Fang, Ying; Yang, XiaoFang; Li, QuHuan; Lin, QinYong; Wu, JianHua

    2014-10-01

    Circulating leukocytes in trafficking to the inflammatory sites, will be first tether to, and then roll on the vascular surface. This event is mediated through specific interaction of P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), and regulated by hemodynamics. Poor data were reported in understanding P-selectin-mediated rolling. With the flow chamber technique, we herein observed HL-60 cell rolling on P-selectin with or without 3% Ficoll at various wall shear stresses from 0.05 to 0.4 dyn/cm2. The results demonstrated that force rather than transport regulated the rolling, similar to rolling on L- and E-selectin. The rolling was accelerated quickly by an increasing force below the optimal shear threshold of 0.15 dyn/cm2 first and then followed by a slowly decelerating phase starting at the optimum, showing a catch-slip transition and serving as a mechanism for the rolling. The catch-slip transition was completely reflected to the tether lifetime and other rolling parameters, such as the mean and fractional stop time. The narrow catch bond regime stabilized the rolling quickly, through steeply increasing fractional stop time to a plateau of about 0.85. Data presented here suggest that the low shear stress threshold serves as a mechanism for most cell rolling events through P-selectin.

  18. Neuroendocrine Regulation of Maternal Behavior

    PubMed Central

    Bridges, Robert S.

    2015-01-01

    The expression of maternal behavior in mammals is regulated by the developmental and experiential events over a female’s lifetime. In this review the relationships between the endocrine and neural systems that play key roles in these developmental and experiential that affect both the establishment and maintenance of maternal care are presented. The involvement of the hormones estrogen, progesterone, and lactogens are discussed in the context of ligand, receptor, and gene activity in rodents and to a lesser extent in higher mammals. The roles of neuroendocrine factors, including oxytocin, vasopressin, classical neurotransmitters, and other neural gene products that regulate aspects of maternal care are set forth, and the interactions of hormones with central nervous system mediators of maternal behavior are discussed. The impact of prior developmental factors, including epigenetic events, and maternal experience on subsequent maternal care are assessed over the course of the female’s lifespan. It is proposed that common neuroendocrine mechanisms underlie the regulation of maternal care in mammals. PMID:25500107

  19. Annexin A4-nuclear factor-κB feedback circuit regulates cell malignant behavior and tumor growth in gallbladder cancer.

    PubMed

    Yao, Hou-Shan; Sun, Chang; Li, Xin-Xing; Wang, Yi; Jin, Kai-Zhou; Zhang, Xiao-Ping; Hu, Zhi-Qian

    2016-01-01

    Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system. However, the mechanisms underlying its tumor initiation, progression, and metastasis are not yet fully understood. The annexin A4 (ANXA4) gene is highly expressed in GBC tissues and may play an important role in the initiation and progression of this disease. In this study, we examined the up-regulation of ANXA4 in human GBC tissues and cell lines. Elevated ANXA4 correlated well with invasion depth in GBC patients and predicted a poor prognosis. In vitro, GBC-SD and NOZ cells with ANXA4 knockdown demonstrated increased apoptosis and inhibited cell growth, migration, and invasion. Interactions between ANXA4 and nuclear factor-κB (NF-κB) p65 proteins were detected. In vivo, ANXA4 knockdown inhibited tumor growth of GBC cells in nude mice and down-regulated the expression of downstream factors in the NF-κB signaling pathway. Taken together, these data indicate that up-regulation of ANXA4 leads to activation of the NF-κB pathway and its target genes in a feedback regulatory mechanism via the p65 subunit, resulting in tumor growth in GBC. PMID:27491820

  20. Annexin A4-nuclear factor-κB feedback circuit regulates cell malignant behavior and tumor growth in gallbladder cancer

    PubMed Central

    Yao, Hou-Shan; Sun, Chang; Li, Xin-Xing; Wang, Yi; Jin, Kai-Zhou; Zhang, Xiao-Ping; Hu, Zhi-Qian

    2016-01-01

    Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system. However, the mechanisms underlying its tumor initiation, progression, and metastasis are not yet fully understood. The annexin A4 (ANXA4) gene is highly expressed in GBC tissues and may play an important role in the initiation and progression of this disease. In this study, we examined the up-regulation of ANXA4 in human GBC tissues and cell lines. Elevated ANXA4 correlated well with invasion depth in GBC patients and predicted a poor prognosis. In vitro, GBC-SD and NOZ cells with ANXA4 knockdown demonstrated increased apoptosis and inhibited cell growth, migration, and invasion. Interactions between ANXA4 and nuclear factor-κB (NF-κB) p65 proteins were detected. In vivo, ANXA4 knockdown inhibited tumor growth of GBC cells in nude mice and down-regulated the expression of downstream factors in the NF-κB signaling pathway. Taken together, these data indicate that up-regulation of ANXA4 leads to activation of the NF-κB pathway and its target genes in a feedback regulatory mechanism via the p65 subunit, resulting in tumor growth in GBC. PMID:27491820

  1. Hippocampal cell fate regulation by chronic cocaine during periods of adolescent vulnerability: Consequences of cocaine exposure during adolescence on behavioral despair in adulthood.

    PubMed

    García-Cabrerizo, R; Keller, B; García-Fuster, M J

    2015-09-24

    Given that adolescence represents a critical moment for shaping adult behavior and may predispose to disease vulnerability later in life, the aim of this study was to find a vulnerable period during adolescence in which hippocampal cell fate regulation was altered by cocaine exposure, and to evaluate the long-term consequences of a cocaine experience during adolescence in affecting hippocampal plasticity and behavioral despair in adulthood. Study I: Male rats were treated with cocaine (15mg/kg, i.p.) or saline for 7 consecutive days during adolescence (early post-natal day (PND) 33-39, mid PND 40-46, late PND 47-53). Hippocampal plasticity (i.e., cell fate regulation, cell genesis) was evaluated 24h after the last treatment dose during the course of adolescence (PND 40, PND 47, PND 54). Study II: The consequences of cocaine exposure during adolescence (PND 33-39 or PND 33-46; 7 or 14days) were measured in adulthood at the behavioral (i.e., forced swim test, PND 62-63) and molecular (hippocampal cell markers, PND 64) levels. Chronic cocaine during early adolescence dysregulated FADD forms only in the hippocampus (HC), as compared to other brain regions, and during mid adolescence, impaired cell proliferation (Ki-67) and increased PARP-1 cleavage (a cell death maker) in the HC. Interestingly, chronic cocaine exposure during adolescence did not alter the time adult rats spent immobile in the forced swim test. These results suggest that this paradigm of chronic cocaine administration during adolescence did not contribute to the later manifestation of behavioral despair (i.e., one pro-depressive symptom) as measured by the forced swim test in adulthood. PMID:26215918

  2. Cell-Specific Transcriptional Profiling of Ciliated Sensory Neurons Reveals Regulators of Behavior and Extracellular Vesicle Biogenesis.

    PubMed

    Wang, Juan; Kaletsky, Rachel; Silva, Malan; Williams, April; Haas, Leonard A; Androwski, Rebecca J; Landis, Jessica N; Patrick, Cory; Rashid, Alina; Santiago-Martinez, Dianaliz; Gravato-Nobre, Maria; Hodgkin, Jonathan; Hall, David H; Murphy, Coleen T; Barr, Maureen M

    2015-12-21

    Cilia and extracellular vesicles (EVs) are signaling organelles [1]. Cilia act as cellular sensory antennae, with defects resulting in human ciliopathies. Cilia both release and bind to EVs [1]. EVs are sub-micron-sized particles released by cells and function in both short- and long-range intercellular communication. In C. elegans and mammals, the autosomal dominant polycystic kidney disease (ADPKD) gene products polycystin-1 and polycystin-2 localize to both cilia and EVs, act in the same genetic pathway, and function in a sensory capacity, suggesting ancient conservation [2]. A fundamental understanding of EV biology and the relationship between the polycystins, cilia, and EVs is lacking. To define properties of a ciliated EV-releasing cell, we performed RNA-seq on 27 GFP-labeled EV-releasing neurons (EVNs) isolated from adult C. elegans. We identified 335 significantly overrepresented genes, of which 61 were validated by GFP reporters. The EVN transcriptional profile uncovered new pathways controlling EV biogenesis and polycystin signaling and also identified EV cargo, which included an antimicrobial peptide and ASIC channel. Tumor-necrosis-associated factor (TRAF) homologs trf-1 and trf-2 and the p38 mitogen-activated protein kinase (MAPK) pmk-1 acted in polycystin-signaling pathways controlling male mating behaviors. pmk-1 was also required for EV biogenesis, independent of the innate immunity MAPK signaling cascade. This first high-resolution transcriptome profile of a subtype of ciliated sensory neurons isolated from adult animals reveals the functional components of an EVN. PMID:26687621

  3. Neuroendocrine regulation of appetitive ingestive behavior

    PubMed Central

    Keen-Rhinehart, Erin; Ondek, Katelynn; Schneider, Jill E.

    2013-01-01

    Food availability in nature is often irregular, and famine is commonplace. Increased motivation to engage in ingestive behaviors increases the chance of survival, providing additional potential opportunities for reproduction. Because of the advantages conferred by entraining ingestive behavior to environmental conditions, neuroendocrine mechanisms regulating the motivation to acquire and ingest food have evolved to be responsive to exogenous (i.e., food stored for future consumption) and endogenous (i.e., body fat stores) fuel availability. Motivated behaviors like eating occur in two phases. The appetitive phase brings animals into contact with food (e.g., foraging, food hoarding), and the more reflexive consummatory phase results in ingestion (e.g., chewing, swallowing). Quantifiable appetitive behaviors are part of the natural ingestive behavioral repertoire of species such as hamsters and humans. This review summarizes current knowledge about neuroendocrine regulators of ingestive behavior, with an emphasis appetitive behavior. We will discuss hormonal regulators of appetitive ingestive behaviors, including the orexigenic hormone ghrelin, which potently stimulates foraging and food hoarding in Siberian hamsters. This section includes a discussion of the hormone leptin, its relation to endogenous fat stores, and its role in food deprivation-induced increases in appetitive ingestive behaviors. Next, we discuss how hormonal regulators interact with neurotransmitters involved in the regulation of ingestive behaviors, such as neuropeptide Y (NPY), agouti-related protein (AgRP) and α-melanocyte stimulating hormone (α-MSH), to regulate ingestive behavior. Finally, we discuss the potential impact that perinatal nutrient availability can have on the neuroendocrine regulation of ingestive behavior. Understanding the hormonal mechanisms that connect metabolic fuel availability to central appetite regulatory circuits should provide a better understanding of the

  4. KChIP-Like Auxiliary Subunits of Kv4 Channels Regulate Excitability of Muscle Cells and Control Male Turning Behavior during Mating in Caenorhabditis elegans

    PubMed Central

    Chen, Xin; Ruan, Mei-Yu

    2015-01-01

    Voltage-gated Kv4 channels control the excitability of neurons and cardiac myocytes by conducting rapidly activating-inactivating currents. The function of Kv4 channels is profoundly modulated by K+ channel interacting protein (KChIP) soluble auxiliary subunits. However, the in vivo mechanism of the modulation is not fully understood. Here, we identified three C. elegans KChIP-like (ceKChIP) proteins, NCS-4, NCS-5, and NCS-7. All three ceKChIPs alter electrical characteristics of SHL-1, a C. elegans Kv4 channel ortholog, currents by slowing down inactivation kinetics and shifting voltage dependence of activation to more hyperpolarizing potentials. Native SHL-1 current is completely abolished in cultured myocytes of Triple KO worms in which all three ceKChIP genes are deleted. Reexpression of NCS-4 partially restored expression of functional SHL-1 channels, whereas NCS-4(efm), a NCS-4 mutant with impaired Ca2+-binding ability, only enhanced expression of SHL-1 proteins, but failed to transport them from the Golgi apparatus to the cell membrane in body wall muscles of Triple KO worms. Moreover, translational reporter revealed that NCS-4 assembles with SHL-1 K+ channels in male diagonal muscles. Deletion of either ncs-4 or shl-1 significantly impairs male turning, a behavior controlled by diagonal muscles during mating. The phenotype of the ncs-4 null mutant could be rescued by reexpression of NCS-4, but not NCS-4(efm), further emphasizing the importance of Ca2+ binding to ceKChIPs in regulating native SHL-1 channel function. Together, these data reveal an evolutionarily conserved mechanism underlying the regulation of Kv4 channels by KChIPs and unravel critical roles of ceKChIPs in regulating muscle cell excitability and animal behavior in C. elegans. PMID:25653349

  5. Zeb1 Regulates E-cadherin and Epcam (Epithelial Cell Adhesion Molecule) Expression to Control Cell Behavior in Early Zebrafish Development*

    PubMed Central

    Vannier, Corinne; Mock, Kerstin; Brabletz, Thomas; Driever, Wolfgang

    2013-01-01

    The ZEB1 transcription factor is best known as an inducer of epithelial-mesenchymal transitions (EMT) in cancer metastasis, acting through transcriptional repression of CDH1 (encoding E-cadherin) and the EMT-suppressing microRNA-200s (miR-200s). Here we analyze roles of the ZEB1 zebrafish orthologs, Zeb1a and Zeb1b, and of miR-200s in control of cell adhesion and morphogenesis during gastrulation and segmentation stages. Loss and gain of function analyses revealed that Zeb1 represses cdh1 expression to fine-tune adhesiveness of migrating deep blastodermal cells. Furthermore, Zeb1 acts as a repressor of epcam in the deep cells of the blastoderm and may contribute to control of epithelial integrity of enveloping layer cells, the outermost cells of the blastoderm. We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter. Thus, Zeb1 proteins employ several evolutionary conserved mechanisms to regulate cell-cell adhesion during development and cancer. PMID:23667256

  6. In vivo imaging of cell behaviors and F-actin reveals LIM-HD transcription factor regulation of peripheral versus central sensory axon development

    PubMed Central

    2011-01-01

    Background Development of specific neuronal morphology requires precise control over cell motility processes, including axon formation, outgrowth and branching. Dynamic remodeling of the filamentous actin (F-actin) cytoskeleton is critical for these processes; however, little is known about the mechanisms controlling motile axon behaviors and F-actin dynamics in vivo. Neuronal structure is specified in part by intrinsic transcription factor activity, yet the molecular and cellular steps between transcription and axon behavior are not well understood. Zebrafish Rohon-Beard (RB) sensory neurons have a unique morphology, with central axons that extend in the spinal cord and a peripheral axon that innervates the skin. LIM homeodomain (LIM-HD) transcription factor activity is required for formation of peripheral RB axons. To understand how neuronal morphogenesis is controlled in vivo and how LIM-HD transcription factor activity differentially regulates peripheral versus central axons, we used live imaging of axon behavior and F-actin distribution in vivo. Results We used an F-actin biosensor containing the actin-binding domain of utrophin to characterize actin rearrangements during specific developmental processes in vivo, including axon initiation, consolidation and branching. We found that peripheral axons initiate from a specific cellular compartment and that F-actin accumulation and protrusive activity precede peripheral axon initiation. Moreover, disruption of LIM-HD transcriptional activity has different effects on the motility of peripheral versus central axons; it inhibits peripheral axon initiation, growth and branching, while increasing the growth rate of central axons. Our imaging revealed that LIM-HD transcription factor activity is not required for F-actin based protrusive activity or F-actin accumulation during peripheral axon initiation, but can affect positioning of F-actin accumulation and axon formation. Conclusion Our ability to image the dynamics of

  7. The electrostatic behavior of the bacterial cell wall using a smoothing function to describe the charge-regulated volume charge density profile.

    PubMed

    Barbosa, Nathalia S V; Lima, Eduardo R A; Tavares, Frederico W

    2015-10-01

    The Donnan potential can be observed in many biological systems due to the presence of polyelectrolytes as proteins and nucleic acids. The aim of this work was to present a useful tool to describe the fixed and charge-regulated volume charge density profile through the use of a smoothing function and to obtain the electrostatic potential profile as well as the Donnan potential of this system by solving Poisson-Boltzmann (PB) equation. When we use the smoothing function, the Donnan potential arises automatically from the solution of only one Poisson-Boltzmann equation and it is not necessary to impose this potential for treating charged system in the presence of a membrane. The electrostatic behavior across the Bacillus brevis wall considering the dependence on the ionization of the cell wall functional groups as a function of the solution pH was analyzed. An important issue was to show that potentiometric titration data could be used together with the Poisson-Boltzmann equation to predict the electrostatic behavior (e.g., zeta potential) of the bacterial cell surface. PMID:26231737

  8. Measuring behavioral regulation in four societies

    PubMed Central

    Wanless, Shannon B.; McClelland, Megan M.; Acock, Alan C.; Ponitz, Claire C.; Son, Seung-Hee; Lan, Xuezhao; Morrison, Frederick J.; Chen, Jo-Lin; Chen, Taiwan Fu-Mei; Lee, Taiwan Kangyi; Sung, Miyoung; Li, Su

    2010-01-01

    The present study examined the psychometric properties of scores from a direct measure of behavioral regulation, the Head-Toes-Knees-Shoulders task (HTKS) with 3- to 6-year-old children in the U.S., Taiwan, South Korea, and China. Specifically, we investigated (1) the nature and variability of HTKS scores including relations to teacher-rated classroom behavioral regulation, and (2) relations between the HTKS and early mathematics, vocabulary, and literacy skills. Higher HTKS scores were significantly related to higher teacher ratings of classroom behavioral regulation in the U.S. and South Korea but not in Taiwan and China. Also, higher HTKS scores were significantly related to higher early mathematics, vocabulary, and literacy skills beyond the influence of demographic variables and teacher-rated classroom behavioral regulation. These initial findings suggest that HTKS scores may be interpreted as reflecting early behavioral regulation in these four societies, and that behavioral regulation is important for early academic success in the U.S. and in Asian countries. PMID:21381840

  9. Tissue morphodynamics: Translating planar polarity cues into polarized cell behaviors.

    PubMed

    Devenport, Danelle

    2016-07-01

    The ability of cells to collectively orient and align their behaviors is essential in multicellular organisms for unidirectional cilia beating, collective cell movements, oriented cell divisions, and asymmetric cell fate specification. The planar cell polarity pathway coordinates a vast and diverse array of collective cell behaviors by intersecting with downstream pathways that regulate cytoskeletal dynamics and intercellular signaling. How the planar polarity pathway translates directional cues to produce polarized cell behaviors is the focus of this review. PMID:26994528

  10. [Relationships between microRNA expressions and prognosis in patients with tongue squamous cell carcinoma and the mechanisms microRNA regulating tongue squamous cell carcinoma biological behavior].

    PubMed

    Jia, Ling-fei; Gan, Ye-hua; Yu, Guang-yan

    2016-02-18

    Tongue squamous cell carcinoma (TSCC) is the most common type of oral cancer and is well known for its high rate of proliferation and lymph nodal metastasis. Exploring the underlying pathways regulating TSCC could provide novel ideas for diagnosis and prognosis of TSCC patients, as well as molecular targets for treatment of TSCC. MicroRNAs (miRNAs) are small noncoding RNAs that inhibit gene expression through the 3' untranslated regions (3'UTRs) of their target messenger RNAs. They play crucial roles in numerous biological processes, including cancer progression. Although great efforts have been made, what role miRNAs may play in the early detection and diagnosis of TSCC is not fully understood. Recently, our team has performed a series of basic and clinical researches in an attempt to investigate the relationships between miRNA expressions and prognosis of patients with TSCC and the mechanisms under regulation of TSCC. The results showed that miR-195, miR-34a, miR-29b, miR-375 and miR-26a could inhibit TSCC cells progression and development via a sophisticated network of genes. Specifically, the anti-tumor effects of miR-195 in TSCC may be partially mediated by its inhibition of CyclinD1 and Bcl-2 expression. The expression of miR-34a could inhibit migration and invasion of TSCC cell lines via targeting MMP9 and MMP14. The function of miR-29b may be through the miR-29b/Sp1/PTEN/AKT axis. Overexpression of miR-375 inhibited Sp1 expression by targeting the 3' untranslated region of the Sp1 transcript. MEG3 and miR-26a inhibited TSCC cell proliferation, cycle progression and promoted cell apoptosis and miR-26a could increase the MEG3 expression through reduction of the expression of DNMT3B in TSCC. In light of the role of those miRNAs in diagnosis and prognosis of TSCC, we reported that decreased miR-195 and miR-375 expression was associated with poor overall survival rate of the TSCC patients, while miR-34a expression was negatively correlated with cervical lymph

  11. Regulation of cell-cell fusion by nanotopography.

    PubMed

    Padmanabhan, Jagannath; Augelli, Michael J; Cheung, Bettina; Kinser, Emily R; Cleary, Barnett; Kumar, Priyanka; Wang, Renhao; Sawyer, Andrew J; Li, Rui; Schwarz, Udo D; Schroers, Jan; Kyriakides, Themis R

    2016-01-01

    Cell-cell fusion is fundamental to a multitude of biological processes ranging from cell differentiation and embryogenesis to cancer metastasis and biomaterial-tissue interactions. Fusogenic cells are exposed to biochemical and biophysical factors, which could potentially alter cell behavior. While biochemical inducers of fusion such as cytokines and kinases have been identified, little is known about the biophysical regulation of cell-cell fusion. Here, we designed experiments to examine cell-cell fusion using bulk metallic glass (BMG) nanorod arrays with varying biophysical cues, i.e. nanotopography and stiffness. Through independent variation of stiffness and topography, we found that nanotopography constitutes the primary biophysical cue that can override biochemical signals to attenuate fusion. Specifically, nanotopography restricts cytoskeletal remodeling-associated signaling, which leads to reduced fusion. This finding expands our fundamental understanding of the nanoscale biophysical regulation of cell fusion and can be exploited in biomaterials design to induce desirable biomaterial-tissue interactions. PMID:27615159

  12. Measuring Behavioral Regulation in Four Societies

    ERIC Educational Resources Information Center

    Wanless, Shannon B.; McClelland, Megan M.; Acock, Alan C.; Ponitz, Claire C.; Son, Seung-Hee; Lan, Xuezhao; Morrison, Frederick J.; Chen, Jo-Lin; Chen, Fu-Mei; Lee, Kangyi; Sung, Miyoung; Li, Su

    2011-01-01

    The present study examined the psychometric properties of scores from a direct measure of behavioral regulation, the Head-Toes-Knees-Shoulders task (HTKS) with 3- to 6-year-old children in the United States, Taiwan, South Korea, and China. Specifically, we investigated (a) the nature and variability of HTKS scores, including relations to…

  13. Negative regulators of cell proliferation

    NASA Technical Reports Server (NTRS)

    Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Cell proliferation is governed by the influence of both mitogens and inhibitors. Although cell contact has long been thought to play a fundamental role in cell cycling regulation, and negative regulators have long been suspected to exist, their isolation and purification has been complicated by a variety of technical difficulties. Nevertheless, over recent years an ever-expanding list of putative negative regulators have emerged. In many cases, their biological inhibitory activities are consistent with density-dependent growth inhibition. Most likely their interactions with mitogenic agents, at an intracellular level, are responsible for either mitotic arrest or continued cell cycling. A review of naturally occurring cell growth inhibitors is presented with an emphasis on those factors shown to be residents of the cell surface membrane. Particular attention is focused on a cell surface sialoglycopeptide, isolated from intact bovine cerebral cortex cells, which has been shown to inhibit the proliferation of an unusually wide range of target cells. The glycopeptide arrest cells obtained from diverse species, both fibroblasts and epithelial cells, and a broad variety of transformed cells. Signal transduction events and a limited spectrum of cells that are refractory to the sialoglycopeptide have provided insight into the molecular events mediated by this cell surface inhibitor.

  14. Emotional context, maternal behavior and emotion regulation.

    PubMed

    Roque, Lisa; Veríssimo, Manuela

    2011-12-01

    This study investigated the importance of emotion-eliciting context (positive and negative) and mother's behaviors (constrained and involved) on toddlers' emotion regulation behavioral strategies, emotional expressiveness and intensity, during three episodes eliciting fear, frustration/anger and positive affect. Fifty-five children between 18 and 26 months of age and their mothers participated in the study. Toddlers' regulatory strategies varied as function of emotion-eliciting context (children exhibited behavioral strategies more frequently during positive affect and frustration/anger episodes and less frequently during fear episodes) and maternal involvement. Toddlers' expression of emotion varied as function of emotion-eliciting context (children exhibited more emotional expressions, both negative and positive during fear and frustration/anger episodes compared to positive affect episodes). Toddlers' expression of emotion was not strongly related to maternal involvement, however, the intensity of emotional expression was related to the interaction of context and maternal involvement. PMID:21764459

  15. Reproductive Steroid Regulation of Mood and Behavior.

    PubMed

    Schiller, Crystal Edler; Johnson, Sarah L; Abate, Anna C; Rubinow, David R; Schmidt, Peter J

    2016-01-01

    In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive-related affective dysregulation. © 2016 American Physiological Society. Compr Physiol 6:1135-1160, 2016e. PMID:27347888

  16. Sequential observation of infant regulated and dysregulated behavior following soothing and stimulating maternal behavior during feeding

    PubMed Central

    Brown, Lisa F.; Pridham, Karen A.; Brown, Roger

    2014-01-01

    Purpose To describe maternal behaviors occurring before infant regulated or dysregulated behavior at three times in early infancy and examine behavioral patterns over time with their prematurely born infants. Method & Design Video-recordings of 37 dyads were coded on infant regulated and dysregulated behaviors following maternal soothing and stimulating behaviors. Results At each time, infants showed more regulation after maternal soothing than after maternal stimulating. Further study is merited. Practice Implications Knowing infant regulation and dysregulation following categories of maternal behavior could help mothers anticipate infant regulatory or dysregulatory behavior in response to their own behavior and identify supportive caregiving strategies. PMID:24417766

  17. Transglutaminase Regulation of Cell Function

    PubMed Central

    Kaartinen, Mari T.; Nurminskaya, Maria; Belkin, Alexey M.; Colak, Gozde; Johnson, Gail V. W.; Mehta, Kapil

    2014-01-01

    Transglutaminases (TGs) are multifunctional proteins having enzymatic and scaffolding functions that participate in regulation of cell fate in a wide range of cellular systems and are implicated to have roles in development of disease. This review highlights the mechanism of action of these proteins with respect to their structure, impact on cell differentiation and survival, role in cancer development and progression, and function in signal transduction. We also discuss the mechanisms whereby TG level is controlled and how TGs control downstream targets. The studies described herein begin to clarify the physiological roles of TGs in both normal biology and disease states. PMID:24692352

  18. Langerhans cell origin and regulation

    PubMed Central

    Collin, Matthew; Milne, Paul

    2015-01-01

    Purpose To summarize recent research on the ontogeny of Langerhans cells and regulation of their homeostasis in quiescent and inflamed conditions Recent findings Langerhans cells (LCs) originate pre-natally and may endure throughout life, independently of bone marrow derived precursors. Fate mapping experiments have recently resolved the relative contribution of primitive yolk sac and fetal liver hematopoiesis to the initial formation of LCs. In post-natal life, local self-renewal restores LC numbers following chronic or low grade inflammatory insults. However, severe inflammation recruits de novo bone marrow derived precursors in two waves; a transient population of classical monocytes followed by uncharacterized myeloid precursors that form a stable self-renewing LC network as inflammation subsides. Human CD1c+ dendritic cells have LC potential in vitro, raising the possibility that DC progenitors provide the second wave. LC development depends upon TGFβ receptor signaling with distinct pathways active during differentiation and homeostasis. LC survival is mediated by multiple pathways including mTOR and ERK signaling, mechanisms that become highly relevant in LC neoplasia. Summary The study of LCs continues to provide novel and unexpected insights into the origin and regulation of myeloid cell populations. The melding of macrophage and DC biology, shaped by a unique habitat, is a special feature of LCs. PMID:26554892

  19. Cell Cycle Regulation and Melanoma.

    PubMed

    Xu, Wen; McArthur, Grant

    2016-06-01

    Dysregulation of cell cycle control is a hallmark of melanomagenesis. Agents targeting the G1-S and G2-M checkpoints, as well as direct anti-mitotic agents, have all shown promising preclinical activity in melanoma. However, in vivo, standalone single agents targeting cell cycle regulation have only demonstrated modest efficacy in unselected patients. The advent of specific CDK 4/6 inhibitors targeting the G1-S transition, with an improved therapeutic index, is a significant step forward. Potential synergy exists with the combination of CDK4/6 inhibitors with existing therapies targeting the MAPK pathway, particularly in subsets of metastatic melanomas such as NRAS and BRAF mutants. This reviews summaries of the latest developments in both preclinical and clinical data with cell cycle-targeted therapies in melanoma. PMID:27106898

  20. Cyclic AMP Regulates Social Behavior in African Trypanosomes

    PubMed Central

    Oberholzer, Michael; Saada, Edwin A.

    2015-01-01

    ABSTRACT The protozoan parasite Trypanosoma brucei engages in surface-induced social behavior, termed social motility, characterized by single cells assembling into multicellular groups that coordinate their movements in response to extracellular signals. Social motility requires sensing and responding to extracellular signals, but the underlying mechanisms are unknown. Here we report that T. brucei social motility depends on cyclic AMP (cAMP) signaling systems in the parasite’s flagellum (synonymous with cilium). Pharmacological inhibition of cAMP-specific phosphodiesterase (PDE) completely blocks social motility without impacting the viability or motility of individual cells. Using a fluorescence resonance energy transfer (FRET)-based sensor to monitor cAMP dynamics in live cells, we demonstrate that this block in social motility correlates with an increase in intracellular cAMP levels. RNA interference (RNAi) knockdown of the flagellar PDEB1 phenocopies pharmacological PDE inhibition, demonstrating that PDEB1 is required for social motility. Using parasites expressing distinct fluorescent proteins to monitor individuals in a genetically heterogeneous community, we found that the social motility defect of PDEB1 knockdowns is complemented by wild-type parasites in trans. Therefore, PDEB1 knockdown cells are competent for social motility but appear to lack a necessary factor that can be provided by wild-type cells. The combined data demonstrate that the role of cyclic nucleotides in regulating microbial social behavior extends to African trypanosomes and provide an example of transcomplementation in parasitic protozoa. PMID:25922395

  1. Quetiapine and repetitive transcranial magnetic stimulation ameliorate depression-like behaviors and up-regulate the proliferation of hippocampal-derived neural stem cells in a rat model of depression: The involvement of the BDNF/ERK signal pathway.

    PubMed

    Chen, Yi-huan; Zhang, Rui-guo; Xue, Fen; Wang, Hua-ning; Chen, Yun-chun; Hu, Guang-tao; Peng, Ye; Peng, Zheng-wu; Tan, Qing-rong

    2015-09-01

    Quetiapine (QUE) and repetitive transcranial magnetic stimulation (rTMS) have been considered to be possible monotherapies for depression or adjunctive therapies for the treatment of the resistant depression, but the underlying mechanisms remain unclear. The present study aimed to assess the effects of combined QUE and rTMS treatment on depressive-like behaviors, hippocampal proliferation, and the in vivo and in vitro expressions of phosphorylated extracellular signal-regulated protein kinase (pERK1/2) and brain-derived neurotrophic factor (BDNF) in male Sprague-Dawley rats. The administration of QUE and rTMS was determined not only to reverse the depressive-like behaviors of rats exposed to chronic unpredictable stress (CUS) but also to restore the protein expressions of pERK1/2 and BDNF and cell proliferation in the hippocampus. Additionally, QUE and rTMS promoted the proliferation and increased the expression of pERK1/2 and BDNF in hippocampal-derived neural stem cells (NSCs), and these effects were abolished by U0126. Taken together, these results suggest that the antidepressive-like effects of QUE and rTMS might be related to the activation of the BDNF/ERK signaling pathway and the up-regulation of cell proliferation in the hippocampus. PMID:26176197

  2. Behavior regulation and learned performance: Some misapprehensions and disagreements

    PubMed Central

    Timberlake, William

    1984-01-01

    The behavior-regulation approach to learned performance has been the subject of misapprehension and disagreement concerning: (1) the nature and importance of behavior regulation, (2) the definition and role of behavioral set-points, (3) the relation of optimal schedule performance to behavioral set-points, and (4) the question of whether deviations from total responding or from response patterns are the primary determinant of molar responding under schedule constraint. After clarifying the nature and role of behavior regulation and set-points, this paper shows that the data used to question optimal schedule performance (Allison, 1981a) actually strongly support the general behavior-regulation approach. These data also indicate a role for response-pattern set-points in determining schedule behavior, but contradict the hypothesis that deviations from response-pattern characteristics are the primary determinant of molar schedule effects. PMID:16812374

  3. Behavioral Regulation and Early Academic Achievement in Taiwan

    ERIC Educational Resources Information Center

    Wanless, Shannon B.; McClelland, Megan M.; Acock, Alan C.; Chen, Fu-Mei; Chen, Jo-Lin

    2011-01-01

    Research Findings: Behavioral regulation (the integration of attention, working memory, and inhibitory control) is critical for school readiness and early academic achievement. In Taiwan, however, where academic success is highly valued, there is a dearth of assessments available to measure young children's behavioral regulation. The present study…

  4. Cell Signaling Underlying Epileptic Behavior

    PubMed Central

    Bozzi, Yuri; Dunleavy, Mark; Henshall, David C.

    2011-01-01

    Epilepsy is a complex disease, characterized by the repeated occurrence of bursts of electrical activity (seizures) in specific brain areas. The behavioral outcome of seizure events strongly depends on the brain regions that are affected by overactivity. Here we review the intracellular signaling pathways involved in the generation of seizures in epileptogenic areas. Pathways activated by modulatory neurotransmitters (dopamine, norepinephrine, and serotonin), involving the activation of extracellular-regulated kinases and the induction of immediate early genes (IEGs) will be first discussed in relation to the occurrence of acute seizure events. Activation of IEGs has been proposed to lead to long-term molecular and behavioral responses induced by acute seizures. We also review deleterious consequences of seizure activity, focusing on the contribution of apoptosis-associated signaling pathways to the progression of the disease. A deep understanding of signaling pathways involved in both acute- and long-term responses to seizures continues to be crucial to unravel the origins of epileptic behaviors and ultimately identify novel therapeutic targets for the cure of epilepsy. PMID:21852968

  5. Regulation of circadian rhythms in mammals by behavioral arousal.

    PubMed

    Webb, Ian C; Antle, Michael C; Mistlberger, Ralph E

    2014-06-01

    Circadian rhythms in most mammals are synchronized to local time by phase and period resetting actions of daily light-dark cycles on a retino-recipient, light-entrainable circadian pacemaker, the suprachiasmatic nucleus (SCN). The SCN receives input from other brain regions, some of which mediate the phase and period resetting actions of behavioral arousal on circadian rhythms. We review historical milestones in the discovery of so-called "nonphotic" circadian clock resetting induced by environmentally stimulated arousal, or by feedback from clock-controlled rest-activity cycles. Topics include species generality, interactions between concurrent or successive photic and nonphotic inputs to the circadian clock, neural pathways, neurotransmitters, and clock cell responses that mediate resetting by behavioral arousal. The role of behavioral inputs to the circadian clock in determining the phase of entrainment to local time in natural environments is not well understood. Nonetheless, nonphotic effects are of sufficient magnitude to raise issues for the design of experiments in behavioral neuroscience (any procedure that is sufficiently arousing may alter the timing of circadian clocks that regulate dependent variables of primary interest). Nonphotic inputs to the clock may be exploited in strategies to reset or strengthen circadian rhythms in humans. PMID:24773430

  6. Metabolic regulation of stem cell function.

    PubMed

    Burgess, R J; Agathocleous, M; Morrison, S J

    2014-07-01

    Stem cell function is regulated by intrinsic mechanisms, such as transcriptional and epigenetic regulators, as well as extrinsic mechanisms, such as short-range signals from the niche and long-range humoral signals. Interactions between these regulatory mechanisms and cellular metabolism are just beginning to be identified. In multiple systems, differentiation is accompanied by changes in glycolysis, oxidative phosphorylation and the levels of reactive oxygen species. Indeed, metabolic pathways regulate proliferation and differentiation by regulating energy production and the generation of substrates for biosynthetic pathways. Some metabolic pathways appear to function differently in stem cells as compared with restricted progenitors and differentiated cells. They also appear to influence stem cell function by regulating signal transduction, epigenetic marks and oxidative stress. Studies to date illustrate the importance of metabolism in the regulation of stem cell function and suggest complex cross-regulation likely exists between metabolism and other stem cell regulatory mechanisms. PMID:24697828

  7. Stem cell regulation: Implications when differentiated cells regulate symmetric stem cell division.

    PubMed

    Høyem, Marte Rørvik; Måløy, Frode; Jakobsen, Per; Brandsdal, Bjørn Olav

    2015-09-01

    We use a mathematical model to show that if symmetric stem cell division is regulated by differentiated cells, then changes in the population dynamics of the differentiated cells can lead to changes in the population dynamics of the stem cells. More precisely, the relative fitness of the stem cells can be affected by modifying the death rate of the differentiated cells. This result is interesting because stem cells are less sensitive than differentiated cells to environmental factors, such as medical therapy. Our result implies that stem cells can be manipulated indirectly by medical treatments that target the differentiated cells. PMID:25997796

  8. Regulation of Expressive Behavior as Reflecting Affect Socialization.

    ERIC Educational Resources Information Center

    Saarni, Carolyn

    Regulated expressiveness (the modification of expressive behavior) is a complex phenomenon. Accomplished basically in four ways, regulated expressiveness has developmental dimensions, motivational precursors, and cognitive antecedents, including perspective-taking ability and the growth of self-awareness. Ability to regulate expressiveness appears…

  9. Cell Cycle Regulation in the Developing Lens

    PubMed Central

    Griep, Anne E.

    2007-01-01

    Regulation of cell proliferation is a critical aspect of the development of multicellular organisms. The ocular lens is an excellent model system in which to unravel the mechanisms controlling cell proliferation during development. In recent years, several cell cycle regulators have been shown to be essential for maintaining normal patterns of lens cell proliferation. Additionally, many growth factor signaling pathways and cell adhesion factors have been shown to have the capacity to regulate lens cell proliferation. Given this complexity, understanding the cross talk between these many signaling pathways and how they are coordinated are important directions for the future. PMID:17218126

  10. Subcellular optogenetics – controlling signaling and single-cell behavior

    PubMed Central

    Karunarathne, W. K. Ajith; O'Neill, Patrick R.; Gautam, Narasimhan

    2015-01-01

    ABSTRACT Variation in signaling activity across a cell plays a crucial role in processes such as cell migration. Signaling activity specific to organelles within a cell also likely plays a key role in regulating cellular functions. To understand how such spatially confined signaling within a cell regulates cell behavior, tools that exert experimental control over subcellular signaling activity are required. Here, we discuss the advantages of using optogenetic approaches to achieve this control. We focus on a set of optical triggers that allow subcellular control over signaling through the activation of G-protein-coupled receptors (GPCRs), receptor tyrosine kinases and downstream signaling proteins, as well as those that inhibit endogenous signaling proteins. We also discuss the specific insights with regard to signaling and cell behavior that these subcellular optogenetic approaches can provide. PMID:25433038

  11. Cell adhesion in regulation of asymmetric stem cell division

    PubMed Central

    Yamashita, Yukiko M.

    2010-01-01

    Adult stem cells inevitably communicate with their cellular neighbors within the tissues they sustain. Indeed, such communication, particularly with components of the stem cell niche, is essential for many aspects of stem cell behavior, including the maintenance of stem cell identity and asymmetric cell division. Cell adhesion mediates this communication by placing stem cells in close proximity to the signaling source and by providing a polarity cue that orients stem cells. Here, I review the recent discovery that cell adhesion molecules govern the behavior of stem cells. PMID:20724132

  12. The effects of harvest regulations on behaviors of duck hunters

    USGS Publications Warehouse

    Haugen, Matthew T.; Powell, Larkin A.; Vrtiska, Mark P.; Pope, Kevin L.

    2015-01-01

    Uncertainty exists as to how duck harvest regulations influence waterfowl hunter behavior. We used the U.S. Fish and Wildlife Service’s Parts Collection Survey to examine how harvest regulations affected behaviors of Central Flyway duck hunters. We stratified hunters into ranked groups based on seasonal harvest and identified three periods (1975–1984, 1988–1993, 2002–2011) that represented different harvest regulations (moderate, restrictive, and liberal, respectively; season length and daily bag limits smallest in restrictive seasons and largest in liberal seasons). We examined variability of seven measures of duck hunter behaviors across the periods: days harvesting ducks, daily harvest, hunter mobility, mallard (Anas platyrhynchos) selectivity, gender selectivity, daily female mallard harvest, and timing of harvest. Hunters reported harvesting ducks on more days, at a higher efficiency, and in slightly more counties during liberal seasons relative to restrictive and moderate seasons. We provide evidence to suggest that future regulation change will affect hunter behaviors.

  13. Molecular regulation of plant cell wall extensibility

    NASA Technical Reports Server (NTRS)

    Cosgrove, D. J.

    1998-01-01

    Gravity responses in plants often involve spatial and temporal changes in cell growth, which is regulated primarily by controlling the ability of the cell wall to extend. The wall is thought to be a cellulose-hemicellulose network embedded in a hydrated matrix of complex polysaccharides and a small amount of structural protein. The wall extends by a form of polymer creep, which is mediated by expansins, a novel group of wall-loosening proteins. Expansins were discovered during a molecular dissection of the "acid growth" behavior of cell walls. Expansin alters the rheology of plant walls in profound ways, yet its molecular mechanism of action is still uncertain. It lacks detectable hydrolytic activity against the major components of the wall, but it is able to disrupt noncovalent adhesion between wall polysaccharides. The discovery of a second family of expansins (beta-expansins) sheds light on the biological role of a major group of pollen allergens and implies that expansins have evolved for diverse developmental functions. Finally, the contribution of other processes to wall extensibility is briefly summarized.

  14. Interspecific nematode signals regulate dispersal behavior

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dispersal is an important nematode behavior. Upon crowding or food depletion, the free living bacteriovorus nematode Caenorhabditis elegans produces stress resistant dispersal larvae, called dauer, which are analogous to second stage juveniles (J2) of plant parasitic Meloidogyne spp. and infective ...

  15. Neuroengineering control and regulation of behavior

    NASA Astrophysics Data System (ADS)

    Wróbel, A.; Radzewicz, C.; Mankiewicz, L.; Hottowy, P.; Knapska, E.; Konopka, W.; Kublik, E.; Radwańska, K.; Waleszczyk, W. J.; Wójcik, D. K.

    2014-11-01

    To monitor neuronal circuits involved in emotional modulation of sensory processing we proposed a plan to establish novel research techniques combining recent biological, technical and analytical discoveries. The project was granted by National Science Center and we started to build a new experimental model for studying the selected circuits of genetically marked and behaviorally activated neurons. To achieve this goal we will combine the pioneering, interdisciplinary expertise of four Polish institutions: (i) the Nencki Institute of Experimental Biology (Polish Academy of Sciences) will deliver the expertise on genetically modified mice and rats, mapping of the neuronal circuits activated by behavior, monitoring complex behaviors measured in the IntelliCage system, electrophysiological brain activity recordings by multielectrodes in behaving animals, analysis and modeling of behavioral and electrophysiological data; (ii) the AGH University of Science and Technology (Faculty of Physics and Applied Computer Sciences) will use its experience in high-throughput electronics to build multichannel systems for recording the brain activity of behaving animals; (iii) the University of Warsaw (Faculty of Physics) and (iv) the Center for Theoretical Physics (Polish Academy of Sciences) will construct optoelectronic device for remote control of opto-animals produced in the Nencki Institute based on the unique experience in laser sources, studies of light propagation and its interaction with condensed media, wireless medical robotic systems, fast readout opto-electronics with control software and micromechanics.

  16. Review: neuroestrogen regulation of socio-sexual behavior of males

    PubMed Central

    Ubuka, Takayoshi; Tsutsui, Kazuyoshi

    2014-01-01

    It is thought that estrogen (neuroestrogen) synthesized by the action of aromatase in the brain from testosterone activates male socio-sexual behaviors, such as aggression and sexual behavior in birds. We recently found that gonadotropin-inhibitory hormone (GnIH), a hypothalamic neuropeptide, inhibits socio-sexual behaviors of male quail by directly activating aromatase and increasing neuroestrogen synthesis in the preoptic area (POA). The POA is thought to be the most critical site of aromatization and neuroestrogen action for the regulation of socio-sexual behavior of male birds. We concluded that GnIH inhibits socio-sexual behaviors of male quail by increasing neuroestrogen concentration beyond its optimal concentration in the brain for expression of socio-sexual behavior. On the other hand, it has been reported that dopamine and glutamate, which stimulate male socio-sexual behavior in birds and mammals, inhibit the activity of aromatase in the POA. Multiple studies also report that the activity of aromatase or neuroestrogen is negatively correlated with changes in male socio-sexual behavior in fish, birds, and mammals including humans. Here, we review previous studies that investigated the role of neuroestrogen in the regulation of male socio-sexual behavior and reconsider the hypothesis that neuroestrogen activates male socio-sexual behavior in vertebrates. It is considered that basal concentration of neuroestrogen is required for the maintenance of male socio-sexual behavior but higher concentration of neuroestrogen may inhibit male socio-sexual behavior. PMID:25352775

  17. Metaboloepigenetic Regulation of Pluripotent Stem Cells

    PubMed Central

    Harvey, Alexandra J.; Gardner, David K.

    2016-01-01

    The differentiation of pluripotent stem cells is associated with extensive changes in metabolism, as well as widespread remodeling of the epigenetic landscape. Epigenetic regulation is essential for the modulation of differentiation, being responsible for cell type specific gene expression patterns through the modification of DNA and histones, thereby establishing cell identity. Each cell type has its own idiosyncratic pattern regarding the use of specific metabolic pathways. Rather than simply being perceived as a means of generating ATP and building blocks for cell growth and division, cellular metabolism can directly influence cellular regulation and the epigenome. Consequently, the significance of nutrients and metabolites as regulators of differentiation is central to understanding how cells interact with their immediate environment. This review serves to integrate studies on pluripotent stem cell metabolism, and the regulation of DNA methylation and acetylation and identifies areas in which current knowledge is limited. PMID:26839556

  18. Genetic Isolation of Hypothalamic Neurons that Regulate Context-Specific Male Social Behavior.

    PubMed

    Soden, Marta E; Miller, Samara M; Burgeno, Lauren M; Phillips, Paul E M; Hnasko, Thomas S; Zweifel, Larry S

    2016-07-12

    Nearly all animals engage in a complex assortment of social behaviors that are essential for the survival of the species. In mammals, these behaviors are regulated by sub-nuclei within the hypothalamus, but the specific cell types within these nuclei responsible for coordinating behavior in distinct contexts are only beginning to be resolved. Here, we identify a population of neurons in the ventral premammillary nucleus of the hypothalamus (PMV) that are strongly activated in male intruder mice in response to a larger resident male but that are not responsive to females. Using a combination of molecular and genetic approaches, we demonstrate that these PMV neurons regulate intruder-specific male social behavior and social novelty recognition in a manner dependent on synaptic release of the excitatory neurotransmitter glutamate. These data provide direct evidence for a unique population of neurons that regulate social behaviors in specific contexts. PMID:27346361

  19. Job Specific Behavioral & Environmental Privacy Regulation.

    ERIC Educational Resources Information Center

    Werner, Carol; Haggard, Lois

    The findings from a study of 42 administrators in a large metropolitan school district supported the hypothesis that the use of privacy regulation mechanisms is deliberate and dynamic. The researchers considered the age and sex of the administrators, the length of time they'd held their current jobs, their tendencies toward Type A or Type B…

  20. Materials as stem cell regulators

    NASA Astrophysics Data System (ADS)

    Murphy, William L.; McDevitt, Todd C.; Engler, Adam J.

    2014-06-01

    The stem cell/material interface is a complex, dynamic microenvironment in which the cell and the material cooperatively dictate one another's fate: the cell by remodelling its surroundings, and the material through its inherent properties (such as adhesivity, stiffness, nanostructure or degradability). Stem cells in contact with materials are able to sense their properties, integrate cues via signal propagation and ultimately translate parallel signalling information into cell fate decisions. However, discovering the mechanisms by which stem cells respond to inherent material characteristics is challenging because of the highly complex, multicomponent signalling milieu present in the stem cell environment. In this Review, we discuss recent evidence that shows that inherent material properties may be engineered to dictate stem cell fate decisions, and overview a subset of the operative signal transduction mechanisms that have begun to emerge. Further developments in stem cell engineering and mechanotransduction are poised to have substantial implications for stem cell biology and regenerative medicine.

  1. Materials as stem cell regulators

    PubMed Central

    Murphy, William L.; McDevitt, Todd C.; Engler, Adam J.

    2014-01-01

    The stem cell/material interface is a complex, dynamic microenvironment in which the cell and the material cooperatively dictate one another's fate: the cell by remodelling its surroundings, and the material through its inherent properties (such as adhesivity, stiffness, nanostructure or degradability). Stem cells in contact with materials are able to sense their properties, integrate cues via signal propagation and ultimately translate parallel signalling information into cell fate decisions. However, discovering the mechanisms by which stem cells respond to inherent material characteristics is challenging because of the highly complex, multicomponent signalling milieu present in the stem cell environment. In this Review, we discuss recent evidence that shows that inherent material properties may be engineered to dictate stem cell fate decisions, and overview a subset of the operative signal transduction mechanisms that have begun to emerge. Further developments in stem cell engineering and mechanotransduction are poised to have substantial implications for stem cell biology and regenerative medicine. PMID:24845994

  2. Hybrid inverse opals for regulating cell adhesion and orientation

    NASA Astrophysics Data System (ADS)

    Lu, Jie; Zheng, Fuyin; Cheng, Yao; Ding, Haibo; Zhao, Yuanjin; Gu, Zhongze

    2014-08-01

    Cell adhesion and alignment are two important considerations in tissue engineering applications as they can regulate the subsequent cell proliferation activity and differentiation program. Although many effects have been applied to regulate the adhesion or alignment of cells by using physical and chemical methods, it is still a challenge to regulate these cell behaviors simultaneously. Here, we present novel substrates with tunable nanoscale patterned structures for regulating the adhesion and alignment of cells. The substrates with different degrees of pattern orientation were achieved by customizing the amount of stretching applied to polymer inverse opal films. Cells cultured on these substrates showed an adjustable morphology and alignment. Moreover, soft hydrogels, which have poor plasticity and are difficult to cast into patterned structures, were applied to infiltrate the inverse opal structure. We demonstrated that the adhesion ratio of cells could be regulated by these hybrid substrates, as well as adjusting the cell morphology and alignment. These features of functional inverse opal substrates make them suitable for important applications in tissue engineering.

  3. Hybrid inverse opals for regulating cell adhesion and orientation.

    PubMed

    Lu, Jie; Zheng, Fuyin; Cheng, Yao; Ding, Haibo; Zhao, Yuanjin; Gu, Zhongze

    2014-09-21

    Cell adhesion and alignment are two important considerations in tissue engineering applications as they can regulate the subsequent cell proliferation activity and differentiation program. Although many effects have been applied to regulate the adhesion or alignment of cells by using physical and chemical methods, it is still a challenge to regulate these cell behaviors simultaneously. Here, we present novel substrates with tunable nanoscale patterned structures for regulating the adhesion and alignment of cells. The substrates with different degrees of pattern orientation were achieved by customizing the amount of stretching applied to polymer inverse opal films. Cells cultured on these substrates showed an adjustable morphology and alignment. Moreover, soft hydrogels, which have poor plasticity and are difficult to cast into patterned structures, were applied to infiltrate the inverse opal structure. We demonstrated that the adhesion ratio of cells could be regulated by these hybrid substrates, as well as adjusting the cell morphology and alignment. These features of functional inverse opal substrates make them suitable for important applications in tissue engineering. PMID:25088946

  4. Genome exposure and regulation in mammalian cells.

    PubMed

    Puck, T T; Webb, P; Johnson, R

    1998-09-01

    A method of measurement of exposed DNA (i.e. hypersensitive to DNase I hydrolysis) as opposed to sequestered (hydrolysis resistant) DNA in isolated nuclei of mammalian cells is described. While cell cultures exhibit some differences in behavior from day to day, the general pattern of exposed and sequestered DNA is satisfactorily reproducible and agrees with results previously obtained by other methods. The general pattern of DNA hydrolysis exhibited by all cells tested consists of a curve which at first rises sharply with increasing DNase I, and then becomes almost horizontal, indicating that roughly about half of the nuclear DNA is highly sequestered. In 4 cases where transformed cells (Raszip6, CHO, HL60 and PC12) were compared, each with its more normal homolog (3T3, and the reverse transformed versions of CHO, HL60 and PC12, achieved by dibutyryl cyclic AMP [DBcAMP], retinoic acid, and nerve growth factor [NGF] respectively), the transformed form displayed less genome exposure than the nontransformed form at every DNase I dose tested. When Ca++ was excluded from the hydrolysis medium in both the Raszip6-3T3 and the CHO-DBcAMP systems, the normal cell forms lost their increased exposure reverting to that of the transformed forms. Therefore Ca++ appears necessary for maintenance of the DNA in the more highly exposed state characteristic of the nontransformed phenotype. LiCl increases the DNA exposure of all transformed cells tested. Dextran sulfate and heparin each can increase the DNA exposure of several different cancers. Colcemid prevents the increase of exposure of CHO by DBcAMP but it must be administered before or simultaneously with the latter compound. Measurements on mouse biopsies reveal large differences in exposure in different normal tissues. Thus, the exposure from adult liver cells was greater than that of adult brain, but both fetal liver and fetal brain had significantly greater exposure than their adult counterparts. Exposure in normal human

  5. Biofunctionalization of a titanium surface with a nano-sawtooth structure regulates the behavior of rat bone marrow mesenchymal stem cells

    PubMed Central

    Zhang, Wenjie; Li, Zihui; Liu, Yan; Ye, Dongxia; Li, Jinhua; Xu, Lianyi; Wei, Bin; Zhang, Xiuli; Liu, Xuanyong; Jiang, Xinquan

    2012-01-01

    Background: The topography of an implant surface can serve as a powerful signaling cue for attached cells and can enhance the quality of osseointegration. A series of improved implant surfaces functionalized with nanoscale structures have been fabricated using various methods. Methods: In this study, using an H2O2 process, we fabricated two size-controllable sawtooth-like nanostructures with different dimensions on a titanium surface. The effects of the two nano-sawtooth structures on rat bone marrow mesenchymal stem cells (BMMSCs) were evaluated without the addition of osteoinductive chemical factors. Results: These new surface modifications did not adversely affect cell viability, and rat BMMSCs demonstrated a greater increase in proliferation ability on the surfaces of the nano-sawtooth structures than on a control plate. Furthermore, upregulated expression of osteogenic-related genes and proteins indicated that the nano-sawtooth structures promote osteoblastic differentiation of rat BMMSCs. Importantly, the large nano-sawtooth structure resulted in the greatest cell responses, including increased adhesion, proliferation, and differentiation. Conclusion: The enhanced adhesion, proliferation, and osteogenic differentiation abilities of rat BMMSCs on the nano-sawtooth structures suggest the potential to induce improvements in bone-titanium integration in vivo. Our study reveals the key role played by the nano-sawtooth structures on a titanium surface for the fate of rat BMMSCs and provides insights into the study of stem cell-nanostructure relationships and the related design of improved biomedical implant surfaces. PMID:22927760

  6. Natural killer cell regulation - beyond the receptors

    PubMed Central

    Urlaub, Doris; Fasbender, Frank; Claus, Maren

    2014-01-01

    Natural killer (NK) cells are lymphocytes that are important for early and effective immune responses against infections and cancer. In the last 40 years, many receptors, their corresponding ligands and signaling pathways that regulate NK cell functions have been identified. However, we now know that additional processes, such as NK cell education, differentiation and also the formation of NK cell memory, have a great impact on the reactivity of these cells. Here, we summarize the current knowledge about these modulatory processes. PMID:25374665

  7. Three-Dimensional Cell Behavior in Microgels

    NASA Astrophysics Data System (ADS)

    Bhattacharjee, Tapomoy; Palmer, Glyn; Ghivizzani, Steven; Keselowsky, Benjamin; Sawyer, W. Gregory; Angelini, Thomas

    The number of dimensions in which particles can freely move strongly influences the collective behavior that emerges from their individual fluctuations. Thus, in 2D systems of cells in petri-dishes, our growing understanding of collective migration may be insufficient to explain cell behavior in 3D tissues. To study cell behavior in 3D, polymer scaffolds are used. Contemporary designs of 3D cell growth scaffolds enable cell migration and proliferative expansion by incorporating of degradable motifs. Matrix degradation creates space for cells to move and proliferate. However, different cell types and experimental conditions require the design of different scaffolds to optimize degradation with specific cell behaviors. By contrast, liquid like solids made from packed microgels can yield under cell generated stresses, allowing for cell motion without the need for scaffold degradation. Moreover, the use of microgels as 3D culture media allows arranging cells in arbitrary structures, harvesting cells, and delivering drugs and nutrients. Preliminary data describing cell behavior in 3D microgel culture will be presented. This material is based on work supported by the National Science Foundation under Grant No. DMR-1352043.

  8. Regulation of NANOG in cancer cells.

    PubMed

    Gong, Shuai; Li, Qiuhui; Jeter, Collene R; Fan, Qingxia; Tang, Dean G; Liu, Bigang

    2015-09-01

    As one of the key pluripotency transcription factors, NANOG plays a critical role in maintaining the self-renewal and pluripotency in normal embryonic stem cells. Recent data indicate that NANOG is expressed in a variety of cancers and its expression correlates with poor survival in cancer patients. Of interest, many studies suggest that NANOG enhances the defined characteristics of cancer stem cells and may thus function as an oncogene to promote carcinogenesis. Therefore, NANOG expression determines the cell fate not only in pluripotent cells but also in cancer cells. Although the regulation of NANOG in normal embryonic stem cells is reasonably well understood, the regulation of NANOG in cancer cells has only emerged recently. The current review provides a most updated summary on how NANOG expression is regulated during tumor development and progression. PMID:26013997

  9. Epigenetic Regulation of Mammalian Stem Cells

    PubMed Central

    Li, Xuekun

    2008-01-01

    Two critical properties of stem cells are self-renewal and multipotency. The maintenance of their “stemness” state and commitment to differentiation are therefore tightly controlled by intricate molecular networks. Epigenetic mechanisms, including DNA methylation, chromatin remodeling and the noncoding RNA-mediated process, have profound regulatory roles in mammalian gene expression. Recent studies have shown that epigenetic regulators are key players in stem cell biology and their dysfunction can result in human diseases such as cancer and neurodevelopmental disorders. Here, we review the recent evidences that advance our knowledge in epigenetic regulations of mammalian stem cells, with focus on embryonic stem cells and neural stem cells. PMID:18393635

  10. Cell Cycle Regulation by Checkpoints

    PubMed Central

    Barnum, Kevin J.; O’Connell, Matthew J.

    2016-01-01

    Cell cycle checkpoints are surveillance mechanisms that monitor the order, integrity, and fidelity of the major events of the cell cycle. These include growth to the appropriate cell size, the replication and integrity of the chromosomes, and their accurate segregation at mitosis. Many of these mechanisms are ancient in origin and highly conserved, and hence have been heavily informed by studies in simple organisms such as the yeasts. Others have evolved in higher organisms, and control alternative cell fates with significant impact on tumor suppression. Here, we consider these different checkpoint pathways and the consequences of their dysfunction on cell fate. PMID:24906307

  11. Evolving gene regulation networks into cellular networks guiding adaptive behavior: an outline how single cells could have evolved into a centralized neurosensory system

    PubMed Central

    Fritzsch, Bernd; Jahan, Israt; Pan, Ning; Elliott, Karen L.

    2014-01-01

    Understanding the evolution of the neurosensory system of man, able to reflect on its own origin, is one of the major goals of comparative neurobiology. Details of the origin of neurosensory cells, their aggregation into central nervous systems and associated sensory organs, their localized patterning into remarkably different cell types aggregated into variably sized parts of the central nervous system begin to emerge. Insights at the cellular and molecular level begin to shed some light on the evolution of neurosensory cells, partially covered in this review. Molecular evidence suggests that high mobility group (HMG) proteins of pre-metazoans evolved into the definitive Sox [SRY (sex determining region Y)-box] genes used for neurosensory precursor specification in metazoans. Likewise, pre-metazoan basic helix-loop-helix (bHLH) genes evolved in metazoans into the group A bHLH genes dedicated to neurosensory differentiation in bilaterians. Available evidence suggests that the Sox and bHLH genes evolved a cross-regulatory network able to synchronize expansion of precursor populations and their subsequent differentiation into novel parts of the brain or sensory organs. Molecular evidence suggests metazoans evolved patterning gene networks early and not dedicated to neuronal development. Only later in evolution were these patterning gene networks tied into the increasing complexity of diffusible factors, many of which were already present in pre-metazoans, to drive local patterning events. It appears that the evolving molecular basis of neurosensory cell development may have led, in interaction with differentially expressed patterning genes, to local network modifications guiding unique specializations of neurosensory cells into sensory organs and various areas of the central nervous system. PMID:25416504

  12. Plant Proteases Involved in Regulated Cell Death.

    PubMed

    Zamyatnin, A A

    2015-12-01

    Each plant genome encodes hundreds of proteolytic enzymes. These enzymes can be divided into five distinct classes: cysteine-, serine-, aspartic-, threonine-, and metalloproteinases. Despite the differences in their structural properties and activities, members of all of these classes in plants are involved in the processes of regulated cell death - a basic feature of eukaryotic organisms. Regulated cell death in plants is an indispensable mechanism supporting plant development, survival, stress responses, and defense against pathogens. This review summarizes recent advances in studies of plant proteolytic enzymes functioning in the initiation and execution of distinct types of regulated cell death. PMID:26878575

  13. Small GTPases as regulators of cell division

    PubMed Central

    Militello, Rodrigo; Colombo, María I.

    2013-01-01

    The superfamily of small GTPases serves as a signal transducer to regulate a diverse array of cellular functions. The members of this superfamily are structurally and functionally classified into at least 5 groups (Ras, Rho/Rac, Rab, Arf, and Ran) and they are involved in the control of cell proliferation and differentiation, regulation of the actin cytoskeleton, membrane trafficking, and nuclear transport. It is widely reported that members of the Rab family participate in the control of intracellular membrane trafficking through the interaction with specific effector molecules. However, many Rabs and other small GTPases have also been shown to function in cell division. In this review, we discuss current knowledge about Rab proteins regulating different stages of the cell cycle, such as the congregation and segregation of chromosomes (during metaphase) and the final stage of cell division known as cytokinesis, in which a cell is cleaved originating 2 daughter cells. PMID:24265858

  14. Regulation of the p19Arf/p53 pathway by histone acetylation underlies neural stem cell behavior in senescence-prone SAMP8 mice

    PubMed Central

    Soriano-Cantón, Raúl; Perez-Villalba, Ana; Morante-Redolat, José Manuel; Marqués-Torrejón, María Ángeles; Pallás, Mercé; Pérez-Sánchez, Francisco; Fariñas, Isabel

    2015-01-01

    Brain aging is associated with increased neurodegeneration and reduced neurogenesis. B1/neural stem cells (B1-NSCs) of the mouse subependymal zone (SEZ) support the ongoing production of olfactory bulb interneurons, but their neurogenic potential is progressively reduced as mice age. Although age-related changes in B1-NSCs may result from increased expression of tumor suppressor proteins, accumulation of DNA damage, metabolic alterations, and microenvironmental or systemic changes, the ultimate causes remain unclear. Senescence-accelerated-prone mice (SAMP8) relative to senescence-accelerated-resistant mice (SAMR1) exhibit signs of hastened senescence and can be used as a model for the study of aging. We have found that the B1-NSC compartment is transiently expanded in young SAMP8 relative to SAMR1 mice, resulting in disturbed cytoarchitecture of the SEZ, B1-NSC hyperproliferation, and higher yields of primary neurospheres. These unusual features are, however, accompanied by premature loss of B1-NSCs. Moreover, SAMP8 neurospheres lack self-renewal and enter p53-dependent senescence after only two passages. Interestingly, in vitro senescence of SAMP8 cells could be prevented by inhibition of histone acetyltransferases and mimicked in SAMR1 cells by inhibition of histone deacetylases (HDAC). Our data indicate that expression of the tumor suppressor p19, but not of p16, is increased in SAMP8 neurospheres, as well as in SAMR1 neurospheres upon HDAC inhibition, and suggest that the SAMP8 phenotype may, at least in part, be due to changes in chromatin status. Interestingly, acute HDAC inhibition in vivo resulted in changes in the SEZ of SAMR1 mice that resembled those found in young SAMP8 mice. PMID:25728253

  15. Regulation of Th2 Cell Immunity by Dendritic Cells

    PubMed Central

    Na, Hyeongjin

    2016-01-01

    Th2 cell immunity is required for host defense against helminths, but it is detrimental in allergic diseases in humans. Unlike Th1 cell and Th17 cell subsets, the mechanism by which dendritic cells modulate Th2 cell responses has been obscure, in part because of the inability of dendritic cells to provide IL-4, which is indispensable for Th2 cell lineage commitment. In this regard, immune cells other than dendritic cells, such as basophils and innate lymphoid cells, have been suggested as Th2 cell inducers. More recently, multiple independent researchers have shown that specialized subsets of dendritic cells mediate Th2 cell responses. This review will discuss the current understanding related to the regulation of Th2 cell responses by dendritic cells and other immune cells. PMID:26937227

  16. Hematopoietic stem cells: multiparameter regulation.

    PubMed

    Song, Kedong; Li, Liying; Wang, Yiwei; Liu, Tianqing

    2016-04-01

    Hematopoietic stem cells (HSCs) are capable to self-renew with multi-potency which generated much excitement in clinical therapy. However, the main obstacle of HSCs in clinical application was insufficient number of HSCs which were derived from either bone marrow, peripheral blood or umbilical cord blood. This review briefly discusses the indispensable utility of growth factors and cytokines, stromal cells, extracellular matrix, bionic scaffold and microenvironment aiming to control the hematopoiesis in all directions and provide a better and comprehensive understanding for in vitro expansion of hematopoietic stem cells. PMID:26883144

  17. Rnd3 regulates lung cancer cell proliferation through notch signaling.

    PubMed

    Tang, Yongjun; Hu, Chengping; Yang, Huaping; Cao, Liming; Li, Yuanyuan; Deng, Pengbo; Huang, Li

    2014-01-01

    Rnd3/RhoE is a small Rho GTPase involved in the regulation of different cell behaviors. Dysregulation of Rnd3 has been linked to tumorigenesis and metastasis. Lung cancers are the leading cause of cancer-related death in the West and around the world. The expression of Rnd3 and its ectopic role in non-small cell lung cancer (NSCLC) remain to be explored. Here, we reported that Rnd3 was down-regulated in three NSCLC cell lines: H358, H520 and A549. The down-regulation of Rnd3 led to hyper-activation of Rho Kinase and Notch signaling. The reintroduction of Rnd3 or selective inhibition of Notch signaling, but not Rho Kinase signaling, blocked the proliferation of H358 and H520 cells. Mechanistically, Notch intracellular domain (NICD) protein abundance in H358 cells was regulated by Rnd3-mediated NICD proteasome degradation. Rnd3 regulated H358 and H520 cell proliferation through a Notch1/NICD/Hes1 signaling axis independent of Rho Kinase. PMID:25372032

  18. Rnd3 Regulates Lung Cancer Cell Proliferation through Notch Signaling

    PubMed Central

    Tang, Yongjun; Hu, Chengping; Yang, Huaping; Cao, Liming; Li, Yuanyuan; Deng, Pengbo; Huang, Li

    2014-01-01

    Rnd3/RhoE is a small Rho GTPase involved in the regulation of different cell behaviors. Dysregulation of Rnd3 has been linked to tumorigenesis and metastasis. Lung cancers are the leading cause of cancer-related death in the West and around the world. The expression of Rnd3 and its ectopic role in non-small cell lung cancer (NSCLC) remain to be explored. Here, we reported that Rnd3 was down-regulated in three NSCLC cell lines: H358, H520 and A549. The down-regulation of Rnd3 led to hyper-activation of Rho Kinase and Notch signaling. The reintroduction of Rnd3 or selective inhibition of Notch signaling, but not Rho Kinase signaling, blocked the proliferation of H358 and H520 cells. Mechanistically, Notch intracellular domain (NICD) protein abundance in H358 cells was regulated by Rnd3-mediated NICD proteasome degradation. Rnd3 regulated H358 and H520 cell proliferation through a Notch1/NICD/Hes1 signaling axis independent of Rho Kinase. PMID:25372032

  19. Cell Size Regulation in Bacteria

    NASA Astrophysics Data System (ADS)

    Amir, Ariel

    2014-05-01

    Various bacteria such as the canonical gram negative Escherichia coli or the well-studied gram positive Bacillus subtilis divide symmetrically after they approximately double their volume. Their size at division is not constant, but is typically distributed over a narrow range. Here, we propose an analytically tractable model for cell size control, and calculate the cell size and interdivision time distributions, as well as the correlations between these variables. We suggest ways of extracting the model parameters from experimental data, and show that existing data for E. coli supports partial size control, and a particular explanation: a cell attempts to add a constant volume from the time of initiation of DNA replication to the next initiation event. This hypothesis accounts for the experimentally observed correlations between mother and daughter cells as well as the exponential dependence of size on growth rate.

  20. The behavior of renal-regulating hormones during hypogravic stress

    NASA Technical Reports Server (NTRS)

    Leonard, J. I.

    1985-01-01

    The regulation of fluid and electrolyte behavior during space flight is believed to be under control, in large part, of a group of hormones which have their major effects on renal excretion. The hormones studied include renin-angitensin, aldosterone, and antidiuretic hormone (ADH). The regulatory systems of these renal-regulating hormones as they act individually and in concert with each other are analyzed. The analysis is based on simulations of the mathematical model of Guyton. A generalized theory is described which accounts for both short-term and long-term behavior of this set of hormones.

  1. Self-regulation assessment among preschoolers with externalizing behavior problems.

    PubMed

    Graziano, Paulo A; Slavec, Janine; Ros, Rosmary; Garb, Leanna; Hart, Katie; Garcia, Alexis

    2015-12-01

    This study examined the construct validity and clinical utility of a brief self-regulation assessment (Head-Toes-Knees-Shoulders, HTKS) among a clinical sample of children with externalizing behavior problems (EBP). Participants for this study included 101 preschool children (72% male; Mage = 5.10 years; 79% Hispanic) with at-risk or clinically elevated levels of EBP. Self-regulation measures included the HTKS task, 4 standardized subtests from the Automated Working Memory Assessment (AWMA), parent and teacher reports of children's executive functioning (EF), and children's self-regulation performance across a series of executive functioning classroom games conducted as part of a summer treatment camp. Additional outcomes included school readiness as measured by standardized achievement tests, and parent and teacher reports of kindergarten readiness and behavioral impairment related to academic functioning. Performance on the HTKS task was moderately correlated with children's performance on the standardized working memory tasks and observed self-regulation performance in the classroom. Low to moderate correlations were observed between performance on the HTKS task and parent report of children's EF difficulties, as well as parent and teacher reports of children's kindergarten readiness and behavioral impairment related to academic functioning. Moderate to high correlations were observed between performance on the HTKS task and standardized academic outcomes. These findings highlight the promise of the HTKS task as a brief, ecologically valid, and integrative EF task tapping into both behavioral and cognitive aspects of self-regulation that are important for children with EBP's success in school. PMID:25822828

  2. The ventromedial hypothalamus oxytocin induces locomotor behavior regulated by estrogen.

    PubMed

    Narita, Kazumi; Murata, Takuya; Matsuoka, Satoshi

    2016-10-01

    Our previous studies demonstrated that excitation of neurons in the rat ventromedial hypothalamus (VMH) induced locomotor activity. An oxytocin receptor (Oxtr) exists in the VMH and plays a role in regulating sexual behavior. However, the role of Oxtr in the VMH in locomotor activity is not clear. In this study we examined the roles of oxytocin in the VMH in running behavior, and also investigated the involvement of estrogen in this behavioral change. Microinjection of oxytocin into the VMH induced a dose-dependent increase in the running behavior in male rats. The oxytocin-induced running activity was inhibited by simultaneous injection of Oxtr-antagonist, (d(CH2)5(1), Try(Me)(2), Orn(8))-oxytocin. Oxytocin injection also induced running behavior in ovariectomized (OVX) female rats. Pretreatment of the OVX rats with estrogen augmented the oxytocin-induced running activity twofold, and increased the Oxtr mRNA in the VMH threefold. During the estrus cycle locomotor activity spontaneously increased in the dark period of proestrus. The Oxtr mRNA was up-regulated in the proestrus afternoon. Blockade of oxytocin neurotransmission by its antagonist before the onset of the dark period of proestrus decreased the following nocturnal locomotor activity. These findings demonstrate that Oxtr in the VMH is involved in the induction of running behavior and that estrogen facilitates this effect by means of Oxtr up-regulation, suggesting the involvement of oxytocin in the locomotor activity of proestrus female rats. PMID:27237044

  3. Revealed: The spy who regulates neuroblastoma stem cells.

    PubMed

    Vora, Parvez; Venugopal, Chitra; Singh, Sheila K

    2014-11-30

    Neuroblastoma (NB), an embryonal tumour of the sympathetic nervous system, is thought to originate from undifferentiated neural crest cells and is known to exhibit extremely heterogeneous biological and clinical behaviors. Occurring in very young children, the median age at diagnosis is 17 months and it accounts for 10% of all pediatric cancer mortalities. The standard treatment regimen for patients with high-risk NB includes induction and surgery followed by isotretinoin or Accutane (13-cis retinoic acid) treatment, which is shown to induce terminal differentiation of NB cells. However, molecular regulators that maintain an undifferentiated phenotype in NB cells are still poorly understood. PMID:25483101

  4. Interstitial Cells: Regulators of Smooth Muscle Function

    PubMed Central

    Sanders, Kenton M.; Ward, Sean M.; Koh, Sang Don

    2014-01-01

    Smooth muscles are complex tissues containing a variety of cells in addition to muscle cells. Interstitial cells of mesenchymal origin interact with and form electrical connectivity with smooth muscle cells in many organs, and these cells provide important regulatory functions. For example, in the gastrointestinal tract, interstitial cells of Cajal (ICC) and PDGFRα+ cells have been described, in detail, and represent distinct classes of cells with unique ultrastructure, molecular phenotypes, and functions. Smooth muscle cells are electrically coupled to ICC and PDGFRα+ cells, forming an integrated unit called the SIP syncytium. SIP cells express a variety of receptors and ion channels, and conductance changes in any type of SIP cell affect the excitability and responses of the syncytium. SIP cells are known to provide pacemaker activity, propagation pathways for slow waves, transduction of inputs from motor neurons, and mechanosensitivity. Loss of interstitial cells has been associated with motor disorders of the gut. Interstitial cells are also found in a variety of other smooth muscles; however, in most cases, the physiological and pathophysiological roles for these cells have not been clearly defined. This review describes structural, functional, and molecular features of interstitial cells and discusses their contributions in determining the behaviors of smooth muscle tissues. PMID:24987007

  5. Cell Cycle Regulation of DNA Replication

    PubMed Central

    Sclafani, R. A.; Holzen, T. M.

    2008-01-01

    Eukaryotic DNA replication is regulated to ensure all chromosomes replicate once and only once per cell cycle. Replication begins at many origins scattered along each chromosome. Except for budding yeast, origins are not defined DNA sequences and probably are inherited by epigenetic mechanisms. Initiation at origins occurs throughout the S phase according to a temporal program that is important in regulating gene expression during development. Most replication proteins are conserved in evolution in eukaryotes and archaea, but not in bacteria. However, the mechanism of initiation is conserved and consists of origin recognition, assembly of pre-replication (pre-RC) initiative complexes, helicase activation, and replisome loading. Cell cycle regulation by protein phosphorylation ensures that pre-RC assembly can only occur in G1 phase, whereas helicase activation and loading can only occur in S phase. Checkpoint regulation maintains high fidelity by stabilizing replication forks and preventing cell cycle progression during replication stress or damage. PMID:17630848

  6. Neuronal serotonin in the regulation of maternal behavior in rodents

    PubMed Central

    Angoa-Pérez, Mariana; Kuhn, Donald M.

    2016-01-01

    Maternal behavior is probably the most important pro-social behavior in female mammals, ensuring both the development and survival of her offspring. Signals driving maternal behaviors are complex and involve several brain areas, most of which are innervated by serotonin. Serotonin transmission influences maternal processes indirectly through release of maternally-relevant hormones such as prolactin, oxytocin and vasopressin, but it can also have more direct effects on survival and the growth rate of offspring, as well as on maternal care, aggression and pup killing. This article aims to examine the basics of the components of maternal behaviors in rodents and the neural systems underpinning these maternal responses with special emphasis on the role of neural serotonin in the regulation of these behaviors. PMID:27148594

  7. Collecting duct intercalated cell function and regulation.

    PubMed

    Roy, Ankita; Al-bataineh, Mohammad M; Pastor-Soler, Núria M

    2015-02-01

    Intercalated cells are kidney tubule epithelial cells with important roles in the regulation of acid-base homeostasis. However, in recent years the understanding of the function of the intercalated cell has become greatly enhanced and has shaped a new model for how the distal segments of the kidney tubule integrate salt and water reabsorption, potassium homeostasis, and acid-base status. These cells appear in the late distal convoluted tubule or in the connecting segment, depending on the species. They are most abundant in the collecting duct, where they can be detected all the way from the cortex to the initial part of the inner medulla. Intercalated cells are interspersed among the more numerous segment-specific principal cells. There are three types of intercalated cells, each having distinct structures and expressing different ensembles of transport proteins that translate into very different functions in the processing of the urine. This review includes recent findings on how intercalated cells regulate their intracellular milieu and contribute to acid-base regulation and sodium, chloride, and potassium homeostasis, thus highlighting their potential role as targets for the treatment of hypertension. Their novel regulation by paracrine signals in the collecting duct is also discussed. Finally, this article addresses their role as part of the innate immune system of the kidney tubule. PMID:25632105

  8. Signaling hierarchy regulating human endothelial cell development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our present knowledge of the regulation of mammalian endothelial cell differentiation has been largely derived from studies of mouse embryonic development. However, unique mechanisms and hierarchy of signals that govern human endothelial cell development are unknown and, thus, explored in these stud...

  9. HEC of a job regulating stem cells.

    PubMed

    Sparks, Erin E; Benfey, Philip N

    2014-02-24

    In this issue of Developmental Cell, Schuster et al. (2014) describe the signals regulated by the bHLH transcription factor HEC1 during Arabidopsis stem cell maintenance. HEC1 acts antagonistically with other factors, integrating multiple cues to provide a balance between cellular differentiation and proliferation. PMID:24576420

  10. Recognition and Regulation of T Cells by NK Cells.

    PubMed

    Pallmer, Katharina; Oxenius, Annette

    2016-01-01

    Regulation of T cell responses by innate lymphoid cells (ILCs) is increasingly documented and studied. Direct or indirect crosstalk between ILCs and T cells early during and after T cell activation can affect their differentiation, polarization, and survival. Natural killer (NK) cells that belong to the ILC1 group were initially described for their function in recognizing and eliminating "altered self" and as source of early inflammatory cytokines, most notably type II interferon. Using signals conveyed by various germ-line encoded activating and inhibitory receptors, NK cells are geared to sense sudden cellular changes that can be caused by infection events, malignant transformation, or cellular stress responses. T cells, when activated by TCR engagement (signal 1), costimulation (signal 2), and cytokines (signal 3), commit to a number of cellular alterations, including entry into rapid cell cycling, metabolic changes, and acquisition of effector functions. These abrupt changes may alert NK cells, and T cells might thereby expose themselves as NK cell targets. Here, we review how activated T cells can be recognized and regulated by NK cells and what consequences such regulation bears for T cell immunity in the context of vaccination, infection, or autoimmunity. Conversely, we will discuss mechanisms by which activated T cells protect themselves against NK cell attack and outline the significance of this safeguard mechanism. PMID:27446081

  11. Recognition and Regulation of T Cells by NK Cells

    PubMed Central

    Pallmer, Katharina; Oxenius, Annette

    2016-01-01

    Regulation of T cell responses by innate lymphoid cells (ILCs) is increasingly documented and studied. Direct or indirect crosstalk between ILCs and T cells early during and after T cell activation can affect their differentiation, polarization, and survival. Natural killer (NK) cells that belong to the ILC1 group were initially described for their function in recognizing and eliminating “altered self” and as source of early inflammatory cytokines, most notably type II interferon. Using signals conveyed by various germ-line encoded activating and inhibitory receptors, NK cells are geared to sense sudden cellular changes that can be caused by infection events, malignant transformation, or cellular stress responses. T cells, when activated by TCR engagement (signal 1), costimulation (signal 2), and cytokines (signal 3), commit to a number of cellular alterations, including entry into rapid cell cycling, metabolic changes, and acquisition of effector functions. These abrupt changes may alert NK cells, and T cells might thereby expose themselves as NK cell targets. Here, we review how activated T cells can be recognized and regulated by NK cells and what consequences such regulation bears for T cell immunity in the context of vaccination, infection, or autoimmunity. Conversely, we will discuss mechanisms by which activated T cells protect themselves against NK cell attack and outline the significance of this safeguard mechanism. PMID:27446081

  12. Examining the Relationship of Children's Behavior to Emotion Regulation Ability

    ERIC Educational Resources Information Center

    Onchwari, Grace; Keengwe, Jared

    2011-01-01

    This study investigated the relationship between children's ability to regulate emotions and display of appropriate behavior in social settings. A sample of 33 children representing a wide range of social economic status was randomly selected from a Head Start Program and an Early Childhood Development Center in the Midwest. Data were collected…

  13. N-Cadherin-Mediated Signaling Regulates Cell Phenotype for Nucleus Pulposus Cells of the Intervertebral Disc

    PubMed Central

    Hwang, Priscilla Y.; Jing, Liufang; Michael, Keith W.; Richardson, William J.; Chen, Jun; Setton, Lori A.

    2015-01-01

    Juvenile nucleus pulposus (NP) cells of the intervertebral disc (IVD) are large, vacuolated cells that form cell clusters with strong cell–cell interactions. With maturation and aging, NP cells lose their ability to form these cell clusters, with aging-associated changes in NP cell phenotype, morphology, and proteoglycan synthesis that may contribute to IVD degeneration. Therefore, it is important to understand the mechanisms governing juvenile NP cell cluster behavior towards the goal of revealing factors that can promote juvenile, healthy NP cell phenotypes. N-cadherin has been identified as a cell–cell adhesion marker that is present in juvenile NP cells, but disappears with age. The goal of this study was to reveal the importance of N-cadherin in regulating cell–cell interactions in juvenile NP cell cluster formation and test for a regulatory role in maintaining a juvenile NP phenotype in vitro. Juvenile porcine IVD cells, of notochordal origin, were promoted to form cell clusters in vitro, and analyzed for preservation of the juvenile NP phenotype. Additionally, cadherin-blocking experiments were performed to prevent cluster formation in order to study the importance of cluster formation in NP cell signaling. Findings reveal N-cadherin-mediated cell–cell contacts promote cell clustering behavior and regulate NP cell matrix production and preservation of NP-specific markers. Inhibition of N-cadherin-mediated contacts resulted in loss of all features of the juvenile NP cell. These results establish a regulatory role for N-cadherin in juvenile NP cells, and suggest that preservation of the N-cadherin mediated cell–cell contact is important for preserving juvenile NP cell phenotype and morphology. PMID:25848407

  14. Programmed Cell Death of Dendritic Cells in Immune Regulation

    PubMed Central

    Chen, Min; Wang, Jin

    2010-01-01

    Summary Programmed cell death is essential for the maintenance of lymphocyte homeostasis and immune tolerance. Dendritic cells (DCs), the most efficient antigen presenting cells, represent a small cell population in the immune system. However, DCs play major roles in the regulation of both innate and adaptive immune responses. Programmed cell death in DCs is essential for regulating DC homeostasis and consequently, the scope of immune responses. Interestingly, different DC subsets show varied turnover rates in vivo. The conventional DCs are relatively short-lived in most lymphoid organs, while plasmacytoid DCs are long-lived cells. Mitochondrion-dependent programmed cell death plays an important role in regulating spontaneous DC turnover. Antigen-specific T cells are also capable of killing DCs, thereby providing a mechanism for negative feedback regulation of immune responses. It has been shown that a surplus of DCs due to defects in programmed cell death leads to overactivation of lymphocytes and the onset of autoimmunity. Studying programmed cell death in DCs will shed light on the roles for DC turnover in the regulation of the duration and magnitude of immune responses in vivo, and in the maintenance of immune tolerance. PMID:20636805

  15. Cell collectivity regulation within migrating cell cluster during Kupffer's vesicle formation in zebrafish

    PubMed Central

    Matsui, Takaaki; Ishikawa, Hiroshi; Bessho, Yasumasa

    2015-01-01

    Although cell adhesion is thought to fasten cells tightly, cells that adhere to each other can migrate directionally. This group behavior, called “collective cell migration,” is observed during normal development, wound healing, and cancer invasion. Loss-of-function of cell adhesion molecules in several model systems of collective cell migration results in delay or inhibition of migration of cell groups but does not lead to dissociation of the cell groups, suggesting that mechanisms of cells staying assembled as a single cell cluster, termed as “cell collectivity,” remain largely unknown. During the formation of Kupffer's vesicle (KV, an organ of laterality in zebrafish), KV progenitors form a cluster and migrate together toward the vegetal pole. Importantly, in this model system of collective cell migration, knockdown of cell adhesion molecules or signal components leads to failure of cell collectivity. In this review, we summarize recent findings in cell collectivity regulation during collective migration of KV progenitor cells and describe our current understanding of how cell collectivity is regulated during collective cell migration. PMID:26000276

  16. Regulation of the metastatic cell phenotype by sialylated glycans

    PubMed Central

    Schultz, Matthew J.; Swindall, Amanda F.

    2014-01-01

    Tumor cells exhibit striking changes in cell surface glycosylation as a consequence of dysregulated glycosyltransferases and glycosidases. In particular, an increase in the expression of certain sialylated glycans is a prominent feature of many transformed cells. Altered sialylation has long been associated with metastatic cell behaviors including invasion and enhanced cell survival; however, there is limited information regarding the molecular details of how distinct sialylated structures or sialylated carrier proteins regulate cell signaling to control responses such as adhesion/migration or resistance to specific apoptotic pathways. The goal of this review is to highlight selected examples of sialylated glycans for which there is some knowledge of molecular mechanisms linking aberrant sialylation to critical processes involved in metastasis. PMID:22699311

  17. Roles of sucrose in guard cell regulation.

    PubMed

    Daloso, Danilo M; Dos Anjos, Leticia; Fernie, Alisdair R

    2016-08-01

    The control of stomatal aperture involves reversible changes in the concentration of osmolytes in guard cells. Sucrose has long been proposed to have an osmolytic role in guard cells. However, direct evidence for such a role is lacking. Furthermore, recent evidence suggests that sucrose may perform additional roles in guard cells. Here, we provide an update covering the multiple roles of sucrose in guard cell regulation, highlighting the knowledge accumulated regarding spatiotemporal differences in the synthesis, accumulation, and degradation of sucrose as well as reviewing the role of sucrose as a metabolic connector between mesophyll and guard cells. Analysis of transcriptomic data from previous studies reveals that several genes encoding sucrose and hexose transporters and genes involved in gluconeogenesis, sucrose and trehalose metabolism are highly expressed in guard cells compared with mesophyll cells. Interestingly, this analysis also showed that guard cells have considerably higher expression of C4 -marker genes than mesophyll cells. We discuss the possible roles of these genes in guard cell function and the role of sucrose in stomatal opening and closure. Finally, we provide a perspective for future experiments which are required to fill gaps in our understanding of both guard cell metabolism and stomatal regulation. PMID:27060199

  18. Regulated cell death and adaptive stress responses.

    PubMed

    Galluzzi, Lorenzo; Bravo-San Pedro, José Manuel; Kepp, Oliver; Kroemer, Guido

    2016-06-01

    Eukaryotic cells react to potentially dangerous perturbations of the intracellular or extracellular microenvironment by activating rapid (transcription-independent) mechanisms that attempt to restore homeostasis. If such perturbations persist, cells may still try to cope with stress by activating delayed and robust (transcription-dependent) adaptive systems, or they may actively engage in cellular suicide. This regulated form of cell death can manifest with various morphological, biochemical and immunological correlates, and constitutes an ultimate attempt of stressed cells to maintain organismal homeostasis. Here, we dissect the general organization of adaptive cellular responses to stress, their intimate connection with regulated cell death, and how the latter operates for the preservation of organismal homeostasis. PMID:27048813

  19. Engineering nanoscale stem cell niche: direct stem cell behavior at cell-matrix interface.

    PubMed

    Zhang, Yan; Gordon, Andrew; Qian, Weiyi; Chen, Weiqiang

    2015-09-16

    Biophysical cues on the extracellular matrix (ECM) have proven to be significant regulators of stem cell behavior and evolution. Understanding the interplay of these cells and their extracellular microenvironment is critical to future tissue engineering and regenerative medicine, both of which require a means of controlled differentiation. Research suggests that nanotopography, which mimics the local, nanoscale, topographic cues within the stem cell niche, could be a way to achieve large-scale proliferation and control of stem cells in vitro. This Progress Report reviews the history and contemporary advancements of this technology, and pays special attention to nanotopographic fabrication methods and the effect of different nanoscale patterns on stem cell response. Finally, it outlines potential intracellular mechanisms behind this response. PMID:26222885

  20. Regulation of motor function and behavior by atypical chemokine receptor 1.

    PubMed

    Schneider, Erich H; Fowler, Stephen C; Lionakis, Michail S; Swamydas, Muthulekha; Holmes, Gibran; Diaz, Vivian; Munasinghe, Jeeva; Peiper, Stephen C; Gao, Ji-Liang; Murphy, Philip M

    2014-09-01

    Atypical Chemokine Receptor 1 (ACKR1), previously known as Duffy Antigen Receptor for Chemokines, stands out among chemokine receptors for high selective expression on cerebellar Purkinje neurons. Although ACKR1 ligands activate Purkinje cells in vitro, evidence for ACKR1 regulation of brain function in vivo is lacking. Here we demonstrate that Ackr1 (-/-) mice have markedly impaired balance and ataxia on a rotating rod and increased tremor when injected with harmaline, which induces whole-body tremor by activating Purkinje cells. Ackr1 (-/-) mice also exhibited impaired exploratory behavior, increased anxiety-like behavior and frequent episodes of marked hypoactivity under low-stress conditions. Surprisingly, Ackr1 (+/-) had similar behavioral abnormalities, indicating pronounced haploinsufficiency. The behavioral phenotype of Ackr1 (-/-) mice was the opposite of mouse models of cerebellar degeneration, and the defects persisted when Ackr1 was deficient only on non-hematopoietic cells. Together, the results suggest that normal motor function and behavior may partly depend on negative regulation of Purkinje cell activity by Ackr1. PMID:24997773

  1. Regulation of pancreatic beta-cell mass.

    PubMed

    Bouwens, Luc; Rooman, Ilse

    2005-10-01

    Beta-cell mass regulation represents a critical issue for understanding diabetes, a disease characterized by a near-absolute (type 1) or relative (type 2) deficiency in the number of pancreatic beta cells. The number of islet beta cells present at birth is mainly generated by the proliferation and differentiation of pancreatic progenitor cells, a process called neogenesis. Shortly after birth, beta-cell neogenesis stops and a small proportion of cycling beta cells can still expand the cell number to compensate for increased insulin demands, albeit at a slow rate. The low capacity for self-replication in the adult is too limited to result in a significant regeneration following extensive tissue injury. Likewise, chronically increased metabolic demands can lead to beta-cell failure to compensate. Neogenesis from progenitor cells inside or outside islets represents a more potent mechanism leading to robust expansion of the beta-cell mass, but it may require external stimuli. For therapeutic purposes, advantage could be taken from the surprising differentiation plasticity of adult pancreatic cells and possibly also from stem cells. Recent studies have demonstrated that it is feasible to regenerate and expand the beta-cell mass by the application of hormones and growth factors like glucagon-like peptide-1, gastrin, epidermal growth factor, and others. Treatment with these external stimuli can restore a functional beta-cell mass in diabetic animals, but further studies are required before it can be applied to humans. PMID:16183912

  2. Substrate stress relaxation regulates cell spreading

    PubMed Central

    Chaudhuri, Ovijit; Gu, Luo; Darnell, Max; Klumpers, Darinka; Bencherif, Sidi A.; Weaver, James C.; Huebsch, Nathaniel; Mooney, David J

    2015-01-01

    Studies of cellular mechanotransduction have converged upon the idea that cells sense extracellular matrix (ECM) elasticity by gauging resistance to the traction forces they exert on the ECM. However, these studies typically utilize purely elastic materials as substrates, whereas physiological ECM are viscoelastic, and exhibit stress relaxation, so that cellular traction forces exerted by cells remodel the ECM. Here we investigate the influence of ECM stress relaxation on cell behavior through computational modeling and cellular experiments. Surprisingly, both our computational model and experiments find that spreading for cells cultured on soft substrates that exhibit stress relaxation is greater than cells spreading on elastic substrates of the same modulus, but similar to that of cells spreading on stiffer elastic substrates. These findings challenge the current view of how cells sense and respond to the ECM. PMID:25695512

  3. Thyroid Hormones as Renal Cell Cancer Regulators

    PubMed Central

    Matak, Damian; Bartnik, Ewa; Szczylik, Cezary; Czarnecka, Anna M.

    2016-01-01

    It is known that thyroid hormone is an important regulator of cancer development and metastasis. What is more, changes across the genome, as well as alternative splicing, may affect the activity of the thyroid hormone receptors. Mechanism of action of the thyroid hormone is different in every cancer; therefore in this review thyroid hormone and its receptor are presented as a regulator of renal cell carcinoma. PMID:27034829

  4. Tip cells: Master regulators of tubulogenesis?

    PubMed Central

    Weavers, Helen; Skaer, Helen

    2014-01-01

    The normal development of an organ depends on the coordinated regulation of multiple cell activities. Focusing on tubulogenesis, we review the role of specialised cells or groups of cells that are selected from within tissue primordia and differentiate at the outgrowing tips or leading edge of developing tubules. Tip or leading cells develop distinctive patterns of gene expression that enable them to act both as sensors and transmitters of intercellular signalling. This enables them to explore the environment, respond to both tissue intrinsic signals and extrinsic cues from surrounding tissues and to regulate the behaviour of their neighbours, including the setting of cell fate, patterning cell division, inducing polarity and promoting cell movement and cell rearrangements by neighbour exchange. Tip cells are also able to transmit mechanical tension to promote tissue remodelling and, by interacting with the extracellular matrix, they can dictate migratory pathways and organ shape. Where separate tubular structures fuse to form networks, as in the airways of insects or the vascular system of vertebrates, specialised fusion tip cells act to interconnect disparate elements of the developing network. Finally, we consider their importance in the maturation of mature physiological function and in the development of disease. PMID:24721475

  5. Cell shape regulation through mechanosensory feedback control

    PubMed Central

    Mohan, Krithika; Luo, Tianzhi; Robinson, Douglas N.; Iglesias, Pablo A.

    2015-01-01

    Cells undergo controlled changes in morphology in response to intracellular and extracellular signals. These changes require a means for sensing and interpreting the signalling cues, for generating the forces that act on the cell's physical material, and a control system to regulate this process. Experiments on Dictyostelium amoebae have shown that force-generating proteins can localize in response to external mechanical perturbations. This mechanosensing, and the ensuing mechanical feedback, plays an important role in minimizing the effect of mechanical disturbances in the course of changes in cell shape, especially during cell division, and likely in other contexts, such as during three-dimensional migration. Owing to the complexity of the feedback system, which couples mechanical and biochemical signals involved in shape regulation, theoretical approaches can guide further investigation by providing insights that are difficult to decipher experimentally. Here, we present a computational model that explains the different mechanosensory and mechanoresponsive behaviours observed in Dictyostelium cells. The model features a multiscale description of myosin II bipolar thick filament assembly that includes cooperative and force-dependent myosin–actin binding, and identifies the feedback mechanisms hidden in the observed mechanoresponsive behaviours of Dictyostelium cells during micropipette aspiration experiments. These feedbacks provide a mechanistic explanation of cellular retraction and hence cell shape regulation. PMID:26224568

  6. Cell shape regulation through mechanosensory feedback control.

    PubMed

    Mohan, Krithika; Luo, Tianzhi; Robinson, Douglas N; Iglesias, Pablo A

    2015-08-01

    Cells undergo controlled changes in morphology in response to intracellular and extracellular signals. These changes require a means for sensing and interpreting the signalling cues, for generating the forces that act on the cell's physical material, and a control system to regulate this process. Experiments on Dictyostelium amoebae have shown that force-generating proteins can localize in response to external mechanical perturbations. This mechanosensing, and the ensuing mechanical feedback, plays an important role in minimizing the effect of mechanical disturbances in the course of changes in cell shape, especially during cell division, and likely in other contexts, such as during three-dimensional migration. Owing to the complexity of the feedback system, which couples mechanical and biochemical signals involved in shape regulation, theoretical approaches can guide further investigation by providing insights that are difficult to decipher experimentally. Here, we present a computational model that explains the different mechanosensory and mechanoresponsive behaviours observed in Dictyostelium cells. The model features a multiscale description of myosin II bipolar thick filament assembly that includes cooperative and force-dependent myosin-actin binding, and identifies the feedback mechanisms hidden in the observed mechanoresponsive behaviours of Dictyostelium cells during micropipette aspiration experiments. These feedbacks provide a mechanistic explanation of cellular retraction and hence cell shape regulation. PMID:26224568

  7. Epigenetic Mechanisms Regulating Mesenchymal Stem Cell Differentiation

    PubMed Central

    Pérez-Campo, Flor M.; Riancho, José A.

    2015-01-01

    Human Mesenchymal Stem Cells (hMSCs) have emerged in the last few years as one of the most promising therapeutic cell sources and, in particular, as an important tool for regenerative medicine of skeletal tissues. Although they present a more restricted potency than Embryonic Stem (ES) cells, the use of hMCS in regenerative medicine avoids many of the drawbacks characteristic of ES cells or induced pluripotent stem cells. The challenge in using these cells lies into developing precise protocols for directing cellular differentiation to generate a specific cell lineage. In order to achieve this goal, it is of the upmost importance to be able to control de process of fate decision and lineage commitment. This process requires the coordinate regulation of different molecular layers at transcriptional, posttranscriptional and translational levels. At the transcriptional level, switching on and off different sets of genes is achieved not only through transcriptional regulators, but also through their interplay with epigenetic modifiers. It is now well known that epigenetic changes take place in an orderly way through development and are critical in the determination of lineage-specific differentiation. More importantly, alteration of these epigenetic changes would, in many cases, lead to disease generation and even tumour formation. Therefore, it is crucial to elucidate how epigenetic factors, through their interplay with transcriptional regulators, control lineage commitment in hMSCs. PMID:27019612

  8. Sensory Integration Regulating Male Courtship Behavior in Drosophila

    PubMed Central

    Krstic, Dimitrije; Boll, Werner; Noll, Markus

    2009-01-01

    The courtship behavior of Drosophila melanogaster serves as an excellent model system to study how complex innate behaviors are controlled by the nervous system. To understand how the underlying neural network controls this behavior, it is not sufficient to unravel its architecture, but also crucial to decipher its logic. By systematic analysis of how variations in sensory inputs alter the courtship behavior of a naïve male in the single-choice courtship paradigm, we derive a model describing the logic of the network that integrates the various sensory stimuli and elicits this complex innate behavior. This approach and the model derived from it distinguish (i) between initiation and maintenance of courtship, (ii) between courtship in daylight and in the dark, where the male uses a scanning strategy to retrieve the decamping female, and (iii) between courtship towards receptive virgin females and mature males. The last distinction demonstrates that sexual orientation of the courting male, in the absence of discriminatory visual cues, depends on the integration of gustatory and behavioral feedback inputs, but not on olfactory signals from the courted animal. The model will complement studies on the connectivity and intrinsic properties of the neurons forming the circuitry that regulates male courtship behavior. PMID:19214231

  9. Adrenergic and noradrenergic regulation of poultry behavior and production.

    PubMed

    Dennis, R L

    2016-07-01

    Norepinephrine and epinephrine (noradrenaline and adrenaline) are integral in maintaining behavioral and physiological homeostasis during both aversive and rewarding events. They regulate the response to stressful stimuli through direct activation of adrenergic receptors in the central and sympathetic nervous systems, hormonal activity and through the interaction of the brain, gut, and microbiome. The multiple functions of these catecholamines work synergistically to prepare an individual for a "fight or flight" response. However, hyper-reactivity of this system can lead to increased fearfulness and aggression, decreased health and productivity, and a reduction in overall well-being. Behaviors, such as aggression and certain fear-related behaviors, are a serious problem in the poultry industry that can lead to injury and cannibalism. For decades, catecholamines have been used as a measure of stress in animals. However, few studies have specifically targeted the adrenergic systems as means to reduce behaviors that are damaging or maladapted to their rearing environments and improve animal well-being. This article attempts to address our current understanding of specific, adrenergic-regulated behaviors that impact chicken well-being and production. PMID:27345328

  10. Fat Metabolism Regulates Satiety Behavior in C. elegans

    PubMed Central

    Hyun, Moonjung; Davis, Kristen; Lee, Inhwan; Kim, Jeongho; Dumur, Catherine; You, Young-Jai

    2016-01-01

    Animals change feeding behavior depending on their metabolic status; starved animals are eager to eat and satiated animals stop eating. C. elegans exhibits satiety quiescence under certain conditions that mimics many aspects of post-prandial sleep in mammals. Here we show that this feeding behavior depends on fat metabolism mediated by the SREBP-SCD pathway, an acetyl-CoA carboxylase (ACC) and certain nuclear hormone receptors (NRs). Mutations of the genes in the SREBP-SCD pathway reduce satiety quiescence. An RNA interference (RNAi) screen of the genes that regulate glucose and fatty acid metabolism identified an ACC necessary for satiety quiescence in C. elegans. ACC catalyzes the first step in de novo fatty acid biosynthesis known to be downstream of the SREBP pathway in mammals. We identified 28 NRs by microarray whose expression changes during refeeding after being starved. When individually knocked down by RNAi, 11 NRs among 28 affect both fat storage and satiety behavior. Our results show that the major fat metabolism pathway regulates feeding behavior and NRs could be the mediators to link the feeding behavior to the metabolic changes. PMID:27097601

  11. Regulation of the T cell response.

    PubMed

    Romagnani, S

    2006-11-01

    The T cell branch of the immune system can respond to a virtually infinite variety of exogenous antigens, thus including the possibility of self-antigen recognition and dangerous autoimmune reactions. Therefore, regulatory mechanisms operate both during ontogeny within the thymus and after birth in the periphery. The control of self-reactive T cells occurs through a process of negative selection that results in apoptosis of T cells showing high affinity for self-peptides expressed at the thymic level by means of promiscuous gene expression. Self-reactive T cells escaped to negative selection are controlled in the periphery by other regulatory mechanisms, the most important being natural Foxp3+ T regulatory (Treg) cells. Regulation is also required to control excessive effector T cell responses against exogenous antigens, when they become dangerous for the body. Three types of effector T cells have been recognized: T helper 1 (Th1) cells, which are protective against intracellular bacteria; Th2 cells, which play some role in the protection against nematodes, but are responsible for allergic reactions; Th17 cells, which are probably effective in the protection against extracellular bacteria, but also play a role in the amplification of autoimmune disorders. Abnormal or excessive Th effector responses are regulated by different mechanisms. Redirection or immune deviation of Th1- or Th2-dominated responses is provided by cytokines [interferon-gamma (IFN-gamma) vs. interleukin-4 (IL-4)] produced by the same cell types and by the CXCR3-binding chemokines CXCL4 and CXCL10. Moreover, both Th1 and Th2 responses can be suppressed by adaptive Treg cells through contact-dependent mechanisms and/or the production of IL-10 and transforming growth factor-beta (TGF-beta). Finally, TGF-beta1 can promote the development of both Th17 effector and adaptive Treg cells, while the contemporaneous production of IL-6 contributes to the development of Th17 cells, but inhibits Treg cells

  12. Synthetic Extracellular Microenvironment for Modulating Stem Cell Behaviors

    PubMed Central

    Chandra, Prafulla; Lee, Sang Jin

    2015-01-01

    The innate ability of stem cells to self-renew and differentiate into multiple cell types makes them a promising source for tissue engineering and regenerative medicine applications. Their capacity for self-renewal and differentiation is largely influenced by the combination of physical, chemical, and biological signals found in the stem cell niche, both temporally and spatially. Embryonic and adult stem cells are potentially useful for cell-based approaches; however, regulating stem cell behavior remains a major challenge in their clinical use. Most of the current approaches for controlling stem cell fate do not fully address all of the complex signaling pathways that drive stem cell behaviors in their natural microenvironments. To overcome this limitation, a new generation of biomaterials is being developed for use as three-dimensional synthetic microenvironments that can mimic the regulatory characteristics of natural extracellular matrix (ECM) proteins and ECM-bound growth factors. These synthetic microenvironments are currently being investigated as a substrate with surface immobilization and controlled release of bioactive molecules to direct the stem cell fate in vitro, as a tissue template to guide and improve the neo-tissue formation both in vitro and in vivo, and as a delivery vehicle for cell therapy in vivo. The continued advancement of such an intelligent biomaterial system as the synthetic extracellular microenvironment holds the promise of improved therapies for numerous debilitating medical conditions for which no satisfactory cure exists today. PMID:26106260

  13. Regulation of cell division in higher plants

    SciTech Connect

    Jacobs, T.W.

    1992-01-01

    Cell division is arguably the most fundamental of all developmental processes. In higher plants, mitotic activity is largely confined to foci of patterned cell divisions called meristems. From these perpetually embryonic tissues arise the plant's essential organs of light capture, support, protection and reproduction. Once an adequate understanding of plant cell mitotic regulation is attained, unprecedented opportunities will ensue for analyzing and genetically controlling diverse aspects of development, including plant architecture, leaf shape, plant height, and root depth. The mitotic cycle in a variety of model eukaryotic systems in under the control of a regulatory network of striking evolutionary conservation. Homologues of the yeast cdc2 gene, its catalytic product, p34, and the cyclin regulatory subunits of the MPF complex have emerged as ubiquitous mitotic regulators. We have cloned cdc2-like and cyclin genes from pea. As in other eukaryotic model systems, p34 of Pisum sativum is a subunit of a high molecular weight complex which binds the fission yeast p13 protein and displays histone H1 kinase activity in vitro. Our primary objective in this study is to gain baseline information about the regulation of this higher plant cell division control complex in non-dividing, differentiated cells as well as in synchronous and asynchronous mitotic cells. We are investigating cdc2 and cyclin expression at the levels of protein abundance, protein phosphorylation and quaternary associations.

  14. TRPM7 Regulates Polarized Cell Movements

    PubMed Central

    Su, Li-Ting; Liu, Wei; Chen, Hsiang-Chin; González-Pagán, Omayra; Habas, Raymond; Runnels, Loren W.

    2012-01-01

    SYNOPSIS TRPM7 is a Ca2+ and Mg2+ permeant ion channel in possession of its own kinase domain. As a kinase, the protein has been linked to the control of actomyosin contractility, whereas the channel has been found to regulate cell adhesion as well as cellular Mg2+ homeostasis. Here we show that depletion of TRPM7 by RNA interference in fibroblasts alters cell morphology, the cytoskeleton, and the ability of cells to form lamellipodia and to execute polarized cell movements. A pulldown purification assay revealed that knockdown of TRPM7 prevents cells from activating Rac and Cdc42 when stimulated to migrate into a cellular wound. Re-expression of TRPM7 reverses these phenotypic changes, as does, unexpectedly, expression of a kinase-inactive mutant of TRPM7. Surprisingly, expression of the Mg2+ transporter SLC41A2 is also effective restoring the change in cell morphology, disruption of the cytoskeleton, and directional cell motility caused by depletion of the channel-kinase. These data uncover an essential role for Mg2+ in TRPM7's control over the cytoskeleton and its ability to regulate polarized cell movements. PMID:21208190

  15. Redox regulation in cancer stem cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Reactive oxygen species (ROS) and ROS-dependent (redox regulation) signaling pathways and transcriptional activities are thought to be critical in stem cell self-renewal and differentiation during growth and organogenesis. Aberrant ROS burst and dysregulation of those ROS-dependent cellular processe...

  16. Gene regulation in hepatic stellate cell.

    PubMed

    Lang, A; Brenner, D A

    1999-03-01

    Hepatic stellate cells are now recognized as the major source of extracellular matrix in hepatic fibrosis. Following liver injury the hepatic stellate cell changes from a quiescent to an activated cell. The activation process includes an increased proliferation rate, a phenotypic change to a myofibroblast-like cell, loss of vitamin A stores, increased extra-cellular matrix protein synthesis and contractility. Furthermore, hepatic stellate cells have been implicated in hepatic inflammation through their ability to secrete cytokines and chemokines. Here, we review the literature on the molecular pathogenesis of hepatic stellate cells activation with emphasis on the most recent findings. The reviewed topics include transcriptional and post-transcriptional regulation of the genes encoding type I collagen in hepatic stellate cells; the role of the transcription factor nuclear factor Kappa B in the hepatic stellate cell activation; focal adhesion kinase and integrin-mediated signal transduction in hepatic stellate cell, and apoptosis in hepatic stellate cells. New insight into hepatic stellate cell activation and death may lead to the development of novel therapies for hepatic fibrosis. PMID:10363203

  17. miR-381 Regulates Neural Stem Cell Proliferation and Differentiation via Regulating Hes1 Expression

    PubMed Central

    Liu, Baoquan; Yang, Chunxiao; Nie, Xuedan; Wang, Xiaokun; Zheng, Jiaolin; Wang, Yue; Zhu, Yulan

    2015-01-01

    Neural stem cells are self-renewing, multipotent and undifferentiated precursors that retain the capacity for differentiation into both glial (astrocytes and oligodendrocytes) and neuronal lineages. Neural stem cells offer cell-based therapies for neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and spinal cord injuries. However, their cellular behavior is poorly understood. MicroRNAs (miRNAs) are a class of small noncoding RNAs involved in cell development, proliferation and differentiation through regulating gene expression at post-transcriptional level. The role of miR–381 in the development of neural stem cells remains unknown. In this study, we showed that overexpression of miR–381 promoted neural stem cells proliferation. It induced the neural stem cells differentiation to neurons and inhibited their differentiation to astrocytes. Furthermore, we identified HES1 as a direct target of miR–381 in neural stem cells. Moreover, re-expression of HES1 impaired miR-381-induced promotion of neural stem cells proliferation and induce neural stem cells differentiation to neurons. In conclusion, miR–381 played important role in neural stem cells proliferation and differentiation. PMID:26431046

  18. Neural stem cells and regulation of cell number.

    PubMed

    Sommer, Lukas; Rao, Mahendra

    2002-01-01

    Normal CNS development involves the sequential differentiation of multipotent stem cells. Alteration of the numbers of stem cells, their self-renewal ability, or their proliferative capacity will have major effects on the appropriate development of the nervous system. In this review, we discuss different mechanisms that regulate neural stem cell differentiation. Proliferation signals and cell cycle regulators may regulate cell kinetics or total number of cell divisions. Loss of trophic support and cytokine receptor activation may differentially contribute to the induction of cell death at specific stages of development. Signaling from differentiated progeny or asymmetric distribution of specific molecules may alter the self-renewal characteristics of stem cells. We conclude that the final decision of a cell to self-renew, differentiate or remain quiescent is dependent on an integration of multiple signaling pathways and at each instant will depend on cell density, metabolic state, ligand availability, type and levels of receptor expression, and downstream cross-talk between distinct signaling pathways. PMID:11897403

  19. Topological regulation of lipid balance in cells.

    PubMed

    Drin, Guillaume

    2014-01-01

    Lipids are unevenly distributed within and between cell membranes, thus defining organelle identity. Such distribution relies on local metabolic branches and mechanisms that move lipids. These processes are regulated by feedback mechanisms that decipher topographical information in organelle membranes and then regulate lipid levels or flows. In the endoplasmic reticulum, the major lipid source, transcriptional regulators and enzymes sense changes in membrane features to modulate lipid production. At the Golgi apparatus, lipid-synthesizing, lipid-flippase, and lipid-transport proteins (LTPs) collaborate to control lipid balance and distribution within the membrane to guarantee remodeling processes crucial for vesicular trafficking. Open questions exist regarding LTPs, which are thought to be lipid sensors that regulate lipid synthesis or carriers that transfer lipids between organelles across long distances or in contact sites. A novel model is that LTPs, by exchanging two different lipids, exploit one lipid gradient between two distinct membranes to build a second lipid gradient. PMID:24606148

  20. Regulation of neural stem cells by choroid plexus cells population.

    PubMed

    Roballo, Kelly C S; Gonçalves, Natalia J N; Pieri, Naira C G; Souza, Aline F; Andrade, André F C; Ambrósio, Carlos E

    2016-07-28

    The choroid plexus is a tissue on the central nervous system responsible for producing cerebrospinal fluid, maintaining homeostasis and neural stem cells support; though, all of its functions still unclear. This study aimed to demonstrate the niches of choroid plexus cells for a better understanding of the cell types and functions, using the porcine as the animal model. The collected material was analyzed by histology, immunohistochemistry, and cell culture. The cell culture was characterizated by immunocytochemistry and flow cytometry. Our results showed OCT-4, TUBIII, Nestin, CD45, CD73, CD90 positive expression and GFAP, CD105 negative expression, also methylene blue histological staining confirmed the presence of telocytes cells. We realized that the choroid plexus is a unique and incomparable tissue with different niches of cells as pluripotent, hematopoietic, neuronal progenitors and telocyte cells, which provide its complexity, differentiated functionality and responsibility on brain balance and neural stem cells regulation. PMID:27181512

  1. Microgel Film Dynamics Modulate Cell Adhesion Behavior

    PubMed Central

    Saxena, Shalini; Spears, Mark W.; Yoshida, Hiroaki; Gaulding, Jeffrey C.; García, Andrés J.; Lyon, L. Andrew

    2014-01-01

    A material’s mechanical properties greatly control cell behavior at the cell-substrate interface. In this work, we demonstrate that microgel multilayers have unique elastic and viscoelastic-like properties that can be modulated to produce morphological changes in fibroblasts cultured on the film. Protein adsorption is also examined and the data are contrasted with the number of cells adhered. The dynamic interaction of cell and substrate is only partially explained by conventional understanding of surface-receptor interactions and substrate elasticity. Viscoelasticity, a mechanical property not often considered, plays a significant role at cellular length and time scales for microgel films. PMID:24634694

  2. Measuring children's regulation of emotion-expressive behavior.

    PubMed

    Bar-Haim, Yair; Bar-Av, Gali; Sadeh, Avi

    2011-04-01

    Emotion regulation has become a pivotal concept in developmental and clinical research. However, the measurement of regulatory processes has proved extremely difficult, particularly in the context of within-subject designs. Here, we describe a formal conceptualization and a new experimental procedure, the Balloons Game, to measure a regulatory component of emotion-expressive behavior. We present the internal consistency and stability of the indices derived from the Balloons Game in a sample of 121 kindergarten children. External validation against measures that have been associated with emotion regulation processes is also provided. The findings suggest that the Balloons Game provides a reliable tool for the study of regulation of emotion expression in young children. PMID:21500890

  3. Regulation of mammalian brain cell volume.

    PubMed

    Law, R O

    1994-02-01

    Maintenance of brain cell volume is of crucial importance for normal central nervous system (CNS) function. This review considers volume regulation primarily in response to disturbances of body fluid osmolality. Brain cells counter the tendency to swell or shrink by appropriate adjustment of their internal osmotic potential. This is achieved by loss or uptake of inorganic ions and low molecular weight organic solutes (osmolytes). The latter comprise mainly amino acids, myoinositol, choline, and methylamines. Taurine may be of particular importance in volume control, especially in young animals. Brain cell volume regulation, however, is only one contributory factor to maintenance of constant brain volume (water content), and operates in parallel with important alterations in bulk fluid and electrolyte movement across the blood-brain barrier and between the interstitium and cerebrospinal fluid, which themselves moderate the requirement for transient alteration in cell volume during acute osmotic imbalance. Although altered cerebral content of inorganic ions and osmolytes are usually regarded as responses, respectively, to acute and chronic osmotic disturbances, osmolytes (especially taurine) may also participate in short-term cell volume regulation. PMID:8301256

  4. Regulation of Cell Death by Transfer RNA

    PubMed Central

    2013-01-01

    Abstract Significance: Both transfer RNA (tRNA) and cytochrome c are essential molecules for the survival of cells. tRNA decodes mRNA codons into amino-acid-building blocks in protein in all organisms, whereas cytochrome c functions in the electron transport chain that powers ATP synthesis in mitochondrion-containing eukaryotes. Additionally, in vertebrates, cytochrome c that is released from mitochondria is a potent inducer of apoptosis, activating apoptotic proteins (caspases) in the cytoplasm to dismantle cells. A better understanding of both tRNA and cytochrome c is essential for an insight into the regulation of cell life and death. Recent Advances: A recent study showed that the mitochondrion-released cytochrome c can be removed from the cell-death pathway by tRNA molecules. The direct binding of cytochrome c by tRNA provides a mechanism for tRNA to regulate cell death, beyond its role in gene expression. Critical Issues: The nature of the tRNA–cytochrome c binding interaction remains unknown. The questions of how this interaction affects tRNA function, cellular metabolism, and apoptotic sensitivity are unanswered. Future Directions: Investigations into the critical issues raised above will improve the understanding of tRNA in the fundamental processes of cell death and metabolism. Such knowledge will inform therapies in cell death-related diseases. Antioxid. Redox Signal. 19, 583–594. PMID:23350625

  5. Mitochondrial Regulation of Cell Cycle and Proliferation

    PubMed Central

    Antico Arciuch, Valeria Gabriela; Elguero, María Eugenia; Poderoso, Juan José

    2012-01-01

    Abstract Eukaryotic mitochondria resulted from symbiotic incorporation of α-proteobacteria into ancient archaea species. During evolution, mitochondria lost most of the prokaryotic bacterial genes and only conserved a small fraction including those encoding 13 proteins of the respiratory chain. In this process, many functions were transferred to the host cells, but mitochondria gained a central role in the regulation of cell proliferation and apoptosis, and in the modulation of metabolism; accordingly, defective organelles contribute to cell transformation and cancer, diabetes, and neurodegenerative diseases. Most cell and transcriptional effects of mitochondria depend on the modulation of respiratory rate and on the production of hydrogen peroxide released into the cytosol. The mitochondrial oxidative rate has to remain depressed for cell proliferation; even in the presence of O2, energy is preferentially obtained from increased glycolysis (Warburg effect). In response to stress signals, traffic of pro- and antiapoptotic mitochondrial proteins in the intermembrane space (B-cell lymphoma-extra large, Bcl-2-associated death promoter, Bcl-2 associated X-protein and cytochrome c) is modulated by the redox condition determined by mitochondrial O2 utilization and mitochondrial nitric oxide metabolism. In this article, we highlight the traffic of the different canonical signaling pathways to mitochondria and the contributions of organelles to redox regulation of kinases. Finally, we analyze the dynamics of the mitochondrial population in cell cycle and apoptosis. Antioxid. Redox Signal. 16, 1150–1180. PMID:21967640

  6. Cell death regulates muscle fiber number.

    PubMed

    Sarkissian, Tatevik; Arya, Richa; Gyonjyan, Seda; Taylor, Barbara; White, Kristin

    2016-07-01

    Cell death can have both cell autonomous and non-autonomous roles in normal development. Previous studies have shown that the central cell death regulators grim and reaper are required for the developmentally important elimination of stem cells and neurons in the developing central nervous system (CNS). Here we show that cell death in the nervous system is also required for normal muscle development. In the absence of grim and reaper, there is an increase in the number of fibers in the ventral abdominal muscles in the Drosophila adult. This phenotype can be partially recapitulated by inhibition of cell death specifically in the CNS, indicating a non-autonomous role for neuronal death in limiting muscle fiber number. We also show that FGFs produced in the cell death defective nervous system are required for the increase in muscle fiber number. Cell death in the muscle lineage during pupal stages also plays a role in specifying fiber number. Our work suggests that FGFs from the CNS act as a survival signal for muscle founder cells. Thus, proper muscle fiber specification requires cell death in both the nervous system and in the developing muscle itself. PMID:27131625

  7. Epigenetic Regulation of Hematopoietic Stem Cells

    PubMed Central

    Sharma, Shilpa; Gurudutta, Gangenahalli

    2016-01-01

    Hematopoietic stem cells are endowed with a distinct potential to bolster self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. Both hematopoietic stem cells and mature cells have the same genome, but their gene expression is controlled by an additional layer of epigenetics such as DNA methylation and post-translational histone modifications, enabling each cell-type to acquire various forms and functions. Until recently, several studies have largely focussed on the transcription factors andniche factors for the understanding of the molecular mechanisms by which hematopoietic cells replicate and differentiate. Several lines of emerging evidence suggest that epigenetic modifications eventually result in a defined chromatin structure and an “individual” gene expression pattern, which play an essential role in the regulation of hematopoietic stem cell self-renewal and differentiation. Distinct epigenetic marks decide which sets of genes may be expressed and which genes are kept silent. Epigenetic mechanisms are interdependent and ensure lifelong production of blood and bone marrow, thereby contributing to stem cell homeostasis. The epigenetic analysis of hematopoiesis raises the exciting possibility that chromatin structure is dynamic enough for regulated expression of genes. Though controlled chromatin accessibility plays an essential role in maintaining blood homeostasis; mutations in chromatin impacts on the regulation of genes critical to the development of leukemia. In this review, we explored the contribution of epigenetic machinery which has implications for the ramification of molecular details of hematopoietic self-renewal for normal development and underlying events that potentially co-operate to induce leukemia. PMID:27426084

  8. Cell cycle checkpoint regulators reach a zillion

    PubMed Central

    Yasutis, Kimberly M.; Kozminski, Keith G.

    2013-01-01

    Entry into mitosis is regulated by a checkpoint at the boundary between the G2 and M phases of the cell cycle (G2/M). In many organisms, this checkpoint surveys DNA damage and cell size and is controlled by both the activation of mitotic cyclin-dependent kinases (Cdks) and the inhibition of an opposing phosphatase, protein phosphatase 2A (PP2A). Misregulation of mitotic entry can often lead to oncogenesis or cell death. Recent research has focused on discovering the signaling pathways that feed into the core checkpoint control mechanisms dependent on Cdk and PP2A. Herein, we review the conserved mechanisms of the G2/M transition, including recently discovered upstream signaling pathways that link cell growth and DNA replication to cell cycle progression. Critical consideration of the human, frog and yeast models of mitotic entry frame unresolved and emerging questions in this field, providing a prediction of signaling molecules and pathways yet to be discovered. PMID:23598718

  9. Cytoskeletal Mechanics Regulating Amoeboid Cell Locomotion

    PubMed Central

    Álvarez-González, Begoña; Meili, Ruedi; Firtel, Richard; Bastounis, Effie; del Álamo, Juan C.; Lasheras, Juan C.

    2014-01-01

    Migrating cells exert traction forces when moving. Amoeboid cell migration is a common type of cell migration that appears in many physiological and pathological processes and is performed by a wide variety of cell types. Understanding the coupling of the biochemistry and mechanics underlying the process of migration has the potential to guide the development of pharmacological treatment or genetic manipulations to treat a wide range of diseases. The measurement of the spatiotemporal evolution of the traction forces that produce the movement is an important aspect for the characterization of the locomotion mechanics. There are several methods to calculate the traction forces exerted by the cells. Currently the most commonly used ones are traction force microscopy methods based on the measurement of the deformation induced by the cells on elastic substrate on which they are moving. Amoeboid cells migrate by implementing a motility cycle based on the sequential repetition of four phases. In this paper we review the role that specific cytoskeletal components play in the regulation of the cell migration mechanics. We investigate the role of specific cytoskeletal components regarding the ability of the cells to perform the motility cycle effectively and the generation of traction forces. The actin nucleation in the leading edge of the cell, carried by the ARP2/3 complex activated through the SCAR/WAVE complex, has shown to be fundamental to the execution of the cyclic movement and to the generation of the traction forces. The protein PIR121, a member of the SCAR/WAVE complex, is essential to the proper regulation of the periodic movement and the protein SCAR, also included in the SCAR/WAVE complex, is necessary for the generation of the traction forces during migration. The protein Myosin II, an important F-actin cross-linker and motor protein, is essential to cytoskeletal contractility and to the generation and proper organization of the traction forces during

  10. Epigenetic regulation of smooth muscle cell plasticity.

    PubMed

    Liu, Renjing; Leslie, Kristen L; Martin, Kathleen A

    2015-04-01

    Smooth muscle cells (SMC) are the major cell type in blood vessels. Their principal function in the body is to regulate blood flow and pressure through vessel wall contraction and relaxation. Unlike many other mature cell types in the adult body, SMC do not terminally differentiate but retain a remarkable plasticity. They have the unique ability to toggle between a differentiated and quiescent "contractile" state and a highly proliferative and migratory "synthetic" phenotype in response to environmental stresses. While there have been major advances in our understanding of SMC plasticity through the identification of growth factors and signals that can influence the SMC phenotype, how these regulate SMC plasticity remains unknown. To date, several key transcription factors and regulatory cis elements have been identified that play a role in modulating SMC state. The frontier in understanding the molecular mechanisms underlying SMC plasticity has now advanced to the level of epigenetics. This review will summarize the epigenetic regulation of SMC, highlighting the role of histone modification, DNA methylation, and our most recent identification of a DNA demethylation pathway in SMC that is pivotal in the regulation of the SMC phenotypic state. Many disorders are associated with smooth muscle dysfunction, including atherosclerosis, the major underlying cause of stroke and coronary heart disease, as well as transplant vasculopathy, aneurysm, asthma, hypertension, and cancer. An increased understanding of the major regulators of SMC plasticity will lead to the identification of novel target molecules that may, in turn, lead to novel drug discoveries for the treatment of these diseases. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity. PMID:24937434

  11. Nuclear myosin I regulates cell membrane tension.

    PubMed

    Venit, Tomáš; Kalendová, Alžběta; Petr, Martin; Dzijak, Rastislav; Pastorek, Lukáš; Rohožková, Jana; Malohlava, Jakub; Hozák, Pavel

    2016-01-01

    Plasma membrane tension is an important feature that determines the cell shape and influences processes such as cell motility, spreading, endocytosis and exocytosis. Unconventional class 1 myosins are potent regulators of plasma membrane tension because they physically link the plasma membrane with adjacent cytoskeleton. We identified nuclear myosin 1 (NM1) - a putative nuclear isoform of myosin 1c (Myo1c) - as a new player in the field. Although having specific nuclear functions, NM1 localizes predominantly to the plasma membrane. Deletion of NM1 causes more than a 50% increase in the elasticity of the plasma membrane around the actin cytoskeleton as measured by atomic force microscopy. This higher elasticity of NM1 knock-out cells leads to 25% higher resistance to short-term hypotonic environment and rapid cell swelling. In contrast, overexpression of NM1 in wild type cells leads to an additional 30% reduction of their survival. We have shown that NM1 has a direct functional role in the cytoplasm as a dynamic linker between the cell membrane and the underlying cytoskeleton, regulating the degree of effective plasma membrane tension. PMID:27480647

  12. Nuclear myosin I regulates cell membrane tension

    PubMed Central

    Venit, Tomáš; Kalendová, Alžběta; Petr, Martin; Dzijak, Rastislav; Pastorek, Lukáš; Rohožková, Jana; Malohlava, Jakub; Hozák, Pavel

    2016-01-01

    Plasma membrane tension is an important feature that determines the cell shape and influences processes such as cell motility, spreading, endocytosis and exocytosis. Unconventional class 1 myosins are potent regulators of plasma membrane tension because they physically link the plasma membrane with adjacent cytoskeleton. We identified nuclear myosin 1 (NM1) - a putative nuclear isoform of myosin 1c (Myo1c) - as a new player in the field. Although having specific nuclear functions, NM1 localizes predominantly to the plasma membrane. Deletion of NM1 causes more than a 50% increase in the elasticity of the plasma membrane around the actin cytoskeleton as measured by atomic force microscopy. This higher elasticity of NM1 knock-out cells leads to 25% higher resistance to short-term hypotonic environment and rapid cell swelling. In contrast, overexpression of NM1 in wild type cells leads to an additional 30% reduction of their survival. We have shown that NM1 has a direct functional role in the cytoplasm as a dynamic linker between the cell membrane and the underlying cytoskeleton, regulating the degree of effective plasma membrane tension. PMID:27480647

  13. Ulk4 Regulates Neural Stem Cell Pool.

    PubMed

    Liu, Min; Guan, Zhenlong; Shen, Qin; Flinter, Frances; Domínguez, Laura; Ahn, Joo Wook; Collier, David A; O'Brien, Timothy; Shen, Sanbing

    2016-09-01

    The size of neural stem cell (NSC) pool at birth determines the starting point of adult neurogenesis. Aberrant neurogenesis is associated with major mental illness, in which ULK4 is proposed as a rare risk factor. Little is known about factors regulating the NSC pool, or function of the ULK4. Here, we showed that Ulk4(tm1a/tm1a) mice displayed a dramatically reduced NSC pool at birth. Ulk4 was expressed in a cell cycle-dependent manner and peaked in G2/M phases. Targeted disruption of the Ulk4 perturbed mid-neurogenesis and significantly reduced cerebral cortex in postnatal mice. Pathway analyses of dysregulated genes in Ulk4(tm1a/tm1a) mice revealed Ulk4 as a key regulator of cell cycle and NSC proliferation, partially through regulation of the Wnt signaling. In addition, we identified hemizygous deletion of ULK4 gene in 1.2/1,000 patients with pleiotropic symptoms including severe language delay and learning difficulties. ULK4, therefore, may significantly contribute to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Stem Cells 2016;34:2318-2331. PMID:27300315

  14. Microfabricated environments to study collective cell behaviors.

    PubMed

    Vedula, Sri Ram Krishna; Ravasio, Andrea; Anon, Ester; Chen, Tianchi; Peyret, Grégoire; Ashraf, Mohammed; Ladoux, Benoit

    2014-01-01

    Coordinated cell movements in epithelial layers are essential for proper tissue morphogenesis and homeostasis. Microfabrication techniques have proven to be very useful for studies of collective cell migration in vitro. In this chapter, we briefly review the use of microfabricated substrates in providing new insights into collective cell behaviors. We first describe the development of micropatterned substrates to study the influence of geometrical constraints on cell migration and coordinated movements. Then, we present an alternative method based on microfabricated pillar substrates to create well-defined gaps within cell sheets and study gap closure. We also provide a discussion that presents possible pitfalls and sheds light onto the important parameters that allow the study of long-term cell culture on substrates of well-defined geometries. PMID:24484669

  15. Sonic Hedgehog regulates thymic epithelial cell differentiation.

    PubMed

    Saldaña, José Ignacio; Solanki, Anisha; Lau, Ching-In; Sahni, Hemant; Ross, Susan; Furmanski, Anna L; Ono, Masahiro; Holländer, Georg; Crompton, Tessa

    2016-04-01

    Sonic Hedgehog (Shh) is expressed in the thymus, where it regulates T cell development. Here we investigated the influence of Shh on thymic epithelial cell (TEC) development. Components of the Hedgehog (Hh) signalling pathway were expressed by TEC, and use of a Gli Binding Site-green fluorescence protein (GFP) transgenic reporter mouse demonstrated active Hh-dependent transcription in TEC in the foetal and adult thymus. Analysis of Shh-deficient foetal thymus organ cultures (FTOC) showed that Shh is required for normal TEC differentiation. Shh-deficient foetal thymus contained fewer TEC than wild type (WT), the proportion of medullary TEC was reduced relative to cortical TEC, and cell surface expression of MHC Class II molecules was increased on both cortical and medullary TEC populations. In contrast, the Gli3-deficient thymus, which shows increased Hh-dependent transcription in thymic stroma, had increased numbers of TEC, but decreased cell surface expression of MHC Class II molecules on both cortical and medullary TEC. Neutralisation of endogenous Hh proteins in WT FTOC led to a reduction in TEC numbers, and in the proportion of mature Aire-expressing medullary TEC, but an increase in cell surface expression of MHC Class II molecules on medullary TEC. Likewise, conditional deletion of Shh from TEC in the adult thymus resulted in alterations in TEC differentiation and consequent changes in T cell development. TEC numbers, and the proportion of mature Aire-expressing medullary TEC were reduced, and cell surface expression of MHC Class II molecules on medullary TEC was increased. Differentiation of mature CD4 and CD8 single positive thymocytes was increased, demonstrating the regulatory role of Shh production by TEC on T cell development. Treatment of human thymus explants with recombinant Shh or neutralising anti-Shh antibody indicated that the Hedgehog pathway is also involved in regulation of differentiation from DP to mature SP T cells in the human thymus. PMID

  16. Sonic Hedgehog regulates thymic epithelial cell differentiation

    PubMed Central

    Saldaña, José Ignacio; Solanki, Anisha; Lau, Ching-In; Sahni, Hemant; Ross, Susan; Furmanski, Anna L.; Ono, Masahiro; Holländer, Georg; Crompton, Tessa

    2016-01-01

    Sonic Hedgehog (Shh) is expressed in the thymus, where it regulates T cell development. Here we investigated the influence of Shh on thymic epithelial cell (TEC) development. Components of the Hedgehog (Hh) signalling pathway were expressed by TEC, and use of a Gli Binding Site-green fluorescence protein (GFP) transgenic reporter mouse demonstrated active Hh-dependent transcription in TEC in the foetal and adult thymus. Analysis of Shh-deficient foetal thymus organ cultures (FTOC) showed that Shh is required for normal TEC differentiation. Shh-deficient foetal thymus contained fewer TEC than wild type (WT), the proportion of medullary TEC was reduced relative to cortical TEC, and cell surface expression of MHC Class II molecules was increased on both cortical and medullary TEC populations. In contrast, the Gli3-deficient thymus, which shows increased Hh-dependent transcription in thymic stroma, had increased numbers of TEC, but decreased cell surface expression of MHC Class II molecules on both cortical and medullary TEC. Neutralisation of endogenous Hh proteins in WT FTOC led to a reduction in TEC numbers, and in the proportion of mature Aire-expressing medullary TEC, but an increase in cell surface expression of MHC Class II molecules on medullary TEC. Likewise, conditional deletion of Shh from TEC in the adult thymus resulted in alterations in TEC differentiation and consequent changes in T cell development. TEC numbers, and the proportion of mature Aire-expressing medullary TEC were reduced, and cell surface expression of MHC Class II molecules on medullary TEC was increased. Differentiation of mature CD4 and CD8 single positive thymocytes was increased, demonstrating the regulatory role of Shh production by TEC on T cell development. Treatment of human thymus explants with recombinant Shh or neutralising anti-Shh antibody indicated that the Hedgehog pathway is also involved in regulation of differentiation from DP to mature SP T cells in the human thymus. PMID

  17. 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

  18. Regulation of Satellite Cell Function in Sarcopenia

    PubMed Central

    Alway, Stephen E.; Myers, Matthew J.; Mohamed, Junaith S.

    2014-01-01

    The mechanisms contributing to sarcopenia include reduced satellite cell (myogenic stem cell) function that is impacted by the environment (niche) of these cells. Satellite cell function is affected by oxidative stress, which is elevated in aged muscles, and this along with changes in largely unknown systemic factors, likely contribute to the manner in which satellite cells respond to stressors such as exercise, disuse, or rehabilitation in sarcopenic muscles. Nutritional intervention provides one therapeutic strategy to improve the satellite cell niche and systemic factors, with the goal of improving satellite cell function in aging muscles. Although many elderly persons consume various nutraceuticals with the hope of improving health, most of these compounds have not been thoroughly tested, and the impacts that they might have on sarcopenia and satellite cell function are not clear. This review discusses data pertaining to the satellite cell responses and function in aging skeletal muscle, and the impact that three compounds: resveratrol, green tea catechins, and β-Hydroxy-β-methylbutyrate have on regulating satellite cell function and therefore contributing to reducing sarcopenia or improving muscle mass after disuse in aging. The data suggest that these nutraceutical compounds improve satellite cell function during rehabilitative loading in animal models of aging after disuse (i.e., muscle regeneration). While these compounds have not been rigorously tested in humans, the data from animal models of aging provide a strong basis for conducting additional focused work to determine if these or other nutraceuticals can offset the muscle losses, or improve regeneration in sarcopenic muscles of older humans via improving satellite cell function. PMID:25295003

  19. Regulation of satellite cell function in sarcopenia.

    PubMed

    Alway, Stephen E; Myers, Matthew J; Mohamed, Junaith S

    2014-01-01

    The mechanisms contributing to sarcopenia include reduced satellite cell (myogenic stem cell) function that is impacted by the environment (niche) of these cells. Satellite cell function is affected by oxidative stress, which is elevated in aged muscles, and this along with changes in largely unknown systemic factors, likely contribute to the manner in which satellite cells respond to stressors such as exercise, disuse, or rehabilitation in sarcopenic muscles. Nutritional intervention provides one therapeutic strategy to improve the satellite cell niche and systemic factors, with the goal of improving satellite cell function in aging muscles. Although many elderly persons consume various nutraceuticals with the hope of improving health, most of these compounds have not been thoroughly tested, and the impacts that they might have on sarcopenia and satellite cell function are not clear. This review discusses data pertaining to the satellite cell responses and function in aging skeletal muscle, and the impact that three compounds: resveratrol, green tea catechins, and β-Hydroxy-β-methylbutyrate have on regulating satellite cell function and therefore contributing to reducing sarcopenia or improving muscle mass after disuse in aging. The data suggest that these nutraceutical compounds improve satellite cell function during rehabilitative loading in animal models of aging after disuse (i.e., muscle regeneration). While these compounds have not been rigorously tested in humans, the data from animal models of aging provide a strong basis for conducting additional focused work to determine if these or other nutraceuticals can offset the muscle losses, or improve regeneration in sarcopenic muscles of older humans via improving satellite cell function. PMID:25295003

  20. Peroxiredoxins and the Regulation of Cell Death

    PubMed Central

    Hampton, Mark B.; O’Connor, Karina M.

    2016-01-01

    Cell death pathways such as apoptosis can be activated in response to oxidative stress, enabling the disposal of damaged cells. In contrast, controlled intracellular redox events are proposed to be a significant event during apoptosis signaling, regardless of the initiating stimulus. In this scenario oxidants act as second messengers, mediating the post-translational modification of specific regulatory proteins. The exact mechanism of this signaling is unclear, but increased understanding offers the potential to promote or inhibit apoptosis through modulating the redox environment of cells. Peroxiredoxins are thiol peroxidases that remove hydroperoxides, and are also emerging as important players in cellular redox signaling. This review discusses the potential role of peroxiredoxins in the regulation of apoptosis, and also their ability to act as biomarkers of redox changes during the initiation and progression of cell death. PMID:26810076

  1. Flavonoids: from cell cycle regulation to biotechnology.

    PubMed

    Woo, Ho-Hyung; Jeong, Byeong Ryong; Hawes, Martha C

    2005-03-01

    Flavonoids have been proposed to play diverse roles in plant growth and development, including defense, symbiosis, pollen development and male fertility, polar auxin transport, and protection against ultraviolet radiation. Recently, a new role in cell cycle regulation has emerged. Genetic alteration of glucuronide metabolism by altered expression of a Pisum sativum UDP-glucuronosyltransferase (PsUGT1) results in an altered cell cycle in pea, alfalfa, and Arabidopsis. In alfalfa, altered expression of PsUGT1 results in accumulation of a flavonoid-like compound that suppresses growth of cultured cells. The results are consistent with the hypothesis that PsUGT1 functions by controlling cellular levels of a factor controlling cell cycle (FCC). PMID:15834800

  2. Targeting cell cycle regulators in hematologic malignancies

    PubMed Central

    Aleem, Eiman; Arceci, Robert J.

    2015-01-01

    Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed. PMID:25914884

  3. Versican and the Regulation of Cell Phenotype in Disease

    PubMed Central

    Wight, Thomas N.; Kinsella, Michael G.; Evanko, Stephen P.; Potter-Perigo, Susan; Merrilees, Mervyn J.

    2014-01-01

    Background Versican is an extracellular matrix (ECM) proteoglycan that is present in the pericellular environment of most tissues and increases in many different diseases. Versican interacts with cells to influence the ability of cells to proliferate, migrate, adhere and assemble an ECM. Scope of Review The structure of the versican molecule is briefly reviewed and studies highlighting those factors that promote versican synthesis and degradation and their impact on cell phenotype in disease are discussed. Particular attention is given to vascular disease, but other diseases where versican is important are covered as well, most notably different forms of cancers. Attention is given to mechanisms(s) by which versican influences cell behaviors through either direct or indirect processes. Versican produced by either stromal cells or myeloid cells can have a major impact influencing immunity and inflammation. Finally, studies controlling versican accumulation that either delay or inhibit the progression of disease will be highlighted. Major Conclusions Versican is one component of the ECM that can influence the ability of cells to proliferate, migrate, adhere, and remodel the ECM. Targeting versican as a way to control cell phenotype offers a novel approach in the treatment of disease. Significance ECM molecules such as versican contribute to the structural integrity of tissues and interact with cells through direct and indirect means to regulate, in part, cellular events that form the basis of disease. PMID:24401530

  4. Glycolytic regulation of cell rearrangement in angiogenesis

    PubMed Central

    Cruys, Bert; Wong, Brian W.; Kuchnio, Anna; Verdegem, Dries; Cantelmo, Anna Rita; Conradi, Lena-Christin; Vandekeere, Saar; Bouché, Ann; Cornelissen, Ivo; Vinckier, Stefan; Merks, Roeland M. H.; Dejana, Elisabetta; Gerhardt, Holger; Dewerchin, Mieke; Bentley, Katie; Carmeliet, Peter

    2016-01-01

    During vessel sprouting, endothelial cells (ECs) dynamically rearrange positions in the sprout to compete for the tip position. We recently identified a key role for the glycolytic activator PFKFB3 in vessel sprouting by regulating cytoskeleton remodelling, migration and tip cell competitiveness. It is, however, unknown how glycolysis regulates EC rearrangement during vessel sprouting. Here we report that computational simulations, validated by experimentation, predict that glycolytic production of ATP drives EC rearrangement by promoting filopodia formation and reducing intercellular adhesion. Notably, the simulations correctly predicted that blocking PFKFB3 normalizes the disturbed EC rearrangement in high VEGF conditions, as occurs during pathological angiogenesis. This interdisciplinary study integrates EC metabolism in vessel sprouting, yielding mechanistic insight in the control of vessel sprouting by glycolysis, and suggesting anti-glycolytic therapy for vessel normalization in cancer and non-malignant diseases. PMID:27436424

  5. Glycolytic regulation of cell rearrangement in angiogenesis.

    PubMed

    Cruys, Bert; Wong, Brian W; Kuchnio, Anna; Verdegem, Dries; Cantelmo, Anna Rita; Conradi, Lena-Christin; Vandekeere, Saar; Bouché, Ann; Cornelissen, Ivo; Vinckier, Stefan; Merks, Roeland M H; Dejana, Elisabetta; Gerhardt, Holger; Dewerchin, Mieke; Bentley, Katie; Carmeliet, Peter

    2016-01-01

    During vessel sprouting, endothelial cells (ECs) dynamically rearrange positions in the sprout to compete for the tip position. We recently identified a key role for the glycolytic activator PFKFB3 in vessel sprouting by regulating cytoskeleton remodelling, migration and tip cell competitiveness. It is, however, unknown how glycolysis regulates EC rearrangement during vessel sprouting. Here we report that computational simulations, validated by experimentation, predict that glycolytic production of ATP drives EC rearrangement by promoting filopodia formation and reducing intercellular adhesion. Notably, the simulations correctly predicted that blocking PFKFB3 normalizes the disturbed EC rearrangement in high VEGF conditions, as occurs during pathological angiogenesis. This interdisciplinary study integrates EC metabolism in vessel sprouting, yielding mechanistic insight in the control of vessel sprouting by glycolysis, and suggesting anti-glycolytic therapy for vessel normalization in cancer and non-malignant diseases. PMID:27436424

  6. Epigenetic regulation of smooth muscle cell plasticity

    PubMed Central

    Liu, Renjing; Leslie, Kristen L.; Martin, Kathleen A.

    2014-01-01

    Smooth muscle cells (SMC) are the major cell type in blood vessels. Their principle function in the body is to regulate blood flow and pressure through vessel wall contraction and relaxation. Unlike many other mature cell types in the adult body, SMC do not terminally differentiate but retain a remarkable plasticity. They have the unique ability to toggle between a differentiated and quiescent “contractile” state and a highly proliferative and migratory “synthetic” phenotype in response to environmental stresses. While there have been major advances in our understanding of SMC plasticity through the identification of growth factors and signals that can influence the SMC phenotype, how these regulate SMC plasticity remains unknown. To date, several key transcription factors and regulatory cis elements have been identified that play a role in modulating SMC state. The frontier in understanding the molecular mechanisms underlying SMC plasticity has now advanced to the level of epigenetics. This review will summarize the epigenetic regulation of SMC, highlighting the role of histone modification, DNA methylation, and our most recent identification of a DNA demethylation pathway in SMC that is pivotal in the regulation of the SMC phenotypic state. Many disorders are associated with smooth muscle dysfunction, including atherosclerosis, the major underlying cause of stroke and coronary heart disease, as well as transplant vasculopathy, aneurysm, asthma, hypertension, and cancer. An increased understanding of the major regulators of SMC plasticity will lead to the identification of novel target molecules that may, in turn, lead to novel drug discoveries for the treatment of these diseases. PMID:24937434

  7. Regulated cell death in diagnostic histopathology.

    PubMed

    Skenderi, Faruk; Vranic, Semir; Damjanov, Ivan

    2015-01-01

    Regulated cell death (RCD) is a controlled cellular process, essential for normal development, tissue integrity and homeostasis, and its dysregulation has been implicated in the pathogenesis of various conditions including developmental and immunological disorders, neurodegenerative diseases, and cancer. In this review, we briefly discuss the historical perspective and conceptual development of RCD, we overview recent classifications and some of the key players in RCD; finally we focus on current applications of RCD in diagnostic histopathology. PMID:26009238

  8. Orquestic regulation of neurotransmitters on reward-seeking behavior

    PubMed Central

    2014-01-01

    The ventral tegmental area is strongly associated with the reward system. Dopamine is released in areas such as the nucleus accumbens and prefrontal cortex as a result of rewarding experiences such as food, sex, and neutral stimuli that become associated with them. Electrical stimulation of the ventral tegmental area or its output pathways can itself serve as a potent reward. Different drugs that increase dopamine levels are intrinsically rewarding. Although the dopaminergic system represent the cornerstone of the reward system, other neurotransmitters such as endogenous opioids, glutamate, γ-Aminobutyric acid, acetylcholine, serotonin, adenosine, endocannabinoids, orexins, galanin and histamine all affect this mesolimbic dopaminergic system. Consequently, genetic variations of neurotransmission are thought influence reward processing that in turn may affect distinctive social behavior and susceptibility to addiction. Here, we discuss current evidence on the orquestic regulation of different neurotranmitters on reward-seeking behavior and its potential effect on drug addiction. PMID:25061480

  9. Auxin regulation of cell polarity in plants.

    PubMed

    Pan, Xue; Chen, Jisheng; Yang, Zhenbiao

    2015-12-01

    Auxin is well known to control pattern formation and directional growth at the organ/tissue levels via the nuclear TIR1/AFB receptor-mediated transcriptional responses. Recent studies have expanded the arena of auxin actions as a trigger or key regulator of cell polarization and morphogenesis. These actions require non-transcriptional responses such as changes in the cytoskeleton and vesicular trafficking, which are commonly regulated by ROP/Rac GTPase-dependent pathways. These findings beg for the question about the nature of auxin receptors that regulate these responses and renew the interest in ABP1 as a cell surface auxin receptor, including the work showing auxin-binding protein 1 (ABP1) interacts with the extracellular domain of the transmembrane kinase (TMK) receptor-like kinases in an auxin-dependent manner, as well as the debate on this auxin binding protein discovered about 40 years ago. This review highlights recent work on the non-transcriptional auxin signaling mechanisms underscoring cell polarity and shape formation in plants. PMID:26599954

  10. Reversible histone methylation regulates brain gene expression and behavior

    PubMed Central

    Xu, Jun; Andreassi, Megan

    2011-01-01

    Epigenetic chromatin remodeling, including reversible histone methylation, regulates gene transcription in brain development and synaptic plasticity. Aberrant chromatin modifications due to mutant chromatin enzymes or chemical exposures have been associated with neurological or psychiatric disorders such as mental retardation, schizophrenia, depression, and drug addiction. Some chromatin enzymes, such as histone demethylases JARID1C and UTX, are coded by X-linked genes which are not X-inactivated in females. The higher expression of JARID1C and UTX in females could contribute to sex differences in brain development and behavior. PMID:20816965

  11. Mechanics Regulates Fate Decisions of Human Embryonic Stem Cells

    PubMed Central

    Sun, Yubing; Villa-Diaz, Luis G.; Lam, Raymond H. W.; Chen, Weiqiang; Krebsbach, Paul H.; Fu, Jianping

    2012-01-01

    Research on human embryonic stem cells (hESCs) has attracted much attention given their great potential for tissue regenerative therapy and fundamental developmental biology studies. Yet, there is still limited understanding of how mechanical signals in the local cellular microenvironment of hESCs regulate their fate decisions. Here, we applied a microfabricated micromechanical platform to investigate the mechanoresponsive behaviors of hESCs. We demonstrated that hESCs are mechanosensitive, and they could increase their cytoskeleton contractility with matrix rigidity. Furthermore, rigid substrates supported maintenance of pluripotency of hESCs. Matrix mechanics-mediated cytoskeleton contractility might be functionally correlated with E-cadherin expressions in cell-cell contacts and thus involved in fate decisions of hESCs. Our results highlighted the important functional link between matrix rigidity, cellular mechanics, and pluripotency of hESCs and provided a novel approach to characterize and understand mechanotransduction and its involvement in hESC function. PMID:22615930

  12. Boundary Stiffness Regulates Fibroblast Behavior in Collagen Gels

    PubMed Central

    John, Jeffrey; Quinlan, Angela Throm; Silvestri, Chiara; Billiar, Kristen

    2010-01-01

    Recent studies have illustrated the profound dependence of cellular behavior on the stiffness of 2D culture substrates. The goal of this study was to develop a method to alter the stiffness cells experience in a standard 3D collagen gel model without affecting the physiochemical properties of the extracellular matrix. A device was developed utilizing compliant anchors (0.048–0.64 N m−1) to tune the boundary stiffness of suspended collagen gels in between the commonly utilized free and fixed conditions (zero and infinite stiffness boundary stiffness). We demonstrate the principle of operation with finite element analyses and a wide range of experimental studies. In all cases, boundary stiffness has a strong influence on cell behavior, most notably eliciting higher basal tension and activated force (in response to KCl) and more pronounced remodeling of the collagen matrix at higher boundary stiffness levels. Measured equibiaxial forces for gels seeded with 3 million human foreskin fibroblasts range from 0.05 to 1 mN increasing monotonically with boundary stiffness. Estimated force per cell ranges from 17 to 100 nN utilizing representative volume element analysis. This device provides a valuable tool to independently study the effect of the mechanical environment of the cell in a 3D collagen matrix. PMID:20012205

  13. Behavior of free-swimming cells under various accelerations.

    PubMed

    Hemmersbach-Krause, R; Briegleb, W

    1994-05-01

    The different steps of the gravity signal-transduction chain on the cellular level are not identified. In our experiments performed up to now we mainly stressed our attention on the last step, the response of the cells. Swimming behavior is a suitable indicator for the physiological status of a Paramecium cell. Depending on membrane potential and/or concentrations of Ca++, cGMP and cAMP the beating direction and the beating velocity of the cilia are influenced in a characteristical way leading to a changed swimming activity of the cell. The behavior of Paramecium is influenced by various stimuli from their environment. Previous studies have demonstrated that under controlled conditions Paramecium shows a clear gravity-dependent behavior resulting in negative gravitaxis and gravikinesis (speed regulation in dependence of gravity). By changing the orienting stimulus (gravity) we expected changes of the swimming behavior. Additional experiments were performed using pawn mutant d4-500r. Due to defective Ca(2+)-channels the membrane of this mutant cannot depolarize. As a consequence d4-500r cannot perform phobic responses and swim backwards. Comparative experiments are also performed with the ciliate Loxodes striatus. In contrast to Paramecium this ciliate possesses statocyst-like organelles--the Müller Organelles. PMID:11538776

  14. Stem cell differentiation increases membrane-actin adhesion regulating cell blebability, migration and mechanics

    PubMed Central

    Sliogeryte, Kristina; Thorpe, Stephen D.; Lee, David A.; Botto, Lorenzo; Knight, Martin M.

    2014-01-01

    This study examines how differentiation of human mesenchymal stem cells regulates the interaction between the cell membrane and the actin cortex controlling cell behavior. Micropipette aspiration was used to measure the pressure required for membrane-cortex detachment which increased from 0.15 kPa in stem cells to 0.71 kPa following chondrogenic differentiation. This effect was associated with reduced susceptibility to mechanical and osmotic bleb formation, reduced migration and an increase in cell modulus. Theoretical modelling of bleb formation demonstrated that the increased stiffness of differentiated cells was due to the increased membrane-cortex adhesion. Differentiated cells exhibited greater F-actin density and slower actin remodelling. Differentiated cells also expressed greater levels of the membrane-cortex ezrin, radixin, moeisin (ERM) linker proteins which was responsible for the reduced blebability, as confirmed by transfection of stem cells with dominant active ezrin-T567D-GFP. This study demonstrates that stem cells have an inherently weak membrane-cortex adhesion which increases blebability thereby regulating cell migration and stiffness. PMID:25471686

  15. Ecdysteroids regulate secretory competence in Inka cells.

    PubMed

    Kingan, T G; Adams, M E

    2000-10-01

    Ecdysis, or molting behavior, in insects requires the sequential action of high levels of ecdysteroids, which induce accumulation of ecdysis-triggering hormone (ETH) in Inka cells, followed by low levels of ecdysteroids, permissive for the onset of the behavior. Here, we show that high ecdysteroid levels suppress the onset of the behavioral sequence by inhibiting the development of competence to secrete ETH. In pharate pupae of Manduca sexta, Inka cells in the epitracheal glands normally develop competence to secrete ETH in response to eclosion hormone (EH) 8 h before pupation. Injection of 20-hydroxyecdysone (20E) into precompetent insects prevents this acquisition of competence, but does not affect EH-evoked accumulation of the second messenger cyclic GMP. Precompetent glands acquire competence in vitro after overnight culture, and this can be prevented by the inclusion of 20E at concentrations greater than 0.1 microg ml(-1)in the culture medium. Actinomycin D completely inhibits the acquisition of competence, demonstrating that it is dependent on transcriptional events. Cultured epitracheal glands become refractory to the inhibitory effects of 20E in the acquisition of competence at least 3 h earlier than for Actinomycin D, indicating that 20E acts on an early step in a sequence of nuclear events leading to transcription of a structural gene. Our findings suggest that declining ecdysteroid levels permit a late event in transcription, the product of which is downstream of EH receptor activation and cyclic GMP accumulation in the cascade leading to ETH secretion. PMID:10976037

  16. Epithelial Cell Regulation of Allergic Diseases.

    PubMed

    Gour, Naina; Lajoie, Stephane

    2016-09-01

    Allergic diseases, which have escalated in prevalence in recent years, arise as a result of maladaptive immune responses to ubiquitous environmental stimuli. Why only certain individuals mount inappropriate type 2 immune responses to these otherwise harmless allergens has remained an unanswered question. Mounting evidence suggests that the epithelium, by sensing its environment, is the central regulator of allergic diseases. Once considered to be a passive barrier to allergens, epithelial cells at mucosal surfaces are now considered to be the cornerstone of the allergic diathesis. Beyond their function as maintaining barrier at mucosal surfaces, mucosal epithelial cells through the secretion of mediators like IL-25, IL-33, and TSLP control the fate of downstream allergic immune responses. In this review, we will discuss the advances in recent years regarding the process of allergen recognition and secretion of soluble mediators by epithelial cells that shape the development of the allergic response. PMID:27534656

  17. Survival regulation of leukemia stem cells.

    PubMed

    Hu, Yiguo; Li, Shaoguang

    2016-03-01

    Leukemia stem cells (LSCs) are a subpopulation cells at the apex of hierarchies in leukemia cells and responsible for disease continuous propagation. In this article, we discuss some cellular and molecular components, which are critical for LSC survival. These components include intrinsic signaling pathways and extrinsic microenvironments. The intrinsic signaling pathways to be discussed include Wnt/β-catenin signaling, Hox genes, Hh pathway, Alox5, and some miRNAs, which have been shown to play important roles in regulating LSC survival and proliferation. The extrinsic components to be discussed include selectins, CXCL12/CXCR4, and CD44, which involve in LSC homing, survival, and proliferation by affecting bone marrow microenvironment. Potential strategies for eradicating LSCs will also discuss. PMID:26686687

  18. Regulator of Calcineurin (RCAN-1) Regulates Thermotaxis Behavior in Caenorhabditis elegans.

    PubMed

    Li, Weixun; Bell, Harold W; Ahnn, Joohong; Lee, Sun-Kyung

    2015-11-01

    Regulator of calcineurin (RCAN) is a calcineurin-interacting protein that inhibits calcineurin phosphatase when overexpressed, often upregulated under neuropathological conditions with impaired learning and memory processes, such as Down syndrome or Alzheimer's disease. Thermotactic behavior in the nematode Caenorhabditis elegans is a form of memory in which calcineurin signaling plays a pivotal role in the thermosensation of AFD neurons. In this study, we found that rcan-1 deletion mutants exhibited cryophilic behavior dependent on tax-6, which was rescued by expressing rcan-1 in AFD neurons. Interaction between RCAN-1 and TAX-6 requires the conserved PxIxIT motif of RCAN-1, without which thermotactic behavior could not be fully rescued. In addition, the loss of crh-1/CREB suppressed the thermotaxis phenotypes of rcan-1 and tax-6 mutants, indicating that crh-1 is crucial in thermotaxis memory in these mutants. Taken together, our results suggest that rcan-1 is an inhibitory regulator of tax-6 and that it acts in the formation of thermosensory behavioral memory in C. elegans. PMID:26232604

  19. Regulation of pigeon cropmilk secretion and parental behaviors by prolactin.

    PubMed

    Horseman, N D; Buntin, J D

    1995-01-01

    Prolactin stimulates the growth and development of specialized epithelial cells lining the cropsac of pigeons and doves (family Columbidae), leading to formation of "cropmilk," which is fed to the newly hatched squab. This system of milk feeding is unique among birds. To support the feeding of cropmilk, a complex array of behavioral adaptations are also supported by high levels of prolactin secretion in columbids during parenting. These specializations include elevated food intake (hyperphagia), nest attendance, and regurgitation feeding of the squab. Although prolactin is clearly important for these behavioral adaptations, the precise physiological and mechanistic bases for these behavioral effects remain controversial. The molecular mechanisms of prolactin action in the cropsac epithelium have been studied by cloning prolactin-induced genes, by cloning and expressing the pigeon prolactin receptor, and by analyzing the transcription factors that are activated after prolactin treatment. The avian (pigeon) prolactin receptor is a member of the cytokine receptor superfamily and uniquely contains a complete duplication of the extracellular ligand-binding domain. One of the early signal-transducing actions of prolactin in cropsac epithelium is the activation of signal transducer and activator of transcription (STAT) proteins via tyrosine phosphorylation. This fundamental signaling pathway is shared with mammalian prolactin target tissues. The convergent evolution of milk feeding and the behaviors that support parenting in columbids and mammals has depended on adaptation of both conserved mechanisms and divergent physiological processes. PMID:8527218

  20. Mast Cells as Regulators of T Cell Responses.

    PubMed

    Bulfone-Paus, Silvia; Bahri, Rajia

    2015-01-01

    Mast cells (MCs) are recognized to participate in the regulation of innate and adaptive immune responses. Owing to their strategic location at the host-environment interface, they control tissue homeostasis and are key cells for starting early host defense against intruders. Upon degranulation induced, e.g., by immunoglobulin E (IgE) and allergen-mediated engagement of the high-affinity IgE receptor, complement or certain neuropeptide receptors, MCs release a wide variety of preformed and newly synthesized products including proteases, lipid mediators, and many cytokines, chemokines, and growth factors. Interestingly, increasing evidence suggests a regulatory role for MCs in inflammatory diseases via the regulation of T cell activities. Furthermore, rather than only serving as effector cells, MCs are now recognized to induce T cell activation, recruitment, proliferation, and cytokine secretion in an antigen-dependent manner and to impact on regulatory T cells. This review synthesizes recent developments in MC-T cell interactions, discusses their biological and clinical relevance, and explores recent controversies in this field of MC research. PMID:26300882

  1. Mast Cells as Regulators of T Cell Responses

    PubMed Central

    Bulfone-Paus, Silvia; Bahri, Rajia

    2015-01-01

    Mast cells (MCs) are recognized to participate in the regulation of innate and adaptive immune responses. Owing to their strategic location at the host–environment interface, they control tissue homeostasis and are key cells for starting early host defense against intruders. Upon degranulation induced, e.g., by immunoglobulin E (IgE) and allergen-mediated engagement of the high-affinity IgE receptor, complement or certain neuropeptide receptors, MCs release a wide variety of preformed and newly synthesized products including proteases, lipid mediators, and many cytokines, chemokines, and growth factors. Interestingly, increasing evidence suggests a regulatory role for MCs in inflammatory diseases via the regulation of T cell activities. Furthermore, rather than only serving as effector cells, MCs are now recognized to induce T cell activation, recruitment, proliferation, and cytokine secretion in an antigen-dependent manner and to impact on regulatory T cells. This review synthesizes recent developments in MC–T cell interactions, discusses their biological and clinical relevance, and explores recent controversies in this field of MC research. PMID:26300882

  2. Beyond behavior modification: Benefits of social-emotional/self-regulation training for preschoolers with behavior problems.

    PubMed

    Graziano, Paulo A; Hart, Katie

    2016-10-01

    The current study evaluated the initial efficacy of three intervention programs aimed at improving school readiness in preschool children with externalizing behavior problems (EBP). Participants for this study included 45 preschool children (76% boys; Mage=5.16years; 84% Hispanic/Latino background) with at-risk or clinically elevated levels of EBP. During the summer between preschool and kindergarten, children were randomized to receive three newly developed intervention packages. The first and most cost effective intervention package was an 8-week School Readiness Parenting Program (SRPP). Families randomized into the second and third intervention packages received not only the weekly SRPP, but children also attended two different versions of an intensive kindergarten summer readiness class (M-F, 8a.m.-5p.m.) that was part of an 8-week summer treatment program for pre-kindergarteners (STP-PreK). One version included the standard behavioral modification system and academic curriculum (STP-PreK) while the other additionally contained social-emotional and self-regulation training (STP-PreK Enhanced). Baseline, post-intervention, and 6-month follow-up data were collected on children's school readiness outcomes including parent, teacher, and objective assessment measures. Analyses using linear mixed models indicated that children's behavioral functioning significantly improved across all groups in a similar magnitude. Children in the STP-PreK Enhanced group, however, experienced greater growth across time in academic achievement, emotion knowledge, emotion regulation, and executive functioning compared to children in the other groups. These findings suggest that while parent training is sufficient to address children's behavioral difficulties, an intensive summer program that goes beyond behavioral modification and academic preparation by targeting socio-emotional and self-regulation skills can have incremental benefits across multiple aspects of school readiness. PMID

  3. Wnt pathway regulation of intestinal stem cells.

    PubMed

    Mah, Amanda T; Yan, Kelley S; Kuo, Calvin J

    2016-09-01

    Wnt signalling is involved in multiple aspects of embryonic development and adult tissue homeostasis, notably via controlling cellular proliferation and differentiation. Wnt signalling is subject to stringent positive and negative regulation to promote proper development and homeostasis yet avoid aberrant growth. Such multi-layer regulation includes post-translational modification and processing of Wnt proteins themselves, R-spondin (Rspo) amplification of Wnt signalling, diverse receptor families, and intracellular and extracellular antagonists and destruction and transcription complexes. In the gastrointestinal tract, Wnt signalling is crucial for development and renewal of the intestinal epithelium. Intestinal stem cells (ISCs) undergo symmetric division and neutral drift dynamics to renew the intestinal epithelium. Sources of Wnts and Wnt amplifers such as R-spondins are beginning to be elucidated as well as their functional contribution to intestinal homeostasis. In this review we focus on regulation of ISCs and intestinal homeostasis by the Wnt/Rspo pathway, the potential cellular sources of Wnt signalling regulators and highlight potential future areas of study. PMID:27581568

  4. The regulation of hematopoietic stem cell populations

    PubMed Central

    Mayani, Hector

    2016-01-01

    Evidence presented over the last few years indicates that the hematopoietic stem cell (HSC) compartment comprises not just one but a number of different cell populations. Based on HSCs’ proliferation and engraftment potential, it has been suggested that there are two classes of HSC, with long- and short-term engraftment potential. HSC heterogeneity seems to involve differentiation capacities as well, since it has been shown that some HSC clones are able to give rise to both myeloid and lymphoid progeny, whereas others are lymphoid deficient. It has been recognized that HSC function depends on intrinsic cell regulators, which are modulated by external signals. Among the former, we can include transcription factors and non-coding RNAs as well as epigenetic modifiers. Among the latter, cytokines and extracellular matrix molecules have been implicated. Understanding the elements and mechanisms that regulate HSC populations is of significant relevance both in biological and in clinical terms, and research in this area still has to face several complex and exciting challenges. PMID:27408695

  5. Biomechanical regulation of cell orientation and fate

    PubMed Central

    Lopez, JI; Mouw, JK; Weaver, VM

    2009-01-01

    Biomechanical regulation of tumor phenotypes have been noted for several decades, yet the function of mechanics in the co-evolution of the tumor epithelium and altered cancer extracellular matrix has not been appreciated until fairly recently. In this review, we examine the dynamic interaction between the developing epithelia and the extracellular matrix, and discuss how similar interactions are exploited by the genetically modified epithelium during tumor progression. We emphasize the process of mechanoreciprocity, which is a phenomenon observed during epithelial transformation, in which tension generated within the extracellular microenvironment induce and cooperate with opposing reactive forces within transformed epithelium to drive tumor progression and metastasis. We highlight the importance of matrix remodeling, and present a new, emerging paradigm that underscores the importance of tissue morphology as a key regulator of epithelial cell invasion and metastasis. PMID:19029939

  6. BCOR regulates myeloid cell proliferation and differentiation.

    PubMed

    Cao, Q; Gearhart, M D; Gery, S; Shojaee, S; Yang, H; Sun, H; Lin, D-C; Bai, J-W; Mead, M; Zhao, Z; Chen, Q; Chien, W-W; Alkan, S; Alpermann, T; Haferlach, T; Müschen, M; Bardwell, V J; Koeffler, H P

    2016-05-01

    BCOR is a component of a variant Polycomb group repressive complex 1 (PRC1). Recently, we and others reported recurrent somatic BCOR loss-of-function mutations in myelodysplastic syndrome and acute myelogenous leukemia (AML). However, the role of BCOR in normal hematopoiesis is largely unknown. Here, we explored the function of BCOR in myeloid cells using myeloid murine models with Bcor conditional loss-of-function or overexpression alleles. Bcor mutant bone marrow cells showed significantly higher proliferation and differentiation rates with upregulated expression of Hox genes. Mutation of Bcor reduced protein levels of RING1B, an H2A ubiquitin ligase subunit of PRC1 family complexes and reduced H2AK119ub upstream of upregulated HoxA genes. Global RNA expression profiling in murine cells and AML patient samples with BCOR loss-of-function mutation suggested that loss of BCOR expression is associated with enhanced cell proliferation and myeloid differentiation. Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. PMID:26847029

  7. Transcriptionally Regulated Cell Adhesion Network Dictates Distal Tip Cell Directionality

    PubMed Central

    Wong, Ming-Ching; Kennedy, William P.; Schwarzbauer, Jean E.

    2015-01-01

    Background The mechanisms that govern directional changes in cell migration are poorly understood. The migratory paths of two distal tip cells (DTC) determine the U-shape of the C. elegans hermaphroditic gonad. The morphogenesis of this organ provides a model system to identify genes necessary for the DTCs to execute two stereotyped turns. Results Using candidate genes for RNAi knockdown in a DTC-specific strain, we identified two transcriptional regulators required for DTC turning: cbp-1, the CBP/p300 transcriptional coactivator homologue, and let-607, a CREBH transcription factor homologue. Further screening of potential target genes uncovered a network of integrin adhesion-related genes that have roles in turning and are dependent on cbp-1 and let-607 for expression. These genes include src-1/Src kinase, tln-1/talin, pat-2/α integrin and nmy-2, a nonmuscle myosin heavy chain. Conclusions Transcriptional regulation by means of cbp-1 and let-607 is crucial for determining directional changes during DTC migration. These regulators coordinate a gene network that is necessary for integrin-mediated adhesion. Overall, these results suggest that directional changes in cell migration rely on the precise gene regulation of adhesion. PMID:24811939

  8. Quantifying cell behaviors during embryonic wound healing

    NASA Astrophysics Data System (ADS)

    Mashburn, David; Ma, Xiaoyan; Crews, Sarah; Lynch, Holley; McCleery, W. Tyler; Hutson, M. Shane

    2011-03-01

    During embryogenesis, internal forces induce motions in cells leading to widespread motion in tissues. We previously developed laser hole-drilling as a consistent, repeatable way to probe such epithelial mechanics. The initial recoil (less than 30s) gives information about physical properties (elasticity, force) of cells surrounding the wound, but the long-term healing process (tens of minutes) shows how cells adjust their behavior in response to stimuli. To study this biofeedback in many cells through time, we developed tools to quantify statistics of individual cells. By combining watershed segmentation with a powerful and efficient user interaction system, we overcome problems that arise in any automatic segmentation from poor image quality. We analyzed cell area, perimeter, aspect ratio, and orientation relative to wound for a wide variety of laser cuts in dorsal closure. We quantified statistics for different regions as well, i.e. cells near to and distant from the wound. Regional differences give a distribution of wound-induced changes, whose spatial localization provides clues into the physical/chemical signals that modulate the wound healing response. Supported by the Human Frontier Science Program (RGP0021/2007 C).

  9. Transcriptional regulation of hepatic stellate cells.

    PubMed

    Mann, Jelena; Mann, Derek A

    2009-07-01

    Hepatic stellate cell (HSC) activation is a process of cellular transdifferentiation in which, upon liver injury, the quiescent vitamin A storing perisinusoidal HSC is converted into a wound-healing myofibroblast and acquires potent pro-inflammatory and pro-fibrogenic activities. This remarkable phenotypic transformation is underpinned by changes in the expression of a vast number of genes. In this review we survey current knowledge of the transcription factors that either control HSC activation or which regulate specific fibrogenic functions of the activated HSC such as collagen expression, proliferation and resistance to apoptosis. PMID:19393271

  10. Cell shape regulates global histone acetylation in human mammaryepithelial cells

    SciTech Connect

    Le Beyec, Johanne; Xu, Ren; Lee, Sun-Young; Nelson, Celeste M.; Rizki, Aylin; Alcaraz, Jordi; Bissell, Mina J.

    2007-02-28

    Extracellular matrix (ECM) regulates cell morphology and gene expression in vivo; these relationships are maintained in three-dimensional (3D) cultures of mammary epithelial cells. In the presence of laminin-rich ECM (lrECM), mammary epithelial cells round up and undergo global histone deacetylation, a process critical for their functional differentiation. However, it remains unclear whether lrECM-dependent cell rounding and global histone deacetylation are indeed part of a common physical-biochemical pathway. Using 3D cultures as well as nonadhesive and micropatterned substrata, here we showed that the cell 'rounding' caused by lrECM was sufficient to induce deacetylation of histones H3 and H4 in the absence of biochemical cues. Microarray and confocal analysis demonstrated that this deacetylation in 3D culture is associated with a global increase in chromatin condensation and a reduction in gene expression. Whereas cells cultured on plastic substrata formed prominent stress fibers, cells grown in 3D lrECM or on micropatterns lacked these structures. Disruption of the actin cytoskeleton with cytochalasin D phenocopied the lrECM-induced cell rounding and histone deacetylation. These results reveal a novel link between ECM-controlled cell shape and chromatin structure, and suggest that this link is mediated by changes in the actin cytoskeleton.

  11. Collective Decision-Making and Oscillatory Behaviors in Cell Populations

    NASA Astrophysics Data System (ADS)

    Fujimoto, Koichi; Sawai, Satoshi

    2013-12-01

    Many examples of oscillations are known in multicellular dynamics, however how properties of individual cells can account for the collective rhythmic behaviors at the tissue level remain elusive. Recently, studies in chemical reactions, synthetic gene circuits, yeast and social amoeba Dictyostelium have greatly enhanced our understanding of collective oscillations in cell populations. From these relatively simple systems, a unified view of how excitable and oscillatory regulations could be tuned and coupled to give rise to tissue-level oscillations is emerging. This chapter reviews recent progress in these and other experimental systems and highlight similarities and differences. We will show how group-level information can be encoded in the oscillations depending on degree of autonomy of single cells and discuss some of their possible biological roles.

  12. Mechanical regulation of mesenchymal stem cell differentiation.

    PubMed

    Steward, Andrew J; Kelly, Daniel J

    2015-12-01

    Biophysical cues play a key role in directing the lineage commitment of mesenchymal stem cells or multipotent stromal cells (MSCs), but the mechanotransductive mechanisms at play are still not fully understood. This review article first describes the roles of both substrate mechanics (e.g. stiffness and topography) and extrinsic mechanical cues (e.g. fluid flow, compression, hydrostatic pressure, tension) on the differentiation of MSCs. A specific focus is placed on the role of such factors in regulating the osteogenic, chondrogenic, myogenic and adipogenic differentiation of MSCs. Next, the article focuses on the cellular components, specifically integrins, ion channels, focal adhesions and the cytoskeleton, hypothesized to be involved in MSC mechanotransduction. This review aims to illustrate the strides that have been made in elucidating how MSCs sense and respond to their mechanical environment, and also to identify areas where further research is needed. PMID:25382217

  13. GATA2 regulates dendritic cell differentiation.

    PubMed

    Onodera, Koichi; Fujiwara, Tohru; Onishi, Yasushi; Itoh-Nakadai, Ari; Okitsu, Yoko; Fukuhara, Noriko; Ishizawa, Kenichi; Shimizu, Ritsuko; Yamamoto, Masayuki; Harigae, Hideo

    2016-07-28

    Dendritic cells (DCs) are critical immune response regulators; however, the mechanism of DC differentiation is not fully understood. Heterozygous germ line GATA2 mutations induce GATA2-deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia/acute myeloid leukemia, and a profoundly reduced DC population, which is associated with increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. To define the role of GATA2 in DC differentiation and function, we studied Gata2 conditional knockout and haploinsufficient mice. Gata2 conditional deficiency significantly reduced the DC count, whereas Gata2 haploinsufficiency did not affect this population. GATA2 was required for the in vitro generation of DCs from Lin(-)Sca-1(+)Kit(+) cells, common myeloid-restricted progenitors, and common dendritic cell precursors, but not common lymphoid-restricted progenitors or granulocyte-macrophage progenitors, suggesting that GATA2 functions in the myeloid pathway of DC differentiation. Moreover, expression profiling demonstrated reduced expression of myeloid-related genes, including mafb, and increased expression of T-lymphocyte-related genes, including Gata3 and Tcf7, in Gata2-deficient DC progenitors. In addition, GATA2 was found to bind an enhancer element 190-kb downstream region of Gata3, and a reporter assay exhibited significantly reduced luciferase activity after adding this enhancer region to the Gata3 promoter, which was recovered by GATA sequence deletion within Gata3 +190. These results suggest that GATA2 plays an important role in cell-fate specification toward the myeloid vs T-lymphocyte lineage by regulating lineage-specific transcription factors in DC progenitors, thereby contributing to DC differentiation. PMID:27259979

  14. Epigenetic regulation of hematopoietic stem cell aging

    SciTech Connect

    Beerman, Isabel

    2014-12-10

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.

  15. Innate lymphoid cells regulate intestinal epithelial cell glycosylation.

    PubMed

    Goto, Yoshiyuki; Obata, Takashi; Kunisawa, Jun; Sato, Shintaro; Ivanov, Ivaylo I; Lamichhane, Aayam; Takeyama, Natsumi; Kamioka, Mariko; Sakamoto, Mitsuo; Matsuki, Takahiro; Setoyama, Hiromi; Imaoka, Akemi; Uematsu, Satoshi; Akira, Shizuo; Domino, Steven E; Kulig, Paulina; Becher, Burkhard; Renauld, Jean-Christophe; Sasakawa, Chihiro; Umesaki, Yoshinori; Benno, Yoshimi; Kiyono, Hiroshi

    2014-09-12

    Fucosylation of intestinal epithelial cells, catalyzed by fucosyltransferase 2 (Fut2), is a major glycosylation mechanism of host-microbiota symbiosis. Commensal bacteria induce epithelial fucosylation, and epithelial fucose is used as a dietary carbohydrate by many of these bacteria. However, the molecular and cellular mechanisms that regulate the induction of epithelial fucosylation are unknown. Here, we show that type 3 innate lymphoid cells (ILC3) induced intestinal epithelial Fut2 expression and fucosylation in mice. This induction required the cytokines interleukin-22 and lymphotoxin in a commensal bacteria-dependent and -independent manner, respectively. Disruption of intestinal fucosylation led to increased susceptibility to infection by Salmonella typhimurium. Our data reveal a role for ILC3 in shaping the gut microenvironment through the regulation of epithelial glycosylation. PMID:25214634

  16. The effect of ethanol on behavioral temperature regulation in mice.

    PubMed

    O'Connor, C S; Crawshaw, L I; Kosobud, A; Bedichek, R C; Crabbe, J C

    1989-06-01

    Mice were injected with 20% ethanol in 0.9% NaCl, or with 0.9% NaCl without ethanol during sessions of behavioral thermoregulation in a tubular temperature gradient (ambient temperature range approximately 9-38 degrees C). Internal temperature was monitored with an implanted telemetry device. An imaging system recorded the position (selected temperature) of the mouse within the gradient every 5 sec. A dose of either 2.25 or 2.60 g ethanol/kg body wt. produced significantly lower body temperatures than control (NaCl) injections. The 2.60 g/kg dose produced significantly lower selected temperatures than either the NaCl or 2.25 g/kg injections. Doses of 2.75 g ethanol/kg and above incapacitated the mice, precluding accurate behavioral thermoregulation. Utilizing a thermoregulatory index to compare the responses following experimental and control injections indicated that 2.25 or 2.60 g ethanol/kg leads to a decrease in the regulated temperature of mice. PMID:2813471

  17. Neuropeptide Regulation of Signaling and Behavior in the BNST

    PubMed Central

    Kash, Thomas L.; Pleil, Kristen E.; Marcinkiewcz, Catherine A.; Lowery-Gionta, Emily G.; Crowley, Nicole; Mazzone, Christopher; Sugam, Jonathan; Hardaway, J. Andrew; McElligott, Zoe A.

    2015-01-01

    Recent technical developments have transformed how neuroscientists can probe brain function. What was once thought to be difficult and perhaps impossible, stimulating a single set of long range inputs among many, is now relatively straight-forward using optogenetic approaches. This has provided an avalanche of data demonstrating causal roles for circuits in a variety of behaviors. However, despite the critical role that neuropeptide signaling plays in the regulation of behavior and physiology of the brain, there have been remarkably few studies demonstrating how peptide release is causally linked to behaviors. This is likely due to both the different time scale by which peptides act on and the modulatory nature of their actions. For example, while glutamate release can effectively transmit information between synapses in milliseconds, peptide release is potentially slower [See the excellent review by Van Den Pol on the time scales and mechanisms of release (van den Pol, 2012)] and it can only tune the existing signals via modulation. And while there have been some studies exploring mechanisms of release, it is still not as clearly known what is required for efficient peptide release. Furthermore, this analysis could be complicated by the fact that there are multiple peptides released, some of which may act in contrast. Despite these limitations, there are a number of groups making progress in this area. The goal of this review is to explore the role of peptide signaling in one specific structure, the bed nucleus of the stria terminalis, that has proven to be a fertile ground for peptide action. PMID:25475545

  18. Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells.

    PubMed

    Chatterjee, Samit; Seifried, Laurie; Feigin, Michael E; Gibbons, Don L; Scuoppo, Claudio; Lin, Wei; Rizvi, Zain H; Lind, Evan; Dissanayake, Dilan; Kurie, Jonathan; Ohashi, Pam; Muthuswamy, Senthil K

    2012-01-01

    Changes in expression and localization of proteins that regulate cell and tissue polarity are frequently observed in carcinoma. However, the mechanisms by which changes in cell polarity proteins regulate carcinoma progression are not well understood. Here, we report that loss of polarity protein expression in epithelial cells primes them for cooperation with oncogenes or changes in tissue microenvironment to promote invasive behavior. Activation of ErbB2 in cells lacking the polarity regulators Scribble, Dlg1 or AF-6, induced invasive properties. This cooperation required the ability of ErbB2 to regulate the Par6/aPKC polarity complex. Inhibition of the ErbB2-Par6 pathway was sufficient to block ErbB2-induced invasion suggesting that two polarity hits may be needed for ErbB2 to promote invasion. Interestingly, in the absence of ErbB2 activation, either a combined loss of two polarity proteins, or exposure of cells lacking one polarity protein to cytokines IL-6 or TNFα induced invasive behavior in epithelial cells. We observed the invasive behavior only when cells were plated on a stiff matrix (Matrigel/Collagen-1) and not when plated on a soft matrix (Matrigel alone). Cells lacking two polarity proteins upregulated expression of EGFR and activated Akt. Inhibition of Akt activity blocked the invasive behavior identifying a mechanism by which loss of polarity promotes invasion of epithelial cells. Thus, we demonstrate that loss of polarity proteins confers phenotypic plasticity to epithelial cells such that they display normal behavior under normal culture conditions but display aggressive behavior in response to activation of oncogenes or exposure to cytokines. PMID:22529912

  19. Focal Adhesion Kinase regulates cell-cell contact formation in epithelial cells via modulation of Rho

    SciTech Connect

    Playford, Martin P.; Vadali, Kavita; Cai Xinming; Burridge, Keith; Schaller, Michael D.

    2008-10-15

    Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase that plays a key role in cellular processes such as cell adhesion, migration, proliferation and survival. Recent studies have also implicated FAK in the regulation of cell-cell adhesion. Here, evidence is presented showing that siRNA-mediated suppression of FAK levels in NBT-II cells and expression of dominant negative mutants of FAK caused loss of epithelial cell morphology and inhibited the formation of cell-cell adhesions. Rac and Rho have been implicated in the regulation of cell-cell adhesions and can be regulated by FAK signaling. Expression of active Rac or Rho in NBT-II cells disrupted formation of cell-cell contacts, thus promoting a phenotype similar to FAK-depleted cells. The loss of intercellular contacts in FAK-depleted cells is prevented upon expression of a dominant negative Rho mutant, but not a dominant negative Rac mutant. Inhibition of FAK decreased tyrosine phosphorylation of p190RhoGAP and elevated the level of GTP-bound Rho. This suggests that FAK regulates cell-cell contact formation by regulation of Rho.

  20. Alteration by p11 of mGluR5 localization regulates depression-like behaviors

    PubMed Central

    Lee, Ko-Woon; Westin, Linda; Kim, Jeongjin; Chang, Jerry C.; Oh, Yong-Seok; Amreen, Bushra; Gresack, Jodi; Flajolet, Marc; Kim, Daesoo; Aperia, Anita; Kim, Yong; Greengard, Paul

    2016-01-01

    Mood disorders and antidepressant therapy involve alterations of monoaminergic and glutamatergic transmission. The protein S100A10 (p11) was identified as a regulator of serotonin receptors, and has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors (SSRIs). Here we report that p11 can also regulate depression-like behaviors via regulation of a glutamatergic receptor in mice. p11 directly binds to the cytoplasmic tail of metabotropic glutamate receptor 5 (mGluR5). p11 and mGluR5 mutually facilitate their accumulation at the plasma membranes, and p11 increases cell surface availability of the receptor. While p11 overexpression potentiates mGluR5 agonist-induced calcium responses, overexpression of mGluR5 mutant, which does not interact with p11, diminishes the calcium responses in cultured cells. Knockout of mGluR5 or p11 specifically in glutamatergic neurons in mice causes depression-like behaviors. Conversely, knockout of mGluR5 or p11 in GABAergic neurons causes antidepressant-like behaviors. Inhibition of mGluR5 with an antagonist, MPEP, induces antidepressant-like behaviors in a p11-dependent manner. Notably, the antidepressant-like action of MPEP is mediated by parvalbumin-positive GABAergic interneurons, resulting in a decrease of inhibitory neuronal firing with a resultant increase of excitatory neuronal firing. These results identify a molecular and cellular basis by which mGluR5 antagonism achieves its antidepressant-like activity. PMID:26370144

  1. Microconfined flow behavior of red blood cells.

    PubMed

    Tomaiuolo, Giovanna; Lanotte, Luca; D'Apolito, Rosa; Cassinese, Antonio; Guido, Stefano

    2016-01-01

    Red blood cells (RBCs) perform essential functions in human body, such as gas exchange between blood and tissues, thanks to their ability to deform and flow in the microvascular network. The high RBC deformability is mainly due to the viscoelastic properties of the cell membrane. Since an impaired RBC deformability could be found in some diseases, such as malaria, sickle cell anemia, diabetes and hereditary disorders, there is the need to provide further insight into measurement of RBC deformability in a physiologically relevant flow field. Here, RBCs deformability has been studied in terms of the minimum apparent plasma-layer thickness by using high-speed video microscopy of RBCs flowing in cylindrical glass capillaries. An in vitro systematic microfluidic investigation of RBCs in micro-confined conditions has been performed, resulting in the determination of the RBCs time recovery constant, RBC volume and surface area and RBC membrane shear elastic modulus and surface viscosity. It has been noticed that the deformability of RBCs induces cells aggregation during flow in microcapillaries, allowing the formation of clusters of cells. Overall, our results provide a novel technique to estimate RBC deformability and also RBCs collective behavior, which can be used for the analysis of pathological RBCs, for which reliable quantitative methods are still lacking. PMID:26071649

  2. Regulated Mucin Secretion from Airway Epithelial Cells

    PubMed Central

    Adler, Kenneth B.; Tuvim, Michael J.; Dickey, Burton F.

    2013-01-01

    Secretory epithelial cells of the proximal airways synthesize and secrete gel-forming polymeric mucins. The secreted mucins adsorb water to form mucus that is propelled by neighboring ciliated cells, providing a mobile barrier which removes inhaled particles and pathogens from the lungs. Several features of the intracellular trafficking of mucins make the airway secretory cell an interesting comparator for the cell biology of regulated exocytosis. Polymeric mucins are exceedingly large molecules (up to 3 × 106 Da per monomer) whose folding and initial polymerization in the ER requires the protein disulfide isomerase Agr2. In the Golgi, mucins further polymerize to form chains and possibly branched networks comprising more than 20 monomers. The large size of mucin polymers imposes constraints on their packaging into transport vesicles along the secretory pathway. Sugar side chains account for >70% of the mass of mucins, and their attachment to the protein core by O-glycosylation occurs in the Golgi. Mature polymeric mucins are stored in large secretory granules ∼1 μm in diameter. These are translocated to the apical membrane to be positioned for exocytosis by cooperative interactions among myristoylated alanine-rich C kinase substrate, cysteine string protein, heat shock protein 70, and the cytoskeleton. Mucin granules undergo exocytic fusion with the plasma membrane at a low basal rate and a high stimulated rate. Both rates are mediated by a regulated exocytic mechanism as indicated by phenotypes in both basal and stimulated secretion in mice lacking Munc13-2, a sensor of the second messengers calcium and diacylglycerol (DAG). Basal secretion is induced by low levels of activation of P2Y2 purinergic and A3 adenosine receptors by extracellular ATP released in paracrine fashion and its metabolite adenosine. Stimulated secretion is induced by high levels of the same ligands, and possibly by inflammatory mediators as well. Activated receptors are coupled to

  3. Hormonal regulation of secondary cell wall formation.

    PubMed

    Didi, Vojtěch; Jackson, Phil; Hejátko, Jan

    2015-08-01

    Secondary cell walls (SCWs) have critical functional importance but also constitute a high proportion of the plant biomass and have high application potential. This is true mainly for the lignocellulosic constituents of the SCWs in xylem vessels and fibres, which form a structured layer between the plasma membrane and the primary cell wall (PCW). Specific patterning of the SCW thickenings contributes to the mechanical properties of the different xylem cell types, providing the plant with mechanical support and facilitating the transport of solutes via vessels. In the last decade, our knowledge of the basic molecular mechanisms controlling SCW formation has increased substantially. Several members of the multi-layered regulatory cascade participating in the initiation and transcriptional regulation of SCW formation have been described, and the first cellular components determining the pattern of SCW at the subcellular resolution are being uncovered. The essential regulatory role of phytohormones in xylem development is well known and the molecular mechanisms that link hormonal signals to SCW formation are emerging. Here, we review recent knowledge about the role of individual plant hormones and hormonal crosstalk in the control over the regulatory cascades guiding SCW formation and patterning. Based on the analogy between many of the mechanisms operating during PCW and SCW formation, recently identified mechanisms underlying the hormonal control of PCW remodelling are discussed as potentially novel mechanisms mediating hormonal regulatory inputs in SCW formation. PMID:26002972

  4. ARNT2 Regulates Tumoral Growth in Oral Squamous Cell Carcinoma

    PubMed Central

    Kimura, Yasushi; Kasamatsu, Atsushi; Nakashima, Dai; Yamatoji, Masanobu; Minakawa, Yasuyuki; Koike, Kazuyuki; Fushimi, Kazuaki; Higo, Morihiro; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-01-01

    Aryl hydrocarbon receptor nuclear translocator (ARNT) 2 is a transcriptional factor related to adaptive responses against cellular stress from a xenobiotic substance. Recent evidence indicates ARNT is involved in carcinogenesis and cancer progression; however, little is known about the relevance of ARNT2 in the behavior of oral squamous cell carcinoma (OSCC). In the current study, we evaluated the ARNT2 mRNA and protein expression levels in OSCC in vitro and in vivo and the clinical relationship between ARNT2 expression levels in primary OSCCs and their clinicopathologic status by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry. Using ARNT2 overexpression models, we performed functional analyses to investigate the critical roles of ARNT2 in OSCC. ARNT2 mRNA and protein were down-regulated significantly (P < 0.05 for both comparisons) in nine OSCC-derived cells and primary OSCC (n=100 patients) compared with normal counterparts. In addition to the data from exogenous experiments that ARNT2-overexpressed cells showed decreased cellular proliferation, ARNT2-positive OSCC cases were correlated significantly (P < 0.05) with tumoral size. Since von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase, a negative regulator of hypoxia-inducible factor (HIF1)-α, is a downstream molecule of ARNT2, we speculated that HIF1-α and its downstream molecules would have key functions in cellular growth. Consistent with our hypothesis, overexpressed ARNT2 cells showed down-regulation of HIF1-α, which causes hypofunctioning of glucose transporter 1, leading to decreased cellular growth. Our results proposed for the first time that the ARNT2 level is an indicator of cellular proliferation in OSCCs. Therefore, ARNT2 may be a potential therapeutic target against progression of OSCCs. PMID:27076852

  5. ARNT2 Regulates Tumoral Growth in Oral Squamous Cell Carcinoma.

    PubMed

    Kimura, Yasushi; Kasamatsu, Atsushi; Nakashima, Dai; Yamatoji, Masanobu; Minakawa, Yasuyuki; Koike, Kazuyuki; Fushimi, Kazuaki; Higo, Morihiro; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-01-01

    Aryl hydrocarbon receptor nuclear translocator (ARNT) 2 is a transcriptional factor related to adaptive responses against cellular stress from a xenobiotic substance. Recent evidence indicates ARNT is involved in carcinogenesis and cancer progression; however, little is known about the relevance of ARNT2 in the behavior of oral squamous cell carcinoma (OSCC). In the current study, we evaluated the ARNT2 mRNA and protein expression levels in OSCC in vitro and in vivo and the clinical relationship between ARNT2 expression levels in primary OSCCs and their clinicopathologic status by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry. Using ARNT2 overexpression models, we performed functional analyses to investigate the critical roles of ARNT2 in OSCC. ARNT2 mRNA and protein were down-regulated significantly (P < 0.05 for both comparisons) in nine OSCC-derived cells and primary OSCC (n=100 patients) compared with normal counterparts. In addition to the data from exogenous experiments that ARNT2-overexpressed cells showed decreased cellular proliferation, ARNT2-positive OSCC cases were correlated significantly (P < 0.05) with tumoral size. Since von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase, a negative regulator of hypoxia-inducible factor (HIF1)-α, is a downstream molecule of ARNT2, we speculated that HIF1-α and its downstream molecules would have key functions in cellular growth. Consistent with our hypothesis, overexpressed ARNT2 cells showed down-regulation of HIF1-α, which causes hypofunctioning of glucose transporter 1, leading to decreased cellular growth. Our results proposed for the first time that the ARNT2 level is an indicator of cellular proliferation in OSCCs. Therefore, ARNT2 may be a potential therapeutic target against progression of OSCCs. PMID:27076852

  6. Cell mediated immune regulation in autoimmunity.

    PubMed

    Gillissen, G; Pusztai-Markos, Z

    1979-01-01

    Autoimmunity is the term for the immune conditions characterized by a specific humoral or cell mediated response to the body's own tissues. The termination of the natural state of self tolerance may lead to immunopathological manifestations with clinical consequences, i.e. autoimmune diseases. In a very general sense, one may classify autoimmune diseases into two groups with respect to the underlying mechanism: 1. There are autoimmune diseases which develop in the presence of a normal intact regulation mechanism. 2. Another group whose development must be understood on the basis of a cellular dysfunction. In the first case, dequestered or semi-sequestered autoantigens are liberated as a consequence of exogenic influences inducing the sensitization of immunocompetent cells. The immune system then reacts with these autoantigens in the same way as with foreign substances. This kind of autoimmune disease will, however, not be dealt with here. In the second case, autoantigens are normally, i.e. in healthy individuals, accessible to the immunocompetent cells. To understand the reason for the development of an autoimmune reaction one must first clarify the mechanism of self tolerance. Then one must examine the way in which a break of this physiological state takes place. One of the major unanswered questions is the relative importance of antibody-mediated and cell-mediated immune mechanisms in the onset and further development of autoimmune diseases. Recently it has been suggested that a dysfunction at the cellular level might represent the basic cause which induces the termination of selftolerance. Most of the conceptions about the mechanism by which autoimmune diseases are triggered were gained through experiments with animals. It is, however, difficult to use these experimental results to explain human diseases; in humans many questions are still open. Undoubtedly, the mechanisms of induction and maintenance of self tolerance and also the ways in which autoimmune

  7. Redox Regulation of Endothelial Cell Fate

    PubMed Central

    Song, Ping; Zou, Ming-Hui

    2014-01-01

    Endothelial cells (ECs) are present throughout blood vessels and have variable roles in both physiological and pathological settings. EC fate is altered and regulated by several key factors in physiological or pathological conditions. Reactive nitrogen species and reactive oxygen species derived from NAD(P)H oxidases, mitochondria, or nitric oxide-producing enzymes are not only cytotoxic but also compose a signaling network in the redox system. The formation, actions, key molecular interactions, and physiological and pathological relevance of redox signals in ECs remain unclear. We review the identities, sources, and biological actions of oxidants and reductants produced during EC function or dysfunction. Further, we discuss how ECs shape key redox sensors and examine the biological functions, transcriptional responses, and post-translational modifications evoked by the redox system in ECs. We summarize recent findings regarding the mechanisms by which redox signals regulate the fate of ECs and address the outcome of altered EC fate in health and disease. Future studies will examine if the redox biology of ECs can be targeted in pathophysiological conditions. PMID:24633153

  8. 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

  9. Planar cell polarity protein Celsr1 regulates endothelial adherens junctions and directed cell rearrangements during valve morphogenesis.

    PubMed

    Tatin, Florence; Taddei, Andrea; Weston, Anne; Fuchs, Elaine; Devenport, Danelle; Tissir, Fadel; Makinen, Taija

    2013-07-15

    Planar cell polarity (PCP) signaling controls tissue morphogenesis by coordinating collective cell behaviors. We show a critical role for the core PCP proteins Celsr1 and Vangl2 in the complex morphogenetic process of intraluminal valve formation in lymphatic vessels. We found that valve-forming endothelial cells undergo elongation, reorientation, and collective migration into the vessel lumen as they initiate valve leaflet formation. During this process, Celsr1 and Vangl2 are recruited from endothelial filopodia to discrete membrane domains at cell-cell contacts. Celsr1- or Vangl2-deficient mice show valve aplasia due to failure of endothelial cells to undergo rearrangements and adopt perpendicular orientation at valve initiation sites. Mechanistically, we show that Celsr1 regulates dynamic cell movements by inhibiting stabilization of VE-cadherin and maturation of adherens junctions. These findings reveal a role for PCP signaling in regulating adherens junctions and directed cell rearrangements during vascular development. PMID:23792146

  10. Sedentary Behavior as a Daily Process Regulated by Habits and Intentions

    PubMed Central

    Conroy, David E.; Maher, Jaclyn P.; Elavsky, Steriani; Hyde, Amanda L.; Doerksen, Shawna E.

    2014-01-01

    Objective Sedentary behavior is a health risk but little is known about the motivational processes that regulate daily sedentary behavior. This study was designed to test a dual-process model of daily sedentary behavior, with an emphasis on the role of intentions and habits in regulating daily sedentary behavior. Methods College students (N = 128) self-reported on their habit strength for sitting and completed a 14-day ecological momentary assessment study that combined daily diaries for reporting motivation and behavior with ambulatory monitoring of sedentary behavior using accelerometers. Results Less than half of the variance in daily sedentary behavior was attributable to between-person differences. People with stronger sedentary habits reported more sedentary behavior on average. People whose intentions for limiting sedentary behavior were stronger, on average, exhibited less self-reported sedentary behavior (and marginally less monitored sedentary behavior). Daily deviations in those intentions were negatively associated with changes in daily sedentary behavior (i.e., stronger than usual intentions to limit sedentary behavior were associated with reduced sedentary behavior). Sedentary behavior also varied within-people as a function of concurrent physical activity, the day of week, and the day in the sequence of the monitoring period. Conclusions Sedentary behavior was regulated by both automatic and controlled motivational processes. Interventions should target both of these motivational processes to facilitate and maintain behavior change. Links between sedentary behavior and daily deviations in intentions also indicate the need for ongoing efforts to support controlled motivational processes on a daily basis. PMID:23477579

  11. Mechanisms regulating dendritic cell specification and development

    PubMed Central

    Watowich, Stephanie S.; Liu, Yong-Jun

    2010-01-01

    Summary Understanding the diversification of dendritic cell (DC) lineages is one of the last frontiers in mapping the developmental hierarchy of the hematopoietic system. DCs are a vital link between the innate and adaptive immune responses, thus elucidating their developmental pathways is crucial for insight into the generation of natural immunity and for learning how to regulate DCs in clinical settings. DCs arise from hematopoietic stem cells through specialized progenitor subsets under the direction of FMS-like tyrosine kinase 3 ligand (Flt3L) and Flt3L receptor (Flt3) signaling. Recent studies have revealed important contributions from granulocyte-macrophage colony-stimulating factor (GM-CSF) and type I interferons (IFNs) in vivo. Furthermore, DC development is guided by lineage-restricted transcription factors such as IRF8, E2-2, and Batf3. A critical question centers on how cytokines and lineage-restricted transcription factors operate molecularly to direct DC diversification. Here we review recent findings that provide new insight into the DC developmental process. PMID:20969586

  12. Epigenetic regulation in adult stem cells and cancers

    PubMed Central

    2013-01-01

    Adult stem cells maintain tissue homeostasis by their ability to both self-renew and differentiate to distinct cell types. Multiple signaling pathways have been shown to play essential roles as extrinsic cues in maintaining adult stem cell identity and activity. Recent studies also show dynamic regulation by epigenetic mechanisms as intrinsic factors in multiple adult stem cell lineages. Emerging evidence demonstrates intimate crosstalk between these two mechanisms. Misregulation of adult stem cell activity could lead to tumorigenesis, and it has been proposed that cancer stem cells may be responsible for tumor growth and metastasis. However, it is unclear whether cancer stem cells share commonalities with normal adult stem cells. In this review, we will focus on recent discoveries of epigenetic regulation in multiple adult stem cell lineages. We will also discuss how epigenetic mechanisms regulate cancer stem cell activity and probe the common and different features between cancer stem cells and normal adult stem cells. PMID:24172544

  13. Inhibition of regulated cell death by cell-penetrating peptides.

    PubMed

    Krautwald, Stefan; Dewitz, Christin; Fändrich, Fred; Kunzendorf, Ulrich

    2016-06-01

    Development of the means to efficiently and continuously renew missing and non-functional proteins in diseased cells remains a major goal in modern molecular medicine. While gene therapy has the potential to achieve this, substantial obstacles must be overcome before clinical application can be considered. A promising alternative approach is the direct delivery of non-permeant active biomolecules, such as oligonucleotides, peptides and proteins, to the affected cells with the purpose of ameliorating an advanced disease process. In addition to receptor-mediated endocytosis, cell-penetrating peptides are widely used as vectors for rapid translocation of conjugated molecules across cell membranes into intracellular compartments and the delivery of these therapeutic molecules is generally referred to as novel prospective protein therapy. As a broad coverage of the enormous amount of published data in this field is unrewarding, this review will provide a brief, focused overview of the technology and a summary of recent studies of the most commonly used protein transduction domains and their potential as therapeutic agents for the treatment of cellular damage and the prevention of regulated cell death. PMID:27048815

  14. Regulating the regulator: Numb acts upstream of p53 to control mammary stem and progenitor cell

    PubMed Central

    Faraldo, Marisa M.

    2015-01-01

    In this issue, Tosoni et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201505037) report that cell fate determinant and tumor suppressor Numb imposes asymmetric cell divisions in mammary stem cells by regulating p53. Numb thereby restricts mammary stem cell expansion and controls the proliferation and lineage-specific characteristics of their progeny. PMID:26598611

  15. Defect behavior of polycrystalline solar cell silicon

    SciTech Connect

    Schroder, D.K.; Park, S.H.; Hwang, I.G.; Mohr, J.B.; Hanly, M.P.

    1993-05-01

    The major objective of this study, conducted from October 1988 to September 1991, was to gain an understanding of the behavior of impurities in polycrystalline silicon and the influence of these impurities on solar cell efficiency. The authors studied edge-defined film-fed growth (EFG) and cast poly-Si materials and solar cells. With EFG Si they concentrated on chromium-doped materials and cells to determine the role of Cr on solar cell performance. Cast poly-Si samples were not deliberately contaminated. Samples were characterized by cell efficiency, current-voltage, deep-level transient spectroscopy (DLTS), surface photovoltage (SPV), open-circuit voltage decay, secondary ion mass spectrometry, and Fourier transform infrared spectroscopy measurements. They find that Cr forms Cr-B pairs with boron at room temperature and these pairs dissociate into Cr{sub i}{sup +} and B{sup {minus}} during anneals at 210{degrees}C for 10 min. Following the anneal, Cr-B pairs reform at room temperature with a time constant of 230 h. Chromium forms CrSi{sub 2} precipitates in heavily contaminated regions and they find evidence of CrSi{sub 2} gettering, but a lack of chromium segregation or precipitation to grain boundaries and dislocations. Cr-B pairs have well defined DLTS peaks. However, DLTS spectra of other defects are not well defined, giving broad peaks indicative of defects with a range of energy levels in the band gap. In some high-stress, low-efficiency cast poly-Si they detect SiC precipitates, but not in low-stress, high-efficiency samples. SPV measurements result in nonlinear SPV curves in some materials that are likely due to varying optical absorption coefficients due to locally varying stress in the material.

  16. Mesenchymal Stem Cells and Myeloid Derived Suppressor Cells: Common Traits in Immune Regulation

    PubMed Central

    Nikolaev, Alexander

    2016-01-01

    To protect host against immune-mediated damage, immune responses are tightly regulated. The regulation of immune responses is mediated by various populations of mature immune cells, such as T regulatory cells and B regulatory cells, but also by immature cells of different origins. In this review, we discuss regulatory properties and mechanisms whereby two distinct populations of immature cells, mesenchymal stem cells, and myeloid derived suppressor cells mediate immune regulation, focusing on their similarities, discrepancies, and potential clinical applications. PMID:27529074

  17. Density enhanced phosphatase-1 down-regulates urokinase receptor surface expression in confluent endothelial cells

    PubMed Central

    Brunner, Patrick M.; Heier, Patricia C.; Mihaly-Bison, Judit; Priglinger, Ute; Binder, Bernd R.

    2011-01-01

    VEGF165, the major angiogenic growth factor, is known to activate various steps in proangiogenic endothelial cell behavior, such as endothelial cell migration and invasion, or endothelial cell survival. Thereby, the urokinase-type plasminogen activator (uPA) system has been shown to play an essential role not only by its proteolytic capacities, but also by induction of intracellular signal transduction. Therefore, expression of its cell surface receptor uPAR is thought to be an essential regulatory mechanism in angiogenesis. We found that uPAR expression on the surface of confluent endothelial cells was down-regulated compared with subconfluent proliferating endothelial cells. Regulation of uPAR expression was most probably affected by extracellular signal-regulated kinase 1/2 (ERK1/2) activation, a downstream signaling event of the VEGF/VEGF-receptor system. Consistently, the receptor-like protein tyrosine phosphatase DEP-1 (density enhanced phosphatase-1/CD148), which is abundantly expressed in confluent endothelial cells, inhibited the VEGF-dependent activation of ERK1/2, leading to down-regulation of uPAR expression. Overexpression of active ERK1 rescued the DEP-1 effect on uPAR. That DEP-1 plays a biologic role in angiogenic endothelial cell behavior was demonstrated in endothelial cell migration, proliferation, and capillary-like tube formation assays in vitro. PMID:21304107

  18. Expression of cell cycle and apoptosis regulators in thymus and thymic epithelial tumors.

    PubMed

    Papoudou-Bai, Alexandra; Barbouti, Alexandra; Galani, Vassiliki; Stefanaki, Kalliopi; Rontogianni, Dimitra; Kanavaros, Panagiotis

    2016-05-01

    The human thymus supports the production of self-tolerant T cells with competent and regulatory functions. Various cellular components of the thymic microenvironment such as thymic epithelial cells (TEC) and dendritic cells play essential roles in thymic T cell differentiation. The multiple cellular events occurring during thymic T cell and TEC differentiation involve proteins regulating cell cycle and apoptosis. Dysregulation of the cell cycle and apoptosis networks is involved in the pathogenesis of thymic epithelial tumors (TET) which are divided into two broad categories, thymomas and thymic carcinomas. The present review focuses on the usefulness of the analysis of the expression patterns of major cell cycle and apoptosis regulators in order to gain insight in the histophysiology of thymus and the histopathology, the clinical behavior and the biology of TET. PMID:25794494

  19. Repeated treatment with oxytocin promotes hippocampal cell proliferation, dendritic maturation and affects socio-emotional behavior.

    PubMed

    Sánchez-Vidaña, Dalinda Isabel; Chan, Ngai-Man Jackie; Chan, Alan H L; Hui, Katy K Y; Lee, Sylvia; Chan, Hoi-Yi; Law, Yuen Shan; Sze, Mei Yi; Tsui, Wai-Ching Sarah; Fung, Timothy K H; Lau, Benson Wui-Man; Lai, Cynthia Y Y

    2016-10-01

    Rewarding social behaviors including positive social interactions and sexual behaviors are shown to regulate adult neurogenesis, but the underlying biological mechanisms remain elusive. Oxytocin, a neurohypophysial hormone secreted after exposure to social interaction or sexual behaviors, has a profound role in the formation of social bonding and regulation of emotional distress. While the acute effect of oxytocin was usually studied, relatively scarce evidence showed the behavioral consequence of repeated oxytocin treatment. The purpose of the current study was to investigate the effect of repeated oxytocin treatment on hippocampal cell proliferation, dendritic maturation of new born neurons and social/emotional behaviors. Adult male Sprague-Dawley rats received treatment with either vehicle or oxytocin (1mg/kg) daily for two weeks. Behavioral tests revealed that oxytocin increased social behaviors and reduced the anxiety- and depression-like behaviors. Cell proliferation, differentiation and the dendritic complexity of new born neurons in the hippocampus were promoted by oxytocin treatment. Depression- and anxiety-like behaviors were induced by repeated treatment of corticosterone (40mg/kg) for two weeks while oxytocin treatment reversed the behavioral disturbances. Suppression of cell proliferation caused by corticosterone was reverted by oxytocin treatment in which cell proliferation, cell differentiation, and dendritic complexity increased. The present findings reveal that oxytocin not only enhances cell proliferation, but also promotes the development of the new neurons which is associated with the induction of positive emotional and social behaviors. The results also suggest that oxytocin may be a potential therapeutic agent for treatment of emotional and social dysfunction. PMID:27418343

  20. Identified nerve cells and insect behavior.

    PubMed

    Comer, C M; Robertson, R M

    2001-03-01

    Studies of insect identified neurons over the past 25 years have provided some of the very best data on sensorimotor integration; tracing information flow from sensory to motor networks. General principles have emerged that have increased the sophistication with which we now understand both sensory processing and motor control. Two overarching themes have emerged from studies of identified sensory interneurons. First, within a species, there are profound differences in neuronal organization associated with both the sex and the social experience of the individual. Second, single neurons exhibit some surprisingly rich examples of computational sophistication in terms of (a) temporal dynamics (coding superimposed upon circadian and shorter-term rhythms), and also (b) what Kenneth Roeder called "neural parsimony": that optimal information can be encoded, and complex acts of sensorimotor coordination can be mediated, by small ensembles of cells. Insect motor systems have proven to be relatively complex, and so studies of their organization typically have not yielded completely defined circuits as are known from some other invertebrates. However, several important findings have emerged. Analysis of neuronal oscillators for rhythmic behavior have delineated a profound influence of sensory feedback on interneuronal circuits: they are not only modulated by feedback, but may be substantially reconfigured. Additionally, insect motor circuits provide potent examples of neuronal restructuring during an organism's lifetime, as well as insights on how circuits have been modified across evolutionary time. Several areas where future advances seem likely to occur include: molecular genetic analyses, neuroecological syntheses, and neuroinformatics--the use of digital resources to organize databases with information on identified nerve cells and behavior. PMID:11163685

  1. SUMOylation-mediated regulation of cell cycle progression and cancer

    PubMed Central

    Eifler, Karolin; Vertegaal, Alfred C.O.

    2016-01-01

    SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. PMID:26601932

  2. The Influence of Demographic Risk Factors on Children's Behavioral Regulation in Prekindergarten and Kindergarten

    ERIC Educational Resources Information Center

    Wanless, Shannon B.; McClelland, Megan M.; Tominey, Shauna L.; Acock, Alan C.

    2011-01-01

    Research Findings: The present study examined the role of demographic risk factors in the development of children's behavioral regulation. We investigated whether being from a low-income family and being an English language learner (ELL) predicted behavioral regulation between prekindergarten and kindergarten. Results indicated that children from…

  3. Links between Preschoolers' Behavioral Regulation and School Readiness Skills: The Role of Child Gender

    ERIC Educational Resources Information Center

    Son, Seung-Hee; Lee, Kangyi; Sung, Miyoung

    2013-01-01

    Research Findings: We examined relations among preschoolers' behavioral regulation, gender, and school readiness outcomes in preacademic and classroom skills using a sample of South Korean preschoolers aged 3-5 ("N" = 229). Behavioral regulation was assessed using a direct measure, the Head-Toes-Knees-Shoulders task, which requires children to…

  4. Predictors of Behavioral Regulation in Kindergarten: Household Chaos, Parenting, and Early Executive Functions

    ERIC Educational Resources Information Center

    Vernon-Feagans, Lynne; Garrett-Peters, Patricia; Willoughby, Michael

    2016-01-01

    Behavioral regulation is an important school readiness skill that has been linked to early executive function (EF) and later success in learning and school achievement. Although poverty and related risks, as well as negative parenting, have been associated with poorer EF and behavioral regulation, chaotic home environments may also play a role in…

  5. Behavior Regulation and Early Math and Vocabulary Knowledge in German Preschool Children

    ERIC Educational Resources Information Center

    von Suchodoletz, Antje; Gunzenhauser, Catherine

    2013-01-01

    Research Findings: Behavior regulation, including paying attention, remembering instructions, and controlling action, contributes to children's successful adaptation to and functioning in preschool and school settings. This study examined the development of behavior regulation in early childhood and its potential contribution to individual…

  6. Links between Behavioral Regulation and Preschoolers' Literacy, Vocabulary, and Math Skills

    ERIC Educational Resources Information Center

    McClelland, Megan M.; Cameron, Claire E.; Connor, Carol McDonald; Farris, Carrie L.; Jewkes, Abigail M.; Morrison, Frederick J.

    2007-01-01

    This study investigated predictive relations between preschoolers' (N=310) behavioral regulation and emergent literacy, vocabulary, and math skills. Behavioral regulation was assessed using a direct measure called the Head-to-Toes Task, which taps inhibitory control, attention, and working memory, and requires children to perform the opposite…

  7. A Structured Observation of Behavioral Self-Regulation and Its Contribution to Kindergarten Outcomes

    ERIC Educational Resources Information Center

    Ponitz, Claire Cameron; McClelland, Megan M.; Matthews, J. S.; Morrison, Frederick J.

    2009-01-01

    The authors examined a new assessment of behavioral regulation and contributions to achievement and teacher-rated classroom functioning in a sample (N = 343) of kindergarteners from 2 geographical sites in the United States. Behavioral regulation was measured with the Head-Toes-Knees-Shoulders (HTKS) task, a structured observation requiring…

  8. Predictors of behavioral regulation in kindergarten: Household chaos, parenting, and early executive functions.

    PubMed

    Vernon-Feagans, Lynne; Willoughby, Michael; Garrett-Peters, Patricia

    2016-03-01

    Behavioral regulation is an important school readiness skill that has been linked to early executive function (EF) and later success in learning and school achievement. Although poverty and related risks, as well as negative parenting, have been associated with poorer EF and behavioral regulation, chaotic home environments may also play a role in understanding both early EF and later behavioral regulation at school age. To explore these relationships, a unique longitudinal and representative sample was used of 1,292 children born to mothers who lived in low-wealth rural America who were followed from birth into early elementary school. This study examined whether household chaos, which was measured across the first 3 years of life, predicted behavioral regulation in kindergarten above and beyond poverty-related variables. In addition, this study tested whether parent responsivity and acceptance behaviors, measured during the first 3 years of life, as well as EF skills, which were measured when children were 3 to 5 years of age, mediated the relationship between early household chaos and kindergarten behavioral regulation. Results suggested that household chaos disorganization indirectly predicted kindergarten behavioral regulation through intermediate impacts on parenting behaviors and children's early EF skills. These findings suggest the importance of early household chaos disorganization, the parenting environment, and early EF skills in understanding behavioral regulation above and beyond poverty-related risks. (PsycINFO Database Record PMID:26751500

  9. Predictors of Behavioral Regulation in Kindergarten: Household Chaos, Parenting and Early Executive Functions

    PubMed Central

    Vernon-Feagans, Lynne; Willoughby, Michael; Garrett-Peters, Patricia

    2015-01-01

    Behavioral regulation is an important school readiness skill that has been linked to early executive function (EF) and later success in learning and school achievement. Although poverty and related risks as well as negative parenting have been associated with poorer EF and behavioral regulation, chaotic home environments may also play a role in understanding both early EF and later behavioral regulation at school age. To explore these relationships, a unique longitudinal and representative sample was used of 1292 children born to mothers who lived in low wealth rural America who were followed from birth into early elementary school. This study examined whether household chaos, which was measured across the first three years of life, predicted behavioral regulation in kindergarten above and beyond poverty related variables. In addition, this study tested whether parent responsivity and acceptance behaviors, measured during the first three years of life, as well as EF skills, which were measured when children were three to five years of age, mediated the relationship between early household chaos and kindergarten behavioral regulation. Results suggested that household chaos disorganization indirectly predicted kindergarten behavioral regulation through intermediate impacts on parenting behaviors and children's early EF skills. These findings suggest the importance of early household chaos disorganization, the parenting environment and early EF skills in understanding behavioral regulation, above and beyond poverty related risks. PMID:26751500

  10. Social Skills and Problem Behaviors as Mediators of the Relationship between Behavioral Self-Regulation and Academic Achievement

    ERIC Educational Resources Information Center

    Montroy, Janelle J.; Bowles, Ryan P.; Skibbe, Lori E.; Foster, Tricia D.

    2014-01-01

    Early behavioral self-regulation is an important predictor of the skills children need to be successful in school. However, little is known about the mechanism(s) through which self-regulation affects academic achievement. The current study investigates the possibility that two aspects of children's social func- tioning, social skills and problem…

  11. Regulation of Water in Plant Cells

    ERIC Educational Resources Information Center

    Kowles, Richard V.

    2010-01-01

    Cell water relationships are important topics to be included in cell biology courses. Differences exist in the control of water relationships in plant cells relative to control in animal cells. One important reason for these differences is that turgor pressure is a consideration in plant cells. Diffusion and osmosis are the underlying factors…

  12. Links between behavioral regulation and preschoolers' literacy, vocabulary, and math skills.

    PubMed

    McClelland, Megan M; Cameron, Claire E; Connor, Carol McDonald; Farris, Carrie L; Jewkes, Abigail M; Morrison, Frederick J

    2007-07-01

    This study investigated predictive relations between preschoolers' (N=310) behavioral regulation and emergent literacy, vocabulary, and math skills. Behavioral regulation was assessed using a direct measure called the Head-to-Toes Task, which taps inhibitory control, attention, and working memory, and requires children to perform the opposite of what is instructed verbally. Hierarchical linear modeling (HLM) was utilized because children were nested in 54 classrooms at 2 geographical sites. Results revealed that behavioral regulation significantly and positively predicted fall and spring emergent literacy, vocabulary, and math skills on the Woodcock Johnson Tests of Achievement (all ps<.05). Moreover, growth in behavioral regulation predicted growth in emergent literacy, vocabulary, and math skills over the prekindergarten year (all ps<.05), after controlling for site, child gender, and other background variables. Discussion focuses on the role of behavioral regulation in early academic achievement and preparedness for kindergarten. PMID:17605527

  13. Adolescent self-regulation as resilience: resistance to antisocial behavior within the deviant peer context.

    PubMed

    Gardner, Theodore W; Dishion, Thomas J; Connell, Arin M

    2008-02-01

    This study tests the hypothesis that self-regulation serves as a resiliency factor in buffering youth from negative influences of peer deviance in middle to late adolescence. The interactive effects between peer deviance and self-regulation were investigated on change in antisocial behavior from age 17 to 19 years in an ethnically diverse sample of adolescents. A multi-agent construct was created using adolescent, parent, and teacher reports of self-regulation and peer deviance. Results indicated that self-regulation shows convergent validity and covaries as expected with developmental patterns of adolescent antisocial behavior. Self-regulation moderated the association of peer deviance with later self-reported adolescent antisocial behavior after controlling for prior levels of antisocial behavior. The implications of these findings for models for the development of antisocial behaviors and for intervention science are discussed. PMID:17899361

  14. Nanomaterials for regulating cancer and stem cell fate

    NASA Astrophysics Data System (ADS)

    Shah, Birju P.

    The realm of nanomedicine has grown exponentially over the past few decades. However, there are several obstacles that need to be overcome, prior to the wide-spread clinical applications of these nanoparticles, such as (i) developing well-defined nanoparticles of varying size, morphology and composition to enable various clinical applications; (ii) overcome various physiological barriers encountered in order to deliver the therapeutics to the target location; and (iii) real-time monitoring of the nano-therapeutics within the human body for tracking their uptake, localization and effect. Hence, this dissertation focuses on developing multimodal nanotechnology-based approaches to overcome the above-mentioned challenges and thus enable regulation of cancer and stem cell fate. The initial part of this dissertation describes the development of multimodal magnetic core-shell nanoparticles (MCNPs), comprised of a highly magnetic core surrounded by a thin gold shell, thus combining magnetic and plasmonic properties. These nanoparticles were utilized for mainly two applications: (i) Magnetically-facilitated delivery of siRNA and plasmid DNA for effective stem cell differentiation and imaging and (ii) Combined hyperthermia and targeted delivery of a mitochondria-targeting peptide for enhancing apoptosis in cancer cells. The following part of this dissertation presents the generation of a multi-functional cyclodextrin-conjugated polymeric delivery platform (known as DexAMs), for co-delivery of anticancer drugs and siRNAs in a target-specific manner to brain tumor cells. This combined delivery of chemotherapeutics and siRNA resulted in a synergistic effect on the apoptosis of brain tumor cells, as compared to the individual treatments. The final part of this thesis presents development of stimuli-responsive uorescence resonance energy transfer (FRET)-based mesoporous silica nanoparticles for real-time monitoring of drug release in cells. The stimuli-responsive behavior of

  15. Role of autophagy in the regulation of epithelial cell junctions.

    PubMed

    Nighot, Prashant; Ma, Thomas

    2016-01-01

    Autophagy is a cell survival mechanism by which bulk cytoplasmic material, including soluble macromolecules and organelles, is targeted for lysosomal degradation. The role of autophagy in diverse cellular processes such as metabolic stress, neurodegeneration, cancer, aging, immunity, and inflammatory diseases is being increasingly recognized. Epithelial cell junctions play an integral role in the cell homeostasis via physical binding, regulating paracellular pathways, integrating extracellular cues into intracellular signaling, and cell-cell communication. Recent data indicates that cell junction composition is very dynamic. The junctional protein complexes are actively regulated in response to various intra- and extra-cellular clues by intracellular trafficking and degradation pathways. This review discusses the recent and emerging information on how autophagy regulates various epithelial cell junctions. The knowledge of autophagy regulation of epithelial junctions will provide further rationale for targeting autophagy in a wide variety of human disease conditions. PMID:27583189

  16. Cytosolic pH: A conserved regulator of cell growth?

    PubMed Central

    Dechant, Reinhard; Peter, Matthias

    2014-01-01

    Although target of rapamycin (TOR) kinase and Ras are central regulators of cell growth in yeast and mammals, the molecular mechanisms underlying their regulation by nutrients are still poorly understood. Interestingly, recent studies identified cytosolic pH as a critical regulatory signal for both pathways, which might have widespread implications for tumor cell biology PMID:27308377

  17. CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects.

    PubMed

    Bilbao, Ainhoa; Rieker, Claus; Cannella, Nazzareno; Parlato, Rosanna; Golda, Slawomir; Piechota, Marcin; Korostynski, Michal; Engblom, David; Przewlocki, Ryszard; Schütz, Günther; Spanagel, Rainer; Parkitna, Jan R

    2014-01-01

    It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naïve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB. PMID:24966820

  18. Maladaptive Behavior in Autism Spectrum Disorder: The Role of Emotion Experience and Emotion Regulation

    ERIC Educational Resources Information Center

    Samson, Andrea C.; Hardan, Antonio Y.; Lee, Ihno A.; Phillips, Jennifer M.; Gross, James J.

    2015-01-01

    Maladaptive behavior is common in Autism Spectrum Disorder (ASD). However, the factors that give rise to maladaptive behavior in this context are not well understood. The present study examined the role of emotion experience and emotion regulation in maladaptive behavior in individuals with ASD and typically developing (TD) participants.…

  19. Self-Regulation, Self-Efficacy and Health Behavior Change in Older Adults.

    ERIC Educational Resources Information Center

    Purdie, Nola; McCrindle, Andrea

    2002-01-01

    Presents an overview of self-regulation models: theory of planned behavior, protection motivation theory, health belief model, action control theory, transtheoretical model of behavior change, health action process, and precaution adoption process. Applies models to health behavior change in older adults with cardiovascular disease or diabetes.…

  20. Diverse mechanisms regulate stem cell self-renewal.

    PubMed

    Molofsky, Anna V; Pardal, Ricardo; Morrison, Sean J

    2004-12-01

    To what extent are the pathways that regulate self-renewal conserved between stem cells at different stages of development and in different tissues? Some pathways play a strikingly conserved role in regulating the self-renewal of diverse stem cells, whereas other pathways are specific to stem cells in certain tissues or at certain stages of development. Recent studies have highlighted differences between the self-renewal of embryonic, fetal and adult stem cells. By understanding these similarities and differences we may come to a molecular understanding of how stem cells replicate themselves and why aspects of this process differ between stem cells. PMID:15530784

  1. Mechanical behavior of open cell aluminum foams

    NASA Astrophysics Data System (ADS)

    Zhou, Jikou

    Open cell metallic foams are relatively new materials with increasingly applications due to their attractive combinations of physical, chemical, mechanical and optical properties. Since plastic deformation in the struts involves dislocation motion, dislocation slip bands are used to track the initiation/propagation and locations of plastic deformation in individual struts. We find that the onset of plastic deformation in struts is far beyond the observable strut/cell shape changes, and both plastic bending and buckling are strut deformation modes. To measure the strut mechanical properties, an existing micro-scale tensile tester was updated to test the individual struts extracted from foams using electro-discharged machining. The micro-tensile testing results show that the foam struts are typically more ductile and one time stronger than the corresponding fully dense alloy. To integrate the measured strut and foam properties, a four-strut structure unit is identified as a structural representative of the open cell foam structure. Based on the observed strut deformation modes, mechanics analysis is performed on the structure unit to predict the foam stiffness and strength. The predictions are in good agreement with the measured data, suggesting the significance of the studies on the foam strut properties and deformation. This model also predicts the bounds of the foam strengths. Under cyclic compression, foams fail due to damage accumulation in individual struts, in which surface cracks initiate and grow. At low stress levels, surface cracks are formed in multiple struts that are distributed across the foam block. This results in an abrupt strain jump due to the crush of foam block, upon foam failure. To meet applications requirements, open cell aluminum foams are usually annealed or strengthened. The studies are carried out in the foams in the as-fabricated (F), annealed (O) and T6-strengthed (T6) conditions. We find that annealing and T6 strengthening

  2. Uses of self-regulation to facilitate and restrain addictive behavior.

    PubMed

    Baumeister, Roy F; Vonasch, Andrew J

    2015-05-01

    We apply self-regulation theory to understand addictive behavior. Self-regulation and volition depend on a limited resource, and when that resource has been depleted, self-regulation becomes prone to fail. Moving beyond traditional models that have emphasized the relevance of self-regulation to quitting addiction, we propose that self-regulation is used both to facilitate and resist addictive behaviors. Self-regulation is often needed to overcome initial aversion to drugs and alcohol, as well as to maintain addictive usage patterns despite situational obstacles (e.g., illegality, erratic availability, family disapproval). Sustaining addiction also requires preventing use from spiraling out of control and interfering with other aspects of life. More generally, the automaticity and irresistibility of addictive responses may have been overrated, as indicated by how addictive behaviors respond rationally to incentives and other concerns. Self-regulation does facilitate quitting, and relapse may be especially likely when self-regulatory capabilities are depleted. PMID:25267213

  3. Microphthalmia transcription factor regulates pancreatic β-cell function.

    PubMed

    Mazur, Magdalena A; Winkler, Marcus; Ganic, Elvira; Colberg, Jesper K; Johansson, Jenny K; Bennet, Hedvig; Fex, Malin; Nuber, Ulrike A; Artner, Isabella

    2013-08-01

    Precise regulation of β-cell function is crucial for maintaining blood glucose homeostasis. Pax6 is an essential regulator of β-cell-specific factors like insulin and Glut2. Studies in the developing eye suggest that Pax6 interacts with Mitf to regulate pigment cell differentiation. Here, we show that Mitf, like Pax6, is expressed in all pancreatic endocrine cells during mouse postnatal development and in the adult islet. A Mitf loss-of-function mutation results in improved glucose tolerance and enhanced insulin secretion but no increase in β-cell mass in adult mice. Mutant β-cells secrete more insulin in response to glucose than wild-type cells, suggesting that Mitf is involved in regulating β-cell function. In fact, the transcription of genes critical for maintaining glucose homeostasis (insulin and Glut2) and β-cell formation and function (Pax4 and Pax6) is significantly upregulated in Mitf mutant islets. The increased Pax6 expression may cause the improved β-cell function observed in Mitf mutant animals, as it activates insulin and Glut2 transcription. Chromatin immunoprecipitation analysis shows that Mitf binds to Pax4 and Pax6 regulatory regions, suggesting that Mitf represses their transcription in wild-type β-cells. We demonstrate that Mitf directly regulates Pax6 transcription and controls β-cell function. PMID:23610061

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

    PubMed Central

    Jiang, Hongyuan; Sun, Sean X.

    2013-01-01

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

  5. Adhesion in the stem cell niche: biological roles and regulation

    PubMed Central

    Chen, Shuyi; Lewallen, Michelle; Xie, Ting

    2013-01-01

    Stem cell self-renewal is tightly controlled by the concerted action of stem cell-intrinsic factors and signals within the niche. Niche signals often function within a short range, allowing cells in the niche to self-renew while their daughters outside the niche differentiate. Thus, in order for stem cells to continuously self-renew, they are often anchored in the niche via adhesion molecules. In addition to niche anchoring, however, recent studies have revealed other important roles for adhesion molecules in the regulation of stem cell function, and it is clear that stem cell-niche adhesion is crucial for stem cell self-renewal and is dynamically regulated. Here, we highlight recent progress in understanding adhesion between stem cells and their niche and how this adhesion is regulated. PMID:23250203

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

    PubMed

    Jiang, Hongyuan; Sun, Sean X

    2013-08-01

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

  7. Mevalonate Pathway Regulates Cell Size Homeostasis and Proteostasis through Autophagy

    PubMed Central

    Miettinen, Teemu P.; Björklund, Mikael

    2015-01-01

    Summary Balance between cell growth and proliferation determines cell size homeostasis, but little is known about how metabolic pathways are involved in the maintenance of this balance. Here, we perform a screen with a library of clinically used drug molecules for their effects on cell size. We find that statins, inhibitors of the mevalonate pathway, reduce cell proliferation and increase cell size and cellular protein density in various cell types, including primary human cells. Mevalonate pathway effects on cell size and protein density are mediated through geranylgeranylation of the small GTPase RAB11, which is required for basal autophagic flux. Our results identify the mevalonate pathway as a metabolic regulator of autophagy and expose a paradox in the regulation of cell size and proteostasis, where inhibition of an anabolic pathway can cause an increase in cell size and cellular protein density. PMID:26686643

  8. Emergence of Critical Behavior in β-Cell Network

    NASA Astrophysics Data System (ADS)

    Westacott, Matthew; Hraha, Thomas; McClatchey, Mason; Pozzoli, Marina; Benninger, Richard

    2014-03-01

    The β-cell is a cell type located in the Islet of Langerhans, a micro-organ of the pancreas which maintains glucose homeostasis through secretion of insulin. An electrophysiological process governing insulin release occurs through initial uptake of blood glucose and generation of ATP which inhibits the ATP sensitive potassium channel (K-ATP) causing membrane depolarization (activation). Neighboring β-cells are electrically coupled through gap junctions which allow passage of cationic molecules, creating a network of coupled electrical oscillators. Cells exhibiting hyperpolzarized (inactive) membrane potential affect behavior of neighboring cells by electrically suppressing their depolarization. Here we observe critical behavior between global active-inactive states by increasing the number of inactive elements with the K-ATP inhibitor Diazoxide and a tunable ATP insensitive transgenic mouse model. We show this behavior occurs due to from cell-cell coupling as mice lacking β-cell gap junctions show no critical behavior. Also, a computational β-cell model was expanded to construct a coupled β-cell network and we show this model replicates the critical behavior seen in-vitro.While electrical activity of single β-cells is well studied these data highlight a newly defined characteristic of their emergent multicellular behavior within the Islet of Langerhans and may elucidate pathophysiology of Diabetes due to mutations in the K-ATP channel.

  9. Microphthalmia Transcription Factor Regulates Pancreatic β-Cell Function

    PubMed Central

    Mazur, Magdalena A.; Winkler, Marcus; Ganić, Elvira; Colberg, Jesper K.; Johansson, Jenny K.; Bennet, Hedvig; Fex, Malin; Nuber, Ulrike A.; Artner, Isabella

    2013-01-01

    Precise regulation of β-cell function is crucial for maintaining blood glucose homeostasis. Pax6 is an essential regulator of β-cell–specific factors like insulin and Glut2. Studies in the developing eye suggest that Pax6 interacts with Mitf to regulate pigment cell differentiation. Here, we show that Mitf, like Pax6, is expressed in all pancreatic endocrine cells during mouse postnatal development and in the adult islet. A Mitf loss-of-function mutation results in improved glucose tolerance and enhanced insulin secretion but no increase in β-cell mass in adult mice. Mutant β-cells secrete more insulin in response to glucose than wild-type cells, suggesting that Mitf is involved in regulating β-cell function. In fact, the transcription of genes critical for maintaining glucose homeostasis (insulin and Glut2) and β-cell formation and function (Pax4 and Pax6) is significantly upregulated in Mitf mutant islets. The increased Pax6 expression may cause the improved β-cell function observed in Mitf mutant animals, as it activates insulin and Glut2 transcription. Chromatin immunoprecipitation analysis shows that Mitf binds to Pax4 and Pax6 regulatory regions, suggesting that Mitf represses their transcription in wild-type β-cells. We demonstrate that Mitf directly regulates Pax6 transcription and controls β-cell function. PMID:23610061

  10. MicroRNA-7a regulates pancreatic β cell function

    PubMed Central

    Latreille, Mathieu; Hausser, Jean; Stützer, Ina; Zhang, Quan; Hastoy, Benoit; Gargani, Sofia; Kerr-Conte, Julie; Pattou, Francois; Zavolan, Mihaela; Esguerra, Jonathan L.S.; Eliasson, Lena; Rülicke, Thomas; Rorsman, Patrik; Stoffel, Markus

    2014-01-01

    Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic β cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of β cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in β cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates β cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in β cells developed diabetes due to impaired insulin secretion and β cell dedifferentiation. Interestingly, perturbation of miR-7a expression in β cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine β cell mass. Furthermore, we found that miR-7a levels are decreased in obese/diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated β cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic β cells and support a role for miR-7 in the adaptation of pancreatic β cell function in obesity and type 2 diabetes. PMID:24789908

  11. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation.

    PubMed

    Tape, Christopher J; Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M; Worboys, Jonathan D; Leong, Hui Sun; Norrie, Ida C; Miller, Crispin J; Poulogiannis, George; Lauffenburger, Douglas A; Jørgensen, Claus

    2016-05-01

    Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRAS(G12D)) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRAS(G12D) signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRAS(G12D) engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRAS(G12D). Consequently, reciprocal KRAS(G12D) produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRAS(G12D) alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. VIDEO ABSTRACT. PMID:27087446

  12. MicroRNAs as novel regulators of stem cell fate

    PubMed Central

    Choi, Eunhyun; Choi, Eunmi; Hwang, Ki-Chul

    2013-01-01

    Mounting evidence in stem cell biology has shown that microRNAs (miRNAs) play a crucial role in cell fate specification, including stem cell self-renewal, lineage-specific differentiation, and somatic cell reprogramming. These functions are tightly regulated by specific gene expression patterns that involve miRNAs and transcription factors. To maintain stem cell pluripotency, specific miRNAs suppress transcription factors that promote differentiation, whereas to initiate differentiation, lineage-specific miRNAs are upregulated via the inhibition of transcription factors that promote self-renewal. Small molecules can be used in a similar manner as natural miRNAs, and a number of natural and synthetic small molecules have been isolated and developed to regulate stem cell fate. Using miRNAs as novel regulators of stem cell fate will provide insight into stem cell biology and aid in understanding the molecular mechanisms and crosstalk between miRNAs and stem cells. Ultimately, advances in the regulation of stem cell fate will contribute to the development of effective medical therapies for tissue repair and regeneration. This review summarizes the current insights into stem cell fate determination by miRNAs with a focus on stem cell self-renewal, differentiation, and reprogramming. Small molecules that control stem cell fate are also highlighted. PMID:24179605

  13. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

    PubMed Central

    Tape, Christopher J.; Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M.; Worboys, Jonathan D.; Leong, Hui Sun; Norrie, Ida C.; Miller, Crispin J.; Poulogiannis, George; Lauffenburger, Douglas A.; Jørgensen, Claus

    2016-01-01

    Summary Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRASG12D) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRASG12D signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRASG12D engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. Video Abstract PMID:27087446

  14. Creatine kinase in cell cycle regulation and cancer.

    PubMed

    Yan, Yong-Bin

    2016-08-01

    The phosphocreatine-creatine kinase (CK) shuttle system is increasingly recognized as a fundamental mechanism for ATP homeostasis in both excitable and non-excitable cells. Many intracellular processes are ATP dependent. Cell division is a process requiring a rapid rate of energy turnover. Cell cycle regulation is also a key point to understanding the mechanisms underlying cancer progression. It has been known for about 40 years that aberrant CK levels are associated with various cancers and for over 30 years that CK is involved in mitosis regulation. However, the underlying molecular mechanisms have not been investigated sufficiently until recently. By maintaining ATP at sites of high-energy demand, CK can regulate cell cycle progression by affecting the intracellular energy status as well as by influencing signaling pathways that are essential to activate cell division and cytoskeleton reorganization. Aberrant CK levels may impair cell viability under normal or stressed conditions and induce cell death. The involvement of CK in cell cycle regulation and cellular energy metabolism makes it a potential diagnostic biomarker and therapeutic target in cancer. To understand the multiple physiological/pathological functions of CK, it is necessary to identify CK-binding partners and regulators including proteins, non-coding RNAs and participating endogenous small molecular weight chemical compounds. This review will focus on molecular mechanisms of CK in cell cycle regulation and cancer progression. It will also discuss the implications of recent mechanistic studies, the emerging problems and future challenges of the multifunctional enzyme CK. PMID:27020776

  15. Regulation of Natural Killer Cell Function by STAT3.

    PubMed

    Cacalano, Nicholas A

    2016-01-01

    Natural killer (NK) cells, key members of a distinct hematopoietic lineage, innate lymphoid cells, are not only critical effectors that mediate cytotoxicity toward tumor and virally infected cells but also regulate inflammation, antigen presentation, and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response, such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell-cell contact, and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The signal transducer and activator of transcription (STAT)-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of "immune surveillance." Even after tumors become established, NK cells are critical components of anticancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients, and the lack of NK cells in the tumor microenvironment often correlates to poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells, which determine the outcome of cancer immunity, are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of NK cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses. PMID:27148255

  16. Laminin regulates PDGFRβ+ cell stemness and muscle development

    PubMed Central

    Yao, Yao; Norris, Erin H.; E. Mason, Christopher; Strickland, Sidney

    2016-01-01

    Muscle-resident PDGFRβ+ cells, which include pericytes and PW1+ interstitial cells (PICs), play a dual role in muscular dystrophy. They can either undergo myogenesis to promote muscle regeneration or differentiate into adipocytes and other cells to compromise regeneration. How the differentiation and fate determination of PDGFRβ+ cells are regulated, however, remains unclear. Here, by utilizing a conditional knockout mouse line, we report that PDGFRβ+ cell-derived laminin inhibits their proliferation and adipogenesis, but is indispensable for their myogenesis. In addition, we show that laminin alone is able to partially reverse the muscle dystrophic phenotype in these mice at the molecular, structural and functional levels. Further RNAseq analysis reveals that laminin regulates PDGFRβ+ cell differentiation/fate determination via gpihbp1. These data support a critical role of laminin in the regulation of PDGFRβ+ cell stemness, identify an innovative target for future drug development and may provide an effective treatment for muscular dystrophy. PMID:27138650

  17. Common stemness regulators of embryonic and cancer stem cells

    PubMed Central

    Hadjimichael, Christiana; Chanoumidou, Konstantina; Papadopoulou, Natalia; Arampatzi, Panagiota; Papamatheakis, Joseph; Kretsovali, Androniki

    2015-01-01

    Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies. PMID:26516408

  18. Metabolic regulation of T cell differentiation and function

    PubMed Central

    Park, Benjamin V.; Pan, Fan

    2016-01-01

    Upon encountering pathogens, T cells mount immune responses by proliferating, increasing cellular mass and differentiating. These cellular changes impose significant energetic challenges on T cells. It was believed that TCR and cytokine-mediated signaling are dominant dictators of T cell-mediated immune responses. Recently, it was recognized that T cells utilize metabolic transporters and metabolic sensors that allow them to rapidly respond to nutrient-limiting inflammatory environments. Metabolic sensors allow T cells to find a balance between energy consumption (anabolic metabolism) and production (catabolic metabolism) in order to mount effective immune responses. Also, metabolic regulators interact with cytokine-dependent transcriptional regulators, suggesting a more integrative and advanced model of T cell activation and differentiation. In this review, we will discuss recent discoveries regarding the roles of metabolic regulators in effector and memory T cell development and their interaction with canonical transcription factors. PMID:26277275

  19. Regulation of antiviral T cell responses by type I interferons.

    PubMed

    Crouse, Josh; Kalinke, Ulrich; Oxenius, Annette

    2015-04-01

    Type I interferons (IFNs) are pro-inflammatory cytokines that are rapidly induced in different cell types during viral infections. The consequences of type I IFN signalling include direct antiviral activity, innate immune cell activation and regulation of adaptive immune responses. In this Review, we discuss recent conceptual advances in our understanding of indirect and direct regulation of T cell immunity by type I IFNs, which can either promote or inhibit T cell activation, proliferation, differentiation and survival. This regulation depends, to a large extent, on the timing of type I IFN exposure relative to T cell receptor signalling. Type I IFNs also provide activated T cells with resistance to natural killer cell-mediated elimination. PMID:25790790

  20. Laminin regulates PDGFRβ(+) cell stemness and muscle development.

    PubMed

    Yao, Yao; Norris, Erin H; E Mason, Christopher; Strickland, Sidney

    2016-01-01

    Muscle-resident PDGFRβ(+) cells, which include pericytes and PW1(+) interstitial cells (PICs), play a dual role in muscular dystrophy. They can either undergo myogenesis to promote muscle regeneration or differentiate into adipocytes and other cells to compromise regeneration. How the differentiation and fate determination of PDGFRβ(+) cells are regulated, however, remains unclear. Here, by utilizing a conditional knockout mouse line, we report that PDGFRβ(+) cell-derived laminin inhibits their proliferation and adipogenesis, but is indispensable for their myogenesis. In addition, we show that laminin alone is able to partially reverse the muscle dystrophic phenotype in these mice at the molecular, structural and functional levels. Further RNAseq analysis reveals that laminin regulates PDGFRβ(+) cell differentiation/fate determination via gpihbp1. These data support a critical role of laminin in the regulation of PDGFRβ(+) cell stemness, identify an innovative target for future drug development and may provide an effective treatment for muscular dystrophy. PMID:27138650

  1. T-Cell Regulation in Lepromatous Leprosy

    PubMed Central

    Bobosha, Kidist; Wilson, Louis; van Meijgaarden, Krista E.; Bekele, Yonas; Zewdie, Martha; van der Ploeg- van Schip, Jolien J.; Abebe, Markos; Hussein, Jemal; Khadge, Saraswoti; Neupane, Kapil D.; Hagge, Deanna A.; Jordanova, Ekaterina S.; Aseffa, Abraham; Ottenhoff, Tom H. M.; Geluk, Annemieke

    2014-01-01

    Regulatory T (Treg) cells are known for their role in maintaining self-tolerance and balancing immune reactions in autoimmune diseases and chronic infections. However, regulatory mechanisms can also lead to prolonged survival of pathogens in chronic infections like leprosy and tuberculosis (TB). Despite high humoral responses against Mycobacterium leprae (M. leprae), lepromatous leprosy (LL) patients have the characteristic inability to generate T helper 1 (Th1) responses against the bacterium. In this study, we investigated the unresponsiveness to M. leprae in peripheral blood mononuclear cells (PBMC) of LL patients by analysis of IFN-γ responses to M. leprae before and after depletion of CD25+ cells, by cell subsets analysis of PBMC and by immunohistochemistry of patients' skin lesions. Depletion of CD25+ cells from total PBMC identified two groups of LL patients: 7/18 (38.8%) gained in vitro responsiveness towards M. leprae after depletion of CD25+ cells, which was reversed to M. leprae-specific T-cell unresponsiveness by addition of autologous CD25+ cells. In contrast, 11/18 (61.1%) remained anergic in the absence of CD25+ T-cells. For both groups mitogen-induced IFN-γ was, however, not affected by depletion of CD25+ cells. In M. leprae responding healthy controls, treated lepromatous leprosy (LL) and borderline tuberculoid leprosy (BT) patients, depletion of CD25+ cells only slightly increased the IFN-γ response. Furthermore, cell subset analysis showed significantly higher (p = 0.02) numbers of FoxP3+ CD8+CD25+ T-cells in LL compared to BT patients, whereas confocal microscopy of skin biopsies revealed increased numbers of CD68+CD163+ as well as FoxP3+ cells in lesions of LL compared to tuberculoid and borderline tuberculoid leprosy (TT/BT) lesions. Thus, these data show that CD25+ Treg cells play a role in M. leprae-Th1 unresponsiveness in LL. PMID:24722473

  2. p120-catenin differentially regulates cell migration by Rho-dependent intracellular and secreted signals

    PubMed Central

    Epifano, Carolina; Megias, Diego; Perez-Moreno, Mirna

    2014-01-01

    The adherens junction protein p120-catenin is implicated in the regulation of cadherin stability, cell migration and inflammatory responses in mammalian epithelial tissues. How these events are coordinated to promote wound repair is not understood. We show that p120 catenin regulates the intrinsic migratory properties of primary mouse keratinocytes, but also influences the migratory behavior of neighboring cells by secreted signals. These events are rooted in the ability of p120-catenin to regulate RhoA GTPase activity, which leads to a two-tiered control of cell migration. One restrains cell motility via an increase in actin stress fibers, reduction in integrin turnover and an increase in the robustness of focal adhesions. The other is coupled to the secretion of inflammatory cytokines including interleukin-24, which causally enhances randomized cell movements. Taken together, our results indicate that p120-RhoA-GTPase-mediated signaling can differentially regulate the migratory behavior of epidermal cells, which has potential implications for chronic wound responses and cancer. PMID:24639556

  3. p120-catenin differentially regulates cell migration by Rho-dependent intracellular and secreted signals.

    PubMed

    Epifano, Carolina; Megias, Diego; Perez-Moreno, Mirna

    2014-05-01

    The adherens junction protein p120-catenin is implicated in the regulation of cadherin stability, cell migration and inflammatory responses in mammalian epithelial tissues. How these events are coordinated to promote wound repair is not understood. We show that p120 catenin regulates the intrinsic migratory properties of primary mouse keratinocytes, but also influences the migratory behavior of neighboring cells by secreted signals. These events are rooted in the ability of p120-catenin to regulate RhoA GTPase activity, which leads to a two-tiered control of cell migration. One restrains cell motility via an increase in actin stress fibers, reduction in integrin turnover and an increase in the robustness of focal adhesions. The other is coupled to the secretion of inflammatory cytokines including interleukin-24, which causally enhances randomized cell movements. Taken together, our results indicate that p120-RhoA-GTPase-mediated signaling can differentially regulate the migratory behavior of epidermal cells, which has potential implications for chronic wound responses and cancer. PMID:24639556

  4. Regulation of Natural Killer Cell Function by STAT3

    PubMed Central

    Cacalano, Nicholas A.

    2016-01-01

    Natural killer (NK) cells, key members of a distinct hematopoietic lineage, innate lymphoid cells, are not only critical effectors that mediate cytotoxicity toward tumor and virally infected cells but also regulate inflammation, antigen presentation, and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response, such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell–cell contact, and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The signal transducer and activator of transcription (STAT)-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of “immune surveillance.” Even after tumors become established, NK cells are critical components of anticancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients, and the lack of NK cells in the tumor microenvironment often correlates to poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells, which determine the outcome of cancer immunity, are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of NK cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses. PMID:27148255

  5. Substrate stress relaxation regulates cell spreading.

    PubMed

    Chaudhuri, Ovijit; Gu, Luo; Darnell, Max; Klumpers, Darinka; Bencherif, Sidi A; Weaver, James C; Huebsch, Nathaniel; Mooney, David J

    2015-01-01

    Studies of cellular mechanotransduction have converged upon the idea that cells sense extracellular matrix (ECM) elasticity by gauging resistance to the traction forces they exert on the ECM. However, these studies typically utilize purely elastic materials as substrates, whereas physiological ECMs are viscoelastic, and exhibit stress relaxation, so that cellular traction forces exerted by cells remodel the ECM. Here we investigate the influence of ECM stress relaxation on cell behaviour through computational modelling and cellular experiments. Surprisingly, both our computational model and experiments find that spreading for cells cultured on soft substrates that exhibit stress relaxation is greater than cells spreading on elastic substrates of the same modulus, but similar to that of cells spreading on stiffer elastic substrates. These findings challenge the current view of how cells sense and respond to the ECM. PMID:25695512

  6. Nutritional regulation of stem and progenitor cells in Drosophila

    PubMed Central

    Shim, Jiwon; Gururaja-Rao, Shubha; Banerjee, Utpal

    2013-01-01

    Stem cells and their progenitors are maintained within a microenvironment, termed the niche, through local cell-cell communication. Systemic signals originating outside the niche also affect stem cell and progenitor behavior. This review summarizes studies that pertain to nutritional effects on stem and progenitor cell maintenance and proliferation in Drosophila. Multiple tissue types are discussed that utilize the insulin-related signaling pathway to convey nutritional information either directly to these progenitors or via other cell types within the niche. The concept of systemic control of these cell types is not limited to Drosophila and may be functional in vertebrate systems, including mammals. PMID:24255094

  7. Bcl-2 family proteins: master regulators of cell survival.

    PubMed

    Hatok, Jozef; Racay, Peter

    2016-08-01

    The most prominent function of proteins of the Bcl-2 family is regulation of the initiation of intrinsic (mitochondrial) pathways of apoptosis. However, recent research has revealed that in addition to regulation of mitochondrial apoptosis, proteins of the Bcl-2 family play important roles in regulating other cellular pathways with a strong impact on cell survival like autophagy, endoplasmic reticulum (ER) stress response, intracellular calcium dynamics, cell cycle progression, mitochondrial dynamics and energy metabolism. This review summarizes the recent knowledge about functions of Bcl-2 family proteins that are related to cell survival. PMID:27505095

  8. Hormones and pheromones in regulation of insect behavior

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Both pheromones and hormones are well recognized regulators of insect biology. However, the interactions between hormones and pheromones in coordinating insect biology are less well understood. We have studied the interactions between juvenile hormone, its precursor methyl farnesoate, and pheromon...

  9. Regulated expression of erythropoietin by two human hepatoma cell lines

    SciTech Connect

    Goldberg, M.A.; Glass, G.A.; Cunningham, J.M.; Bunn, H.F.

    1987-11-01

    The development of a cell culture system that produces erythropoietin (Epo) in a regulated manner has been the focus of much effort. The authors have screened multiple renal and hepatic cell lines for either constitutive or regulated expression of Epo. Only the human hepatoma cell lines, Hep3B and HepG2, made significant amounts of Epo as measured both by radioimmunoassay and in vitro bioassay (as much as 330 milliunits per 10/sup 6/ cells in 24 hr). The constitutive production of Epo increased dramatically as a function of cell density in both cell lines. At cell densities < 3.3 x 10/sup 5/ cells per cm/sup 2/, there was little constitutive release of Epo in the medium. With Hep3B cells grown at low cell densities, a mean 18-fold increase in Epo expression was seen in response to hypoxia and a 6-fold increase was observed in response to incubation in medium containing 50 ..mu..M cobalt(II) chloride. At similar low cell densities, Epo production in HepG2 cells could be enhanced an average of about 3-fold by stimulation with either hypoxia or cobalt(II) chloride. Upon such stimulation, both cell lines demonstrated markedly elevated levels of Epo mRNA. Hence, both Hep3B and HepG2 cell lines provide an excellent in vitro system in which to study the physiological regulation of Epo expression.

  10. Peer victimization and subsequent disruptive behavior in school: The protective functions of anger regulation coping

    PubMed Central

    Kaynak, Övgü; Lepore, Stephen J.; Kliewer, Wendy; Jaggi, Lena

    2014-01-01

    Peer victimization is linked to adjustment problems in youth, including aggressive behavior, yet not all victimized youth are aggressive. The present study investigated whether youth’s anger regulation coping might attenuate the positive association between peer victimization and subsequent aggressive behavior. Longitudinal data from 485 7th-grade students (55% female, mean age = 12.84 years) and their teachers were collected in the fall and six months later. Teacher ratings of youth aggressive behavior at follow-up were the primary outcome, with statistical adjustments for baseline aggressive behavior and demographics. Results from multilevel models showed significant interactive effects of baseline anger regulation and peer victimization on residualized teacher-rated aggressive behaviors that were consistent with the hypothesis that anger regulation played a protective role: under high levels of peer victimization, youth with higher levels of anger regulation displayed lower levels of aggressive behavior than their counterparts with lower levels of anger regulation. These findings suggest that targeting and improving students’ ability to regulate their anger may be protective in the face of peer victimization and reduce subsequent aggressive behavior. PMID:25309013