Gas1 extends the range of Hedgehog action by facilitating its signaling

PubMed Central

Martinelli, David C.; Fan, Chen-Ming

2007-01-01

Cellular signaling initiated by Hedgehog binding to Patched1 has profound importance in mammalian embryogenesis, genetic disease, and cancer. Hedgehog acts as a morphogen to specify distinctive cell fates using different concentration thresholds, but our knowledge of how the concentration gradient is interpreted into the activity gradient is incomplete. The membrane protein Growth Arrest-Specific Gene 1 (GAS1) was thought to be a negative regulator of the Hedgehog concentration gradient. Here, we report unexpected genetic evidence that Gas1 positively regulates Hedgehog signaling in multiple developmental contexts, an effect particularly noticeable at regions where Hedgehog acts at low concentration. Using a combination of in vitro cell culture and in ovo electroporation assays, we demonstrate that GAS1 acts cooperatively with Patched1 for Hedgehog binding and enhances signaling activity in a cell-autonomous manner. Our data support a model in which GAS1 helps transform the Hedgehog protein gradient into the observed activity gradient. We propose that Gas1 is an evolutionarily novel, vertebrate-specific Hedgehog pathway regulator. PMID:17504940

FOXN1 Transcription Factor in Epithelial Growth and Wound Healing.

PubMed

Grabowska, Anna I; Wilanowski, Tomasz

2017-09-01

FOXN1 is a prodifferentiation transcription factor in the skin epithelium. Recently, it has also emerged as an important player in controlling the skin wound healing process, as it actively participates in reepithelialization and is thought to be responsible for scar formation. FOXN1 positivity is also a feature of pigmented keratinocytes, including nevi, and FOXN1 is an attribute of benign epithelial tumors. The lack of FOXN1 favors the skin regeneration process displayed by nude mice, pointing to FOXN1 as a switch between regeneration and reparative processes. The stem cell niche provides a functional source of cells after the loss of tissue following wounding. The involvement of prodifferentiation factors in the regulation of this pool of stem cells is suggested. However, the exact mechanism is still under question, and we speculate that the FOXN1 transcription factor is involved in this process. This review analyzes the pleiotropic effects of FOXN1 in the skin, its function in the tumorigenesis process, and its potential role in depletion of the stem cell niche after injury, as well as its suggested mechanistic role, acting in a cell-autonomous and a non-cell-autonomous manner during skin self-renewal. Copyright © 2017 American Society for Microbiology.

Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

NASA Astrophysics Data System (ADS)

van de Pavert, Serge A.; Ferreira, Manuela; Domingues, Rita G.; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F.; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R.; Habani, Yasmin; Haak, Esther; Santori, Fabio R.; Littman, Dan R.; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J. Pedro; Mebius, Reina E.; Veiga-Fernandes, Henrique

2014-04-01

The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity.

PubMed

van de Pavert, Serge A; Ferreira, Manuela; Domingues, Rita G; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R; Habani, Yasmin; Haak, Esther; Santori, Fabio R; Littman, Dan R; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J Pedro; Mebius, Reina E; Veiga-Fernandes, Henrique

2014-04-03

The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

Transposable elements at the center of the crossroads between embryogenesis, embryonic stem cells, reprogramming, and long non-coding RNAs.

PubMed

Hutchins, Andrew Paul; Pei, Duanqing

Transposable elements (TEs) are mobile genomic sequences of DNA capable of autonomous and non-autonomous duplication. TEs have been highly successful, and nearly half of the human genome now consists of various families of TEs. Originally thought to be non-functional, these elements have been co-opted by animal genomes to perform a variety of physiological functions ranging from TE-derived proteins acting directly in normal biological functions, to innovations in transcription factor logic and influence on epigenetic control of gene expression. During embryonic development, when the genome is epigenetically reprogrammed and DNA-demethylated, TEs are released from repression and show embryonic stage-specific expression, and in human and mouse embryos, intact TE-derived endogenous viral particles can even be detected. A similar process occurs during the reprogramming of somatic cells to pluripotent cells: When the somatic DNA is demethylated, TEs are released from repression. In embryonic stem cells (ESCs), where DNA is hypomethylated, an elaborate system of epigenetic control is employed to suppress TEs, a system that often overlaps with normal epigenetic control of ESC gene expression. Finally, many long non-coding RNAs (lncRNAs) involved in normal ESC function and those assisting or impairing reprogramming contain multiple TEs in their RNA. These TEs may act as regulatory units to recruit RNA-binding proteins and epigenetic modifiers. This review covers how TEs are interlinked with the epigenetic machinery and lncRNAs, and how these links influence each other to modulate aspects of ESCs, embryogenesis, and somatic cell reprogramming.

Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma

PubMed Central

Li, Chung-Pin; Buza, Elizabeth L.; Blomberg, Rachel; Govindaraju, Priya; Avery, Diana; Monslow, James; Hsiao, Michael

2017-01-01

Pancreatic ductal adenocarcinomas (PDAs) are desmoplastic and can undergo epithelial-to-mesenchymal transition to confer metastasis and chemoresistance. Studies have demonstrated that phenotypically and functionally distinct stromal cell populations exist in PDAs. Fibroblast activation protein–expressing (FAP-expressing) cells act to enhance PDA progression, while α–smooth muscle actin myofibroblasts can restrain PDA. Thus, identification of precise molecular targets that mediate the protumorigenic activity of FAP+ cells will guide development of therapy for PDA. Herein, we demonstrate that FAP overexpression in the tumor microenvironment correlates with poor overall and disease-free survival of PDA patients. Genetic deletion of FAP delayed onset of primary tumor and prolonged survival of mice in the KPC mouse model of PDA. While genetic deletion of FAP did not affect primary tumor weight in advanced disease, FAP deficiency increased tumor necrosis and impeded metastasis to multiple organs. Lineage-tracing studies unexpectedly showed that FAP is not only expressed by stromal cells, but can also be detected in a subset of CD90+ mesenchymal PDA cells, representing up to 20% of total intratumoral FAP+ cells. These data suggest that FAP may regulate PDA progression and metastasis in cell-autonomous and/or non-cell-autonomous fashions. Together, these data support pursuing FAP as a therapeutic target in PDA. PMID:28978805

Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse

PubMed Central

Ding, Jiaxi; Jiang, DeChen; Kurczy, Michael; Nalepka, Jennifer; Dudley, Brian; Merkel, Erin I; Porter, Forbes D; Ewing, Andrew G; Winograd, Nicholas; Burgess, James; Molyneaux, Kathleen

2008-01-01

Background Primordial germ cells (PGCs) are the embryonic precursors of the sperm and eggs. Environmental or genetic defects that alter PGC development can impair fertility or cause formation of germ cell tumors. Results We demonstrate a novel role for cholesterol during germ cell migration in mice. Cholesterol was measured in living tissue dissected from mouse embryos and was found to accumulate within the developing gonads as germ cells migrate to colonize these structures. Cholesterol synthesis was blocked in culture by inhibiting the activity of HMG CoA reductase (HMGCR) resulting in germ cell survival and migration defects. These defects were rescued by co-addition of isoprenoids and cholesterol, but neither compound alone was sufficient. In contrast, loss of the last or penultimate enzyme in cholesterol biosynthesis did not alter PGC numbers or position in vivo. However embryos that lack these enzymes do not exhibit cholesterol defects at the stage at which PGCs are migrating. This demonstrates that during gestation, the cholesterol required for PGC migration can be supplied maternally. Conclusion In the mouse, cholesterol is required for PGC survival and motility. It may act cell-autonomously by regulating clustering of growth factor receptors within PGCs or non cell-autonomously by controlling release of growth factors required for PGC guidance and survival. PMID:19117526

Exploring the genetics and non-cell autonomous mechanisms underlying ALS/FTLD.

PubMed

Chen, Hongbo; Kankel, Mark W; Su, Susan C; Han, Steve W S; Ofengeim, Dimitry

2018-03-01

Although amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, was first described in 1874, a flurry of genetic discoveries in the last 10 years has markedly increased our understanding of this disease. These findings have not only enhanced our knowledge of mechanisms leading to ALS, but also have revealed that ALS shares many genetic causes with another neurodegenerative disease, frontotemporal lobar dementia (FTLD). In this review, we survey how recent genetic studies have bridged our mechanistic understanding of these two related diseases and how the genetics behind ALS and FTLD point to complex disorders, implicating non-neuronal cell types in disease pathophysiology. The involvement of non-neuronal cell types is consistent with a non-cell autonomous component in these diseases. This is further supported by studies that identified a critical role of immune-associated genes within ALS/FTLD and other neurodegenerative disorders. The molecular functions of these genes support an emerging concept that various non-autonomous functions are involved in neurodegeneration. Further insights into such a mechanism(s) will ultimately lead to a better understanding of potential routes of therapeutic intervention. Facts ALS and FTLD are severe neurodegenerative disorders on the same disease spectrum. Multiple cellular processes including dysregulation of RNA homeostasis, imbalance of proteostasis, contribute to ALS/FTLD pathogenesis. Aberrant function in non-neuronal cell types, including microglia, contributes to ALS/FTLD. Strong neuroimmune and neuroinflammatory components are associated with ALS/FTLD patients. Open Questions Why can patients with similar mutations have different disease manifestations, i.e., why do C9ORF72 mutations lead to motor neuron loss in some patients while others exhibit loss of neurons in the frontotemporal lobe? Do ALS causal mutations result in microglial dysfunction and contribute to ALS/FTLD pathology? How do microglia normally act to mitigate neurodegeneration in ALS/FTLD? To what extent do cellular signaling pathways mediate non-cell autonomous communications between distinct central nervous system (CNS) cell types during disease? Is it possible to therapeutically target specific cell types in the CNS?

Conditional Deletion of Kit in Melanocytes: White Spotting Phenotype Is Cell Autonomous.

PubMed

Aoki, Hitomi; Tomita, Hiroyuki; Hara, Akira; Kunisada, Takahiro

2015-07-01

It is well established that cell-intrinsic signaling through the receptor tyrosine kinase KIT is critical for the development of neural crest-derived melanocytes. Nevertheless, it is not entirely clear whether Kit acts exclusively in a melanocyte-autonomous manner or in addition indirectly through other cell types. To address this question in vivo, we generated a targeted allele of Kit that allowed for CRE recombinase-mediated deletion of the transmembrane domain of KIT. Mice carrying one copy of the targeted allele and expressing CRE under the melanoblast/melanocyte-specific tyrosinase promoter exhibited a white spotting phenotype that was even more extensive compared with that found in mice heterozygous for a Kit-null allele. This phenotype is unlikely the result of sequestration of KIT ligand by neighboring cells or by potentially secreted forms of KIT because the spotting phenotype could not be rescued by overexpression of KITL. Likewise, overexpression of endothelin-3 or hepatocyte growth factor was unable to rescue melanocytes in these mice. Although the severity of the observed phenotype remains to be explained, the findings indicate that melanocyte-selective impairment of Kit is sufficient to interfere with normal melanocyte development.

A Concept of Operations for the Use of Emergent Open Internet Technologies as the Basis for a Network-Centric Environment

DTIC Science & Technology

2006-09-01

automated agents , such as chatbots to acts as a relay between chatrooms and blogs or other systems. In particular, chatbots could be used to monitor...bandwidth connections and legacy systems. Chatbot Integration The use of connected autonomous agents that monitor chatrooms to allow users access...of Cell Phone GPS Tracking. .............84 Figure 35. Example of a Chatbot Creating a Blog Entry

Pten Cell Autonomously Modulates the Hematopoietic Stem Cell Response to Inflammatory Cytokines.

PubMed

Porter, Shaina N; Cluster, Andrew S; Signer, Robert A J; Voigtmann, Jenna; Monlish, Darlene A; Schuettpelz, Laura G; Magee, Jeffrey A

2016-06-14

Pten negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway and is required to maintain quiescent adult hematopoietic stem cells (HSCs). Pten has been proposed to regulate HSCs cell autonomously and non-cell autonomously, but the relative importance of each mechanism has not been directly tested. Furthermore, the cytokines that activate the PI3K pathway upstream of Pten are not well defined. We sought to clarify whether Pten cell autonomously or non-cell autonomously regulates HSC mobilization. We also tested whether Pten deficiency affects the HSC response to granulocyte colony-stimulating factor (G-CSF) and interferon-α (IFNα) since these cytokines induce HSC mobilization or proliferation, respectively. We show that Pten regulates HSC mobilization and expansion in the spleen primarily via cell-autonomous mechanisms. Pten-deficient HSCs do not require G-CSF to mobilize, although they are hyper-sensitized to even low doses of exogenous G-CSF. Pten-deficient HSCs are similarly sensitized to IFNα. Pten therefore modulates the HSC response to inflammatory cytokines. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The THO Complex Non-Cell-Autonomously Represses Female Germline Specification through the TAS3-ARF3 Module.

PubMed

Su, Zhenxia; Zhao, Lihua; Zhao, Yuanyuan; Li, Shaofang; Won, SoYoun; Cai, Hanyang; Wang, Lulu; Li, Zhenfang; Chen, Piaojuan; Qin, Yuan; Chen, Xuemei

2017-06-05

In most sexually reproducing plants, a single somatic, sub-epidermal cell in an ovule is selected to differentiate into a megaspore mother cell, which is committed to giving rise to the female germline. However, it remains unclear how intercellular signaling among somatic cells results in only one cell in the sub-epidermal layer differentiating into the megaspore mother cell. Here we uncovered a role of the THO complex in restricting the megaspore mother cell fate to a single cell. Mutations in TEX1, HPR1, and THO6, components of the THO/TREX complex, led to the formation of multiple megaspore mother cells, which were able to initiate gametogenesis. We demonstrated that TEX1 repressed the megaspore mother cell fate by promoting the biogenesis of TAS3-derived trans-acting small interfering RNA (ta-siRNA), which represses ARF3 expression. The TEX1 protein was present in epidermal cells, but not in the germline, and, through TAS3-derived ta-siRNA, restricted ARF3 expression to the medio domain of ovule primordia. Expansion of ARF3 expression into lateral epidermal cells in a TAS3 ta-siRNA-insensitive mutant led to the formation of supernumerary megaspore mother cells, suggesting that TEX1- and TAS3-mediated restriction of ARF3 expression limits excessive megaspore mother cell formation non-cell-autonomously. Our findings reveal the role of a small-RNA pathway in the regulation of female germline specification in Arabidopsis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Glibenclamide treatment blocks metabolic dysfunctions and improves vagal activity in monosodium glutamate-obese male rats.

PubMed

Franco, Claudinéia C S; Prates, Kelly V; Previate, Carina; Moraes, Ana M P; Matiusso, Camila C I; Miranda, Rosiane A; de Oliveira, Júlio C; Tófolo, Laize P; Martins, Isabela P; Barella, Luiz F; Ribeiro, Tatiane A; Malta, Ananda; Pavanello, Audrei; Francisco, Flávio A; Gomes, Rodrigo M; Alves, Vander S; Moreira, Veridiana M; Rigo, Késia P; Almeida, Douglas L; de Sant Anna, Juliane R; Prado, Marialba A A C; Mathias, Paulo C F

2017-05-01

Autonomic nervous system imbalance is associated with metabolic diseases, including diabetes. Glibenclamide is an antidiabetic drug that acts by stimulating insulin secretion from pancreatic beta cells and is widely used in the treatment of type 2 diabetes. Since there is scarce data concerning autonomic nervous system activity and diabetes, the aim of this work was to test whether glibenclamide can improve autonomic nervous system activity and muscarinic acetylcholine receptor function in pre-diabetic obese male rats. Pre-diabetes was induced by treatment with monosodium L-glutamate in neonatal rats. The monosodium L-glutamate group was treated with glibenclamide (2 mg/kg body weight /day) from weaning to 100 days of age, and the control group was treated with water. Body weight, food intake, Lee index, fasting glucose, insulin levels, homeostasis model assessment of insulin resistance, omeostasis model assessment of β-cell function, and fat tissue accumulation were measured. The vagus and sympathetic nerve electrical activity were recorded. Insulin secretion was measured in isolated islets challenged with glucose, acetylcholine, and the selective muscarinic acetylcholine receptor antagonists by radioimmunoassay technique. Glibenclamide treatment prevented the onset of obesity and diminished the retroperitoneal (18%) and epididymal (25%) fat pad tissues. In addition, the glibenclamide treatment also reduced the parasympathetic activity by 28% and glycemia by 20% in monosodium L-glutamate-treated rats. The insulinotropic effect and unaltered cholinergic actions in islets from monosodium L-glutamate groups were increased. Early glibenclamide treatment prevents monosodium L-glutamate-induced obesity onset by balancing autonomic nervous system activity.

The Glide/Gcm fate determinant controls initiation of collective cell migration by regulating Frazzled

PubMed Central

Gupta, Tripti; Kumar, Arun; Cattenoz, Pierre B.; VijayRaghavan, K; Giangrande, Angela

2016-01-01

Collective migration is a complex process that contributes to build precise tissue and organ architecture. Several molecules implicated in cell interactions also control collective migration, but their precise role and the finely tuned expression that orchestrates this complex developmental process are poorly understood. Here, we show that the timely and threshold expression of the Netrin receptor Frazzled triggers the initiation of glia migration in the developing Drosophila wing. Frazzled expression is induced by the transcription factor Glide/Gcm in a dose-dependent manner. Thus, the glial determinant also regulates the efficiency of collective migration. NetrinB but not NetrinA serves as a chemoattractant and Unc5 contributes as a repellant Netrin receptor for glia migration. Our model includes strict spatial localization of a ligand, a cell autonomously acting receptor and a fate determinant that act coordinately to direct glia toward their final destination. DOI: http://dx.doi.org/10.7554/eLife.15983.001 PMID:27740455

Sonic hedgehog acts cell-autonomously on muscle precursor cells to generate limb muscle diversity

PubMed Central

Anderson, Claire; Williams, Victoria C.; Moyon, Benjamin; Daubas, Philippe; Tajbakhsh, Shahragim; Buckingham, Margaret E.; Shiroishi, Toshihiko; Hughes, Simon M.; Borycki, Anne-Gaëlle

2012-01-01

How muscle diversity is generated in the vertebrate body is poorly understood. In the limb, dorsal and ventral muscle masses constitute the first myogenic diversification, as each gives rise to distinct muscles. Myogenesis initiates after muscle precursor cells (MPCs) have migrated from the somites to the limb bud and populated the prospective muscle masses. Here, we show that Sonic hedgehog (Shh) from the zone of polarizing activity (ZPA) drives myogenesis specifically within the ventral muscle mass. Shh directly induces ventral MPCs to initiate Myf5 transcription and myogenesis through essential Gli-binding sites located in the Myf5 limb enhancer. In the absence of Shh signaling, myogenesis is delayed, MPCs fail to migrate distally, and ventral paw muscles fail to form. Thus, Shh production in the limb ZPA is essential for the spatiotemporal control of myogenesis and coordinates muscle and skeletal development by acting directly to regulate the formation of specific ventral muscles. PMID:22987640

The transcription factor Foxg1 regulates telencephalic progenitor proliferation cell autonomously, in part by controlling Pax6 expression levels

PubMed Central

2011-01-01

Background The transcription factor Foxg1 is an important regulator of telencephalic cell cycles. Its inactivation causes premature lengthening of telencephalic progenitor cell cycles and increased neurogenic divisions, leading to severe hypoplasia of the telencephalon. These proliferation defects could be a secondary consequence of the loss of Foxg1 caused by the abnormal expression of several morphogens (Fibroblast growth factor 8, bone morphogenetic proteins) in the telencephalon of Foxg1 null mutants. Here we investigated whether Foxg1 has a cell autonomous role in the regulation of telencephalic progenitor proliferation. We analysed Foxg1+/+↔Foxg1-/- chimeras, in which mutant telencephalic cells have the potential to interact with, and to have any cell non-autonomous defects rescued by, normal wild-type cells. Results Our analysis showed that the Foxg1-/- cells are under-represented in the chimeric telencephalon and the proportion of them in S-phase is significantly smaller than that of their wild-type neighbours, indicating that their under-representation is caused by a cell autonomous reduction in their proliferation. We then analysed the expression of the cell-cycle regulator Pax6 and found that it is cell-autonomously downregulated in Foxg1-/- dorsal telencephalic cells. We went on to show that the introduction into Foxg1-/- embryos of a transgene designed to reverse Pax6 expression defects resulted in a partial rescue of the telencephalic progenitor proliferation defects. Conclusions We conclude that Foxg1 exerts control over telencephalic progenitor proliferation by cell autonomous mechanisms that include the regulation of Pax6, which itself is known to regulate proliferation cell autonomously in a regional manner. PMID:21418559

Biophysical markers of the peripheral vasoconstriction response to pain in sickle cell disease

PubMed Central

Khaleel, Maha; Sunwoo, John; Shah, Payal; Detterich, Jon A.; Kato, Roberta M.; Thuptimdang, Wanwara; Meiselman, Herbert J.; Sposto, Richard; Tsao, Jennie; Wood, John C.; Zeltzer, Lonnie; Coates, Thomas D.; Khoo, Michael C. K.

2017-01-01

Painful vaso-occlusive crisis (VOC), a complication of sickle cell disease (SCD), occurs when sickled red blood cells obstruct flow in the microvasculature. We postulated that exaggerated sympathetically mediated vasoconstriction, endothelial dysfunction and the synergistic interaction between these two factors act together to reduce microvascular flow, promoting regional vaso-occlusions, setting the stage for VOC. We previously found that SCD subjects had stronger vasoconstriction response to pulses of heat-induced pain compared to controls but the relative degrees to which autonomic dysregulation, peripheral vascular dysfunction and their interaction are present in SCD remain unknown. In the present study, we employed a mathematical model to decompose the total vasoconstriction response to pain into: 1) the neurogenic component, 2) the vascular response to blood pressure, 3) respiratory coupling and 4) neurogenic-vascular interaction. The model allowed us to quantify the contribution of each component to the total vasoconstriction response. The most salient features of the components were extracted to represent biophysical markers of autonomic and vascular impairment in SCD and controls. These markers provide a means of phenotyping severity of disease in sickle-cell anemia that is based more on underlying physiology than on genotype. The marker of the vascular component (BMv) showed stronger contribution to vasoconstriction in SCD than controls (p = 0.0409), suggesting a dominant myogenic response in the SCD subjects as a consequence of endothelial dysfunction. The marker of neurogenic-vascular interaction (BMn-v) revealed that the interaction reinforced vasoconstriction in SCD but produced vasodilatory response in controls (p = 0.0167). This marked difference in BMn-v suggests that it is the most sensitive marker for quantifying combined alterations in autonomic and vascular function in SCD in response to heat-induced pain. PMID:28542469

Cell-autonomous excitation of midbrain dopamine neurons by endocannabinoid-dependent lipid signaling

PubMed Central

Gantz, Stephanie C.; Bean, Bruce P.

2017-01-01

SUMMARY The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate Gq/11-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase α. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating IA. PMID:28262417

Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

PubMed Central

Sampathkumar, Charanya; Wu, Yuan-Ju; Vadhvani, Mayur; Trimbuch, Thorsten; Eickholt, Britta; Rosenmund, Christian

2016-01-01

Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system. DOI: http://dx.doi.org/10.7554/eLife.19374.001 PMID:27782879

The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy - a perspective on cell biological mechanisms.

PubMed

Tang, Bor Luen

2017-10-26

Recent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.

Central cell-derived peptides regulate early embryo patterning in flowering plants.

PubMed

Costa, Liliana M; Marshall, Eleanor; Tesfaye, Mesfin; Silverstein, Kevin A T; Mori, Masashi; Umetsu, Yoshitaka; Otterbach, Sophie L; Papareddy, Ranjith; Dickinson, Hugh G; Boutiller, Kim; VandenBosch, Kathryn A; Ohki, Shinya; Gutierrez-Marcos, José F

2014-04-11

Plant embryogenesis initiates with the establishment of an apical-basal axis; however, the molecular mechanisms accompanying this early event remain unclear. Here, we show that a small cysteine-rich peptide family is required for formation of the zygotic basal cell lineage and proembryo patterning in Arabidopsis. EMBRYO SURROUNDING FACTOR 1 (ESF1) peptides accumulate before fertilization in central cell gametes and thereafter in embryo-surrounding endosperm cells. Biochemical and structural analyses revealed cleavage of ESF1 propeptides to form biologically active mature peptides. Further, these peptides act in a non-cell-autonomous manner and synergistically with the receptor-like kinase SHORT SUSPENSOR to promote suspensor elongation through the YODA mitogen-activated protein kinase pathway. Our findings demonstrate that the second female gamete and its sexually derived endosperm regulate early embryonic patterning in flowering plants.

Enhancer of polycomb coordinates multiple signaling pathways to promote both cyst and germline stem cell differentiation in the Drosophila adult testis

PubMed Central

Feng, Lijuan; Shi, Zhen; Chen, Xin

2017-01-01

Stem cells reside in a particular microenvironment known as a niche. The interaction between extrinsic cues originating from the niche and intrinsic factors in stem cells determines their identity and activity. Maintenance of stem cell identity and stem cell self-renewal are known to be controlled by chromatin factors. Herein, we use the Drosophila adult testis which has two adult stem cell lineages, the germline stem cell (GSC) lineage and the cyst stem cell (CySC) lineage, to study how chromatin factors regulate stem cell differentiation. We find that the chromatin factor Enhancer of Polycomb [E(Pc)] acts in the CySC lineage to negatively control transcription of genes associated with multiple signaling pathways, including JAK-STAT and EGF, to promote cellular differentiation in the CySC lineage. E(Pc) also has a non-cell-autonomous role in regulating GSC lineage differentiation. When E(Pc) is specifically inactivated in the CySC lineage, defects occur in both germ cell differentiation and maintenance of germline identity. Furthermore, compromising Tip60 histone acetyltransferase activity in the CySC lineage recapitulates loss-of-function phenotypes of E(Pc), suggesting that Tip60 and E(Pc) act together, consistent with published biochemical data. In summary, our results demonstrate that E(Pc) plays a central role in coordinating differentiation between the two adult stem cell lineages in Drosophila testes. PMID:28196077

Abnormal cardiac autonomic control in sickle cell disease following transient hypoxia.

PubMed

Sangkatumvong, Suvimol; Khoo, Michael C K; Coates, Thomas D

2008-01-01

Abnormalities in autonomic control in sickle cell anemia (SCA) patients have been reported by multiple researchers. However their potential causal association with sickle cell crisis remains unknown. We employed hypoxia, a known trigger to sickle cell crisis, to perturb the autonomic systems of the subjects. Cardiac autonomic control was non-invasively assessed by tracking the changes in heart rate variability (HRV) that occur following brief exposure to a hypoxia stimulus. Time varying spectral analysis of HRV was applied to estimate the cardiac autonomic response to the transient episode of hypoxia. The results demonstrate that cardiovascular autonomic response to hypoxia is substantially more sensitive in SCA than in normal controls. We also developed a model to compensate for the confounding effects of respiration on the HRV spectral indices by using the corresponding respiration signal to compensate for the respiratory correlated part of the HRV. This technique improved the resolution with which the effect of hypoxia on changes in HRV could be measured.

Act-and-wait time-delayed feedback control of autonomous systems

NASA Astrophysics Data System (ADS)

Pyragas, Viktoras; Pyragas, Kestutis

2018-02-01

Recently an act-and-wait modification of time-delayed feedback control has been proposed for the stabilization of unstable periodic orbits in nonautonomous dynamical systems (Pyragas and Pyragas, 2016 [30]). The modification implies a periodic switching of the feedback gain and makes the closed-loop system finite-dimensional. Here we extend this modification to autonomous systems. In order to keep constant the phase difference between the controlled orbit and the act-and-wait switching function an additional small-amplitude periodic perturbation is introduced. The algorithm can stabilize periodic orbits with an odd number of real unstable Floquet exponents using a simple single-input single-output constraint control.

A Computational Framework for 3D Mechanical Modeling of Plant Morphogenesis with Cellular Resolution

PubMed Central

Gilles, Benjamin; Hamant, Olivier; Boudaoud, Arezki; Traas, Jan; Godin, Christophe

2015-01-01

The link between genetic regulation and the definition of form and size during morphogenesis remains largely an open question in both plant and animal biology. This is partially due to the complexity of the process, involving extensive molecular networks, multiple feedbacks between different scales of organization and physical forces operating at multiple levels. Here we present a conceptual and modeling framework aimed at generating an integrated understanding of morphogenesis in plants. This framework is based on the biophysical properties of plant cells, which are under high internal turgor pressure, and are prevented from bursting because of the presence of a rigid cell wall. To control cell growth, the underlying molecular networks must interfere locally with the elastic and/or plastic extensibility of this cell wall. We present a model in the form of a three dimensional (3D) virtual tissue, where growth depends on the local modulation of wall mechanical properties and turgor pressure. The model shows how forces generated by turgor-pressure can act both cell autonomously and non-cell autonomously to drive growth in different directions. We use simulations to explore lateral organ formation at the shoot apical meristem. Although different scenarios lead to similar shape changes, they are not equivalent and lead to different, testable predictions regarding the mechanical and geometrical properties of the growing lateral organs. Using flower development as an example, we further show how a limited number of gene activities can explain the complex shape changes that accompany organ outgrowth. PMID:25569615

Conditions for Fully Autonomous Anticipation

NASA Astrophysics Data System (ADS)

Collier, John

2006-06-01

Anticipation allows a system to adapt to conditions that have not yet come to be, either externally to the system or internally. Autonomous systems actively control the conditions of their own existence so as to increase their overall viability. This paper will first give minimal necessary and sufficient conditions for autonomous anticipation, followed by a taxonomy of autonomous anticipation. In more complex systems, there can be semi-autonomous subsystems that can anticipate and adapt on their own. Such subsystems can be integrated into a system's overall autonomy, typically with greater efficiency due to modularity and specialization of function. However, it is also possible that semi-autonomous subsystems can act against the viability of the overall system, and have their own functions that conflict with overall system functions.

Microcapsule-based techniques for improving the safety of lithium-ion batteries

NASA Astrophysics Data System (ADS)

Baginska, Marta

Lithium-ion batteries are vital energy storage devices due to their high specific energy density, lack of memory effect, and long cycle life. While they are predominantly used in small consumer electronics, new strategies for improving battery safety and lifetime are critical to the successful implementation of high-capacity, fast-charging materials required for advanced Li-ion battery applications. Currently, the presence of a volatile, combustible electrolyte and an oxidizing agent (Lithium oxide cathodes) make the Li-ion cell susceptible to fire and explosions. Thermal overheating, electrical overcharging, or mechanical damage can trigger thermal runaway, and if left unchecked, combustion of battery materials. To improve battery safety, autonomic, thermally-induced shutdown of Li-ion batteries is demonstrated by depositing thermoresponsive polymer microspheres onto battery anodes. When the internal temperature of the cell reaches a critical value, the microspheres melt and conformally coat the anode and/or separator with an ion insulating barrier, halting Li-ion transport and shutting down the cell permanently. Charge and discharge capacity is measured for Li-ion coin cells containing microsphere-coated anodes or separators as a function of capsule coverage. Scanning electron microscopy images of electrode surfaces from cells that have undergone autonomic shutdown provides evidence of melting, wetting, and re-solidification of polyethylene (PE) into the anode and polymer film formation at the anode/separator interface. As an extension of this autonomic shutdown approach, a particle-based separator capable of performing autonomic shutdown, but which reduces the shorting hazard posed by current bi- and tri-polymer commercial separators, is presented. This dual-particle separator is composed of hollow glass microspheres acting as a physical spacer between electrodes, and PE microspheres to impart autonomic shutdown functionality. An oil-immersion technique is developed to simulate an overheating condition while the cell is cycling. Experimental protocols are developed to assess the performance of the separator in terms of its ability to perform autonomic shutdown and examine tested battery materials using scanning electron microscopy. Another approach to improving battery functionality is via the microencapsulation of battery additives. Currently, additives are added directly into a battery electrolyte, and while they typically perform their function given a sufficient loading, these additives often do so at the expense of battery performance. Microencapsulation allows for a high loading of additives to be incorporated into the cell and their release triggered only when and where they are needed. In this work, microencapsulation techniques are developed to successfully encapsulate 3-hexylthiophene, a stabilizing agent for high-voltage cathodes in Li-ion batteries and conductive polymer precursor, as well as the flame retardant Tris(2-choloroethyl phosphate) (TCP). Microcapsules containing 3-hexylthiophene are coated onto model battery electrodes and immersed in electrolyte. The microcapsule shell wall insulates the 3-hexylthiophene until the microcapsules are mechanically crushed and electropolymerization of the released core to form poly(3-ht) occurs under cyclic voltammetry. In addition, TCP was encapsulated using in situ polymerization. TCP-containing microcapsules are stable in electrolyte at room temperature, but are thermally triggered to release their payload at elevated temperatures. Experimental protocols are developed to study the in situ triggering and release of microencapsulated additives.

Conventional light chains inhibit the autonomous signaling capacity of the B cell receptor.

PubMed

Meixlsperger, Sonja; Köhler, Fabian; Wossning, Thomas; Reppel, Michael; Müschen, Markus; Jumaa, Hassan

2007-03-01

Signals from the B cell antigen receptor (BCR), consisting of mu heavy chain (muHC) and conventional light chain (LC), and its precursor the pre-BCR, consisting of muHC and surrogate light chain (SLC), via the adaptor protein SLP-65 regulate the development and function of B cells. Here, we compare the effect of SLC and conventional LC expression on receptor-induced Ca(2+) flux in B cells expressing an inducible form of SLP-65. We found that SLC expression strongly enhanced an autonomous ability of muHC to induce Ca(2+) flux irrespective of additional receptor crosslinking. In contrast, LC expression reduced this autonomous muHC ability and resulted in antigen-dependent Ca(2+) flux. These data indicate that autonomous ligand-independent signaling can be induced by receptor forms other than the pre-BCR. In addition, our data suggest that conventional LCs play an important role in the inhibition of autonomous receptor signaling, thereby allowing further B cell differentiation.

The double-stranded RNA binding protein RDE-4 can act cell autonomously during feeding RNAi in C. elegans

PubMed Central

Raman, Pravrutha; Zaghab, Soriayah M.; Traver, Edward C.

2017-01-01

Abstract Long double-stranded RNA (dsRNA) can silence genes of matching sequence upon ingestion in many invertebrates and is therefore being developed as a pesticide. Such feeding RNA interference (RNAi) is best understood in the worm Caenorhabditis elegans, where the dsRNA-binding protein RDE-4 initiates silencing by recruiting an endonuclease to process long dsRNA into short dsRNA. These short dsRNAs are thought to move between cells because muscle-specific rescue of rde-4 using repetitive transgenes enables silencing in other tissues. Here, we extend this observation using additional promoters, report an inhibitory effect of repetitive transgenes, and discover conditions for cell-autonomous silencing in animals with tissue-specific rescue of rde-4. While expression of rde-4(+) in intestine, hypodermis, or neurons using a repetitive transgene can enable silencing also in unrescued tissues, silencing can be inhibited wihin tissues that express a repetitive transgene. Single-copy transgenes that express rde-4(+) in body-wall muscles or hypodermis, however, enable silencing selectively in the rescued tissue but not in other tissues. These results suggest that silencing by the movement of short dsRNA between cells is not an obligatory feature of feeding RNAi in C. elegans. We speculate that similar control of dsRNA movement could modulate tissue-specific silencing by feeding RNAi in other invertebrates. PMID:28541563

Maintenance of Glia in the Optic Lamina Is Mediated by EGFR Signaling by Photoreceptors in Adult Drosophila

PubMed Central

Lee, Yuan-Ming; Sun, Y. Henry

2015-01-01

The late onset of neurodegeneration in humans indicates that the survival and function of cells in the nervous system must be maintained throughout adulthood. In the optic lamina of the adult Drosophila, the photoreceptor axons are surrounded by multiple types of glia. We demonstrated that the adult photoreceptors actively contribute to glia maintenance in their target field within the optic lamina. This effect is dependent on the epidermal growth factor receptor (EGFR) ligands produced by the R1-6 photoreceptors and transported to the optic lamina to act on EGFR in the lamina glia. EGFR signaling is necessary and sufficient to act in a cell-autonomous manner in the lamina glia. Our results suggest that EGFR signaling is required for the trafficking of the autophagosome/endosome to the lysosome. The loss of EGFR signaling results in cell degeneration most likely because of the accumulation of autophagosomes. Our findings provide in vivo evidence for the role of adult neurons in the maintenance of glia and a novel role for EGFR signaling in the autophagic flux. PMID:25909451

Persistence, period and precision of autonomous cellular oscillators from the zebrafish segmentation clock

PubMed Central

Webb, Alexis B; Lengyel, Iván M; Jörg, David J; Valentin, Guillaume; Jülicher, Frank; Morelli, Luis G; Oates, Andrew C

2016-01-01

In vertebrate development, the sequential and rhythmic segmentation of the body axis is regulated by a “segmentation clock”. This clock is comprised of a population of coordinated oscillating cells that together produce rhythmic gene expression patterns in the embryo. Whether individual cells autonomously maintain oscillations, or whether oscillations depend on signals from neighboring cells is unknown. Using a transgenic zebrafish reporter line for the cyclic transcription factor Her1, we recorded single tailbud cells in vitro. We demonstrate that individual cells can behave as autonomous cellular oscillators. We described the observed variability in cell behavior using a theory of generic oscillators with correlated noise. Single cells have longer periods and lower precision than the tissue, highlighting the role of collective processes in the segmentation clock. Our work reveals a population of cells from the zebrafish segmentation clock that behave as self-sustained, autonomous oscillators with distinctive noisy dynamics. DOI: http://dx.doi.org/10.7554/eLife.08438.001 PMID:26880542

Critically Reflective Work Behaviour within Autonomous Professionals' Learning Communities

ERIC Educational Resources Information Center

de Groot, Esther; van den Berg, B. A. M.; Endedijk, M. D.; van Beukelen, P.; Simons, P. R. J.

2011-01-01

Informal learning communities in which participants show critically reflective work behaviour (CRWB) have the potential to support lifelong learning. In practice this behaviour does not always occur in groups of autonomous professionals. This study explores design principles (DPs) that could act as social affordances for CRWB, within the context…

Huntingtin Acts Non Cell-Autonomously on Hippocampal Neurogenesis and Controls Anxiety-Related Behaviors in Adult Mouse

PubMed Central

Pla, Patrick; Orvoen, Sophie; Benstaali, Caroline; Dodier, Sophie; Gardier, Alain M.; David, Denis J.; Humbert, Sandrine; Saudou, Frédéric

2013-01-01

Huntington’s disease (HD) is a fatal neurodegenerative disease, characterized by motor defects and psychiatric symptoms, including mood disorders such as anxiety and depression. HD is caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin (HTT) protein. The development and analysis of various mouse models that express pathogenic polyQ-HTT revealed a link between mutant HTT and the development of anxio-depressive behaviors and various hippocampal neurogenesis defects. However, it is unclear whether such phenotype is linked to alteration of HTT wild-type function in adults. Here, we report the analysis of a new mouse model in which HTT is inducibly deleted from adult mature cortical and hippocampal neurons using the CreERT2/Lox system. These mice present defects in both the survival and the dendritic arborization of hippocampal newborn neurons. Our data suggest that these non-cell autonomous effects are linked to defects in both BDNF transport and release upon HTT silencing in hippocampal neurons, and in BDNF/TrkB signaling. The controlled deletion of HTT also had anxiogenic-like effects. Our results implicate endogenous wild-type HTT in adult hippocampal neurogenesis and in the control of mood disorders. PMID:24019939

In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons.

PubMed

Thomas, Elizabeth A; Coppola, Giovanni; Tang, Bin; Kuhn, Alexandre; Kim, SoongHo; Geschwind, Daniel H; Brown, Timothy B; Luthi-Carter, Ruth; Ehrlich, Michelle E

2011-03-15

Huntington's disease (HD), caused by a CAG repeat expansion in the huntingtin (HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatum in vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared with those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support. While genes related to excitotoxicity, dopamine signaling and trophic support were altered in both DE5 and R6/2 mice, which may be either cell autonomous or non-cell autonomous, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell-autonomous mechanisms. Overall, HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt, in the absence of expression in cortical neurons.

Endocardial Hippo signaling regulates myocardial growth and cardiogenesis.

PubMed

Artap, Stanley; Manderfield, Lauren J; Smith, Cheryl L; Poleshko, Andrey; Aghajanian, Haig; See, Kelvin; Li, Li; Jain, Rajan; Epstein, Jonathan A

2018-08-01

The Hippo signaling pathway has been implicated in control of cell and organ size, proliferation, and endothelial-mesenchymal transformation. This pathway impacts upon two partially redundant transcription cofactors, Yap and Taz, that interact with other factors, including members of the Tead family, to affect expression of downstream genes. Yap and Taz have been shown to regulate, in a cell-autonomous manner, myocardial proliferation, myocardial hypertrophy, regenerative potential, and overall size of the heart. Here, we show that Yap and Taz also play an instructive, non-cell-autonomous role in the endocardium of the developing heart to regulate myocardial growth through release of the paracrine factor, neuregulin. Without endocardial Yap and Taz, myocardial growth is impaired causing early post-natal lethality. Thus, the Hippo signaling pathway regulates cell size via both cell-autonomous and non-cell-autonomous mechanisms. Furthermore, these data suggest that Hippo may regulate organ size via a sensing and paracrine function in endothelial cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Oncogenic Kit signals on endolysosomes and endoplasmic reticulum are essential for neoplastic mast cell proliferation

PubMed Central

Obata, Yuuki; Toyoshima, Shota; Wakamatsu, Ei; Suzuki, Shunichi; Ogawa, Shuhei; Esumi, Hiroyasu; Abe, Ryo

2014-01-01

Kit is a receptor-type tyrosine kinase found on the plasma membrane. It can transform mast cells through activating mutations. Here, we show that a mutant Kit from neoplastic mast cells from mice, Kit(D814Y), is permanently active and allows cells to proliferate autonomously. It does so by activating two signalling pathways from different intracellular compartments. Mutant Kit from the cell surface accumulates on endolysosomes through clathrin-mediated endocytosis, which requires Kit’s kinase activity. Kit(D814Y) is constitutively associated with phosphatidylinositol 3-kinase, but the complex activates Akt only on the cytoplasmic surface of endolysosomes. It resists destruction because it is under-ubiquitinated. Kit(D814Y) also appears in the endoplasmic reticulum soon after biosynthesis, and there, can activate STAT5 aberrantly. These mechanisms of oncogenic signalling are also seen in rat and human mast cell leukemia cells. Thus, oncogenic Kit signalling occurs from different intracellular compartments, and the mutation acts by altering Kit trafficking as well as activation. PMID:25493654

α3 Chains of type V collagen regulate breast tumour growth via glypican-1

PubMed Central

Huang, Guorui; Ge, Gaoxiang; Izzi, Valerio; Greenspan, Daniel S.

2017-01-01

Pericellular α3(V) collagen can affect the functioning of cells, such as adipocytes and pancreatic β cells. Here we show that α3(V) chains are an abundant product of normal mammary gland basal cells, and that α3(V) ablation in a mouse mammary tumour model inhibits mammary tumour progression by reducing the proliferative potential of tumour cells. These effects are shown to be primarily cell autonomous, from loss of α3(V) chains normally produced by tumour cells, in which they affect growth by enhancing the ability of cell surface proteoglycan glypican-1 to act as a co-receptor for FGF2. Thus, a mechanism is presented for microenvironmental influence on tumour growth. α3(V) chains are produced in both basal-like and luminal human breast tumours, and its expression levels are tightly coupled with those of glypican-1 across breast cancer types. Evidence indicates α3(V) chains as potential targets for inhibiting tumour growth and as markers of oncogenic transformation. PMID:28102194

Intercellular interaction mechanisms for the origination of blast crisis in chronic myeloid leukemia

PubMed Central

Sachs, Rainer; Johnsson, Kerstin; Hahnfeldt, Philip; Luo, Janet; Chen, Allen; Hlatky, Lynn

2011-01-01

Chronic myeloid leukemia (CML) is characterized by a specific chromosome translocation, and its pathobiology is considered comparatively well understood. Thus, quantitative analysis of CML and its progression to blast crisis may help elucidate general mechanisms of carcinogenesis and cancer progression. Hitherto it has been widely postulated that CML blast crisis originates mainly via cell-autonomous mechanisms such as secondary mutations or genomic instability, rather than by intercellular interactions. However, recent results suggest that intercellular interactions play an important role in carcinogenesis. In this study, we analyzed alternative mechanisms, including pairwise intercellular interactions, for CML blast crisis origination. A quantitative, mechanistic cell population dynamics model was employed. This model used recent data on imatinib-treated CML; it also used earlier clinical data, not previously incorporated into current mathematical CML/imatinib models. With the pre-imatinib data, which include results on many more blast crises, we obtained evidence that the driving mechanism for blast crisis origination is intercellular interaction between specific cell types. Assuming leukemic-normal interactions resulted in a statistically significant improvement over assuming either cell-autonomous mechanisms or interactions between leukemic cells. This conclusion was robust with regard to changes in the model’s adjustable parameters. Application of the results to patients treated with imatinib suggests that imatinib may act not only on malignant blast precursors, but also, to a limited degree, on the malignant blasts themselves. Major Findings A comprehensive mechanistic model gives evidence that the main driving mechanisms for CML blast crisis origination are interactions between leukemic and normal cells. PMID:21487044

Agent Technology, Complex Adaptive Systems, and Autonomic Systems: Their Relationships

NASA Technical Reports Server (NTRS)

Truszkowski, Walt; Rash, James; Rouff, Chistopher; Hincheny, Mike

2004-01-01

To reduce the cost of future spaceflight missions and to perform new science, NASA has been investigating autonomous ground and space flight systems. These goals of cost reduction have been further complicated by nanosatellites for future science data-gathering which will have large communications delays and at times be out of contact with ground control for extended periods of time. This paper describes two prototype agent-based systems, the Lights-out Ground Operations System (LOGOS) and the Agent Concept Testbed (ACT), and their autonomic properties that were developed at NASA Goddard Space Flight Center (GSFC) to demonstrate autonomous operations of future space flight missions. The paper discusses the architecture of the two agent-based systems, operational scenarios of both, and the two systems autonomic properties.

Distinct palisade tissue development processes promoted by leaf autonomous signalling and long-distance signalling in Arabidopsis thaliana.

PubMed

Munekage, Yuri Nakajima; Inoue, Shio; Yoneda, Yuki; Yokota, Akiho

2015-06-01

Plants develop palisade tissue consisting of cylindrical mesophyll cells located at the adaxial side of leaves in response to high light. To understand high light signalling in palisade tissue development, we investigated leaf autonomous and long-distance signal responses of palisade tissue development using Arabidopsis thaliana. Illumination of a developing leaf with high light induced cell height elongation, whereas illumination of mature leaves with high light increased cell density and suppressed cell width expansion in palisade tissue of new leaves. Examination using phototropin1 phototropin2 showed that blue light signalling mediated by phototropins was involved in cell height elongation of the leaf autonomous response rather than the cell density increase induced by long-distance signalling. Hydrogen peroxide treatment induced cylindrical palisade tissue cell formation in both a leaf autonomous and long-distance manner, suggesting involvement of oxidative signals. Although constitutive expression of transcription factors involved in systemic-acquired acclimation to excess light, ZAT10 and ZAT12, induced cylindrical palisade tissue cell formation, knockout of these genes did not affect cylindrical palisade tissue cell formation. We conclude that two distinct signalling pathways - leaf autonomous signalling mostly dependent on blue light signalling and long-distance signalling from mature leaves that sense high light and oxidative stress - control palisade tissue development in A. thaliana. © 2014 John Wiley & Sons Ltd.

[Occupational health in the Autonomous Community of the Basque Country. OSALAN-Instituto Vasco de Seguridad y Salud Laborales].

PubMed

Martínez Castillo, A; Achutegui Basagoiti, G

1996-01-01

O.S.A.L.A.N.-Instituto Vasco de Seguridad y Salud Laborales is an autonomous administrative body depending on the Basque Government, ascribed to the Dept. of Justice, Economy, Work and Social Security, which is in charge of managing the general occupational health policies in the Autonomous Community of the Basque Country. Its objectives are: To promote an ongoing improvement in safety and occupational health for all the workers in the Basque Autonomous Region, through the management of programmes in matters affecting safety, hygiene, the environment and occupational health. To co-ordinate and concentrate the different activities related to occupational health, unifying and giving coherence to the functions which were previously the jurisdiction of different departments. Making companies aware of national and E.U. regulations, taking the measures that are set out by the European Directives and the Prevention of Occupational Hazards Act and the rest of the employment regulations, establishing the training and information channels required for promoting and applying these in the companies. It acts: from an overall perspective as regards the prevention of occupational hazards, thanks to co-ordination with all the disciplines involved, applying a multi-disciplinary treatment to the study of each and every one of the occupational hazard factors, which is aimed at the prevention of risks at their source. Providing companies with the ideal means for managing the safety and health of their workers. Promoting the implementation of systems which guarantee an ongoing improvement in occupational safety and health in the companies of the Basque Autonomous Region. Providing the technical and research support that makes it possible to tackle prevention efficiently. The provision established in the Creation Act (O.S.A.L.A.N.) should also be mentioned, as regards its application in public administration and the field of social economy, which was later endorsed and ratified through inclusion in the recent Prevention of Occupational Hazards Act.

Activin-like signal activates dorsal-specific maternal RNA between 8- and 16-cell stages of Xenopus.

PubMed

Hainski, A M; Moody, S A

1996-01-01

In many animals the dorsal-ventral axis forms by an initial localization of maternal molecules, which then regulate the spatial location of signals that directly influence the expression of axis-specific fates. Several recent studies have demonstrated that dorsal-animal blastomeres of the Xenopus morula (8-32 cells) are biased toward dorsal fates prior to mesoderm inductive signaling. In this study we ask whether the dorsal bias is the result of autonomous expression of maternal molecules specifically localized within dorsal cells or of early activating signals. It was found that although 16-cell dorsal-animal blastomeres (D1.1) can differentiate into dorsal tissues when cultured alone, the 8-cell mothers (D1) can not. Likewise, although RNA extracted from D1.1 can induce an extra dorsal axis when injected into vegetal blastomeres, RNA extracted from D1 can not. However, D1 does express dorsal tissues if co-cultured with dorsal-vegetal cells or with culture medium containing a mixture of activins (PIF-medium). Furthermore, short-term culture of D1 in PIF-medium enables the D1 RNA to induce an ectopic dorsal axis. Ventral-animal blastomeres also can express dorsal axial tissues when co-cultured with dorsal-vegetal blastomeres or in PIF-medium, but the RNA from the activin-treated ventral cells cannot induce ectopic dorsal axes. These studies demonstrate that there are maternal RNAs that, shortly after fertilization, are present only in the dorsal-animal region. They do not act cell autonomously, but require an activin-like signal. These RNAs may function by increasing the responsiveness of dorsal-animal blastomeres to the mesoderm inductive signals present in both the morula and the blastula.

PCP Signaling between Migrating Neurons and their Planar-Polarized Neuroepithelial Environment Controls Filopodial Dynamics and Directional Migration

PubMed Central

Moens, Cecilia B.

2016-01-01

The planar cell polarity (PCP) pathway is a cell-contact mediated mechanism for transmitting polarity information between neighboring cells. PCP “core components” (Vangl, Fz, Pk, Dsh, and Celsr) are essential for a number of cell migratory events including the posterior migration of facial branchiomotor neurons (FBMNs) in the plane of the hindbrain neuroepithelium in zebrafish and mice. While the mechanism by which PCP signaling polarizes static epithelial cells is well understood, how PCP signaling controls highly dynamic processes like neuronal migration remains an important outstanding question given that PCP components have been implicated in a range of directed cell movements, particularly during vertebrate development. Here, by systematically disrupting PCP signaling in a rhombomere-restricted manner we show that PCP signaling is required both within FBMNs and the hindbrain rhombomere 4 environment at the time when they initiate their migration. Correspondingly, we demonstrate planar polarized localization of PCP core components Vangl2 and Fzd3a in the hindbrain neuroepithelium, and transient localization of Vangl2 at the tips of retracting FBMN filopodia. Using high-resolution timelapse imaging of FBMNs in genetic chimeras we uncover opposing cell-autonomous and non-cell-autonomous functions for Fzd3a and Vangl2 in regulating FBMN protrusive activity. Within FBMNs, Fzd3a is required to stabilize filopodia while Vangl2 has an antagonistic, destabilizing role. However, in the migratory environment Fzd3a acts to destabilize FBMN filopodia while Vangl2 has a stabilizing role. Together, our findings suggest a model in which PCP signaling between the planar polarized neuroepithelial environment and FBMNs directs migration by the selective stabilization of FBMN filopodia. PMID:26990447

Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology

PubMed Central

Ballas, Nurit; Lioy, Daniel T.; Grunseich, Christopher; Mandel, Gail

2011-01-01

The neurodevelopmental disorder Rett Syndrome (RTT) is caused by sporadic mutations in the transcriptional factor methyl-CpG binding protein 2 (MeCP2). Although it is thought that the primary cause of RTT is cell autonomous due to lack of functional MeCP2 in neurons, whether non-cell autonomous factors contribute to the disease, is unknown. Here, we show that loss of MeCP2 occurs not only in neurons but also in glial cells of RTT brain. Using an in vitro co-culture system, we find that mutant astrocytes from a RTT mouse model, and their conditioned medium, fail to support normal dendritic morphology of either wild-type or mutant hippocampal neurons. Our studies suggest that in RTT brain, astrocytes carrying MeCP2 mutations have a non-cell autonomous effect on neuronal properties, likely due to aberrant secretion of soluble factor(s). PMID:19234456

Computational modeling of the cell-autonomous mammalian circadian oscillator.

PubMed

Podkolodnaya, Olga A; Tverdokhleb, Natalya N; Podkolodnyy, Nikolay L

2017-02-24

This review summarizes various mathematical models of cell-autonomous mammalian circadian clock. We present the basics necessary for understanding of the cell-autonomous mammalian circadian oscillator, modern experimental data essential for its reconstruction and some special problems related to the validation of mathematical circadian oscillator models. This work compares existing mathematical models of circadian oscillator and the results of the computational studies of the oscillating systems. Finally, we discuss applications of the mathematical models of mammalian circadian oscillator for solving specific problems in circadian rhythm biology.

β-Catenin activation regulates tissue growth non-cell autonomously in the hair stem cell niche.

PubMed

Deschene, Elizabeth R; Myung, Peggy; Rompolas, Panteleimon; Zito, Giovanni; Sun, Thomas Yang; Taketo, Makoto M; Saotome, Ichiko; Greco, Valentina

2014-03-21

Wnt/β-catenin signaling is critical for tissue regeneration. However, it is unclear how β-catenin controls stem cell behaviors to coordinate organized growth. Using live imaging, we show that activation of β-catenin specifically within mouse hair follicle stem cells generates new hair growth through oriented cell divisions and cellular displacement. β-Catenin activation is sufficient to induce hair growth independently of mesenchymal dermal papilla niche signals normally required for hair regeneration. Wild-type cells are co-opted into new hair growths by β-catenin mutant cells, which non-cell autonomously activate Wnt signaling within the neighboring wild-type cells via Wnt ligands. This study demonstrates a mechanism by which Wnt/β-catenin signaling controls stem cell-dependent tissue growth non-cell autonomously and advances our understanding of the mechanisms that drive coordinated regeneration.

Choice and ego-depletion: the moderating role of autonomy.

PubMed

Moller, Arlen C; Deci, Edward L; Ryan, Richard M

2006-08-01

The self-regulatory strength model maintains that all acts of self-regulation, self-control, and choice result in a state of fatigue called ego-depletion. Self-determination theory differentiates between autonomous regulation and controlled regulation. Because making decisions represents one instance of self-regulation, the authors also differentiate between autonomous choice and controlled choice. Three experiments support the hypothesis that whereas conditions representing controlled choice would be egodepleting, conditions that represented autonomous choice would not. In Experiment 3, the authors found significant mediation by perceived self-determination of the relation between the choice condition (autonomous vs. controlled) and ego-depletion as measured by performance.

The double-stranded RNA binding protein RDE-4 can act cell autonomously during feeding RNAi in C. elegans.

PubMed

Raman, Pravrutha; Zaghab, Soriayah M; Traver, Edward C; Jose, Antony M

2017-08-21

Long double-stranded RNA (dsRNA) can silence genes of matching sequence upon ingestion in many invertebrates and is therefore being developed as a pesticide. Such feeding RNA interference (RNAi) is best understood in the worm Caenorhabditis elegans, where the dsRNA-binding protein RDE-4 initiates silencing by recruiting an endonuclease to process long dsRNA into short dsRNA. These short dsRNAs are thought to move between cells because muscle-specific rescue of rde-4 using repetitive transgenes enables silencing in other tissues. Here, we extend this observation using additional promoters, report an inhibitory effect of repetitive transgenes, and discover conditions for cell-autonomous silencing in animals with tissue-specific rescue of rde-4. While expression of rde-4(+) in intestine, hypodermis, or neurons using a repetitive transgene can enable silencing also in unrescued tissues, silencing can be inhibited wihin tissues that express a repetitive transgene. Single-copy transgenes that express rde-4(+) in body-wall muscles or hypodermis, however, enable silencing selectively in the rescued tissue but not in other tissues. These results suggest that silencing by the movement of short dsRNA between cells is not an obligatory feature of feeding RNAi in C. elegans. We speculate that similar control of dsRNA movement could modulate tissue-specific silencing by feeding RNAi in other invertebrates. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

The Hippo Pathway Regulates Homeostatic Growth of Stem Cell Niche Precursors in the Drosophila Ovary

PubMed Central

Sarikaya, Didem P.; Extavour, Cassandra G.

2015-01-01

The Hippo pathway regulates organ size, stem cell proliferation and tumorigenesis in adult organs. Whether the Hippo pathway influences establishment of stem cell niche size to accommodate changes in organ size, however, has received little attention. Here, we ask whether Hippo signaling influences the number of stem cell niches that are established during development of the Drosophila larval ovary, and whether it interacts with the same or different effector signaling pathways in different cell types. We demonstrate that canonical Hippo signaling regulates autonomous proliferation of the soma, while a novel hippo-independent activity of Yorkie regulates autonomous proliferation of the germ line. Moreover, we demonstrate that Hippo signaling mediates non-autonomous proliferation signals between germ cells and somatic cells, and contributes to maintaining the correct proportion of these niche precursors. Finally, we show that the Hippo pathway interacts with different growth pathways in distinct somatic cell types, and interacts with EGFR and JAK/STAT pathways to regulate non-autonomous proliferation of germ cells. We thus provide evidence for novel roles of the Hippo pathway in establishing the precise balance of soma and germ line, the appropriate number of stem cell niches, and ultimately regulating adult female reproductive capacity. PMID:25643260

Synthetic Deletion of the Interleukin 23 Receptor (IL-23R) Stalk Region Led to Autonomous IL-23R Homodimerization and Activation.

PubMed

Hummel, Thorben M; Ackfeld, Theresa; Schönberg, Marco; Ciupka, Gregor; Schulz, Falk; Oberdoerster, Anne; Grötzinger, Joachim; Scheller, Jürgen; Floss, Doreen M

2017-09-01

Interleukin 23 (IL-23) regulates the development of TH17 cells, which are important for antimicrobial and antifungal responses and autoimmune and chronic inflammatory diseases. IL-23-induced Jak/STAT signaling is mediated via the heterodimeric IL-23 receptor (IL-23R)-IL-12 receptor β1 (IL-12Rβ1) complex. The typical signal-transducing receptor of the IL-6/IL-12 family contains three extracellular-membrane-proximal fibronectin type III (FNIII) domains, which are not involved in cytokine binding but are mandatory for signal transduction. In place of FNIII-type domains, IL-23R has a structurally undefined stalk. We hypothesized that the IL-23R stalk acts as a spacer to position the cytokine binding domains at a defined distance from the plasma membrane to enable signal transduction. Minor deletions of the murine, but not of the human, IL-23R stalk resulted in unresponsiveness to IL-23. Complete deletion of the human IL-23R stalk and the extended murine IL-23R stalk, including a 20-amino-acid-long duplication of domain 3, however, induced ligand-independent, autonomous receptor activation, as determined by STAT3 phosphorylation and cell proliferation. Ligand-independent, autonomous activity was caused by IL-23R homodimers and was independent of IL-12Rβ1. Our data show that deletion of the stalk results in biologically active IL-23R homodimers, thereby creating an as-yet-undescribed receptor complex of the IL-6/IL-12 cytokine family. Copyright © 2017 American Society for Microbiology.

Clinical findings associated with cardiovascular autonomic dysfunction in adult sickle cell anaemia patients.

PubMed

Oguanobi, Nelson I; Onwubere, Basden J C; Anisiuba, Benedict C; Ike, Samuel O; Ejim, Emmanuel C; Ibegbulam, Obike G

2012-04-01

Involvement of the cardiovascular autonomic nervous system in various diseases is often associated with increased morbidity and mortality. The objective of this study was to examine the clinical features associated with cardiovascular autonomic neuropathy (CAN) in adult Nigerians with sickle cell anaemia. A cross-sectional study was carried out on 62 steady state sickle cell anaemia patients recruited from the adult out-patient clinic. Cardiovascular autonomic dysfunction was determined based on abnormal values in at least two of five non-invasive tests: Valsalva manoeuvre, heart rate variation during deep breathing, heart rate response to standing, blood pressure response to sustained handgrip, and blood pressure response to standing. All the subjects were initially evaluated in the clinic for symptoms of cardiovascular disease and peripheral vascular disease, and then clinically examined to assess their cardiovascular and neurological status at rest. Out of the 44 patients with cardiovascular autonomic neuropathy 23 were males, while 21 were females. The mean ages were 28.3 +/- 5.8 y for patients with CAN and 28.0 +/- 5.0 y for patients without CAN (P = 0.817). Sickle cell anaemia patients with CAN had significantly lower ankle systolic blood pressure, reduced ankle brachial blood pressure index, mean arterial blood pressure and haematocrit than patients without CAN. Of all the variables evaluated leg ulcers, postural dizziness, erectile dysfunction in men, and history of recurrent acute chest syndromes were found significantly more in patients with CAN than without. Clinical abnormalities tend to worsen with increasing degree of cardiovascular autonomic dysfunction. Significant cardiac morbidity is associated with abnormal cardiovascular autonomic function in sickle cell anaemia.

Framing the ultimatum game: gender differences and autonomic responses.

PubMed

Sarlo, Michela; Lotto, Lorella; Palomba, Daniela; Scozzari, Simona; Rumiati, Rino

2013-01-01

The present study aimed at investigating whether the way offers are framed in the Ultimatum Game (UG) affects behavioral and autonomic responses in men and women. The "I give you" and "I take" expressions were used as gain and loss frames, respectively. Skin conductance and heart rate were recorded as indices of autonomic activation in response to unfair, mid-value, and fair offers. Acceptance rates were higher in men than in women under the gain frame. Moreover, men showed higher acceptance rates under the gain than under the loss frame with mid-value offers, whereas women's choices were not affected by frame. On the physiological level, men produced differential autonomic response patterns during decision-making when offers were presented under gain and loss framing. The "I take" frame, by acting as a loss frame, elicited in men the characteristic defensive response pattern that is evoked by aversive stimulation, in which increases in skin conductance are coupled with increases in heart rate. On the other hand, the "I give you" frame, by acting as a gain frame, elicited in men increases in skin conductance associated with prevailing heart rate deceleratory responses, reflecting a state of enhanced attention and orienting. In contrast, women's autonomic reactivity was not affected by frame, consistent with behavioral results. Phasic changes in heart rate were crucial in revealing differential functional significance of skin conductance responses under different frames in men, thus questioning the assumption that this autonomic measure can be used as an index of negative emotional arousal in the UG.

Olfactory ensheathing cells but not fibroblasts reduce the duration of autonomic dysreflexia in spinal cord injured rats.

PubMed

Cloutier, Frank; Kalincik, Tomas; Lauschke, Jenny; Tuxworth, Gervase; Cavanagh, Brenton; Meedeniya, Adrian; Mackay-Sim, Alan; Carrive, Pascal; Waite, Phil

2016-12-01

Autonomic dysreflexia is a common complication after high level spinal cord injury and can be life-threatening. We have previously shown that the acute transplantation of olfactory ensheathing cells into the lesion site of rats transected at the fourth thoracic spinal cord level reduced autonomic dysreflexia up to 8weeks after spinal cord injury. This beneficial effect was correlated with changes in the morphology of sympathetic preganglionic neurons despite the olfactory cells surviving no longer than 3weeks. Thus the transitory presence of olfactory ensheathing cells at the injury site initiated long-term functional as well as morphological changes in the sympathetic preganglionic neurons. The primary aim of the present study was to evaluate whether olfactory ensheathing cells survive after transplantation within the parenchyma close to sympathetic preganglionic neurons and whether, in this position, they still reduce the duration of autonomic dysreflexia and modulate sympathetic preganglionic neuron morphology. The second aim was to quantify the density of synapses on the somata of sympathetic preganglionic neurons with the hypothesis that the reduction of autonomic dysreflexia requires synaptic changes. As a third aim, we evaluated the cell type-specificity of olfactory ensheathing cells by comparing their effects with a control group transplanted with fibroblasts. Animals transplanted with OECs had a faster recovery from hypertension induced by colorectal distension at 6 and 7weeks but not at 8weeks after T4 spinal cord transection. Olfactory ensheathing cells survived for at least 8weeks and were observed adjacent to sympathetic preganglionic neurons whose overall number of primary dendrites was reduced and the synaptic density on the somata increased, both caudal to the lesion site. Our results showed a long term cell type-specific effects of olfactory ensheathing cells on sympathetic preganglionic neurons morphology and on the synaptic density on their somata, and a transient cell type-specific reduction of autonomic dysreflexia. Copyright © 2016 Elsevier B.V. All rights reserved.

The Drosophila BCL6 homolog Ken and Barbie promotes somatic stem cell self-renewal in the testis niche.

PubMed

Issigonis, Melanie; Matunis, Erika

2012-08-15

Stem cells sustain tissue regeneration by their remarkable ability to replenish the stem cell pool and to generate differentiating progeny. Signals from local microenvironments, or niches, control stem cell behavior. In the Drosophila testis, a group of somatic support cells called the hub creates a stem cell niche by locally activating the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway in two adjacent types of stem cells: germline stem cells (GSCs) and somatic cyst stem cells (CySCs). Here, we find that ken and barbie (ken) is autonomously required for the self-renewal of CySCs but not GSCs. Furthermore, Ken misexpression in the CySC lineage induces the cell-autonomous self-renewal of somatic cells as well as the nonautonomous self-renewal of germ cells outside the niche. Thus, Ken, like Stat92E and its targets ZFH1 (Leatherman and Dinardo, 2008) and Chinmo (Flaherty et al., 2010), is necessary and sufficient for CySC renewal. However, ken is not a JAK-STAT target in the testis, but instead acts in parallel to Stat92E to ensure CySC self-renewal. Ken represses a subset of Stat92E targets in the embryo (Arbouzova et al., 2006) suggesting that Ken maintains CySCs by repressing differentiation factors. In support of this hypothesis, we find that the global JAK-STAT inhibitor Protein tyrosine phosphatase 61F (Ptp61F) is a JAK-STAT target in the testis that is repressed by Ken. Together, our work demonstrates that Ken has an important role in the inhibition of CySC differentiation. Studies of ken may inform our understanding of its vertebrate orthologue B-Cell Lymphoma 6 (BCL6) and how misregulation of this oncogene leads to human lymphomas. Copyright © 2012 Elsevier Inc. All rights reserved.

The fern sporangium: an ultrafast natural catapult

NASA Astrophysics Data System (ADS)

Noblin, Xavier; Argentina, Mederic; Westbrook, Jared; Llorens, Coraline; Rojas, Nicolas; Dumais, Jacques

2012-02-01

Plants have developed fascinating mechanisms to create ultra fast movements that often reach the upper limit allowed by physical laws. Inspiration for new technologies is one of the reasons for the strong interest for these mechanisms, along with the deep interest of understanding complex, natural systems. The fern sporangium is a capsule that contains the spores, it is surrounded by a row of cells called the annulus which acts as a beam. Due to the water evaporation from its cells, the annulus bends strongly and induces elastic energy storage during an opening phase. The tension in the cells breaks when cavitation bubbles appear in the cells, leading to a fast release of the elastic energy. The fern sporangium then acts as a catapult which ejects rapidly its spores by closing back to the initial closed shape. We have analyzed the slow opening motion and the fast catapulting mechanism. We found that the catapult motion involves two time scales, showing a very original behavior. In man-made catapults, the recoil motion needs to be arrested by a cross bar so that the projectile is released from the arm. We show here that the fern sporangium replaces the essential cross bar by an elegant poroelastic damping, leading to a completely autonomous, efficient device.

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

Towards autonomous lab-on-a-chip devices for cell phone biosensing.

PubMed

Comina, Germán; Suska, Anke; Filippini, Daniel

2016-03-15

Modern cell phones are a ubiquitous resource with a residual capacity to accommodate chemical sensing and biosensing capabilities. From the different approaches explored to capitalize on such resource, the use of autonomous disposable lab-on-a-chip (LOC) devices-conceived as only accessories to complement cell phones-underscores the possibility to entirely retain cell phones' ubiquity for distributed biosensing. The technology and principles exploited for autonomous LOC devices are here selected and reviewed focusing on their potential to serve cell phone readout configurations. Together with this requirement, the central aspects of cell phones' resources that determine their potential for analytical detection are examined. The conversion of these LOC concepts into universal architectures that are readable on unaccessorized phones is discussed within this context. Copyright © 2015 Elsevier B.V. All rights reserved.

New transmitters and new targets in the autonomic nervous system.

PubMed

Barajas-López, C; Huizinga, J D

1993-12-01

Several recent findings have made research into the autonomic nervous system even more exciting, such as the revelation that nitric oxide is a major neurotransmitter, the delineation of the physiological roles for purines and vasoactive intestinal peptide, and the discovery that the interstitial cells of Cajal are major target cells for enteric innervation. Nitric oxide is probably the major neurotransmitter evoking inhibitory junction potentials in smooth muscle. ATP is a mediator of non-adrenergic non-cholinergic enteric innervation, as well as being a fast neurotransmitter in peripheral and autonomic neuro-neuronal synapses. The interactions between enteric nerves and both immune cells and interstitial cells of Cajal (as pacemaker cells of gut smooth muscle) are forcing a rethink of many aspects of gut physiology.

Performance assessment of polymer based electrodes for in vitro electrophysiological sensing: the role of the electrode impedance

NASA Astrophysics Data System (ADS)

Medeiros, Maria C. R.; Mestre, Ana L. G.; Inácio, Pedro M. C.; Santos, José M. L.; Araujo, Inês M.; Bragança, José; Biscarini, Fabio; Gomes, Henrique L.

2016-09-01

Conducting polymer electrodes based on poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) are used to record extracellular signals from autonomous cardiac contractile cells and glioma cell cultures. The performance of these conducting polymer electrodes is compared with Au electrodes. A small-signal impedance analysis shows that in the presence of an electrolyte, both Au and polymer electrodes establish high capacitive double-layers. However, the polymer/electrolyte interfacial resistance is 3 orders of magnitude lower than the resistance of the metal/electrolyte interface. The polymer low interfacial resistance minimizes the intrinsic thermal noise and increases the system sensitivity. However, when measurements are carried out in current mode a low interfacial resistance partially acts as a short circuit of the interfacial capacitance, this affects the signal shape.

naked cuticle targets dishevelled to antagonize Wnt signal transduction

PubMed Central

Rousset, Raphaël; Mack, Judith A.; Wharton, Keith A.; Axelrod, Jeffrey D.; Cadigan, Ken M.; Fish, Matthew P.; Nusse, Roel; Scott, Matthew P.

2001-01-01

In Drosophila embryos the protein Naked cuticle (Nkd) limits the effects of the Wnt signal Wingless (Wg) during early segmentation. nkd loss of function results in segment polarity defects and embryonic death, but how nkd affects Wnt signaling is unknown. Using ectopic expression, we find that Nkd affects, in a cell-autonomous manner, a transduction step between the Wnt signaling components Dishevelled (Dsh) and Zeste-white 3 kinase (Zw3). Zw3 is essential for repressing Wg target-gene transcription in the absence of a Wg signal, and the role of Wg is to relieve this inhibition. Our double-mutant analysis shows that, in contrast to Zw3, Nkd acts when the Wg pathway is active to restrain signal transduction. Yeast two hybrid and in vitro experiments indicate that Nkd directly binds to the basic-PDZ region of Dsh. Specially timed Nkd overexpression is capable of abolishing Dsh function in a distinct signaling pathway that controls planar-cell polarity. Our results suggest that Nkd acts directly through Dsh to limit Wg activity and thus determines how efficiently Wnt signals stabilize Armadillo (Arm)/β-catenin and activate downstream genes. PMID:11274052

Anterior pituitary cells defective in the cell-autonomous factor, df, undergo cell lineage specification but not expansion.

PubMed

Gage, P J; Roller, M L; Saunders, T L; Scarlett, L M; Camper, S A

1996-01-01

The Ames dwarf mouse transmits a recessive mutation (df) resulting in a profound anterior pituitary hypocellularity due to a general lack of thyrotropes, somatotropes and lactotropes. These cell types are also dependent on the pituitary-specific transcription factor, Pit-1. We present evidence that expression of Pit-1 and limited commitment to these cells lineages occurs in df/df pituitaries. Thus, the crucial role of df may be in lineage-specific proliferation, rather than cytodifferentiation. The presence of all three Pit-1-dependent cell types in clonally derived clusters provides compelling evidence that these three lineages share a common, pluripotent precursor cell. Clusters containing different combinations of Pit-1-dependent cell types suggests that the Pit-1+ precursor cells choose from multiple developmental options during ontogeny. Characterization of df/df<-->+/+ chimeric mice demonstrated that df functions by a cell-autonomous mechanism. Therefore, df and Pit-1 are both cell-autonomous factors required for thyrotrope, somatotrope and lactotrope ontogeny, but their relative roles are different.

Micronuclear DNA of Oxytricha nova contains sequences with autonomously replicating activity in Saccharomyces cerevisiae.

PubMed Central

Colombo, M M; Swanton, M T; Donini, P; Prescott, D M

1984-01-01

Oxytricha nova is a hypotrichous ciliate with micronuclei and macronuclei. Micronuclei, which contain large, chromosomal-sized DNA, are genetically inert but undergo meiosis and exchange during cell mating. Macronuclei, which contain only small, gene-sized DNA molecules, provide all of the nuclear RNA needed to run the cell. After cell mating the macronucleus is derived from a micronucleus, a derivation that includes excision of the genes from chromosomes and elimination of the remaining DNA. The eliminated DNA includes all of the repetitious sequences and approximately 95% of the unique sequences. We cloned large restriction fragments from the micronucleus that confer replication ability on a replication-deficient plasmid in Saccharomyces cerevisiae. Sequences that confer replication ability are called autonomously replicating sequences. The frequency and effectiveness of autonomously replicating sequences in micronuclear DNA are similar to those reported for DNAs of other organisms introduced into yeast cells. Of the 12 micronuclear fragments with autonomously replicating sequence activity, 9 also showed homology to macronuclear DNA, indicating that they contain a macronuclear gene sequence. We conclude from this that autonomously replicating sequence activity is nonrandomly distributed throughout micronuclear DNA and is preferentially associated with those regions of micronuclear DNA that contain genes. Images PMID:6092934

Zebrafish narrowminded suggests a genetic link between formation of neural crest and primary sensory neurons

PubMed Central

Bruk Artinger, Kristin; Chitnis, Ajay B.; Mercola, Mark; Driever, Wolfgang

2014-01-01

SUMMARY In the developing vertebrate nervous system, both neural crest and sensory neurons form at the boundary between non-neural ectoderm and the neural plate. From an in situ hybridization based expression analysis screen, we have identified a novel zebrafish mutation, narrowminded (nrd), which reduces the number of early neural crest cells and eliminates Rohon-Beard (RB) sensory neurons. Mosaic analysis has shown that the mutation acts cell autonomously suggesting that nrd is involved in either the reception or interpretation of signals at the lateral neural plate boundary. Characterization of the mutant phenotype indicates that nrd is required for a primary wave of neural crest cell formation during which progenitors generate both RB sensory neurons and neural crest cells. Moreover, the early deficit in neural crest cells in nrd homozygotes is compensated later in development. Thus, we propose that a later wave can compensate for the loss of early neural crest cells but, interestingly, not the RB sensory neurons. We discuss the implications of these findings for the possibility that RB sensory neurons and neural crest cells share a common evolutionary origin. PMID:10457007

Long-Term Dynamics of Autonomous Fractional Differential Equations

NASA Astrophysics Data System (ADS)

Liu, Tao; Xu, Wei; Xu, Yong; Han, Qun

This paper aims to investigate long-term dynamic behaviors of autonomous fractional differential equations with effective numerical method. The long-term dynamic behaviors predict where systems are heading after long-term evolution. We make some modification and transplant cell mapping methods to autonomous fractional differential equations. The mapping time duration of cell mapping is enlarged to deal with the long memory effect. Three illustrative examples, i.e. fractional Lotka-Volterra equation, fractional van der Pol oscillator and fractional Duffing equation, are studied with our revised generalized cell mapping method. We obtain long-term dynamics, such as attractors, basins of attraction, and saddles. Compared with some existing stability and numerical results, the validity of our method is verified. Furthermore, we find that the fractional order has its effect on the long-term dynamics of autonomous fractional differential equations.

Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii

PubMed Central

Boychuk, Carie R.; Gyarmati, Peter; Xu, Hong

2015-01-01

Changes in blood glucose concentration alter autonomic function in a manner consistent with altered neural activity in brain regions controlling digestive processes, including neurons in the brain stem nucleus tractus solitarii (NTS), which process viscerosensory information. With whole cell or on-cell patch-clamp recordings, responses to elevating glucose concentration from 2.5 to 15 mM were assessed in identified GABAergic NTS neurons in slices from transgenic mice that express EGFP in a subset of GABA neurons. Single-cell real-time RT-PCR was also performed to detect glutamic acid decarboxylase (GAD67) in recorded neurons. In most identified GABA neurons (73%), elevating glucose concentration from 2.5 to 15 mM resulted in either increased (40%) or decreased (33%) neuronal excitability, reflected by altered membrane potential and/or action potential firing. Effects on membrane potential were maintained when action potentials or fast synaptic inputs were blocked, suggesting direct glucose sensing by GABA neurons. Glucose-inhibited GABA neurons were found predominantly in the lateral NTS, whereas glucose-excited cells were mainly in the medial NTS, suggesting regional segregation of responses. Responses were prevented in the presence of glucosamine, a glucokinase (GCK) inhibitor. Depolarizing responses were prevented when KATP channel activity was blocked with tolbutamide. Whereas effects on synaptic input to identified GABAergic neurons were variable in GABA neurons, elevating glucose increased glutamate release subsequent to stimulation of tractus solitarius in unlabeled, unidentified neurons. These results indicate that GABAergic NTS neurons act as GCK-dependent glucose sensors in the vagal complex, providing a means of modulating central autonomic signals when glucose is elevated. PMID:26084907

Autonomic deficit not the cause of death in West Nile virus neurological disease.

PubMed

Wang, Hong; Siddharthan, Venkatraman; Hall, Jeffery O; Morrey, John D

2014-02-01

Some West Nile virus (WNV)-infected patients have been reported to manifest disease signs consistent with autonomic dysfunction. Moreover, WNV infection in hamsters causes reduced electromyography amplitudes of the gastrointestinal tract and diaphragm, and they have reduced heart rate variability (HRV), a read-out for the parasympathetic autonomic function. HRV was measured in both hamsters and mice using radiotelemetry to identify autonomic deficits. To identify areas of WNV infection within the medulla oblongata mapping to the dorsal motor nucleus of vagus (DMNV) and the nucleus ambiguus (NA), fluorogold dye was injected into the cervical trunk of the vagus nerve of hamsters. As a measurement of the loss of parasympathetic function, tachycardia was monitored contiguously over the time course of the disease. Decrease of HRV did not occur in all animals that died, which is not consistent with autonomic function being the mechanism of death. Fluorogold-stained cells in the DMNV were not stained for WNV envelope protein. Fourteen percent of WNV-stained cells were co-localized with fluorogold-stained cells in the NA. These data, however, did not suggest a fatal loss of autonomic functions because tachycardia was not observed in WNV-infected hamsters. Parasympathetic autonomic function deficit was not a likely mechanism of death in WNV-infected rodents and possibly in human patients with fatal WN neurological disease.

Cloning and Sequencing of Defective Particles Derived from the Autonomous Parvovirus Minute Virus of Mice for the Construction of Vectors with Minimal cis-Acting Sequences

PubMed Central

Clément, Nathalie; Avalosse, Bernard; El Bakkouri, Karim; Velu, Thierry; Brandenburger, Annick

2001-01-01

The production of wild-type-free stocks of recombinant parvovirus minute virus of mice [MVM(p)] is difficult due to the presence of homologous sequences in vector and helper genomes that cannot easily be eliminated from the overlapping coding sequences. We have therefore cloned and sequenced spontaneously occurring defective particles of MVM(p) with very small genomes to identify the minimal cis-acting sequences required for DNA amplification and virus production. One of them has lost all capsid-coding sequences but is still able to replicate in permissive cells when nonstructural proteins are provided in trans by a helper plasmid. Vectors derived from this particle produce stocks with no detectable wild-type MVM after cotransfection with new, matched, helper plasmids that present no homology downstream from the transgene. PMID:11152501

Both cell-autonomous mechanisms and hormones contribute to sexual development in vertebrates and insects.

PubMed

Bear, Ashley; Monteiro, Antónia

2013-08-01

The differentiation of male and female characteristics in vertebrates and insects has long been thought to proceed via different mechanisms. Traditionally, vertebrate sexual development was thought to occur in two phases: a primary and a secondary phase, the primary phase involving the differentiation of the gonads, and the secondary phase involving the differentiation of other sexual traits via the influence of sex hormones secreted by the gonads. In contrast, insect sexual development was thought to depend exclusively on cell-autonomous expression of sex-specific genes. Recently, however, new evidence indicates that both vertebrates and insects rely on sex hormones as well as cell-autonomous mechanisms to develop sexual traits. Collectively, these new data challenge the traditional vertebrate definitions of primary and secondary sexual development, call for a redefinition of these terms, and indicate the need for research aimed at explaining the relative dependence on cell-autonomous versus hormonally guided sexual development in animals. © 2013 The Authors. BioEssays published by WILEY Periodicals, Inc.

Power optimization in body sensor networks: the case of an autonomous wireless EMG sensor powered by PV-cells.

PubMed

Penders, J; Pop, V; Caballero, L; van de Molengraft, J; van Schaijk, R; Vullers, R; Van Hoof, C

2010-01-01

Recent advances in ultra-low-power circuits and energy harvesters are making self-powered body sensor nodes a reality. Power optimization at the system and application level is crucial in achieving ultra-low-power consumption for the entire system. This paper reviews system-level power optimization techniques, and illustrates their impact on the case of autonomous wireless EMG monitoring. The resulting prototype, an Autonomous wireless EMG sensor power by PV-cells, is presented.

Reactive oxygen species-dependent Toll/NF-κB activation in the Drosophila hematopoietic niche confers resistance to wasp parasitism.

PubMed

Louradour, Isabelle; Sharma, Anurag; Morin-Poulard, Ismael; Letourneau, Manon; Vincent, Alain; Crozatier, Michèle; Vanzo, Nathalie

2017-11-01

Hematopoietic stem/progenitor cells in the adult mammalian bone marrow ensure blood cell renewal. Their cellular microenvironment, called 'niche', regulates hematopoiesis both under homeostatic and immune stress conditions. In the Drosophila hematopoietic organ, the lymph gland, the posterior signaling center (PSC) acts as a niche to regulate the hematopoietic response to immune stress such as wasp parasitism. This response relies on the differentiation of lamellocytes, a cryptic cell type, dedicated to pathogen encapsulation and killing. Here, we establish that Toll/NF-κB pathway activation in the PSC in response to wasp parasitism non-cell autonomously induces the lymph gland immune response. Our data further establish a regulatory network where co-activation of Toll/NF-κB and EGFR signaling by ROS levels in the PSC/niche controls lymph gland hematopoiesis under parasitism. Whether a similar regulatory network operates in mammals to control emergency hematopoiesis is an open question.

Autonomous Repair Mechanism of Creep Damage in Fe-Au and Fe-Au-B-N Alloys

NASA Astrophysics Data System (ADS)

Zhang, S.; Kwakernaak, C.; Tichelaar, F. D.; Sloof, W. G.; Kuzmina, M.; Herbig, M.; Raabe, D.; Brück, E.; van der Zwaag, S.; van Dijk, N. H.

2015-12-01

The autonomous repair mechanism of creep cavitation during high-temperature deformation has been investigated in Fe-Au and Fe-Au-B-N alloys. Combined electron-microscopy techniques and atom probe tomography reveal how the improved creep properties result from Au precipitation within the creep cavities, preferentially formed on grain boundaries oriented perpendicular to the applied stress. The selective precipitation of Au atoms at the free creep cavity surface results in pore filling, and thereby, autonomous repair of the creep damage. The large difference in atomic size between the Au and Fe strongly hampers the nucleation of precipitates in the matrix. As a result, the matrix acts as a reservoir for the supersaturated solute until damage occurs. Grain boundaries and dislocations are found to act as fast transport routes for solute gold from the matrix to the creep cavities. The mechanism responsible for the self-healing can be characterized by a simple model for cavity growth and cavity filling.

NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence.

PubMed

Parry, Aled J; Hoare, Matthew; Bihary, Dóra; Hänsel-Hertsch, Robert; Smith, Stephen; Tomimatsu, Kosuke; Mannion, Elizabeth; Smith, Amy; D'Santos, Paula; Russell, I Alasdair; Balasubramanian, Shankar; Kimura, Hiroshi; Samarajiwa, Shamith A; Narita, Masashi

2018-05-09

Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes. We have recently identified that NOTCH1 can drive 'lateral induction' of a unique senescence phenotype in adjacent cells by specifically upregulating the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells exhibit a massive increase in chromatin accessibility. NOTCH signalling suppresses SAHF and increased chromatin accessibility in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, drive similar chromatin architectural changes in adjacent cells through cell-cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in multiple human cancers. Thus, HMGA1 is involved not only in SAHFs but also in RIS-driven chromatin accessibility. In conclusion, this study identifies that the JAG1-NOTCH-HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.

Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1

PubMed Central

Cvetanovic, Marija; Hu, Yuan-Shih; Opal, Puneet

2017-01-01

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (Q) repeat tract in the protein ataxin-1 (ATXN1). Beginning as a cerebellar ataxic disorder, SCA1 progresses to involve the cerebral cortex, hippocampus, and brainstem. Using SCA1 knock-in mice that mirror the complexity of the human disease, we report a significant decrease in the capacity of adult neuronal progenitor cells (NPCs) to proliferate. Remarkably, a decrease in NPCs proliferation can be observed in vitro, outside the degenerative milieu of surrounding neurons or glia, demonstrating that mutant ATXN1 acting cell autonomously within progenitor cells interferes with their ability to proliferate. Our findings suggest that compromised adult neurogenesis contributes to the progressive pathology of the disease particularly in areas such as the hippocampus and cerebral cortex where stem cells provide neurotropic factors and participate in adult neurogenesis. These findings not only shed light on the biology of the disease but also have therapeutic implications in any future stem cell- based clinical trials. PMID:27306906

Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1.

PubMed

Cvetanovic, Marija; Hu, Yuan-Shih; Opal, Puneet

2017-04-01

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (Q) repeat tract in the protein ataxin-1 (ATXN1). Beginning as a cerebellar ataxic disorder, SCA1 progresses to involve the cerebral cortex, hippocampus, and brainstem. Using SCA1 knock-in mice that mirror the complexity of the human disease, we report a significant decrease in the capacity of adult neuronal progenitor cells (NPCs) to proliferate. Remarkably, a decrease in NPCs proliferation can be observed in vitro, outside the degenerative milieu of surrounding neurons or glia, demonstrating that mutant ATXN1 acting cell autonomously within progenitor cells interferes with their ability to proliferate. Our findings suggest that compromised adult neurogenesis contributes to the progressive pathology of the disease particularly in areas such as the hippocampus and cerebral cortex where stem cells provide neurotropic factors and participate in adult neurogenesis. These findings not only shed light on the biology of the disease but also have therapeutic implications in any future stem cell-based clinical trials.

A monoclonal antibody against KCNK9 K(+) channel extracellular domain inhibits tumour growth and metastasis.

PubMed

Sun, Han; Luo, Liqun; Lal, Bachchu; Ma, Xinrong; Chen, Lieping; Hann, Christine L; Fulton, Amy M; Leahy, Daniel J; Laterra, John; Li, Min

2016-02-04

Two-pore domain potassium (K2P) channels act to maintain cell resting membrane potential--a prerequisite for many biological processes. KCNK9, a member of K2P family, is implicated in cancer, owing to its overexpression in human tumours and its ability to promote neoplastic cell survival and growth. However, KCNK9's underlying contributions to malignancy remain elusive due to the absence of specific modulators. Here we describe the development of monoclonal antibodies against the KCNK9 extracellular domain and their functional effects. We show that one antibody (Y4) with the highest affinity binding induces channel internalization. The addition of Y4 to KCNK9-expressing carcinoma cells reduces cell viability and increases cell death. Systemic administration of Y4 effectively inhibits growth of human lung cancer xenografts and murine breast cancer metastasis in mice. Evidence for Y4-mediated carcinoma cell autonomous and immune-dependent cytotoxicity is presented. Our study reveals that antibody-based KCNK9 targeting is a promising therapeutic strategy in KCNK9-expressing malignancies.

Autonomic regulation of hepatic glucose production.

PubMed

Bisschop, Peter H; Fliers, Eric; Kalsbeek, Andries

2015-01-01

Glucose produced by the liver is a major energy source for the brain. Considering its critical dependence on glucose, it seems only natural that the brain is capable of monitoring and controlling glucose homeostasis. In addition to neuroendocrine pathways, the brain uses the autonomic nervous system to communicate with peripheral organs. Within the brain, the hypothalamus is the key region to integrate signals on energy status, including signals from lipid, glucose, and hormone sensing cells, with afferent neural signals from the internal and external milieu. In turn, the hypothalamus regulates metabolism in peripheral organs, including the liver, not only via the anterior pituitary gland but also via multiple neuropeptidergic pathways in the hypothalamus that have been identified as regulators of hepatic glucose metabolism. These pathways comprise preautonomic neurons projecting to nuclei in the brain stem and spinal cord, which relay signals from the hypothalamus to the liver via the autonomic nervous system. The neuroendocrine and neuronal outputs of the hypothalamus are not separate entities. They appear to act as a single integrated regulatory system, far more subtle, and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and neural influences. As a result, our endocrine-based understanding of diseases such as diabetes and obesity should be expanded by integration of neural inputs into our concept of the pathophysiological process. © 2014 American Physiological Society.

Room Temperature Operable Autonomously Moving Bio-Microrobot Powered by Insect Dorsal Vessel Tissue

PubMed Central

Akiyama, Yoshitake; Hoshino, Takayuki; Iwabuchi, Kikuo; Morishima, Keisuke

2012-01-01

Living muscle tissues and cells have been attracting attention as potential actuator candidates. In particular, insect dorsal vessel tissue (DVT) seems to be well suited for a bio-actuator since it is capable of contracting autonomously and the tissue itself and its cells are more environmentally robust under culturing conditions compared with mammalian tissues and cells. Here we demonstrate an autonomously moving polypod microrobot (PMR) powered by DVT excised from an inchworm. We fabricated a prototype of the PMR by assembling a whole DVT onto an inverted two-row micropillar array. The prototype moved autonomously at a velocity of 3.5×10−2 µm/s, and the contracting force of the whole DVT was calculated as 20 µN. Based on the results obtained by the prototype, we then designed and fabricated an actual PMR. We were able to increase the velocity significantly for the actual PMR which could move autonomously at a velocity of 3.5 µm/s. These results indicate that insect DVT has sufficient potential as the driving force for a bio-microrobot that can be utilized in microspaces. PMID:22808004

TGFbeta receptor saxophone non-autonomously regulates germline proliferation in a Smox/dSmad2-dependent manner in Drosophila testis.

PubMed

Li, Chun-Yan; Guo, Zheng; Wang, Zhaohui

2007-09-01

Elucidating the regulatory mechanism of cell proliferation is central to the understanding of cancer development or organ size control. Drosophila spermatogenesis provides an excellent model to study cell proliferation since the germline cells mitotically amplify in a precise manner. However, the underlying molecular mechanism remains elusive. Germ cells derived from each gonialblast develop synchronously as one unit encapsulated by two somatic support cells (called cyst cells). Components of TGFbeta pathway have previously been found to restrict germ cell proliferation via their functions in cyst cells. Here we report that saxophone (sax), a TGFbeta type I receptor, is required in somatic cells to prevent the mitotically dividing spermatogonia from over-amplifying. Using various approaches, we demonstrate that Mad (Mothers against Dpp), a receptor-Smad usually associated with Sax-mediated TGFbeta/BMP signaling, is dispensable in this process. Instead, Smox (Smad on X, Drosophila Smad2), the other receptor-Smad formerly characterized in TGFbeta/activin signaling, is necessary for the precise mitotic divisions of spermatogonia. Furthermore, over-expressing Smox in cyst cells can partially rescue the proliferation phenotype induced by sax mutation. We propose that Smox acts downstream of Sax to prevent spermatogonial over-proliferation in Drosophila.

Memory and modularity in cell-fate decision making

NASA Astrophysics Data System (ADS)

Norman, Thomas M.; Lord, Nathan D.; Paulsson, Johan; Losick, Richard

2013-11-01

Genetically identical cells sharing an environment can display markedly different phenotypes. It is often unclear how much of this variation derives from chance, external signals, or attempts by individual cells to exert autonomous phenotypic programs. By observing thousands of cells for hundreds of consecutive generations under constant conditions, we dissect the stochastic decision between a solitary, motile state and a chained, sessile state in Bacillus subtilis. We show that the motile state is `memoryless', exhibiting no autonomous control over the time spent in the state. In contrast, the time spent as connected chains of cells is tightly controlled, enforcing coordination among related cells in the multicellular state. We show that the three-protein regulatory circuit governing the decision is modular, as initiation and maintenance of chaining are genetically separable functions. As stimulation of the same initiating pathway triggers biofilm formation, we argue that autonomous timing allows a trial commitment to multicellularity that external signals could extend.

Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia

PubMed Central

Minici, Claudia; Gounari, Maria; Übelhart, Rudolf; Scarfò, Lydia; Dühren-von Minden, Marcus; Schneider, Dunja; Tasdogan, Alpaslan; Alkhatib, Alabbas; Agathangelidis, Andreas; Ntoufa, Stavroula; Chiorazzi, Nicholas; Jumaa, Hassan; Stamatopoulos, Kostas; Ghia, Paolo; Degano, Massimo

2017-01-01

Cell-autonomous B-cell receptor (BcR)-mediated signalling is a hallmark feature of the neoplastic B lymphocytes in chronic lymphocytic leukaemia (CLL). Here we elucidate the structural basis of autonomous activation of CLL B cells, showing that BcR immunoglobulins initiate intracellular signalling through homotypic interactions between epitopes that are specific for each subgroup of patients with homogeneous clinicobiological profiles. The molecular details of the BcR–BcR interactions apparently dictate the clinical course of disease, with stronger affinities and longer half-lives in indolent cases, and weaker, short-lived contacts mediating the aggressive ones. The diversity of homotypic BcR contacts leading to cell-autonomous signalling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL and offers opportunities for innovative treatment strategies. PMID:28598442

[Shades and shadows in the application of the long-term care law].

PubMed

Correa, Manuel; Jiménez-Aguilera, Juan de Dios

2016-01-01

The aim of this study was to provide a brief overview of the most controversial aspects of the Spanish Act of Promotion of Personal Autonomy and Long-Term Care 39/2006, which, in the last few years, has led to heated debates between the state and the autonomous regions. Because of the funding problems due to initial poor planning, the decline of contributions from the Spanish Government in the last few years, including the suppression of the agreed level, and low cash collection from the user through copayment, the autonomous regions have had to provide significant economic resources to maintain this social policy in an environment characterised by a lack of transparency of the system. In addition, the regulatory reforms of mid-2012 to ease the burden on state and autonomous budgets have represented a clear setback to the spirit of the act and a loss of welfare to dependent individuals and their families. All these circumstances have contributed to a widely heterogeneous picture in the territorial implementation of the act, with clear differences in waiting lists, abuse in the granting of cash benefits in some regions, and differences in the number of applications for benefits and services. Copyright © 2015 SESPAS. Published by Elsevier Espana. All rights reserved.

A light-driven artificial flytrap

PubMed Central

Wani, Owies M.; Zeng, Hao; Priimagi, Arri

2017-01-01

The sophistication, complexity and intelligence of biological systems is a continuous source of inspiration for mankind. Mimicking the natural intelligence to devise tiny systems that are capable of self-regulated, autonomous action to, for example, distinguish different targets, remains among the grand challenges in biomimetic micro-robotics. Herein, we demonstrate an autonomous soft device, a light-driven flytrap, that uses optical feedback to trigger photomechanical actuation. The design is based on light-responsive liquid-crystal elastomer, fabricated onto the tip of an optical fibre, which acts as a power source and serves as a contactless probe that senses the environment. Mimicking natural flytraps, this artificial flytrap is capable of autonomous closure and object recognition. It enables self-regulated actuation within the fibre-sized architecture, thus opening up avenues towards soft, autonomous small-scale devices. PMID:28534872

Intrinsic Cholinergic Mechanisms Regulating Cerebral Blood Flow as a Target for Organophosphate Action

DTIC Science & Technology

1988-10-01

acetyltransferase (ChAT), the ACh- C= synthesizing enzyme. ChAT-immunoreactive cell bodies and processes were localized to autonomic or limbic nuclei throughout...the neuraxis and close appositions with brainstemn microvessels and ependymal cells . Moreover, theA DO , U03 Eoirlo oil ov wavs I 69LET9 SCCUmTYV...spinal preganglionic neurons of the intermediolateral cell columns ([ML). ChAT-immunoreactive cell bodies and processes were localized to autonomic or

Emotions induced by operatic music: psychophysiological effects of music, plot, and acting: a scientist's tribute to Maria Callas.

PubMed

Balteş, Felicia Rodica; Avram, Julia; Miclea, Mircea; Miu, Andrei C

2011-06-01

Operatic music involves both singing and acting (as well as rich audiovisual background arising from the orchestra and elaborate scenery and costumes) that multiply the mechanisms by which emotions are induced in listeners. The present study investigated the effects of music, plot, and acting performance on emotions induced by opera. There were three experimental conditions: (1) participants listened to a musically complex and dramatically coherent excerpt from Tosca; (2) they read a summary of the plot and listened to the same musical excerpt again; and (3) they re-listened to music while they watched the subtitled film of this acting performance. In addition, a control condition was included, in which an independent sample of participants succesively listened three times to the same musical excerpt. We measured subjective changes using both dimensional, and specific music-induced emotion questionnaires. Cardiovascular, electrodermal, and respiratory responses were also recorded, and the participants kept track of their musical chills. Music listening alone elicited positive emotion and autonomic arousal, seen in faster heart rate, but slower respiration rate and reduced skin conductance. Knowing the (sad) plot while listening to the music a second time reduced positive emotions (peacefulness, joyful activation), and increased negative ones (sadness), while high autonomic arousal was maintained. Watching the acting performance increased emotional arousal and changed its valence again (from less positive/sad to transcendent), in the context of continued high autonomic arousal. The repeated exposure to music did not by itself induce this pattern of modifications. These results indicate that the multiple musical and dramatic means involved in operatic performance specifically contribute to the genesis of music-induced emotions and their physiological correlates. Copyright © 2011 Elsevier Inc. All rights reserved.

When helping helps: autonomous motivation for prosocial behavior and its influence on well-being for the helper and recipient.

PubMed

Weinstein, Netta; Ryan, Richard M

2010-02-01

Self-determination theory posits that the degree to which a prosocial act is volitional or autonomous predicts its effect on well-being and that psychological need satisfaction mediates this relation. Four studies tested the impact of autonomous and controlled motivation for helping others on well-being and explored effects on other outcomes of helping for both helpers and recipients. Study 1 used a diary method to assess daily relations between prosocial behaviors and helper well-being and tested mediating effects of basic psychological need satisfaction. Study 2 examined the effect of choice on motivation and consequences of autonomous versus controlled helping using an experimental design. Study 3 examined the consequences of autonomous versus controlled helping for both helpers and recipients in a dyadic task. Finally, Study 4 manipulated motivation to predict helper and recipient outcomes. Findings support the idea that autonomous motivation for helping yields benefits for both helper and recipient through greater need satisfaction. Limitations and implications are discussed. Copyright 2009 APA, all rights reserved

Non-cell autonomous cell death caused by transmission of Huntingtin aggregates in Drosophila.

PubMed

Babcock, Daniel T; Ganetzky, Barry

2015-01-01

Recent evidence indicates that protein aggregates can spread between neurons in several neurodegenerative diseases but much remains unknown regarding the underlying mechanisms responsible for this spreading and its role in disease progression. We recently demonstrated that mutant Huntingtin aggregates spread between cells within the Drosophila brain resulting in non-cell autonomous loss of a pair of large neurons in the posterior protocerebrum. However, the full extent of neuronal loss throughout the brain was not determined. Here we examine the effects of driving expression of mutant Huntingtin in Olfactory Receptor Neurons (ORNs) by using a marker for cleaved caspase activity to monitor neuronal apoptosis as a function of age. We find widespread caspase activity in various brain regions over time, demonstrating that non-cell autonomous damage is widespread. Improved understanding of which neurons are most vulnerable and why should be useful in developing treatment strategies for neurodegenerative diseases that involve transcellular spreading of aggregates.

The unfolded protein response in a pair of sensory neurons promotes entry of C. elegans into dauer diapause.

PubMed

Kulalert, Warakorn; Kim, Dennis H

2013-12-16

In response to unfavorable environmental conditions such as starvation, crowding, and elevated temperature, Caenorhabditis elegans larvae enter an alternative developmental stage known as dauer, which is characterized by adaptive changes in stress resistance and metabolism. The genetic dissection of the molecular mechanisms of the C. elegans dauer developmental decision has defined evolutionarily conserved signaling pathways of organismal neuroendocrine physiology. Here, we have identified a mechanism by which a dominant mutation in a neuronal insulin gene, daf-28(sa191), causes constitutive entry into dauer diapause. We demonstrate that expression of the mutant DAF-28 insulin peptide results in endoplasmic reticulum (ER) stress in the ASI pair of chemosensory neurons. The neuronal ER stress does not compromise cellular survival but activates PEK-1, the C. elegans ortholog of the mammalian eIF2α kinase PERK, which in turn phosphorylates Ser49 of eIF2α, specifically in the ASI neuron pair, to promote entry into dauer diapause. Our data establish a novel role for ER stress and the unfolded protein response (UPR) in promoting entry into dauer diapause and suggest that, in addition to cell-autonomous activities in the maintenance of ER homeostasis, the UPR may act in a non-cell-autonomous manner to promote organismal adaptation to stress during larval development. Copyright © 2013 Elsevier Ltd. All rights reserved.

Assessment of the relationship between hypoglycaemia awareness and autonomic function following islet cell/pancreas transplantation.

PubMed

Kamel, Jordan T; Goodman, David J; Howe, Kathy; Cook, Mark J; Ward, Glenn M; Roberts, Leslie J

2015-09-01

This study assesses the autonomic function of patients who have regained awareness of hypoglycaemia following islet cell or whole pancreas transplant. Five patients with type 1 diabetes and either islet cell (four patients) or whole pancreas (one patient) transplant were assessed. These patients were age-matched and gender-matched to five patients with type 1 diabetes without transplant and preserved hypoglycaemia awareness and five healthy control participants without diabetes. All participants underwent (i) a battery of five cardiovascular autonomic function tests, (ii) quantitative sudomotor axonal reflex testing, and (iii) sympathetic skin response testing. Total recorded hypoglycaemia episodes per month fell from 76 pre-transplant to 13 at 0- to 3-month post-transplant (83% reduction). The percentage of hypoglycaemia episodes that patients were unaware of decreased from 97 to 69% at 0-3 months (p < 0.001, Fisher's exact test) and to 20% after 12 months (p < 0.0001, Fisher's exact test). This amelioration was maintained at the time of testing (mean time: 4.1 years later, range: 2-6 years). Presence of significant autonomic neuropathy was seen in all five transplanted patients (at least 2/3 above modalities abnormal) but in only one of the patients with diabetes without transplantation. The long-term maintenance of hypoglycaemia awareness that returns after islet cell/pancreas transplantation in patients with diabetes is not prevented by significant autonomic neuropathy and is better accounted for by other factors such as reversal of hypoglycaemia-associated autonomic failure. Copyright © 2015 John Wiley & Sons, Ltd.

A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization.

PubMed

Akerman, Simon; Holland, Philip R; Summ, Oliver; Lasalandra, Michele P; Goadsby, Peter J

2012-12-01

Trigeminal autonomic cephalalgias are highly disabling primary headache disorders, characterized by severe unilateral head pain and associated ipsilateral cranial autonomic features. There is limited understanding of their pathophysiology and how and where treatments act to reduce symptoms; this is significantly hindered by a lack of animal models. We have developed the first animal model to explore trigeminal autonomic cephalalgias, using stimulation within the brainstem, at the level of the superior salivatory nucleus, to activate the trigeminal autonomic reflex arc. Using electrophysiological recording of neurons of the trigeminocervical complex and laser Doppler blood flow changes around the ipsilateral lacrimal duct, superior salivatory nucleus stimulation exhibited both neuronal trigeminovascular and cranial autonomic manifestations. These responses were specifically inhibited by the autonomic ganglion blocker hexamethonium bromide. These data demonstrate that brainstem activation may be the driver of both sensory and autonomic symptoms in these disorders, and part of this activation may be via the parasympathetic outflow to the cranial vasculature. Additionally, both sensory and autonomic manifestations were significantly inhibited by highly effective treatments for trigeminal autonomic cephalalgias, such as oxygen, indomethacin and triptans, and some part of their therapeutic action appears to be specifically on the parasympathetic outflow to the cranial vasculature. Treatments more used to migraine, such as naproxen and a calcitonin gene-related peptide receptor inhibitor, olcegepant, were less effective in this model. This is the first model to represent the phenotype of trigeminal autonomic cephalalgias and their response to therapies, and indicates the parasympathetic pathway may be uniquely involved in their pathophysiology and targeted to relieve symptoms.

Essential roles for lines in mediating leg and antennal proximodistal patterning and generating a stable Notch signaling interface at segment borders.

PubMed

Greenberg, Lina; Hatini, Victor

2009-06-01

The Drosophila leg imaginal disc provides a paradigm with which to understand the fundamental developmental mechanisms that generate an intricate appendage structure. Leg formation depends on the subdivision of the leg proximodistal (PD) axis into broad domains by the leg gap genes. The leg gap genes act combinatorially to initiate the expression of the Notch ligands Delta (Dl) and Serrate (Ser) in a segmental pattern. Dl and Ser induce the expression of a set of transcriptional regulators along the segment border, which mediate leg segment growth and joint morphogenesis. Here we show that Lines accumulates in nuclei in the presumptive tarsus and the inter-joints of proximal leg segments and governs the formation of these structures by destabilizing the nuclear protein Bowl. Across the presumptive tarsus, lines modulates the opposing expression landscapes of the leg gap gene dachshund (dac) and the tarsal PD genes, bric-a-brac 2 (bab), apterous (ap) and BarH1 (Bar). In this manner, lines inhibits proximal tarsal fates and promotes medial and distal tarsal fates. Across proximal leg segments, lines antagonizes bowl to promote Dl expression by relief-of-repression. In turn, Dl signals asymmetrically to stabilize Bowl in adjacent distal cells. Bowl, then, acts cell-autonomously, together with one or more redundant factors, to repress Dl expression. Together, lines and bowl act as a binary switch to generate a stable Notch signaling interface between Dl-expressing cells and adjacent distal cell. lines plays analogous roles in developing antennae, which are serially homologous to legs, suggesting evolutionarily conserved roles for lines in ventral appendage formation.

IGFBP-4 regulates adult skeletal growth in a sex-specific manner.

PubMed

Maridas, David E; DeMambro, Victoria E; Le, Phuong T; Nagano, Kenichi; Baron, Roland; Mohan, Subburaman; Rosen, Clifford J

2017-04-01

Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actions in vitro Yet, in vivo studies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-old Igfbp4 -/- mice. Both male and female adult Igfbp4 -/- mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-old Igfbp4 -/- females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-old Igfbp4 -/- females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation in Igfbp4 -/- females. In contrast, Igfbp4 -/- males had lower mineralized surface/bone surface. Femoral expression of Sost and circulating levels of sclerostin were reduced but only in Igfbp4 -/- males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells from Igfbp4 -/- females but decreased in males. In sum, our results indicate that loss of Igfbp4 affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor. © 2017 The authors.

S1P1 inhibits sprouting angiogenesis during vascular development.

PubMed

Ben Shoham, Adi; Malkinson, Guy; Krief, Sharon; Shwartz, Yulia; Ely, Yona; Ferrara, Napoleone; Yaniv, Karina; Zelzer, Elazar

2012-10-01

Coordination between the vascular system and forming organs is essential for proper embryonic development. The vasculature expands by sprouting angiogenesis, during which tip cells form filopodia that incorporate into capillary loops. Although several molecules, such as vascular endothelial growth factor A (Vegfa), are known to induce sprouting, the mechanism that terminates this process to ensure neovessel stability is still unknown. Sphingosine-1-phosphate receptor 1 (S1P(1)) has been shown to mediate interaction between endothelial and mural cells during vascular maturation. In vitro studies have identified S1P(1) as a pro-angiogenic factor. Here, we show that S1P(1) acts as an endothelial cell (EC)-autonomous negative regulator of sprouting angiogenesis during vascular development. Severe aberrations in vessel size and excessive sprouting found in limbs of S1P(1)-null mouse embryos before vessel maturation imply a previously unknown, mural cell-independent role for S1P(1) as an anti-angiogenic factor. A similar phenotype observed when S1P(1) expression was blocked specifically in ECs indicates that the effect of S1P(1) on sprouting is EC-autonomous. Comparable vascular abnormalities in S1p(1) knockdown zebrafish embryos suggest cross-species evolutionary conservation of this mechanism. Finally, genetic interaction between S1P(1) and Vegfa suggests that these factors interplay to regulate vascular development, as Vegfa promotes sprouting whereas S1P(1) inhibits it to prevent excessive sprouting and fusion of neovessels. More broadly, because S1P, the ligand of S1P(1), is blood-borne, our findings suggest a new mode of regulation of angiogenesis, whereby blood flow closes a negative feedback loop that inhibits sprouting angiogenesis once the vascular bed is established and functional.

Glass promotes the differentiation of neuronal and non-neuronal cell types in the Drosophila eye

PubMed Central

Morrison, Carolyn A.; Chen, Hao; Cook, Tiffany; Brown, Stuart

2018-01-01

Transcriptional regulators can specify different cell types from a pool of equivalent progenitors by activating distinct developmental programs. The Glass transcription factor is expressed in all progenitors in the developing Drosophila eye, and is maintained in both neuronal and non-neuronal cell types. Glass is required for neuronal progenitors to differentiate as photoreceptors, but its role in non-neuronal cone and pigment cells is unknown. To determine whether Glass activity is limited to neuronal lineages, we compared the effects of misexpressing it in neuroblasts of the larval brain and in epithelial cells of the wing disc. Glass activated overlapping but distinct sets of genes in these neuronal and non-neuronal contexts, including markers of photoreceptors, cone cells and pigment cells. Coexpression of other transcription factors such as Pax2, Eyes absent, Lozenge and Escargot enabled Glass to induce additional genes characteristic of the non-neuronal cell types. Cell type-specific glass mutations generated in cone or pigment cells using somatic CRISPR revealed autonomous developmental defects, and expressing Glass specifically in these cells partially rescued glass mutant phenotypes. These results indicate that Glass is a determinant of organ identity that acts in both neuronal and non-neuronal cells to promote their differentiation into functional components of the eye. PMID:29324767

Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity.

PubMed

O'Leary, L; van der Sloot, A M; Reis, C R; Deegan, S; Ryan, A E; Dhami, S P S; Murillo, L S; Cool, R H; Correa de Sampaio, P; Thompson, K; Murphy, G; Quax, W J; Serrano, L; Samali, A; Szegezdi, E

2016-03-10

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand cytokine known for its cytotoxic activity against malignantly transformed cells. TRAIL induces cell death through binding to death receptors DR4 and DR5. The inhibitory decoy receptors (DcR1 and DcR2) co-expressed with death receptor 4 (DR4)/DR5 on the same cell can block the transmission of the apoptotic signal. Here, we show that DcRs also regulate TRAIL sensitivity at a supracellular level and thus represent a mechanism by which the microenvironment can diminish tumour TRAIL sensitivity. Mathematical modelling and layered or spheroid stroma-extracellular matrix-tumour cultures were used to model the tumour microenvironment. By engineering TRAIL to escape binding by DcRs, we found that DcRs do not only act in a cell-autonomous or cis-regulatory manner, but also exert trans-cellular regulation originating from stromal cells and affect tumour cells, highlighting the potent inhibitory effect of DcRs in the tumour tissue and the necessity of selective targeting of the two death-inducing TRAIL receptors to maximise efficacy.

Stabilizing Motifs in Autonomous Boolean Networks and the Yeast Cell Cycle Oscillator

NASA Astrophysics Data System (ADS)

Sevim, Volkan; Gong, Xinwei; Socolar, Joshua

2009-03-01

Synchronously updated Boolean networks are widely used to model gene regulation. Some properties of these model networks are known to be artifacts of the clocking in the update scheme. Autonomous updating is a less artificial scheme that allows one to introduce small timing perturbations and study stability of the attractors. We argue that the stabilization of a limit cycle in an autonomous Boolean network requires a combination of motifs such as feed-forward loops and auto-repressive links that can correct small fluctuations in the timing of switching events. A recently published model of the transcriptional cell-cycle oscillator in yeast contains the motifs necessary for stability under autonomous updating [1]. [1] D. A. Orlando, et al. Nature (London), 4530 (7197):0 944--947, 2008.

Stem cell activation by light guides plant organogenesis.

PubMed

Yoshida, Saiko; Mandel, Therese; Kuhlemeier, Cris

2011-07-01

Leaves originate from stem cells located at the shoot apical meristem. The meristem is shielded from the environment by older leaves, and leaf initiation is considered to be an autonomous process that does not depend on environmental cues. Here we show that light acts as a morphogenic signal that controls leaf initiation and stabilizes leaf positioning. Leaf initiation in tomato shoot apices ceases in the dark but resumes in the light, an effect that is mediated through the plant hormone cytokinin. Dark treatment also affects the subcellular localization of the auxin transporter PIN1 and the concomitant formation of auxin maxima. We propose that cytokinin is required for meristem propagation, and that auxin redirects cytokinin-inducible meristem growth toward organ formation. In contrast to common wisdom over the last 150 years, the light environment controls the initiation of lateral organs by regulating two key hormones: auxin and cytokinin.

Stem cell activation by light guides plant organogenesis

PubMed Central

Yoshida, Saiko; Mandel, Therese; Kuhlemeier, Cris

2011-01-01

Leaves originate from stem cells located at the shoot apical meristem. The meristem is shielded from the environment by older leaves, and leaf initiation is considered to be an autonomous process that does not depend on environmental cues. Here we show that light acts as a morphogenic signal that controls leaf initiation and stabilizes leaf positioning. Leaf initiation in tomato shoot apices ceases in the dark but resumes in the light, an effect that is mediated through the plant hormone cytokinin. Dark treatment also affects the subcellular localization of the auxin transporter PIN1 and the concomitant formation of auxin maxima. We propose that cytokinin is required for meristem propagation, and that auxin redirects cytokinin-inducible meristem growth toward organ formation. In contrast to common wisdom over the last 150 years, the light environment controls the initiation of lateral organs by regulating two key hormones: auxin and cytokinin. PMID:21724835

High-frequency transformation of a methylotrophic yeast, Candida boidinii, with autonomously replicating plasmids which are also functional in Saccharomyces cerevisiae.

PubMed

Sakai, Y; Goh, T K; Tani, Y

1993-06-01

We have developed a transformation system which uses autonomous replicating plasmids for a methylotrophic yeast, Candida boidinii. Two autonomous replication sequences, CARS1 and CARS2, were newly cloned from the genome of C. boidinii. Plasmids having both a CARS fragment and the C. boidinii URA3 gene transformed C. boidinii ura3 cells to Ura+ phenotype at frequencies of up to 10(4) CFU/micrograms of DNA. From Southern blot analysis, CARS plasmids seemed to exist in polymeric forms as well as in monomeric forms in C. boidinii cells. The C. boidinii URA3 gene was overexpressed in C. boidinii on these CARS vectors. CARS1 and CARS2 were found to function as an autonomous replicating element in Saccharomyces cerevisiae as well. Different portions of the CARS1 sequence were needed for autonomous replicating activity in C. boidinii and S. cerevisiae. C. boidinii could also be transformed with vectors harboring a CARS fragment and the S. cerevisiae URA3 gene.

Cell-autonomous sex determination outside of the gonad

PubMed Central

Arnold, Arthur P.; Chen, Xuqi; Link, Jenny C.; Itoh, Yuichiro; Reue, Karen

2013-01-01

The classic model of sex determination in mammals states that the sex of the individual is determined by the type of gonad that develops, which in turn determines the gonadal hormonal milieu that creates sex differences outside of the gonads. However, XX and XY cells are intrinsically different because of the cell-autonomous sex-biasing action of X and Y genes. Recent studies of mice, in which sex chromosome complement is independent of gonadal sex, reveal that sex chromosome complement has strong effects contributing to sex differences in phenotypes such as metabolism. Adult mice with two X chromosomes (relative to mice with one X chromosome) show dramatically greater increases in body weight and adiposity after gonadectomy, irrespective of their gonadal sex. When fed a high fat diet, XX mice develop striking hyperinsulinemia and fatty liver, relative to XY mice. The sex chromosome effects are modulated by the presence of gonadal hormones, indicating an interaction of the sex-biasing effects of gonadal hormones and sex chromosome genes. Other cell-autonomous sex chromosome effects are detected in mice in many phenotypes. Birds (relative to eutherian mammals) are expected to show more widespread cell-autonomous sex determination in non-gonadal tissues, because of ineffective sex chromosome dosage compensation mechanisms. PMID:23361913

Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.

PubMed

Ahluwalia, Neil; Grasberger, Paula E; Mugo, Brian M; Feghali-Bostwick, Carol; Pardo, Annie; Selman, Moisés; Lagares, David; Tager, Andrew M

2016-06-01

Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-β, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.

Neuronal Target Identification Requires AHA-1-Mediated Fine-Tuning of Wnt Signaling in C. elegans

PubMed Central

Zhang, Jingyan; Li, Xia; Jevince, Angela R.; Guan, Liying; Wang, Jiaming; Hall, David H.; Huang, Xun; Ding, Mei

2013-01-01

Electrical synaptic transmission through gap junctions is a vital mode of intercellular communication in the nervous system. The mechanism by which reciprocal target cells find each other during the formation of gap junctions, however, is poorly understood. Here we show that gap junctions are formed between BDU interneurons and PLM mechanoreceptors in C. elegans and the connectivity of BDU with PLM is influenced by Wnt signaling. We further identified two PAS-bHLH family transcription factors, AHA-1 and AHR-1, which function cell-autonomously within BDU and PLM to facilitate the target identification process. aha-1 and ahr-1 act genetically upstream of cam-1. CAM-1, a membrane-bound receptor tyrosine kinase, is present on both BDU and PLM cells and likely serves as a Wnt antagonist. By binding to a cis-regulatory element in the cam-1 promoter, AHA-1 enhances cam-1 transcription. Our study reveals a Wnt-dependent fine-tuning mechanism that is crucial for mutual target cell identification during the formation of gap junction connections. PMID:23825972

Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin.

PubMed

Gui, Dan Y; Sullivan, Lucas B; Luengo, Alba; Hosios, Aaron M; Bush, Lauren N; Gitego, Nadege; Davidson, Shawn M; Freinkman, Elizaveta; Thomas, Craig J; Vander Heiden, Matthew G

2016-11-08

Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin's anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis. However, complex I is only one of many inputs that determines the cellular NAD+/NADH ratio, and dependency on complex I is dictated by the activity of other pathways that affect NAD+ regeneration and aspartate levels. This suggests that cancer drug sensitivity and resistance are not intrinsic properties of cancer cells, and demonstrates that the environment can dictate sensitivity to therapies that impact cell metabolism. Copyright © 2016 Elsevier Inc. All rights reserved.

NPM1 Silencing Reduces Tumour Growth and MAPK Signalling in Prostate Cancer Cells

PubMed Central

Loubeau, Gaëlle; Boudra, Rafik; Maquaire, Sabrina; Lours-Calet, Corinne; Beaudoin, Claude; Verrelle, Pierre; Morel, Laurent

2014-01-01

The chaperone nucleophosmin (NPM1) is over-expressed in the epithelial compartment of prostate tumours compared to adjacent healthy epithelium and may represent one of the key actors that support the neoplastic phenotype of prostate adenocarcinoma cells. Yet, the mechanisms that underlie NPM1 mediated phenotype remain elusive in the prostate. To better understand NPM1 functions in prostate cancer cells, we sought to characterize its impact on prostate cancer cells behaviour and decipher the mechanisms by which it may act. Here we show that NPM1 favors prostate tumour cell migration, invasion and colony forming. Furthermore, knockdown of NPM1 leads to a decrease in the growth of LNCaP-derived tumours grafted in Nude mice in vivo. Such oncogenic-like properties are found in conjunction with a positive regulation of NPM1 on the ERK1/2 (Extracellular signal-Regulated Kinases 1/2) kinase phosphorylation in response to EGF (Epidermal Growth Factor) stimulus, which is critical for prostate cancer progression following the setting of an autonomous production of the growth factor. NPM1 could then be a target to switch off specifically ERK1/2 pathway activation in order to decrease or inhibit cancer cell growth and migration. PMID:24796332

LIN-12/Notch signaling instructs postsynaptic muscle arm development by regulating UNC-40/DCC and MADD-2 in Caenorhabditis elegans

PubMed Central

Li, Pengpeng; Collins, Kevin M; Koelle, Michael R; Shen, Kang

2013-01-01

The diverse cell types and the precise synaptic connectivity between them are the cardinal features of the nervous system. Little is known about how cell fate diversification is linked to synaptic target choices. Here we investigate how presynaptic neurons select one type of muscles, vm2, as a synaptic target and form synapses on its dendritic spine-like muscle arms. We found that the Notch-Delta pathway was required to distinguish target from non-target muscles. APX-1/Delta acts in surrounding cells including the non-target vm1 to activate LIN-12/Notch in the target vm2. LIN-12 functions cell-autonomously to up-regulate the expression of UNC-40/DCC and MADD-2 in vm2, which in turn function together to promote muscle arm formation and guidance. Ectopic expression of UNC-40/DCC in non-target vm1 muscle is sufficient to induce muscle arm extension from these cells. Therefore, the LIN-12/Notch signaling specifies target selection by selectively up-regulating guidance molecules and forming muscle arms in target cells. DOI: http://dx.doi.org/10.7554/eLife.00378.001 PMID:23539368

Autoimmune autonomic ganglionopathy

PubMed Central

Wang, Z.; Low, P.A.; Jordan, J.; Freeman, R.; Gibbons, C.H.; Schroeder, C.; Sandroni, P.; Vernino, S.

2008-01-01

Background Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated form of diffuse autonomic failure. Many patients have serum antibodies that bind to the ganglionic acetylcholine receptors (AChRs) that mediate fast synaptic transmission in autonomic ganglia. Previous clinical studies and observations in animal models suggest that AAG is an antibody-mediated neurologic disorder. Methods Using whole-cell patch clamp techniques, we recorded ganglionic AChR currents in cultured human IMR-32 cells and examined the effects of bath application of IgG derived from patients with AAG. Results IgG from seven patients with AAG all produced a progressive decline in whole-cell ganglionic AChR current, whereas IgG from control subjects had no effect. The effect was abolished at low temperature. Fab antibody fragments had no effect unless a secondary antibody was added concurrently. IgG from one patient also produced a more immediate reduction of ganglionic AChR current. Conclusions The characteristics of antibody-mediated inhibition of ganglionic acetylcholine receptor (AChR) current are consistent with modulation and blocking of the membrane AChR, analogous to the effects of muscle AChR antibodies in myasthenia gravis. Our observations demonstrate that antibodies in patients with autoimmune autonomic ganglionopathy (AAG) cause physiologic changes in ganglionic AChR function and confirm that AAG is an antibody-mediated disorder. PMID:17536048

Barley disease susceptibility factor RACB acts in epidermal cell polarity and positioning of the nucleus

PubMed Central

Scheler, Björn; Schnepf, Vera; Galgenmüller, Carolina; Ranf, Stefanie; Hückelhoven, Ralph

2016-01-01

RHO GTPases are regulators of cell polarity and immunity in eukaryotes. In plants, RHO-like RAC/ROP GTPases are regulators of cell shaping, hormone responses, and responses to microbial pathogens. The barley (Hordeum vulgare L.) RAC/ROP protein RACB is required for full susceptibility to penetration by Blumeria graminis f.sp. hordei (Bgh), the barley powdery mildew fungus. Disease susceptibility factors often control host immune responses. Here we show that RACB does not interfere with early microbe-associated molecular pattern-triggered immune responses such as the oxidative burst or activation of mitogen-activated protein kinases. RACB also supports rather than restricts expression of defence-related genes in barley. Instead, silencing of RACB expression by RNAi leads to defects in cell polarity. In particular, initiation and maintenance of root hair growth and development of stomatal subsidiary cells by asymmetric cell division is affected by silencing expression of RACB. Nucleus migration is a common factor of developmental cell polarity and cell-autonomous interaction with Bgh. RACB is required for positioning of the nucleus near the site of attack from Bgh. We therefore suggest that Bgh profits from RACB’s function in cell polarity rather than from immunity-regulating functions of RACB. PMID:27056842

Barley disease susceptibility factor RACB acts in epidermal cell polarity and positioning of the nucleus.

PubMed

Scheler, Björn; Schnepf, Vera; Galgenmüller, Carolina; Ranf, Stefanie; Hückelhoven, Ralph

2016-05-01

RHO GTPases are regulators of cell polarity and immunity in eukaryotes. In plants, RHO-like RAC/ROP GTPases are regulators of cell shaping, hormone responses, and responses to microbial pathogens. The barley (Hordeum vulgare L.) RAC/ROP protein RACB is required for full susceptibility to penetration by Blumeria graminis f.sp. hordei (Bgh), the barley powdery mildew fungus. Disease susceptibility factors often control host immune responses. Here we show that RACB does not interfere with early microbe-associated molecular pattern-triggered immune responses such as the oxidative burst or activation of mitogen-activated protein kinases. RACB also supports rather than restricts expression of defence-related genes in barley. Instead, silencing of RACB expression by RNAi leads to defects in cell polarity. In particular, initiation and maintenance of root hair growth and development of stomatal subsidiary cells by asymmetric cell division is affected by silencing expression of RACB. Nucleus migration is a common factor of developmental cell polarity and cell-autonomous interaction with Bgh RACB is required for positioning of the nucleus near the site of attack from Bgh We therefore suggest that Bgh profits from RACB's function in cell polarity rather than from immunity-regulating functions of RACB. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

A Mouse Model for Conditional Secretion of Specific Single-Chain Antibodies Provides Genetic Evidence for Regulation of Cortical Plasticity by a Non-cell Autonomous Homeoprotein Transcription Factor.

PubMed

Bernard, Clémence; Vincent, Clémentine; Testa, Damien; Bertini, Eva; Ribot, Jérôme; Di Nardo, Ariel A; Volovitch, Michel; Prochiantz, Alain

2016-05-01

During postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells). In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid. Otx2 secretion and internalization requires two small peptidic domains that are part of the DNA-binding domain. Thus, mutating these "transfer" sequences also modifies cell autonomous transcription, precluding this approach to obtain a cell autonomous-only mouse. Here, we develop a mouse model with inducible secretion of an anti-Otx2 single-chain antibody to trap Otx2 in the extracellular milieu. Postnatal secretion of this single-chain antibody by PV cells delays PV maturation and reduces plasticity gene expression. Induced adult expression of this single-chain antibody in cerebrospinal fluid decreases Otx2 internalization by PV cells, strongly induces plasticity gene expression and reopens physiological plasticity. We provide the first mammalian genetic evidence for a signaling mechanism involving intercellular transfer of a homeoprotein transcription factor. Our single-chain antibody mouse model is a valid strategy for extracellular neutralization that could be applied to other homeoproteins and signaling molecules within and beyond the nervous system.

AMPK modulates tissue and organismal aging in a cell-non-autonomous manner

PubMed Central

Ulgherait, Matthew; Rana, Anil; Rera, Michael; Graniel, Jacqueline; Walker, David W.

2014-01-01

AMPK exerts pro-longevity effects in diverse species; however, the tissue-specific mechanisms involved are poorly understood. Here, we show that up-regulation of AMPK in the adult Drosophila nervous system induces autophagy both in the brain and also in the intestinal epithelium. Induction of autophagy is linked to improved intestinal homeostasis during aging and extended lifespan. Neuronal up-regulation of the autophagy-specific protein kinase Atg1 is both necessary and sufficient to induce these inter-tissue effects during aging and to prolong lifespan. Furthermore, up-regulation of AMPK in the adult intestine induces autophagy both cell autonomously and non-autonomously in the brain, slows systemic aging and prolongs lifespan. We show that the organism-wide response to tissue-specific AMPK/Atg1 activation is linked to reduced insulin-like peptide levels in the brain and a systemic increase in 4E-BP expression. Together, these results reveal that localized activation of AMPK and/or Atg1 in key tissues can slow aging in a cell-non-autonomous manner. PMID:25199830

F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner

PubMed Central

Yumimoto, Kanae; Akiyoshi, Sayuri; Ueo, Hiroki; Sagara, Yasuaki; Onoyama, Ichiro; Ueo, Hiroaki; Ohno, Shinji; Mori, Masaki; Mimori, Koshi; Nakayama, Keiichi I.

2015-01-01

The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis. PMID:25555218

Autonomous assembly of epithelial structures by subrenal implantation of dissociated embryonic inner-ear cells.

PubMed

Wang, Li; Zhang, Kaiqing; Zhu, Helen He; Gao, Wei-Qiang

2015-05-27

Microenvironment and cell-cell interactions play an important role during embryogenesis and are required for the stemness and differentiation of stem cells. The inner-ear sensory epithelium, containing hair cells and supporting cells, is derived from the stem cells within the otic vesicle at early embryonic stages. However, whether or not such microenvironment or cell-cell interactions within the embryonic otic tissue have the capacity to regulate the proliferation and differentiation of stem cells and to autonomously reassemble the cells into epithelial structures is unknown. Here, we report that on enzymatic digestion and dissociation to harvest all the single cells from 13.5-day-old rat embryonic (E13.5) inner-ear tissue as well as on implantation of these cells under renal capsules; the dissociated cells are able to reassemble themselves to form epithelial structures as early as 7 days after implantation. By 25 days after implantation, more mature epithelial structures are formed. Immunostaining with cell-type-specific markers reveals that hair cells and supporting cells are not only formed, but are also well aligned with the hair cells located in the apical layer surrounded by the supporting cells. These findings suggest that microenvironment and cell-cell interactions within the embryonic inner-ear tissue have the autonomous signals to induce the formation of sensory epithelial structures. This method may also provide a useful system to study the potential of stem cells to differentiate into hair cells in vivo.

75 FR 30459 - Assistance to the Autonomous Government of Southern Sudan and the United States Contribution to...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-01

... Section 202(d)(4)(A)(ii) of the United States Leadership against HIV/AIDS, Tuberculosis, and Malaria Act... Section 202(d)(4)(A)(ii) of the United States Leadership Against HIV/AIDS, Tuberculosis, and Malaria Act of 2003, as amended by the Tom Lantos and Henry J. Hyde United States Global Leadership Against HIV...

76 FR 82346 - Assistance to the Autonomous Government of Southern Sudan and the United States Contribution to...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-30

... Section 202(d)(4)(A)(ii) of the United States Leadership against HIV/AIDS, Tuberculosis, and Malaria Act... Section 202(d)(4)(A)(ii) of the United States Leadership Against HIV/AIDS, Tuberculosis, and Malaria Act of 2003, as amended by the Tom Lantos and Henry J. Hyde United States Global Leadership Against HIV...

Transmembrane proteins UNC-40/DCC, PTP-3/LAR, and MIG-21 control anterior-posterior neuroblast migration with left-right functional asymmetry in Caenorhabditis elegans.

PubMed

Sundararajan, Lakshmi; Lundquist, Erik A

2012-12-01

Migration of neurons and neural crest cells is of central importance to the development of nervous systems. In Caenorhabditis elegans, the QL neuroblast on the left migrates posteriorly, and QR on the right migrates anteriorly, despite similar lineages and birth positions with regard to the left-right axis. Initial migration is independent of a Wnt signal that controls later anterior-posterior Q descendant migration. Previous studies showed that the transmembrane proteins UNC-40/DCC and MIG-21, a novel thrombospondin type I repeat containing protein, act redundantly in left-side QL posterior migration. Here we show that the LAR receptor protein tyrosine phosphatase PTP-3 acts with MIG-21 in parallel to UNC-40 in QL posterior migration. We also show that in right-side QR, the UNC-40 and PTP-3/MIG-21 pathways mutually inhibit each other's role in posterior migration, allowing anterior QR migration. Finally, we present evidence that these proteins act autonomously in the Q neuroblasts. These studies indicate an inherent left-right asymmetry in the Q neuroblasts with regard to UNC-40, PTP-3, and MIG-21 function that results in posterior vs. anterior migration.

A synthetic peptide derived from alpha-fetoprotein inhibits the estradiol-induced proliferation of mammary tumor cells in culture through the modulation of p21.

PubMed

Sierralta, Walter D; Epuñan, María J; Reyes, José M; Valladares, Luis E; Pino, Ana M

2008-01-01

A stable cyclized 9-mer peptide (cP) containing the active site of alpha-alpha fetoprotein (alphaFP) has been shown to be effective for prevention of estrogen-stimulated tumor cell proliferation in culture or of xenographt growth in immunodeficient mice. cP does not block 17beta-estradiol (E2) binding to its receptors, but rather appears to interfere with intracellular processing of the signal that supports growth. To obtain insight on that mechanism we studied the effect of cP on the proliferation of MCF-7 cells in culture. Proliferation in the presence of 2 microM E2 is decreased up to 40% upon addition of 2 microg ml(-1) cP to the medium; the presence of cP did not increase cell death, cP reduced also the proliferation of estrogen-dependent ZR75-1 cells but had no effect on autonomous MDA-MB-231 cells, cP did not modify the number of binding sites for labeled E2 or affected cell death. We detected increased nuclear p21Cip1 immunoreactivity after cP treatment. Our results suggest that cP acts via p21Cip1 to slow the process of MCF-7 cells through the cycle.

Droxidopa in neurogenic orthostatic hypotension

PubMed Central

Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto

2015-01-01

Neurogenic orthostatic hypotension (nOH) is a fall in blood pressure on standing due to reduced norepinephrine release from sympathetic nerve terminals. nOH is a feature of several neurological disorders that affect the autonomic nervous system, most notably Parkinson disease (PD), multiple system atrophy, pure autonomic failure and other autonomic neuropathies. Droxidopa, an orally active synthetic amino acid that is converted to norepinephrine by the enzyme aromatic L-amino acid decarboxylase (dopa-decarboxylase), was recently approved by the FDA for the short-term treatment of nOH. It is presumed to raise blood pressure by acting at the neurovascular junction to increase vascular tone. This review summarizes the pharmacological properties of droxidopa, its mechanism of action, and the efficacy and safety results of clinical trials. PMID:26092297

Droxidopa in neurogenic orthostatic hypotension.

PubMed

Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto

2015-01-01

Neurogenic orthostatic hypotension (nOH) is a fall in blood pressure (BP) on standing due to reduced norepinephrine release from sympathetic nerve terminals. nOH is a feature of several neurological disorders that affect the autonomic nervous system, most notably Parkinson disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), and other autonomic neuropathies. Droxidopa, an orally active synthetic amino acid that is converted to norepinephrine by the enzyme aromatic L-amino acid decarboxylase (dopa-decarboxylase), was recently approved by the FDA for the short-term treatment of nOH. It is presumed to raise BP by acting at the neurovascular junction to increase vascular tone. This article summarizes the pharmacological properties of droxidopa, its mechanism of action, and the efficacy and safety results of clinical trials.

Autonomous Instrument Placement for Mars Exploration Rovers

NASA Technical Reports Server (NTRS)

Leger, P. Chris; Maimone, Mark

2009-01-01

Autonomous Instrument Placement (AutoPlace) is onboard software that enables a Mars Exploration Rover to act autonomously in using its manipulator to place scientific instruments on or near designated rock and soil targets. Prior to the development of AutoPlace, it was necessary for human operators on Earth to plan every motion of the manipulator arm in a time-consuming process that included downlinking of images from the rover, analysis of images and creation of commands, and uplinking of commands to the rover. AutoPlace incorporates image analysis and planning algorithms into the onboard rover software, eliminating the need for the downlink/uplink command cycle. Many of these algorithms are derived from the existing groundbased image analysis and planning algorithms, with modifications and augmentations for onboard use.

Genetics Home Reference: hereditary sensory and autonomic neuropathy type II

MedlinePlus

... and autonomic neurons. It is involved in the recycling of worn-out cell parts (autophagy), specifically a ... endoplasmic reticulum . When the RETREG1 protein is nonfunctional, recycling of the endoplasmic reticulum is impaired. The buildup ...

The cytoskeleton in cell-autonomous immunity: structural determinants of host defence

PubMed Central

Mostowy, Serge; Shenoy, Avinash R.

2016-01-01

Host cells use antimicrobial proteins, pathogen-restrictive compartmentalization and cell death in their defence against intracellular pathogens. Recent work has revealed that four components of the cytoskeleton — actin, microtubules, intermediate filaments and septins, which are well known for their roles in cell division, shape and movement — have important functions in innate immunity and cellular self-defence. Investigations using cellular and animal models have shown that these cytoskeletal proteins are crucial for sensing bacteria and for mobilizing effector mechanisms to eliminate them. In this Review, we highlight the emerging roles of the cytoskeleton as a structural determinant of cell-autonomous host defence. PMID:26292640

Drosophila male and female germline stem cell niches require the nuclear lamina protein Otefin.

PubMed

Barton, Lacy J; Lovander, Kaylee E; Pinto, Belinda S; Geyer, Pamela K

2016-07-01

The nuclear lamina is an extensive protein network that underlies the inner nuclear envelope. This network includes the LAP2-emerin-MAN1-domain (LEM-D) protein family, proteins that share an association with the chromatin binding protein Barrier-to-autointegration factor (BAF). Loss of individual LEM-D proteins causes progressive, tissue-restricted diseases, known as laminopathies. Mechanisms associated with laminopathies are not yet understood. Here we present our studies of one of the Drosophila nuclear lamina LEM-D proteins, Otefin (Ote), a homologue of emerin. Previous studies have shown that Ote is autonomously required for the survival of female germline stem cells (GSCs). We demonstrate that Ote is also required for survival of somatic cells in the ovarian niche, with loss of Ote causing a decrease in cap cell number and altered signal transduction. We show germ cell-restricted expression of Ote rescues these defects, revealing a non-autonomous function for Ote in niche maintenance and emphasizing that GSCs contribute to the maintenance of their own niches. Further, we investigate the requirement of Ote in the male fertility. We show that ote mutant males become prematurely sterile as they age. Parallel to observations in females, this sterility is associated with GSC loss and changes in somatic cells of the niche, phenotypes that are largely rescued by germ cell-restricted Ote expression. Taken together, our studies demonstrate that Ote is required autonomously for survival of two stem cell populations, as well as non-autonomously for maintenance of two somatic niches. Finally, our data add to growing evidence that LEM-D proteins have critical roles in stem cell survival and tissue homeostasis. Copyright © 2016 Elsevier Inc. All rights reserved.

Nonautonomous Roles of MAB-5/Hox and the Secreted Basement Membrane Molecule SPON-1/F-Spondin in Caenorhabditis elegans Neuronal Migration.

PubMed

Josephson, Matthew P; Miltner, Adam M; Lundquist, Erik A

2016-08-01

Nervous system development and circuit formation requires neurons to migrate from their birthplaces to specific destinations.Migrating neurons detect extracellular cues that provide guidance information. In Caenorhabditis elegans, the Q right (QR) and Q left (QL) neuroblast descendants migrate long distances in opposite directions. The Hox gene lin-39 cell autonomously promotes anterior QR descendant migration, and mab-5/Hox cell autonomously promotes posterior QL descendant migration. Here we describe a nonautonomous role of mab-5 in regulating both QR and QL descendant migrations, a role masked by redundancy with lin-39 A third Hox gene, egl-5/Abdominal-B, also likely nonautonomously regulates Q descendant migrations. In the lin-39 mab-5 egl-5 triple mutant, little if any QR and QL descendant migration occurs. In addition to well-described roles of lin-39 and mab-5 in the Q descendants, our results suggest that lin-39, mab-5, and egl-5 might also pattern the posterior region of the animal for Q descendant migration. Previous studies showed that the spon-1 gene might be a target of MAB-5 in Q descendant migration. spon-1 encodes a secreted basement membrane molecule similar to vertebrate F-spondin. Here we show that spon-1 acts nonautonomously to control Q descendant migration, and might function as a permissive rather than instructive signal for cell migration. We find that increased levels of MAB-5 in body wall muscle (BWM) can drive the spon-1 promoter adjacent to the Q cells, and loss of spon-1 suppresses mab-5 gain of function. Thus, MAB-5 might nonautonomously control Q descendant migrations by patterning the posterior region of the animal to which Q cells respond. spon-1 expression from BWMs might be part of the posterior patterning necessary for directed Q descendant migration. Copyright © 2016 by the Genetics Society of America.

Nonautonomous Roles of MAB-5/Hox and the Secreted Basement Membrane Molecule SPON-1/F-Spondin in Caenorhabditis elegans Neuronal Migration

PubMed Central

Josephson, Matthew P.; Miltner, Adam M.; Lundquist, Erik A.

2016-01-01

Nervous system development and circuit formation requires neurons to migrate from their birthplaces to specific destinations.Migrating neurons detect extracellular cues that provide guidance information. In Caenorhabditis elegans, the Q right (QR) and Q left (QL) neuroblast descendants migrate long distances in opposite directions. The Hox gene lin-39 cell autonomously promotes anterior QR descendant migration, and mab-5/Hox cell autonomously promotes posterior QL descendant migration. Here we describe a nonautonomous role of mab-5 in regulating both QR and QL descendant migrations, a role masked by redundancy with lin-39. A third Hox gene, egl-5/Abdominal-B, also likely nonautonomously regulates Q descendant migrations. In the lin-39mab-5egl-5 triple mutant, little if any QR and QL descendant migration occurs. In addition to well-described roles of lin-39 and mab-5 in the Q descendants, our results suggest that lin-39, mab-5, and egl-5 might also pattern the posterior region of the animal for Q descendant migration. Previous studies showed that the spon-1 gene might be a target of MAB-5 in Q descendant migration. spon-1 encodes a secreted basement membrane molecule similar to vertebrate F-spondin. Here we show that spon-1 acts nonautonomously to control Q descendant migration, and might function as a permissive rather than instructive signal for cell migration. We find that increased levels of MAB-5 in body wall muscle (BWM) can drive the spon-1 promoter adjacent to the Q cells, and loss of spon-1 suppresses mab-5 gain of function. Thus, MAB-5 might nonautonomously control Q descendant migrations by patterning the posterior region of the animal to which Q cells respond. spon-1 expression from BWMs might be part of the posterior patterning necessary for directed Q descendant migration. PMID:27225683

The zebrafish gene cloche acts upstream of a flk-1 homologue to regulate endothelial cell differentiation.

PubMed

Liao, W; Bisgrove, B W; Sawyer, H; Hug, B; Bell, B; Peters, K; Grunwald, D J; Stainier, D Y

1997-01-01

The zebrafish cloche mutation affects both the endothelial and hematopoietic lineages at a very early stage (Stainier, D. Y. R., Weinstein, B. M., Detrich, H. W., Zon, L. I. and Fishman, M. C. (1995). Development 121, 3141-3150). The most striking vascular phenotype is the absence of endocardial cells from the heart. Microscopic examination of mutant embryos reveals the presence of endothelial-like cells in the lower trunk and tail regions while head vessels appear to be missing, indicating a molecular diversification of the endothelial lineage. Cell transplantation experiments show that cloche acts cell-autonomously within the endothelial lineage. To analyze further the role of cloche in regulating endothelial cell differentiation, we have examined the expression of flk-1 and tie, two receptor tyrosine kinase genes expressed early and sequentially in the endothelial lineage. In wild-type fish, flk-1-positive cells are found throughout the embryo and differentiate to form the nascent vasculature. In cloche mutants, flk-1-positive cells are found only in the lower trunk and tail regions, and this expression is delayed as compared to wild-type. Unlike the flk-1-positive cells in wild-type embryos, those in cloche mutants do not go on to express tie, suggesting that their differentiation is halted at an early stage. We also find that the cloche mutation is not linked to flk-1. These data indicate that cloche affects the differentiation of all endothelial cells and that it acts at a very early stage, either by directly regulating flk-1 expression or by controlling the differentiation of cells that normally develop to express flk-1. cloche mutants also have a blood deficit and their hematopoietic tissues show no expression of the hematopoietic transcription factor genes GATA-1 or GATA-2 at early stages. Because the appearance of distinct levels of flk-1 expression is delayed in cloche mutants, we examined GATA-1 expression at late embryonic stages and found some blood cell differentiation that appears to be limited to the region lined by the flk-1-expressing cells. The spatial restriction of blood in the ventroposterior-most region of cloche mutant embryos may be indicative of a ventral source of signal(s) controlling hematopoietic differentiation. In addition, the restricted colocalization of blood and endothelium in cloche mutants suggests that important interactions occur between these two lineages during normal development.

A novel cell-based assay for inhibitory anti-muscarinic type 3 receptor antibodies in primary Sjögren's syndrome.

PubMed

Bastian, Isabell; Gordon, Tom P; Jackson, Michael W

2015-12-01

Inhibitory autoantibodies acting at the muscarinic acetylcholine receptor type 3 (M3R) are postulated to mediate autonomic dysfunction, including decreased salivary and lacrimal gland output and extra-glandular manifestations, in patients with primary Sjögren's syndrome. However, the contention that anti-M3R antibodies are pathogenic in patients remains untested, due to a lack of assays both sophisticated enough to detect inhibitory anti-M3R antibodies yet suitable for screening large patient cohorts. In the current study, we have established a cell-based bioassay of M3R activity, based on dual transfection of the M3R and a luciferase reporter gene. The bioassay is capable of capturing real-time agonist-mediated signalling of the M3R, which is inhibited specifically by patient IgG that have previously been demonstrated to have anti-M3R activity. The assay can be run in multi-well culture plates, and analysed using simple luminescence readers. As such, the new bioassay incorporating M3R-mediated luciferase transduction is the first assay adaptable to common diagnostic platforms that is capable of determining the presence in patient serum of functionally active anti-M3R autoantibodies. The new bioassay should prove useful for large cohort screening studies aiming to correlate the presence in patients of inhibitory anti-M3R antibodies with symptoms of both glandular and extra-glandular autonomic dysfunction. Copyright © 2015 Elsevier B.V. All rights reserved.

The C. elegans Spalt-like protein SEM-4 functions through the SoxC transcription factor SEM-2 to promote a proliferative blast cell fate in the postembryonic mesoderm.

PubMed

Shen, Qinfang; Shi, Herong; Tian, Chenxi; Ghai, Vikas; Liu, Jun

2017-09-01

Proper development of a multicellular organism relies on well-coordinated regulation of cell fate specification, cell proliferation and cell differentiation. The C. elegans postembryonic mesoderm provides a useful system for uncovering factors involved in these processes and for further dissecting their regulatory relationships. The single Spalt-like zinc finger containing protein SEM-4/SALL is known to be involved in specifying the proliferative sex myoblast (SM) fate. We have found that SEM-4/SALL is sufficient to promote the SM fate and that it does so in a cell autonomous manner. We further showed that SEM-4/SALL acts through the SoxC transcription factor SEM-2 to promote the SM fate. SEM-2 is known to promote the SM fate by inhibiting the expression of two BWM-specifying transcription factors. In light of recent findings in mammals showing that Sall4, one of the mammalian homologs of SEM-4, contributes to pluripotency regulation by inhibiting differentiation, our work suggests that the function of SEM-4/SALL proteins in regulating pluripotency versus differentiation appears to be evolutionarily conserved. Copyright © 2017 Elsevier Inc. All rights reserved.

The heparan sulfate-modifying enzyme glucuronyl C5-epimerase HSE-5 controls Caenorhabditis elegans Q neuroblast polarization during migration.

PubMed

Wang, Xiangming; Liu, Jianhong; Zhu, Zhiwen; Ou, Guangshuo

2015-03-15

Directional cell migration is fundamental for neural development, and extracellular factors are pivotal for this process. Heparan sulfate proteoglycans (HSPGs) that carry long chains of differentially modified sugar residues contribute to extracellular matrix; however, the functions of HSPG in guiding cell migration remain elusive. Here, we used the Caenorhabditis elegans mutant pool from the Million Mutation Project and isolated a mutant allele of the heparan sulfate-modifying enzyme glucuronyl C5-epimerase HSE-5. Loss-of-function of this enzyme resulted in defective Q neuroblast migration. We showed that hse-5 controlled Q cell migration in a cell non-autonomous manner. By performing live cell imaging in hse-5 mutant animals, we found that hse-5 controlled initial polarization during Q neuroblast migration. Furthermore, our genetic epistasis analysis demonstrated that lon-2 might act downstream of hse-5. Finally, rescue of the hse-5 mutant phenotype by expression of human and mouse hse-5 homologs suggested a conserved function for this gene in neural development. Taken together, our results indicated that proper HSPG modification in the extracellular matrix by HSE-5 is essential for neuroblast polarity during migration. Copyright © 2015 Elsevier Inc. All rights reserved.

AUTONOMOUS AND NONAUTONOMOUS REGULATION OF WNT-MEDIATED NEURONAL POLARITY BY THE C. ELEGANS ROR KINASE CAM-1

PubMed Central

Chien, Shih-Chieh Jason; Gurling, Mark; Kim, Changsung; Craft, Teresa; Forrester, Wayne; Garriga, Gian

2015-01-01

Wnts are a conserved family of secreted glycoproteins that regulate various developmental processes in metazoans. Three of the five C. elegans Wnts, CWN-1, CWN-2 and EGL-20, and the sole Wnt receptor of the Ror kinase family, CAM-1, are known to regulate the anterior polarization of the mechanosensory neuron ALM. Here we show that CAM-1 and the Frizzled receptor MOM-5 act in parallel pathways to control ALM polarity. We also show that CAM-1 has two functions in this process: an autonomous signaling function that promotes anterior polarization and a nonautonomous Wnt-antagonistic function that inhibits anterior polarization. These antagonistic activities can account for the weak ALM phenotypes displayed by cam-1 mutants. Our observations suggest that CAM-1 could function as a Wnt receptor in many developmental processes, but the analysis of cam-1 mutants may fail to reveal CAM-1’s role as a receptor in these processes because of its Wnt-antagonistic activity. In this model, loss of CAM-1 results in increased levels of Wnts that act through other Wnt receptors, masking CAM-1’s autonomous role as a Wnt receptor. PMID:25917219

Autonomy in chimpanzees.

PubMed

Beauchamp, Tom L; Wobber, Victoria

2014-04-01

Literature on the mental capacities and cognitive mechanisms of the great apes has been silent about whether they can act autonomously. This paper provides a philosophical theory of autonomy supported by psychological studies of the cognitive mechanisms that underlie chimpanzee behavior to argue that chimpanzees can act autonomously even though their psychological mechanisms differ from those of humans. Chimpanzees satisfy the two basic conditions of autonomy: (1) liberty (the absence of controlling influences) and (2) agency (self-initiated intentional action), each of which is specified here in terms of conditions of understanding, intention, and self-control. In this account, chimpanzees make knowledge-based choices reflecting a richly information-based and socially sophisticated understanding of the world. Finally, two major theories of autonomy (Kantian theory and two-level theory) are rejected as too narrow to adequately address these issues, necessitating the modifications made in the present approach.

Chemical-Induced Erythrocytosis in Wistar Rats: Assessment as a Model for Human Polycythemia.

DTIC Science & Technology

1985-05-01

polycythemic condition are unusual features that are more typically found in polycythemia vera, an autonomous myeloproliferative disorder in man that results...polycythemia vera, an autonomous myeloproliferative disorder in man that results from clonal neoplasia of bone marrow stem cells. However, the data described...5 and stroma cell lines [55]. These diseases are commonly termed ’ myeloproliferative disorders’, or better, ’myelodysplastic disease’ which emphasizes

Cadherin-2 Is Required Cell Autonomously for Collective Migration of Facial Branchiomotor Neurons.

PubMed

Rebman, Jane K; Kirchoff, Kathryn E; Walsh, Gregory S

2016-01-01

Collective migration depends on cell-cell interactions between neighbors that contribute to their overall directionality, yet the mechanisms that control the coordinated migration of neurons remains to be elucidated. During hindbrain development, facial branchiomotor neurons (FBMNs) undergo a stereotypic tangential caudal migration from their place of birth in rhombomere (r)4 to their final location in r6/7. FBMNs engage in collective cell migration that depends on neuron-to-neuron interactions to facilitate caudal directionality. Here, we demonstrate that Cadherin-2-mediated neuron-to-neuron adhesion is necessary for directional and collective migration of FBMNs. We generated stable transgenic zebrafish expressing dominant-negative Cadherin-2 (Cdh2ΔEC) driven by the islet1 promoter. Cell-autonomous inactivation of Cadherin-2 function led to non-directional migration of FBMNs and a defect in caudal tangential migration. Additionally, mosaic analysis revealed that Cdh2ΔEC-expressing FBMNs are not influenced to migrate caudally by neighboring wild-type FBMNs due to a defect in collective cell migration. Taken together, our data suggest that Cadherin-2 plays an essential cell-autonomous role in mediating the collective migration of FBMNs.

A dye-sensitized solar cell acting as the electrical reading box of an immunosensor: Application to CEA determination.

PubMed

Truta, Liliana A A N A; Moreira, Felismina T C; Sales, M Goreti F

2018-06-01

Monitoring cancer biomarkers in biological fluids has become a key tool for disease diagnosis, which should be of easy access anywhere in the world. The possibility of reducing basic requirements in the field of electrochemical biosensing may open doors in this direction. This work proposes for this purpose an innovative electrochemical immunosensing system using a photovoltaic cell as an electrical reading box. Immunosensing ensures accuracy, the electrochemical-ground of the device ensures sensitivity and detectability, and the photovoltaic cell drives the system towards electrical autonomy. As proof-of-concept, Carcinoembryonic antigen (CEA) was used herein, a cancer biomarker of clinical relevance. In brief, a conductive glass with a fluorine doped tin oxide film was used as conductive support and modified with anti-CEA by means of a bottom-up approach. All stages involved in the biochemical modification of the FTO surface were followed by electrochemical techniques, namely electrochemical impedance spectroscopy and cyclic voltammetry. This electrode acted as counter electrode of a dye-sensitized solar cells, and the electrical output of this cell was monitored for the different concentrations of CEA. Under optimized conditions, the device displayed a linear behaviour against CEA concentration, from 5 pg/mL to 15 ng/mL. The immunosensor was applied to the analysis of CEA in urine from healthy individual and spiked with the antigen. Overall, the presented approach demonstrates that photovoltaic cells may be employed as an electrical reading box of electrochemical biosensors, yielding a new direction towards autonomous electrochemical biosensing. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans.

PubMed

Grants, Jennifer M; Ying, Lisa T L; Yoda, Akinori; You, Charlotte C; Okano, Hideyuki; Sawa, Hitoshi; Taubert, Stefan

2016-02-01

Cell signaling pathways that control proliferation and determine cell fates are tightly regulated to prevent developmental anomalies and cancer. Transcription factors and coregulators are important effectors of signaling pathway output, as they regulate downstream gene programs. In Caenorhabditis elegans, several subunits of the Mediator transcriptional coregulator complex promote or inhibit vulva development, but pertinent mechanisms are poorly defined. Here, we show that Mediator's dissociable cyclin dependent kinase 8 (CDK8) module (CKM), consisting of cdk-8, cic-1/Cyclin C, mdt-12/dpy-22, and mdt-13/let-19, is required to inhibit ectopic vulval cell fates downstream of the epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK) pathway. cdk-8 inhibits ectopic vulva formation by acting downstream of mpk-1/ERK, cell autonomously in vulval cells, and in a kinase-dependent manner. We also provide evidence that the CKM acts as a corepressor for the Ets-family transcription factor LIN-1, as cdk-8 promotes transcriptional repression by LIN-1. In addition, we find that CKM mutation alters Mediator subunit requirements in vulva development: the mdt-23/sur-2 subunit, which is required for vulva development in wild-type worms, is dispensable for ectopic vulva formation in CKM mutants, which instead display hallmarks of unrestrained Mediator tail module activity. We propose a model whereby the CKM controls EGFR-Ras-ERK transcriptional output by corepressing LIN-1 and by fine tuning Mediator specificity, thus balancing transcriptional repression vs. activation in a critical developmental signaling pathway. Collectively, these data offer an explanation for CKM repression of EGFR signaling output and ectopic vulva formation and provide the first evidence of Mediator CKM-tail module subunit crosstalk in animals. Copyright © 2016 by the Genetics Society of America.

Optogenetic analysis of a nociceptor neuron and network reveals ion channels acting downstream of primary sensors.

PubMed

Husson, Steven J; Costa, Wagner Steuer; Wabnig, Sebastian; Stirman, Jeffrey N; Watson, Joseph D; Spencer, W Clay; Akerboom, Jasper; Looger, Loren L; Treinin, Millet; Miller, David M; Lu, Hang; Gottschalk, Alexander

2012-05-08

Nociception generally evokes rapid withdrawal behavior in order to protect the tissue from harmful insults. Most nociceptive neurons responding to mechanical insults display highly branched dendrites, an anatomy shared by Caenorhabditis elegans FLP and PVD neurons, which mediate harsh touch responses. Although several primary molecular nociceptive sensors have been characterized, less is known about modulation and amplification of noxious signals within nociceptor neurons. First, we analyzed the FLP/PVD network by optogenetics and studied integration of signals from these cells in downstream interneurons. Second, we investigated which genes modulate PVD function, based on prior single-neuron mRNA profiling of PVD. Selectively photoactivating PVD, FLP, and downstream interneurons via Channelrhodopsin-2 (ChR2) enabled the functional dissection of this nociceptive network, without interfering signals by other mechanoreceptors. Forward or reverse escape behaviors were determined by PVD and FLP, via integration by command interneurons. To identify mediators of PVD function, acting downstream of primary nocisensor molecules, we knocked down PVD-specific transcripts by RNAi and quantified light-evoked PVD-dependent behavior. Cell-specific disruption of synaptobrevin or voltage-gated Ca(2+) channels (VGCCs) showed that PVD signals chemically to command interneurons. Knocking down the DEG/ENaC channel ASIC-1 and the TRPM channel GTL-1 indicated that ASIC-1 may extend PVD's dynamic range and that GTL-1 may amplify its signals. These channels act cell autonomously in PVD, downstream of primary mechanosensory molecules. Our work implicates TRPM channels in modifying excitability of and DEG/ENaCs in potentiating signal output from a mechano-nociceptor neuron. ASIC-1 and GTL-1 homologs, if functionally conserved, may denote valid targets for novel analgesics. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Notch pathway regulates the Second Mitotic Wave cell cycle independently of bHLH proteins.

PubMed

Bhattacharya, Abhishek; Li, Ke; Quiquand, Manon; Rimesso, Gerard; Baker, Nicholas E

2017-11-15

Notch regulates both neurogenesis and cell cycle activity to coordinate precursor cell generation in the differentiating Drosophila eye. Mosaic analysis with mitotic clones mutant for Notch components was used to identify the pathway of Notch signaling that regulates the cell cycle in the Second Mitotic Wave. Although S phase entry depends on Notch signaling and on the transcription factor Su(H), the transcriptional co-activator Mam and the bHLH repressor genes of the E(spl)-Complex were not essential, although these are Su(H) coactivators and targets during the regulation of neurogenesis. The Second Mitotic Wave showed little dependence on ubiquitin ligases neuralized or mindbomb, and although the ligand Delta is required non-autonomously, partial cell cycle activity occurred in the absence of known Notch ligands. We found that myc was not essential for the Second Mitotic Wave. The Second Mitotic Wave did not require the HLH protein Extra macrochaetae, and the bHLH protein Daughterless was required only cell-nonautonomously. Similar cell cycle phenotypes for Daughterless and Atonal were consistent with requirement for neuronal differentiation to stimulate Delta expression, affecting Notch activity in the Second Mitotic Wave indirectly. Therefore Notch signaling acts to regulate the Second Mitotic Wave without activating bHLH gene targets. Copyright © 2017 Elsevier Inc. All rights reserved.

Non-cell-autonomous effects yield lower clonal diversity in expanding tumors.

PubMed

Tissot, Tazzio; Thomas, Frédéric; Roche, Benjamin

2017-09-11

Recent cancer research has investigated the possibility that non-cell-autonomous (NCA) driving tumor growth can support clonal diversity (CD). Indeed, mutations can affect the phenotypes not only of their carriers ("cell-autonomous", CA effects), but also sometimes of other cells (NCA effects). However, models that have investigated this phenomenon have only considered a restricted number of clones. Here, we designed an individual-based model of tumor evolution, where clones grow and mutate to yield new clones, among which a given frequency have NCA effects on other clones' growth. Unlike previously observed for smaller assemblages, most of our simulations yield lower CD with high frequency of mutations with NCA effects. Owing to NCA effects increasing competition in the tumor, clones being already dominant are more likely to stay dominant, and emergent clones not to thrive. These results may help personalized medicine to predict intratumor heterogeneity across different cancer types for which frequency of NCA effects could be quantified.

Toward the human cellular microRNAome.

PubMed

McCall, Matthew N; Kim, Min-Sik; Adil, Mohammed; Patil, Arun H; Lu, Yin; Mitchell, Christopher J; Leal-Rojas, Pamela; Xu, Jinchong; Kumar, Manoj; Dawson, Valina L; Dawson, Ted M; Baras, Alexander S; Rosenberg, Avi Z; Arking, Dan E; Burns, Kathleen H; Pandey, Akhilesh; Halushka, Marc K

2017-10-01

MicroRNAs are short RNAs that serve as regulators of gene expression and are essential components of normal development as well as modulators of disease. MicroRNAs generally act cell-autonomously, and thus their localization to specific cell types is needed to guide our understanding of microRNA activity. Current tissue-level data have caused considerable confusion, and comprehensive cell-level data do not yet exist. Here, we establish the landscape of human cell-specific microRNA expression. This project evaluated 8 billion small RNA-seq reads from 46 primary cell types, 42 cancer or immortalized cell lines, and 26 tissues. It identified both specific and ubiquitous patterns of expression that strongly correlate with adjacent superenhancer activity. Analysis of unaligned RNA reads uncovered 207 unknown minor strand (passenger) microRNAs of known microRNA loci and 495 novel putative microRNA loci. Although cancer cell lines generally recapitulated the expression patterns of matched primary cells, their isomiR sequence families exhibited increased disorder, suggesting DROSHA- and DICER1-dependent microRNA processing variability. Cell-specific patterns of microRNA expression were used to de-convolute variable cellular composition of colon and adipose tissue samples, highlighting one use of these cell-specific microRNA expression data. Characterization of cellular microRNA expression across a wide variety of cell types provides a new understanding of this critical regulatory RNA species. © 2017 McCall et al.; Published by Cold Spring Harbor Laboratory Press.

A New Paradigm for Robotic Rovers

NASA Astrophysics Data System (ADS)

Clark, P. E.; Curtis, S. A.; Rilee, M. L.

We are in the process of developing rovers with extreme mobility needed to explore remote, rugged terrain. We call these systems Tetrahedral Explorer Technologies (TETs). Architecture is based on conformable tetrahedra, the simplest space-filling form, as building blocks, single or networked, where apices act as nodes from which struts reversibly deploy. The tetrahedral framework acts as a simple skeletal muscular structure. We have already prototyped a simple robotic walker from a single reconfigurable tetrahedron capable of tumbling and a more evolved 12Tetrahedral Walker, the Autonomous Landed Investigator (ALI), which has interior nodes for payload, more continuous motion, and is commandable through a user friendly interface. ALI is an EMS level mission concept which would allow autonomous in situ exploration of the lunar poles within the next decade. ALI would consist of one or more 12tetrahedral walkers capable of rapid locomotion with the many degrees of freedom and equipped for navigation in the unilluminated, inaccessible and thus largely unexplored rugged terrains where lunar resources are likely to be found: the Polar Regions. ALI walkers would act as roving reconnaissance teams for unexplored regions, analyzing samples along the way.

Interoceptive inference: From computational neuroscience to clinic.

PubMed

Owens, Andrew P; Allen, Micah; Ondobaka, Sasha; Friston, Karl J

2018-04-22

The central and autonomic nervous systems can be defined by their anatomical, functional and neurochemical characteristics, but neither functions in isolation. For example, fundamental components of autonomically mediated homeostatic processes are afferent interoceptive signals reporting the internal state of the body and efferent signals acting on interoceptive feedback assimilated by the brain. Recent predictive coding (interoceptive inference) models formulate interoception in terms of embodied predictive processes that support emotion and selfhood. We propose interoception may serve as a way to investigate holistic nervous system function and dysfunction in disorders of brain, body and behaviour. We appeal to predictive coding and (active) interoceptive inference, to describe the homeostatic functions of the central and autonomic nervous systems. We do so by (i) reviewing the active inference formulation of interoceptive and autonomic function, (ii) survey clinical applications of this formulation and (iii) describe how it offers an integrative approach to human physiology; particularly, interactions between the central and peripheral nervous systems in health and disease. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

Is variety a spice of (an active) life?: perceived variety, exercise behavior, and the mediating role of autonomous motivation.

PubMed

Sylvester, Benjamin D; Standage, Martyn; Ark, Tavinder K; Sweet, Shane N; Crocker, Peter R; Zumbo, Bruno D; Beauchamp, Mark R

2014-10-01

In this study, we examined whether perceived variety in exercise prospectively predicts unique variance in exercise behavior when examined alongside satisfaction of the three basic psychological needs (for competence, relatedness, and autonomy) embedded within self-determination theory (Ryan & Deci, 2002), through the mediating role of autonomous and controlled motivation. A convenience sample of community adults (N = 363) completed online questionnaires twice over a 6-week period. The results of structural equation modeling showed perceived variety and satisfaction of the needs for competence and relatedness to be unique indirect positive predictors of exercise behavior (through autonomous motivation) 6 weeks later. In addition, satisfaction of the need for autonomy was found to negatively predict controlled motivation. Perceived variety in exercise complemented satisfaction of the needs for competence, relatedness, and autonomy in predicting motivation and (indirectly) exercise behavior, and may act as a salient mechanism in the prediction of autonomous motivation and behavior in exercise settings.

Control technique for planetary rover

NASA Technical Reports Server (NTRS)

Nakatani, Ichiro; Kubota, Takashi; Adachi, Tadashi; Saitou, Hiroaki; Okamoto, Sinya

1994-01-01

Beginning next century, several schemes for sending a planetary rover to the moon or Mars are being planned. As part of the development program, autonomous navigation technology is being studied to allow the rover the ability to move autonomously over a long range of unknown planetary surface. In the previous study, we ran the autonomous navigation experiment on an outdoor test terrain by using a rover test-bed that was controlled by a conventional sense-plan-act method. In some cases during the experiment, a problem occurred with the rover moving into untraversable areas. To improve this situation, a new control technique has been developed that gives the rover the ability of reacting to the outputs of the proximity sensors, a reaction behavior if you will. We have developed a new rover test-bed system on which an autonomous navigation experiment was performed using the newly developed control technique. In this outdoor experiment, the new control technique effectively produced the control command for the rover to avoid obstacles and be guided to the goal point safely.

Cellular Self-Defense: How Cell-Autonomous Immunity Protects Against Pathogens

PubMed Central

Randow, Felix; MacMicking, John D.; James, Leo C.

2013-01-01

Our prevailing view of vertebrate host defense is strongly shaped by the notion of a specialized set of immune cells as sole guardians of antimicrobial resistance. Yet this view greatly underestimates a capacity for most cell lineages—the majority of which fall outside the traditional province of the immune system—to defend themselves against infection. This ancient and ubiquitous form of host protection is termed cell-autonomous immunity and operates across all three domains of life. Here, we discuss the organizing principles that govern cellular self-defense and how intracellular compartmentalization has shaped its activities to provide effective protection against a wide variety of microbial pathogens. PMID:23661752

Cellular self-defense: how cell-autonomous immunity protects against pathogens.

PubMed

Randow, Felix; MacMicking, John D; James, Leo C

2013-05-10

Our prevailing view of vertebrate host defense is strongly shaped by the notion of a specialized set of immune cells as sole guardians of antimicrobial resistance. Yet this view greatly underestimates a capacity for most cell lineages-the majority of which fall outside the traditional province of the immune system-to defend themselves against infection. This ancient and ubiquitous form of host protection is termed cell-autonomous immunity and operates across all three domains of life. Here, we discuss the organizing principles that govern cellular self-defense and how intracellular compartmentalization has shaped its activities to provide effective protection against a wide variety of microbial pathogens.

Human tRNA genes function as chromatin insulators

PubMed Central

Raab, Jesse R; Chiu, Jonathan; Zhu, Jingchun; Katzman, Sol; Kurukuti, Sreenivasulu; Wade, Paul A; Haussler, David; Kamakaka, Rohinton T

2012-01-01

Insulators help separate active chromatin domains from silenced ones. In yeast, gene promoters act as insulators to block the spread of Sir and HP1 mediated silencing while in metazoans most insulators are multipartite autonomous entities. tDNAs are repetitive sequences dispersed throughout the human genome and we now show that some of these tDNAs can function as insulators in human cells. Using computational methods, we identified putative human tDNA insulators. Using silencer blocking, transgene protection and repressor blocking assays we show that some of these tDNA-containing fragments can function as barrier insulators in human cells. We find that these elements also have the ability to block enhancers from activating RNA pol II transcribed promoters. Characterization of a putative tDNA insulator in human cells reveals that the site possesses chromatin signatures similar to those observed at other better-characterized eukaryotic insulators. Enhanced 4C analysis demonstrates that the tDNA insulator makes long-range chromatin contacts with other tDNAs and ETC sites but not with intervening or flanking RNA pol II transcribed genes. PMID:22085927

Mind bomb-1 is an essential modulator of long-term memory and synaptic plasticity via the Notch signaling pathway

PubMed Central

2012-01-01

Background Notch signaling is well recognized as a key regulator of the neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-1 (Mib1) is an essential positive regulator in the Notch pathway, acting non-autonomously in the signal-sending cells. Therefore, genetic ablation of Mib1 in mature neuron would give valuable insight to understand the cell-to-cell interaction between neurons via Notch signaling for their proper function. Results Here we show that the inactivation of Mib1 in mature neurons in forebrain results in impaired hippocampal dependent spatial memory and contextual fear memory. Consistently, hippocampal slices from Mib1-deficient mice show impaired late-phase, but not early-phase, long-term potentiation and long-term depression without change in basal synaptic transmission at SC-CA1 synapses. Conclusions These data suggest that Mib1-mediated Notch signaling is essential for long-lasting synaptic plasticity and memory formation in the rodent hippocampus. PMID:23111145

Towards implementation of cellular automata in Microbial Fuel Cells.

PubMed

Tsompanas, Michail-Antisthenis I; Adamatzky, Andrew; Sirakoulis, Georgios Ch; Greenman, John; Ieropoulos, Ioannis

2017-01-01

The Microbial Fuel Cell (MFC) is a bio-electrochemical transducer converting waste products into electricity using microbial communities. Cellular Automaton (CA) is a uniform array of finite-state machines that update their states in discrete time depending on states of their closest neighbors by the same rule. Arrays of MFCs could, in principle, act as massive-parallel computing devices with local connectivity between elementary processors. We provide a theoretical design of such a parallel processor by implementing CA in MFCs. We have chosen Conway's Game of Life as the 'benchmark' CA because this is the most popular CA which also exhibits an enormously rich spectrum of patterns. Each cell of the Game of Life CA is realized using two MFCs. The MFCs are linked electrically and hydraulically. The model is verified via simulation of an electrical circuit demonstrating equivalent behaviours. The design is a first step towards future implementations of fully autonomous biological computing devices with massive parallelism. The energy independence of such devices counteracts their somewhat slow transitions-compared to silicon circuitry-between the different states during computation.

Towards implementation of cellular automata in Microbial Fuel Cells

PubMed Central

Adamatzky, Andrew; Sirakoulis, Georgios Ch.; Greenman, John; Ieropoulos, Ioannis

2017-01-01

The Microbial Fuel Cell (MFC) is a bio-electrochemical transducer converting waste products into electricity using microbial communities. Cellular Automaton (CA) is a uniform array of finite-state machines that update their states in discrete time depending on states of their closest neighbors by the same rule. Arrays of MFCs could, in principle, act as massive-parallel computing devices with local connectivity between elementary processors. We provide a theoretical design of such a parallel processor by implementing CA in MFCs. We have chosen Conway’s Game of Life as the ‘benchmark’ CA because this is the most popular CA which also exhibits an enormously rich spectrum of patterns. Each cell of the Game of Life CA is realized using two MFCs. The MFCs are linked electrically and hydraulically. The model is verified via simulation of an electrical circuit demonstrating equivalent behaviours. The design is a first step towards future implementations of fully autonomous biological computing devices with massive parallelism. The energy independence of such devices counteracts their somewhat slow transitions—compared to silicon circuitry—between the different states during computation. PMID:28498871

HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling

PubMed Central

Scortegagna, Marzia; Cataisson, Christophe; Martin, Rebecca J.; Hicklin, Daniel J.; Schreiber, Robert D.; Yuspa, Stuart H.

2008-01-01

Hypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non–cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor κ B (NFκB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1–induced NFκB activation was composed of 2 elements, IκB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFκB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFα) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFα immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFκB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression. PMID:18199827

Convective exosome-tracing microfluidics for analysis of cell-non-autonomous neurogenesis.

PubMed

Oh, Hyun Jeong; Shin, Yoojin; Chung, Seok; Hwang, Do Won; Lee, Dong Soo

2017-01-01

The effective role of exosome delivering neurogenic microRNA (miRNA) enables to induce efficient differentiation process during neurogenesis. The microfludic system capable of visualizing the exosomal behavior such as secretion, migration, and uptake of individual exosomes can be used as a robust technique to understand the exosome-mediated change of cellular behavior. Here, we developed the exosome-tracing microfluidic system to visualize exosomal transport carrying the neurogenic miRNA from leading to neighboring cells, and found a new mode of exosome-mediated cell-non-autonomous neurogenesis. The miR-193a facilitated neurogenesis in F11 cells by blocking proliferation-related target genes. In addition to time-lapse live-cell imaging using microfluidics visualized the convective transport of exosomes from differentiated to undifferentiated cells. Individual exosomes containing miR-193a from differentiated donor cells were taken up by undifferentiated cells to lead them to neurogenesis. Induction of anti-miR-193a was sufficient to block neurogenesis in F11 cells. Inhibition of the exosomal production by manumycin-A and treatment of anti-miR-193a in the differentiated donor cells failed to induce neurogenesis in undifferentiated recipient cells. These findings indicate that exosomes of neural progenitors and neurogenic miRNA within these exosomes propagate cell-non-autonomous differentiation to neighboring progenitors, to delineate the roles of exosome mediating neurogenesis of population of homologous neural progenitor cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reciprocal phosphorylation and glycosylation recognition motifs control NCAPP1 interaction with pumpkin phloem proteins and their cell-to-cell movement.

PubMed

Taoka, Ken-Ichiro; Ham, Byung-Kook; Xoconostle-Cázares, Beatriz; Rojas, Maria R; Lucas, William J

2007-06-01

In plants, cell-to-cell trafficking of non-cell-autonomous proteins (NCAPs) involves protein-protein interactions, and a role for posttranslational modification has been implicated. In this study, proteins contained in pumpkin (Cucurbita maxima cv Big Max) phloem sap were used as a source of NCAPs to further explore the molecular basis for selective NCAP trafficking. Protein overlay assays and coimmunoprecipitation experiments established that phosphorylation and glycosylation, on both Nicotiana tabacum NON-CELL-AUTONOMOUS PATHWAY PROTEIN1 (Nt-NCAPP1) and the phloem NCAPs, are essential for their interaction. Detailed molecular analysis of a representative phloem NCAP, Cm-PP16-1, identified the specific residues on which glycosylation and phosphorylation must occur for effective binding to NCAPP1. Microinjection studies confirmed that posttranslational modification on these residues is essential for cell-to-cell movement of Cm-PP16-1. Lastly, a glutathione S-transferase (GST)-Cm-PP16-1 fusion protein system was employed to test whether the peptide region spanning these residues was required for cell-to-cell movement. These studies established that a 36-amino acid peptide was sufficient to impart cell-to-cell movement capacity to GST, a normally cell-autonomous protein. These findings are consistent with the hypothesis that a phosphorylation-glycosylation recognition motif functions to control the binding of a specific subset of phloem NCAPs to NCAPP1 and their subsequent transport through plasmodesmata.

Reciprocal Phosphorylation and Glycosylation Recognition Motifs Control NCAPP1 Interaction with Pumpkin Phloem Proteins and Their Cell-to-Cell Movement[W

PubMed Central

Taoka, Ken-ichiro; Ham, Byung-Kook; Xoconostle-Cázares, Beatriz; Rojas, Maria R.; Lucas, William J.

2007-01-01

In plants, cell-to-cell trafficking of non-cell-autonomous proteins (NCAPs) involves protein–protein interactions, and a role for posttranslational modification has been implicated. In this study, proteins contained in pumpkin (Cucurbita maxima cv Big Max) phloem sap were used as a source of NCAPs to further explore the molecular basis for selective NCAP trafficking. Protein overlay assays and coimmunoprecipitation experiments established that phosphorylation and glycosylation, on both Nicotiana tabacum NON-CELL-AUTONOMOUS PATHWAY PROTEIN1 (Nt-NCAPP1) and the phloem NCAPs, are essential for their interaction. Detailed molecular analysis of a representative phloem NCAP, Cm-PP16-1, identified the specific residues on which glycosylation and phosphorylation must occur for effective binding to NCAPP1. Microinjection studies confirmed that posttranslational modification on these residues is essential for cell-to-cell movement of Cm-PP16-1. Lastly, a glutathione S-transferase (GST)–Cm-PP16-1 fusion protein system was employed to test whether the peptide region spanning these residues was required for cell-to-cell movement. These studies established that a 36–amino acid peptide was sufficient to impart cell-to-cell movement capacity to GST, a normally cell-autonomous protein. These findings are consistent with the hypothesis that a phosphorylation-glycosylation recognition motif functions to control the binding of a specific subset of phloem NCAPs to NCAPP1 and their subsequent transport through plasmodesmata. PMID:17601822

Autonomous Agents on Expedition: Humans and Progenitor Ants and Planetary Exploration

NASA Astrophysics Data System (ADS)

Rilee, M. L.; Clark, P. E.; Curtis, S. A.; Truszkowski, W. F.

2002-01-01

The Autonomous Nano-Technology Swarm (ANTS) is an advanced mission architecture based on a social insect analog of many specialized spacecraft working together to achieve mission goals. The principal mission concept driving the ANTS architecture is a Main Belt Asteroid Survey in the 2020s that will involve a thousand or more nano-technology enabled, artificially intelligent, autonomous pico-spacecraft (< 1 kg). The objective of this survey is to construct a compendium of composition, shape, and other physical parameter observations of a significant fraction of asteroid belt objects. Such an atlas will be of primary scientific importance for the understanding of Solar System origins and evolution and will lay the foundation for future exploration and capitalization of space. As the capabilities enabling ANTS are developed over the next two decades, these capabilities will need to be proven. Natural milestones for this process include the deployment of progenitors to ANTS on human expeditions to space and remote missions with interfaces for human interaction and control. These progenitors can show up in a variety of forms ranging from spacecraft subsystems and advanced handheld sensors, through complete prototypical ANTS spacecraft. A critical capability to be demonstrated is reliable, long-term autonomous operations across the ANTS architecture. High level, mission-oriented behaviors are to be managed by a control / communications layer of the swarm, whereas common low level functions required of all spacecraft, e.g. attitude control and guidance and navigation, are handled autonomically on each spacecraft. At the higher levels of mission planning and social interaction deliberative techniques are to be used. For the asteroid survey, ANTS acts as a large community of cooperative agents while for precursor missions there arises the intriguing possibility of Progenitor ANTS and humans acting together as agents. For optimal efficiency and responsiveness for individual spacecraft at the lowest levels of control we have been studying control methods based on nonlinear dynamical systems. We describe the critically important autonomous control architecture of the ANTS mission concept and a sequence of partial implementations that feature increasingly autonomous behaviors. The scientific and engineering roles that these Progenitor ANTS could play in human missions or remote missions with near real time human interactions, particularly to the Moon and Mars, will be discussed.

Synaptogenesis Is Modulated by Heparan Sulfate in Caenorhabditis elegans

PubMed Central

Lázaro-Peña, María I.; Díaz-Balzac, Carlos A.; Bülow, Hannes E.; Emmons, Scott W.

2018-01-01

The nervous system regulates complex behaviors through a network of neurons interconnected by synapses. How specific synaptic connections are genetically determined is still unclear. Male mating is the most complex behavior in Caenorhabditis elegans. It is composed of sequential steps that are governed by > 3000 chemical connections. Here, we show that heparan sulfates (HS) play a role in the formation and function of the male neural network. HS, sulfated in position 3 by the HS modification enzyme HST-3.1/HS 3-O-sulfotransferase and attached to the HS proteoglycan glypicans LON-2/glypican and GPN-1/glypican, functions cell-autonomously and nonautonomously for response to hermaphrodite contact during mating. Loss of 3-O sulfation resulted in the presynaptic accumulation of RAB-3, a molecule that localizes to synaptic vesicles, and disrupted the formation of synapses in a component of the mating circuits. We also show that the neural cell adhesion protein NRX-1/neurexin promotes and the neural cell adhesion protein NLG-1/neuroligin inhibits the formation of the same set of synapses in a parallel pathway. Thus, neural cell adhesion proteins and extracellular matrix components act together in the formation of synaptic connections. PMID:29559501

Evidence for vestibular regulation of autonomic functions in a mouse genetic model

NASA Technical Reports Server (NTRS)

Murakami, Dean M.; Erkman, Linda; Hermanson, Ola; Rosenfeld, Michael G.; Fuller, Charles A.

2002-01-01

Physiological responses to changes in the gravitational field and body position, as well as symptoms of patients with anxiety-related disorders, have indicated an interrelationship between vestibular function and stress responses. However, the relative significance of cochlear and vestibular information in autonomic regulation remains unresolved because of the difficulties in distinguishing the relative contributions of other proprioceptive and interoceptive inputs, including vagal and somatic information. To investigate the role of cochlear and vestibular function in central and physiological responses, we have examined the effects of increased gravity in wild-type mice and mice lacking the POU homeodomain transcription factor Brn-3.1 (Brn-3bPou4f3). The only known phenotype of the Brn-3.1(-/-) mouse is related to hearing and balance functions, owing to the failure of cochlear and vestibular hair cells to differentiate properly. Here, we show that normal physiological responses to increased gravity (2G exposure), such as a dramatic drop in body temperature and concomitant circadian adjustment, were completely absent in Brn-3.1(-/-) mice. In line with the lack of autonomic responses, the massive increase in neuronal activity after 2G exposure normally detected in wild-type mice was virtually abolished in Brn-3.1(-/-) mice. Our results suggest that cochlear and vestibular hair cells are the primary regulators of autonomic responses to altered gravity and provide genetic evidence that these cells are sufficient to alter neural activity in regions involved in autonomic and neuroendocrine control.

A SERIES OF SUPPRESSIVE SIGNALS WITHIN THE DROSOPHILA CIRCADIAN NEURAL CIRCUIT GENERATES SEQUENTIAL DAILY OUTPUTS

PubMed Central

Liang, Xitong; Holy, Timothy E; Taghert, Paul H

2017-01-01

Summary We studied the Drosophila circadian neural circuit using whole brain imaging in vivo. Five major groups of pacemaker neurons display synchronized molecular clocks, yet each exhibits a distinct phase of daily Ca2+ activation. Light and neuropeptide PDF from morning cells (s-LNv) together delay the phase of the evening (LNd) group by ~12 h; PDF alone delays the phase of the DN3 group, by ~17 h. Neuropeptide sNPF, released from s-LNv and LNd pacemakers, produces latenight Ca2+ activation in the DN1 group. The circuit also features negative feedback by PDF to truncate the s-LNv Ca2+ wave and terminate PDF release. Both PDF and sNPF suppress basal Ca2+ levels in target pacemakers with long durations by cell autonomous actions. Thus, light and neuropeptides act dynamically at distinct hubs of the circuit to produce multiple suppressive events that create the proper tempo and sequence of circadian pacemaker neuronal activities. PMID:28552314

Muscle contraction is required to maintain the pool of muscle progenitors via YAP and NOTCH during fetal myogenesis.

PubMed

Esteves de Lima, Joana; Bonnin, Marie-Ange; Birchmeier, Carmen; Duprez, Delphine

2016-08-24

The importance of mechanical activity in the regulation of muscle progenitors during chick development has not been investigated. We show that immobilization decreases NOTCH activity and mimics a NOTCH loss-of-function phenotype, a reduction in the number of muscle progenitors and increased differentiation. Ligand-induced NOTCH activation prevents the reduction of muscle progenitors and the increase of differentiation upon immobilization. Inhibition of NOTCH ligand activity in muscle fibers suffices to reduce the progenitor pool. Furthermore, immobilization reduces the activity of the transcriptional co-activator YAP and the expression of the NOTCH ligand JAG2 in muscle fibers. YAP forced-activity in muscle fibers prevents the decrease of JAG2 expression and the number of PAX7+ cells in immobilization conditions. Our results identify a novel mechanism acting downstream of muscle contraction, where YAP activates JAG2 expression in muscle fibers, which in turn regulates the pool of fetal muscle progenitors via NOTCH in a non-cell-autonomous manner.

Paradox of pattern separation and adult neurogenesis: A dual role for new neurons balancing memory resolution and robustness.

PubMed

Johnston, Stephen T; Shtrahman, Matthew; Parylak, Sarah; Gonçalves, J Tiago; Gage, Fred H

2016-03-01

Hippocampal adult neurogenesis is thought to subserve pattern separation, the process by which similar patterns of neuronal inputs are transformed into distinct neuronal representations, permitting the discrimination of highly similar stimuli in hippocampus-dependent tasks. However, the mechanism by which immature adult-born dentate granule neurons cells (abDGCs) perform this function remains unknown. Two theories of abDGC function, one by which abDGCs modulate and sparsify activity in the dentate gyrus and one by which abDGCs act as autonomous coding units, are generally suggested to be mutually exclusive. This review suggests that these two mechanisms work in tandem to dynamically regulate memory resolution while avoiding memory interference and maintaining memory robustness. Copyright © 2015 Elsevier Inc. All rights reserved.

Autonomy in Depressive Patients Undergoing DBS-Treatment: Informed Consent, Freedom of Will and DBS' Potential to Restore It.

PubMed

Beeker, Timo; Schlaepfer, Thomas E; Coenen, Volker A

2017-01-01

According to the World Health Organization, depression is one of the most common and most disabling psychiatric disorders, affecting at any given time approximately 325 million people worldwide. As there is strong evidence that depressive disorders are associated with a dynamic dysregulation of neural circuits involved in emotional processing, recently several attempts have been made to intervene directly in these circuits via deep brain stimulation (DBS) in patients with treatment-resistant major depressive disorder (MDD). Given the promising results of most of these studies, the rising medical interest in this new treatment correlates with a growing sensitivity to ethical questions. One of the most crucial concerns is that DBS might interfere with patients' ability to make autonomous decisions. Thus, the goal of this article is to evaluate the impact DBS presumably has on the capacity to decide and act autonomously in patients with MDD in the light of the autonomy-undermining effects depression has itself. Following the chronological order of the procedure, special attention will first be paid to depression's effects on patients' capacity to make use of their free will in giving valid Informed Consent. We suggest that while the majority of patients with MDD appear capable of autonomous choices, as it is required for Informed Consent, they might still be unable to effectively act according to their own will whenever acting includes significant personal effort. In reducing disabling depressive symptoms like anhedonia and decrease of energy, DBS for treatment resistant MDD thus rather seems to be an opportunity to substantially increase autonomy than a threat to it.

IGFBP-4 regulates adult skeletal growth in a sex-specific manner

PubMed Central

DeMambro, Victoria E; Le, Phuong T; Nagano, Kenichi; Baron, Roland; Mohan, Subburaman; Rosen, Clifford J

2017-01-01

Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actions in vitro. Yet, in vivo studies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-old Igfbp4−/− mice. Both male and female adult Igfbp4−/− mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-old Igfbp4−/− females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-old Igfbp4−/− females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation in Igfbp4−/− females. In contrast, Igfbp4−/− males had lower mineralized surface/bone surface. Femoral expression of Sost and circulating levels of sclerostin were reduced but only in Igfbp4−/− males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells from Igfbp4−/− females but decreased in males. In sum, our results indicate that loss of Igfbp4 affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor. PMID:28184001

Retinoic acid plays an evolutionarily conserved and biphasic role in pancreas development

PubMed Central

Huang, Wei; Wang, Guangliang; Delaspre, Fabien; Vitery, Maria del Carmen; Beer, Rebecca L.

2015-01-01

As the developing zebrafish pancreas matures, hormone-producing endocrine cells differentiate from pancreatic Notch-responsive cells (PNCs) that reside within the ducts. These new endocrine cells form small clusters known as secondary (2°) islets. We use the formation of 2° islets in the pancreatic tail of the larval zebrafish as a model of β-cell neogenesis. Pharmacological inhibition of Notch signaling leads to precocious endocrine differentiation and the early appearance of 2° islets in the tail of the pancreas. Following a chemical screen, we discovered that blocking the retinoic acid (RA)-signaling pathway also leads to the induction of 2° islets. Conversely, the addition of exogenous RA blocks the differentiation caused by Notch inhibition. In this report we characterize the interaction of these two pathways. We first verified that signaling via both RA and Notch ligands act together to regulate pancreatic progenitor differentiation. We produced a transgenic RA reporter, which demonstrated that PNCs directly respond to RA signaling through the canonical transcriptional pathway. Next, using a genetic lineage tracing approach, we demonstrated these progenitors produce endocrine cells following inhibition of RA signaling. Lastly, inhibition of RA signaling using a cell-type specific inducible cre/lox system revealed that RA signaling acts cell-autonomously in PNCs to regulate their differentiation. Importantly, the action of RA inhibition on endocrine formation is evolutionarily conserved, as shown by the differentiation of human embryonic stem cells in a model of human pancreas development. Together, these results revealed a biphasic function for RA in pancreatogenesis. As previously shown by others, RA initially plays an essential role during embryogenesis as it patterns the endoderm and specifies the pancreatic field. We reveal here that later in development RA is involved in negatively regulating the further differentiation of pancreatic progenitors and expands upon the developmental mechanisms by which this occurs. PMID:25127993

The F-box-containing protein UFO and AGAMOUS participate in antagonistic pathways governing early petal development in Arabidopsis.

PubMed

Durfee, Tim; Roe, Judith L; Sessions, R Allen; Inouye, Carla; Serikawa, Kyle; Feldmann, Kenneth A; Weigel, Detlef; Zambryski, Patricia C

2003-07-08

The UNUSUAL FLORAL ORGANS (UFO) gene is required for multiple processes in the developing Arabidopsis flower, including the proper patterning and identity of both petals and stamens. The gene encodes an F-box-containing protein, UFO, which interacts physically and genetically with the Skp1 homolog, ASK1. In this report, we describe four ufo alleles characterized by the absence of petals, which uncover another role for UFO in promoting second whorl development. This UFO-dependent pathway is required regardless of the second whorl organ to be formed, arguing that it affects a basic process acting in parallel with those establishing organ identity. However, the pathway is dispensable in the absence of AGAMOUS (AG), a known inhibitor of petal development. In situ hybridization results argue that AG is not transcribed in the petal region, suggesting that it acts non-cell-autonomously to inhibit second whorl development in ufo mutants. These results are combined into a genetic model explaining early second whorl initiation/proliferation, in which UFO functions to inhibit an AG-dependent activity.

Cells as strain-cued automata

NASA Astrophysics Data System (ADS)

Cox, Brian N.; Snead, Malcolm L.

2016-02-01

We argue in favor of representing living cells as automata and review demonstrations that autonomous cells can form patterns by responding to local variations in the strain fields that arise from their individual or collective motions. An autonomous cell's response to strain stimuli is assumed to be effected by internally-generated, internally-powered forces, which generally move the cell in directions other than those implied by external energy gradients. Evidence of cells acting as strain-cued automata have been inferred from patterns observed in nature and from experiments conducted in vitro. Simulations that mimic particular cases of pattern forming share the idealization that cells are assumed to pass information among themselves solely via mechanical boundary conditions, i.e., the tractions and displacements present at their membranes. This assumption opens three mechanisms for pattern formation in large cell populations: wavelike behavior, kinematic feedback in cell motility that can lead to sliding and rotational patterns, and directed migration during invasions. Wavelike behavior among ameloblast cells during amelogenesis (the formation of dental enamel) has been inferred from enamel microstructure, while strain waves in populations of epithelial cells have been observed in vitro. One hypothesized kinematic feedback mechanism, "enhanced shear motility", accounts successfully for the spontaneous formation of layered patterns during amelogenesis in the mouse incisor. Directed migration is exemplified by a theory of invader cells that sense and respond to the strains they themselves create in the host population as they invade it: analysis shows that the strain fields contain positional information that could aid the formation of cell network structures, stabilizing the slender geometry of branches and helping govern the frequency of branch bifurcation and branch coalescence (the formation of closed networks). In simulations of pattern formation in homogeneous populations and network formation by invaders, morphological outcomes are governed by the ratio of the rates of two competing time dependent processes, one a migration velocity and the other a relaxation velocity related to the propagation of strain information. Relaxation velocities are approximately constant for different species and organs, whereas cell migration rates vary by three orders of magnitude. We conjecture that developmental processes use rapid cell migration to achieve certain outcomes, and slow migration to achieve others. We infer from analysis of host relaxation during network formation that a transition exists in the mechanical response of a host cell from animate to inanimate behavior when its strain changes at a rate that exceeds 10-4-10-3 s-1. The transition has previously been observed in experiments conducted in vitro.

Optimization of interneuron function by direct coupling of cell migration and axonal targeting.

PubMed

Lim, Lynette; Pakan, Janelle M P; Selten, Martijn M; Marques-Smith, André; Llorca, Alfredo; Bae, Sung Eun; Rochefort, Nathalie L; Marín, Oscar

2018-06-18

Neural circuit assembly relies on the precise synchronization of developmental processes, such as cell migration and axon targeting, but the cell-autonomous mechanisms coordinating these events remain largely unknown. Here we found that different classes of interneurons use distinct routes of migration to reach the embryonic cerebral cortex. Somatostatin-expressing interneurons that migrate through the marginal zone develop into Martinotti cells, one of the most distinctive classes of cortical interneurons. For these cells, migration through the marginal zone is linked to the development of their characteristic layer 1 axonal arborization. Altering the normal migratory route of Martinotti cells by conditional deletion of Mafb-a gene that is preferentially expressed by these cells-cell-autonomously disrupts axonal development and impairs the function of these cells in vivo. Our results suggest that migration and axon targeting programs are coupled to optimize the assembly of inhibitory circuits in the cerebral cortex.

[Level of funding in the Long-Term Care Law: the cost of moving toward real dependency variables].

PubMed

Correa Gómez, Manuel; Montero Granados, Roberto; Jiménez Aguilera, Juan de Dios

2011-12-01

The system for the Promotion of Personal Autonomy and Care of Dependent Persons established by Act 39/2006 is funded through private contributions of dependent individuals and earmarked transfers in three main funds: a minimum level, an agreed level distributed among the various autonomous regions according to their relative needs, and a further voluntary additional contribution by Spain's autonomous regions. The resources distributed by the state to the regions are assigned, among other less important variables, according to the potentially dependent population and, to a lesser extent, according to the population already evaluated as dependent. Because the concept of what constitutes disability has changed over the years from the population potentially dependent according to an estimate (estimated dependent individuals) to the actual number of dependent individuals recognized as such (declared dependent), some autonomous regions may have been overfunded or underfunded. The funding obtained by the autonomous regions each year from 2007 to 2011 was compared with the funding that would have been assigned to each region if, since 2007, the variables and weighting that will be representative of the funding needs for 2013 (distribution mainly according to declared dependent individuals) had been taken into account. From 2007-2011, regions where declared dependent persons outnumbered estimated disabled persons were underfunded (in Andalusia by more than 100 million euros). In contrast, regions where the situation was reversed were overfunded (by 49 million euros in Madrid and 37 million euros in the region of Valencia). There is wide variation in public funding to the autonomous regions, depending on the number of individuals declared as dependent. Among other no less serious consequences, this situation could hamper the implantation of the Promotion of Personal Autonomy and Care of Dependent Persons Act in underfunded regions. Copyright © 2011 SESPAS. Published by Elsevier Espana. All rights reserved.

A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP.

PubMed

Spanò, Stefania; Gao, Xiang; Hannemann, Sebastian; Lara-Tejero, María; Galán, Jorge E

2016-02-10

Cell-autonomous defense mechanisms are potent strategies that protect individual cells against intracellular pathogens. The Rab-family GTPase Rab32 was previously shown to restrict the intracellular human pathogen Salmonella Typhi, but its potential broader role in antimicrobial defense remains unknown. We show that Rab32 represents a general cell-autonomous, antimicrobial defense that is counteracted by two Salmonella effectors. Mice lacking Rab-32 or its nucleotide exchange factor BLOC-3 are permissive to S. Typhi infection and exhibit increased susceptibility to S. Typhimurium. S. Typhimurium counters this defense pathway by delivering two type III secretion effectors, SopD2, a Rab32 GAP, and GtgE, a specific Rab32 protease. An S. Typhimurium mutant strain lacking these two effectors exhibits markedly reduced virulence, which is fully restored in BLOC-3-deficient mice. These results demonstrate that a cell-autonomous, Rab32-dependent host defense pathway plays a central role in the defense against vacuolar pathogens and describe a mechanism evolved by a bacterial pathogen to counter it. Copyright © 2016 Elsevier Inc. All rights reserved.

Autonomous and nonautonomous regulation of axis formation by antagonistic signaling via 7-span cAMP receptors and GSK3 in Dictyostelium.

PubMed

Ginsburg, G T; Kimmel, A R

1997-08-15

Early during Dictyostelium development a fundamental cell-fate decision establishes the anteroposterior (prestalk/prespore) axis. Signaling via the 7-transmembrane cAMP receptor CAR4 is essential for creating and maintaining a normal pattern; car4-null alleles have decreased levels of prestalk-specific mRNAs but enhanced expression of prespore genes. car4- cells produce all of the signals required for prestalk differentiation but lack an extracellular factor necessary for prespore differentiation of wild-type cells. This secreted factor decreases the sensitivity of prespore cells to inhibition by the prestalk morphogen DIF-1. At the cell autonomous level, CAR4 is linked to intracellular circuits that activate prestalk but inhibit prespore differentiation. The autonomous action of CAR4 is antagonistic to the positive intracellular signals mediated by another cAMP receptor, CAR1 and/or CAR3. Additional data indicate that these CAR-mediated pathways converge at the serine/threonine protein kinase GSK3, suggesting that the anterior (prestalk)/posterior (prespore) axis of Dictyostelium is regulated by an ancient mechanism that is shared by the Wnt/Fz circuits for dorsoventral patterning during early Xenopus development and establishing Drosophila segment polarity.

SERCA directs cell migration and branching across species and germ layers

PubMed Central

Lansdale, Nick; Navarro, Sonia; Truong, Thai V.; Bower, Dan J.; Featherstone, Neil C.; Connell, Marilyn G.; Al Alam, Denise; Frey, Mark R.; Trinh, Le A.; Fernandez, G. Esteban; Warburton, David; Fraser, Scott E.; Bennett, Daimark; Jesudason, Edwin C.

2017-01-01

ABSTRACT Branching morphogenesis underlies organogenesis in vertebrates and invertebrates, yet is incompletely understood. Here, we show that the sarco-endoplasmic reticulum Ca2+ reuptake pump (SERCA) directs budding across germ layers and species. Clonal knockdown demonstrated a cell-autonomous role for SERCA in Drosophila air sac budding. Live imaging of Drosophila tracheogenesis revealed elevated Ca2+ levels in migratory tip cells as they form branches. SERCA blockade abolished this Ca2+ differential, aborting both cell migration and new branching. Activating protein kinase C (PKC) rescued Ca2+ in tip cells and restored cell migration and branching. Likewise, inhibiting SERCA abolished mammalian epithelial budding, PKC activation rescued budding, while morphogens did not. Mesoderm (zebrafish angiogenesis) and ectoderm (Drosophila nervous system) behaved similarly, suggesting a conserved requirement for cell-autonomous Ca2+ signaling, established by SERCA, in iterative budding. PMID:28821490

TACI is required for efficient plasma cell differentiation in response to T-independent type 2 antigens.

PubMed

Mantchev, George T; Cortesão, Catarina S; Rebrovich, Michelle; Cascalho, Marilia; Bram, Richard J

2007-08-15

The control of systemic infection by encapsulated microorganisms requires T-independent type II (TI-2) Ab responses to bacterial polysaccharides. To understand how such responses evolve, we explored the function of transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI), a member of the TNFR family, required for TI-2 Ab production. Quasimonoclonal (QM) mice produce robust TI-2 responses to 4-hydroxy-3-nitrophenylacetate (NP)-Ficoll, owing to the high precursor frequency of NP-specific B cells in the marginal zone of the spleen. QM mice that lack TACI produce decreased numbers of IgM (2-fold) and IgG (1.6-fold) NP-specific ASCs, compared with TACI-positive QM mice in response to immunization with NP-Ficoll. Our studies indicate that TACI acts at a remote time from activation because TACI is not necessary for activation and proliferation of B cells both in vitro and in vivo. Instead, TACI-deficient QM B cells remained in the cell cycle longer than TACI-proficient QM cells and had impaired plasma cell differentiation in response to NP-Ficoll. We conclude that TACI has dual B cell-autonomous functions, inhibiting prolonged B cell proliferation and stimulating plasma cell differentiation, thus resolving the longstanding paradox that TACI may have both B cell-inhibitory and -stimulatory functions. By promoting plasma cell differentiation earlier during clonal expansion, TACI may decrease the chances of autoantibody production by somatic hypermutation of Ig genes in response to T-independent Ags.

Transmembrane Proteins UNC-40/DCC, PTP-3/LAR, and MIG-21 Control Anterior–Posterior Neuroblast Migration with Left–Right Functional Asymmetry in Caenorhabditis elegans

PubMed Central

Sundararajan, Lakshmi; Lundquist, Erik A.

2012-01-01

Migration of neurons and neural crest cells is of central importance to the development of nervous systems. In Caenorhabditis elegans, the QL neuroblast on the left migrates posteriorly, and QR on the right migrates anteriorly, despite similar lineages and birth positions with regard to the left–right axis. Initial migration is independent of a Wnt signal that controls later anterior–posterior Q descendant migration. Previous studies showed that the transmembrane proteins UNC-40/DCC and MIG-21, a novel thrombospondin type I repeat containing protein, act redundantly in left-side QL posterior migration. Here we show that the LAR receptor protein tyrosine phosphatase PTP-3 acts with MIG-21 in parallel to UNC-40 in QL posterior migration. We also show that in right-side QR, the UNC-40 and PTP-3/MIG-21 pathways mutually inhibit each other’s role in posterior migration, allowing anterior QR migration. Finally, we present evidence that these proteins act autonomously in the Q neuroblasts. These studies indicate an inherent left–right asymmetry in the Q neuroblasts with regard to UNC-40, PTP-3, and MIG-21 function that results in posterior vs. anterior migration. PMID:23051647

Autonomic Modification of Intestinal Smooth Muscle Contractility

ERIC Educational Resources Information Center

Montgomery, Laura E. A.; Tansey, Etain A.; Johnson, Chris D.; Roe, Sean M.; Quinn, Joe G.

2016-01-01

Intestinal smooth muscle contracts rhythmically in the absence of nerve and hormonal stimulation because of the activity of pacemaker cells between and within the muscle layers. This means that the autonomic nervous system modifies rather than initiates intestinal contractions. The practical described here gives students an opportunity to observe…

The Actions of Piperidine Alkaloids at Fetal Muscle-Type and Autonomic-Type Nicotinic Acetylcholine Receptors

USDA-ARS?s Scientific Manuscript database

Piperidine alkaloids are found in many species of plants including Conium maculatum, Nicotiana spp., and Lupinus spp. A pharmacodynamic comparison was made of the alkaloids ammodendrine, anabasine, anabaseine, and coniine in; SH-SY5Y cells which express autonomic-type nicotinic acetylcholine recept...

A Barley Powdery Mildew Fungus Non-Autonomous Retrotransposon Encodes a Peptide that Supports Penetration Success on Barley.

PubMed

Nottensteiner, Mathias; Zechmann, Bernd; McCollum, Christopher; Hückelhoven, Ralph

2018-05-11

Pathogens overcome plant immunity by the means of secreted effectors. Host effector targets often act in pathogen defense but might also support fungal accommodation or nutrition. The barley ROP GTPase HvRACB is involved in accommodation of fungal haustoria of the powdery mildew fungus Blumeria graminis f.sp. hordei (Bgh) in barley epidermal cells. We found that HvRACB interacts with the ROP-interactive peptide 1 (ROPIP1) that is encoded on the active non-long terminal repeat retroelement Eg-R1 of Bgh. Over-expression of ROPIP1 in barley epidermal cells and host-induced post-transcriptional gene silencing (HIGS) of ROPIP1 suggested that ROPIP1 is involved in virulence of Bgh. Bimolecular fluorescence complementation and co-localization supported that ROPIP1 can interact with activated HvRACB in planta. We show that ROPIP1 is expressed by Bgh on barley and translocated into the cytoplasm of infected barley cells. ROPIP1 is recruited to microtubules upon co-expression of microtubule associated ROP GTPase ACTIVATING PROTEIN (HvMAGAP1) and can destabilize cortical microtubules. Data suggest that Bgh ROPIP targets HvRACB and manipulates host cell microtubule organization for facilitated host cell entry. This points to a possible neo-functionalization of retroelement-derived transcripts for the evolution of a pathogen virulence effector.

Protein tyrosine phosphatase PTP1 negatively regulates Dictyostelium STATa and is required for proper cell-type proportioning.

PubMed

Early, A; Gamper, M; Moniakis, J; Kim, E; Hunter, T; Williams, J G; Firtel, R A

2001-04-01

The protein tyrosine phosphatase PTP1, which mediates reversible phosphorylation on tyrosine, has been shown to play an important regulatory role during Dictyostelium development. Mutants lacking PTP1 develop more rapidly than normal, while strains that overexpress PTP1 display aberrant morphology. However, the signalling pathways involved have not been characterised. In reexamining these strains, we have found that there is an inverse correlation between levels of PTP1 activity, the extent of tyrosine phosphorylation on Dictyostelium STATa after treatment with cAMP, and the proportion of the slug population exhibiting STATa nuclear enrichment in vivo. This suggests that PTP1 acts to attenuate the tyrosine phosphorylation of STATa and downstream STATa-mediated pathways. Consistent with this, we show that when PTP1 is overexpressed, there is increased expression of a prestalk cell marker at the slug posterior, a phenocopy of STATa null slugs. In ptp1 null strains, STATa tyrosine phosphorylation and nuclear enrichment in the slug anterior is increased. There is also a change in the prestalk to prespore cell ratio. Synergy experiments suggest that this is due to a cell-autonomous defect in forming the subset of prespore cells that are located in the anterior prespore region. Copyright 2001 Academic Press.

Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections

PubMed Central

2018-01-01

ABSTRACT Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability. PMID:29764948

Drosophila heart cell movement to the midline occurs through both cell autonomous migration and dorsal closure.

PubMed

Haack, Timm; Schneider, Matthias; Schwendele, Bernd; Renault, Andrew D

2014-12-15

The Drosophila heart is a linear organ formed by the movement of bilaterally specified progenitor cells to the midline and adherence of contralateral heart cells. This movement occurs through the attachment of heart cells to the overlying ectoderm which is undergoing dorsal closure. Therefore heart cells are thought to move to the midline passively. Through live imaging experiments and analysis of mutants that affect the speed of dorsal closure we show that heart cells in Drosophila are autonomously migratory and part of their movement to the midline is independent of the ectoderm. This means that heart formation in flies is more similar to that in vertebrates than previously thought. We also show that defects in dorsal closure can result in failure of the amnioserosa to properly degenerate, which can physically hinder joining of contralateral heart cells leading to a broken heart phenotype. Copyright © 2014 Elsevier Inc. All rights reserved.

The Caenorhabditis elegans Ephrin EFN-4 Functions Non-cell Autonomously with Heparan Sulfate Proteoglycans to Promote Axon Outgrowth and Branching

PubMed Central

Schwieterman, Alicia A.; Steves, Alyse N.; Yee, Vivian; Donelson, Cory J.; Bentley, Melissa R.; Santorella, Elise M.; Mehlenbacher, Taylor V.; Pital, Aaron; Howard, Austin M.; Wilson, Melissa R.; Ereddia, Danielle E.; Effrein, Kelsie S.; McMurry, Jonathan L.; Ackley, Brian D.; Chisholm, Andrew D.; Hudson, Martin L.

2016-01-01

The Eph receptors and their cognate ephrin ligands play key roles in many aspects of nervous system development. These interactions typically occur within an individual tissue type, serving either to guide axons to their terminal targets or to define boundaries between the rhombomeres of the hindbrain. We have identified a novel role for the Caenorhabditis elegans ephrin EFN-4 in promoting primary neurite outgrowth in AIY interneurons and D-class motor neurons. Rescue experiments reveal that EFN-4 functions non-cell autonomously in the epidermis to promote primary neurite outgrowth. We also find that EFN-4 plays a role in promoting ectopic axon branching in a C. elegans model of X-linked Kallmann syndrome. In this context, EFN-4 functions non-cell autonomously in the body-wall muscle and in parallel with HS modification genes and HSPG core proteins. This is the first report of an epidermal ephrin providing a developmental cue to the nervous system. PMID:26645816

Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation

PubMed Central

Wolf, Yochai; Shemer, Anat; Polonsky, Michal; Gross, Mor; Mildner, Alexander; David, Eyal; Amit, Ido; Heikenwalder, Mathias; Nedospasov, Sergei; Prinz, Marco; Friedman, Nir

2017-01-01

Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor (TNF) and its receptors are up-regulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such as the spinal cord, during experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro and in vivo assays, we show that monocytes deficient for TNF or TNF receptors are outcompeted by their wild-type counterpart. Moreover, monocyte-autonomous TNF is critical for the function of these cells, as TNF ablation in monocytes/macrophages, but not in microglia, delayed the onset of EAE in challenged animals and was associated with reduced acute spinal cord infiltration of Ly6Chi effector monocytes. Collectively, our data reveal a previously unappreciated critical cell-autonomous role of TNF on monocytes for their survival, maintenance, and function. PMID:28330904

Microglia PACAP and glutamate: Friends or foes in seizure-induced autonomic dysfunction and SUDEP?

PubMed

Bhandare, Amol M; Kapoor, Komal; Farnham, Melissa M J; Pilowsky, Paul M

2016-06-01

Seizure-induced cardiorespiratory autonomic dysfunction is a major cause of sudden unexpected death in epilepsy (SUDEP), and the underlying mechanism is unclear. Seizures lead to increased synthesis, and release of glutamate, pituitary adenylate cyclase activating polypeptide (PACAP), and other neurotransmitters, and cause extensive activation of microglia at multiple regions in the brain including central autonomic cardiorespiratory brainstem nuclei. Glutamate contributes to neurodegeneration, and inflammation in epilepsy. PACAP has neuroprotective, and anti-inflammatory properties, whereas microglia are key players in inflammatory responses in CNS. Seizure-induced increase in PACAP is neuroprotective. PACAP produces neuroprotective effects acting on microglial PAC1 and VPAC1 receptors. Microglia also express glutamate transporters, and their expression can be increased by PACAP in response to harmful or stressful situations such as seizures. Here we discuss the mechanism of autonomic cardiorespiratory dysfunction in seizure, and the role of PACAP, glutamate and microglia in regulating cardiorespiratory brainstem neurons in their physiological state that could provide future therapeutic options for SUDEP. Copyright © 2016 Elsevier B.V. All rights reserved.

Working and Learning with Knowledge in the Lobes of a Humanoid's Mind

NASA Technical Reports Server (NTRS)

Ambrose, Robert; Savely, Robert; Bluethmann, William; Kortenkamp, David

2003-01-01

Humanoid class robots must have sufficient dexterity to assist people and work in an environment designed for human comfort and productivity. This dexterity, in particular the ability to use tools, requires a cognitive understanding of self and the world that exceeds contemporary robotics. Our hypothesis is that the sense-think-act paradigm that has proven so successful for autonomous robots is missing one or more key elements that will be needed for humanoids to meet their full potential as autonomous human assistants. This key ingredient is knowledge. The presented work includes experiments conducted on the Robonaut system, a NASA and the Defense Advanced research Projects Agency (DARPA) joint project, and includes collaborative efforts with a DARPA Mobile Autonomous Robot Software technical program team of researchers at NASA, MIT, USC, NRL, UMass and Vanderbilt. The paper reports on results in the areas of human-robot interaction (human tracking, gesture recognition, natural language, supervised control), perception (stereo vision, object identification, object pose estimation), autonomous grasping (tactile sensing, grasp reflex, grasp stability) and learning (human instruction, task level sequences, and sensorimotor association).

Effects of a small talking facial image on autonomic activity: the moderating influence of dispositional BIS and BAS sensitivities and emotions.

PubMed

Ravaja, Niklas

2004-01-01

We examined the moderating influence of dispositional behavioral inhibition system and behavioral activation system (BAS) sensitivities, Negative Affect, and Positive Affect on the relationship between a small moving vs. static facial image and autonomic responses when viewing/listening to news messages read by a newscaster among 36 young adults. Autonomic parameters measured were respiratory sinus arrhythmia (RSA), low-frequency (LF) component of heart rate variability (HRV), electrodermal activity, and pulse transit time (PTT). The results showed that dispositional BAS sensitivity, particularly BAS Fun Seeking, and Negative Affect interacted with facial image motion in predicting autonomic nervous system activity. A moving facial image was related to lower RSA and LF component of HRV and shorter PTTs as compared to a static facial image among high BAS individuals. Even a small talking facial image may contribute to sustained attentional engagement among high BAS individuals, given that the BAS directs attention toward the positive cue and a moving social stimulus may act as a positive incentive for high BAS individuals.

Organization of the Drosophila circadian control circuit.

PubMed

Nitabach, Michael N; Taghert, Paul H

2008-01-22

Molecular genetics has revealed the identities of several components of the fundamental circadian molecular oscillator - an evolutionarily conserved molecular mechanism of transcription and translation that can operate in a cell-autonomous manner. Therefore, it was surprising when studies of circadian rhythmic behavior in the fruit fly Drosophila suggested that the normal operations of circadian clock cells, which house the molecular oscillator, in fact depend on non-cell-autonomous effects - interactions between the clock cells themselves. Here we review several genetic analyses that broadly extend that viewpoint. They support a model whereby the approximately 150 circadian clock cells in the brain of the fly are sub-divided into functionally discrete rhythmic centers. These centers alternatively cooperate or compete to control the different episodes of rhythmic behavior that define the fly's daily activity profile.

Boredom proneness in a psychiatric inpatient population.

PubMed

Newell, Susan E; Harries, Priscilla; Ayers, Susan

2012-09-01

Boredom has been reported as a common experience for service users of acute psychiatric wards. It has been associated with negative mental and physical health. Research has yet to show what factors are associated with boredom proneness within the acute psychiatric population. (1) To investigate the distribution of boredom proneness in a population of mentally ill inpatients according to age, gender, diagnosis, Mental Health Act status and length of stay in hospital. (2) To test the hypothesis that boredom proneness is negatively correlated with autonomous activity levels. Two self-report questionnaires were used with 55 inpatients of acute psychiatric wards: the Boredom Proneness Scale (Farmer & Sundberg, 1986) and the Hospital Anxiety and Depression Scale (Zigmond & Snaith, 1983). Questions were also asked about individuals' activity engagement during their current admission. Data on age, gender, diagnosis, ethnicity, Mental Health Act status and length of stay were collected from case notes. The highest incidence of boredom proneness was in participants with depression. Those detained under the Mental Health Act appeared less boredom prone than those admitted voluntarily. Boredom proneness was not associated with age, gender or length of stay. There was an association between engagement in more autonomous activities and lower boredom proneness.

Engineered cell-cell communication via DNA messaging

PubMed Central

2012-01-01

Background Evolution has selected for organisms that benefit from genetically encoded cell-cell communication. Engineers have begun to repurpose elements of natural communication systems to realize programmed pattern formation and coordinate other population-level behaviors. However, existing engineered systems rely on system-specific small molecules to send molecular messages among cells. Thus, the information transmission capacity of current engineered biological communication systems is physically limited by specific biomolecules that are capable of sending only a single message, typically “regulate transcription.” Results We have engineered a cell-cell communication platform using bacteriophage M13 gene products to autonomously package and deliver heterologous DNA messages of varying lengths and encoded functions. We demonstrate the decoupling of messages from a common communication channel via the autonomous transmission of various arbitrary genetic messages. Further, we increase the range of engineered DNA messaging across semisolid media by linking message transmission or receipt to active cellular chemotaxis. Conclusions We demonstrate decoupling of a communication channel from message transmission within engineered biological systems via the autonomous targeted transduction of user-specified heterologous DNA messages. We also demonstrate that bacteriophage M13 particle production and message transduction occurs among chemotactic bacteria. We use chemotaxis to improve the range of DNA messaging, increasing both transmission distance and communication bit rates relative to existing small molecule-based communication systems. We postulate that integration of different engineered cell-cell communication platforms will allow for more complex spatial programming of dynamic cellular consortia. PMID:22958599

C. elegans Notch signaling regulates adult chemosensory response and larval molting quiescence

PubMed Central

Singh, Komudi; Chao, Michael Y.; Somers, Gerard A.; Komatsu, Hidetoshi; Corkins, Mark E.; Larkins-Ford, Jonah; Tucey, Tim; Dionne, Heather M.; Walsh, Melissa B.; Beaumont, Emma K.; Hart, Douglas P.; Lockery, Shawn; Hart, Anne C.

2011-01-01

Summary Background The conserved DOS motif proteins OSM-7 and OSM-11 function as co-ligands with canonical DSL ligands to activate C. elegans Notch receptors during development. We report herein that Notch ligands, co-ligands and the receptors LIN-12 and GLP-1 regulate two C. elegans behaviors: chemosensory avoidance of octanol and quiescence during molting lethargus. Results C. elegans lacking osm-7 or osm-11 are defective in their response to octanol. We find that OSM-11 is secreted from hypodermal seam cells into the pseudocoelomic body cavity and acts non-cell autonomously as a diffusible factor. OSM-11 acts with the DSL ligand LAG-2 to activate LIN-12 and GLP-1 Notch receptors in the neurons of adult animals,- thereby regulating octanol avoidance response. In adult animals, over-expression of osm-11 and consequent Notch receptor activation induces anachronistic sleep-like quiescence. Perturbation of Notch signaling altered basal activity in adults as well as arousal thresholds and quiescence during molting lethargus. Genetic epistasis studies revealed that Notch signaling regulates quiescence via previously identified circuits and genetic pathways including the egl-4 cGMP-dependent kinase. Conclusions Our findings indicate that the conserved Notch pathway modulates behavior in adult C. elegans in response to environmental stress. Additionally, Notch signaling regulates sleep-like quiescence in C. elegans suggesting Notch may regulate sleep in other species. PMID:21549604

AUTONOMIC AND BEHAVIORAL RESPONSES OF SELECTIVELY BRED HYPERCHOLINERGIC RATS TO OXOTREMORINE AND DIISOPROPYL FLUOROPHOSPHATE

EPA Science Inventory

The hypercholinergic Flinders Sensitive Line (FSL) rat was significantly more sensitive than the Flinders Resistant Line (FRL) rat to the biotelemetrically recorded hypothermic effects of oxotremorine, a directly acting muscarinic agonist, and diisopropyl fluorophosphate (DFP), a...

Plagiarisms, Authorships, and the Academic Death Penalty.

ERIC Educational Resources Information Center

Howard, Rebecca Moore

1995-01-01

Suggests a plagiarism policy that would respect present concerns and discipline but would allow for an enlarged range of definitions of and motivations for plagiarism. Brings to bear contemporary theoretical approaches that take issue with authoring as an autonomous, individual, original act. (TB)

Community motivations to engage in conservation behavior to conserve the Sumatran orangutan.

PubMed

Nilsson, Danielle; Gramotnev, Galina; Baxter, Greg; Butler, James R A; Wich, Serge A; McAlpine, Clive A

2016-08-01

Community-based conservation programs in developing countries are often based on the assumption that heteronomous motivation (e.g., extrinsic incentives such as economic rewards and pressure or coercion to act) will incite local communities to adopt conservation behaviors. However, this may not be as effective or sustainable as autonomous motivations (e.g., an intrinsic desire to act due to inherent enjoyment or self-identification with a behavior and through freedom of choice). We analyzed the comparative effectiveness of heteronomous versus autonomous approaches to community-based conservation programs through a case study of Sumatran orangutan (Pongo abelii) conservation in 3 villages in Indonesia. Each village had a different conservation program design. We surveyed people (n = 240) to determine their motivations for and behavior changes relative to orangutan and orangutan habitat (forest) protection. Heteronomous motivations (e.g., income from tourism) led to greater self-reporting of behavior change toward orangutan protection. However, they did not change self-reported behavior toward forest (i.e., orangutan habitat) protection. The most effective approach to creating self-reported behavior change throughout the community was a combination of autonomous and heteronomous motivations. Individuals who were heteronomously motivated to protect the orangutan were more likely to have changed attitudes than to have changed their self-reported behavior. These findings demonstrate that the current paradigm of motivating communities in developing countries to adopt conservation behaviors primarily through monetary incentives and rewards should consider integrating autonomous motivational techniques that promote the intrinsic values of conservation. Such a combination has a greater potential to achieve sustainable and cost-effective conservation outcomes. Our results highlight the importance of using in-depth sociopsychological analyses to inform the design and implementation of community-based conservation programs. © 2016 Society for Conservation Biology.

Autonomy in Depressive Patients Undergoing DBS-Treatment: Informed Consent, Freedom of Will and DBS’ Potential to Restore It

PubMed Central

Beeker, Timo; Schlaepfer, Thomas E.; Coenen, Volker A.

2017-01-01

According to the World Health Organization, depression is one of the most common and most disabling psychiatric disorders, affecting at any given time approximately 325 million people worldwide. As there is strong evidence that depressive disorders are associated with a dynamic dysregulation of neural circuits involved in emotional processing, recently several attempts have been made to intervene directly in these circuits via deep brain stimulation (DBS) in patients with treatment-resistant major depressive disorder (MDD). Given the promising results of most of these studies, the rising medical interest in this new treatment correlates with a growing sensitivity to ethical questions. One of the most crucial concerns is that DBS might interfere with patients’ ability to make autonomous decisions. Thus, the goal of this article is to evaluate the impact DBS presumably has on the capacity to decide and act autonomously in patients with MDD in the light of the autonomy-undermining effects depression has itself. Following the chronological order of the procedure, special attention will first be paid to depression’s effects on patients’ capacity to make use of their free will in giving valid Informed Consent. We suggest that while the majority of patients with MDD appear capable of autonomous choices, as it is required for Informed Consent, they might still be unable to effectively act according to their own will whenever acting includes significant personal effort. In reducing disabling depressive symptoms like anhedonia and decrease of energy, DBS for treatment resistant MDD thus rather seems to be an opportunity to substantially increase autonomy than a threat to it. PMID:28642690

Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems

PubMed Central

Dusi, Veronica; Ghidoni, Alice; Ravera, Alice; De Ferrari, Gaetano M.; Calvillo, Laura

2016-01-01

Among the chemokines discovered to date, nineteen are presently considered to be relevant in heart disease and are involved in all stages of cardiovascular response to injury. Chemokines are interesting as biomarkers to predict risk of cardiovascular events in apparently healthy people and as possible therapeutic targets. Moreover, they could have a role as mediators of crosstalk between immune and cardiovascular system, since they seem to act as a “working-network” in deep linkage with the autonomic nervous system. In this paper we will describe the single chemokines more involved in heart diseases; then we will present a comprehensive perspective of them as a complex network connecting the cardiovascular system to both the immune and the autonomic nervous systems. Finally, some recent evidences indicating chemokines as a possible new tool to predict cardiovascular risk will be described. PMID:27242392

Autonomous System Technologies for Resilient Airspace Operations

NASA Technical Reports Server (NTRS)

Houston, Vincent E.; Le Vie, Lisa R.

2017-01-01

Increasing autonomous systems within the aircraft cockpit begins with an effort to understand what autonomy is and developing the technology that encompasses it. Autonomy allows an agent, human or machine, to act independently within a circumscribed set of goals; delegating responsibility to the agent(s) to achieve overall system objective(s). Increasingly Autonomous Systems (IAS) are the highly sophisticated progression of current automated systems toward full autonomy. Working in concert with humans, these types of technologies are expected to improve the safety, reliability, costs, and operational efficiency of aviation. IAS implementation is imminent, which makes the development and the proper performance of such technologies, with respect to cockpit operation efficiency, the management of air traffic and data communication information, vital. A prototype IAS agent that attempts to optimize the identification and distribution of "relevant" air traffic data to be utilized by human crews during complex airspace operations has been developed.

Nuclear Trapping Controls the Position-Dependent Localization of CAPRICE in the Root Epidermis of Arabidopsis1[C][W

PubMed Central

Kang, Yeon Hee; Song, Sang-Kee; Schiefelbein, John; Lee, Myeong Min

2013-01-01

Cell fate determination and differentiation are central processes in the development of multicellular organisms, and the Arabidopsis (Arabidopsis thaliana) root epidermis provides a model system to study the molecular basis of these processes. A lateral inhibition mechanism mediated by an R3 single-repeat MYB protein, CAPRICE (CPC), has been proposed to explain the specification of the two types of root epidermal cells (hair cells and nonhair cells). However, it is not clear how CPC acts preferentially in the H-position cells, rather than the N-position cells, where its gene is expressed. To explore this issue, we examined the effect of misexpressed CPC on cell fate specification and CPC localization in the root epidermis. We show that CPC is able to move readily within the root epidermis when its expression level is high and that CPC can induce the hair cell fate in a cell-autonomous manner. We provide evidence that CPC is capable of moving from the stele tissue in the center of the root to the outermost epidermal layer, where it can induce the hair cell fate. In addition, we show that CPC protein accumulates primarily in the nuclei of H-position cells in the early meristematic region, and this localization requires the H-cell-expressed ENHANCER OF GLABRA3 (EGL3) basic helix-loop-helix transcription factor. These results suggest that cell-cell movement of CPC occurs readily within the meristematic region of the root and that EGL3 preferentially traps the CPC protein in the H-position cells of the epidermis. PMID:23832626

Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist.

PubMed

Steiner, Michel A; Gatfield, John; Brisbare-Roch, Catherine; Dietrich, Hendrik; Treiber, Alexander; Jenck, Francois; Boss, Christoph

2013-06-01

Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Deterioration of autonomic neuronal receptor signaling and mechanisms intrinsic to heart pacemaker cells contribute to age-associated alterations in heart rate variability in vivo.

PubMed

Yaniv, Yael; Ahmet, Ismayil; Tsutsui, Kenta; Behar, Joachim; Moen, Jack M; Okamoto, Yosuke; Guiriba, Toni-Rose; Liu, Jie; Bychkov, Rostislav; Lakatta, Edward G

2016-08-01

We aimed to determine how age-associated changes in mechanisms extrinsic and intrinsic to pacemaker cells relate to basal beating interval variability (BIV) reduction in vivo. Beating intervals (BIs) were measured in aged (23-25 months) and adult (3-4 months) C57BL/6 male mice (i) via ECG in vivo during light anesthesia in the basal state, or in the presence of 0.5 mg mL(-1) atropine + 1 mg mL(-1) propranolol (in vivo intrinsic conditions), and (ii) via a surface electrogram, in intact isolated pacemaker tissue. BIV was quantified in both time and frequency domains using linear and nonlinear indices. Although the average basal BI did not significantly change with age under intrinsic conditions in vivo and in the intact isolated pacemaker tissue, the average BI was prolonged in advanced age. In vivo basal BIV indices were found to be reduced with age, but this reduction diminished in the intrinsic state. However, in pacemaker tissue BIV indices increased in advanced age vs. adults. In the isolated pacemaker tissue, the sensitivity of the average BI and BIV in response to autonomic receptor stimulation or activation of mechanisms intrinsic to pacemaker cells by broad-spectrum phosphodiesterase inhibition declined in advanced age. Thus, changes in mechanisms intrinsic to pacemaker cells increase the average BIs and BIV in the mice of advanced age. Autonomic neural input to pacemaker tissue compensates for failure of molecular intrinsic mechanisms to preserve average BI. But this compensation reduces the BIV due to both the imbalance of autonomic neural input to the pacemaker cells and altered pacemaker cell responses to neural input. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Cardiomyocyte Circadian Oscillations Are Cell-Autonomous, Amplified by β-Adrenergic Signaling, and Synchronized in Cardiac Ventricle Tissue

PubMed Central

Welsh, David K.

2016-01-01

Circadian clocks impact vital cardiac parameters such as blood pressure and heart rate, and adverse cardiac events such as myocardial infarction and sudden cardiac death. In mammals, the central circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, synchronizes cellular circadian clocks in the heart and many other tissues throughout the body. Cardiac ventricle explants maintain autonomous contractions and robust circadian oscillations of clock gene expression in culture. In the present study, we examined the relationship between intrinsic myocardial function and circadian rhythms in cultures from mouse heart. We cultured ventricular explants or dispersed cardiomyocytes from neonatal mice expressing a PER2::LUC bioluminescent reporter of circadian clock gene expression. We found that isoproterenol, a β-adrenoceptor agonist known to increase heart rate and contractility, also amplifies PER2 circadian rhythms in ventricular explants. We found robust, cell-autonomous PER2 circadian rhythms in dispersed cardiomyocytes. Single-cell rhythms were initially synchronized in ventricular explants but desynchronized in dispersed cells. In addition, we developed a method for long-term, simultaneous monitoring of clock gene expression, contraction rate, and basal intracellular Ca2+ level in cardiomyocytes using PER2::LUC in combination with GCaMP3, a genetically encoded fluorescent Ca2+ reporter. In contrast to robust PER2 circadian rhythms in cardiomyocytes, we detected no rhythms in contraction rate and only weak rhythms in basal Ca2+ level. In summary, we found that PER2 circadian rhythms of cardiomyocytes are cell-autonomous, amplified by adrenergic signaling, and synchronized by intercellular communication in ventricle explants, but we detected no robust circadian rhythms in contraction rate or basal Ca2+. PMID:27459195

Autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells.

PubMed

Morita, Ken; Noura, Mina; Tokushige, Chieko; Maeda, Shintaro; Kiyose, Hiroki; Kashiwazaki, Gengo; Taniguchi, Junichi; Bando, Toshikazu; Yoshida, Kenichi; Ozaki, Toshifumi; Matsuo, Hidemasa; Ogawa, Seishi; Liu, Pu Paul; Nakahata, Tatsutoshi; Sugiyama, Hiroshi; Adachi, Souichi; Kamikubo, Yasuhiko

2017-11-30

Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-β (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in response to RUNX1 depletion, and their mutual interaction causes the physiological resistance against chemotherapy for acute myeloid leukemia (AML) cells. Mechanistically, p53 induced by RUNX1 gene silencing directly binds to CBFB promoter and stimulates its transcription as well as its translation, which in turn acts as a platform for the stabilization of RUNX1, thereby creating a compensative RUNX1-p53-CBFB feedback loop. Indeed, AML cells derived from relapsed cases exhibited higher CBFB expression levels compared to those from primary AML cells at diagnosis, and these CBFB expressions were positively correlated to those of p53. Our present results underscore the importance of RUNX1-p53-CBFB regulatory loop in the development and/or maintenance of AML cells, which could be targeted at any sides of this triangle in strategizing anti-leukemia therapies.

Autonomous quantum Maxwell's demon based on two exchange-coupled quantum dots

NASA Astrophysics Data System (ADS)

Ptaszyński, Krzysztof

2018-01-01

I study an autonomous quantum Maxwell's demon based on two exchange-coupled quantum dots attached to the spin-polarized leads. The principle of operation of the demon is based on the coherent oscillations between the spin states of the system which act as a quantum iSWAP gate. Due to the operation of the iSWAP gate, one of the dots acts as a feedback controller which blocks the transport with the bias in the other dot, thus inducing the electron pumping against the bias; this leads to the locally negative entropy production. Operation of the demon is associated with the information transfer between the dots, which is studied quantitatively by mapping the analyzed setup onto the thermodynamically equivalent auxiliary system. The calculated entropy production in a single subsystem and information flow between the subsystems are shown to obey a local form of the second law of thermodynamics, similar to the one previously derived for classical bipartite systems.

[The health care system requires individuals to take more personal responsibility].

PubMed

Schaefer, Corinna; Weißbach, Lothar

2012-01-01

In the health care context, the phrase "personal responsibility" is frequently used as a euphemism for restricting publicly funded health care services. The concept of responsibility, however, primarily comprises the individual's own autonomous choices in consideration of their possible implications. In order to be able to act responsibly in respect to health care issues, the individual must rely on objective information about the possible consequences of his or her decision. The current profit-oriented competitive medical care environment prevents the distribution of objective information. A mutually supportive community benefits from its members acting responsibly, since citizens are capable of supporting themselves before they avail themselves of community support. This requires the State to respect the individual and his or her autonomous decision-making. If the community established rules as to what is considered a healthy lifestyle or even required people to adopt one, it would, to a large part, take away the citizens' autonomy and thus prevent them to assume responsibility. Copyright © 2012. Published by Elsevier GmbH.

Skeletal muscle-specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism.

PubMed

Miyake, Masato; Nomura, Akitoshi; Ogura, Atsushi; Takehana, Kenji; Kitahara, Yoshihiro; Takahara, Kazuna; Tsugawa, Kazue; Miyamoto, Chinobu; Miura, Naoko; Sato, Ryosuke; Kurahashi, Kiyoe; Harding, Heather P; Oyadomari, Miho; Ron, David; Oyadomari, Seiichi

2016-02-01

The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle-specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non-cell-autonomous metabolic regulation by induced expression of a potent myokine. © FASEB.

Adaxial cell migration in the zebrafish embryo is an active cell autonomous property that requires the Prdm1a transcription factor.

PubMed

Ono, Yosuke; Yu, Weimiao; Jackson, Harriet E; Parkin, Caroline A; Ingham, Philip W

2015-01-01

Adaxial cells, the progenitors of slow-twitch muscle fibres in zebrafish, exhibit a stereotypic migratory behaviour during somitogenesis. Although this process is known to be disrupted in various mutants, its precise nature has remained unclear. Here, using in vivo imaging and chimera analysis, we show that adaxial cell migration is a cell autonomous process, during which cells become polarised and extend filopodia at their leading edge. Loss of function of the Prdm1a transcription factor disrupts the polarisation and migration of adaxial cells, reflecting a role that is independent of its repression of sox6 expression. Expression of the M- and N-cadherins, previously implicated in driving adaxial cell migration, is largely unaffected by loss of Prdm1a function, suggesting that differential cadherin expression is not sufficient for adaxial cell migration. Copyright © 2015 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Angiomodulin is required for cardiogenesis of embryonic stem cells and is maintained by a feedback loop network of p63 and Activin-A.

PubMed

Wolchinsky, Zohar; Shivtiel, Shoham; Kouwenhoven, Evelyn Nathalie; Putin, Daria; Sprecher, Eli; Zhou, Huiqing; Rouleau, Matthieu; Aberdam, Daniel

2014-01-01

The transcription factor p63, member of the p53 gene family, encodes for two main isoforms, TAp63 and ΔNp63 with distinct functions on epithelial homeostasis and cancer. Recently, we discovered that TAp63 is essential for in vitro cardiogenesis and heart development in vivo. TAp63 is expressed by embryonic endoderm and acts on cardiac progenitors by a cell-non-autonomous manner. In the present study, we search for cardiogenic secreted factors that could be regulated by TAp63 and, by ChIP-seq analysis, identified Angiomodulin (AGM), also named IGFBP7 or IGFBP-rP1. We demonstrate that AGM is necessary for cardiac commitment of embryonic stem cells (ESCs) and its regulation depends on TAp63 isoform. TAp63 directly activates both AGM and Activin-A during ESC cardiogenesis while these secreted factors modulate TAp63 gene expression by a feedback loop mechanism. The molecular circuitry controlled by TAp63 on AGM/Activin-A signaling pathway and thus on cardiogenesis emphasizes the importance of p63 during early cardiac development. © 2013.

Incunabular Immunological Events in Prion Trafficking

PubMed Central

Michel, Brady; Meyerett-Reid, Crystal; Johnson, Theodore; Ferguson, Adam; Wyckoff, Christy; Pulford, Bruce; Bender, Heather; Avery, Anne; Telling, Glenn; Dow, Steven; Zabel, Mark D.

2012-01-01

While prions probably interact with the innate immune system immediately following infection, little is known about this initial confrontation. Here we investigated incunabular events in lymphotropic and intranodal prion trafficking by following highly enriched, fluorescent prions from infection sites to draining lymph nodes. We detected biphasic lymphotropic transport of prions from the initial entry site upon peripheral prion inoculation. Prions arrived in draining lymph nodes cell autonomously within two hours of intraperitoneal administration. Monocytes and dendritic cells (DCs) required Complement for optimal prion delivery to lymph nodes hours later in a second wave of prion trafficking. B cells constituted the majority of prion-bearing cells in the mediastinal lymph node by six hours, indicating intranodal prion reception from resident DCs or subcapsulary sinus macrophages or directly from follicular conduits. These data reveal novel, cell autonomous prion lymphotropism, and a prominent role for B cells in intranodal prion movement. PMID:22679554

Autonomous beating rate adaptation in human stem cell-derived cardiomyocytes

PubMed Central

Eng, George; Lee, Benjamin W.; Protas, Lev; Gagliardi, Mark; Brown, Kristy; Kass, Robert S.; Keller, Gordon; Robinson, Richard B.; Vunjak-Novakovic, Gordana

2016-01-01

The therapeutic success of human stem cell-derived cardiomyocytes critically depends on their ability to respond to and integrate with the surrounding electromechanical environment. Currently, the immaturity of human cardiomyocytes derived from stem cells limits their utility for regenerative medicine and biological research. We hypothesize that biomimetic electrical signals regulate the intrinsic beating properties of cardiomyocytes. Here we show that electrical conditioning of human stem cell-derived cardiomyocytes in three-dimensional culture promotes cardiomyocyte maturation, alters their automaticity and enhances connexin expression. Cardiomyocytes adapt their autonomous beating rate to the frequency at which they were stimulated, an effect mediated by the emergence of a rapidly depolarizing cell population, and the expression of hERG. This rate-adaptive behaviour is long lasting and transferable to the surrounding cardiomyocytes. Thus, electrical conditioning may be used to promote cardiomyocyte maturation and establish their automaticity, with implications for cell-based reduction of arrhythmia during heart regeneration. PMID:26785135

Pigment cell interactions and differential xanthophore recruitment underlying zebrafish stripe reiteration and Danio pattern evolution

PubMed Central

Patterson, Larissa B.; Bain, Emily J.; Parichy, David M.

2014-01-01

Fishes have diverse pigment patterns, yet mechanisms of pattern evolution remain poorly understood. In zebrafish, Danio rerio, pigment-cell autonomous interactions generate dark stripes of melanophores that alternate with light interstripes of xanthophores and iridophores. Here, we identify mechanisms underlying the evolution of a uniform pattern in D. albolineatus in which all three pigment cell classes are intermingled. We show that in this species xanthophores differentiate precociously over a wider area, and that cis regulatory evolution has increased expression of xanthogenic Colony Stimulating Factor-1 (Csf1). Expressing Csf1 similarly in D. rerio has cascading effects, driving the intermingling of all three pigment cell classes and resulting in the loss of stripes, as in D. albolineatus. Our results identify novel mechanisms of pattern development and illustrate how pattern diversity can be generated when a core network of pigment-cell autonomous interactions is coupled with changes in pigment cell differentiation. PMID:25374113

ALI (Autonomous Lunar Investigator): Revolutionary Approach to Exploring the Moon with Addressable Reconfigurable Technology

NASA Technical Reports Server (NTRS)

Clark, P. E.; Curtis, S. A.; Rilee, M. L.; Floyd, S. R.

2005-01-01

Addressable Reconfigurable Technology (ART) based structures: Mission Concepts based on Addressable Reconfigurable Technology (ART), originally studied for future ANTS (Autonomous Nanotechnology Swarm) Space Architectures, are now being developed as rovers for nearer term use in lunar and planetary surface exploration. The architecture is based on the reconfigurable tetrahedron as a building block. Tetrahedra are combined to form space-filling networks, shaped for the required function. Basic structural components are highly modular, addressable arrays of robust nodes (tetrahedral apices) from which highly reconfigurable struts (tetrahedral edges), acting as supports or tethers, are efficiently reversibly deployed/stowed, transforming and reshaping the structures as required.

DNA "nano-claw": logic-based autonomous cancer targeting and therapy.

PubMed

You, Mingxu; Peng, Lu; Shao, Na; Zhang, Liqin; Qiu, Liping; Cui, Cheng; Tan, Weihong

2014-01-29

Cell types, both healthy and diseased, can be classified by inventories of their cell-surface markers. Programmable analysis of multiple markers would enable clinicians to develop a comprehensive disease profile, leading to more accurate diagnosis and intervention. As a first step to accomplish this, we have designed a DNA-based device, called "Nano-Claw". Combining the special structure-switching properties of DNA aptamers with toehold-mediated strand displacement reactions, this claw is capable of performing autonomous logic-based analysis of multiple cancer cell-surface markers and, in response, producing a diagnostic signal and/or targeted photodynamic therapy. We anticipate that this design can be widely applied in facilitating basic biomedical research, accurate disease diagnosis, and effective therapy.

Interferon-inducible effector mechanisms in cell-autonomous immunity

PubMed Central

MacMicking, John D.

2014-01-01

Interferons (IFNs) induce the expression of hundreds of genes as part of an elaborate antimicrobial programme designed to combat infection in all nucleated cells — a process termed cell-autonomous immunity. As described in this Review, recent genomic and subgenomic analyses have begun to assign functional properties to novel IFN-inducible effector proteins that restrict bacteria, protozoa and viruses in different subcellular compartments and at different stages of the pathogen life cycle. Several newly described host defence factors also participate in canonical oxidative and autophagic pathways by spatially coordinating their activities to enhance microbial killing. Together, these IFN-induced effector networks help to confer vertebrate host resistance to a vast and complex microbial world. PMID:22531325

[Times of gender equity: a description of the inequalities between autonomous communities, Spain 2006-2014].

PubMed

Fernández-Sáez, José; Ruiz-Cantero, María Teresa; Guijarro-Garvi, Marta; Rodenas-Calatayud, Carmen; Martí-Sempere, Mónica; Jiménez-Alegre, María Dolores

2016-01-01

Gender equity (GE) is a structural determinant of health inequalities. In this light, our objective is to show the evolution of gender equity in the Spanish autonomous communities since 2006, prior to the enactment of the Equality Act (2007) and the economic crisis (2008), until 2014. Ecological study of gender equity in the 17 Spanish autonomous communities from 2006-2011-2014. We have calculated: 1) modified gender equity index (MGEI) for the autonomous communities (0=equity, ±1=inequity); 2) interregional and temporal convergences in gender equity. The MGEI in the autonomous communities in 2014 has negative values close to 0 (inequity towards women). There is no interregional convergence due to the dispersion increase (2006: 0.1503; 2011: 0.2280; 2014: 0.4964), and no temporal convergence due to the lack of progress of the autonomous communities with poor gender equity. The gender gap in economic activity continues to be unfavourable to women, decreasing in all communities between 2006 and 2011 but increasing in six communities in 2014. The gender gap in education from 2006-2011-2014 has positive values close to 0 (unfavourable to men), while the gender gap in empowerment is unfavourable to women, representing the most significant gender equity disparity. Inter-community dispersion of economic activity and education did not change between 2006 and 2014, while inter-community dispersion of empowerment increased. The level of gender equity achieved in the Spanish autonomous communities in 2006 was lost during the economic crisis, as gender equity disparities between the communities had increased by 2014. Gender inequity continues to be unfavourable to women. Copyright © 2016 SESPAS. Published by Elsevier Espana. All rights reserved.

Hypomorphic alleles reveal FCA-independent roles for FY in the regulation of FLOWERING LOCUS C.

PubMed

Feng, Wei; Jacob, Yannick; Veley, Kira M; Ding, Lei; Yu, Xuhong; Choe, Goh; Michaels, Scott D

2011-03-01

The autonomous floral promotion pathway plays a key role in the regulation of flowering in rapid-cycling Arabidopsis (Arabidopsis thaliana) by providing constitutive repression of the floral inhibitor FLOWERING LOCUS C (FLC). As a result, autonomous pathway mutants contain elevated levels of FLC and are late flowering. Winter annual Arabidopsis, in contrast, contain functional alleles of FRIGIDA (FRI), which acts epistatically to the autonomous pathway to up-regulate FLC and delay flowering. To further explore the relationship between FRI and the autonomous pathway, we placed autonomous pathway mutants in a FRI-containing background. Unexpectedly, we found that a hypomorphic allele of the autonomous pathway gene fy (fy null alleles are embryo lethal) displayed background-specific effects on FLC expression and flowering time; in a rapid-cycling background fy mutants contained elevated levels of FLC and were late flowering, whereas in a winter annual background fy decreased FLC levels and partially suppressed the late-flowering phenotype conferred by FRI. Because FY has been shown to have homology to polyadenylation factors, we examined polyadenylation site selection in FLC transcripts. In wild type, two polyadenylation sites were detected and used at similar levels. In fy mutant backgrounds, however, the ratio of products was shifted to favor the distally polyadenylated form. FY has previously been shown to physically interact with another member of the autonomous pathway, FCA. Interestingly, we found that fy can partially suppress FLC expression in an fca null background and promote proximal polyadenylation site selection usage in the absence of FCA. Taken together, these results indicate novel and FCA-independent roles for FY in the regulation of FLC.

Hypomorphic Alleles Reveal FCA-Independent Roles for FY in the Regulation of FLOWERING LOCUS C1[C][W][OA

PubMed Central

Feng, Wei; Jacob, Yannick; Veley, Kira M.; Ding, Lei; Yu, Xuhong; Choe, Goh; Michaels, Scott D.

2011-01-01

The autonomous floral promotion pathway plays a key role in the regulation of flowering in rapid-cycling Arabidopsis (Arabidopsis thaliana) by providing constitutive repression of the floral inhibitor FLOWERING LOCUS C (FLC). As a result, autonomous pathway mutants contain elevated levels of FLC and are late flowering. Winter annual Arabidopsis, in contrast, contain functional alleles of FRIGIDA (FRI), which acts epistatically to the autonomous pathway to up-regulate FLC and delay flowering. To further explore the relationship between FRI and the autonomous pathway, we placed autonomous pathway mutants in a FRI-containing background. Unexpectedly, we found that a hypomorphic allele of the autonomous pathway gene fy (fy null alleles are embryo lethal) displayed background-specific effects on FLC expression and flowering time; in a rapid-cycling background fy mutants contained elevated levels of FLC and were late flowering, whereas in a winter annual background fy decreased FLC levels and partially suppressed the late-flowering phenotype conferred by FRI. Because FY has been shown to have homology to polyadenylation factors, we examined polyadenylation site selection in FLC transcripts. In wild type, two polyadenylation sites were detected and used at similar levels. In fy mutant backgrounds, however, the ratio of products was shifted to favor the distally polyadenylated form. FY has previously been shown to physically interact with another member of the autonomous pathway, FCA. Interestingly, we found that fy can partially suppress FLC expression in an fca null background and promote proximal polyadenylation site selection usage in the absence of FCA. Taken together, these results indicate novel and FCA-independent roles for FY in the regulation of FLC. PMID:21209277

Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure.

PubMed

Arnold, Amy C; Okamoto, Luis E; Gamboa, Alfredo; Black, Bonnie K; Raj, Satish R; Elijovich, Fernando; Robertson, David; Shibao, Cyndya A; Biaggioni, Italo

2016-02-01

Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin-angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson's disease; 7 male; 70±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P=0.016), with no effect on nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL eplerenone, P=0.492; nocturnal weight loss: -1.19±0.15 kg placebo versus -1.18±0.15 kg eplerenone, P=0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients. © 2015 American Heart Association, Inc.

Mechanism of development of ionocytes rich in vacuolar-type H+-ATPase in the skin of zebrafish larvae

PubMed Central

Esaki, Masahiro; Hoshijima, Kazuyuki; Nakamura, Nobuhiro; Munakata, Keijiro; Tanaka, Mikiko; Ookata, Kayoko; Asakawa, Kazuhide; Kawakami, Koichi; Wang, Weiyi; Weinberg, Eric S.; Hirose, Shigehisa

2009-01-01

Mitochondrion-rich cells (MRCs), or ionocytes, play a central role in aquatic species, maintaining body fluid ionic homeostasis by actively taking up or excreting ions. Since their first description in 1932 in eel gills, extensive morphological and physiological analyses have yielded important insights into ionocyte structure and function, but understanding the developmental pathway specifying these cells remains an ongoing challenge. We previously succeeded in identifying a key transcription factor, Foxi3a, in zebrafish larvae by database mining. In the present study, we analyzed a zebrafish mutant, quadro (quo), deficient in foxi1 gene expression and found that foxi1 is essential for development of an MRC subpopulation rich in vacuolar-type H+-ATPase (vH-MRC). foxi1 acts upstream of Delta-Notch signaling that determines sporadic distribution of vH-MRC and regulates foxi3a expression. Through gain- and loss-of-function assays and cell transplantation experiments, we further clarified that (1) the expression level of foxi3a is maintained by a positive feedback loop between foxi3a and its downstream gene gcm2 and (2) Foxi3a functions cell-autonomously in the specification of vH-MRC. These observations provide a better understanding of the differentiation and distribution of the vH-MRC subtype. PMID:19268451

Multiple circadian transcriptional elements cooperatively regulate cell-autonomous transcriptional oscillation of Period3, a mammalian clock gene.

PubMed

Matsumura, Ritsuko; Akashi, Makoto

2017-09-29

Cell-autonomous oscillation in clock gene expression drives circadian rhythms. The development of comprehensive analytical techniques, such as bioinformatics and ChIP-sequencing, has enabled the genome-wide identification of potential circadian transcriptional elements that regulate the transcriptional oscillation of clock genes. However, detailed analyses using traditional biochemical and molecular-biological approaches, such as binding and reporter assays, are still necessary to determine whether these potential circadian transcriptional elements are actually functional and how significantly they contribute to driving transcriptional oscillation. Here, we focused on the molecular mechanism of transcriptional oscillations in the mammalian clock gene Period3 ( Per3 ). The PER3 protein is essential for robust peripheral clocks and is a key component in circadian output processes. We found three E box-like elements located upstream of human Per3 transcription start sites that additively contributed to cell-autonomous transcriptional oscillation. However, we also found that Per3 is still expressed in a circadian manner when all three E box-like elements are functionally impaired. We noted that Per3 transcription was activated by the synergistic actions of two D box-like elements and the three E box-like elements, leading to a drastic increase in circadian amplitude. Interestingly, circadian expression of Per3 was completely disrupted only when all five transcriptional elements were functionally impaired. These results indicate that three E box-like and two D box-like elements cooperatively and redundantly regulate cell-autonomous transcriptional oscillation of Per3 . © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

A direct repeat of E-box-like elements is required for cell-autonomous circadian rhythm of clock genes

PubMed Central

Nakahata, Yasukazu; Yoshida, Mayumi; Takano, Atsuko; Soma, Haruhiko; Yamamoto, Takuro; Yasuda, Akio; Nakatsu, Toru; Takumi, Toru

2008-01-01

Background The circadian expression of the mammalian clock genes is based on transcriptional feedback loops. Two basic helix-loop-helix (bHLH) PAS (for Period-Arnt-Sim) domain-containing transcriptional activators, CLOCK and BMAL1, are known to regulate gene expression by interacting with a promoter element termed the E-box (CACGTG). The non-canonical E-boxes or E-box-like sequences have also been reported to be necessary for circadian oscillation. Results We report a new cis-element required for cell-autonomous circadian transcription of clock genes. This new element consists of a canonical E-box or a non-canonical E-box and an E-box-like sequence in tandem with the latter with a short interval, 6 base pairs, between them. We demonstrate that both E-box or E-box-like sequences are needed to generate cell-autonomous oscillation. We also verify that the spacing nucleotides with constant length between these 2 E-elements are crucial for robust oscillation. Furthermore, by in silico analysis we conclude that several clock and clock-controlled genes possess a direct repeat of the E-box-like elements in their promoter region. Conclusion We propose a novel possible mechanism regulated by double E-box-like elements, not to a single E-box, for circadian transcriptional oscillation. The direct repeat of the E-box-like elements identified in this study is the minimal required element for the generation of cell-autonomous transcriptional oscillation of clock and clock-controlled genes. PMID:18177499

Drosophila glypican Dally-like acts in FGF-receiving cells to modulate FGF signaling during tracheal morphogenesis

PubMed Central

Yan, Dong; Lin, Xinhua

2007-01-01

Summary Previous studies in Drosophila have shown that heparan sulfate proteoglycans (HSPGs) are involved in both breathless (btl)- and heartless (htl)-mediated FGF signaling during embryogenesis. However, the mechanism(s) by which HSPGs control Btl and Htl signaling is unknown. Here we show that dally-like (dlp, a Drosophila glypican) mutant embryos exhibit severe defects in tracheal morphogenesis and show a reduction in btl-mediated FGF signaling activity. However, htl-dependent mesodermal cell migration is not affected in dlp mutant embryos. Furthermore, expression of Dlp, but not other Drosophila HSPGs, can restore effectively the tracheal morphogenesis in dlp embryos. Rescue experiments in dlp embryos demonstrate that Dlp functions only in Bnl/FGF receiving cells in a cell-autonomous manner, but is not essential for Bnl/FGF expression cells. To further dissect the mechanism(s) of Dlp in Btl signaling, we analyzed the role of Dlp in Btl-mediated air sac tracheoblast formation in wing discs. Mosaic analysis experiments show that removal of HSPG activity in FGF-producing or other surrounding cells does not affect tracheoblasts migration, while HSPG mutant tracheoblast cells fail to receive FGF signaling. Together, our results argue strongly that HSPGs regulate Btl signaling exclusively in FGF-receiving cells as co-receptors, but are not essential for the secretion and distribution of the FGF ligand. This mechanism is distinct from HSPG functions in morphogen distribution, and is likely a general paradigm for HSPG functions in FGF signaling in Drosophila. PMID:17959166

Cell-autonomous defense, re-organization and trafficking of membranes in plant-microbe interactions.

PubMed

Dörmann, Peter; Kim, Hyeran; Ott, Thomas; Schulze-Lefert, Paul; Trujillo, Marco; Wewer, Vera; Hückelhoven, Ralph

2014-12-01

Plant cells dynamically change their architecture and molecular composition following encounters with beneficial or parasitic microbes, a process referred to as host cell reprogramming. Cell-autonomous defense reactions are typically polarized to the plant cell periphery underneath microbial contact sites, including de novo cell wall biosynthesis. Alternatively, host cell reprogramming converges in the biogenesis of membrane-enveloped compartments for accommodation of beneficial bacteria or invasive infection structures of filamentous microbes. Recent advances have revealed that, in response to microbial encounters, plasma membrane symmetry is broken, membrane tethering and SNARE complexes are recruited, lipid composition changes and plasma membrane-to-cytoskeleton signaling is activated, either for pre-invasive defense or for microbial entry. We provide a critical appraisal on recent studies with a focus on how plant cells re-structure membranes and the associated cytoskeleton in interactions with microbial pathogens, nitrogen-fixing rhizobia and mycorrhiza fungi. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

Overexpression of Hif-1α in Mesenchymal Stem Cells Affects Cell-Autonomous Angiogenic and Osteogenic Parameters.

PubMed

Lampert, F M; Kütscher, C; Stark, G B; Finkenzeller, G

2016-03-01

Reconstruction of large bone defects still represents a major medical challenge. In recent years tissue engineering has developed techniques based on adult mesenchymal stem cells (MSCs) that could represent an attractive therapeutical option to treat large bone defects in the future. It has been demonstrated in various animal models that ex vivo expanded MSCs are capable of promoting the regeneration of skeletal defects after implantation. However, for the efficient regeneration of bone in tissue engineering applications, a rapid vascularization of implanted grafts is essential to ensure the survival of cells in the early post-implantational phase. A promising strategy to enhance vascularization of MSC-containing implants could consist of overexpression of the angiogenic master transcription factor Hypoxia-inducible factor 1 (Hif-1) in the MSCs in order to induce angiogenesis and support osteogenesis. In the present study, we overexpressed Hif-1α in MSCs by using recombinant adenoviruses and investigated cell-autonomous effects. Overexpression of Hif-1α enhanced proliferation, migration, cell survival and expression of pro-angiogenic genes. Other parameters such as expression of the osteogenic markers BMP-2 and RunX2 were decreased. Hif-1α overexpression had no effect on invasion, senescence and osteogenic differentiation of MSCs. Our experiments revealed multifarious effects of Hif-1α overexpression on cell-autonomous parameters. Therefore, Hif-1α overexpression may represent a therapeutic option to improve cellular functions of MSCs to treat critical sized bone defects. © 2015 Wiley Periodicals, Inc.

Amnioserosa cell constriction but not epidermal actin cable tension autonomously drives dorsal closure.

PubMed

Pasakarnis, Laurynas; Frei, Erich; Caussinus, Emmanuel; Affolter, Markus; Brunner, Damian

2016-11-01

Tissue morphogenesis requires coordination of multiple force-producing components. During dorsal closure in fly embryogenesis, an epidermis opening closes. A tensioned epidermal actin/MyosinII cable, which surrounds the opening, produces a force that is thought to combine with another MyosinII force mediating apical constriction of the amnioserosa cells that fill the opening. A model proposing that each force could autonomously drive dorsal closure was recently challenged by a model in which the two forces combine in a ratchet mechanism. Acute force elimination via selective MyosinII depletion in one or the other tissue shows that the amnioserosa tissue autonomously drives dorsal closure while the actin/MyosinII cable cannot. These findings exclude both previous models, although a contribution of the ratchet mechanism at dorsal closure onset remains likely. This shifts the current view of dorsal closure being a combinatorial force-component system to a single tissue-driven closure event.

Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells.

PubMed

Vander Griend, Donald J; D'Antonio, Jason; Gurel, Bora; Antony, Lizamma; Demarzo, Angelo M; Isaacs, John T

2010-01-01

The lethality of prostate cancer is due to the continuous growth of cancer initiating cells (CICs) which are often stimulated by androgen receptor (AR) signaling. However, the underlying molecular mechanism(s) for such AR-mediated growth stimulation are not fully understood. Such mechanisms may involve cancer cell-dependent induction of tumor stromal cells to produce paracrine growth factors or could involve cancer cell autonomous autocrine and/or intracellular AR signaling pathways. We utilized clinical samples, animal models and a series of AR-positive human prostate cancer cell lines to evaluate AR-mediated growth stimulation of prostate CICs. The present studies document that stromal AR expression is not required for prostate cancer growth, since tumor stroma surrounding AR-positive human prostate cancer metastases (N = 127) are characteristically AR-negative. This lack of a requirement for AR expression in tumor stromal cells is also documented by the fact that human AR-positive prostate cancer cells grow equally well when xenografted in wild-type versus AR-null nude mice. AR-dependent growth stimulation was documented to involve secretion, extracellular binding, and signaling by autocrine growth factors. Orthotopic xenograft animal studies documented that the cellautonomous autocrine growth factors which stimulate prostate CIC growth are not the andromedins secreted by normal prostate stromal cells. Such cell autonomous and extracellular autocrine signaling is necessary but not sufficient for the optimal growth of prostate CICs based upon the response to anti-androgen plus/or minus preconditioned media. AR-induced growth stimulation of human prostate CICs requires AR-dependent intracellular pathways. The identification of such AR-dependent intracellular pathways offers new leads for the development of effective therapies for prostate cancer. (c) 2009 Wiley-Liss, Inc.

BRCA1 haploinsufficiency cell-autonomously activates RANKL expression and generates denosumab-responsive breast cancer-initiating cells.

PubMed

Cuyàs, Elisabet; Corominas-Faja, Bruna; Martín, María Muñoz-San; Martin-Castillo, Begoña; Lupu, Ruth; Brunet, Joan; Bosch-Barrera, Joaquim; Menendez, Javier A

2017-05-23

Denosumab, a monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), might be a novel preventative therapy for BRCA1-mutation carriers at high risk of developing breast cancer. Beyond its well-recognized bone-targeted activity impeding osteoclastogenesis, denosumab has been proposed to interfere with the cross-talk between RANKL-producing sensor cells and cancer-initiating RANK+ responder cells that reside within premalignant tissues of BRCA1-mutation carriers. We herein tested the alternative but not mutually exclusive hypothesis that BRCA1 deficiency might cell-autonomously activate RANKL expression to generate cellular states with cancer stem cell (CSC)-like properties. Using isogenic pairs of normal-like human breast epithelial cells in which the inactivation of a single BRCA1 allele results in genomic instability, we assessed the impact of BRCA1 haploinsufficiency on the expression status of RANK and RANKL. RANK expression remained unaltered but RANKL was dramatically up-regulated in BRCA1mut/+ haploinsufficient cells relative to isogenic BRCA1+/+ parental cells. Neutralizing RANKL with denosumab significantly abrogated the ability of BRCA1 haploinsufficient cells to survive and proliferate as floating microtumors or "mammospheres" under non-adherent/non-differentiating conditions, an accepted surrogate of the relative proportion and survival of CSCs. Intriguingly, CSC-like states driven by epithelial-to-mesenchymal transition or HER2 overexpression traits responded to some extent to denosumab. We propose that breast epithelium-specific mono-allelic inactivation of BRCA1 might suffice to cell-autonomously generate RANKL-addicted, denosumab-responsive CSC-like states. The convergent addiction to a hyperactive RANKL/RANK axis of CSC-like states from genetically diverse breast cancer subtypes might inaugurate a new era of cancer prevention and treatment based on denosumab as a CSC-targeted agent.

ADAM10 Regulates Notch Function in Intestinal Stem Cells of Mice

PubMed Central

Tsai, Yu-Hwai; VanDussen, Kelli L.; Sawey, Eric T.; Wade, Alex W.; Kasper, Chelsea; Rakshit, Sabita; Bhatt, Riha G.; Stoeck, Alex; Maillard, Ivan; Crawford, Howard C.; Samuelson, Linda C.; Dempsey, Peter J.

2014-01-01

BACKGROUND & AIMS ADAM10 is a cell surface sheddase that regulates physiological processes including Notch signaling. ADAM10 is expressed in all intestinal epithelial cell types but the requirement for ADAM10 signaling in crypt homeostasis is not well defined. METHODS We analyzed intestinal tissues from mice with constitutive (Vil-Cre;Adam10f/f mice) and conditional (Vil-CreER;Adam10f/f and Lgr5-CreER;Adam10f/f mice) deletion of ADAM10. We performed cell lineage tracing experiments in mice that expressed a gain-of-function allele of Notch in the intestine (Rosa26NICD) or mice with intestine-specific disruption of Notch (Rosa26DN-MAML), to examine the effects of ADAM10 deletion on cell fate specification and intestinal stem cell maintenance. RESULTS Loss of ADAM10 from developing and adult intestine caused lethality associated with altered intestinal morphology, reduced progenitor cell proliferation, and increased secretory cell differentiation. ADAM10 deletion led to the replacement of intestinal cell progenitors with 2 distinct, post-mitotic, secretory cell lineages: intermediate-like (Paneth/goblet) and enteroendocrine cells. Based on analysis of Rosa26NICD and Rosa26DN-MAML mice, we determined that ADAM10 controls these cell fate decisions by regulating Notch signaling. Cell lineage tracing experiments showed that ADAM10 is required for survival of Lgr5+ crypt-based columnar cells. Our findings indicate that Notch-activated stem cells have a competitive advantage for occupation of the stem cell niche. CONCLUSIONS ADAM10 acts in a cell autonomous manner within the intestinal crypt compartment to regulate Notch signaling. This process is required for progenitor cell lineage specification and crypt-based columnar cell maintenance. PMID:25038433

Three-bead steering microswimmers

NASA Astrophysics Data System (ADS)

Rizvi, Mohd Suhail; Farutin, Alexander; Misbah, Chaouqi

2018-02-01

The self-propelled microswimmers have recently attracted considerable attention as model systems for biological cell migration as well as artificial micromachines. A simple and well-studied microswimmer model consists of three identical spherical beads joined by two springs in a linear fashion with active oscillatory forces being applied on the beads to generate self-propulsion. We have extended this linear microswimmer configuration to a triangular geometry where the three beads are connected by three identical springs in an equilateral triangular manner. The active forces acting on each spring can lead to autonomous steering motion; i.e., allowing the swimmer to move along arbitrary paths. We explore the microswimmer dynamics analytically and pinpoint its rich character depending on the nature of the active forces. The microswimmers can translate along a straight trajectory, rotate at a fixed location, as well as perform a simultaneous translation and rotation resulting in complex curved trajectories. The sinusoidal active forces on the three springs of the microswimmer contain naturally four operating parameters which are more than required for the steering motion. We identify the minimal operating parameters which are essential for the motion of the microswimmer along any given arbitrary trajectory. Therefore, along with providing insights into the mechanics of the complex motion of the natural and artificial microswimmers, the triangular three-bead microswimmer can be utilized as a model for targeted drug delivery systems and autonomous underwater vehicles where intricate trajectories are involved.

Rotenone and Paraquat do not Directly Activate Microglia or Induce Inflammatory Cytokine Release

PubMed Central

Klintworth, Heather; Garden, Gwenn; Xia, Zhengui

2009-01-01

Both epidemiological and pathological data suggest an inflammatory response including microglia activation and neuro-inflammation in the Parkinsonian brain. Treatments with lipopolysacchride (LPS), rotenone and paraquat have been used as models for Parkinson’s disease, as they cause dopaminergic neuron degeneration in culture and in animals. Recent studies have suggested that rotenone and paraquat induce neuro-inflammation, however, it is not known if they can directly activate microglia. Here, we use primary cultured microglia to address this question. Microglia activation was analyzed by morphological changes and release of nitric oxide and inflammatory cytokines. Treatment with LPS was used as a positive control. While LPS induced morphological changes characteristic of microglial activation and release of nitric oxide and inflammatory cytokines, rotenone and paraquat did not. Our results suggest that paraquat and rotenone do not act directly on microglia and that neuro-inflammation and microglial activation in animals treated with these agents is likely non-cell autonomous, and may occur as a result of dopaminergic neuron damage or factors released by neurons and other cells. PMID:19559752

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

PubMed

Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

2017-06-01

Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43 Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43 Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

Role of ghrelin and leptin in the regulation of carbohydrate metabolism. Part II. Leptin.

PubMed

Otto-Buczkowska, Ewa; Chobot, Agata

2012-10-26

Leptin is produced by mature adipocytes. Its amount correlates positively with the mass of the adipose tissue. Leptin plays a crucial role in maintaining body weight and glucose homeostasis. It is transported through the blood-brain barrier to the central nervous system, where it activates the autonomic nervous system, causing the feeling of satiety and inhibiting appetite. It also acts through central and peripheral pathways, including the regulation of insulin secretion by pancreatic β cells. Leptin may also directly affect the metabolism and function of peripheral tissues. It has been found to play a role in peripheral insulin resistance by attenuating insulin action, and perhaps also insulin signaling, in various insulin-responsive cell types. Recent data provide convincing evidence that leptin has a beneficial influence on glucose homeostasis. Studies suggest that leptin could be used as an adjunct of insulin therapy in insulin-deficient diabetes, thereby providing an insight into the therapeutic implications of leptin as an anti-diabetic agent. Extensive research will be needed to determine long-term safety and efficacy of such a therapy.

Muscle contraction is required to maintain the pool of muscle progenitors via YAP and NOTCH during fetal myogenesis

PubMed Central

Esteves de Lima, Joana; Bonnin, Marie-Ange; Birchmeier, Carmen; Duprez, Delphine

2016-01-01

The importance of mechanical activity in the regulation of muscle progenitors during chick development has not been investigated. We show that immobilization decreases NOTCH activity and mimics a NOTCH loss-of-function phenotype, a reduction in the number of muscle progenitors and increased differentiation. Ligand-induced NOTCH activation prevents the reduction of muscle progenitors and the increase of differentiation upon immobilization. Inhibition of NOTCH ligand activity in muscle fibers suffices to reduce the progenitor pool. Furthermore, immobilization reduces the activity of the transcriptional co-activator YAP and the expression of the NOTCH ligand JAG2 in muscle fibers. YAP forced-activity in muscle fibers prevents the decrease of JAG2 expression and the number of PAX7+ cells in immobilization conditions. Our results identify a novel mechanism acting downstream of muscle contraction, where YAP activates JAG2 expression in muscle fibers, which in turn regulates the pool of fetal muscle progenitors via NOTCH in a non-cell-autonomous manner. DOI: http://dx.doi.org/10.7554/eLife.15593.001 PMID:27554485

Expression of genomic AtCYCD2;1 in Arabidopsis induces cell division at smaller cell sizes: implications for the control of plant growth.

PubMed

Qi, Ruhu; John, Peter Crook Lloyd

2007-07-01

The Arabidopsis (Arabidopsis thaliana) CYCD2;1 gene introduced in genomic form increased cell formation in the Arabidopsis root apex and leaf, while generating full-length mRNA, raised CDK/CYCLIN enzyme activity, reduced G1-phase duration, and reduced size of cells at S phase and division. Other cell cycle genes, CDKA;1, CYCLIN B;1, and the cDNA form of CYCD2;1 that produced an aberrantly spliced mRNA, produced smaller or zero increases in CDK/CYCLIN activity and did not increase the number of cells formed. Plants with a homozygous single insert of genomic CYCD2;1 grew with normal morphology and without accelerated growth of root or shoot, not providing evidence that cell formation or CYCLIN D2 controls growth of postembryonic vegetative tissues. At the root apex, cells progressed normally from meristem to elongation, but their smaller size enclosed less growth and a 40% reduction in final size of epidermal and cortical cells was seen. Smaller elongated cell size inhibited endoreduplication, indicating a cell size requirement. Leaf cells were also smaller and more numerous during proliferation and epidermal pavement and palisade cells attained 59% and 69% of controls, whereas laminas reached normal size. Autonomous control of expansion was therefore not evident in abundant cell types that formed tissues of root or leaf. Cell size was reduced by a greater number formed in a tissue prior to cell and tissue expansion. Initiation and termination of expansion did not correlate with cell dimension or number and may be determined by tissue-wide signals acting across cellular boundaries.

Photonic Microhand with Autonomous Action.

PubMed

Martella, Daniele; Nocentini, Sara; Nuzhdin, Dmitry; Parmeggiani, Camilla; Wiersma, Diederik S

2017-11-01

Grabbing and holding objects at the microscale is a complex function, even for microscopic living animals. Inspired by the hominid-type hand, a microscopic equivalent able to catch microelements is engineered. This microhand is light sensitive and can be either remotely controlled by optical illumination or can act autonomously and grab small particles on the basis of their optical properties. Since the energy is delivered optically, without the need for wires or batteries, the artificial hand can be shrunk down to the micrometer scale. Soft material is used, in particular, a custom-made liquid-crystal network that is patterned by a photolithographic technique. The elastic reshaping properties of this material allow finger movement, using environmental light as the only energy source. The hand can be either controlled externally (via the light field), or else the conditions in which it autonomously grabs a particle in its vicinity can be created. This microrobot has the unique feature that it can distinguish between particles of different colors and gray levels. The realization of this autonomous hand constitutes a crucial element in the development of microscopic creatures that can perform tasks without human intervention and self-organized automation at the micrometer scale. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Agent Based Software for the Autonomous Control of Formation Flying Spacecraft

NASA Technical Reports Server (NTRS)

How, Jonathan P.; Campbell, Mark; Dennehy, Neil (Technical Monitor)

2003-01-01

Distributed satellite systems is an enabling technology for many future NASA/DoD earth and space science missions, such as MMS, MAXIM, Leonardo, and LISA [1, 2, 3]. While formation flying offers significant science benefits, to reduce the operating costs for these missions it will be essential that these multiple vehicles effectively act as a single spacecraft by performing coordinated observations. Autonomous guidance, navigation, and control as part of a coordinated fleet-autonomy is a key technology that will help accomplish this complex goal. This is no small task, as most current space missions require significant input from the ground for even relatively simple decisions such as thruster burns. Work for the NMP DS1 mission focused on the development of the New Millennium Remote Agent (NMRA) architecture for autonomous spacecraft control systems. NMRA integrates traditional real-time monitoring and control with components for constraint-based planning, robust multi-threaded execution, and model-based diagnosis and reconfiguration. The complexity of using an autonomous approach for space flight software was evident when most of its capabilities were stripped off prior to launch (although more capability was uplinked subsequently, and the resulting demonstration was very successful).

Stability of distributed MPC in an intersection scenario

NASA Astrophysics Data System (ADS)

Sprodowski, T.; Pannek, J.

2015-11-01

The research topic of autonomous cars and the communication among them has attained much attention in the last years and is developing quickly. Among others, this research area spans fields such as image recognition, mathematical control theory, communication networks, and sensor fusion. We consider an intersection scenario where we divide the shared road space in different cells. These cells form a grid. The cars are modelled as an autonomous multi-agent system based on the Distributed Model Predictive Control algorithm (DMPC). We prove that the overall system reaches stability using Optimal Control for each multi-agent and demonstrate that by numerical results.

Self-Determination Theory: The Importance of Autonomy to Well-Being across Cultures

ERIC Educational Resources Information Center

Wichmann, Sonia Secher

2011-01-01

According to proponents of self-determination theory, autonomous regulation is a universal psychological human need. Researchers have found autonomy (defined as acting in accordance with one's values) related to well-being across cultures. Encouraging client autonomy is therefore fundamental to the practice of humanistic counseling.

Political Socialisation at British and West German Universities--or: Whistling in the Dark?

ERIC Educational Resources Information Center

Tilford, Roger

1985-01-01

British universities remain autonomous and continue to act as effective agencies of political socialization. The historical ambivalence in the structure of the German university between academic freedom and state regulation remains, inhibiting the German university's value as an agency of political socialization. (Author/RM)

78 FR 79411 - Announcement of Competition Under the America COMPETES Act

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-30

... announces the Cyber Grand Challenge (CGC), a prize competition under 15 U.S.C. 3719, the America COMPETES... cyber defense systems. The CGC seeks to engender a new generation of autonomous cyber defense... experts. FOR FURTHER INFORMATION CONTACT: All questions regarding the competition may be sent to Cyber...

Self-propelled carbon nanotube based microrockets for rapid capture and isolation of circulating tumor cells

NASA Astrophysics Data System (ADS)

Banerjee, Shashwat S.; Jalota-Badhwar, Archana; Zope, Khushbu R.; Todkar, Kiran J.; Mascarenhas, Russel R.; Chate, Govind P.; Khutale, Ganesh V.; Bharde, Atul; Calderon, Marcelo; Khandare, Jayant J.

2015-05-01

Here, we report a non-invasive strategy for isolating cancer cells by autonomously propelled carbon nanotube (CNT) microrockets. H2O2-driven oxygen (O2) bubble-propelled microrockets were synthesized using CNT and Fe3O4 nanoparticles in the inner surface and covalently conjugating transferrin on the outer surface. Results show that self-propellant microrockets can specifically capture cancer cells.Here, we report a non-invasive strategy for isolating cancer cells by autonomously propelled carbon nanotube (CNT) microrockets. H2O2-driven oxygen (O2) bubble-propelled microrockets were synthesized using CNT and Fe3O4 nanoparticles in the inner surface and covalently conjugating transferrin on the outer surface. Results show that self-propellant microrockets can specifically capture cancer cells. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr01797a

An Autonomous BMP2 Regulatory Element in Mesenchymal Cells

PubMed Central

Kruithof, Boudewijn P.T.; Fritz, David T.; Liu, Yijun; Garsetti, Diane E.; Frank, David B.; Pregizer, Steven K.; Gaussin, Vinciane; Mortlock, Douglas P.; Rogers, Melissa B.

2014-01-01

BMP2 is a morphogen that controls mesenchymal cell differentiation and behavior. For example, BMP2 concentration controls the differentiation of mesenchymal precursors into myocytes, adipocytes, chondrocytes, and osteoblasts. Sequences within the 3′untranslated region (UTR) of the Bmp2 mRNA mediate a post-transcriptional block of protein synthesis. Interaction of cell and developmental stage-specific trans-regulatory factors with the 3′UTR is a nimble and versatile mechanism for modulating this potent morphogen in different cell types. We show here, that an ultra-conserved sequence in the 3′UTR functions independently of promoter, coding region, and 3′UTR context in primary and immortalized tissue culture cells and in transgenic mice. Our findings indicate that the ultra-conserved sequence is an autonomously functioning post-transcriptional element that may be used to modulate the level of BMP2 and other proteins while retaining tissue specific regulatory elements. PMID:21268088

Consequences for patients of health care professionals' conscientious actions: the ban on abortions in South Australia.

PubMed Central

Cannold, L

1994-01-01

The legitimacy of the refusal of South Australian nurses to care for second trimester abortion patients on grounds of conscience is examined as a test case for a theory of permissible limits on the autonomy of health care professionals. In cases of health care professional (HCP) conscientious refusal, it is argued that a balance be struck between the HCPs' claims to autonomous action and the consequences to them of having their autonomous action restricted, and the entitlement of patients to care and the consequences for them of being refused such care. Conscientious action that results in the disruption or termination of health care services, however, is always impermissible on two grounds. Firstly, because it is at this point that the action '... invades a patient's autonomy, puts a patient at serious risk ... [and] treats a patient unjustly' (1) Secondly, because the consequences of such refusals turn them into political acts--acts of civil disobedience. It is arguable that in order for acts of civil disobedience to be legitimate, certain obligations are required of the dissenter by the community. It is concluded that the actions of the South Australian nurses, which have over the last few years both terminated and disrupted second trimester services, are morally impermissible. PMID:8083879

Consequences for patients of health care professionals' conscientious actions: the ban on abortions in South Australia.

PubMed

Cannold, L

1994-06-01

The legitimacy of the refusal of South Australian nurses to care for second trimester abortion patients on grounds of conscience is examined as a test case for a theory of permissible limits on the autonomy of health care professionals. In cases of health care professional (HCP) conscientious refusal, it is argued that a balance be struck between the HCPs' claims to autonomous action and the consequences to them of having their autonomous action restricted, and the entitlement of patients to care and the consequences for them of being refused such care. Conscientious action that results in the disruption or termination of health care services, however, is always impermissible on two grounds. Firstly, because it is at this point that the action '... invades a patient's autonomy, puts a patient at serious risk ... [and] treats a patient unjustly' (1) Secondly, because the consequences of such refusals turn them into political acts--acts of civil disobedience. It is arguable that in order for acts of civil disobedience to be legitimate, certain obligations are required of the dissenter by the community. It is concluded that the actions of the South Australian nurses, which have over the last few years both terminated and disrupted second trimester services, are morally impermissible.

Autonomy and Non-autonomy of Angiogenic Cell Movements Revealed by Experiment-Driven Mathematical Modeling.

PubMed

Sugihara, Kei; Nishiyama, Koichi; Fukuhara, Shigetomo; Uemura, Akiyoshi; Arima, Satoshi; Kobayashi, Ryo; Köhn-Luque, Alvaro; Mochizuki, Naoki; Suda, Toshio; Ogawa, Hisao; Kurihara, Hiroki

2015-12-01

Angiogenesis is a multicellular phenomenon driven by morphogenetic cell movements. We recently reported morphogenetic vascular endothelial cell (EC) behaviors to be dynamic and complex. However, the principal mechanisms orchestrating individual EC movements in angiogenic morphogenesis remain largely unknown. Here we present an experiment-driven mathematical model that enables us to systematically dissect cellular mechanisms in branch elongation. We found that cell-autonomous and coordinated actions governed these multicellular behaviors, and a cell-autonomous process sufficiently illustrated essential features of the morphogenetic EC dynamics at both the single-cell and cell-population levels. Through refining our model and experimental verification, we further identified a coordinated mode of tip EC behaviors regulated via a spatial relationship between tip and follower ECs, which facilitates the forward motility of tip ECs. These findings provide insights that enhance our mechanistic understanding of not only angiogenic morphogenesis, but also other types of multicellular phenomenon. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Adult hematopoietic stem cells lacking Hif-1α self-renew normally.

PubMed

Vukovic, Milica; Sepulveda, Catarina; Subramani, Chithra; Guitart, Amélie V; Mohr, Jasmine; Allen, Lewis; Panagopoulou, Theano I; Paris, Jasmin; Lawson, Hannah; Villacreces, Arnaud; Armesilla-Diaz, Alejandro; Gezer, Deniz; Holyoake, Tessa L; Ratcliffe, Peter J; Kranc, Kamil R

2016-06-09

The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance. © 2016 by The American Society of Hematology.

Adult hematopoietic stem cells lacking Hif-1α self-renew normally

PubMed Central

Vukovic, Milica; Sepulveda, Catarina; Subramani, Chithra; Guitart, Amélie V.; Mohr, Jasmine; Allen, Lewis; Panagopoulou, Theano I.; Paris, Jasmin; Lawson, Hannah; Villacreces, Arnaud; Armesilla-Diaz, Alejandro; Gezer, Deniz; Holyoake, Tessa L.; Ratcliffe, Peter J.

2016-01-01

The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α–deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α–deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance. PMID:27060169

Reactor Power for Large Displacement Autonomous Underwater Vehicles

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

McClure, Patrick Ray; Reid, Robert Stowers; Poston, David Irvin

This is a PentaChart on reactor power for large displacement autonomous underwater vehicles. Currently AUVs use batteries or combinations of batteries and fuel cells for power. Battery/fuel cell technology is limited by duration. Batteries and cell fuels are a good match for some missions, but other missions could benefit greatly by a longer duration. The goal is the following: to design nuclear systems to power an AUV and meet design constraints including non-proliferation issues, power level, size constraints, and power conversion limitations. The action plan is to continue development of a range of systems for terrestrial systems and focus onmore » a system for Titan Moon as alternative to Pu-238 for NASA.« less

Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression.

PubMed

Zhu, Kezhou; Liang, Wei; Ma, Zaijun; Xu, Daichao; Cao, Shuangyi; Lu, Xiaojuan; Liu, Nan; Shan, Bing; Qian, Lihui; Yuan, Junying

2018-04-27

Necroptosis, a form of regulated necrotic cell death, is mediated by receptor interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). However, the mechanism by which necroptosis promotes inflammation is still unclear. Here we report that the expression of cytokines is robustly upregulated in a cell-autonomous manner during necroptosis induced by tumor necrosis factor alpha (TNFα). We demonstrate that TNFα-induced necroptosis leads to two waves of cytokine production. The first wave, more transient and weaker than the second, is in response to TNFα alone; whereas the second wave depends upon the necroptotic signaling. We show that necroptosis promotes the transcription of TNFα-target genes in a cell-intrinsic manner. The activation of both NF-κB and p38 by the necroptotic machinery, RIPK1, RIPK3, and MLKL, is involved in mediating the robust induction of cytokine expression in the second wave. In contrast, necroptosis induced by direct oligomerization of MLKL promotes cytokine production at much lower levels than that of necroptosis induced with TNFα. Thus, we conclude that TNFα-induced necroptosis signaling events mediated by RIPK1 and RIPK3 activation, in addition to the MLKL oligomerization, promotes the expression of cytokines involving multiple intracellular signaling mechanisms including NF-κB pathway and p38. These findings reveal that the necroptotic cell death machinery mounts an immune response by promoting cell-autonomous production of cytokines. Our study provides insights into the mechanism by which necroptosis promotes inflammation in human diseases.

Small Leucine-Rich Proteoglycans in Renal Inflammation: Two Sides of the Coin.

PubMed

Nastase, Madalina V; Janicova, Andrea; Roedig, Heiko; Hsieh, Louise Tzung-Harn; Wygrecka, Malgorzata; Schaefer, Liliana

2018-04-01

It is now well-established that members of the small leucine-rich proteoglycan (SLRP) family act in their soluble form, released proteolytically from the extracellular matrix (ECM), as danger-associated molecular patterns (DAMPs). By interacting with Toll-like receptors (TLRs) and the inflammasome, the two SLRPs, biglycan and decorin, autonomously trigger sterile inflammation. Recent data indicate that these SLRPs, besides their conventional role as pro-inflammatory DAMPs, additionally trigger anti-inflammatory signaling pathways to tightly control inflammation. This is brought about by selective employment of TLRs, their co-receptors, various adaptor molecules, and through crosstalk between SLRP-, reactive oxygen species (ROS)-, and sphingolipid-signaling. In this review, the complexity of SLRP signaling in immune and kidney resident cells and its relevance for renal inflammation is discussed. We propose that the dichotomy in SLRP signaling (pro- and anti-inflammatory) allows for fine-tuning the inflammatory response, which is decisive for the outcome of inflammatory kidney diseases.

Erythrocytes Are Oxygen-Sensing Regulators of the Cerebral Microcirculation.

PubMed

Wei, Helen Shinru; Kang, Hongyi; Rasheed, Izad-Yar Daniel; Zhou, Sitong; Lou, Nanhong; Gershteyn, Anna; McConnell, Evan Daniel; Wang, Yixuan; Richardson, Kristopher Emil; Palmer, Andre Francis; Xu, Chris; Wan, Jiandi; Nedergaard, Maiken

2016-08-17

Energy production in the brain depends almost exclusively on oxidative metabolism. Neurons have small energy reserves and require a continuous supply of oxygen (O2). It is therefore not surprising that one of the hallmarks of normal brain function is the tight coupling between cerebral blood flow and neuronal activity. Since capillaries are embedded in the O2-consuming neuropil, we have here examined whether activity-dependent dips in O2 tension drive capillary hyperemia. In vivo analyses showed that transient dips in tissue O2 tension elicit capillary hyperemia. Ex vivo experiments revealed that red blood cells (RBCs) themselves act as O2 sensors that autonomously regulate their own deformability and thereby flow velocity through capillaries in response to physiological decreases in O2 tension. This observation has broad implications for understanding how local changes in blood flow are coupled to synaptic transmission. Copyright © 2016 Elsevier Inc. All rights reserved.

Design and Fabrication of an MRI-Compatible, Autonomous Incubation System.

PubMed

Khalilzad-Sharghi, Vahid; Xu, Huihui

2015-10-01

Tissue engineers have long sought access to an autonomous, imaging-compatible tissue incubation system that, with minimum operator handling, can provide real-time visualization and quantification of cells, tissue constructs, and organs. This type of screening system, capable of operating noninvasively to validate tissue, can overcome current limitations like temperature shock, unsustainable cellular environments, sample contamination, and handling/stress. However, this type of system has been a major challenge, until now. Here, we describe the design, fabrication, and characterization of an innovative, autonomous incubation system that is compatible with a 9.4 T magnetic resonance imaging (MRI) scanner. Termed the e-incubator (patent pending; application number: 13/953,984), this microcontroller-based system is integrated into an MRI scanner and noninvasively screens cells and tissue cultures in an environment where temperature, pH, and media/gas handling are regulated. The 4-week study discussed herein details the continuous operation of the e-incubator for a tissue-engineered osteogenic construct, validated by LIVE/DEAD(®) cell assays and histology. The evolving MR quantitative parameters of the osteogenic construct were used as biomarkers for bone tissue engineering and to further validate the quality of the product noninvasively before harvesting. Importantly, the e-incubator reliably facilitates culturing cells and tissue constructs to create engineered tissues and/or investigate disease therapies.

Quantifying Stochastic Noise in Cultured Circadian Reporter Cells

DOE PAGES

John, Peter C.; Doyle, III, Francis J.

2015-11-20

We report that stochastic noise at the cellular level has been shown to play a fundamental role in circadian oscillations, influencing how groups of cells entrain to external cues and likely serving as the mechanism by which cell-autonomous rhythms are generated. Despite this importance, few studies have investigated how clock perturbations affect stochastic noise—even as increasing numbers of high-throughput screens categorize how gene knockdowns or small molecules can change clock period and amplitude. This absence is likely due to the difficulty associated with measuring cell-autonomous stochastic noise directly, which currently requires the careful collection and processing of single-cell data. Inmore » this study, we show that the damping rate of population-level bioluminescence recordings can serve as an accurate measure of overall stochastic noise, and one that can be applied to future and existing high-throughput circadian screens. Using cell-autonomous fibroblast data, we first show directly that higher noise at the single-cell results in faster damping at the population level. Next, we show that the damping rate of cultured cells can be changed in a dose-dependent fashion by small molecule modulators, and confirm that such a change can be explained by single-cell noise using a mathematical model. We further demonstrate the insights that can be gained by applying our method to a genome-wide siRNA screen, revealing that stochastic noise is altered independently from period, amplitude, and phase. Finally, we hypothesize that the unperturbed clock is highly optimized for robust rhythms, as very few gene perturbations are capable of simultaneously increasing amplitude and lowering stochastic noise. Ultimately, this study demonstrates the importance of considering the effect of circadian perturbations on stochastic noise, particularly with regard to the development of small-molecule circadian therapeutics.« less

Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children

PubMed Central

Kroenke, Candyce H; Epel, Elissa; Adler, Nancy; Bush, Nicole R.; Obradović, Jelena; Lin, Jue; Blackburn, Elizabeth; Stamperdahl, Juliet Lise; Boyce, W. Thomas

2011-01-01

Objective To examine associations between autonomic nervous system and adrenocortical reactivity to laboratory stressors and buccal cell telomere length (BTL) in children. Methods The study sample comprised 78 five- and six-year-old children from a longitudinal cohort study of kindergarten social hierarchies, biological responses to adversity, and child health. Buccal cell samples and reactivity measures were collected in the spring of the kindergarten year. BTL was measured by realtime PCR, as the telomere-to-single copy gene (T/S) ratio. Parents provided demographic information; parents and teachers reported children’s internalizing and externalizing behavior problems. Components of children’s autonomic (heart rate (HR), respiratory sinus arrhythmia (RSA), pre-ejection period (PEP)) and adrenocortical (salivary cortisol) responses were monitored during standardized laboratory challenges. We examined relations between reactivity, internalizing and externalizing behavior, and BTL, adjusted for age, race, and gender. Results Heart rate and cortisol reactivity were inversely related to BTL, PEP was positively related to BTL, and RSA was unrelated. Internalizing behaviors were also inversely related to BTL (standardized β=−0.33, p=0.004). Split at the median of reactivity parameters, children with high sympathetic activation (decreasing PEP) and high parasympathetic withdrawal (decreasing RSA) did not differ with regard to BTL. However, children with both this profile and high cortisol reactivity (N=12) had significantly shorter BTL (0.80 vs. 1.00, χ2=7.6, p=0.006), compared with other children. Conclusions Autonomic and adrenocortical reactivity in combination were associated with shorter buccal cell telomere length in children. These data suggest that psychophysiological processes may influence, and that BTL may be a useful marker of, early biological aging. PMID:21873585

Autophagy induction for the treatment of cancer.

PubMed

Pietrocola, Federico; Pol, Jonathan; Vacchelli, Erika; Baracco, Elisa E; Levesque, Sarah; Castoldi, Francesca; Maiuri, Maria Chiara; Madeo, Frank; Kroemer, Guido

2016-10-02

Cancer can be viewed in 2 rather distinct ways, namely (i) as a cell-autonomous disease in which malignant cells have escaped control from cell-intrinsic barriers against proliferation and dissemination or (ii) as a systemic disease that involves failing immune control of aberrant cells. Since macroautophagy/autophagy generally increases the fitness of cells as well as their resistance against endogenous or iatrogenic (i.e., relating to illness due to medical intervention) stress, it has been widely proposed that inhibition of autophagy would constitute a valid strategy for sensitizing cancer cells to chemotherapy or radiotherapy. Colliding with this cell-autonomous vision, however, we found that immunosurveillance against transplantable, carcinogen-induced or genetically engineered cancers can be improved by pharmacologically inducing autophagy with caloric restriction mimetics. This positive effect depends on autophagy induction in cancer cells and is mediated by alterations in extracellular ATP metabolism, namely increased release of immunostimulatory ATP and reduced adenosine-dependent recruitment of immunosuppressive regulatory T cells into the tumor bed. The combination of autophagy inducers and chemotherapeutic agents is particularly efficient in reducing cancer growth through the stimulation of CD8 + T lymphocyte-dependent anticancer immune responses.

Cell-Autonomous Control of IL-7 Response Revealed In a Novel Stage of Precursor B Cells

PubMed Central

Sandoval, Gabriel J.; Graham, Daniel B.; Bhattacharya, Deepta; Sleckman, Barry P.; Xavier, Ramnik J.; Swat, Wojciech

2013-01-01

During early stages of B-lineage differentiation in bone marrow, signals emanating from IL-7 receptor and pre-B cell receptor (pre-BCR) are thought to synergistically induce proliferative expansion of progenitor cells. Paradoxically, loss of pre-BCR signaling components is associated with leukemia in both mice and humans. Exactly how progenitor B cells perform the task of balancing proliferative burst dependent on IL-7 with the termination of IL-7 signals and the initiation of LC gene rearrangement remains to be elucidated. In this report, we provide genetic and functional evidence that the cessation of IL-7 response of pre-B cells is controlled via a cell-autonomous mechanism that operates at a discreet developmental transition inside Fraction C’ (Large Pre-BII) marked by transient expression of c-Myc. Our data indicates that pre-BCR cooperates with IL-7R in expanding pre-B cell pool, but it is also critical to control differentiation program shutting off c-Myc gene in large pre-B cells. PMID:23420891

Vital Signs Evaluation of Human Behaviour via an Autonomous Body Area Network System

NASA Astrophysics Data System (ADS)

Hussin, S.; Takayama, S.

2016-11-01

Enhancing Quality of Life (QOL) has long been an explicit and implicit goal for individuals, nations, and the world. QOL involves diverse multidimensional factors spanning wealth, physical health, social well-being, and international relationships. This study presents a definition of QOL combining the measurement of health-related QOL with an autonomous Body Area Network System (BANs). A method of evaluating vital signs is performed and linked to physical intensity assistance in exercise. Specifically, BAN acts as a supportive system which can assist a user in monitoring his or her body's parameters, providing real-time feedbacks and dynamically sharing information from any location to one or more users.

Leech segmental repeats develop normally in the absence of signals from either anterior or posterior segments

NASA Technical Reports Server (NTRS)

Seaver, E. C.; Shankland, M.

2000-01-01

We have investigated whether the development of segmental repeats is autonomous in the embryo of the leech Helobdella robusta. The segmental tissues of the germinal band arise from progeny of five stem cells called teloblasts. Asymmetric divisions of the teloblasts form chains of segment founder cells (called primary blast cells) that divide in a stereotypical manner to produce differentiated descendants. Using two distinct techniques, we have looked for potential interactions between neighboring blast cell clones along the anterior-posterior axis. In one technique, we prevented the birth of primary blast cells by injection of DNase I into the teloblast, thereby depriving the last blast cell produced before the ablation of its normal posterior neighbors. We also ablated single blast cells with a laser microbeam, which allowed us to assess potential signals acting on either more anterior or more posterior primary blast cell clones. Our results suggest that interactions along the anterior-posterior axis between neighboring primary blast cell clones are not required for development of normal segmental organization within the blast cell clone. We also examined the possibility that blast cells receive redundant signals from both anterior and posterior neighboring clones and that either is sufficient for normal development. Using double blast cell laser ablations to isolate a primary blast cell clone by removal of both its anterior and its posterior neighbor, we found that the isolated clone still develops normally. These results reveal that the fundamental segmental repeat in the leech embryo, the primary blast cell clone, can develop normally in the apparent absence of signals from adjacent repeats along the anterior-posterior axis.

Dally Proteoglycan Mediates the Autonomous and Nonautonomous Effects on Tissue Growth Caused by Activation of the PI3K and TOR Pathways

PubMed Central

Ferreira, Ana; Milán, Marco

2015-01-01

How cells acquiring mutations in tumor suppressor genes outcompete neighboring wild-type cells is poorly understood. The phosphatidylinositol 3-kinase (PI3K)–phosphatase with tensin homology (PTEN) and tuberous sclerosis complex (TSC)-target of rapamycin (TOR) pathways are frequently activated in human cancer, and this activation is often causative of tumorigenesis. We utilized the Gal4-UAS system in Drosophila imaginal primordia, highly proliferative and growing tissues, to analyze the impact of restricted activation of these pathways on neighboring wild-type cell populations. Activation of these pathways leads to an autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations. This nonautonomous response occurs independently of where these pathways are activated, is functional all throughout development, takes place across compartments, and is distinct from cell competition. The observed autonomous and nonautonomous effects on tissue growth rely on the up-regulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor β(TGF-β) signaling molecule. Our findings indicate that a reduction in the amount of available growth factors contributes to the outcompetition of wild-type cells by overgrowing cell populations. During normal development, the PI3K/PTEN and TSC/TOR pathways play a major role in sensing nutrient availability and modulating the final size of any developing organ. We present evidence that Dally also contributes to integrating nutrient sensing and organ scaling, the fitting of pattern to size. PMID:26313758

Dual roles for FY in the regulation of FLC

PubMed Central

Feng, Wei

2011-01-01

In Arabidopsis, the flowering decision is determined by multiple pathways that integrate information from both endogenous signals and environmental cues. The genes of the autonomous pathway promote flowering by suppressing the expression of the floral repressor FLOWERING LOCUS C (FLC). Thus, autonomous-pathway mutants have elevated levels of FLC and are late flowering. Previous work has shown that two autonomous pathway proteins, FCA and FY, physically interact and this interaction is important in the repression of FLC. Recent work from our laboratory has shown that a hypomorphic allele of FY (fy-5) can cause earlier or later flowering, depending on the genetic background. These results suggest that FY has the potential to act as both an activator and a repressor of FLC. The FLC-activating activity of FY appears to be FCA-independent, as fy-5 causes earlier flowering in an fca-null background. Here we present a speculative model that reconciles these opposing phenotypes by proposing a dual role for FY in the regulation of flowering time. PMID:21633188

Dual roles for FY in the regulation of FLC.

PubMed

Feng, Wei; Michaels, Scott D

2011-05-01

In Arabidopsis, the flowering decision is determined by multiple pathways that integrate information from both endogenous signals and environmental cues. The genes of the autonomous pathway promote flowering by suppressing the expression of the floral repressor FLOWERING LOCUS C (FLC). Thus, autonomous-pathway mutants have elevated levels of FLC and are late flowering. Previous work has shown that two autonomous pathway proteins, FCA and FY, physically interact and this interaction is important in the repression of FLC. Recent work from our laboratory has shown that a hypomorphic allele of FY (fy-5) can cause earlier or later flowering, depending on the genetic background. These results suggest that FY has the potential to act as both an activator and a repressor of FLC. The FLC-activating activity of FY appears to be FCA-independent, as fy-5 causes earlier flowering in an fca-null background. Here we present a speculative model that reconciles these opposing phenotypes by proposing a dual role for FY in the regulation of flowering time.

Homeostatic systems, biocybernetics, and autonomic neuroscience.

PubMed

Goldstein, David S; Kopin, Irwin J

2017-12-01

In this review we describe a series of major concepts introduced during the past 150years that have contributed to our current understanding about how physiological processes required for well-being and survival are regulated. One can theorize that hierarchical networks involving input-output relationships continuously orchestrate and learn adaptive patterns of observable behaviors, cognition, memory, mood, and autonomic systems. Taken together, these networks function as "good regulators" determining levels of internal variables and act as if there were homeostatic comparators ("homeostats"). The consequences of models with vs. without homeostats remain the same in terms of allostatic load and the eventual switch from stabilizing negative feedback loops to destabilizing, pathogenic positive feedback loops. Understanding this switch seems important for comprehending senescence-related, neurodegenerative disorders that involve the autonomic nervous system. Our general proposal is that disintegration of homeostatic systems causes disorders of regulation in degenerative diseases and that medical cybernetics can inspire and rationalize new approaches to treatment and prevention. Published by Elsevier B.V.

Homo sapiens Systemic RNA Interference-defective-1 Transmembrane Family Member 1 (SIDT1) Protein Mediates Contact-dependent Small RNA Transfer and MicroRNA-21-driven Chemoresistance*

PubMed Central

Elhassan, Mohamed O.; Christie, Jennifer; Duxbury, Mark S.

2012-01-01

Locally initiated RNA interference (RNAi) has the potential for spatial propagation, inducing posttranscriptional gene silencing in distant cells. In Caenorhabditis elegans, systemic RNAi requires a phylogenetically conserved transmembrane channel, SID-1. Here, we show that a human SID-1 orthologue, SIDT1, facilitates rapid, contact-dependent, bidirectional small RNA transfer between human cells, resulting in target-specific non-cell-autonomous RNAi. Intercellular small RNA transfer can be both homotypic and heterotypic. We show SIDT1-mediated intercellular transfer of microRNA-21 to be a driver of resistance to the nucleoside analog gemcitabine in human adenocarcinoma cells. Documentation of a SIDT1-dependent small RNA transfer mechanism and the associated phenotypic effects on chemoresistance in human cancer cells raises the possibility that conserved systemic RNAi pathways contribute to the acquisition of drug resistance. Mediators of non-cell-autonomous RNAi may be tractable targets for novel therapies aimed at improving the efficacy of current cytotoxic agents. PMID:22174421

Extra-embryonic tissue spreading directs early embryo morphogenesis in killifish

PubMed Central

Reig, Germán; Cerda, Mauricio; Sepúlveda, Néstor; Flores, Daniela; Castañeda, Victor; Tada, Masazumi; Härtel, Steffen; Concha, Miguel L.

2017-01-01

The spreading of mesenchymal-like cell layers is critical for embryo morphogenesis and tissue repair, yet we know little of this process in vivo. Here we take advantage of unique developmental features of the non-conventional annual killifish embryo to study the principles underlying tissue spreading in a simple cellular environment, devoid of patterning signals and major morphogenetic cell movements. Using in vivo experimentation and physical modelling we reveal that the extra-embryonic epithelial enveloping cell layer, thought mainly to provide protection to the embryo, directs cell migration and the spreading of embryonic tissue during early development. This function relies on the ability of embryonic cells to couple their autonomous random motility to non-autonomous signals arising from the expansion of the extra-embryonic epithelium, mediated by cell membrane adhesion and tension. Thus, we present a mechanism of extra-embryonic control of embryo morphogenesis that couples the mechanical properties of adjacent tissues in the early killifish embryo. PMID:28580937

Islet-1 Controls the Differentiation of Retinal Bipolar and Cholinergic Amacrine Cells

PubMed Central

Elshatory, Yasser; Everhart, Drew; Deng, Min; Xie, Xiaoling; Barlow, Robert B.; Gan, Lin

2010-01-01

Whereas the mammalian retina possesses a repertoire of factors known to establish general retinal cell types, these factors alone cannot explain the vast diversity of neuronal subtypes. In other CNS regions, the differentiation of diverse neuronal pools is governed by coordinately acting LIM-homeodomain proteins including the Islet-class factor Islet-1 (Isl1). We report that deletion of Isl1 profoundly disrupts retinal function as assessed by electroretinograms and vision as assessed by optomotor behavior. These deficits are coupled with marked reductions in mature ON- and OFF-bipolar (>76%), cholinergic amacrine (93%), and ganglion (71%) cells. Mosaic deletion of Isl1 permitted a chimeric analysis of “wild-type” cells in a predominantly Isl1-null environment, demonstrating a cell-autonomous role for Isl1 in rod bipolar and cholinergic amacrine development. Furthermore, the effects on bipolar cell development appear to be dissociable from the preceding retinal ganglion cell loss, because Pou4f2-null mice are devoid of similar defects in bipolar cell marker expression. Expression of the ON- and OFF-bipolar cell differentiation factors Bhlhb4 and Vsx1, respectively, requires the presence of Isl1, whereas the early bipolar cell marker Prox1 initially did not. Thus, Isl1 is required for engaging bipolar differentiation pathways but not for general bipolar cell specification. Spatiotemporal expression analysis of additional LIM-homeobox genes identifies a LIM-homeobox gene network during bipolar cell development that includes Lhx3 and Lhx4. We conclude that Isl1 has an indispensable role in retinal neuron differentiation within restricted cell populations and this function may reflect a broader role for other LIM-homeobox genes in retinal development, and perhaps in establishing neuronal subtypes. PMID:18003851

A Multi-Robot Sense-Act Approach to Lead to a Proper Acting in Environmental Incidents

PubMed Central

Conesa-Muñoz, Jesús; Valente, João; del Cerro, Jaime; Barrientos, Antonio; Ribeiro, Angela

2016-01-01

Many environmental incidents affect large areas, often in rough terrain constrained by natural obstacles, which makes intervention difficult. New technologies, such as unmanned aerial vehicles, may help address this issue due to their suitability to reach and easily cover large areas. Thus, unmanned aerial vehicles may be used to inspect the terrain and make a first assessment of the affected areas; however, nowadays they do not have the capability to act. On the other hand, ground vehicles rely on enough power to perform the intervention but exhibit more mobility constraints. This paper proposes a multi-robot sense-act system, composed of aerial and ground vehicles. This combination allows performing autonomous tasks in large outdoor areas by integrating both types of platforms in a fully automated manner. Aerial units are used to easily obtain relevant data from the environment and ground units use this information to carry out interventions more efficiently. This paper describes the platforms and sensors required by this multi-robot sense-act system as well as proposes a software system to automatically handle the workflow for any generic environmental task. The proposed system has proved to be suitable to reduce the amount of herbicide applied in agricultural treatments. Although herbicides are very polluting, they are massively deployed on complete agricultural fields to remove weeds. Nevertheless, the amount of herbicide required for treatment is radically reduced when it is accurately applied on patches by the proposed multi-robot system. Thus, the aerial units were employed to scout the crop and build an accurate weed distribution map which was subsequently used to plan the task of the ground units. The whole workflow was executed in a fully autonomous way, without human intervention except when required by Spanish law due to safety reasons. PMID:27517934

Ready or Not: What Happens When We Treat Children as Small Adults.

ERIC Educational Resources Information Center

Hymowitz, Kay S.

Maintaining that profound transformations over the last 30 years in the way children look and act are connected to many troubling social problems, this book demonstrates how anticulturalism--the belief that children are autonomous, independent individuals discovering their own reality and that development occurs best independent of or in…

Students with Disabilities Who Contact the School Counselor for College Information

ERIC Educational Resources Information Center

Rainer, Paula L.

2012-01-01

The purpose of this study was to examine the characteristics of students with disabilities who contact the school counselor for college information. "Self-determination" was the theoretical framework guiding this study. Self-determination refers to a student's ability to (a) act autonomously, (b) identify goals, (c) engage in problem…

Development of Sensor Component for Terrain Evaluation and Obstacle Detection for an Unmanned Autonomous Vehicle

DTIC Science & Technology

2007-05-01

WALTER M. WALTZ SANDRA R. MEEKER, DR-IV Work Unit Manager Acting Chief, Force Protection Branch ___//signature...thank David Armstrong, for his support as a project manager . I thank Dr Mike Griffis, for putting all the efforts in building the NaviGator. I...21 Uncertainty Management

Is there consistency and specificity of autonomic changes during emotional episodes? Guidance from the conceptual act theory and psychophysiology

PubMed Central

Quigley, Karen S.; Barrett, Lisa Feldman

2014-01-01

The consistency and specificity of autonomic nervous system (ANS) responses during emotional episodes remains a topic of debate with relevance for emotional concordance. We present a recent model of how mental states are constructed, the Conceptual Act Theory (CAT), and then review findings from existing meta-analyses and a qualitative review along with studies using pattern classification of multivariate ANS patterns to determine if there is across-study evidence for consistency and specificity of ANS responses during emotional episodes. We conclude that there is thus far minimal evidence for ANS response consistency and specificity across studies. We then review the current understanding of the functional and anatomical features of ANS including its efferent and afferent connections with the central nervous system, which suggests the need to reformulate how we conceptualize ANS response consistency and specificity. We conclude by showing how this reformulation is consistent with the CAT, and how we suggest the model to propose when we would and would not expect to see consistency and specificity in ANS responses, and concordance more generally, during emotional episodes. PMID:24388802

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

PubMed Central

Karuppaiah, Kannan; Yu, Kai; Lim, Joohyun; Chen, Jianquan; Smith, Craig; Long, Fanxin

2016-01-01

ABSTRACT Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an ∼50% reduction in body weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cell-autonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth. PMID:27052727

GlioLab-a space system for Glioblastoma multiforme cells on orbit behavior study

NASA Astrophysics Data System (ADS)

Cappelletti, Chantal; Twiggs, Robert J.

Microgravity conditions and ionizing radiation pose significant health risks for human life in space. This is a concern for future missions and also for future space tourism flights. Nev-ertheless, at the same time it is very interesting to study the effects of these conditions in unhealthy organism like biological samples affected by cancer. It is possible that space envi-ronment increases, decreases or doesn't have any effect on cancer cells. In any case the test results give important informations about cancer treatment or space tourism flight for people affected by cancer. GlioLab is a joint project between GAUSS-Group of Astrodynamics at the "Sapienza" University of Roma and the Morehead State University (MSU) Space Science Center in Kentucky. The main goal of this project is the design and manufacturing of an autonomous space system to investigate potential effects of the space environment exposure on a human glioblastoma multiforme cell line derived from a 65-year-old male and on Normal Human Astrocytes (NHA). In particular the samples are Glioblastoma multiforme cancer cells because the radiotherapy using ionizing radiation is the only treatment after surgery that can give on ground an improvement on the survival rate for this very malignant cancer. During a mission on the ISS, GlioLab mission has to test the in orbit behavior of glioblastoma cancer cells and healthy neuronal cells, which are extremely fragile and require complex experimentation and testing. In this paper engineering solutions to design and manufacturing of an autonomous space system that can allow to keep alive these kind of cells are described. This autonomous system is characterized also by an optical device dedicated to cells behavior analysis and by microdosimeters for monitoring space radiation environment.

The transcription factor Foxg1 regulates the competence of telencephalic cells to adopt subpallial fates in mice

PubMed Central

Manuel, Martine; Martynoga, Ben; Yu, Tian; West, John D.; Mason, John O.; Price, David J.

2010-01-01

Summary Foxg1 is required for development of the ventral telencephalon in the embryonic mammalian forebrain. Although one existing hypothesis suggests that failed ventral telencephalic development in the absence of Foxg1 is due to reduced production of the morphogens sonic hedgehog (Shh) and fibroblast growth factor 8 (Fgf8), the possibility that telencephalic cells lacking Foxg1 are intrinsically incompetent to generate the ventral telencephalon has remained untested. We examined the ability of Foxg1−/− telencephalic cells to respond to Shh and Fgf8 by examining the expression of genes whose activation requires Shh or Fgf8 in vivo and by testing their responses to Shh and Fgf8 in culture. We found that many elements of the Shh and Fgf8 signalling pathways continue to function in the absence of Foxg1 but, nevertheless, we were unable to elicit normal responses of key ventral telencephalic marker genes in Foxg1−/− telencephalic tissue following a range of in vivo and in vitro manipulations. We explored the development of Foxg1−/− cells in Foxg1−/− Foxg1+/+ chimeric embryos that contained ventral telencephalon created by normally patterned wild-type cells. We found that Foxg1−/− cells contributed to the chimeric ventral telencephalon, but that they retained abnormal specification, expressing dorsal rather than ventral telencephalic markers. These findings indicate that, in addition to regulating the production of ventralising signals, Foxg1 acts cell-autonomously in the telencephalon to ensure that cells develop the competence to adopt ventral identities. PMID:20081193

Adeno-associated virus type 2 enhances goose parvovirus replication in embryonated goose eggs

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

Malkinson, Mertyn; Winocour, Ernest

The autonomous goose parvovirus (GPV) and the human helper-dependent adeno-associated virus type 2 (AAV2) share a high degree of homology. To determine if this evolutionary relationship has a biological impact, we studied viral replication in human 293 cells and in embryonated goose eggs coinfected with both viruses. Similar experiments were performed with the minute virus of mice (MVM), an autonomous murine parvovirus with less homology to AAV2. In human 293 cells, both GPV and MVM augmented AAV2 replication. In contrast, AAV2 markedly enhanced GPV replication in embryonated goose eggs under conditions where a similar effect was not observed with MVM.more » AAV2 did not replicate in embryonated goose eggs and AAV2 inactivated by UV-irradiation also enhanced GPV replication. To our knowledge, this is the first report that a human helper-dependent member of the Parvoviridae can provide helper activity for an autonomous parvovirus in a natural host.« less

Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

PubMed Central

Wang, Manqi; Wang, Qian; Whim, Matthew D.

2016-01-01

During fasting, activation of the counter-regulatory response (CRR) prevents hypoglycemia. A major effector arm is the autonomic nervous system that controls epinephrine release from adrenal chromaffin cells and, consequently, hepatic glucose production. However, whether modulation of autonomic function determines the relative strength of the CRR, and thus the ability to withstand food deprivation and maintain euglycemia, is not known. Here we show that fasting leads to altered transmission at the preganglionic → chromaffin cell synapse. The dominant effect is a presynaptic, long-lasting increase in synaptic strength. Using genetic and pharmacological approaches we show this plasticity requires neuropeptide Y, an adrenal cotransmitter and the activation of adrenal Y5 receptors. Loss of neuropeptide Y prevents a fasting-induced increase in epinephrine release and results in hypoglycemia in vivo. These findings connect plasticity within the sympathetic nervous system to a physiological output and indicate the strength of the final synapse in this descending pathway plays a decisive role in maintaining euglycemia. PMID:27092009

RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice.

PubMed

Song, Yurong; Sullivan, Teresa; Klarmann, Kimberly; Gilbert, Debra; O'Sullivan, T Norene; Lu, Lucy; Wang, Sophie; Haines, Diana C; Van Dyke, Terry; Keller, Jonathan R

2017-01-01

Thymic epithelial cells (TEC), as part of thymic stroma, provide essential growth factors/cytokines and self-antigens to support T cell development and selection. Deletion of Rb family proteins in adult thymic stroma leads to T cell hyperplasia in vivo. To determine whether deletion of Rb specifically in keratin (K) 18 positive TEC was sufficient for thymocyte hyperplasia, we conditionally inactivated Rb and its family members p107 and p130 in K18+ TEC in genetically engineered mice (TgK18GT121; K18 mice). We found that thymocyte hyperproliferation was induced in mice with Rb inactivation in K18+ TEC, while normal T cell development was maintained; suggesting that inactivation of Rb specifically in K18+ TEC was sufficient and responsible for the phenotype. Transplantation of wild type bone marrow cells into mice with Rb inactivation in K18+ TEC resulted in donor T lymphocyte hyperplasia confirming the non-cell autonomous requirement for Rb proteins in K18+ TEC in regulating T cell proliferation. Our data suggests that thymic epithelial cells play an important role in regulating lymphoid proliferation and thymus size.

Animal model of neuropathic tachycardia syndrome

NASA Technical Reports Server (NTRS)

Carson, R. P.; Appalsamy, M.; Diedrich, A.; Davis, T. L.; Robertson, D.

2001-01-01

Clinically relevant autonomic dysfunction can result from either complete or partial loss of sympathetic outflow to effector organs. Reported animal models of autonomic neuropathy have aimed to achieve complete lesions of sympathetic nerves, but incomplete lesions might be more relevant to certain clinical entities. We hypothesized that loss of sympathetic innervation would result in a predicted decrease in arterial pressure and a compensatory increase in heart rate. Increased heart rate due to loss of sympathetic innervation is seemingly paradoxical, but it provides a mechanistic explanation for clinical autonomic syndromes such as neuropathic postural tachycardia syndrome. Partially dysautonomic animals were generated by selectively lesioning postganglionic sympathetic neurons with 150 mg/kg 6-hydroxydopamine hydrobromide in male Sprague-Dawley rats. Blood pressure and heart rate were monitored using radiotelemetry. Systolic blood pressure decreased within hours postlesion (Delta>20 mm Hg). Within 4 days postlesion, heart rate rose and remained elevated above control levels. The severity of the lesion was determined functionally and pharmacologically by spectral analysis and responsiveness to tyramine. Low-frequency spectral power of systolic blood pressure was reduced postlesion and correlated with the diminished tyramine responsiveness (r=0.9572, P=0.0053). The tachycardia was abolished by treatment with the beta-antagonist propranolol, demonstrating that it was mediated by catecholamines acting on cardiac beta-receptors. Partial lesions of the autonomic nervous system have been hypothesized to underlie many disorders, including neuropathic postural tachycardia syndrome. This animal model may help us better understand the pathophysiology of autonomic dysfunction and lead to development of therapeutic interventions.

The effects of views of nature on autonomic control.

PubMed

Gladwell, V F; Brown, D K; Barton, J L; Tarvainen, M P; Kuoppa, P; Pretty, J; Suddaby, J M; Sandercock, G R H

2012-09-01

Previously studies have shown that nature improves mood and self-esteem and reduces blood pressure. Walking within a natural environment has been suggested to alter autonomic nervous system control, but the mechanisms are not fully understood. Heart rate variability (HRV) is a non-invasive method of assessing autonomic control and can give an insight into vagal modulation. Our hypothesis was that viewing nature alone within a controlled laboratory environment would induce higher levels of HRV as compared to built scenes. Heart rate (HR) and blood pressure (BP) were measured during viewing different scenes in a controlled environment. HRV was used to investigate alterations in autonomic activity, specifically parasympathetic activity. Each participant lay in the semi-supine position in a laboratory while we recorded 5 min (n = 29) of ECG, BP and respiration as they viewed two collections of slides (one containing nature views and the other built scenes). During viewing of nature, markers of parasympathetic activity were increased in both studies. Root mean squared of successive differences increased 4.2 ± 7.7 ms (t = 2.9, p = 0.008) and natural logarithm of high frequency increased 0.19 ± 0.36 ms(2) Hz(-1) (t = 2.9, p = 0.007) as compared to built scenes. Mean HR and BP were not significantly altered. This study provides evidence that autonomic control of the heart is altered by the simple act of just viewing natural scenes with an increase in vagal activity.

mTOR Signaling Confers Resistance to Targeted Cancer Drugs.

PubMed

Guri, Yakir; Hall, Michael N

2016-11-01

Cancer is a complex disease and a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, the clinical benefits of such drugs are at best transient due to tumors displaying intrinsic or adaptive resistance. The underlying compensatory pathways that allow cancer cells to circumvent a drug blockade are poorly understood. We review here recent studies suggesting that mammalian TOR (mTOR) signaling is a major compensatory pathway conferring resistance to many cancer drugs. mTOR-mediated resistance can be cell-autonomous or non-cell-autonomous. These findings suggest that mTOR signaling should be monitored routinely in tumors and that an mTOR inhibitor should be considered as a co-therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Cytokinins in Symbiotic Nodulation: When, Where, What For?

PubMed

Gamas, Pascal; Brault, Mathias; Jardinaud, Marie-Françoise; Frugier, Florian

2017-09-01

Substantial progress has been made in the understanding of early stages of the symbiotic interaction between legume plants and rhizobium bacteria. Those include the specific recognition of symbiotic partners, the initiation of bacterial infection in root hair cells, and the inception of a specific organ in the root cortex, the nodule. Increasingly complex regulatory networks have been uncovered in which cytokinin (CK) phytohormones play essential roles in different aspects of early symbiotic stages. Intriguingly, these roles can be either positive or negative, cell autonomous or non-cell autonomous, and vary, depending on time, root tissues, and possibly legume species. Recent developments on CK symbiotic functions and interconnections with other signaling pathways during nodule initiation are the focus of this review. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bacterial Unculturability and the Formation of Intercellular Metabolic Networks.

PubMed

Pande, Samay; Kost, Christian

2017-05-01

The majority of known bacterial species cannot be cultivated under laboratory conditions. Here we argue that the adaptive emergence of obligate metabolic interactions in natural bacterial communities can explain this pattern. Bacteria commonly release metabolites into the external environment. Accumulating pools of extracellular metabolites create an ecological niche that benefits auxotrophic mutants, which have lost the ability to autonomously produce the corresponding metabolites. In addition to a diffusion-based metabolite transfer, auxotrophic cells can use contact-dependent means to obtain nutrients from other co-occurring cells. Spatial colocalisation and a continuous coevolution further increase the nutritional dependency and optimise fluxes through combined metabolic networks. Thus, bacteria likely function as networks of interacting cells that reciprocally exchange nutrients and biochemical functions rather than as physiologically autonomous units. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease.

PubMed

Wang, Liqun; Xia, Jing; Li, Jonathan; Hagemann, Tracy L; Jones, Jeffrey R; Fraenkel, Ernest; Weitz, David A; Zhang, Su-Chun; Messing, Albee; Feany, Mel B

2018-05-15

Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis.

Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity.

PubMed

Marusyk, Andriy; Tabassum, Doris P; Altrock, Philipp M; Almendro, Vanessa; Michor, Franziska; Polyak, Kornelia

2014-10-02

Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumours. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumour phenotypes and the competitive expansion of individual clones. We found that tumour growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumour by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumour collapse. We developed a mathematical modelling framework to identify the rules underlying the generation of intra-tumour clonal heterogeneity. We found that non-cell-autonomous driving of tumour growth, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.

HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons.

PubMed

Heilman, Patrick L; Song, SungWon; Miranda, Carlos J; Meyer, Kathrin; Srivastava, Amit K; Knapp, Amy; Wier, Christopher G; Kaspar, Brian K; Kolb, Stephen J

2017-11-01

Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with hereditary neuropathy are unknown. HSPB1 also displays neuroprotective properties in many neuronal disease models, including the motor neuron disease amyotrophic lateral sclerosis (ALS). HSPB1 is upregulated in SOD1-ALS animal models during disease progression, predominately in glial cells. Glial cells are known to contribute to motor neuron loss in ALS through a non-cell autonomous mechanism. In this study, we examined the non-cell autonomous role of wild type and mutant HSPB1 in an astrocyte-motor neuron co-culture model system of ALS. Astrocyte-specific overexpression of wild type HSPB1 was sufficient to attenuate SOD1(G93A) astrocyte-mediated toxicity in motor neurons, whereas, overexpression of mutHSPB1 failed to ameliorate motor neuron toxicity. Expression of a phosphomimetic HSPB1 mutant in SOD1(G93A) astrocytes also reduced toxicity to motor neurons, suggesting that phosphorylation may contribute to HSPB1 mediated-neuroprotection. These data provide evidence that astrocytic HSPB1 expression may play a central role in motor neuron health and maintenance. Copyright © 2017 Elsevier Inc. All rights reserved.

Distinct gene networks modulate floral induction of autonomous maize and photoperiod-dependent teosinte.

PubMed

Minow, Mark A A; Ávila, Luis M; Turner, Katie; Ponzoni, Elena; Mascheretti, Iride; Dussault, Forest M; Lukens, Lewis; Rossi, Vincenzo; Colasanti, Joseph

2018-05-25

Temperate maize was domesticated from its tropical ancestor, teosinte. Whereas temperate maize is an autonomous day-neutral plant, teosinte is an obligate short-day plant that requires uninterrupted long nights to induce flowering. Leaf-derived florigenic signals trigger reproductive growth in both teosinte and temperate maize. To study the genetic mechanisms underlying floral inductive pathways in maize and teosinte, mRNA and small RNA genome-wide expression analyses were conducted on leaf tissue from plants that were induced or not induced to flower. Transcriptome profiles reveal common differentially expressed genes during floral induction, but a comparison of candidate flowering time genes indicates that photoperiod and autonomous pathways act independently. Expression differences in teosinte are consistent with the current paradigm for photoperiod-induced flowering, where changes in circadian clock output trigger florigen production. Conversely, differentially expressed genes in temperate maize link carbon partitioning and flowering, but also show altered expression of circadian clock genes that are distinct from those altered upon photoperiodic induction in teosinte. Altered miRNA399 levels in both teosinte and maize suggest a novel common connection between flowering and phosphorus perception. These findings provide insights into the molecular mechanisms underlying a strengthened autonomous pathway that enabled maize growth throughout temperate regions.

How simple autonomous decisions evolve into robust behaviours? A review from neurorobotics, cognitive, self-organized and artificial immune systems fields.

PubMed

Fernandez-Leon, Jose A; Acosta, Gerardo G; Rozenfeld, Alejandro

2014-10-01

Researchers in diverse fields, such as in neuroscience, systems biology and autonomous robotics, have been intrigued by the origin and mechanisms for biological robustness. Darwinian evolution, in general, has suggested that adaptive mechanisms as a way of reaching robustness, could evolve by natural selection acting successively on numerous heritable variations. However, is this understanding enough for realizing how biological systems remain robust during their interactions with the surroundings? Here, we describe selected studies of bio-inspired systems that show behavioral robustness. From neurorobotics, cognitive, self-organizing and artificial immune system perspectives, our discussions focus mainly on how robust behaviors evolve or emerge in these systems, having the capacity of interacting with their surroundings. These descriptions are twofold. Initially, we introduce examples from autonomous robotics to illustrate how the process of designing robust control can be idealized in complex environments for autonomous navigation in terrain and underwater vehicles. We also include descriptions of bio-inspired self-organizing systems. Then, we introduce other studies that contextualize experimental evolution with simulated organisms and physical robots to exemplify how the process of natural selection can lead to the evolution of robustness by means of adaptive behaviors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Dual-Schemata Model

NASA Astrophysics Data System (ADS)

Taniguchi, Tadahiro; Sawaragi, Tetsuo

In this paper, a new machine-learning method, called Dual-Schemata model, is presented. Dual-Schemata model is a kind of self-organizational machine learning methods for an autonomous robot interacting with an unknown dynamical environment. This is based on Piaget's Schema model, that is a classical psychological model to explain memory and cognitive development of human beings. Our Dual-Schemata model is developed as a computational model of Piaget's Schema model, especially focusing on sensori-motor developing period. This developmental process is characterized by a couple of two mutually-interacting dynamics; one is a dynamics formed by assimilation and accommodation, and the other dynamics is formed by equilibration and differentiation. By these dynamics schema system enables an agent to act well in a real world. This schema's differentiation process corresponds to a symbol formation process occurring within an autonomous agent when it interacts with an unknown, dynamically changing environment. Experiment results obtained from an autonomous facial robot in which our model is embedded are presented; an autonomous facial robot becomes able to chase a ball moving in various ways without any rewards nor teaching signals from outside. Moreover, emergence of concepts on the target movements within a robot is shown and discussed in terms of fuzzy logics on set-subset inclusive relationships.

Atrial Fibrillation: The Science behind Its Defiance

PubMed Central

Czick, Maureen E.; Shapter, Christine L.; Silverman, David I.

2016-01-01

Atrial fibrillation (AF) is the most prevalent arrhythmia in the world, due both to its tenacious treatment resistance, and to the tremendous number of risk factors that set the stage for the atria to fibrillate. Cardiopulmonary, behavioral, and psychological risk factors generate electrical and structural alterations of the atria that promote reentry and wavebreak. These culminate in fibrillation once atrial ectopic beats set the arrhythmia process in motion. There is growing evidence that chronic stress can physically alter the emotion centers of the limbic system, changing their input to the hypothalamic-limbic-autonomic network that regulates autonomic outflow. This leads to imbalance of the parasympathetic and sympathetic nervous systems, most often in favor of sympathetic overactivation. Autonomic imbalance acts as a driving force behind the atrial ectopy and reentry that promote AF. Careful study of AF pathophysiology can illuminate the means that enable AF to elude both pharmacological control and surgical cure, by revealing ways in which antiarrhythmic drugs and surgical and ablation procedures may paradoxically promote fibrillation. Understanding AF pathophysiology can also help clarify the mechanisms by which emerging modalities aiming to correct autonomic imbalance, such as renal sympathetic denervation, may offer potential to better control this arrhythmia. Finally, growing evidence supports lifestyle modification approaches as adjuncts to improve AF control. PMID:27699086

GAL4 transactivation-based assay for the detection of selective intercellular protein movement.

PubMed

Kumar, Dhinesh; Chen, Huan; Rim, Yeonggil; Kim, Jae-Yean

2015-01-01

Several plant proteins function as intercellular messenger to specify cell fate and coordinate plant development. Such intercellular communication can be achieved by direct, selective, or nonselective (diffusion-based) trafficking through plasmodesmata (PD), the symplasmic membrane-lined nanochannels adjoining two cells. A trichome rescue trafficking assay was reported to allow the detection of protein movement in Arabidopsis leaf tissue using transgenic gene expression. Here, we provide a protocol to dissect the mode of intercellular protein movement in Arabidopsis root. This assay system involves a root ground tissue-specific GAL4/UAS transactivation expression system in combination with fluorescent reporter proteins. In this system, mCherry, a red fluorescent protein, can move cell to cell via diffusion, while mCherry-H2B is tightly cell autonomous. Thus, a protein fused to mCherry-H2B that can move out from the site of synthesis likely contains a selective trafficking signal to impart a cell-to-cell gain-of-trafficking function to the cell-autonomous mCherry-H2B. This approach can be adapted to investigate the cell-to-cell trafficking properties of any protein of interest.

An intelligent algorithm for autonomous scientific sampling with the VALKYRIE cryobot

NASA Astrophysics Data System (ADS)

Clark, Evan B.; Bramall, Nathan E.; Christner, Brent; Flesher, Chris; Harman, John; Hogan, Bart; Lavender, Heather; Lelievre, Scott; Moor, Joshua; Siegel, Vickie

2018-07-01

The development of algorithms for agile science and autonomous exploration has been pursued in contexts ranging from spacecraft to planetary rovers to unmanned aerial vehicles to autonomous underwater vehicles. In situations where time, mission resources and communications are limited and the future state of the operating environment is unknown, the capability of a vehicle to dynamically respond to changing circumstances without human guidance can substantially improve science return. Such capabilities are difficult to achieve in practice, however, because they require intelligent reasoning to utilize limited resources in an inherently uncertain environment. Here we discuss the development, characterization and field performance of two algorithms for autonomously collecting water samples on VALKYRIE (Very deep Autonomous Laser-powered Kilowatt-class Yo-yoing Robotic Ice Explorer), a glacier-penetrating cryobot deployed to the Matanuska Glacier, Alaska (Mission Control location: 61°42'09.3''N 147°37'23.2''W). We show performance on par with human performance across a wide range of mission morphologies using simulated mission data, and demonstrate the effectiveness of the algorithms at autonomously collecting samples with high relative cell concentration during field operation. The development of such algorithms will help enable autonomous science operations in environments where constant real-time human supervision is impractical, such as penetration of ice sheets on Earth and high-priority planetary science targets like Europa.

Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children.

PubMed

Kroenke, Candyce H; Epel, Elissa; Adler, Nancy; Bush, Nicole R; Obradovic, Jelena; Lin, Jue; Blackburn, Elizabeth; Stamperdahl, Juliet Lise; Boyce, W Thomas

2011-09-01

To examine associations between autonomic nervous system and adrenocortical reactivity to laboratory stressors and buccal cell telomere length (BTL) in children. The study sample comprised 78 children, aged 5 to 6 years, from a longitudinal cohort study of kindergarten social hierarchies, biologic responses to adversity, and child health. Buccal cell samples and reactivity measures were collected in the spring of the kindergarten year. BTL was measured by real-time polymerase chain reaction, as the telomere-to-single-copy gene ratio. Parents provided demographic information; parents and teachers reported children's internalizing and externalizing behavior problems. Components of children's autonomic (heart rate, respiratory sinus arrhythmia [RSA], and preejection period [PEP]) and adrenocortical (salivary cortisol) responses were monitored during standardized laboratory challenges. We examined relationships between reactivity, internalizing and externalizing behaviors, and BTL, adjusted for age, race, and sex. Heart rate and cortisol reactivity were inversely related to BTL, PEP was positively related to BTL, and RSA was unrelated to BTL. Internalizing behaviors were also inversely related to BTL (standardized β = -0.33, p = .004). Split at the median of reactivity parameters, children with high sympathetic activation (decreasing PEP), and parasympathetic withdrawal (decreasing RSA) did not differ with regard to BTL. However, children with both this profile and high cortisol reactivity (n = 12) had significantly shorter BTL (0.80 versus 1.00; χ² = 7.6, p = .006), compared with other children. The combination of autonomic and adrenocortical reactivity was associated with shorter BTL in children. These data suggest that psychophysiological processes may influence, and that BTL may be a useful marker of, early biologic aging.

Materials learning from life: concepts for active, adaptive and autonomous molecular systems.

PubMed

Merindol, Rémi; Walther, Andreas

2017-09-18

Bioinspired out-of-equilibrium systems will set the scene for the next generation of molecular materials with active, adaptive, autonomous, emergent and intelligent behavior. Indeed life provides the best demonstrations of complex and functional out-of-equilibrium systems: cells keep track of time, communicate, move, adapt, evolve and replicate continuously. Stirred by the understanding of biological principles, artificial out-of-equilibrium systems are emerging in many fields of soft matter science. Here we put in perspective the molecular mechanisms driving biological functions with the ones driving synthetic molecular systems. Focusing on principles that enable new levels of functionalities (temporal control, autonomous structures, motion and work generation, information processing) rather than on specific material classes, we outline key cross-disciplinary concepts that emerge in this challenging field. Ultimately, the goal is to inspire and support new generations of autonomous and adaptive molecular devices fueled by self-regulating chemistry.

Autoantibody-mediated bowel and bladder dysfunction in a patient with chronic, nondiabetic neuropathy.

PubMed

Jackson, Michael W; Gordon, Thomas P; McCombe, Pamela A

2008-04-01

Physiological techniques can be used to detect novel autoantibodies causing alteration of autonomic function after passive transfer to mice. Previously, such antibodies have been detected in patients with type I diabetes mellitus, myasthenia gravis, and Sjogren's syndrome. We now describe a patient with an idiopathic nondiabetic neuropathy with prominent autonomic symptoms, including bladder and bowel dysfunction. Physiological assays of whole colon and bladder were used to determine the presence in the patient serum of functional autoantibodies capable of mediating autonomic dysfunction. Immunoglobulin G (IgG) from this patient was able to disrupt bladder and bowel function on passive transfer to mice. This is a new pattern of autoantibody-mediated abnormality. Although the target antigen is unknown, it is likely to be a cell-surface receptor or ion channel. This case highlights the usefulness of passive transfer studies in detecting functional antibodies in patients with autonomic neuropathy.

Genomic fossils reveal adaptation of non-autonomous pararetroviruses driven by concerted evolution of noncoding regulatory sequences.

PubMed

Chen, Sunlu; Zheng, Huizhen; Kishima, Yuji

2017-06-01

The interplay of different virus species in a host cell after infection can affect the adaptation of each virus. Endogenous viral elements, such as endogenous pararetroviruses (PRVs), have arisen from vertical inheritance of viral sequences integrated into host germline genomes. As viral genomic fossils, these sequences can thus serve as valuable paleogenomic data to study the long-term evolutionary dynamics of virus-virus interactions, but they have rarely been applied for this purpose. All extant PRVs have been considered autonomous species in their parasitic life cycle in host cells. Here, we provide evidence for multiple non-autonomous PRV species with structural defects in viral activity that have frequently infected ancient grass hosts and adapted through interplay between viruses. Our paleogenomic analyses using endogenous PRVs in grass genomes revealed that these non-autonomous PRV species have participated in interplay with autonomous PRVs in a possible commensal partnership, or, alternatively, with one another in a possible mutualistic partnership. These partnerships, which have been established by the sharing of noncoding regulatory sequences (NRSs) in intergenic regions between two partner viruses, have been further maintained and altered by the sequence homogenization of NRSs between partners. Strikingly, we found that frequent region-specific recombination, rather than mutation selection, is the main causative mechanism of NRS homogenization. Our results, obtained from ancient DNA records of viruses, suggest that adaptation of PRVs has occurred by concerted evolution of NRSs between different virus species in the same host. Our findings further imply that evaluation of within-host NRS interactions within and between populations of viral pathogens may be important.

Electrophysiological and morphological properties of pre-autonomic neurones in the rat hypothalamic paraventricular nucleus.

PubMed

Stern, J E

2001-11-15

1. The cellular properties of pre-autonomic neurones in the hypothalamic paraventricular nucleus (PVN) were characterized by combining in vivo retrograde tracing techniques, in vitro patch-clamp recordings and three-dimensional reconstruction of recorded neurones in adult hypothalamic slices. 2. The results showed that PVN pre-autonomic neurones constitute a heterogeneous neuronal population. Based on morphological criteria, neurones were classified into three subgroups. Type A neurones (52 %) were located in the ventral parvocellular (PaV) subnucleus, and showed an oblique orientation with respect to the third ventricle (3V). Type B neurones (25 %) were located in the posterior parvocellular (PaPo) subnucleus, and were oriented perpendicularly with respect to the 3V. Type C neurones (23 %) were located in both the PaPo (82 %) and the PaV (18 %) subnuclei, and displayed a concentric dendritic configuration. 3. A morphometric analysis revealed significant differences in the dendritic configuration among neuronal types. Type B neurones had the most complex dendritic arborization, with longer and more branching dendritic trees. 4. Several electrophysiological properties, including cell input resistance and action potential waveforms, differed between cell types, suggesting that the expression and/or properties of a variety of ion channels differ between neuronal types. 5. Common features of PVN pre-autonomic neurones included the expression of a low-threshold spike and strong inward rectification. These properties distinguished them from neighbouring magnocellular vasopressin neurones. 6. In summary, these results indicate that PVN pre-autonomic neurones constitute a heterogeneous neuronal population, and provide a cellular basis for the study of their involvement in the pathophysiology of hypertension and congestive heart failure disorders.

Electrophysiological and morphological properties of pre-autonomic neurones in the rat hypothalamic paraventricular nucleus

PubMed Central

Stern, Javier E

2001-01-01

The cellular properties of pre-autonomic neurones in the hypothalamic paraventricular nucleus (PVN) were characterized by combining in vivo retrograde tracing techniques, in vitro patch-clamp recordings and three-dimensional reconstruction of recorded neurones in adult hypothalamic slices. The results showed that PVN pre-autonomic neurones constitute a heterogeneous neuronal population. Based on morphological criteria, neurones were classified into three subgroups. Type A neurones (52 %) were located in the ventral parvocellular (PaV) subnucleus, and showed an oblique orientation with respect to the third ventricle (3V). Type B neurones (25 %) were located in the posterior parvocellular (PaPo) subnucleus, and were oriented perpendicularly with respect to the 3V. Type C neurones (23 %) were located in both the PaPo (82 %) and the PaV (18 %) subnuclei, and displayed a concentric dendritic configuration. A morphometric analysis revealed significant differences in the dendritic configuration among neuronal types. Type B neurones had the most complex dendritic arborization, with longer and more branching dendritic trees. Several electrophysiological properties, including cell input resistance and action potential waveforms, differed between cell types, suggesting that the expression and/or properties of a variety of ion channels differ between neuronal types. Common features of PVN pre-autonomic neurones included the expression of a low-threshold spike and strong inward rectification. These properties distinguished them from neighbouring magnocellular vasopressin neurones. In summary, these results indicate that PVN pre-autonomic neurones constitute a heterogeneous neuronal population, and provide a cellular basis for the study of their involvement in the pathophysiology of hypertension and congestive heart failure disorders. PMID:11711570

BRN 3.1 Knockouts Affect the Vestibular, Autonomic, and Circadian Rhythm Responses to 2G Exposure

NASA Technical Reports Server (NTRS)

Murakami, D. M.; Erkman, L.; Rosenfeld, M. G.; Fuller, C. A.

1999-01-01

Our previous studies have demonstrated that 2G exposure via centrifugation significantly attenuated the daily mean and circadian rhythm amplitude of rat body temperature (Tb), heart rate, and activity (Act). In addition, 2G exposure activates neural responses in several vestibular, autonomic, and circadian nuclei. Although we have characterized the effect of 2G on an animal's physiological, neuronal, and behavioral responses, it will be important to understand the underlying neural and physiological mechanisms that mediate those responses. For example, the vestibular responses, proprioceptive feedback, or fluid shifts may be the critical factors that mediate the responses to 2G. As a first step to understand the relative importance of these different response pathways to altered gravitational fields, this study examined the contribution of the vestibular system by utilizing an animal model from molecular biology. Brain 3.1 (Bm 3.1) is a POU domain homeobox gene involved in the normal development of the vestibular and auditory system. Brn 3.1 deletion results in a loss of hair cells in the otoliths, semicircular canals, and cochlea. As a result mice with a Brn 3.1 deletion do not have a functioning vestibular or auditory system. The BRN 3.1 knockout mouse could be a very useful animal model for isolating the role of the vestibular system in mediating the physiological responses to 2G exposure. Therefore, this study compared the effect of 2G exposure via centrifugation between Brn 3.1 knockout (KO) versus Wildtype (W) mice.

Two Principles of Early Moral Education: A Condition for the Law, Reflection and Autonomy

ERIC Educational Resources Information Center

Krek, Janez

2015-01-01

We establish the thesis that in moral education, particularly in the first years of the child's development, unreflexive acts or "unreflexiveness" in certain behaviours of adults is a condition for the development of the personality structure and virtues that enable autonomous ethical reflection and a relation to the Other. With the…

Measures of Autonomic Nervous System

DTIC Science & Technology

2011-04-01

activation encompass non-invasive tools, which measure cardiac, skin conductance, respiratory , and vascular activity. Choice of tools is dependent upon...digestion, excretion, and cardiac and respiratory activity. The ANS consists of the sympathetic and parasympathetic divisions and acts through a... respiratory cycles. Generally, these two systems should be seen as permanently modulating vital functions to achieve homeostasis. Since both systems are

Teaching Autonomy: The Obligations of Liberal Education in Plural Societies

ERIC Educational Resources Information Center

Kerr, Donald

2006-01-01

Existing conceptions of autonomy tend to fall to one of two criticisms: they either fail to capture our intuitive understanding that autonomy implies an ability to act congruently with the demands of justice and equality, or they are unclear as to whether particular actions must be good by some standard to be considered autonomous. In this article…

Responsibility beyond Rationality: The Case for Rhizomatic Consequentialism

ERIC Educational Resources Information Center

Stables, Andrew

2004-01-01

A key challenge for education is to encourage children to act responsibly. If "spiritual literacy" does not involve an autonomous, rational soul capable of "reading and writing the world as God intended", it must refer to ethical (and perhaps religious) capacity in relation to contingent actions in a context free of moral absolutes. In relation to…

Structural centrosome aberrations promote non-cell-autonomous invasiveness.

PubMed

Ganier, Olivier; Schnerch, Dominik; Oertle, Philipp; Lim, Roderick Yh; Plodinec, Marija; Nigg, Erich A

2018-05-02

Centrosomes are the main microtubule-organizing centers of animal cells. Although centrosome aberrations are common in tumors, their consequences remain subject to debate. Here, we studied the impact of structural centrosome aberrations, induced by deregulated expression of ninein-like protein (NLP), on epithelial spheres grown in Matrigel matrices. We demonstrate that NLP-induced structural centrosome aberrations trigger the escape ("budding") of living cells from epithelia. Remarkably, all cells disseminating into the matrix were undergoing mitosis. This invasive behavior reflects a novel mechanism that depends on the acquisition of two distinct properties. First, NLP-induced centrosome aberrations trigger a re-organization of the cytoskeleton, which stabilizes microtubules and weakens E-cadherin junctions during mitosis. Second, atomic force microscopy reveals that cells harboring these centrosome aberrations display increased stiffness. As a consequence, mitotic cells are pushed out of mosaic epithelia, particularly if they lack centrosome aberrations. We conclude that centrosome aberrations can trigger cell dissemination through a novel, non-cell-autonomous mechanism, raising the prospect that centrosome aberrations contribute to the dissemination of metastatic cells harboring normal centrosomes. © 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Effects of Elevated Pax6 Expression and Genetic Background on Mouse Eye Development

PubMed Central

Chanas, Simon A.; Collinson, J. Martin; Ramaesh, Thaya; Dorà, Natalie; Kleinjan, Dirk A.; Hill, Robert E.; West, John D.

2009-01-01

Purpose To analyze the effects of Pax6 overexpression and its interaction with genetic background on eye development. Methods Histologic features of eyes from hemizygous PAX77+/− transgenic (high Pax6 gene dose) and wild-type mice were compared on different genetic backgrounds. Experimental PAX77+/−↔wild-type and control wild-type↔wild-type chimeras were analyzed to investigate the causes of abnormal eye development in PAX77+/− mice. Results PAX77+/− mice showed an overlapping but distinct spectrum of eye abnormalities to Pax6+/− heterozygotes (low Pax6 dose). Some previously reported PAX77+/− eye abnormalities did not occur on all three genetic backgrounds examined. Several types of eye abnormalities occurred in the experimental PAX77+/−↔wild-type chimeras, and they occurred more frequently in chimeras with higher contributions of PAX77+/− cells. Groups of RPE cells intruded into the optic nerve sheath, indicating that the boundary between the retina and optic nerve may be displaced. Both PAX77+/− and wild-type cells were involved in this ingression and in retinal folds, suggesting that neither effect was cell-autonomous. Cell-autonomous effects included failure of PAX77+/− and wild-type cells to mix normally and overrepresentation of PAX77+/− in the lens epithelium and RPE. Conclusions The extent of PAX77+/− eye abnormalities depended on PAX77+/− genotype, genetic background, and stochastic variation. Chimera analysis identified two types of cell-autonomous effects of the PAX77+/− genotype. Abnormal cell mixing between PAX77+/− and wild-type cells suggests altered expression of cell surface adhesion molecules. Some phenotypic differences between PAX77+/−↔wild-type and Pax6+/−↔wild-type chimeras may reflect differences in the levels of PAX77+/− and Pax6+/− contributions to chimeric lenses. PMID:19387074

The many faces of autonomy.

PubMed

Gracia, Diego

2012-02-01

What does autonomy mean from a moral point of view? Throughout Western history, autonomy has had no less than four different meanings. The first is political: the capacity of old cities and modern states to give themselves their own laws. The second is metaphysical, and was introduced by Kant in the second half of the 18th century. In this meaning, autonomy is understood as an intrinsic characteristic of all rational beings. Opposed to this is the legal meaning, in which actions are called autonomous when performed with due information and competency and without coercion. This last meaning, the most frequently used in bioethics, is primarily legal instead of moral. Is there a proper moral meaning of the word autonomy? If so, this would be a fourth meaning. Acts can only be called moral when they are postconventional (using the terminology coined by Lawrence Kohlberg), inner-directed (as expressed by David Riesman), and responsible (according to Hannah Arendt). Such acts are autonomous in this new, fourth, and to my mind, the only one proper, moral meaning. The goal of ethics cannot be other than forming human beings capable of making autonomous and responsible decisions, and doing so because they think this is their duty and not because of any other nonmoral motivation, like comfort, convenience, or satisfaction. The goal of ethics is to promote postconventional and mature human beings. This was what Socrates tried to do with the young people of Athens. And it is also the objective of every course of ethics and of any process of training.

Human Induced Hepatic Lineage-Oriented Stem Cells: Autonomous Specification of Human iPS Cells toward Hepatocyte-Like Cells without Any Exogenous Differentiation Factors

PubMed Central

Yanagi, Satoshi; Kato, Chika; Takashima, Ryokichi; Kobayashi, Eiji; Hagiwara, Keitaro; Ochiya, Takahiro

2015-01-01

Preparing targeted cells for medical applications from human induced pluripotent stem cells (hiPSCs) using growth factors, compounds, or gene transfer has been challenging. Here, we report that human induced hepatic lineage-oriented stem cells (hiHSCs) were generated and expanded as a new type of hiPSC under non-typical coculture with feeder cells in a chemically defined hiPSC medium at a very high density. Self-renewing hiHSCs expressed markers of both human embryonic stem cells (hESCs) and hepatocytes. Those cells were highly expandable, markedly enhancing gene expression of serum hepatic proteins and cytochrome P450 enzymes with the omission of FGF-2 from an undefined hiPSC medium. The hepatic specification of hiHSCs was not attributable to the genetic and epigenetic backgrounds of the starting cells, as they were established from distinct donors and different types of cells. Approximately 90% of hiHSCs autonomously differentiated to hepatocyte-like cells, even in a defined minimum medium without any of the exogenous growth factors necessary for hepatic specification. After 12 days of this culture, the differentiated cells significantly enhanced gene expression of serum hepatic proteins (ALB, SERPINA1, TTR, TF, FABP1, FGG, AGT, RBP4, and AHSG), conjugating enzymes (UGT2B4, UGT2B7, UGT2B10, GSTA2, and GSTA5), transporters (SULT2A1, SLC13A5, and SLCO2B1), and urea cycle-related enzymes (ARG1 and CPS1). In addition, the hepatocyte-like cells performed key functions of urea synthesis, albumin secretion, glycogen storage, indocyanine green uptake, and low-density lipoprotein uptake. The autonomous hepatic specification of hiHSCs was due to their culture conditions (coculture with feeder cells in a defined hiPSC medium at a very high density) in self-renewal rather than in differentiation. These results suggest the feasibility of preparing large quantities of hepatocytes as a convenient and inexpensive hiPSC differentiation. Our study also suggests the necessity of optimizing culture conditions to generate other specific lineage-oriented hiPSCs, allowing for a very simple differentiation. PMID:25875613

Distinct subsets of Eve-positive pericardial cells stabilise cardiac outflow and contribute to Hox gene-triggered heart morphogenesis in Drosophila.

PubMed

Zmojdzian, Monika; de Joussineau, Svetlana; Da Ponte, Jean Philippe; Jagla, Krzysztof

2018-01-17

The Drosophila heart, composed of discrete subsets of cardioblasts and pericardial cells, undergoes Hox-triggered anterior-posterior morphogenesis, leading to a functional subdivision into heart proper and aorta, with its most anterior part forming a funnel-shaped cardiac outflow. Cardioblasts differentiate into Tin-positive 'working myocytes' and Svp-expressing ostial cells. However, developmental fates and functions of heart-associated pericardial cells remain elusive. Here, we show that the pericardial cells that express the transcription factor Even Skipped adopt distinct fates along the anterior-posterior axis. Among them, the most anterior Antp-Ubx-AbdA - negative cells form a novel cardiac outflow component we call the outflow hanging structure, whereas the Antp-expressing cells differentiate into wing heart precursors. Interestingly, Hox gene expression in the Even Skipped-positive cells not only underlies their antero-posterior diversification, but also influences heart morphogenesis in a non-cell-autonomous way. In brief, we identify a new cardiac outflow component derived from a subset of Even Skipped-expressing cells that stabilises the anterior heart tip, and demonstrate non-cell-autonomous effects of Hox gene expression in the Even Skipped-positive cells on heart morphogenesis. © 2018. Published by The Company of Biologists Ltd.

Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression.

PubMed

Chen, Limo; Gibbons, Don L; Goswami, Sangeeta; Cortez, Maria Angelica; Ahn, Young-Ho; Byers, Lauren A; Zhang, Xuejun; Yi, Xiaohui; Dwyer, David; Lin, Wei; Diao, Lixia; Wang, Jing; Roybal, Jonathon; Patel, Mayuri; Ungewiss, Christin; Peng, David; Antonia, Scott; Mediavilla-Varela, Melanie; Robertson, Gordon; Suraokar, Milind; Welsh, James W; Erez, Baruch; Wistuba, Ignacio I; Chen, Lieping; Peng, Di; Wang, Shanshan; Ullrich, Stephen E; Heymach, John V; Kurie, Jonathan M; Qin, F Xiao-Feng

2014-10-28

Immunosuppression of tumour-infiltrating lymphocytes (TIL) is a common feature of advanced cancer, but its biological basis has remained obscure. We demonstrate here a molecular link between epithelial-to-mesenchymal transition (EMT) and CD8(+) TIL immunosuppression, two key drivers of cancer progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumour cells, leading to CD8(+) T-cell immunosuppression and metastasis. These findings are supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets. In addition to revealing a link between EMT and T-cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists.

Preliminary Design of an Autonomous Underwater Vehicle Using Multi-Objective Optimization

DTIC Science & Technology

2014-03-01

fuel cell PC propulsive coefficient PEMFC proton exchange membrane fuel cell PHP propulsive horsepower PO Pareto optimal PSO particle swarm...membrane fuel cell ( PEMFC ), molten carbonate fuel cell (MCFC), solid oxide fuel cell (SOFC) and direct and indirect methanol fuel cell (DMFC). Figure...of fuel cells in depth, I will note that PEMFCs are smaller and have a lower operating temperature compared to the other types. Those are the main

Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

PubMed Central

Risson, Valérie; Mazelin, Laetitia; Roceri, Mila; Sanchez, Hervé; Moncollin, Vincent; Corneloup, Claudine; Richard-Bulteau, Hélène; Vignaud, Alban; Baas, Dominique; Defour, Aurélia; Freyssenet, Damien; Tanti, Jean-François; Le-Marchand-Brustel, Yannick; Ferrier, Bernard; Conjard-Duplany, Agnès; Romanino, Klaas; Bauché, Stéphanie; Hantaï, Daniel; Mueller, Matthias; Kozma, Sara C.; Thomas, George; Rüegg, Markus A.; Ferry, Arnaud; Pende, Mario; Bigard, Xavier; Koulmann, Nathalie

2009-01-01

Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent. PMID:20008564

Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons

PubMed Central

Soler-Llavina, Gilberto J.; Fuccillo, Marc V.; Malenka, Robert C.; Südhof, Thomas C.

2011-01-01

Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic cell adhesion molecules that bind to presynaptic neurexins. In this paper, we show that short hairpin ribonucleic acid–mediated knockdowns (KDs) of LRRTM1, LRRTM2, and/or NL-3, alone or together as double or triple KDs (TKDs) in cultured hippocampal neurons, did not decrease synapse numbers. In neurons cultured from NL-1 knockout mice, however, TKD of LRRTMs and NL-3 induced an ∼40% loss of excitatory but not inhibitory synapses. Strikingly, synapse loss triggered by the LRRTM/NL deficiency was abrogated by chronic blockade of synaptic activity as well as by chronic inhibition of Ca2+ influx or Ca2+/calmodulin (CaM) kinases. Furthermore, postsynaptic KD of CaM prevented synapse loss in a cell-autonomous manner, an effect that was reversed by CaM rescue. Our results suggest that two neurexin ligands, LRRTMs and NLs, act redundantly to maintain excitatory synapses and that synapse elimination caused by the absence of NLs and LRRTMs is promoted by synaptic activity and mediated by a postsynaptic Ca2+/CaM-dependent signaling pathway. PMID:21788371

Epithelial and ectomesenchymal role of the type I TGF-β receptor ALK5 during facial morphogenesis and palatal fusion

PubMed Central

Dudas, Marek; Kim, Jieun; Li, Wai-Yee; Nagy, Andre; Larsson, Jonas; Karlsson, Stefan; Chai, Yang; Kaartinen, Vesa

2006-01-01

Transforming growth factor beta (TGF-β) proteins play important roles in morphogenesis of many craniofacial tissues; however, detailed biological mechanisms of TGF-β action, particularly in vivo, are still poorly understood. Here, we deleted the TGF-β type I receptor gene Alk5 specifically in the embryonic ectodermal and neural crest cell lineages. Failure in signaling via this receptor, either in the epithelium or in the mesenchyme, caused severe craniofacial defects including cleft palate. Moreover, the facial phenotypes of neural crest-specific Alk5 mutants included devastating facial cleft and appeared significantly more severe than the defects seen in corresponding mutants lacking the TGF-β type II receptor (TGFβRII), a prototypical binding partner of ALK5. Our data indicate that ALK5 plays unique, non-redundant cell-autonomous roles during facial development. Remarkable divergence between Tgfbr2 and Alk5 phenotypes, together with our biochemical in vitro data, imply that (1) ALK5 mediates signaling of a diverse set of ligands not limited to the three isoforms of TGF-β, and (2) ALK5 acts also in conjunction with type II receptors other than TGFβRII. PMID:16806156

Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease

PubMed Central

Lennon, Vanda A.; Ermilov, Leonid G.; Szurszewski, Joseph H.; Vernino, Steven

2003-01-01

Neuronal nicotinic AChRs (nAChRs) are implicated in the pathogenesis of diverse neurological disorders and in the regulation of small-cell lung carcinoma growth. Twelve subunits have been identified in vertebrates, and mutations of one are recognized in a rare form of human epilepsy. Mice with genetically manipulated neuronal nAChR subunits exhibit behavioral or autonomic phenotypes. Here, we report the first model of an acquired neuronal nAChR disorder and evidence for its pertinence to paraneoplastic neurological autoimmunity. Rabbits immunized once with recombinant α3 subunit (residues 1–205) develop profound gastrointestinal hypomotility, dilated pupils with impaired light response, and grossly distended bladders. As in patients with idiopathic and paraneoplastic autoimmune autonomic neuropathy, the severity parallels serum levels of ganglionic nAChR autoantibody. Failure of neurotransmission through abdominal sympathetic ganglia, with retention of neuronal viability, confirms that the disorder is a postsynaptic channelopathy. In addition, we found ganglionic nAChR protein in small-cell carcinoma lines, identifying this cancer as a potential initiator of ganglionic nAChR autoimmunity. The data support our hypothesis that immune responses driven by distinct neuronal nAChR subtypes expressed in small-cell carcinomas account for several lung cancer–related paraneoplastic disorders affecting cholinergic systems, including autoimmune autonomic neuropathy, seizures, dementia, and movement disorders. PMID:12639997

Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia.

PubMed

Schäfer, M; Schäfer, C; Ewald, N; Piper, H M; Noll, Th

2003-05-16

Endothelial cells exhibit an autonomous proliferative response to hypoxia, independent of paracrine effectors. In cultured endothelial cells of porcine aorta, we analyzed the signaling of this response, with a focus on the roles of redox signaling and the MEK/ERK pathway. Transient hypoxia (1 hour) stimulated proliferation by 61+/-4% (n=16; P<0.05 versus control), quantified after 24 hours normoxic postincubation. Hypoxia induced an activation of ERK2 and of NAD(P)H oxidase and a burst of reactive oxygen species (ROS), determined by DCF fluorescence. To inhibit the MEK/ERK pathway, we used PD 98059 (PD, 20 micromol/L); to downregulate NAD(P)H oxidase, we applied p22phox antisense oligonucleotides; and to inhibit mitochondrial ROS generation, we used the ubiquinone derivate mitoQ (MQ, 10 micromol/L). All three inhibitions suppressed the proliferative response: PD inhibited NAD(P)H oxidase activation; p22phox antisense transfection did not inhibit ERK2 activation, but suppressed ROS production; and MQ inhibited ERK2 activation and ROS production. The autonomous proliferative response depends on the MEK/ERK pathway and redox signaling steps upstream and downstream of ERK. Located upstream is ROS generation by mitochondria, downstream is NAD(P)H oxidase.

Delayed innocent bystander cell death following hypoxia in Caenorhabditis elegans

PubMed Central

Sun, C-L; Kim, E; Crowder, C M

2014-01-01

After hypoxia, cells may die immediately or have a protracted course, living or dying depending on an incompletely understood set of cell autonomous and nonautonomous factors. In stroke, for example, some neurons are thought to die from direct hypoxic injury by cell autonomous primary mechanisms, whereas other so called innocent bystander neurons die from factors released from the primarily injured cells. A major limitation in identifying these factors is the inability of current in vivo models to selectively target a set of cells for hypoxic injury so that the primarily injured cells and the innocent bystanders are clearly delineated. In order to develop such a model, we generated transgenic Caenorhabditis elegans strains where 2–3% of somatic cells were made selectively sensitive to hypoxia. This was accomplished by cell type-specific wild-type rescue in either pharyngeal myocytes or GABAergic neurons of a hypoxia resistance-producing translation factor mutation. Surprisingly, hypoxic targeting of these relatively small subsets of non-essential cells produced widespread innocent bystander cell injury, behavioral dysfunction and eventual organismal death. The hypoxic injury phenotypes of the myocyte or neuron sensitized strains were virtually identical. Using this model, we show that the C. elegans insulin receptor/FOXO transcription factor pathway improves survival when activated only after hypoxic injury and blocks innocent bystander death. PMID:24317200

Delayed innocent bystander cell death following hypoxia in Caenorhabditis elegans.

PubMed

Sun, C-L; Kim, E; Crowder, C M

2014-04-01

After hypoxia, cells may die immediately or have a protracted course, living or dying depending on an incompletely understood set of cell autonomous and nonautonomous factors. In stroke, for example, some neurons are thought to die from direct hypoxic injury by cell autonomous primary mechanisms, whereas other so called innocent bystander neurons die from factors released from the primarily injured cells. A major limitation in identifying these factors is the inability of current in vivo models to selectively target a set of cells for hypoxic injury so that the primarily injured cells and the innocent bystanders are clearly delineated. In order to develop such a model, we generated transgenic Caenorhabditis elegans strains where 2-3% of somatic cells were made selectively sensitive to hypoxia. This was accomplished by cell type-specific wild-type rescue in either pharyngeal myocytes or GABAergic neurons of a hypoxia resistance-producing translation factor mutation. Surprisingly, hypoxic targeting of these relatively small subsets of non-essential cells produced widespread innocent bystander cell injury, behavioral dysfunction and eventual organismal death. The hypoxic injury phenotypes of the myocyte or neuron sensitized strains were virtually identical. Using this model, we show that the C. elegans insulin receptor/FOXO transcription factor pathway improves survival when activated only after hypoxic injury and blocks innocent bystander death.

Motivation Counts: Autonomous But Not Obligated Sharing Promotes Happiness in Preschoolers.

PubMed

Wu, Zhen; Zhang, Zhen; Guo, Rui; Gros-Louis, Julie

2017-01-01

Research has demonstrated that prosocial sharing is emotionally rewarding, which leads to further prosocial actions; such a positive feedback loop suggests a proximal mechanism of human's tendency to act prosocially. However, it leaves open a question as to how the emotional benefits from sharing develop in young children and whether sharing under pressure promotes happiness as well. The current study directly compared 3- and 5-year-old Chinese children's happiness when sharing was autonomous (the recipient did not contribute to getting the reward) with when sharing was obligated (the recipient and the actor jointly earned the reward). We found that children shared more items overall when sharing was obligated than autonomous, demonstrating their conformity to social norms of merit-based sharing. In children who eventually shared with others, 5-year-olds gave out more stickers in the obligated sharing condition than in the autonomous sharing condition, but 3-year-olds shared the same amount between the conditions, suggesting that 5-year-olds adhered to the merit-based sharing norm more strictly than 3-year-olds. Moreover, in the autonomous sharing condition, children displayed greater happiness when they shared with the recipient than when they kept stickers for themselves, suggesting that costly prosocial giving benefited children with positive mood; however, children did not gain happiness when they shared with the recipient in the obligated sharing condition. These findings demonstrate that children's affective benefits depend on the motivation underlying their prosocial behavior, and further imply that normative force and emotional gains may independently drive preschoolers' prosocial behaviors.

Motivation Counts: Autonomous But Not Obligated Sharing Promotes Happiness in Preschoolers

PubMed Central

Wu, Zhen; Zhang, Zhen; Guo, Rui; Gros-Louis, Julie

2017-01-01

Research has demonstrated that prosocial sharing is emotionally rewarding, which leads to further prosocial actions; such a positive feedback loop suggests a proximal mechanism of human’s tendency to act prosocially. However, it leaves open a question as to how the emotional benefits from sharing develop in young children and whether sharing under pressure promotes happiness as well. The current study directly compared 3- and 5-year-old Chinese children’s happiness when sharing was autonomous (the recipient did not contribute to getting the reward) with when sharing was obligated (the recipient and the actor jointly earned the reward). We found that children shared more items overall when sharing was obligated than autonomous, demonstrating their conformity to social norms of merit-based sharing. In children who eventually shared with others, 5-year-olds gave out more stickers in the obligated sharing condition than in the autonomous sharing condition, but 3-year-olds shared the same amount between the conditions, suggesting that 5-year-olds adhered to the merit-based sharing norm more strictly than 3-year-olds. Moreover, in the autonomous sharing condition, children displayed greater happiness when they shared with the recipient than when they kept stickers for themselves, suggesting that costly prosocial giving benefited children with positive mood; however, children did not gain happiness when they shared with the recipient in the obligated sharing condition. These findings demonstrate that children’s affective benefits depend on the motivation underlying their prosocial behavior, and further imply that normative force and emotional gains may independently drive preschoolers’ prosocial behaviors. PMID:28620328

Distinct and Atypical Intrinsic and Extrinsic Cell Death Pathways between Photoreceptor Cell Types upon Specific Ablation of Ranbp2 in Cone Photoreceptors

PubMed Central

Cho, Kyoung-in; Yu, Minzhong; Hao, Ying; Qiu, Sunny; Pillai, Indulekha C. L.; Peachey, Neal S.; Ferreira, Paulo A.

2013-01-01

Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (Ranbp2), a cell context-dependent pleiotropic protein linked to neuroprotection, familial necrotic encephalopathies, acute transverse myelitis and tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of metalloproteinase 11/stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of caspase-7 without apoptosis. Conversely, PARP1+-apoptotic rods develop upon sequential activation of caspase-9 and caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct retinal spatial signatures as well as with other etiologically distinct neurodegenerative disorders. PMID:23818861

Extrinsic Repair of Injured Dendrites as a Paradigm for Regeneration by Fusion in Caenorhabditis elegans

PubMed Central

Oren-Suissa, Meital; Gattegno, Tamar; Kravtsov, Veronika; Podbilewicz, Benjamin

2017-01-01

Injury triggers regeneration of axons and dendrites. Research has identified factors required for axonal regeneration outside the CNS, but little is known about regeneration triggered by dendrotomy. Here, we study neuronal plasticity triggered by dendrotomy and determine the fate of complex PVD arbors following laser surgery of dendrites. We find that severed primary dendrites grow toward each other and reconnect via branch fusion. Simultaneously, terminal branches lose self-avoidance and grow toward each other, meeting and fusing at the tips via an AFF-1-mediated process. Ectopic branch growth is identified as a step in the regeneration process required for bypassing the lesion site. Failure of reconnection to the severed dendrites results in degeneration of the distal end of the neuron. We discover pruning of excess branches via EFF-1 that acts to recover the original wild-type arborization pattern in a late stage of the process. In contrast, AFF-1 activity during dendritic auto-fusion is derived from the lateral seam cells and not autonomously from the PVD neuron. We propose a model in which AFF-1-vesicles derived from the epidermal seam cells fuse neuronal dendrites. Thus, EFF-1 and AFF-1 fusion proteins emerge as new players in neuronal arborization and maintenance of arbor connectivity following injury in Caenorhabditis elegans. Our results demonstrate that there is a genetically determined multi-step pathway to repair broken dendrites in which EFF-1 and AFF-1 act on different steps of the pathway. EFF-1 is essential for dendritic pruning after injury and extrinsic AFF-1 mediates dendrite fusion to bypass injuries. PMID:28283540

ADAM10 regulates Notch function in intestinal stem cells of mice.

PubMed

Tsai, Yu-Hwai; VanDussen, Kelli L; Sawey, Eric T; Wade, Alex W; Kasper, Chelsea; Rakshit, Sabita; Bhatt, Riha G; Stoeck, Alex; Maillard, Ivan; Crawford, Howard C; Samuelson, Linda C; Dempsey, Peter J

2014-10-01

A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a cell surface sheddase that regulates physiologic processes, including Notch signaling. ADAM10 is expressed in all intestinal epithelial cell types, but the requirement for ADAM10 signaling in crypt homeostasis is not well defined. We analyzed intestinal tissues from mice with constitutive (Vil-Cre;Adam10(f/f) mice) and conditional (Vil-CreER;Adam10(f/f) and Leucine-rich repeat-containing GPCR5 [Lgr5]-CreER;Adam10(f/f) mice) deletion of ADAM10. We performed cell lineage-tracing experiments in mice that expressed a gain-of-function allele of Notch in the intestine (Rosa26(NICD)), or mice with intestine-specific disruption of Notch (Rosa26(DN-MAML)), to examine the effects of ADAM10 deletion on cell fate specification and intestinal stem cell maintenance. Loss of ADAM10 from developing and adult intestine caused lethality associated with altered intestinal morphology, reduced progenitor cell proliferation, and increased secretory cell differentiation. ADAM10 deletion led to the replacement of intestinal cell progenitors with 2 distinct, post-mitotic, secretory cell lineages: intermediate-like (Paneth/goblet) and enteroendocrine cells. Based on analysis of Rosa26(NICD) and Rosa26(DN-MAML) mice, we determined that ADAM10 controls these cell fate decisions by regulating Notch signaling. Cell lineage-tracing experiments showed that ADAM10 is required for survival of Lgr5(+) crypt-based columnar cells. Our findings indicate that Notch-activated stem cells have a competitive advantage for occupation of the stem cell niche. ADAM10 acts in a cell autonomous manner within the intestinal crypt compartment to regulate Notch signaling. This process is required for progenitor cell lineage specification and crypt-based columnar cell maintenance. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

A mechanistic framework for noncell autonomous stem cell induction in Arabidopsis.

PubMed

Daum, Gabor; Medzihradszky, Anna; Suzaki, Takuya; Lohmann, Jan U

2014-10-07

Cell-cell communication is essential for multicellular development and, consequently, evolution has brought about an array of distinct mechanisms serving this purpose. Consistently, induction and maintenance of stem cell fate by noncell autonomous signals is a feature shared by many organisms and may depend on secreted factors, direct cell-cell contact, matrix interactions, or a combination of these mechanisms. Although many basic cellular processes are well conserved between animals and plants, cell-to-cell signaling is one function where substantial diversity has arisen between the two kingdoms of life. One of the most striking differences is the presence of cytoplasmic bridges, called plasmodesmata, which facilitate the exchange of molecules between neighboring plant cells and provide a unique route for cell-cell communication in the plant lineage. Here, we provide evidence that the stem cell inducing transcription factor WUSCHEL (WUS), expressed in the niche, moves to the stem cells via plasmodesmata in a highly regulated fashion and that this movement is required for WUS function and, thus, stem cell activity in Arabidopsis thaliana. We show that cell context-independent mobility is encoded in the WUS protein sequence and mediated by multiple domains. Finally, we demonstrate that parts of the protein that restrict movement are required for WUS homodimerization, suggesting that formation of WUS dimers might contribute to the regulation of apical stem cell activity.

Association Between Autonomic Impairment and Structural Deficit in Parkinson Disease

PubMed Central

Chen, Meng-Hsiang; Lu, Cheng-Hsien; Chen, Pei-Chin; Tsai, Nai-Wen; Huang, Chih-Cheng; Chen, Hsiu-Ling; Yang, I-Hsiao; Yu, Chiun-Chieh; Lin, Wei-Che

2016-01-01

Abstract Patients with Parkinson disease (PD) have impaired autonomic function and altered brain structure. This study aimed to evaluate the relationship of gray matter volume (GMV) determined by voxel-based morphometry (VBM) to autonomic impairment in patients with PD. Whole-brain VBM analysis was performed on 3-dimensional T1-weighted images in 23 patients with PD and 15 sex- and age-matched healthy volunteers. The relationship of cardiovascular autonomic function (determined by survey) to baroreflex sensitivity (BRS) (determined from changes in heart rate and blood pressure during the early phase II of the Valsalva maneuver) was tested using least-squares regression analysis. The differences in GMV, autonomic parameters, and clinical data were correlated after adjusting for age and sex. Compared with controls, patients with PD had low BRS, suggesting worse cardiovascular autonomic function, and smaller GMV in several brain locations, including the right amygdala, left hippocampal formation, bilateral insular cortex, bilateral caudate nucleus, bilateral cerebellum, right fusiform, and left middle frontal gyri. The decreased GMVs of the selected brain regions were also associated with increased presence of epithelial progenitor cells (EPCs) in the circulation. In patients with PD, decrease in cardiovascular autonomic function and increase in circulating EPC level are associated with smaller GMV in several areas of the brain. Because of its possible role in the modulation of the circulatory EPC pool and baroreflex control, the left hippocampal formation may be a bio-target for disease-modifying therapy and treatment monitoring in PD. PMID:26986144

Association Between Autonomic Impairment and Structural Deficit in Parkinson Disease.

PubMed

Chen, Meng-Hsiang; Lu, Cheng-Hsien; Chen, Pei-Chin; Tsai, Nai-Wen; Huang, Chih-Cheng; Chen, Hsiu-Ling; Yang, I-Hsiao; Yu, Chiun-Chieh; Lin, Wei-Che

2016-03-01

Patients with Parkinson disease (PD) have impaired autonomic function and altered brain structure. This study aimed to evaluate the relationship of gray matter volume (GMV) determined by voxel-based morphometry (VBM) to autonomic impairment in patients with PD. Whole-brain VBM analysis was performed on 3-dimensional T1-weighted images in 23 patients with PD and 15 sex- and age-matched healthy volunteers. The relationship of cardiovascular autonomic function (determined by survey) to baroreflex sensitivity (BRS) (determined from changes in heart rate and blood pressure during the early phase II of the Valsalva maneuver) was tested using least-squares regression analysis. The differences in GMV, autonomic parameters, and clinical data were correlated after adjusting for age and sex. Compared with controls, patients with PD had low BRS, suggesting worse cardiovascular autonomic function, and smaller GMV in several brain locations, including the right amygdala, left hippocampal formation, bilateral insular cortex, bilateral caudate nucleus, bilateral cerebellum, right fusiform, and left middle frontal gyri. The decreased GMVs of the selected brain regions were also associated with increased presence of epithelial progenitor cells (EPCs) in the circulation. In patients with PD, decrease in cardiovascular autonomic function and increase in circulating EPC level are associated with smaller GMV in several areas of the brain. Because of its possible role in the modulation of the circulatory EPC pool and baroreflex control, the left hippocampal formation may be a bio-target for disease-modifying therapy and treatment monitoring in PD.

Remote detection of human toxicants in real time using a human-optimized, bioluminescent bacterial luciferase gene cassette bioreporter

NASA Astrophysics Data System (ADS)

Close, Dan; Webb, James; Ripp, Steven; Patterson, Stacey; Sayler, Gary

2012-06-01

Traditionally, human toxicant bioavailability screening has been forced to proceed in either a high throughput fashion using prokaryotic or lower eukaryotic targets with minimal applicability to humans, or in a more expensive, lower throughput manner that uses fluorescent or bioluminescent human cells to directly provide human bioavailability data. While these efforts are often sufficient for basic scientific research, they prevent the rapid and remote identification of potentially toxic chemicals required for modern biosecurity applications. To merge the advantages of high throughput, low cost screening regimens with the direct bioavailability assessment of human cell line use, we re-engineered the bioluminescent bacterial luciferase gene cassette to function autonomously (without exogenous stimulation) within human cells. Optimized cassette expression provides for fully endogenous bioluminescent production, allowing continuous, real time monitoring of the bioavailability and toxicology of various compounds in an automated fashion. To access the functionality of this system, two sets of bioluminescent human cells were developed. The first was programed to suspend bioluminescent production upon toxicological challenge to mimic the non-specific detection of a toxicant. The second induced bioluminescence upon detection of a specific compound to demonstrate autonomous remote target identification. These cells were capable of responding to μM concentrations of the toxicant n-decanal, and allowed for continuous monitoring of cellular health throughout the treatment process. Induced bioluminescence was generated through treatment with doxycycline and was detectable upon dosage at a 100 ng/ml concentration. These results demonstrate that leveraging autonomous bioluminescence allows for low-cost, high throughput direct assessment of toxicant bioavailability.

A role for the Drosophila zinc transporter Zip88E in protecting against dietary zinc toxicity.

PubMed

Richards, Christopher D; Warr, Coral G; Burke, Richard

2017-01-01

Zinc absorption in animals is thought to be regulated in a local, cell autonomous manner with intestinal cells responding to dietary zinc content. The Drosophila zinc transporter Zip88E shows strong sequence similarity to Zips 42C.1, 42C.2 and 89B as well as mammalian Zips 1, 2 and 3, suggesting that it may act in concert with the apically-localised Drosophila zinc uptake transporters to facilitate dietary zinc absorption by importing ions into the midgut enterocytes. However, the functional characterisation of Zip88E presented here indicates that Zip88E may instead play a role in detecting and responding to zinc toxicity. Larvae homozygous for a null Zip88E allele are viable yet display heightened sensitivity to elevated levels of dietary zinc. This decreased zinc tolerance is accompanied by an overall decrease in Metallothionein B transcription throughout the larval midgut. A Zip88E reporter gene is expressed only in the salivary glands, a handful of enteroendocrine cells at the boundary between the anterior and middle midgut regions, and in two parallel strips of sensory cell projections connecting to the larval ventral ganglion. Zip88E expression solely in this restricted subset of cells is sufficient to rescue the Zip88E mutant phenotype. Together, our data suggest that Zip88E may be functioning in a small subset of cells to detect excessive zinc levels and induce a systemic response to reduce dietary zinc absorption and hence protect against toxicity.

Enhanced autonomic shutdown of Li-ion batteries by polydopamine coated polyethylene microspheres

DOE PAGES

Baginska, Marta; Blaiszik, Benjamin J.; Rajh, Tijana; ...

2014-07-17

Thermally triggered autonomic shutdown of a Lithium-ion (Li-ion) battery is demonstrated using polydopamine (PDA)-coated polyethylene microspheres applied onto a battery anode. The microspheres are dispersed in a buffered 10 mM dopamine salt solution and the pH is raised to initiate the polymerization and coat the microspheres. Coated microspheres are then mixed with an aqueous binder, applied onto a battery anode surface, dried, and incorporated into Li-ion coin cells. FTIR and Raman spectroscopy are used to verify the presence of the polydopamine on the surface of the microspheres. Scanning electron microscopy is used to examine microsphere surface morphology and resulting anodemore » coating quality. Charge and discharge capacity, as well as impedance, are measured for Li-ion coin cells as a function of microsphere content. Autonomous shutdown is achieved by applying 1.7 mg cm –2 of PDA-coated microspheres to the electrode. Furthermore, the PDA coating significantly reduces the mass of microspheres for effective shutdown compared to our prior work with uncoated microspheres.« less

The Markov blankets of life: autonomy, active inference and the free energy principle

PubMed Central

Palacios, Ensor; Friston, Karl; Kiverstein, Julian

2018-01-01

This work addresses the autonomous organization of biological systems. It does so by considering the boundaries of biological systems, from individual cells to Home sapiens, in terms of the presence of Markov blankets under the active inference scheme—a corollary of the free energy principle. A Markov blanket defines the boundaries of a system in a statistical sense. Here we consider how a collective of Markov blankets can self-assemble into a global system that itself has a Markov blanket; thereby providing an illustration of how autonomous systems can be understood as having layers of nested and self-sustaining boundaries. This allows us to show that: (i) any living system is a Markov blanketed system and (ii) the boundaries of such systems need not be co-extensive with the biophysical boundaries of a living organism. In other words, autonomous systems are hierarchically composed of Markov blankets of Markov blankets—all the way down to individual cells, all the way up to you and me, and all the way out to include elements of the local environment. PMID:29343629

From Extended Nanofluidics to an Autonomous Solar-Light-Driven Micro Fuel-Cell Device.

PubMed

Pihosh, Yuriy; Uemura, Jin; Turkevych, Ivan; Mawatari, Kazuma; Kazoe, Yutaka; Smirnova, Adelina; Kitamori, Takehiko

2017-07-03

Autonomous micro/nano mechanical, chemical, and biomedical sensors require persistent power sources scaled to their size. Realization of autonomous micro-power sources is a challenging task, as it requires combination of wireless energy supply, conversion, storage, and delivery to the sensor. Herein, we realized a solar-light-driven power source that consists of a micro fuel cell (μFC) and a photocatalytic micro fuel generator (μFG) integrated on a single microfluidic chip. The μFG produces hydrogen by photocatalytic water splitting under solar light. The hydrogen fuel is then consumed by the μFC to generate electricity. Importantly, the by-product water returns back to the photocatalytic μFG via recirculation loop without losses. Both devices rely on novel phenomena in extended-nano-fluidic channels that ensure ultra-fast proton transport. As a proof of concept, we demonstrate that μFG/μFC source achieves remarkable energy density of ca. 17.2 mWh cm -2 at room temperature. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Federal Vision for Future Computing: A Nanotechnology-Inspired Grand Challenge

DTIC Science & Technology

2016-07-29

Science Foundation (NSF), Department of Defense (DOD), National Institute of Standards and Technology (NIST), Intelligence Community (IC) Introduction...multiple Federal agencies: • Intelligent big data sensors that act autonomously and are programmable via the network for increased flexibility, and... intelligence for scientific discovery enabled by rapid extreme-scale data analysis, capable of understanding and making sense of results and thereby

Beyond Knowledge Transfer: The Social Construction of Autonomous Academic Science in University-Industry Agricultural Biotechnology Research Collaborations

ERIC Educational Resources Information Center

Biscotti, Dina Louise

2010-01-01

Autonomy is a social product. Although some might view autonomy as the absence of social interference in individual action, it is in fact produced through social institutions. It enables social actors to act; it is the justification for the allocation of enormous public resources into institutions classified as "public" or "nonprofit;" it can lead…

Multiple independent autonomous hydraulic oscillators driven by a common gravity head.

PubMed

Kim, Sung-Jin; Yokokawa, Ryuji; Lesher-Perez, Sasha Cai; Takayama, Shuichi

2015-06-15

Self-switching microfluidic circuits that are able to perform biochemical experiments in a parallel and autonomous manner, similar to instruction-embedded electronics, are rarely implemented. Here, we present design principles and demonstrations for gravity-driven, integrated, microfluidic pulsatile flow circuits. With a common gravity head as the only driving force, these fluidic oscillator arrays realize a wide range of periods (0.4 s-2 h) and flow rates (0.10-63 μl min(-1)) with completely independent timing between the multiple oscillator sub-circuits connected in parallel. As a model application, we perform systematic, parallel analysis of endothelial cell elongation response to different fluidic shearing patterns generated by the autonomous microfluidic pulsed flow generation system.

Choosing Health and the inner citadel.

PubMed

Allmark, P

2006-01-01

It is argued in this paper that the latest UK government white paper on public health, Choosing Health, is vulnerable to a charge of paternalism. For some years libertarians have levelled this charge at public health policies. The white paper tries to avoid it by constant reference to informed choice and choice related terms. The implication is that the government aims only to inform the public of health issues; how they respond is up to them. It is argued here, however, that underlying the notion of informed choice is a Kantian, "inner citadel" view of autonomy. According to this view, each of us acts autonomously only when we act in accord with reason. On such a view it is possible to justify coercing, cajoling, and conning people on the basis that their current behaviour is not autonomous because it is subject to forces that cause irrational choice, such as addiction. "Informed choice" in this sense is compatible with paternalism. This paternalism can be seen in public health policies such as deceptive advertising and the treatment of "bad habits" as addictions. Libertarians are bound to object to this. In the concluding section, however, it is suggested that public health can, nonetheless, find ethical succour from alternative approaches.

Existence and stability of periodic solutions of an impulsive differential equation and application to CD8 T-cell differentiation.

PubMed

Girel, Simon; Crauste, Fabien

2018-06-01

Unequal partitioning of the molecular content at cell division has been shown to be a source of heterogeneity in a cell population. We propose to model this phenomenon with the help of a scalar, nonlinear impulsive differential equation (IDE). To study the effect of molecular partitioning at cell division on the effector/memory cell-fate decision in a CD8 T-cell lineage, we study an IDE describing the concentration of the protein Tbet in a CD8 T-cell, where impulses are associated to cell division. We discuss how the degree of asymmetry of molecular partitioning can affect the process of cell differentiation and the phenotypical heterogeneity of a cell population. We show that a moderate degree of asymmetry is necessary and sufficient to observe irreversible differentiation. We consider, in a second part, a general autonomous IDE with fixed times of impulse and a specific form of impulse function. We establish properties of the solutions of that equation, most of them obtained under the hypothesis that impulses occur periodically. In particular, we show how to investigate the existence of periodic solutions and their stability by studying the flow of an autonomous differential equation. Then we apply those properties to prove the results presented in the first part.

Cell-autonomous CCL5 transcription by memory CD8 T cells is regulated by IL-4.

PubMed

Marçais, Antoine; Coupet, Charles-Antoine; Walzer, Thierry; Tomkowiak, Martine; Ghittoni, Raffaella; Marvel, Jacqueline

2006-10-01

Immunological memory is associated with the display of improved effector functions. The maintenance by CD8 memory cells of high levels of untranslated CCL5 mRNA allows these cells to immediately secrete this chemokine upon Ag stimulation. Untranslated mRNA storage is a newly described process supporting the immediate display of an effector function by memory lymphocytes. We have tested the capacity of different cytokines to regulate the memorization of CCL5 by memory CD8 T cells. We found that IL-4 treatment of murine CD8 T cells impairs immediate CCL5 secretion capacity by inhibiting CCL5 mRNA transcription through a STAT6-dependent pathway. The inhibition by IL-4 is reversible, as memory CD8 T cells reconstitute their CCL5 mRNA stores and reacquire their immediate CCL5 secretion capacity when IL-4 is withdrawn. This recovery is cell autonomous because it proceeds in culture medium in the absence of exogenous growth factors, suggesting that CCL5 expression by memory CD8 T cells is a default process. Overall, these results indicate that the expression of CCL5 is an intrinsic property acquired by memory CD8 T cells that is regulated by environmental factors.

Hybrid multiscale modeling and prediction of cancer cell behavior

PubMed Central

Habibi, Jafar

2017-01-01

Background Understanding cancer development crossing several spatial-temporal scales is of great practical significance to better understand and treat cancers. It is difficult to tackle this challenge with pure biological means. Moreover, hybrid modeling techniques have been proposed that combine the advantages of the continuum and the discrete methods to model multiscale problems. Methods In light of these problems, we have proposed a new hybrid vascular model to facilitate the multiscale modeling and simulation of cancer development with respect to the agent-based, cellular automata and machine learning methods. The purpose of this simulation is to create a dataset that can be used for prediction of cell phenotypes. By using a proposed Q-learning based on SVR-NSGA-II method, the cells have the capability to predict their phenotypes autonomously that is, to act on its own without external direction in response to situations it encounters. Results Computational simulations of the model were performed in order to analyze its performance. The most striking feature of our results is that each cell can select its phenotype at each time step according to its condition. We provide evidence that the prediction of cell phenotypes is reliable. Conclusion Our proposed model, which we term a hybrid multiscale modeling of cancer cell behavior, has the potential to combine the best features of both continuum and discrete models. The in silico results indicate that the 3D model can represent key features of cancer growth, angiogenesis, and its related micro-environment and show that the findings are in good agreement with biological tumor behavior. To the best of our knowledge, this paper is the first hybrid vascular multiscale modeling of cancer cell behavior that has the capability to predict cell phenotypes individually by a self-generated dataset. PMID:28846712

Hybrid multiscale modeling and prediction of cancer cell behavior.

PubMed

Zangooei, Mohammad Hossein; Habibi, Jafar

2017-01-01

Understanding cancer development crossing several spatial-temporal scales is of great practical significance to better understand and treat cancers. It is difficult to tackle this challenge with pure biological means. Moreover, hybrid modeling techniques have been proposed that combine the advantages of the continuum and the discrete methods to model multiscale problems. In light of these problems, we have proposed a new hybrid vascular model to facilitate the multiscale modeling and simulation of cancer development with respect to the agent-based, cellular automata and machine learning methods. The purpose of this simulation is to create a dataset that can be used for prediction of cell phenotypes. By using a proposed Q-learning based on SVR-NSGA-II method, the cells have the capability to predict their phenotypes autonomously that is, to act on its own without external direction in response to situations it encounters. Computational simulations of the model were performed in order to analyze its performance. The most striking feature of our results is that each cell can select its phenotype at each time step according to its condition. We provide evidence that the prediction of cell phenotypes is reliable. Our proposed model, which we term a hybrid multiscale modeling of cancer cell behavior, has the potential to combine the best features of both continuum and discrete models. The in silico results indicate that the 3D model can represent key features of cancer growth, angiogenesis, and its related micro-environment and show that the findings are in good agreement with biological tumor behavior. To the best of our knowledge, this paper is the first hybrid vascular multiscale modeling of cancer cell behavior that has the capability to predict cell phenotypes individually by a self-generated dataset.

Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

USDA-ARS?s Scientific Manuscript database

Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate tha...

Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit

PubMed Central

Hatzold, Julia; Beleggia, Filippo; Herzig, Hannah; Altmüller, Janine; Nürnberg, Peter; Bloch, Wilhelm; Wollnik, Bernd; Hammerschmidt, Matthias

2016-01-01

The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a, encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress). Blockade of the ensuing PI3K-AKT-mTORC1-NFκB-MMP9 pathway activation in basal cells, as well as systemic isotonicity, prevents malignant transformation. Our results identify hypotonic stress as a (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression. DOI: http://dx.doi.org/10.7554/eLife.14277.001 PMID:27240166

Planar polarity pathway and Nance-Horan syndrome-like 1b have essential cell-autonomous functions in neuronal migration.

PubMed

Walsh, Gregory S; Grant, Paul K; Morgan, John A; Moens, Cecilia B

2011-07-01

Components of the planar cell polarity (PCP) pathway are required for the caudal tangential migration of facial branchiomotor (FBM) neurons, but how PCP signaling regulates this migration is not understood. In a forward genetic screen, we identified a new gene, nhsl1b, required for FBM neuron migration. nhsl1b encodes a WAVE-homology domain-containing protein related to human Nance-Horan syndrome (NHS) protein and Drosophila GUK-holder (Gukh), which have been shown to interact with components of the WAVE regulatory complex that controls cytoskeletal dynamics and with the polarity protein Scribble, respectively. Nhsl1b localizes to FBM neuron membrane protrusions and interacts physically and genetically with Scrib to control FBM neuron migration. Using chimeric analysis, we show that FBM neurons have two modes of migration: one involving interactions between the neurons and their planar-polarized environment, and an alternative, collective mode involving interactions between the neurons themselves. We demonstrate that the first mode of migration requires the cell-autonomous functions of Nhsl1b and the PCP components Scrib and Vangl2 in addition to the non-autonomous functions of Scrib and Vangl2, which serve to polarize the epithelial cells in the environment of the migrating neurons. These results define a role for Nhsl1b as a neuronal effector of PCP signaling and indicate that proper FBM neuron migration is directly controlled by PCP signaling between the epithelium and the migrating neurons.

Planar polarity pathway and Nance-Horan syndrome-like 1b have essential cell-autonomous functions in neuronal migration

PubMed Central

Walsh, Gregory S.; Grant, Paul K.; Morgan, John A.; Moens, Cecilia B.

2011-01-01

Components of the planar cell polarity (PCP) pathway are required for the caudal tangential migration of facial branchiomotor (FBM) neurons, but how PCP signaling regulates this migration is not understood. In a forward genetic screen, we identified a new gene, nhsl1b, required for FBM neuron migration. nhsl1b encodes a WAVE-homology domain-containing protein related to human Nance-Horan syndrome (NHS) protein and Drosophila GUK-holder (Gukh), which have been shown to interact with components of the WAVE regulatory complex that controls cytoskeletal dynamics and with the polarity protein Scribble, respectively. Nhsl1b localizes to FBM neuron membrane protrusions and interacts physically and genetically with Scrib to control FBM neuron migration. Using chimeric analysis, we show that FBM neurons have two modes of migration: one involving interactions between the neurons and their planar-polarized environment, and an alternative, collective mode involving interactions between the neurons themselves. We demonstrate that the first mode of migration requires the cell-autonomous functions of Nhsl1b and the PCP components Scrib and Vangl2 in addition to the non-autonomous functions of Scrib and Vangl2, which serve to polarize the epithelial cells in the environment of the migrating neurons. These results define a role for Nhsl1b as a neuronal effector of PCP signaling and indicate that proper FBM neuron migration is directly controlled by PCP signaling between the epithelium and the migrating neurons. PMID:21693519

Model-Unified Planning and Execution for Distributed Autonomous System Control

NASA Technical Reports Server (NTRS)

Aschwanden, Pascal; Baskaran, Vijay; Bernardini, Sara; Fry, Chuck; Moreno, Maria; Muscettola, Nicola; Plaunt, Chris; Rijsman, David; Tompkins, Paul

2006-01-01

The Intelligent Distributed Execution Architecture (IDEA) is a real-time architecture that exploits artificial intelligence planning as the core reasoning engine for interacting autonomous agents. Rather than enforcing separate deliberation and execution layers, IDEA unifies them under a single planning technology. Deliberative and reactive planners reason about and act according to a single representation of the past, present and future domain state. The domain state behaves the rules dictated by a declarative model of the subsystem to be controlled, internal processes of the IDEA controller, and interactions with other agents. We present IDEA concepts - modeling, the IDEA core architecture, the unification of deliberation and reaction under planning - and illustrate its use in a simple example. Finally, we present several real-world applications of IDEA, and compare IDEA to other high-level control approaches.

Autonomous assembly with collision avoidance of a fleet of flexible spacecraft based on disturbance observer

NASA Astrophysics Data System (ADS)

Chen, Ti; Wen, Hao

2018-06-01

This paper presents a distributed control law with disturbance observer for the autonomous assembly of a fleet of flexible spacecraft to construct a large flexible space structure. The fleet of flexible spacecraft is driven to the pre-assembly configuration firstly, and then to the desired assembly configuration. A distributed assembly control law with disturbance observer is proposed by treating the flexible dynamics as disturbances acting on the rigid motion of the flexible spacecraft. Theoretical analysis shows that the control law can actuate the fleet to the desired configuration. Moreover, the collision avoidance between the members is also considered in the process from initial configuration to pre-assembly configuration. Finally, a numerical example is presented to verify the feasibility of proposed mission planning and the effectiveness of control law.

Cell theory, specificity, and reproduction, 1837-1870.

PubMed

Müller-Wille, Staffan

2010-09-01

The cell is not only the structural, physiological, and developmental unit of life, but also the reproductive one. So far, however, this aspect of the cell has received little attention from historians and philosophers of biology. I will argue that cell theory had far-reaching consequences for how biologists conceptualized the reproductive relationships between germs and adult organisms. Cell theory, as formulated by Theodor Schwann in 1839, implied that this relationship was a specific and lawful one, that is, that germs of a certain kind, all else being equal, would produce adult organisms of the same kind, and vice versa. Questions of preformation and epigenesis took on a new meaning under this presupposition. The question then became one of whether cells could be considered as autonomous agents producing adult organisms of a given species, or whether they were the product of external, organizing forces and thus only a stage in the development of the whole organism. This question became an important issue for nineteenth-century biology. As I will demonstrate, it was the view of cells as autonomous agents which helped both Charles Darwin and Gregor Mendel to think of inheritance as a lawful process. Copyright © 2010 Elsevier Ltd. All rights reserved.

The GATA transcription factor gene gtaG is required for terminal differentiation in Dictyostelium.

PubMed

Katoh-Kurasawa, Mariko; Santhanam, Balaji; Shaulsky, Gad

2016-03-09

The GATA transcription factor GtaG is conserved in Dictyostelids and essential for terminal differentiation in Dictyostelium discoideum, but its function is not well understood. Here we show that gtaG is expressed in prestalk cells at the anterior region of fingers and in the extending stalk during culmination. The gtaG - phenotype is cell-autonomous in prestalk cells and non-cell-autonomous in prespore cells. Transcriptome analyses reveal that GtaG regulates prestalk gene expression during cell differentiation before culmination and is required for progression into culmination. GtaG-dependent genes include genetic suppressors of the Dd-STATa-defective phenotype as well as Dd-STATa target-genes, including extra cellular matrix genes. We show that GtaG may be involved in the production of two culmination-signaling molecules, cyclic di-GMP and the spore differentiation factor SDF-1 and that addition of c-di-GMP rescues the gtaG - culmination and spore formation deficiencies. We propose that GtaG is a regulator of terminal differentiation that functions in concert with Dd-STATa and controls culmination through regulating c-di-GMP and SDF-1 production in prestalk cells. © 2016. Published by The Company of Biologists Ltd.

Autonomous replication of nucleic acids by polymerization/nicking enzyme/DNAzyme cascades for the amplified detection of DNA and the aptamer-cocaine complex.

PubMed

Wang, Fuan; Freage, Lina; Orbach, Ron; Willner, Itamar

2013-09-03

The progressive development of amplified DNA sensors and aptasensors using replication/nicking enzymes/DNAzyme machineries is described. The sensing platforms are based on the tailoring of a DNA template on which the recognition of the target DNA or the formation of the aptamer-substrate complex trigger on the autonomous isothermal replication/nicking processes and the displacement of a Mg(2+)-dependent DNAzyme that catalyzes the generation of a fluorophore-labeled nucleic acid acting as readout signal for the analyses. Three different DNA sensing configurations are described, where in the ultimate configuration the target sequence is incorporated into a nucleic acid blocker structure associated with the sensing template. The target-triggered isothermal autonomous replication/nicking process on the modified template results in the formation of the Mg(2+)-dependent DNAzyme tethered to a free strand consisting of the target sequence. This activates additional template units for the nucleic acid self-replication process, resulting in the ultrasensitive detection of the target DNA (detection limit 1 aM). Similarly, amplified aptamer-based sensing platforms for cocaine are developed along these concepts. The modification of the cocaine-detection template by the addition of a nucleic acid sequence that enables the autonomous secondary coupled activation of a polymerization/nicking machinery and DNAzyme generation path leads to an improved analysis of cocaine (detection limit 10 nM).

Deployable reconnaissance from a VTOL UAS in urban environments

NASA Astrophysics Data System (ADS)

Barnett, Shane; Bird, John; Culhane, Andrew; Sharkasi, Adam; Reinholtz, Charles

2007-04-01

Reconnaissance collection in unknown or hostile environments can be a dangerous and life threatening task. To reduce this risk, the Unmanned Systems Group at Virginia Tech has produced a fully autonomous reconnaissance system able to provide live video reconnaissance from outside and inside unknown structures. This system consists of an autonomous helicopter which launches a small reconnaissance pod inside a building and an operator control unit (OCU) on a ground station. The helicopter is a modified Bergen Industrial Twin using a Rotomotion flight controller and can fly missions of up to one half hour. The mission planning OCU can control the helicopter remotely through teleoperation or fully autonomously by GPS waypoints. A forward facing camera and template matching aid in navigation by identifying the target building. Once the target structure is identified, vision algorithms will center the UAS adjacent to open windows or doorways. Tunable parameters in the vision algorithm account for varying launch distances and opening sizes. Launch of the reconnaissance pod may be initiated remotely through a human in the loop or autonomously. Compressed air propels the half pound stationary pod or the larger mobile pod into the open portals. Once inside the building, the reconnaissance pod will then transmit live video back to the helicopter. The helicopter acts as a repeater node for increased video range and simplification of communication back to the ground station.

brother of cdo (umleitung) is cell-autonomously required for Hedgehog-mediated ventral CNS patterning in the zebrafish

PubMed Central

Bergeron, Sadie A.; Tyurina, Oksana V.; Miller, Emily; Bagas, Andrea; Karlstrom, Rolf O.

2011-01-01

The transmembrane protein Brother of Cdo (Boc) has been implicated in Shh-mediated commissural axon guidance, and can both positively and negatively regulate Hedgehog (Hh) target gene transcription, however, little is known about in vivo requirements for Boc during vertebrate embryogenesis. The zebrafish umleitung (umlty54) mutant was identified by defects in retinotectal axon projections. Here, we show that the uml locus encodes Boc and that Boc function is cell-autonomously required for Hh-mediated neural patterning. Our phenotypic analysis suggests that Boc is required as a positive regulator of Hh signaling in the spinal cord, hypothalamus, pituitary, somites and upper jaw, but that Boc might negatively regulate Hh signals in the lower jaw. This study reveals a role for Boc in ventral CNS cells that receive high levels of Hh and uncovers previously unknown roles for Boc in vertebrate embryogenesis. PMID:21115611

Synthesis and cell-free cloning of DNA libraries using programmable microfluidics

PubMed Central

Yehezkel, Tuval Ben; Rival, Arnaud; Raz, Ofir; Cohen, Rafael; Marx, Zipora; Camara, Miguel; Dubern, Jean-Frédéric; Koch, Birgit; Heeb, Stephan; Krasnogor, Natalio; Delattre, Cyril; Shapiro, Ehud

2016-01-01

Microfluidics may revolutionize our ability to write synthetic DNA by addressing several fundamental limitations associated with generating novel genetic constructs. Here we report the first de novo synthesis and cell-free cloning of custom DNA libraries in sub-microliter reaction droplets using programmable digital microfluidics. Specifically, we developed Programmable Order Polymerization (POP), Microfluidic Combinatorial Assembly of DNA (M-CAD) and Microfluidic In-vitro Cloning (MIC) and applied them to de novo synthesis, combinatorial assembly and cell-free cloning of genes, respectively. Proof-of-concept for these methods was demonstrated by programming an autonomous microfluidic system to construct and clone libraries of yeast ribosome binding sites and bacterial Azurine, which were then retrieved in individual droplets and validated. The ability to rapidly and robustly generate designer DNA molecules in an autonomous manner should have wide application in biological research and development. PMID:26481354

Up-regulated Ectonucleotidases in Fas-Associated Death Domain Protein- and Receptor-Interacting Protein Kinase 1-Deficient Jurkat Leukemia Cells Counteract Extracellular ATP/AMP Accumulation via Pannexin-1 Channels during Chemotherapeutic Drug-Induced Apoptosis.

PubMed

Boyd-Tressler, Andrea M; Lane, Graham S; Dubyak, George R

2017-07-01

Pannexin-1 (Panx1) channels mediate the efflux of ATP and AMP from cancer cells in response to induction of extrinsic apoptosis by death receptors or intrinsic apoptosis by chemotherapeutic agents. We previously described the accumulation of extracellular ATP /AMP during chemotherapy-induced apoptosis in Jurkat human leukemia cells. In this study, we compared how different signaling pathways determine extracellular nucleotide pools in control Jurkat cells versus Jurkat lines that lack the Fas-associated death domain (FADD) or receptor-interacting protein kinase 1 (RIP1) cell death regulatory proteins. Tumor necrosis factor- α induced extrinsic apoptosis in control Jurkat cells and necroptosis in FADD-deficient cells; treatment of both lines with chemotherapeutic drugs elicited similar intrinsic apoptosis. Robust extracellular ATP/AMP accumulation was observed in the FADD-deficient cells during necroptosis, but not during apoptotic activation of Panx1 channels. Accumulation of extracellular ATP/AMP was similarly absent in RIP1-deficient Jurkat cells during apoptotic responses to chemotherapeutic agents. Apoptotic activation triggered equivalent proteolytic gating of Panx1 channels in all three Jurkat cell lines. The differences in extracellular ATP/AMP accumulation correlated with cell-line-specific expression of ectonucleotidases that metabolized the released ATP/AMP. CD73 mRNA, and α β -methylene-ADP-inhibitable ecto-AMPase activity were elevated in the FADD-deficient cells. In contrast, the RIP1-deficient cells were defined by increased expression of tartrate-sensitive prostatic acid phosphatase as a broadly acting ectonucleotidase. Thus, extracellular nucleotide accumulation during regulated tumor cell death involves interplay between ATP/AMP efflux pathways and different cell-autonomous ectonucleotidases. Differential expression of particular ectonucleotidases in tumor cell variants will determine whether chemotherapy-induced activation of Panx1 channels drives accumulation of immunostimulatory ATP versus immunosuppressive adenosine within the tumor microenvironment. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Effects of Antiretroviral Therapy on Autonomic Function in Early HIV Infection: A Preliminary Report

PubMed Central

Chow, Dominic; Kocher, Morgan; Shikuma, Cecilia; Parikh, Nisha; Grandinetti, Andrew; Nakamoto, Beau; Seto, Todd; Low, Phillip

2012-01-01

Background: A prospective study was conducted in human immunodeficiency virus (HIV)-infected patients as they undergo alterations in their antiretroviral therapy (ART) to determine the effect of ART on autonomic function. Methods: HIV-infected subjects who were either 1) naïve to ART and initiating ART, or 2) receiving ART and in HIV virologic failure for at least 4 months and were about to switch ART were enrolled in this study. Autonomic function assessment (cardiovagal, adrenergic, and sudomotor tests) was performed prior to and 4 months after initiating the new ART. Changes in clinical autonomic symptoms and virologic assessment were assessed. Results: Twelve subjects completed the study: 92% male; median age (Q1, Q3) was 41.0 (28.0, 48.2) years; and 50% White/Non-Hispanic. Seventy-five percent were ART naïve while 25% were failing their ART regimen. The median CD4 count was 336.5 (245.3, 372.3) cells/mm3. All subjects achieved an undetectable HIV viral load by the 4-month follow-up visit. The majority of naïve subjects were started on an ART regimen of tenofovir / emtricitabine / efavirenz. There were no significant differences in autonomic function assessment, as measured by cardiovagal, adrenergic, and sudomotor tests, with regards to ART initiation. Conclusion: This is the first study to examine the effects of initiating ART on autonomic function in early HIV infection. This study found no appreciable differences of ART on the autonomic nervous system when ART is initiated early in the course of HIV disease. ART may not contribute to short-term changes in autonomic function. PMID:22859899

Effects of the augmenter of liver regeneration on the biological behavior of hepatocellular carcinoma.

PubMed

Tang, Lin; Sun, Hang; Zhang, Lin; Deng, Jian C; Guo, Hui; Zhang, Ling; Liu, Qi

2009-08-01

To take advantage of the small interfering ribonucleic acid (siRNA) targeting the human augmenter of liver regeneration (hALR) and anti-hALR monoclonal antibody (McAb) to inhibit the function of hALR, and to demonstrate whether the growth of hepatoma is influenced by siRNA targeting hALR and anti-hALR McAb through inhibiting expression of hALR. This study was conducted in the Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Chongqing Medical University, China, between January 2005 and May 2007. We transfected siRNA plasmid pSIALR-A, which targeted the complementary deoxyribonucleic acid (cDNA) of hALR and the unrelated control plasmid pSIALR-B into human hepatocellular liver carcinoma cell line (HepG2) cells. Then, the proliferation of HepG2 cells, after being treated with pSIALR-A and anti-hALR McAb was detected. The growth of the xenograft tumor was observed after being treated with pSIALR-A and anti-hALR McAb in nude mice. We successfully constructed expressing plasmid pSIALR-A and pSIALR-B. The pSIALR-A inhibited the expression of hALR in HepG2 cells significantly. The siRNA targeting hALR and anti-hALR McAb inhibited obviously the growth of HepG2 cells in vitro. siRNA targeting hALR and anti-hALR McAb significantly inhibited the growth of xenograft tumor in 5 nude mice. Anti-hALR McAb inhibited apparently the autonomous growth of HepG2 cells. Our results demonstrated that anti-hALR McAb inhibited the autonomous growth of hepatoma cells obviously, moreover, hALR maintained the autonomous growth of hepatoma cells in vitro through an autocrine mechanism.

Autonomously Self-Adhesive Hydrogels as Building Blocks for Additive Manufacturing.

PubMed

Deng, Xudong; Attalla, Rana; Sadowski, Lukas P; Chen, Mengsu; Majcher, Michael J; Urosev, Ivan; Yin, Da-Chuan; Selvaganapathy, P Ravi; Filipe, Carlos D M; Hoare, Todd

2018-01-08

We report a simple method of preparing autonomous and rapid self-adhesive hydrogels and their use as building blocks for additive manufacturing of functional tissue scaffolds. Dynamic cross-linking between 2-aminophenylboronic acid-functionalized hyaluronic acid and poly(vinyl alcohol) yields hydrogels that recover their mechanical integrity within 1 min after cutting or shear under both neutral and acidic pH conditions. Incorporation of this hydrogel in an interpenetrating calcium-alginate network results in an interfacially stiffer but still rapidly self-adhesive hydrogel that can be assembled into hollow perfusion channels by simple contact additive manufacturing within minutes. Such channels withstand fluid perfusion while retaining their dimensions and support endothelial cell growth and proliferation, providing a simple and modular route to produce customized cell scaffolds.

Multiresolution motion planning for autonomous agents via wavelet-based cell decompositions.

PubMed

Cowlagi, Raghvendra V; Tsiotras, Panagiotis

2012-10-01

We present a path- and motion-planning scheme that is "multiresolution" both in the sense of representing the environment with high accuracy only locally and in the sense of addressing the vehicle kinematic and dynamic constraints only locally. The proposed scheme uses rectangular multiresolution cell decompositions, efficiently generated using the wavelet transform. The wavelet transform is widely used in signal and image processing, with emerging applications in autonomous sensing and perception systems. The proposed motion planner enables the simultaneous use of the wavelet transform in both the perception and in the motion-planning layers of vehicle autonomy, thus potentially reducing online computations. We rigorously prove the completeness of the proposed path-planning scheme, and we provide numerical simulation results to illustrate its efficacy.

Integrated control strategy for autonomous decentralized conveyance systems based on distributed MEMS arrays

NASA Astrophysics Data System (ADS)

Zhou, Lingfei; Chapuis, Yves-Andre; Blonde, Jean-Philippe; Bervillier, Herve; Fukuta, Yamato; Fujita, Hiroyuki

2004-07-01

In this paper, the authors proposed to study a model and a control strategy of a two-dimensional conveyance system based on the principles of the Autonomous Decentralized Microsystems (ADM). The microconveyance system is based on distributed cooperative MEMS actuators which can produce a force field onto the surface of the device to grip and move a micro-object. The modeling approach proposed here is based on a simple model of a microconveyance system which is represented by a 5 x 5 matrix of cells. Each cell is consisted of a microactuator, a microsensor, and a microprocessor to provide actuation, autonomy and decentralized intelligence to the cell. Thus, each cell is able to identify a micro-object crossing on it and to decide by oneself the appropriate control strategy to convey the micro-object to its destination target. The control strategy could be established through five simple decision rules that the cell itself has to respect at each calculate cycle time. Simulation and FPGA implementation results are given in the end of the paper in order to validate model and control approach of the microconveyance system.

Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS.

PubMed

Hall, Claire E; Yao, Zhi; Choi, Minee; Tyzack, Giulia E; Serio, Andrea; Luisier, Raphaelle; Harley, Jasmine; Preza, Elisavet; Arber, Charlie; Crisp, Sarah J; Watson, P Marc D; Kullmann, Dimitri M; Abramov, Andrey Y; Wray, Selina; Burley, Russell; Loh, Samantha H Y; Martins, L Miguel; Stevens, Molly M; Luscombe, Nicholas M; Sibley, Christopher R; Lakatos, Andras; Ule, Jernej; Gandhi, Sonia; Patani, Rickie

2017-05-30

Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Immunomodulatory Yersinia outer proteins (Yops)–useful tools for bacteria and humans alike

PubMed Central

Grabowski, Benjamin; Schmidt, M. Alexander; Rüter, Christian

2017-01-01

ABSTRACT Human-pathogenic Yersinia produce plasmid-encoded Yersinia outer proteins (Yops), which are necessary to down-regulate anti-bacterial responses that constrict bacterial survival in the host. These Yops are effectively translocated directly from the bacterial into the target cell cytosol by the type III secretion system (T3SS). Cell-penetrating peptides (CPPs) in contrast are characterized by their ability to autonomously cross cell membranes and to transport cargo – independent of additional translocation systems. The recent discovery of bacterial cell-penetrating effector proteins (CPEs) – with the prototype being the T3SS effector protein YopM – established a new class of autonomously translocating immunomodulatory proteins. CPEs represent a vast source of potential self-delivering, anti-inflammatory therapeutics. In this review, we give an update on the characteristic features of the plasmid-encoded Yops and, based on recent findings, propose the further development of these proteins for potential therapeutic applications as natural or artificial cell-penetrating forms of Yops might be of value as bacteria-derived biologics. PMID:28296562

Clonal analysis of human embryonic stem cell differentiation into teratomas.

PubMed

Blum, Barak; Benvenisty, Nissim

2007-08-01

Differentiation of human embryonic stem cells (HESCs) can be studied in vivo through the induction of teratomas in immune-deficient mice. Cells within the teratomas differentiate into all three embryonic germ layers. However, the exact nature of the proliferation and differentiation of HESCs within the teratoma is not fully characterized, and it is not clear whether the differentiation is cell autonomous or affected by neighboring cells. Here, we establish a genetic approach to study the clonality of differentiation in teratomas using a mixture of HESC lines. We first demonstrate, by means of 5-bromo-2'-deoxyuridine incorporation, that cell proliferation occurs throughout the teratoma, and that there are no clusters of undifferentiated-proliferating cells. Using a combination of laser capture microdissection and DNA fingerprinting analysis, we show that different cell lines contribute mutually to the same distinctive tissue structures. Further support for the nonclonal differentiation within the teratoma was achieved by fluorescence in situ hybridization analysis of sex chromosomes. We therefore suggest that in vivo differentiation of HESCs is polyclonal and, thus, may not be cell autonomous, stressing the need for a three-dimensional growth in order to achieve complex differentiation of HESCs. Disclosure of potential conflicts of interest is found at the end of this article.

Adult epidermal Notch activity induces dermal accumulation of T cells and neural crest derivatives through upregulation of jagged 1.

PubMed

Ambler, Carrie A; Watt, Fiona M

2010-11-01

Notch signalling regulates epidermal differentiation and tumour formation via non-cell autonomous mechanisms that are incompletely understood. This study shows that epidermal Notch activation via a 4-hydroxy-tamoxifen-inducible transgene caused epidermal thickening, focal detachment from the underlying dermis and hair clumping. In addition, there was dermal accumulation of T lymphocytes and stromal cells, some of which localised to the blisters at the epidermal-dermal boundary. The T cell infiltrate was responsible for hair clumping but not for other Notch phenotypes. Notch-induced stromal cells were heterogeneous, expressing markers of neural crest, melanocytes, smooth muscle and peripheral nerve. Although Slug1 expression was expanded in the epidermis, the stromal cells did not arise through epithelial-mesenchymal transition. Epidermal Notch activation resulted in upregulation of jagged 1 in both epidermis and dermis. When Notch was activated in the absence of epidermal jagged 1, jagged 1 was not upregulated in the dermis, and epidermal thickening, blister formation, accumulation of T cells and stromal cells were inhibited. Gene expression profiling revealed that epidermal Notch activation resulted in upregulation of several growth factors and cytokines, including TNFα, the expression of which was dependent on epidermal jagged 1. We conclude that jagged 1 is a key mediator of non-cell autonomous Notch signalling in skin.

crm-1 facilitates BMP signaling to control body size in Caenorhabditis elegans.

PubMed

Fung, Wong Yan; Fat, Ko Frankie Chi; Eng, Cheah Kathryn Song; Lau, Chow King

2007-11-01

We have identified in Caenorhabditis elegans a homologue of the vertebrate Crim1, crm-1, which encodes a putative transmembrane protein with multiple cysteine-rich (CR) domains known to have bone morphogenetic proteins (BMPs) binding activity. Using the body morphology of C. elegans as an indicator, we showed that attenuation of crm-1 activity leads to a small body phenotype reminiscent of that of BMP pathway mutants. We showed that the crm-1 loss-of-function phenotype can be rescued by constitutive supply of sma-4 activity. crm-1 can enhance BMP signaling and this activity is dependent on the presence of the DBL-1 ligand and its receptors. crm-1 is expressed in neurons at the ventral nerve cord, where the DBL-1 ligand is produced. However, ectopic expression experiments reveal that crm-1 gene products act outside the DBL-1 producing cells and function non-autonomously to facilitate dbl/sma pathway signaling to control body size.

Unfolding a chordate developmental program, one cell at a time: invariant cell lineages, short-range inductions and evolutionary plasticity in ascidians.

PubMed

Lemaire, Patrick

2009-08-01

Ascidians were historically the first metazoans in which experimental embryology was carried out. These early works by Chabry and Conklin [Chabry, L., 1887. Embryologie normale et tératologique des Ascidie. Felix Alcan Editeur, Paris; Conklin, E., 1905. The organization and cell lineage of the ascidian egg. J. Acad., Nat. Sci. Phila. 13, 1], in particular, led to the idea that the developmental program of these animals was driven by the cell-autonomous inheritance of localised maternal determinants, rendered precise by the stereotyped pattern of invariant cell cleavages. Work in the past 20 years indeed identified several localised maternal determinants of the position of cleavage planes or of some early cell fates. The overwhelming majority of cells in the three germ layers, however, do not follow a cell-autonomous differentiation program. Instead, they respond to short-range signals, as described in this review. Careful analysis of cell-cell contacts suggests that a major function of the invariant position of cleavage plans, besides segregating competence factors, is to control the relative positions of inducing cells and those competent to respond. Surprisingly, while the cell lineage is very well conserved between the divergent species Halocynthia roretzi and Ciona intestinalis, the molecular nature of inducing signals can vary. The constraints on embryo anatomy thus appear stronger than those on the choice of individual regulatory molecules.

An extreme bias in the germ line of XY C57BL/6<->XY FVB/N chimaeric mice

PubMed Central

MacGregor, G. R.

2011-01-01

Chimaeric analysis is a powerful method to address questions about the cell-autonomous nature of defects in spermatogenesis. Symplastic spermatids (sys) mice have a recessive mutation that causes male sterility due to an arrest in germ-cell development during spermiogenesis. Chimaeric mice were generated by aggregation of eight-cell embryos from sys (FVB/N genetic background) and wild-type C57BL/6 (B6) mice to determine whether the male germ-cell defect is cell-autonomous. The resulting FVB/N<->B6 chimaeras (<-> denotes fusion of embryos) were mated with FVB/N mice and coat colour of offspring was used to identify transmission of FVB/N or B6 gametes. Regardless of the relative contribution of B6 to somatic tissues of the chimaeras, almost all (282 of 284; 99.3%) offspring of B6 XY<->XY FVB/N (+/+ or sys/+) males (n = 9) received a FVB/N-derived paternal gamete. After mating of female B6<->FVB/N chimaeras, 51 of 73 (69.9%) offspring received an FVB-derived maternal gamete. Southern blot analysis of different tissues from chimaeric males indicated that, despite the presence of balanced chimaerism in somatic tissues, the germ line in B6 XY<->XY FVB/N mice was essentially FVB/N in composition. Thus there is a strong selective advantage for FVB/N male germ cells over B6 male germ cells in B6<->FVB/N-aggregation chimaeras at some stage during development of the male germ line. Each of three male chimaeras that were either B6 XY<->XY FVB/N (sys/sys) or B6 XX<->XY FVB/N (sys/sys) in composition was sterile, and testis histology was essentially sys mutant. This finding indicates that the function of the gene(s) affected in the sys mutation may be required in the testis, although whether expression is required in germ cells, somatic cells or both remains unknown. The extreme bias in transmission of male gametes has implications for experimental design in studies that use chimaeric analysis to address questions regarding the cell-autonomous nature of germ-cell defects in mice. PMID:12201811

Basic emotions induced by odorants: a new approach based on autonomic pattern results.

PubMed

Vernet-Maury, E; Alaoui-Ismaïli, O; Dittmar, A; Delhomme, G; Chanel, J

1999-02-15

The aim of this study was to link the effects of odorants with the emotional process, through autonomic nervous system (ANS) responses. Taking Ekman's data and our previous results into account, we tried to verify a possible evocation by odorants of some basic emotions, i.e. anger, fear, sadness, surprise, disgust and happiness. The question investigated was: would it be possible to associate any of these emotions with a pattern of autonomic responses? A total of 15 subjects inhaled five odorants: lavender, ethyl aceto acetate, camphor, acetic acid and butyric acid acting as olfactory stimuli. After inhaling the odorant, subjects were requested to fill out an 11-point hedonic scale to rate its 'pleasantness' vs. 'unpleasantness'. ANS parameters monitored were skin potential and resistance, skin blood flow and temperature, instantaneous respiratory frequency and instantaneous heart rate. Simultaneous recording of these six autonomic parameters permitted the analysis of phasic responses through specific ANS patterns. An analysis of variance made it possible to differentiate among the five odorants. Two-by-two odorant comparisons for autonomic responses using Tukey's HSD multiple comparison test only permitted differentiation between 'pleasant' and 'unpleasant' odors. Camphor was differentiated from both types. For instance, long duration responses were associated with 'unpleasant' odors whereas camphor elicited intermediate responses. Taking into account each subject's preferential channel, it was possible to associate each ANS pattern with a basic emotion by means of a decision tree. The computation of subjects' responses made it possible to associate an odorant with a basic emotion, over the whole group: lavender elicited mostly 'happiness', as did, to a lesser degree ethyl aceto acetate; camphor induced either 'happiness', 'surprise' or 'sadness' according to subjects' past histories; butyric and acetic acids mainly induced negative emotions: 'anger' and 'disgust'. A high correlation was evidenced between subjects' hedonic evaluation and autonomic estimation of basic emotions. These results obtained from 15 subjects were compared to those observed in two similar experiments. These approaches showed comparable results. Thus, more than 60 subjects showed similar autonomic responses which can be transcribed into basic emotions. Thus, a multiparametric autonomic analysis allows the identification of the quality of the response, i.e. the type of basic emotion in addition to the intensity.

The C. elegans Hox gene egl-5 is required for correct development of the hermaphrodite hindgut and for the response to rectal infection by Microbacterium nematophilum.

PubMed

Nicholas, Hannah R; Hodgkin, Jonathan

2009-05-01

Members of the Hox gene family encode transcription factors that specify positional identity along the anterior-posterior axis of nearly all metazoans. One among the Caenorhabditis elegans Hox genes is egl-5. A deletion allele of egl-5 was isolated in a screen for animals which fail to develop swollen tails when exposed to the bacterial pathogen Microbacterium nematophilum. We show that compromised rectal development, which occurs as a result of loss of egl-5 function, results in a failure of rectal epithelial cells to express the ERK MAP kinase mpk-1, which was previously shown to mediate tail-swelling in response to bacterial infection. Tissue-specific rescue experiments demonstrated that egl-5 and mpk-1 act autonomously in rectal cells in the morphological response. The weak egl-5 allele (n1439), which does not compromise rectal development, fails to affect tail-swelling. We find that this allele carries an inserted repeat element approximately 13.8 kb upstream of the egl-5 open reading frame, which specifically disrupts the cell-specific expression of this gene in HSN egg-laying neurons. Together these findings extend the complexity of regulation and function of Hox genes in C. elegans and demonstrate the importance of their tissue-specific expression for correct development and response to infection.

The class III PI(3)K Vps34 promotes autophagy and endocytosis but not TOR signaling in Drosophila.

PubMed

Juhász, Gábor; Hill, Jahda H; Yan, Ying; Sass, Miklós; Baehrecke, Eric H; Backer, Jonathan M; Neufeld, Thomas P

2008-05-19

Degradation of cytoplasmic components by autophagy requires the class III phosphatidylinositol 3 (PI(3))-kinase Vps34, but the mechanisms by which this kinase and its lipid product PI(3) phosphate (PI(3)P) promote autophagy are unclear. In mammalian cells, Vps34, with the proautophagic tumor suppressors Beclin1/Atg6, Bif-1, and UVRAG, forms a multiprotein complex that initiates autophagosome formation. Distinct Vps34 complexes also regulate endocytic processes that are critical for late-stage autophagosome-lysosome fusion. In contrast, Vps34 may also transduce activating nutrient signals to mammalian target of rapamycin (TOR), a negative regulator of autophagy. To determine potential in vivo functions of Vps34, we generated mutations in the single Drosophila melanogaster Vps34 orthologue, causing cell-autonomous disruption of autophagosome/autolysosome formation in larval fat body cells. Endocytosis is also disrupted in Vps34(-/-) animals, but we demonstrate that this does not account for their autophagy defect. Unexpectedly, TOR signaling is unaffected in Vps34 mutants, indicating that Vps34 does not act upstream of TOR in this system. Instead, we show that TOR/Atg1 signaling regulates the starvation-induced recruitment of PI(3)P to nascent autophagosomes. Our results suggest that Vps34 is regulated by TOR-dependent nutrient signals directly at sites of autophagosome formation.

Bhlhb5 is Required for the Subtype Development of Retinal Amacrine and Bipolar Cells in Mice

PubMed Central

Huang, Liang; Hu, Fang; Feng, Liang; Luo, Xiong-Jian; Liang, Guoqing; Zeng, Xiang-Yun; Yi, Jing-Lin; Gan, Lin

2014-01-01

Background BHLHB5, an OLIG-related basic helix-loop-helix transcription factor, is required for the development of a subset of gamma-amino butyric acid–releasing (GABAergic) amacrine cells and OFF-cone bipolar (CB) cells in mouse retinas. In order to determine BHLHB5’s functional mechanism in retinogenesis, we used the Cre-loxP recombination system to genetically trace the lineage of BHLHB5+ cells in normal and Bhlhb5-null retinas. The Bhlhb5-Cre knock-in allele was used to activate the constitutive expression of a GFP reporter in the Bhlhb5-expressing cells, and the cell fates of Bhlhb5-lineage cells were identified by using specific cell markers and were compared between normal and Bhlhb5-null retinas. Results In addition to GABAergic amacrine and OFF-CB cells, Bhlhb5 lineage cells give rise to ganglion, glycinergic amacrine, rod bipolar, ON-bipolar, and rod photoreceptor cells during normal retinal development. Targeted deletion of Bhlhb5 resulted in the loss of GABAergic amacrine, glycinergic amacrine, dopaminergic amacrine, and Type 2 OFF-CB cells. Furthermore, in the absence of BHLHB5, a portion of Bhlhb5 lineage cells switch their fate and differentiate into cholinergic amacrine cells. Conclusions Our data reveal a broad expression pattern of Bhlhb5 throughout retinogenesis and demonstrate the cell-autonomous as well as non-cell-autonomous role of Bhlhb5 in the specification of amacrine and bipolar subtypes. PMID:24123365

Bhlhb5 is required for the subtype development of retinal amacrine and bipolar cells in mice.

PubMed

Huang, Liang; Hu, Fang; Feng, Liang; Luo, Xiong-Jian; Liang, Guoqing; Zeng, Xiang-Yun; Yi, Jing-Lin; Gan, Lin

2014-02-01

BHLHB5, an OLIG-related basic helix-loop-helix transcription factor, is required for the development of a subset of gamma-amino butyric acid-releasing (GABAergic) amacrine cells and OFF-cone bipolar (CB) cells in mouse retinas. In order to determine BHLHB5's functional mechanism in retinogenesis, we used the Cre-loxP recombination system to genetically trace the lineage of BHLHB5+ cells in normal and Bhlhb5-null retinas. The Bhlhb5-Cre knock-in allele was used to activate the constitutive expression of a GFP reporter in the Bhlhb5-expressing cells, and the cell fates of Bhlhb5-lineage cells were identified by using specific cell markers and were compared between normal and Bhlhb5-null retinas. In addition to GABAergic amacrine and OFF-CB cells, Bhlhb5 lineage cells give rise to ganglion, glycinergic amacrine, rod bipolar, ON-bipolar, and rod photoreceptor cells during normal retinal development. Targeted deletion of Bhlhb5 resulted in the loss of GABAergic amacrine, glycinergic amacrine, dopaminergic amacrine, and Type 2 OFF-CB cells. Furthermore, in the absence of BHLHB5, a portion of Bhlhb5 lineage cells switch their fate and differentiate into cholinergic amacrine cells. Our data reveal a broad expression pattern of Bhlhb5 throughout retinogenesis and demonstrate the cell-autonomous as well as non-cell-autonomous role of Bhlhb5 in the specification of amacrine and bipolar subtypes. Copyright © 2013 Wiley Periodicals, Inc.

Autonomous and Connected Vehicles: A Law Enforcement Primer

DTIC Science & Technology

2015-12-01

CYBERSECURITY FOR AUTOMOBILES Intelligent Transportation Systems (ITS) that are emerging around the globe achieve that classification based on the convergence...Car Works,” October 18, 2011, IEEE Spectrum, http://spectrum.ieee.org/automaton/robotics/ artificial - intelligence /how-google-self-driving-car-works...whereby artificial intelligence acts on behalf of a human, but carries the same life or death consequences.435 States should encourage and engage in

Living "a Life like Ours": Support Workers' Accounts of Substitute Decision-Making in Residential Care Homes for Adults with Intellectual Disabilities

ERIC Educational Resources Information Center

Dunn, M. C.; Clare, I. C. H.; Holland, A. J.

2010-01-01

Background: In England and Wales, the "Mental Capacity Act 2005" (MCA) provides a new legal framework to regulate substitute decision-making relating to the welfare of adults who lack the capacity to make one or more autonomous decisions about their care and support. Any substitute decision made on behalf of an adult lacking capacity…

Diversifying biological fuel cell designs by use of nanoporous filters.

PubMed

Biffinger, Justin C; Ray, Ricky; Little, Brenda; Ringeisen, Bradley R

2007-02-15

The use of proton exchange membranes (PEMs) in biological fuel cells limits the diversity of novel designs for increasing output power or enabling autonomous function in unique environments. Here we show that selected nanoporous polymer filters (nylon, cellulose, or polycarbonate) can be used effectively in place of PEMs in a miniature microbial fuel cell (mini-MFC, device cross-section 2 cm2), generating a power density of 16 W/m3 with an uncoated graphite felt oxygen reduction reaction (ORR) cathode. The incorporation of polycarbonate or nylon membranes into biological fuel cell designs produced comparable power and durability to Nafion-117 membranes. Also, high power densities for novel larger (5 cm3 anode volume, 0.6 W/m3) and smaller (0.025 cm3 projected geometric volume, average power density 10 W/m3) chamberless and pumpless microbial fuel cells were observed. As an additional benefit, the nanoporous membranes isolated the anode from invading natural bacteria, increasing the potential applications for MFCs beyond aquatic sediment environments. This work is a practical solution for decreasing the cost of biological fuel cells while incorporating new features for powering long-term autonomous devices.

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

PubMed Central

Adi Harel, S; Bossel Ben-Moshe, N; Aylon, Y; Bublik, D R; Moskovits, N; Toperoff, G; Azaiza, D; Biagoni, F; Fuchs, G; Wilder, S; Hellman, A; Blandino, G; Domany, E; Oren, M

2015-01-01

MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumor-suppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5′aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such ‘epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy. PMID:25591738

Status of development of the power plants on the base of MCFC in TFNC-VNIIEF

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

Novitski, E.Z.; Savkin, G.G.

1996-04-01

VNIIF started work on Molten Carbonate Fuel cells and power plants in 1991. Some results of VNIIF work in the direction of Autonomous Power Engineering are presented. Topics include molten carbonate fuel cell components, separator plates, manufacturing and testing, design, and goals.

Manipulation of norepinephrine metabolism with yohimbine in the treatment of autonomic failure

NASA Technical Reports Server (NTRS)

Biaggioni, I.; Robertson, R. M.; Robertson, D.

1994-01-01

It has been postulated that alpha 2-adrenergic receptors play a modulatory role in the regulation of blood pressure. Activation of alpha 2-receptors located in the central nervous system results in inhibition of sympathetic tone and decrease of blood pressure. This indeed may be the mechanism of action of central sympatholytic antihypertensives such as alpha-methyldopa. Presynaptic alpha 2-receptors also are found in adrenergic nerve terminals. These receptors act as a negative feedback mechanism by inhibiting the release of norepinephrine. The relevance of alpha 2-adrenergic receptors for blood pressure regulation can be explored with yohimbine, a selective antagonist of these receptors. Yohimbine increases blood pressure in resting normal volunteers. This effect is associated with an increase in both sympathetic nerve activity, reflecting an increase in central sympathetic outflow, and in norepinephrine spillover, reflecting potentiation of the release of norepinephrine from adrenergic nerve terminals. These actions, therefore, underscore the importance of alpha 2-adrenergic receptors for blood pressure regulation even under resting conditions. Patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yohimbine. This increased responsiveness can be explained by sensitization of adrenergic receptors, analogous to denervation supersensitivity, and by the lack of autonomic reflexes that would normally buffer any increase in blood pressure. Preliminary studies suggest that the effectiveness of yohimbine in autonomic failure can be enhanced with monoamine oxidase inhibitors. Used in combination, yohimbine increases norepinephrine release, whereas monoamine oxidase inhibitors inhibit its degradation. Therefore, yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction.

Comparison of three control methods for an autonomous vehicle

NASA Astrophysics Data System (ADS)

Deshpande, Anup; Mathur, Kovid; Hall, Ernest

2010-01-01

The desirability and challenge of developing a completely autonomous vehicle and the rising need for more efficient use of energy by automobiles motivate this research- a study for an optimum solution to computer control of energy efficient vehicles. The purpose of this paper is to compare three control methods - mechanical, hydraulic and electric that have been used to convert an experimental all terrain vehicle to drive by wire which would eventually act as a test bed for conducting research on various technologies for autonomous operation. Computer control of basic operations in a vehicle namely steering, braking and speed control have been implemented and will be described in this paper. The output from a 3 axis motion controller is used for this purpose. The motion controller is interfaced with a software program using WSDK (Windows Servo Design Kit) as an intermediate tuning layer for tuning and parameter settings in autonomous operation. The software program is developed in C++. The voltage signal sent to the motion controller can be varied through the control program for desired results in controlling the steering motor, activating the hydraulic brakes and varying the vehicle's speed. The vehicle has been tested for its basic functionality which includes testing of street legal operations and also a 1000 mile test while running in a hybrid mode. The vehicle has also been tested for control when it is interfaced with devices such as a keyboard, joystick and sensors under full autonomous operation. The vehicle is currently being tested in various safety studies and is being used as a test bed for experiments in control courses and research studies. The significance of this research is in providing a greater understanding of conventional driving controls and the possibility of improving automobile safety by removing human error in control of a motor vehicle.

Instrument-Free and Autonomous Generation of H2O2 from Mg-ZnO/Au Hybrids for Disinfection and Organic Pollutant Degradations

NASA Astrophysics Data System (ADS)

Park, Seon Yeong; Jung, Yeon Wook; Hwang, Si Hyun; Jang, Gun Hyuk; Seo, Hyunseon; Kim, Yu-Chan; Ok, Myoung-Ryul

2018-03-01

We proposed a new hybrid system that autonomously generates H2O2 without any instrument or external energy source, such as light. Electrons formed during spontaneous degradation process of Mg were conveyed to ZnO/Au oxygen-reduction-reaction nanocatalysts, and these transferred electrons converted O2 molecules in aqueous solution into H2O2. Autonomously released H2O2 from Mg-ZnO/Au hybrids effectively killed 97% of Escherichia coli cells within 1 h. Moreover, Mg-ZnO/Au nanohybrids could gradually degrade methylene blue over time with Fe2+. We believe our approach utilizing degradable metals and catalytic metal oxides in mesoporous-film form can be a promising method in the field of environment remediation.

Instrument-Free and Autonomous Generation of H2O2 from Mg-ZnO/Au Hybrids for Disinfection and Organic Pollutant Degradations

NASA Astrophysics Data System (ADS)

Park, Seon Yeong; Jung, Yeon Wook; Hwang, Si Hyun; Jang, Gun Hyuk; Seo, Hyunseon; Kim, Yu-Chan; Ok, Myoung-Ryul

2018-05-01

We proposed a new hybrid system that autonomously generates H2O2 without any instrument or external energy source, such as light. Electrons formed during spontaneous degradation process of Mg were conveyed to ZnO/Au oxygen-reduction-reaction nanocatalysts, and these transferred electrons converted O2 molecules in aqueous solution into H2O2. Autonomously released H2O2 from Mg-ZnO/Au hybrids effectively killed 97% of Escherichia coli cells within 1 h. Moreover, Mg-ZnO/Au nanohybrids could gradually degrade methylene blue over time with Fe2+. We believe our approach utilizing degradable metals and catalytic metal oxides in mesoporous-film form can be a promising method in the field of environment remediation.

MDA-9/Syntenin and IGFBP-2 Promote Angiogenesis in Human Melanoma

PubMed Central

Das, Swadesh K.; Bhutia, Sujit K.; Azab, Belal; Kegelman, Timothy P.; Peachy, Leyla; Santhekadur, Prasanna K.; Dasgupta, Santanu; Dash, Rupesh; Dent, Paul; Grant, Steven; Emdad, Luni; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B.

2012-01-01

Melanoma differentiation associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacological approaches were employed to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, CAM assays and xenograft tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several pro-angiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/syntenin in which MDA-9/syntenin interacts with the ECM activating Src and FAK resulting in activation by phosphorylation of Akt, which induces HIF-1α. The HIF-1α activates transcription of Insulin Growth Factor Binding Protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell non-autonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (non-autonomous). PMID:23233738

TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-autonomously in Caenorhabditis elegans

PubMed Central

McCallum, Katie C.; Liu, Bin; Fierro-González, Juan Carlos; Swoboda, Peter; Arur, Swathi; Miranda-Vizuete, Antonio; Garsin, Danielle A.

2016-01-01

The Caenorhabditis elegans oxidative stress response transcription factor, SKN-1, is essential for the maintenance of redox homeostasis and is a functional ortholog of the Nrf family of transcription factors. The numerous levels of regulation that govern these transcription factors underscore their importance. Here, we add a thioredoxin, encoded by trx-1, to the expansive list of SKN-1 regulators. We report that loss of trx-1 promotes nuclear localization of intestinal SKN-1 in a redox-independent, cell non-autonomous fashion from the ASJ neurons. Furthermore, this regulation is not general to the thioredoxin family, as two other C. elegans thioredoxins, TRX-2 and TRX-3, do not play a role in this process. Moreover, TRX-1-dependent regulation requires signaling from the p38 MAPK-signaling pathway. However, while TRX-1 regulates SKN-1 nuclear localization, classical SKN-1 transcriptional activity associated with stress response remains largely unaffected. Interestingly, RNA-Seq analysis revealed that loss of trx-1 elicits a general, organism-wide down-regulation of several classes of genes; those encoding for collagens and lipid transport being most prevalent. Together, these results uncover a novel role for a thioredoxin in regulating intestinal SKN-1 nuclear localization in a cell non-autonomous manner, thereby contributing to the understanding of the processes involved in maintaining redox homeostasis throughout an organism. PMID:26920757

TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-autonomously in Caenorhabditis elegans.

PubMed

McCallum, Katie C; Liu, Bin; Fierro-González, Juan Carlos; Swoboda, Peter; Arur, Swathi; Miranda-Vizuete, Antonio; Garsin, Danielle A

2016-05-01

The Caenorhabditis elegans oxidative stress response transcription factor, SKN-1, is essential for the maintenance of redox homeostasis and is a functional ortholog of the Nrf family of transcription factors. The numerous levels of regulation that govern these transcription factors underscore their importance. Here, we add a thioredoxin, encoded by trx-1, to the expansive list of SKN-1 regulators. We report that loss of trx-1 promotes nuclear localization of intestinal SKN-1 in a redox-independent, cell non-autonomous fashion from the ASJ neurons. Furthermore, this regulation is not general to the thioredoxin family, as two other C. elegans thioredoxins, TRX-2 and TRX-3, do not play a role in this process. Moreover, TRX-1-dependent regulation requires signaling from the p38 MAPK-signaling pathway. However, while TRX-1 regulates SKN-1 nuclear localization, classical SKN-1 transcriptional activity associated with stress response remains largely unaffected. Interestingly, RNA-Seq analysis revealed that loss of trx-1 elicits a general, organism-wide down-regulation of several classes of genes; those encoding for collagens and lipid transport being most prevalent. Together, these results uncover a novel role for a thioredoxin in regulating intestinal SKN-1 nuclear localization in a cell non-autonomous manner, thereby contributing to the understanding of the processes involved in maintaining redox homeostasis throughout an organism. Copyright © 2016 by the Genetics Society of America.

Self-Sealing Wet Chemistry Cell for Field Analysis

NASA Technical Reports Server (NTRS)

Beegle, Luther W.; Soto, Juancarlos; Lasnik, James; Roark, Shane

2012-01-01

In most analytical investigations, there is a need to process complex field samples for the unique detection of analytes, especially when detecting low concentration organic molecules that may identify extraterrestrial life. Wet chemistry based instruments are the techniques of choice for most laboratory- based analysis of organic molecules due to several factors including less fragmentation of fragile biomarkers, and ability to concentrate target species resulting in much lower limits of detection. Development of an automated wet chemistry preparation system that can operate autonomously on Earth and is also designed to operate under Martian ambient conditions will demonstrate the technical feasibility of including wet chemistry on future missions. An Automated Sample Processing System (ASPS) has recently been developed that receives fines, extracts organics through solvent extraction, processes the extract by removing non-organic soluble species, and delivers sample to multiple instruments for analysis (including for non-organic soluble species). The key to this system is a sample cell that can autonomously function under field conditions. As a result, a self-sealing sample cell was developed that can autonomously hermetically seal fines and powder into a container, regardless of orientation of the apparatus. The cap is designed with a beveled edge, which allows the cap to be self-righted as the capping motor engages. Each cap consists of a C-clip lock ring below a crucible O-ring that is placed into a groove cut into the sample cap.

Neuropeptides and nitric oxide synthase in the gill and the air-breathing organs of fishes.

PubMed

Zaccone, Giacomo; Mauceri, Angela; Fasulo, Salvatore

2006-05-01

Anatomical and histochemical studies have demonstrated that the bulk of autonomic neurotransmission in fish gill is attributed to cholinergic and adrenergic mechanisms (Nilsson. 1984. In: Hoar WS, Randall DJ, editors. Fish physiology, Vol. XA. Orlando: Academic Press. p 185-227; Donald. 1998. In: Evans DH, editor. The physiology of fishes, 2nd edition. Boca Raton: CRC Press. p 407-439). In many tissues, blockade of adrenergic and cholinergic transmission results in residual responses to nerve stimulation, which are termed NonAdrenergic, NonCholinergic (NANC). The discovery of nitric oxide (NO) has provided a basis for explaining many examples of NANC transmissions with accumulated physiological and pharmacological data indicating its function as a primary NANC transmitter. Little is known about the NANC neurotransmission, and studies on neuropeptides and NOS (Nitric Oxide Synthase) are very fragmentary in the gill and the air-breathing organs of fishes. Knowledge of the distribution of nerves and effects of perfusing agonists may help to understand the mechanisms of perfusion regulation in the gill (Olson. 2002. J Exp Zool 293:214-231). Air breathing as a mechanism for acquiring oxygen has evolved independently in several groups of fishes, necessitating modifications of the organs responsible for the exchange of gases. Aquatic hypoxia in freshwaters has been probably the more important selective force in the evolution of air breathing in vertebrates. Fishes respire with gills that are complex structures with many different effectors and potential control systems. Autonomic innervation of the gill has received considerable attention. An excellent review on branchial innervation includes Sundin and Nilsson's (2002. J Exp Zool 293:232-248) with an emphasis on the anatomy and basic functioning of afferent and efferent fibers of the branchial nerves. The chapters by Evans (2002. J Exp Zool 293:336-347) and Olson (2002) provide new challenges about a variety of neurocrine, endocrine, paracrine and autocrine signals that modulate gill perfusion and ionic transport. The development of the immunohistochemical techniques has led to a new phase of experimentation and to information mainly related to gills rather than air-breathing organs of fishes. During the last few years, identification of new molecules as autonomic neurotransmitters, monoamines and NO, and of their multiple roles as cotransmitters, has reshaped our knowledge of the mechanisms of autonomic regulation of various functions in the organs of teleosts (Donald, '98).NO acts as neurotransmitter and is widely distributed in the nerves and the neuroepithelial cells of the gill, the nerves of visceral muscles of the lung of polypterids, the vascular endothelial cells in the air sac of Heteropneustes fossilis and the respiratory epithelium in the swimbladder of the catfish Pangasius hypophthalmus. In addition, 5-HT, enkephalins and some neuropeptides, such as VIP and PACAP, seem to be NANC transmitter candidates in the fish gill and polypterid lung. The origin and function of NANC nerves in the lung of air-breathing fishes await investigation. Several mechanisms have developed in the Vertebrates to control the flow of blood to respiratory organs. These mechanisms include a local production of vasoactive substances, a release of endocrine hormones into the circulation and neuronal mechanisms. Air breathers may be expected to have different control mechanisms compared with fully aquatic fishes. Therefore, we need to know the distribution and function of autonomic nerves in the air-breathing organs of the fishes.

Downregulation of adaptor protein MyD88 compromises the angiogenic potential of B16 murine melanoma

PubMed Central

Araya, Paula; Nuñez, Nicolás Gonzalo; Mena, Hebe Agustina; Bocco, José Luis; Negrotto, Soledad; Maccioni, Mariana

2017-01-01

The mechanisms that link inflammatory responses to cancer development remain a subject of intense investigation, emphasizing the need to better understand the cellular and molecular pathways that create a tumor promoting microenvironment. The myeloid differentiation primary response protein MyD88 acts as a main adaptor molecule for the signaling cascades initiated from Toll-like receptors (TLRs) and the interleukin 1 receptor (IL-1R). MyD88 has been shown to contribute to tumorigenesis in many inflammation-associated cancer models. In this study, we sought to better define the role of MyD88 in neoplastic cells using a murine melanoma model. Herein, we have demonstrated that MyD88 expression is required to maintain the angiogenic switch that supports B16 melanoma growth. By knocking down MyD88 we reduced TLR-mediated NF-κB activation with no evident effects over cell proliferation and survival. In addition, MyD88 downregulation was associated with a decrease of HIF1α levels and its target gene VEGF, in correlation with an impaired capability to induce capillary sprouting and tube formation of endothelial cells. Melanomas developed from cells lacking MyD88 showed an enhanced secretion of chemoattractant ligands such as CCL2, CXCL10 and CXCL1 and have an improved infiltration of macrophages to the tumor site. Our results imply that cell-autonomous signaling through MyD88 is required to sustain tumor growth and underscore its function as an important positive modulator of tumor angiogenesis. PMID:28662055

Functional significance and control of release of pulmonary surfactant in the lizard lung.

PubMed

Wood, P G; Daniels, C B; Orgeig, S

1995-10-01

The amount of pulmonary surfactant in the lungs of the bearded dragon (Pogona vitticeps) increases with increasing body temperature. This increase coincides with a decrease in lung compliance. The relationship between surfactant and lung compliance and the principal stimuli for surfactant release and composition (temperature, ventilatory pattern, and autonomic neurotransmitters) were investigated. We chose to investigate ventilatory pattern (which causes mechanical deformation of the type II cells) and adrenergic agents, because they are the major stimuli for surfactant release in mammals. To examine the effects of body temperature and ventilatory pattern, isolated lungs were ventilated at either 18 or 37 degrees C at different ventilatory regimens. An isolated perfused lung preparation at 27 degrees C was used to analyze the effects of autonomic neurotransmitters. Ventilatory pattern did not affect surfactant release, composition, or lung compliance at either 18 or 37 degrees C. An increase in temperature increased phospholipid reuptake and disproportionately increased cholesterol degradation/uptake. Epinephrine and acetylcholine stimulated phospholipid but not cholesterol release. Removal of surfactant caused a decrease in compliance, regardless of the experimental temperature. Temperature appears to be the principal determinant of lung compliance in the bearded dragon, acting directly to increase the tone of the smooth muscle. Increasing the ambient temperature may result in greater surfactant turnover by increasing cholesterol reuptake/degradation directly and by increasing circulating epinephrine, thereby indirectly increasing phospholipid secretion. We suggest that changing ventilatory pattern may be inadequate as a mechanism for maintaining surfactant homeostasis, given the discontinuous, highly variable reptilian breathing pattern.

Thymus-autonomous T cell development in the absence of progenitor import.

PubMed

Martins, Vera C; Ruggiero, Eliana; Schlenner, Susan M; Madan, Vikas; Schmidt, Manfred; Fink, Pamela J; von Kalle, Christof; Rodewald, Hans-Reimer

2012-07-30

Thymus function is thought to depend on a steady supply of T cell progenitors from the bone marrow. The notion that the thymus lacks progenitors with self-renewal capacity is based on thymus transplantation experiments in which host-derived thymocytes replaced thymus-resident cells within 4 wk. Thymus grafting into T cell-deficient mice resulted in a wave of T cell export from the thymus, followed by colonization of the thymus by host-derived progenitors, and cessation of T cell development. Compound Rag2(-/-)γ(c)(-/-)Kit(W/Wv) mutants lack competitive hematopoietic stem cells (HSCs) and are devoid of T cell progenitors. In this study, using this strain as recipients for wild-type thymus grafts, we noticed thymus-autonomous T cell development lasting several months. However, we found no evidence for export of donor HSCs from thymus to bone marrow. A diverse T cell antigen receptor repertoire in progenitor-deprived thymus grafts implied that many thymocytes were capable of self-renewal. Although the process was most efficient in Rag2(-/-)γ(c)(-/-)Kit(W/Wv) hosts, γ(c)-mediated signals alone played a key role in the competition between thymus-resident and bone marrow-derived progenitors. Hence, the turnover of each generation of thymocytes is not only based on short life span but is also driven via expulsion of resident thymocytes by fresh progenitors entering the thymus.

Simulation of Cell Patterning Triggered by Cell Death and Differential Adhesion in Drosophila Wing.

PubMed

Nagai, Tatsuzo; Honda, Hisao; Takemura, Masahiko

2018-02-27

The Drosophila wing exhibits a well-ordered cell pattern, especially along the posterior margin, where hair cells are arranged in a zigzag pattern in the lateral view. Based on an experimental result observed during metamorphosis of Drosophila, we considered that a pattern of initial cells autonomously develops to the zigzag pattern through cell differentiation, intercellular communication, and cell death (apoptosis) and performed computer simulations of a cell-based model of vertex dynamics for tissues. The model describes the epithelial tissue as a monolayer cell sheet of polyhedral cells. Their vertices move according to equations of motion, minimizing the sum total of the interfacial and elastic energies of cells. The interfacial energy densities between cells are introduced consistently with an ideal zigzag cell pattern, extracted from the experimental result. The apoptosis of cells is modeled by gradually reducing their equilibrium volume to zero and by assuming that the hair cells prohibit neighboring cells from undergoing apoptosis. Based on experimental observations, we also assumed wing elongation along the proximal-distal axis. Starting with an initial cell pattern similar to the micrograph experimentally obtained just before apoptosis, we carried out the simulations according to the model mentioned above and successfully reproduced the ideal zigzag cell pattern. This elucidates a physical mechanism of patterning triggered by cell apoptosis theoretically and exemplifies, to our knowledge, a new framework to study apoptosis-induced patterning. We conclude that the zigzag cell pattern is formed by an autonomous communicative process among the participant cells. Copyright © 2018 Biophysical Society. All rights reserved.

Compute Element and Interface Box for the Hazard Detection System

NASA Technical Reports Server (NTRS)

Villalpando, Carlos Y.; Khanoyan, Garen; Stern, Ryan A.; Some, Raphael R.; Bailey, Erik S.; Carson, John M.; Vaughan, Geoffrey M.; Werner, Robert A.; Salomon, Phil M.; Martin, Keith E.;

Autonomous navigation system and method

DOEpatents

Bruemmer, David J [Idaho Falls, ID; Few, Douglas A [Idaho Falls, ID

2009-09-08

A robot platform includes perceptors, locomotors, and a system controller, which executes instructions for autonomously navigating a robot. The instructions repeat, on each iteration through an event timing loop, the acts of defining an event horizon based on the robot's current velocity, detecting a range to obstacles around the robot, testing for an event horizon intrusion by determining if any range to the obstacles is within the event horizon, and adjusting rotational and translational velocity of the robot accordingly. If the event horizon intrusion occurs, rotational velocity is modified by a proportion of the current rotational velocity reduced by a proportion of the range to the nearest obstacle and translational velocity is modified by a proportion of the range to the nearest obstacle. If no event horizon intrusion occurs, translational velocity is set as a ratio of a speed factor relative to a maximum speed.

An Autonomous Flight Safety System

NASA Technical Reports Server (NTRS)

Bull, James B.; Lanzi, Raymond J.

2007-01-01

The Autonomous Flight Safety System (AFSS) being developed by NASA s Goddard Space Flight Center s Wallops Flight Facility and Kennedy Space Center has completed two successful developmental flights and is preparing for a third. AFSS has been demonstrated to be a viable architecture for implementation of a completely vehicle based system capable of protecting life and property in event of an errant vehicle by terminating the flight or initiating other actions. It is capable of replacing current human-in-the-loop systems or acting in parallel with them. AFSS is configured prior to flight in accordance with a specific rule set agreed upon by the range safety authority and the user to protect the public and assure mission success. This paper discusses the motivation for the project, describes the method of development, and presents an overview of the evolving architecture and the current status.

Full autonomous microline trace robot

NASA Astrophysics Data System (ADS)

Yi, Deer; Lu, Si; Yan, Yingbai; Jin, Guofan

2000-10-01

Optoelectric inspection may find applications in robotic system. In micro robotic system, smaller optoelectric inspection system is preferred. However, as miniaturizing the size of the robot, the number of the optoelectric detector becomes lack. And lack of the information makes the micro robot difficult to acquire its status. In our lab, a micro line trace robot has been designed, which autonomous acts based on its optoelectric detection. It has been programmed to follow a black line printed on the white colored ground. Besides the optoelectric inspection, logical algorithm in the microprocessor is also important. In this paper, we propose a simply logical algorithm to realize robot's intelligence. The robot's intelligence is based on a AT89C2051 microcontroller which controls its movement. The technical details of the micro robot are as follow: dimension: 30mm*25mm*35*mm; velocity: 60mm/s.

Autonomously Propelled Motors for Value-Added Product Synthesis and Purification.

PubMed

Srivastava, Sarvesh K; Schmidt, Oliver G

2016-06-27

A proof-of-concept design for autonomous, self-propelling motors towards value-added product synthesis and separation is presented. The hybrid motor design consists of two distinct functional blocks. The first, a sodium borohydride (NaBH4 ) granule, serves both as a reaction prerequisite for the reduction of vanillin and also as a localized solid-state fuel in the reaction mixture. The second capping functional block consisting of a graphene-polymer composite serves as a hydrophobic matrix to attract the reaction product vanillyl alcohol (VA), resulting in facile separation of this edible value-added product. These autonomously propelled motors were fabricated at a length scale down to 400 μm, and once introduced in the reaction environment showed rapid bubble-propulsion followed by high-purity separation of the reaction product (VA) by the virtue of the graphene-polymer cap acting as a mesoporous sponge. The concept has excellent potential towards the synthesis/isolation of industrially important compounds, affinity-based product separation, pollutant remediation (such as heavy metal chelation/adsorption), as well as localized fuel-gradients as an alternative to external fuel dependency. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DARPA Orbital Express program: effecting a revolution in space-based systems

NASA Astrophysics Data System (ADS)

Whelan, David A.; Adler, E. A.; Wilson, Samuel B., III; Roesler, Gordon M., Jr.

2000-11-01

A primary goal of the Defense Advanced Research Projects Agency is to develop innovative, high-risk technologies with the potential of a revolutionary impact on missions of the Department of Defense. DARPA is developing a space experiment to prove the feasibility of autonomous on- orbit servicing of spacecraft. The Orbital Express program will demonstrate autonomous on-orbit refueling, as well as autonomous delivery of a small payload representing an avionics upgrade package. The maneuverability provided to spacecraft from a ready refueling infrastructure will enable radical new capabilities for the military, civil and commercial spacecraft. Module replacement has the potential to extend bus lifetimes, and to upgrade the performance of key subsystems (e.g. processors) at the pace of technology development. The Orbital Express technology development effort will include the necessary autonomy for a viable servicing infrastructure; a universal interface for docking, refueling and module transfers; and a spacecraft bus design compatible with this servicing concept. The servicer spacecraft of the future may be able to act as a host platform for microsatellites, extending their capabilities while reducing risk. An infrastructure based on Orbital Express also benefits from, and stimulates the development of, lower-cost launch strategies.

An evaluation of a training placement in general practice for paramedic practitioner students: improving patient-centred care through greater interprofessional understanding and supporting the development of autonomous practitioners.

PubMed

Ruston, Annmarie; Tavabie, Abdol

2011-01-01

To report the extent to which the placement of paramedic practitioner students (PPSs) in accredited general practice (GP) training practices supported their development as autonomous, patient-centred practitioners and fostered interprofessional learning. A case study method was used. Sources of data included semi-structured telephone interviews (eight PPSs, eight GP trainers), an online end of placement survey and placement and assessment documentation. Interview data were transcribed and analysed using the constant comparative method. Accredited training practices in South East England. All respondents were positive that the placement provided a high-quality interprofessional learning environment which provided PPSs with learning opportunities based on assessed need, the support of experienced trainers and access to a wide range of patients and learning situations. The placement enabled PPSs to acquire the appropriate skills, knowledge and understanding to act as autonomous, patient-centred practitioners. The placement provides a sound model for expanding the skills of paramedic practitioners in order to meet the increasing demands for patient-centred, community based health care. It provided them with the skills to treat patients closer to home rather than automatically transporting them to hospital.

The GATA transcription factor gene gtaG is required for terminal differentiation in Dictyostelium

PubMed Central

2016-01-01

ABSTRACT The GATA transcription factor GtaG is conserved in Dictyostelids and is essential for terminal differentiation in Dictyostelium discoideum, but its function is not well understood. Here, we show that gtaG is expressed in prestalk cells at the anterior region of fingers and in the extending stalk during culmination. The gtaG− phenotype is cell-autonomous in prestalk cells and non-cell-autonomous in prespore cells. Transcriptome analyses reveal that GtaG regulates prestalk gene expression during cell differentiation before culmination and is required for progression into culmination. GtaG-dependent genes include genetic suppressors of the Dd-STATa-defective phenotype (Dd-STATa is also known as DstA) as well as Dd-STATa target-genes, including extracellular matrix genes. We show that GtaG might be involved in the production of two culmination-signaling molecules, cyclic di-GMP (c-di-GMP) and the spore differentiation factor SDF-1, and that addition of c-di-GMP rescues the gtaG− culmination and spore formation deficiencies. We propose that GtaG is a regulator of terminal differentiation that functions in concert with Dd-STATa and controls culmination through regulating c-di-GMP and SDF-1 production in prestalk cells. PMID:26962009

NF-κB Activation Protects Oligodendrocytes against Inflammation

PubMed Central

Stone, Sarrabeth; Jamison, Stephanie; Yue, Yuan; Durose, Wilaiwan

2017-01-01

NF-κB is a key player in inflammatory diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the effects of NF-κB activation on oligodendrocytes in MS and EAE remain unknown. We generated a mouse model that expresses IκBαΔN, a super-suppressor of NF-κB, specifically in oligodendrocytes and demonstrated that IκBαΔN expression had no effect on oligodendrocytes under normal conditions (both sexes). Interestingly, we showed that oligodendrocyte-specific expression of IκBαΔN blocked NF-κB activation in oligodendrocytes and resulted in exacerbated oligodendrocyte death and hypomyelination in young, developing mice that express IFN-γ ectopically in the CNS (both sexes). We also showed that NF-κB inactivation in oligodendrocytes aggravated IFN-γ-induced remyelinating oligodendrocyte death and remyelination failure in the cuprizone model (male mice). Moreover, we found that NF-κB inactivation in oligodendrocytes increased the susceptibility of mice to EAE (female mice). These findings imply the cytoprotective effects of NF-κB activation on oligodendrocytes in MS and EAE. SIGNIFICANCE STATEMENT Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. NF-κB is a major player in inflammatory diseases that acts by regulating inflammation and cell viability. Data indicate that NF-κB activation in inflammatory cells facilitates the development of MS. However, to date, attempts to understand the role of NF-κB activation in oligodendrocytes in MS have been unsuccessful. Herein, we generated a mouse model that allows for inactivation of NF-κB specifically in oligodendrocytes and then used this model to determine the precise role of NF-κB activation in oligodendrocytes in models of MS. The results presented in this study represent the first demonstration that NF-κB activation acts cell autonomously to protect oligodendrocytes against inflammation in animal models of MS. PMID:28842413

EGL-20/Wnt and MAB-5/Hox Act Sequentially to Inhibit Anterior Migration of Neuroblasts in C. elegans

PubMed Central

Josephson, Matthew P.; Chai, Yongping; Ou, Guangshuo; Lundquist, Erik A.

2016-01-01

Directed neuroblast and neuronal migration is important in the proper development of nervous systems. In C. elegans the bilateral Q neuroblasts QR (on the right) and QL (on the left) undergo an identical pattern of cell division and differentiation but migrate in opposite directions (QR and descendants anteriorly and QL and descendants posteriorly). EGL-20/Wnt, via canonical Wnt signaling, drives the expression of MAB-5/Hox in QL but not QR. MAB-5 acts as a determinant of posterior migration, and mab-5 and egl-20 mutants display anterior QL descendant migrations. Here we analyze the behaviors of QR and QL descendants as they begin their anterior and posterior migrations, and the effects of EGL-20 and MAB-5 on these behaviors. The anterior and posterior daughters of QR (QR.a/p) after the first division immediately polarize and begin anterior migration, whereas QL.a/p remain rounded and non-migratory. After ~1 hour, QL.a migrates posteriorly over QL.p. We find that in egl-20/Wnt, bar-1/β-catenin, and mab-5/Hox mutants, QL.a/p polarize and migrate anteriorly, indicating that these molecules normally inhibit anterior migration of QL.a/p. In egl-20/Wnt mutants, QL.a/p immediately polarize and begin migration, whereas in bar-1/β-catenin and mab-5/Hox, the cells transiently retain a rounded, non-migratory morphology before anterior migration. Thus, EGL-20/Wnt mediates an acute inhibition of anterior migration independently of BAR-1/β-catenin and MAB-5/Hox, and a later, possible transcriptional response mediated by BAR-1/β-catenin and MAB-5/Hox. In addition to inhibiting anterior migration, MAB-5/Hox also cell-autonomously promotes posterior migration of QL.a (and QR.a in a mab-5 gain-of-function). PMID:26863303

Extrinsic Repair of Injured Dendrites as a Paradigm for Regeneration by Fusion in Caenorhabditis elegans.

PubMed

Oren-Suissa, Meital; Gattegno, Tamar; Kravtsov, Veronika; Podbilewicz, Benjamin

2017-05-01

Injury triggers regeneration of axons and dendrites. Research has identified factors required for axonal regeneration outside the CNS, but little is known about regeneration triggered by dendrotomy. Here, we study neuronal plasticity triggered by dendrotomy and determine the fate of complex PVD arbors following laser surgery of dendrites. We find that severed primary dendrites grow toward each other and reconnect via branch fusion. Simultaneously, terminal branches lose self-avoidance and grow toward each other, meeting and fusing at the tips via an AFF-1-mediated process. Ectopic branch growth is identified as a step in the regeneration process required for bypassing the lesion site. Failure of reconnection to the severed dendrites results in degeneration of the distal end of the neuron. We discover pruning of excess branches via EFF-1 that acts to recover the original wild-type arborization pattern in a late stage of the process. In contrast, AFF-1 activity during dendritic auto-fusion is derived from the lateral seam cells and not autonomously from the PVD neuron. We propose a model in which AFF-1-vesicles derived from the epidermal seam cells fuse neuronal dendrites. Thus, EFF-1 and AFF-1 fusion proteins emerge as new players in neuronal arborization and maintenance of arbor connectivity following injury in Caenorhabditis elegans Our results demonstrate that there is a genetically determined multi-step pathway to repair broken dendrites in which EFF-1 and AFF-1 act on different steps of the pathway. EFF-1 is essential for dendritic pruning after injury and extrinsic AFF-1 mediates dendrite fusion to bypass injuries. Copyright © 2017 by the Genetics Society of America.

Turtle Functions Downstream of Cut in Differentially Regulating Class Specific Dendrite Morphogenesis in Drosophila

PubMed Central

Sulkowski, Mikolaj J.; Iyer, Srividya Chandramouli; Kurosawa, Mathieu S.; Iyer, Eswar Prasad R.; Cox, Daniel N.

2011-01-01

Background Dendritic morphology largely determines patterns of synaptic connectivity and electrochemical properties of a neuron. Neurons display a myriad diversity of dendritic geometries which serve as a basis for functional classification. Several types of molecules have recently been identified which regulate dendrite morphology by acting at the levels of transcriptional regulation, direct interactions with the cytoskeleton and organelles, and cell surface interactions. Although there has been substantial progress in understanding the molecular mechanisms of dendrite morphogenesis, the specification of class-specific dendritic arbors remains largely unexplained. Furthermore, the presence of numerous regulators suggests that they must work in concert. However, presently, few genetic pathways regulating dendrite development have been defined. Methodology/Principal Findings The Drosophila gene turtle belongs to an evolutionarily conserved class of immunoglobulin superfamily members found in the nervous systems of diverse organisms. We demonstrate that Turtle is differentially expressed in Drosophila da neurons. Moreover, MARCM analyses reveal Turtle acts cell autonomously to exert class specific effects on dendritic growth and/or branching in da neuron subclasses. Using transgenic overexpression of different Turtle isoforms, we find context-dependent, isoform-specific effects on mediating dendritic branching in class II, III and IV da neurons. Finally, we demonstrate via chromatin immunoprecipitation, qPCR, and immunohistochemistry analyses that Turtle expression is positively regulated by the Cut homeodomain transcription factor and via genetic interaction studies that Turtle is downstream effector of Cut-mediated regulation of da neuron dendrite morphology. Conclusions/Significance Our findings reveal that Turtle proteins differentially regulate the acquisition of class-specific dendrite morphologies. In addition, we have established a transcriptional regulatory interaction between Cut and Turtle, representing a novel pathway for mediating class specific dendrite development. PMID:21811639

Role of the autonomic nervous system in tumorigenesis and metastasis

PubMed Central

Magnon, Claire

2015-01-01

Convergence of multiple stromal cell types is required to develop a tumorigenic niche that nurtures the initial development of cancer and its dissemination. Although the immune and vascular systems have been shown to have strong influences on cancer, a growing body of evidence points to a role of the nervous system in promoting cancer development. This review discusses past and current research that shows the intriguing role of autonomic nerves, aided by neurotrophic growth factors and axon cues, in creating a favorable environment for the promotion of tumor formation and metastasis. PMID:27308436

Role of the autonomic nervous system in tumorigenesis and metastasis.

PubMed

Magnon, Claire

2015-01-01

Convergence of multiple stromal cell types is required to develop a tumorigenic niche that nurtures the initial development of cancer and its dissemination. Although the immune and vascular systems have been shown to have strong influences on cancer, a growing body of evidence points to a role of the nervous system in promoting cancer development. This review discusses past and current research that shows the intriguing role of autonomic nerves, aided by neurotrophic growth factors and axon cues, in creating a favorable environment for the promotion of tumor formation and metastasis.

Proliferation of murine midbrain neural stem cells depends upon an endogenous sonic hedgehog (Shh) source.

PubMed

Martínez, Constanza; Cornejo, Víctor Hugo; Lois, Pablo; Ellis, Tammy; Solis, Natalia P; Wainwright, Brandon J; Palma, Verónica

2013-01-01

The Sonic Hedgehog (Shh) pathway is responsible for critical patterning events early in development and for regulating the delicate balance between proliferation and differentiation in the developing and adult vertebrate brain. Currently, our knowledge of the potential role of Shh in regulating neural stem cells (NSC) is largely derived from analyses of the mammalian forebrain, but for dorsal midbrain development it is mostly unknown. For a detailed understanding of the role of Shh pathway for midbrain development in vivo, we took advantage of mouse embryos with cell autonomously activated Hedgehog (Hh) signaling in a conditional Patched 1 (Ptc1) mutant mouse model. This animal model shows an extensive embryonic tectal hypertrophy as a result of Hh pathway activation. In order to reveal the cellular and molecular origin of this in vivo phenotype, we established a novel culture system to evaluate neurospheres (nsps) viability, proliferation and differentiation. By recreating the three-dimensional (3-D) microenvironment we highlight the pivotal role of endogenous Shh in maintaining the stem cell potential of tectal radial glial cells (RGC) and progenitors by modulating their Ptc1 expression. We demonstrate that during late embryogenesis Shh enhances proliferation of NSC, whereas blockage of endogenous Shh signaling using cyclopamine, a potent Hh pathway inhibitor, produces the opposite effect. We propose that canonical Shh signaling plays a central role in the control of NSC behavior in the developing dorsal midbrain by acting as a niche factor by partially mediating the response of NSC to epidermal growth factor (EGF) and fibroblast growth factor (FGF) signaling. We conclude that endogenous Shh signaling is a critical mechanism regulating the proliferation of stem cell lineages in the embryonic dorsal tissue.

S6K links cell fate, cell cycle and nutrient response in C. elegans germline stem/progenitor cells

PubMed Central

Korta, Dorota Z.; Tuck, Simon; Hubbard, E. Jane Albert

2012-01-01

Coupling of stem/progenitor cell proliferation and differentiation to organismal physiological demands ensures the proper growth and homeostasis of tissues. However, in vivo mechanisms underlying this control are poorly characterized. We investigated the role of ribosomal protein S6 kinase (S6K) at the intersection of nutrition and the establishment of a stem/progenitor cell population using the C. elegans germ line as a model. We find that rsks-1 (which encodes the worm homolog of mammalian p70S6K) is required germline-autonomously for proper establishment of the germline progenitor pool. In the germ line, rsks-1 promotes cell cycle progression and inhibits larval progenitor differentiation, promotes growth of adult tumors and requires a conserved TOR phosphorylation site. Loss of rsks-1 and ife-1 (eIF4E) together reduces the germline progenitor pool more severely than either single mutant and similarly to reducing the activity of let-363 (TOR) or daf-15 (RAPTOR). Moreover, rsks-1 acts in parallel with the glp-1 (Notch) and daf-2 (insulin-IGF receptor) pathways, and does not share the same genetic dependencies with its role in lifespan control. We show that overall dietary restriction and amino acid deprivation cause germline defects similar to a subset of rsks-1 mutant phenotypes. Consistent with a link between diet and germline proliferation via rsks-1, loss of rsks-1 renders the germ line largely insensitive to the effects of dietary restriction. Our studies establish the C. elegans germ line as an in vivo model to understand TOR-S6K signaling in proliferation and differentiation and suggest that this pathway is a key nutrient-responsive regulator of germline progenitors. PMID:22278922

Adult epidermal Notch activity induces dermal accumulation of T cells and neural crest derivatives through upregulation of jagged 1

PubMed Central

Ambler, Carrie A.; Watt, Fiona M.

2010-01-01

Notch signalling regulates epidermal differentiation and tumour formation via non-cell autonomous mechanisms that are incompletely understood. This study shows that epidermal Notch activation via a 4-hydroxy-tamoxifen-inducible transgene caused epidermal thickening, focal detachment from the underlying dermis and hair clumping. In addition, there was dermal accumulation of T lymphocytes and stromal cells, some of which localised to the blisters at the epidermal-dermal boundary. The T cell infiltrate was responsible for hair clumping but not for other Notch phenotypes. Notch-induced stromal cells were heterogeneous, expressing markers of neural crest, melanocytes, smooth muscle and peripheral nerve. Although Slug1 expression was expanded in the epidermis, the stromal cells did not arise through epithelial-mesenchymal transition. Epidermal Notch activation resulted in upregulation of jagged 1 in both epidermis and dermis. When Notch was activated in the absence of epidermal jagged 1, jagged 1 was not upregulated in the dermis, and epidermal thickening, blister formation, accumulation of T cells and stromal cells were inhibited. Gene expression profiling revealed that epidermal Notch activation resulted in upregulation of several growth factors and cytokines, including TNFα, the expression of which was dependent on epidermal jagged 1. We conclude that jagged 1 is a key mediator of non-cell autonomous Notch signalling in skin. PMID:20940224

Emergent behavior of cells on microfabricated soft polymeric substrates

NASA Astrophysics Data System (ADS)

Anand, Sandeep Venkit

In recent years, cell based bio-actuators like cardiomyocytes and skeletal muscle cells have emerged as popular choices for powering biological machines consisting of soft polymeric scaffolds at the micro and macro scales. This is owing to their unique ability to generate spontaneous, synchronous contractions either autonomously or under externally applied fields. Most of the biological machine designs reported in literature use single cells or cell clusters conjugated with biocompatible soft polymers like polydimethylsiloxane (PDMS) and hydrogels to produce some form of locomotion by converting chemical energy of the cells to mechanical energy. The mode of locomotion may vary, but the fundamental mechanism that these biological machines exploit to achieve locomotion stems from cell substrate interactions leading to large deformations of the substrates (relative to the cell size). However, the effect of such large scale, dynamic deformation of the substrates on the cellular and cluster level organization of the cells remains elusive. This dissertation tries to explore the emergent behavior of cells on different types of micro-scale deformable, soft polymeric substrates. In the first part of the dissertation, contractile dynamics of primary cardiomyocyte clusters is studied by culturing them on deformable thin polymeric films. The cell clusters beat and generate sufficient forces to deform the substrates out of plane. Over time, the clusters reorient their force dipoles along the direction of maximum compliance. This suggests that the cells are capable of sensing substrate deformations through a mechanosensitive feedback mechanism and dynamically reorganizing themselves. Results are further validated through finite element analysis. The development, characterization and quantification of a novel 1D/2D like polymeric platform for cell culture is presented in the second part. The platform consists of a 2D surface anchoring a long (few millimeters) narrow filament (1D) with a single cell scale (micro scale) cross section. We plate C2C12 cells on the platform and characterize their migration, proliferation, and differentiation patterns in contrast to 2D culture. We find that the cells land on the 2D surface, and then migrate to the filament only when the 2D surface has become nearly confluent. Individual and isolated cells randomly approaching the filament always retract away towards the 2D surface. Once on the filament, their differentiation to myotubes is expedited compared to that on 2D substrate. The myotubes generate periodic twitching forces that deform the filament producing more than 17 um displacement at the tip. Such flagellar motion can be used to develop autonomous micro scale bio-bots. Finally, the design and fabrication of a polymeric micro-pillar based force sensor capable of measuring cellular focal-adhesion forces under externally applied stretch is discussed. The force sensor consists of arrays of uniformly spaced PDMS micro-pillars of 1-2 um diameter and 2-3 um spacing on a macroscale PDMS substrate. The tips of the micro-pillars are selectively patterned with fluorescently labeled ECM proteins using micro-contact printing to promote cell adhesion while simultaneously acting as markers for strain measurements. Cells adhere and spread on top of the pillars causing them to deform. When stretched, the cells reorganize their internal structure and modulate their traction forces in response to the applied stretch. The dynamically varying cellular forces in response to the stretch are computed by measuring the cell induced displacements estimated by isolating the displacements caused by the applied stretch from the net displacements of the tips.

Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy.

PubMed

Noguchi, Satoru; Ogawa, Megumu; Malicdan, May Christine; Nonaka, Ikuya; Nishino, Ichizo

2017-02-01

Congenital muscular dystrophies with collagen VI deficiency are inherited muscle disorders with a broad spectrum of clinical presentation and are caused by mutations in one of COL6A1-3 genes. Muscle pathology is characterized by fiber size variation and increased interstitial fibrosis and adipogenesis. In this study, we define critical events that contribute to muscle weakness and fibrosis in a mouse model with collagen VI deficiency. The Col6a1 GT/GT mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, the Col6a1 GT/GT mice have high numbers of interstitial skeletal muscle mesenchymal progenitor cells, which dramatically increase with repeated myofiber necrosis/regeneration. Our results suggest that impaired neonatal muscle growth and the activation of the mesenchymal cells in skeletal muscles contribute to the pathology of collagen VI deficient muscular dystrophy, and more importantly, provide the insights on the therapeutic strategies for collagen VI deficiency. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Fine-tuned SRF activity controls asymmetrical neuronal outgrowth: implications for cortical migration, neural tissue lamination and circuit assembly

PubMed Central

Scandaglia, Marilyn; Benito, Eva; Morenilla-Palao, Cruz; Fiorenza, Anna; del Blanco, Beatriz; Coca, Yaiza; Herrera, Eloísa; Barco, Angel

2015-01-01

The stimulus-regulated transcription factor Serum Response Factor (SRF) plays an important role in diverse neurodevelopmental processes related to structural plasticity and motile functions, although its precise mechanism of action has not yet been established. To further define the role of SRF in neural development and distinguish between cell-autonomous and non cell-autonomous effects, we bidirectionally manipulated SRF activity through gene transduction assays that allow the visualization of individual neurons and their comparison with neighboring control cells. In vitro assays showed that SRF promotes survival and filopodia formation and is required for normal asymmetric neurite outgrowth, indicating that its activation favors dendrite enlargement versus branching. In turn, in vivo experiments demonstrated that SRF-dependent regulation of neuronal morphology has important consequences in the developing cortex and retina, affecting neuronal migration, dendritic and axonal arborization and cell positioning in these laminated tissues. Overall, our results show that the controlled and timely activation of SRF is essential for the coordinated growth of neuronal processes, suggesting that this event regulates the switch between neuronal growth and branching during developmental processes. PMID:26638868

Neuronal autoantibodies in epilepsy patients with peri-ictal autonomic findings.

PubMed

Baysal-Kirac, Leyla; Tuzun, Erdem; Erdag, Ece; Ulusoy, Canan; Vanli-Yavuz, Ebru Nur; Ekizoglu, Esme; Peach, Sian; Sezgin, Mine; Bebek, Nerses; Gurses, Candan; Gokyigit, Aysen; Vincent, Angela; Baykan, Betul

2016-03-01

Autonomic dysfunction has frequently been reported in autoimmune encephalitis associated with seizures and there is growing evidence that epilepsy patients may display neuronal autoantibodies (NAAb). The aim of this study was to investigate the frequency of NAAb in epilepsy patients with peri-ictal autonomic findings. Fifty-eight patients (37 women/21 men; average age of 34.2 ± 9.9 years and epilepsy duration of 19.1 ± 9.6 years) who had at least one video-EEG recorded focal or secondary generalized seizure with clear-cut documented peri-ictal autonomic findings, or consistently reported seizures with autonomic semiology, were included. NAAb were tested by RIA or cell based assays. NAAb were present in 17 of 58 (29.3%) patients. Among seropositive patients, antibodies were directed against N-methyl-D-aspartate receptor (NMDAR) in 5 (29%), contactin-associated protein-like 2 (CASPR2) in 5 (29%), uncharacterized voltage gated potassium channel (VGKC)-complex antigens in 3 (18%), glutamic acid decarboxylase (GAD) in 2 (12%), glycine receptor (GLYR) in one (6%) and type A gamma aminobutyric acid receptor (GABAAR) in one patient (6%). Peri-ictal gastrointestinal manifestations, piloerection, ictal fever, urinary urge, and cough occurred more commonly in the seropositive group. The prevalences of psychotic attacks and status epilepticus were significantly increased in the seropositive group. Seropositivity prevalence in our patient group with peri-ictal autonomic findings is higher than other previously reported epilepsy cohorts. In our study, ictal fever-VGKC-complex antibody and pilomotor seizure-GABAAR antibody associations were documented for the first time. Chronic epilepsy patients with peri-ictal autonomic semiology, history of status epilepticus and psychotic disorder may benefit from autoantibody screening.

Teaching Students to Build Historical Buildings in Virtual Reality: A Didactic Strategy for Learning History of Art in Secondary Education

ERIC Educational Resources Information Center

Frontera, Eloi Biosca

2009-01-01

This article is a summary and conclusions of a field study carried out in a secondary education classroom with the aim of experimenting and observing how 13-year-old students learn the history of architecture by using complex virtual reality software. Within the framework of autonomous and active learning, students act as builders of some of the…

The medial prefrontal cortex: coordinator of autonomic, neuroendocrine and behavioural responses to stress.

PubMed

McKlveen, J M; Myers, B; Herman, J P

2015-06-01

Responding to real or potential threats in the environment requires the coordination of autonomic, neuroendocrine and behavioural processes to promote adaptation and survival. These diverging systems necessitate input from the limbic forebrain to integrate and modulate functional output in accordance with contextual demand. In the present review, we discuss the potential role of the medial prefrontal cortex (mPFC) as a coordinator of behavioural and physiological stress responses across multiple temporal and contextual domains. Furthermore, we highlight converging evidence from rodent and human research indicating the necessity of the mPFC for modulating physiological energetic systems to mobilise or limit energetic resources as needed to ultimately promote behavioural adaptation in the face of stress. We review the literature indicating that glucocorticoids act as one of the primary messengers in the reallocation of energetic resources having profound effects locally within the mPFC, as well as shaping how the mPFC acts within a network of brain structures to modulate responses to stress. Finally, we discuss how both rodent and human studies point toward a critical role of the mPFC in the coordination of anticipatory responses to stress and why this distinction is an important one to make in stress neurobiology. © 2015 British Society for Neuroendocrinology.

Choosing Health and the inner citadel

PubMed Central

Allmark, P

2006-01-01

It is argued in this paper that the latest UK government white paper on public health, Choosing Health, is vulnerable to a charge of paternalism. For some years libertarians have levelled this charge at public health policies. The white paper tries to avoid it by constant reference to informed choice and choice related terms. The implication is that the government aims only to inform the public of health issues; how they respond is up to them. It is argued here, however, that underlying the notion of informed choice is a Kantian, “inner citadel” view of autonomy. According to this view, each of us acts autonomously only when we act in accord with reason. On such a view it is possible to justify coercing, cajoling, and conning people on the basis that their current behaviour is not autonomous because it is subject to forces that cause irrational choice, such as addiction. “Informed choice” in this sense is compatible with paternalism. This paternalism can be seen in public health policies such as deceptive advertising and the treatment of “bad habits” as addictions. Libertarians are bound to object to this. In the concluding section, however, it is suggested that public health can, nonetheless, find ethical succour from alternative approaches. PMID:16373514

Design of an autonomous lunar construction utility vehicle

NASA Technical Reports Server (NTRS)

1990-01-01

In order to prepare a site for a lunar base, an autonomously operated construction vehicle is necessary. Discussed here is a Lunar Construction Utility Vehicle (LCUV), which uses interchangeable construction implements. Design of an elastic loop track system has advanced to the testing stage. A standard coupling device has been designed to insure a proper connection between the different construction tools and the LCUV. Autonomous control of the track drive motors was simulated successfully through the use of a joystick and a computer interface. A study of hydrogen-oxygen fuel cells produced estimates of reactant and product requirements and identified multilayer insulation needs. Research on the 100-kW heat rejection system determined that it is necessary to transport the radiator panel on a utility trailer. Extensive logistical support for the 720 hour use cycle requires further study.

Epithelial control of gut-associated lymphoid tissue formation through p38α-dependent restraint of NF-κB signaling

PubMed Central

Caballero-Franco, Celia; Guma, Monica; Choo, Min-Kyung; Sano, Yasuyo; Enzler, Thomas; Karin, Michael; Mizoguchi, Atsushi; Park, Jin Mo

2015-01-01

The protein kinase p38α mediates cellular responses to environmental and endogenous cues that direct tissue homeostasis and immune responses. Studies of mice lacking p38α in several different cell types have demonstrated that p38α signaling is essential to maintaining the proliferation-differentiation balance in developing and steady-state tissues. The mechanisms underlying these roles involve cell-autonomous control of signaling and gene expression by p38α. Here we show that p38α regulates gut-associated lymphoid tissue (GALT) formation in a non-cell-autonomous manner. From an investigation of mice with intestinal epithelial cell-specific deletion of the p38α gene, we find that p38α serves to limit NF-κB signaling and thereby attenuate GALT-promoting chemokine expression in the intestinal epithelium. Loss of this regulation results in GALT hyperplasia and, in some animals, mucosa-associated B cell lymphoma. These anomalies occur independently of luminal microbial stimuli and are likely driven by direct epithelial-lymphoid interactions. Our study illustrates a novel p38α-dependent mechanism preventing excessive generation of epithelial-derived signals that drive lymphoid tissue overgrowth and malignancy. PMID:26792803

Two autonomous structural modules in the fimbrial shaft adhesin FimA mediate Actinomyces interactions with streptococci and host cells during oral biofilm development

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

Mishra, Arunima; Devarajan, Bharanidharan; Reardon, Melissa E.

2011-09-06

By combining X-ray crystallography and modelling, we describe here the atomic structure of distinct adhesive moieties of FimA, the shaft fimbrillin of Actinomyces type 2 fimbriae, which uniquely mediates the receptor-dependent intercellular interactions between Actinomyces and oral streptococci as well as host cells during the development of oral biofilms. The FimA adhesin is built with three IgG-like domains, each of which harbours an intramolecular isopeptide bond, previously described in several Gram-positive pilins. Genetic and biochemical studies demonstrate that although these isopeptide bonds are dispensable for fimbrial assembly, cell-cell interactions and biofilm formation, they contribute significantly to the proteolytic stability ofmore » FimA. Remarkably, FimA harbours two autonomous adhesive modules, which structurally resemble the Staphylococcus aureus Cna B domain. Each isolated module can bind the plasma glycoprotein asialofetuin as well as the polysaccharide receptors present on the surface of oral streptococci and epithelial cells. Thus, FimA should serve as an excellent paradigm for the development of therapeutic strategies and elucidating the precise molecular mechanisms underlying the interactions between cellular receptors and Gram-positive fimbriae.« less

Two Autonomous Structural Modules in the Fimbrial Shaft Adhesin FimA Mediate Actinomyces Interactions with Streptococci and Host Cells during Oral Biofilm Development

PubMed Central

Mishra, Arunima; Devarajan, Bharanidharan; Reardon, Melissa E.; Dwivedi, Prabhat; Krishnan, Vengadesan; Cisar, John O.; Das, Asis; Narayana, Sthanam V. L; Ton-That, Hung

2011-01-01

By combining X-ray crystallography and modeling, we describe here the atomic structure of distinct adhesive moieties of FimA, the shaft fimbrillin of Actinomyces type 2 fimbriae, which uniquely mediates the receptor-dependent intercellular interactions between Actinomyces and oral streptococci as well as host cells during the development of oral biofilms. The FimA adhesin is built with three IgG-like domains, each of which harbors an intramolecular isopeptide bond, previously described in several Gram-positive pilins. Genetic and biochemical studies demonstrate that although these isopeptide bonds are dispensable for fimbrial assembly, cell-cell interactions and biofilm formation, they contribute significantly to the proteolytic stability of FimA. Remarkably, FimA harbors two autonomous adhesive modules, which structurally resemble the Staphylococcus aureus Cna B domain. Each isolated module can bind the plasma glycoprotein asialofetuin as well as the polysaccharide receptors present on the surface of oral streptococci and epithelial cells. Thus, FimA should serve as an excellent paradigm for the development of therapeutic strategies and elucidating the precise molecular mechanisms underlying the interactions between cellular receptors and Gram-positive fimbriae. PMID:21696465

Oxytocin stimulates hippocampal neurogenesis via oxytocin receptor expressed in CA3 pyramidal neurons.

PubMed

Lin, Yu-Ting; Chen, Chien-Chung; Huang, Chiung-Chun; Nishimori, Katsuhiko; Hsu, Kuei-Sen

2017-09-14

In addition to the regulation of social and emotional behaviors, the hypothalamic neuropeptide oxytocin has been shown to stimulate neurogenesis in adult dentate gyrus; however, the mechanisms underlying the action of oxytocin are still unclear. Taking advantage of the conditional knockout mouse model, we show here that endogenous oxytocin signaling functions in a non-cell autonomous manner to regulate survival and maturation of newly generated dentate granule cells in adult mouse hippocampus via oxytocin receptors expressed in CA3 pyramidal neurons. Through bidirectional chemogenetic manipulations, we also uncover a significant role for CA3 pyramidal neuron activity in regulating adult neurogenesis in the dentate gyrus. Retrograde neuronal tracing combined with immunocytochemistry revealed that the oxytocin neurons in the paraventricular nucleus project directly to the CA3 region of the hippocampus. Our findings reveal a critical role for oxytocin signaling in adult neurogenesis.Oxytocin (OXT) has been implicated in adult neurogenesis. Here the authors show that CA3 pyramidal cells in the adult mouse hippocampus express OXT receptors and receive inputs from hypothalamic OXT neurons; activation of OXT signaling in CA3 pyramidal cells promotes the survival and maturation of newborn neurons in the dentate gyrus in a non-cell autonomous manner.

Single unit activity in the medial prefrontal cortex during Pavlovian heart rate conditioning: Effects of peripheral autonomic blockade.

PubMed

Powell, D A; Ginsberg, Jay P

2005-11-01

Electrical activity was recorded from single neurons in the medial prefrontal cortex of rabbits during differential Pavlovian heart rate (HR) conditioning. A heterogeneous population of cells were found, some of which showed CS-evoked increases and others CS-evoked decreases in discharge, while some cells were biphasic. A subset of cells also showed trial-related changes in discharge that were related to acquisition of the HR discrimination between the reinforced CS+ and non-reinforced CS-. Administration of the peripheral cholinergic antagonist, methylscopolamine, and the andrenergic antagonist, atenolol, either increased or decreased maintained baseline activity of many cells, but had little or no effect on the CS-evoked activity of these cells. Waveform changes also did not result from administration of these drugs. This finding suggests that CS-evoked mPFC activity is not being driven by cardiac afferent input to CNS cardiac control centers. Previous studies have shown that ibotenic acid lesions of this area greatly decreases the magnitude of decelerative heart rate conditioned responses; the latter finding, plus the results of the present study, suggest that processing of CS/US contingencies by the prefrontal cortex contributes to the acquisition of autonomic changes during Pavlovian conditioning.

Regulation of Glucose Homeostasis by GLP-1

PubMed Central

Nadkarni, Prashant; Chepurny, Oleg G.; Holz, George G.

2014-01-01

Glucagon-like peptide-1(7–36)amide (GLP-1) is a secreted peptide that acts as a key determinant of blood glucose homeostasis by virtue of its abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and to suppress pancreatic glucagon secretion. GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and the blood glucose-lowering action of GLP-1 is terminated due to its enzymatic degradation by dipeptidyl-peptidase-IV (DPP-IV). Released GLP-1 activates enteric and autonomic reflexes while also circulating as an incretin hormone to control endocrine pancreas function. The GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is activated directly or indirectly by blood glucose-lowering agents currently in use for the treatment of type 2 diabetes mellitus (T2DM). These therapeutic agents include GLP-1R agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and langlenatide) and DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin). Investigational agents for use in the treatment of T2DM include GPR119 and GPR40 receptor agonists that stimulate the release of GLP-1 from L cells. Summarized here is the role of GLP-1 to control blood glucose homeo-stasis, with special emphasis on the advantages and limitations of GLP-1-based therapeutics. PMID:24373234

Macrophages under pressure: the role of macrophage polarization in hypertension.

PubMed

Harwani, Sailesh C

2018-01-01

Hypertension is a multifactorial disease involving the nervous, renal, and cardiovascular systems. Macrophages are the most abundant and ubiquitous immune cells, placing them in a unique position to serve as key mediators between these components. The polarization of macrophages confers vast phenotypic and functional plasticity, allowing them to act as proinflammatory, homeostatic, and anti-inflammatory agents. Key differences between the M1 and M2 phenotypes, the 2 subsets at the extremes of this polarization spectrum, place macrophages at a juncture to mediate many mechanisms involved in the pathogenesis of hypertension. Neuronal and non-neuronal regulation of the immune system, that is, the "neuroimmuno" axis, plays an integral role in the polarization of macrophages. In hypertension, the neuroimmuno axis results in synchronization of macrophage mobilization from immune cell reservoirs and their chemotaxis, via increased expression of chemoattractants, to end organs critical in the development of hypertension. This complicated system is largely coordinated by the dichotomous actions of the autonomic neuronal and non-neuronal activation of cholinergic, adrenergic, and neurohormonal receptors on macrophages, leading to their ability to "switch" between phenotypes at sites of active inflammation. Data from experimental models and human studies are in concordance with each other and support a central role for macrophage polarization in the pathogenesis of hypertension. Copyright © 2017 Elsevier Inc. All rights reserved.

Octopus gonadotrophin-releasing hormone: a multifunctional peptide in the endocrine and nervous systems of the cephalopod.

PubMed

Minakata, H; Shigeno, S; Kano, N; Haraguchi, S; Osugi, T; Tsutsui, K

2009-03-01

The optic gland, which is analogous to the anterior pituitary in the context of gonadal maturation, is found on the upper posterior edge of the optic tract of the octopus Octopus vulgaris. In mature octopus, the optic glands enlarge and secrete a gonadotrophic hormone. A peptide with structural features similar to that of vertebrate gonadotrophin-releasing hormone (GnRH) was isolated from the brain of octopus and was named oct-GnRH. Oct-GnRH showed luteinising hormone-releasing activity in the anterior pituitary cells of the Japanese quail Coturnix coturnix. Oct-GnRH immunoreactive signals were observed in the glandular cells of the mature optic gland. Oct-GnRH stimulated the synthesis and release of sex steroids from the ovary and testis, and elicited contractions of the oviduct. Oct-GnRH receptor was expressed in the gonads and accessory organs, such as the oviduct and oviducal gland. These results suggest that oct-GnRH induces the gonadal maturation and oviposition by regulating sex steroidogenesis and a series of egg-laying behaviours via the oct-GnRH receptor. The distribution and expression of oct-GnRH in the central and peripheral nervous systems suggest that oct-GnRH acts as a multifunctional modulatory factor in feeding, memory processing, sensory, movement and autonomic functions.

Fatty Acid Synthase Cooperates with Glyoxalase 1 to Protect against Sugar Toxicity

PubMed Central

Garrido, Damien; Rubin, Thomas; Poidevin, Mickael; Maroni, Brigitte; Le Rouzic, Arnaud; Parvy, Jean-Philippe; Montagne, Jacques

2015-01-01

Fatty acid (FA) metabolism is deregulated in several human diseases including metabolic syndrome, type 2 diabetes and cancers. Therefore, FA-metabolic enzymes are potential targets for drug therapy, although the consequence of these treatments must be precisely evaluated at the organismal and cellular levels. In healthy organism, synthesis of triacylglycerols (TAGs)—composed of three FA units esterified to a glycerol backbone—is increased in response to dietary sugar. Saturation in the storage and synthesis capacity of TAGs is associated with type 2 diabetes progression. Sugar toxicity likely depends on advanced-glycation-end-products (AGEs) that form through covalent bounding between amine groups and carbonyl groups of sugar or their derivatives α-oxoaldehydes. Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that is derived from glycolysis through a non-enzymatic reaction. Glyoxalase 1 (Glo1) works to neutralize MG, reducing its deleterious effects. Here, we have used the power of Drosophila genetics to generate Fatty acid synthase (FASN) mutants, allowing us to investigate the consequence of this deficiency upon sugar-supplemented diets. We found that FASN mutants are lethal but can be rescued by an appropriate lipid diet. Rescued animals do not exhibit insulin resistance, are dramatically sensitive to dietary sugar and accumulate AGEs. We show that FASN and Glo1 cooperate at systemic and cell-autonomous levels to protect against sugar toxicity. We observed that the size of FASN mutant cells decreases as dietary sucrose increases. Genetic interactions at the cell-autonomous level, where glycolytic enzymes or Glo1 were manipulated in FASN mutant cells, revealed that this sugar-dependent size reduction is a direct consequence of MG-derived-AGE accumulation. In summary, our findings indicate that FASN is dispensable for cell growth if extracellular lipids are available. In contrast, FA-synthesis appears to be required to limit a cell-autonomous accumulation of MG-derived-AGEs, supporting the notion that MG is the most deleterious α-oxoaldehyde at the intracellular level. PMID:25692475

Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism.

PubMed

Krishnaiah, Saikumari Y; Wu, Gang; Altman, Brian J; Growe, Jacqueline; Rhoades, Seth D; Coldren, Faith; Venkataraman, Anand; Olarerin-George, Anthony O; Francey, Lauren J; Mukherjee, Sarmistha; Girish, Saiveda; Selby, Christopher P; Cal, Sibel; Er, Ubeydullah; Sianati, Bahareh; Sengupta, Arjun; Anafi, Ron C; Kavakli, I Halil; Sancar, Aziz; Baur, Joseph A; Dang, Chi V; Hogenesch, John B; Weljie, Aalim M

2017-04-04

The intricate connection between the circadian clock and metabolism remains poorly understood. We used high temporal resolution metabolite profiling to explore clock regulation of mouse liver and cell-autonomous metabolism. In liver, ∼50% of metabolites were circadian, with enrichment of nucleotide, amino acid, and methylation pathways. In U2 OS cells, 28% were circadian, including amino acids and NAD biosynthesis metabolites. Eighteen metabolites oscillated in both systems and a subset of these in primary hepatocytes. These 18 metabolites were enriched in methylation and amino acid pathways. To assess clock dependence of these rhythms, we used genetic perturbation. BMAL1 knockdown diminished metabolite rhythms, while CRY1 or CRY2 perturbation generally shortened or lengthened rhythms, respectively. Surprisingly, CRY1 knockdown induced 8 hr rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite from transcriptional rhythms, with potential impact on nutrient sensing in vivo. These results provide the first comprehensive views of circadian liver and cell-autonomous metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

Autonomic nervous system involvement in sickle cell disease.

PubMed

Coates, Thomas D; Chalacheva, Patjanaporn; Zeltzer, Lonnie; Khoo, Michael C K

2018-01-01

Sickle cell disease (SCD) is a genetic disorder of hemoglobin producing hemoglobin-S (HbS) and resulting in recurrent severe episodes of pain, organ damage and premature death due to vaso- occlusion. Deoxy HbS polymerizes, causing red cells to become rigid and lodge in the microvasculature if they do not escape into larger vessels before this transformation occurs. The mechanism that triggers this transition from steady state to vaso-occlusive crisis (VOC) is not known. Patients state that cold, emotional stress, and pain itself can trigger these events. In spite of the connection between these symptoms and the autonomic nervous system (ANS), and the fact that the ANS regulates regional microvascular blood flow, the role of the ANS in sickle pathophysiology has not been significantly investigated. We will briefly review the mechanism of SCD vaso-occlusion, the dysautonomia associated with SCD and sickle trait, and the role that the ANS may play in the genesis of sickle vaso-occlusive crisis.

Programming Enzyme-Initiated Autonomous DNAzyme Nanodevices in Living Cells.

PubMed

Chen, Feng; Bai, Min; Cao, Ke; Zhao, Yue; Cao, Xiaowen; Wei, Jing; Wu, Na; Li, Jiang; Wang, Lihua; Fan, Chunhai; Zhao, Yongxi

2017-12-26

Molecular nanodevices are computational assemblers that switch defined states upon external stimulation. However, interfacing artificial nanodevices with natural molecular machineries in living cells remains a great challenge. Here, we delineate a generic method for programming assembly of enzyme-initiated DNAzyme nanodevices (DzNanos). Two programs including split assembly of two partzymes and toehold exchange displacement assembly of one intact DNAzyme initiated by telomerase are computed. The intact one obtains higher assembly yield and catalytic performance ascribed to proper conformation folding and active misplaced assembly. By employing MnO 2 nanosheets as both DNA carriers and source of Mn 2+ as DNAzyme cofactor, we find that this DzNano is well assembled via a series of conformational states in living cells and operates autonomously with sustained cleavage activity. Other enzymes can also induce corresponding DzNano assembly with defined programming modules. These DzNanos not only can monitor enzyme catalysis in situ but also will enable the implementation of cellular stages, behaviors, and pathways for basic science, diagnostic, and therapeutic applications as genetic circuits.

Endothelial Cell Autonomous Role of Akt1: Regulation of Vascular Tone and Ischemia-Induced Arteriogenesis.

PubMed

Lee, Monica Y; Gamez-Mendez, Ana; Zhang, Jiasheng; Zhuang, Zhenwu; Vinyard, David J; Kraehling, Jan; Velazquez, Heino; Brudvig, Gary W; Kyriakides, Themis R; Simons, Michael; Sessa, William C

2018-04-01

The importance of PI3K/Akt signaling in the vasculature has been demonstrated in several models, as global loss of Akt1 results in impaired postnatal ischemia- and VEGF-induced angiogenesis. The ubiquitous expression of Akt1, however, raises the possibility of cell-type-dependent Akt1-driven actions, thereby necessitating tissue-specific characterization. Herein, we used an inducible, endothelial-specific Akt1-deleted adult mouse model (Akt1iECKO) to characterize the endothelial cell autonomous functions of Akt1 in the vascular system. Endothelial-targeted ablation of Akt1 reduces eNOS (endothelial nitric oxide synthase) phosphorylation and promotes both increased vascular contractility in isolated vessels and elevated diastolic blood pressures throughout the diurnal cycle in vivo. Furthermore, Akt1iECKO mice subject to the hindlimb ischemia model display impaired blood flow and decreased arteriogenesis. Endothelial Akt1 signaling is necessary for ischemic resolution post-injury and likely reflects the consequence of NO insufficiency critical for vascular repair. © 2018 American Heart Association, Inc.

Engineering Sensorial Delay to Control Phototaxis and Emergent Collective Behaviors

NASA Astrophysics Data System (ADS)

Mijalkov, Mite; McDaniel, Austin; Wehr, Jan; Volpe, Giovanni

2016-01-01

Collective motions emerging from the interaction of autonomous mobile individuals play a key role in many phenomena, from the growth of bacterial colonies to the coordination of robotic swarms. For these collective behaviors to take hold, the individuals must be able to emit, sense, and react to signals. When dealing with simple organisms and robots, these signals are necessarily very elementary; e.g., a cell might signal its presence by releasing chemicals and a robot by shining light. An additional challenge arises because the motion of the individuals is often noisy; e.g., the orientation of cells can be altered by Brownian motion and that of robots by an uneven terrain. Therefore, the emphasis is on achieving complex and tunable behaviors from simple autonomous agents communicating with each other in robust ways. Here, we show that the delay between sensing and reacting to a signal can determine the individual and collective long-term behavior of autonomous agents whose motion is intrinsically noisy. We experimentally demonstrate that the collective behavior of a group of phototactic robots capable of emitting a radially decaying light field can be tuned from segregation to aggregation and clustering by controlling the delay with which they change their propulsion speed in response to the light intensity they measure. We track this transition to the underlying dynamics of this system, in particular, to the ratio between the robots' sensorial delay time and the characteristic time of the robots' random reorientation. Supported by numerics, we discuss how the same mechanism can be applied to control active agents, e.g., airborne drones, moving in a three-dimensional space. Given the simplicity of this mechanism, the engineering of sensorial delay provides a potentially powerful tool to engineer and dynamically tune the behavior of large ensembles of autonomous mobile agents; furthermore, this mechanism might already be at work within living organisms such as chemotactic cells.

The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system

PubMed Central

Chaverra, Marta; George, Lynn; Thorne, Julian; Grindeland, Andrea; Ueki, Yumi; Eiger, Steven; Cusick, Cassie; Babcock, A. Michael; Carlson, George A.

2017-01-01

ABSTRACT Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that, in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed. PMID:28167615

Genetics Home Reference: multiple system atrophy

MedlinePlus

... inability to hold the body upright and balanced (postural instability). The other type of multiple system atrophy , ... cells in parts of the nervous system that control movement, balance and coordination, and autonomic functioning. The ...

Nonlinear Dynamic Theory of Acute Cell Injuries and Brain Ischemia

NASA Astrophysics Data System (ADS)

Taha, Doaa; Anggraini, Fika; Degracia, Donald; Huang, Zhi-Feng

2015-03-01

Cerebral ischemia in the form of stroke and cardiac arrest brain damage affect over 1 million people per year in the USA alone. In spite of close to 200 clinical trials and decades of research, there are no treatments to stop post-ischemic neuron death. We have argued that a major weakness of current brain ischemia research is lack of a deductive theoretical framework of acute cell injury to guide empirical studies. A previously published autonomous model based on the concept of nonlinear dynamic network was shown to capture important facets of cell injury, linking the concept of therapeutic to bistable dynamics. Here we present an improved, non-autonomous formulation of the nonlinear dynamic model of cell injury that allows multiple acute injuries over time, thereby allowing simulations of both therapeutic treatment and preconditioning. Our results are connected to the experimental data of gene expression and proteomics of neuron cells. Importantly, this new model may be construed as a novel approach to pharmacodynamics of acute cell injury. The model makes explicit that any pro-survival therapy is always a form of sub-lethal injury. This insight is expected to widely influence treatment of acute injury conditions that have defied successful treatment to date. This work is supported by NIH NINDS (NS081347) and Wayne State University President's Research Enhancement Award.

Central control of glucose homeostasis: the brain--endocrine pancreas axis.

PubMed

Thorens, B

2010-10-01

A large body of data gathered over the last decades has delineated the neuronal pathways that link the central nervous system with the autonomic innervation of the endocrine pancreas, which controls alpha- and beta-cell secretion activity and mass. These are important regulatory functions that are certainly keys for preserving the capacity of the endocrine pancreas to control glucose homeostasis over a lifetime. Identifying the cells involved in controlling the autonomic innervation of the endocrine pancreas, in response to nutrient, hormonal and environmental cues and how these cues are detected to activate neuronal activity are important goals of current research. Elucidation of these questions may possibly lead to new means for preserving or restoring defects in insulin and glucagon secretion associated with type 2 diabetes. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure.

PubMed

Fan, Ling; Chen, Li-Feng; Fan, Jing

2017-12-01

To investigate the electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure. Guinea pigs model of iron deficiency anemia complicated with chronic heart failure in 10 guinea pigs of the experimental group was made by feeding a low iron diet, pure water and subcutaneous injection of isoproterenol. The control group consisting of 11 guinea pigs was given normal food, normal water and injected with normal saline. The left ventricular outflow tract model specimen was also prepared. The standard microelectrode technique was used to observe electrophysiological changes of autonomic cells in the outflow tract of left ventricular heart failure complicated with iron deficiency anemia in guinea pig model. The indicators of observation were maximal diastolic potential, action potential amplitude, 0 phase maximal depolarization velocity, 4 phase automatic depolarization velocity, repolarization 50% and 90%, and spontaneous discharge frequency. Compared with the control group, 4 phase automatic depolarization velocity, spontaneous discharge frequency and 0 phase maximal depolarization velocity decreased significantly (P < 0.01) and action potential amplitude reduced (P < 0.01) in model group. Moreover, repolarization 50% and 90% increased (P < 0.01). There are electrophysiological abnormalities of the left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with heart failure. Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

Robot Lies in Health Care: When Is Deception Morally Permissible?

PubMed

Matthias, Andreas

2015-06-01

Autonomous robots are increasingly interacting with users who have limited knowledge of robotics and are likely to have an erroneous mental model of the robot's workings, capabilities, and internal structure. The robot's real capabilities may diverge from this mental model to the extent that one might accuse the robot's manufacturer of deceiving the user, especially in cases where the user naturally tends to ascribe exaggerated capabilities to the machine (e.g. conversational systems in elder-care contexts, or toy robots in child care). This poses the question, whether misleading or even actively deceiving the user of an autonomous artifact about the capabilities of the machine is morally bad and why. By analyzing trust, autonomy, and the erosion of trust in communicative acts as consequences of deceptive robot behavior, we formulate four criteria that must be fulfilled in order for robot deception to be morally permissible, and in some cases even morally indicated.

Human-Robot Control Strategies for the NASA/DARPA Robonaut

NASA Technical Reports Server (NTRS)

Diftler, M. A.; Culbert, Chris J.; Ambrose, Robert O.; Huber, E.; Bluethmann, W. J.

2003-01-01

The Robotic Systems Technology Branch at the NASA Johnson Space Center (JSC) is currently developing robot systems to reduce the Extra-Vehicular Activity (EVA) and planetary exploration burden on astronauts. One such system, Robonaut, is capable of interfacing with external Space Station systems that currently have only human interfaces. Robonaut is human scale, anthropomorphic, and designed to approach the dexterity of a space-suited astronaut. Robonaut can perform numerous human rated tasks, including actuating tether hooks, manipulating flexible materials, soldering wires, grasping handrails to move along space station mockups, and mating connectors. More recently, developments in autonomous control and perception for Robonaut have enabled dexterous, real-time man-machine interaction. Robonaut is now capable of acting as a practical autonomous assistant to the human, providing and accepting tools by reacting to body language. A versatile, vision-based algorithm for matching range silhouettes is used for monitoring human activity as well as estimating tool pose.

Self-powered enzyme micropumps

NASA Astrophysics Data System (ADS)

Sengupta, Samudra; Patra, Debabrata; Ortiz-Rivera, Isamar; Agrawal, Arjun; Shklyaev, Sergey; Dey, Krishna K.; Córdova-Figueroa, Ubaldo; Mallouk, Thomas E.; Sen, Ayusman

2014-05-01

Non-mechanical nano- and microscale pumps that function without the aid of an external power source and provide precise control over the flow rate in response to specific signals are needed for the development of new autonomous nano- and microscale systems. Here we show that surface-immobilized enzymes that are independent of adenosine triphosphate function as self-powered micropumps in the presence of their respective substrates. In the four cases studied (catalase, lipase, urease and glucose oxidase), the flow is driven by a gradient in fluid density generated by the enzymatic reaction. The pumping velocity increases with increasing substrate concentration and reaction rate. These rechargeable pumps can be triggered by the presence of specific analytes, which enables the design of enzyme-based devices that act both as sensor and pump. Finally, we show proof-of-concept enzyme-powered devices that autonomously deliver small molecules and proteins in response to specific chemical stimuli, including the release of insulin in response to glucose.

Road Nail: Experimental Solar Powered Intelligent Road Marking System

NASA Astrophysics Data System (ADS)

Samardžija, Dragan; Teslić, Nikola; Todorović, Branislav M.; Kovač, Erne; Isailović, Đorđe; Miladinović, Bojan

2012-03-01

Driving in low visibility conditions (night time, fog or heavy precipitation) is particularly challenging task with an increased probability of traffic accidents and possible injuries. Road Nail is a solar powered intelligent road marking system of wirelessly networked signaling devices that improve driver safety in low visibility conditions along hazardous roadways. Nails or signaling devices are autonomous nodes with capability to accumulate energy, exchange wireless messages, detect approaching vehicles and emit signalization light. We have built an experimental test-bed that consists of 20 nodes and a cellular gateway. Implementation details of the above system, including extensive measurements and performance evaluations in realistic field deployments are presented. A novel distributed network topology discovery scheme is proposed which integrates both sensor and wireless communication aspects, where nodes act autonomously. Finally, integration of the Road Nail system with the cellular network and the Internet is described.

Peritoneal and hematogenous metastases of ovarian cancer cells are both controlled by the p90RSK through a self-reinforcing cell autonomous mechanism.

PubMed

Torchiaro, Erica; Lorenzato, Annalisa; Olivero, Martina; Valdembri, Donatella; Gagliardi, Paolo Armando; Gai, Marta; Erriquez, Jessica; Serini, Guido; Di Renzo, Maria Flavia

2016-01-05

The molecular mechanisms orchestrating peritoneal and hematogenous metastases of ovarian cancer cells are assumed to be distinct. We studied the p90RSK family of serine/threonine kinases that lie downstream the RAS-ERK/MAPK pathway and modulate a variety of cellular processes including cell proliferation, survival, motility and invasiveness. We found the RSK1 and RSK2 isoforms expressed in a number of human ovarian cancer cell lines, where they played redundant roles in sustaining in vitro motility and invasiveness. In vivo, silencing of both RSK1 and RSK2 almost abrogated short-term and long-term metastatic engraftment of ovarian cancer cells in the peritoneum. In addition, RSK1/RSK2 silenced cells failed to colonize the lungs after intravenous injection and to form hematogenous metastasis from subcutaneous xenografts. RSK1/RSK2 suppression resulted in lessened ovarian cancer cell spreading on endogenous fibronectin (FN). Mechanistically, RSK1/RSK2 knockdown diminished FN transcription, α5β1 integrin activation and TGF-β1 translation. Reduced endogenous FN deposition and TGF-β1 secretion depended on the lack of activating phosphorylation of the transcription/translation factor YB-1 by p90RSK. Altogether data show how p90RSK activates a self-reinforcing cell autonomous pro-adhesive circuit necessary for metastatic seeding of ovarian cancer cells. Thus, p90RSK inhibitors might hinder both the hematogenous and the peritoneal metastatic spread of human ovarian cancer.

Persistent hyperplastic primary vitreous due to somatic mosaic deletion of the arf tumor suppressor.

PubMed

Thornton, J Derek; Swanson, Doug J; Mary, Michelle N; Pei, Deqing; Martin, Amy C; Pounds, Stanley; Goldowitz, Dan; Skapek, Stephen X

2007-02-01

Mice lacking the Arf tumor-suppressor gene develop eye disease reminiscent of persistent hyperplastic primary vitreous (PHPV). The current work explores mechanisms by which Arf promotes eye development, and its absence causes a PHPV-like disease. Chimeric mice were made by fusing wild-type and Arf(-/-) morulae. In these experiments, wild-type cells are identified by transgenic expression of GFP from a constitutive promoter. PCR-based genotyping and quantitative analyses after immunofluorescence staining of tissue and cultured cells documented the relative contribution of wild-type and Arf(-/-) cells to different tissues in the eye and different types of cells in the vitreous. The contributions of the Arf(-/-) lineage to the tail DNA, cornea, retina, and retina pigment epithelium (RPE) correlated with each other in wild-type<-->Arf(-/-) chimeric mice. Newborn chimeras had primary vitreous hyperplasia, evident as a retrolental mass. The mass was usually present when the proportion of Arf(-/-) cells was relatively high and absent when the Arf(-/-) proportion was low. The Pdgfrbeta- and Sma-expressing cells within the mass arose predominantly from the Arf(-/-) population. Ectopic Arf expression induced smooth muscle proteins in cultured pericyte-like cells, and Arf and Sma expression overlapped in hyaloid vessels. In the mouse model, loss of Arf in only a subset of cells causes a PHPV-like disease. The data indicate that both cell autonomous and non-cell autonomous effects of Arf may contribute to its role in vitreous development.

Advanced Modular "All in One" Battery System with Intelligent Autonomous Cell Balancing Management

NASA Astrophysics Data System (ADS)

Petitdidier, X.; Pasquier, E.; Defer, M.; Koch, M.; Knorr, W.

2008-09-01

A new generation of energy storage systems based on Li-ion technology emerged at the end of the last century.To perform the first tests in safe conditions, Saft designed a simple electronic.Today, all Li-ion batteries for autonomous applications such as drones, launchers, missiles, torpedoes and "human" applications such as cellular, laptop, hybrid vehicle and nearly sub-marines need a Battery Management System.The minimum in terms of functions is the overcharge and over-discharge protections.For a battery made of 2 cells connected in series or more, a balancing system is added to maintain the available energy during all the life of the battery. For stringent/demanding applications, the state of charge and state of health are calculated by one or more computers.It is now time to take benefit of the past 10 years of Saft's experience in the domain to re-evaluate the constraints of Li-ion batteries and provide customers with improved products by optimizing the battery management.Benefits of electronic for satellite applications:• Full control over battery.• Confidence whatever the possible change of conditions in environment.• The battery system can resist long exposure to gradient conditions with mitigated and stabilized impact on performances.• The balancing function allow to use all the energy of all the cells: optimize of installed energy (compact design, mass saving). It started out with the basic fact that electrochemists are not intended to be space rated electronic experts and vice versa, even if Saft has a good heritage in the electronic battery management system. Consequently, considering heritage and expertise in their respective core businesses, Saft and ASP teamed up.It became necessary to provide an "all in one" modular energy storage system with intelligent autonomous cell balancing management.

YAP/TAZ enhance mammalian embryonic neural stem cell characteristics in a Tead-dependent manner

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

Han, Dasol; Byun, Sung-Hyun; Park, Soojeong

Mammalian brain development is regulated by multiple signaling pathways controlling cell proliferation, migration and differentiation. Here we show that YAP/TAZ enhance embryonic neural stem cell characteristics in a cell autonomous fashion using diverse experimental approaches. Introduction of retroviral vectors expressing YAP or TAZ into the mouse embryonic brain induced cell localization in the ventricular zone (VZ), which is the embryonic neural stem cell niche. This change in cell distribution in the cortical layer is due to the increased stemness of infected cells; YAP-expressing cells were colabeled with Sox2, a neural stem cell marker, and YAP/TAZ increased the frequency and sizemore » of neurospheres, indicating enhanced self-renewal- and proliferative ability of neural stem cells. These effects appear to be TEA domain family transcription factor (Tead)–dependent; a Tead binding-defective YAP mutant lost the ability to promote neural stem cell characteristics. Consistently, in utero gene transfer of a constitutively active form of Tead2 (Tead2-VP16) recapitulated all the features of YAP/TAZ overexpression, and dominant negative Tead2-EnR resulted in marked cell exit from the VZ toward outer cortical layers. Taken together, these results indicate that the Tead-dependent YAP/TAZ signaling pathway plays important roles in neural stem cell maintenance by enhancing stemness of neural stem cells during mammalian brain development. - Highlights: • Roles of YAP and Tead in vivo during mammalian brain development are clarified. • Expression of YAP promotes embryonic neural stem cell characteristics in vivo in a cell autonomous fashion. • Enhancement of neural stem cell characteristics by YAP depends on Tead. • Transcriptionally active form of Tead alone can recapitulate the effects of YAP. • Transcriptionally repressive form of Tead severely reduces stem cell characteristics.« less

Nuclear Export Factor CRM1 Interacts with Nonstructural Proteins NS2 from Parvovirus Minute Virus of Mice

PubMed Central

Bodendorf, Ursula; Cziepluch, Celina; Jauniaux, Jean-Claude; Rommelaere, Jean; Salomé, Nathalie

1999-01-01

The nonstructural NS2 proteins of autonomous parvoviruses are known to act in a host cell-dependent manner and to play a role in viral DNA replication, efficient translation of viral mRNA, and/or encapsidation. Their exact function during the parvovirus life cycle remains, however, still obscure. We report here the characterization of the interaction with the NS2 proteins from the parvovirus minute virus of mice (MVM) and rat as well as mouse homologues of the human CRM1 protein, a member of the importin-beta family recently identified as an essential nuclear export factor. Using the two-hybrid system, we could detect the interaction between the carboxy-terminal region of rat CRM1 and each of the three isoforms of NS2 (P [or major], Y [or minor], and L [or rare]). NS2 proteins were further shown to interact with the full-length CRM1 by coimmunoprecipitation experiments using extracts from both mouse and rat cell lines. Our data show that CRM1 preferentially binds to the nonphosphorylated isoforms of NS2. Moreover, we observed that the treatment of MVM-infected cells with leptomycin B, a drug that specifically inhibits the CRM1-dependent nuclear export pathway, leads to a drastic accumulation of NS2 proteins in the nucleus. Both NS2 interaction with CRM1 and nuclear accumulation upon leptomycin B treatment strongly suggest that these nonstructural viral proteins are actively exported out of the nuclei of infected cells via a CRM1-mediated nuclear export pathway. PMID:10438867

Reducing the Use of Short-Acting Nifedipine by Hypertensives Using a Pharmaceutical Database

DTIC Science & Technology

2005-01-01

66 (4) Esophageal spasm, achalasia, or dysphagia 56 (3.4) Angina 24 (1.5) Migraine headache 10 (0.6) Various other 48 (3) None listed 534...prescriptions, or 45 percent). Other indications (23 percent) were primarily for autonomic dysreflexia, Raynaud’s syndrome, esophageal spasm...achalasia or dysphagia , angina, and migraine headache. The remaining 32 percent did not have an indication listed in the report form (Table 1). An action

Apprentissage de l'expression orale en autonomie. Implications de l'approche fonctionelle (Learning Oral Expression in Independent Study. Implications of the Functional Approach). Melanges pedagogiques.

ERIC Educational Resources Information Center

Abe, D.; And Others

Within the CRAPEL autonomous learning scheme, modular material is being developed for communicative oral expression. The purpose of this material is twofold: (1) to enable the learner to define his or her own needs in communicative terms, that is, to analyse a situation in terms of communicative acts needed in a given situation, the relationships…

Autonomously folded α-helical lockers promote RNAi*

NASA Astrophysics Data System (ADS)

Guyader, Christian P. E.; Lamarre, Baptiste; de Santis, Emiliana; Noble, James E.; Slater, Nigel K.; Ryadnov, Maxim G.

2016-10-01

RNAi is an indispensable research tool with a substantial therapeutic potential. However, the complete transition of the approach to an applied capability remains hampered due to poorly understood relationships between siRNA delivery and gene suppression. Here we propose that interfacial tertiary contacts between α-helices can regulate siRNA cytoplasmic delivery and RNAi. We introduce a rationale of helical amphipathic lockers that differentiates autonomously folded helices, which promote gene silencing, from helices folded with siRNA, which do not. Each of the helical designs can deliver siRNA into cells via energy-dependent endocytosis, while only autonomously folded helices with pre-locked hydrophobic interfaces were able to promote statistically appreciable gene silencing. We propose that it is the amphipathic locking of interfacing helices prior to binding to siRNA that enables RNAi. The rationale offers structurally balanced amphipathic scaffolds to advance the exploitation of functional RNAi.

Autonomously folded α-helical lockers promote RNAi*

PubMed Central

Guyader, Christian P. E.; Lamarre, Baptiste; De Santis, Emiliana; Noble, James E.; Slater, Nigel K.; Ryadnov, Maxim G.

2016-01-01

RNAi is an indispensable research tool with a substantial therapeutic potential. However, the complete transition of the approach to an applied capability remains hampered due to poorly understood relationships between siRNA delivery and gene suppression. Here we propose that interfacial tertiary contacts between α-helices can regulate siRNA cytoplasmic delivery and RNAi. We introduce a rationale of helical amphipathic lockers that differentiates autonomously folded helices, which promote gene silencing, from helices folded with siRNA, which do not. Each of the helical designs can deliver siRNA into cells via energy-dependent endocytosis, while only autonomously folded helices with pre-locked hydrophobic interfaces were able to promote statistically appreciable gene silencing. We propose that it is the amphipathic locking of interfacing helices prior to binding to siRNA that enables RNAi. The rationale offers structurally balanced amphipathic scaffolds to advance the exploitation of functional RNAi. PMID:27721465

Autonomously folded α-helical lockers promote RNAi.

PubMed

Guyader, Christian P E; Lamarre, Baptiste; De Santis, Emiliana; Noble, James E; Slater, Nigel K; Ryadnov, Maxim G

2016-10-10

RNAi is an indispensable research tool with a substantial therapeutic potential. However, the complete transition of the approach to an applied capability remains hampered due to poorly understood relationships between siRNA delivery and gene suppression. Here we propose that interfacial tertiary contacts between α-helices can regulate siRNA cytoplasmic delivery and RNAi. We introduce a rationale of helical amphipathic lockers that differentiates autonomously folded helices, which promote gene silencing, from helices folded with siRNA, which do not. Each of the helical designs can deliver siRNA into cells via energy-dependent endocytosis, while only autonomously folded helices with pre-locked hydrophobic interfaces were able to promote statistically appreciable gene silencing. We propose that it is the amphipathic locking of interfacing helices prior to binding to siRNA that enables RNAi. The rationale offers structurally balanced amphipathic scaffolds to advance the exploitation of functional RNAi.

Design of an autonomous Lunar construction utility vehicle

NASA Technical Reports Server (NTRS)

Ash, Robert L.; Chew, Mason; Dixon, Iain (Editor)

1990-01-01

In order to prepare a site for a manned lunar base, an autonomously operated construction vehicle is necessary. A Lunar Construction Utility Vehicle (LCUV), which utilizes interchangeable construction implements, was designed conceptually. Some elements of the machine were studied in greater detail. Design of an elastic loop track system has advanced to the testing stage. A standard coupling device was designed to insure a proper connection between the different construction tools and the LCUV. Autonomous control of the track drive motors was simulated successfully through the use of a joystick and computer interface. A study of hydrogen-oxygen fuel cells has produced estimates of reactant and product size requirements and identified multi-layer insulation techniques. Research on a 100 kW heat rejection system has determined that it is necessary to house a radiator panel on a utility trailer. The impact of a 720 hr use cycle has produced a very large logistical support lien which requires further study.

Non-equilibrium assembly of microtubules: from molecules to autonomous chemical robots.

PubMed

Hess, H; Ross, Jennifer L

2017-09-18

Biological systems have evolved to harness non-equilibrium processes from the molecular to the macro scale. It is currently a grand challenge of chemistry, materials science, and engineering to understand and mimic biological systems that have the ability to autonomously sense stimuli, process these inputs, and respond by performing mechanical work. New chemical systems are responding to the challenge and form the basis for future responsive, adaptive, and active materials. In this article, we describe a particular biochemical-biomechanical network based on the microtubule cytoskeletal filament - itself a non-equilibrium chemical system. We trace the non-equilibrium aspects of the system from molecules to networks and describe how the cell uses this system to perform active work in essential processes. Finally, we discuss how microtubule-based engineered systems can serve as testbeds for autonomous chemical robots composed of biological and synthetic components.

Airborne Signals from a Wounded Leaf Facilitate Viral Spreading and Induce Antibacterial Resistance in Neighboring Plants

PubMed Central

Dorokhov, Yuri L.; Komarova, Tatiana V.; Petrunia, Igor V.; Frolova, Olga Y.; Pozdyshev, Denis V.; Gleba, Yuri Y.

2012-01-01

Many plants release airborne volatile compounds in response to wounding due to pathogenic assault. These compounds serve as plant defenses and are involved in plant signaling. Here, we study the effects of pectin methylesterase (PME)-generated methanol release from wounded plants (“emitters”) on the defensive reactions of neighboring “receiver” plants. Plant leaf wounding resulted in the synthesis of PME and a spike in methanol released into the air. Gaseous methanol or vapors from wounded PME-transgenic plants induced resistance to the bacterial pathogen Ralstonia solanacearum in the leaves of non-wounded neighboring “receiver” plants. In experiments with different volatile organic compounds, gaseous methanol was the only airborne factor that could induce antibacterial resistance in neighboring plants. In an effort to understand the mechanisms by which methanol stimulates the antibacterial resistance of “receiver” plants, we constructed forward and reverse suppression subtractive hybridization cDNA libraries from Nicotiana benthamiana plants exposed to methanol. We identified multiple methanol-inducible genes (MIGs), most of which are involved in defense or cell-to-cell trafficking. We then isolated the most affected genes for further analysis: β-1,3-glucanase (BG), a previously unidentified gene (MIG-21), and non-cell-autonomous pathway protein (NCAPP). Experiments with Tobacco mosaic virus (TMV) and a vector encoding two tandem copies of green fluorescent protein as a tracer of cell-to-cell movement showed the increased gating capacity of plasmodesmata in the presence of BG, MIG-21, and NCAPP. The increased gating capacity is accompanied by enhanced TMV reproduction in the “receivers”. Overall, our data indicate that methanol emitted by a wounded plant acts as a signal that enhances antibacterial resistance and facilitates viral spread in neighboring plants. PMID:22496658

Autonomous Bacterial Localization and Gene Expression Based on Nearby Cell Receptor Density

DTIC Science & Technology

2013-01-22

synthesis of novel products (Kwok, 2010). In such cases, cell populations are aligned for optimal production . While Nature’s biosynthetic toolbox is vast...less commonly examined but equally innovative strategy envisions a repro- grammed cell itself or small collections of cells as the end products of...to surfaces. In Figure 2B, we depict the level of NF binding and AI-2 production as a function of coated avidin. We used a mathematical model for E

Communications Network Design, Simulation, and Analysis for an Autonomous Unmanned Vehicle System

DTIC Science & Technology

2011-06-01

of which type to use depends on the type of demands placed on the network. 1. Central Control Network Architecture Cell phones, the IEEE 802.11, and...distances that do not exceed the wireless transmission distances of the BS and SSs. This BS coverage region is sometimes referred to as a cell . To...In this manner, multiple cells can be connected together by connecting the cell BSs. In so doing, a large geographical area can be covered by a

Complex interplay of three transcription factors in controlling the tormogen differentiation program of Drosophila mechanoreceptors

PubMed Central

Miller, Steven W.; Avidor-Reiss, Tomer; Polyanovsky, Andrey; Posakony, James W.

2009-01-01

We have investigated the expression and function of the Sox15 transcription factor during the development of the external mechanosensory organs of Drosophila. We find that Sox15 is expressed specifically in the socket cell, and have identified the transcriptional cis-regulatory module that controls this activity. We show that Suppressor of Hairless [Su(H)] and the POU-domain factor Ventral veins lacking (Vvl) bind conserved sites in this enhancer and provide critical regulatory input. In particular, we find that Vvl contributes to the activation of the enhancer following relief of Su(H)-mediated default repression by the Notch signaling event that specifies the socket cell fate. Loss of Sox15 gene activity was found to severely impair the electrophysiological function of mechanosensory organs, due to both cell-autonomous and cell-non-autonomous effects on the differentiation of post-mitotic cells in the bristle lineage. Lastly, we find that simultaneous loss of both Sox15 and the autoregulatory activity of Su(H) reveals an important role for these factors in inhibiting transcription of the Pax family gene shaven in the socket cell, which serves to prevent inappropriate expression of the shaft differentiation program. Our results indicate that the later phases of socket cell differentiation are controlled by multiple transcription factors in a collaborative, and not hierarchical, manner. PMID:19232522

C1 neurons: the body's EMTs

PubMed Central

Stornetta, Ruth L.; Bochorishvili, Genrieta; DePuy, Seth D.; Burke, Peter G. R.; Abbott, Stephen B. G.

2013-01-01

The C1 neurons reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM, IVLM). They use glutamate as a fast transmitter and synthesize catecholamines plus various neuropeptides. These neurons regulate the hypothalamic pituitary axis via direct projections to the paraventricular nucleus and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The presympathetic C1 cells, located in the RVLM, are probably organized in a roughly viscerotopic manner and most of them regulate the circulation. C1 cells are variously activated by hypoglycemia, infection or inflammation, hypoxia, nociception, and hypotension and contribute to most glucoprivic responses. C1 cells also stimulate breathing and activate brain stem noradrenergic neurons including the locus coeruleus. Based on the various effects attributed to the C1 cells, their axonal projections and what is currently known of their synaptic inputs, subsets of C1 cells appear to be differentially recruited by pain, hypoxia, infection/inflammation, hemorrhage, and hypoglycemia to produce a repertoire of stereotyped autonomic, metabolic, and neuroendocrine responses that help the organism survive physical injury and its associated cohort of acute infection, hypoxia, hypotension, and blood loss. C1 cells may also contribute to glucose and cardiovascular homeostasis in the absence of such physical stresses, and C1 cell hyperactivity may contribute to the increase in sympathetic nerve activity associated with diseases such as hypertension. PMID:23697799

C1 neurons: the body's EMTs.

PubMed

Guyenet, Patrice G; Stornetta, Ruth L; Bochorishvili, Genrieta; Depuy, Seth D; Burke, Peter G R; Abbott, Stephen B G

2013-08-01

The C1 neurons reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM, IVLM). They use glutamate as a fast transmitter and synthesize catecholamines plus various neuropeptides. These neurons regulate the hypothalamic pituitary axis via direct projections to the paraventricular nucleus and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The presympathetic C1 cells, located in the RVLM, are probably organized in a roughly viscerotopic manner and most of them regulate the circulation. C1 cells are variously activated by hypoglycemia, infection or inflammation, hypoxia, nociception, and hypotension and contribute to most glucoprivic responses. C1 cells also stimulate breathing and activate brain stem noradrenergic neurons including the locus coeruleus. Based on the various effects attributed to the C1 cells, their axonal projections and what is currently known of their synaptic inputs, subsets of C1 cells appear to be differentially recruited by pain, hypoxia, infection/inflammation, hemorrhage, and hypoglycemia to produce a repertoire of stereotyped autonomic, metabolic, and neuroendocrine responses that help the organism survive physical injury and its associated cohort of acute infection, hypoxia, hypotension, and blood loss. C1 cells may also contribute to glucose and cardiovascular homeostasis in the absence of such physical stresses, and C1 cell hyperactivity may contribute to the increase in sympathetic nerve activity associated with diseases such as hypertension.

A photovoltaic-driven and energy-autonomous CMOS implantable sensor.

PubMed

Ayazian, Sahar; Akhavan, Vahid A; Soenen, Eric; Hassibi, Arjang

2012-08-01

An energy-autonomous, photovoltaic (PV)-driven and MRI-compatible CMOS implantable sensor is presented. On-chip P+/N-well diode arrays are used as CMOS-compatible PV cells to harvest μW's of power from the light that penetrates into the tissue. In this 2.5 mm × 2.5 mm sub-μW integrated system, the in-vivo physiological signals are first measured by using a subthreshold ring oscillator-based sensor, the acquired data is then modulated into a frequency-shift keying (FSK) signal, and finally transmitted neuromorphically to the skin surface by using a pair of polarized electrodes.

Regulation of AMP-activated protein kinase by natural and synthetic activators

PubMed Central

Grahame Hardie, David

2015-01-01

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is almost universally expressed in eukaryotic cells. While it appears to have evolved in single-celled eukaryotes to regulate energy balance in a cell-autonomous manner, during the evolution of multicellular animals its role has become adapted so that it also regulates energy balance at the whole body level, by responding to hormones that act primarily on the hypothalamus. AMPK monitors energy balance at the cellular level by sensing the ratios of AMP/ATP and ADP/ATP, and recent structural analyses of the AMPK heterotrimer that have provided insight into the complex mechanisms for these effects will be discussed. Given the central importance of energy balance in diseases that are major causes of morbidity or death in humans, such as type 2 diabetes, cancer and inflammatory disorders, there has been a major drive to develop pharmacological activators of AMPK. Many such activators have been described, and the various mechanisms by which these activate AMPK will be discussed. A particularly large class of AMPK activators are natural products of plants derived from traditional herbal medicines. While the mechanism by which most of these activate AMPK has not yet been addressed, I will argue that many of them may be defensive compounds produced by plants to deter infection by pathogens or grazing by insects or herbivores, and that many of them will turn out to be inhibitors of mitochondrial function. PMID:26904394

SDN-1/syndecan regulates growth factor signaling in distal tip cell migrations in C. elegans.

PubMed

Schwabiuk, Megan; Coudiere, Ludivine; Merz, David C

2009-10-01

Mutations in the sdn-1/syndecan gene act as genetic enhancers of the ventral-to-dorsal distal tip cell (DTC) migration defects caused by a weak allele of the netrin receptor gene unc-5. The sdn-1(ev697) allele was identified in a genetic screen for enhancers of unc-5 DTC migration defects, and carried a nonsense mutation predicted to truncate the SDN-1 protein prior to the transmembrane domain. The enhancement of unc-5 caused by an sdn-1 mutation was rescued by expression of wild-type sdn-1 in the hypodermis or nervous system rather than the DTCs, indicating a cell non-autonomous function of sdn-1. The enhancement was also partially reversed by mutations in the egl-17/FGF or egl-20/Wnt genes, suggesting that sdn-1 affects UNC-5 function through a mis-regulation of signaling in growth factor pathways. egl-20 reporter constructs exhibited increased and mis-localized EGL-20 distribution in sdn-1 mutants compared to wild-type animals. Finally, using loss of function mutations, we show that egl-17/Fgf and egl-20/Wnt are partially redundant in regulating the migration pattern of the posterior DTC, as double mutants exhibit significant frequencies of defects in migration phases along both the anteroposterior and dorsoventral axes. Together these results suggest that SDN-1 affects UNC-5 function by regulating the proper extracellular distribution of growth factors.

Distinct roles for motor neuron autophagy early and late in the SOD1G93A mouse model of ALS

PubMed Central

Rudnick, Noam D.; Griffey, Christopher J.; Guarnieri, Paolo; Gerbino, Valeria; Wang, Xueyong; Piersaint, Jason A.; Tapia, Juan Carlos; Rich, Mark M.; Maniatis, Tom

2017-01-01

Mutations in autophagy genes can cause familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of autophagy in ALS pathogenesis is poorly understood, in part due to the lack of cell type-specific manipulations of this pathway in animal models. Using a mouse model of ALS expressing mutant superoxide dismutase 1 (SOD1G93A), we show that motor neurons form large autophagosomes containing ubiquitinated aggregates early in disease progression. To investigate whether this response is protective or detrimental, we generated mice in which the critical autophagy gene Atg7 was specifically disrupted in motor neurons (Atg7 cKO). Atg7 cKO mice were viable but exhibited structural and functional defects at a subset of vulnerable neuromuscular junctions. By crossing Atg7 cKO mice to the SOD1G93A mouse model, we found that autophagy inhibition accelerated early neuromuscular denervation of the tibialis anterior muscle and the onset of hindlimb tremor. Surprisingly, however, lifespan was extended in Atg7 cKO; SOD1G93A double-mutant mice. Autophagy inhibition did not prevent motor neuron cell death, but it reduced glial inflammation and blocked activation of the stress-related transcription factor c-Jun in spinal interneurons. We conclude that motor neuron autophagy is required to maintain neuromuscular innervation early in disease but eventually acts in a non–cell-autonomous manner to promote disease progression. PMID:28904095

High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

PubMed Central

Gerby, Bastien; Veiga, Diogo F.T.; Krosl, Jana; Nourreddine, Sami; Ouellette, Julianne; Haman, André; Lavoie, Geneviève; Fares, Iman; Tremblay, Mathieu; Litalien, Véronique; Ottoni, Elizabeth; Geoffrion, Dominique; Maddox, Paul S.; Chagraoui, Jalila; Hébert, Josée; Sauvageau, Guy; Kwok, Benjamin H.; Roux, Philippe P.

2016-01-01

Current chemotherapies for T cell acute lymphoblastic leukemia (T-ALL) efficiently reduce tumor mass. Nonetheless, disease relapse attributed to survival of preleukemic stem cells (pre-LSCs) is associated with poor prognosis. Herein, we provide direct evidence that pre-LSCs are much less chemosensitive to existing chemotherapy drugs than leukemic blasts because of a distinctive lower proliferative state. Improving therapies for T-ALL requires the development of strategies to target pre-LSCs that are absolutely dependent on their microenvironment. Therefore, we designed a robust protocol for high-throughput screening of compounds that target primary pre-LSCs maintained in a niche-like environment, on stromal cells that were engineered for optimal NOTCH1 activation. The multiparametric readout takes into account the intrinsic complexity of primary cells in order to specifically monitor pre-LSCs, which were induced here by the SCL/TAL1 and LMO1 oncogenes. We screened a targeted library of compounds and determined that the estrogen derivative 2-methoxyestradiol (2-ME2) disrupted both cell-autonomous and non–cell-autonomous pathways. Specifically, 2-ME2 abrogated pre-LSC viability and self-renewal activity in vivo by inhibiting translation of MYC, a downstream effector of NOTCH1, and preventing SCL/TAL1 activity. In contrast, normal hematopoietic stem/progenitor cells remained functional. These results illustrate how recapitulating tissue-like properties of primary cells in high-throughput screening is a promising avenue for innovation in cancer chemotherapy. PMID:27797342

Stromal cells can contribute oncogenic signals

NASA Technical Reports Server (NTRS)

Tlsty, T. D.

2001-01-01

The majority of studies of neoplastic transformation have focused attention on events that occur within transformed cells. These cell autonomous events result in the disruption of molecular pathways that regulate basic activities of the cells such as proliferation, death, movement and genomic integrity. Other studies have addressed the microenvironment of tumor cells and documented its importance in supporting tumor progression. Recent work has begun to expand on these initial studies of tumor microenvironment and now provide novel insights into the possible initiation and progression of malignant cells. This review will address the transforming effect of stromal cells on epithelial components. Copyright 2001 Academic Press.

Cannabinoids suppress synaptic input to neurones of the rat dorsal motor nucleus of the vagus nerve

PubMed Central

Derbenev, Andrei V; Stuart, Thomas C; Smith, Bret N

2004-01-01

Cannabinoids bind central type 1 receptors (CB1R) and modify autonomic functions, including feeding and anti-emetic behaviours, when administered peripherally or into the dorsal vagal complex. Western blots and immunohistochemistry indicated the expression of CB1R in the rat dorsal vagal complex, and tissue polymerase chain reaction confirmed that CB1R message was made within the region. To identify a cellular substrate for the central autonomic effects of cannabinoids, whole-cell patch-clamp recordings were made in brainstem slices to determine the effects of CB1R activation on synaptic transmission to neurones of the dorsal motor nucleus of the vagus (DMV). A subset of these neurones was identified as gastric related after being labelled retrogradely from the stomach. The CB1R agonists WIN55,212-2 and anandamide decreased the frequency of spontaneous excitatory or inhibitory postsynaptic currents in a concentration-related fashion, an effect that persisted in the presence of tetrodotoxin. Paired pulse ratios of electrically evoked postsynaptic currents were also increased by WIN55,212-2. The effects of WIN55,212-2 were sensitive to the selective CB1R antagonist AM251. Cannabinoid agonist effects on synaptic input originating from neurones in the nucleus tractus solitarius (NTS) were determined by evoking activity in the NTS with local glutamate application. Excitatory and inhibitory synaptic inputs arising from the NTS were attenuated by WIN55,212-2. Our results indicate that cannabinoids inhibit transfer of synaptic information to the DMV, including that arising from the NTS, in part by acting at receptors located on presynaptic terminals contacting DMV neurones. Inhibition of synaptic input to DMV neurones is likely to contribute to the suppression of visceral motor responses by cannabinoids. PMID:15272041

Autonomous support for microorganism research in space

NASA Technical Reports Server (NTRS)

Fleet, Mary L.; Miller, Mark S.; Shipley, Derek, E.; Smith, Jeff D.

1992-01-01

A preliminary design for performing on orbit, autonomous research on microorganisms and cultured cells/tissues is presented. An understanding of gravity and its effects on cells is crucial for space exploration as well as for terrestrial applications. The payload is designed to be compatible with the Commercial Experiment Transporter (COMET) launch vehicle, an orbiter middeck locker interface, and with Space Station Freedom. Uplink/downlink capabilities and sample return through controlled reentry are available for all carriers. Autonomous testing activities are preprogrammed with in-flight reprogrammability. Sensors for monitoring temperature, pH, light, gravity levels, vibrations, and radiation are provided for environmental regulation and experimental data collection. Additional experimental data acquisition includes optical density measurement, microscopy, video, and film photography. On-board full data storage capabilities are provided. A fluid transfer mechanism is utilized for inoculation, sampling, and nutrient replenishment of experiment cultures. In addition to payload design, representative experiments were developed to ensure scientific objectives remained compatible with hardware capabilities. The project is defined to provide biological data pertinent to extended duration crewed space flight including crew health issues and development of a Controlled Ecological Life Support System (CELSS). In addition, opportunities are opened for investigations leading to commercial applications of space, such as pharmaceutical development, modeling of terrestrial diseases, and material processing.

Autonomous support for microorganism research in space

NASA Technical Reports Server (NTRS)

Luttges, M. W.; Klaus, D. M.; Fleet, M. L.; Miller, M. S.; Shipley, D. E.; Smith, J. D.

1992-01-01

A preliminary design for performing on-orbit, autonomous research on microorganisms and cultured cells/tissues is presented. An understanding of gravity and its effects on cells is crucial for space exploration as well as for terrestrial applications. The payload is designed to be compatible with the COMmercial Experiment Transported (COMET) launch vehicle, an orbiter middeck locker interface, and with Space Station Freedom. Uplink/downlink capabilities and sample return through controlled reentry are available for all carriers. Autonomous testing activities are preprogrammed with inflight reprogrammability. Sensors for monitoring temperature, pH, light, gravity levels, vibration, and radiation are provided for environmental regulation and experimental data collection. Additional experiment data acquisition includes optical density measurement, microscopy, video, and file photography. Onboard full data storage capabilities are provided. A fluid transfer mechanism is utilized for inoculation, sampling, and nutrient replenishment of experiment cultures. In addition to payload design, representative experiments were developed to ensure scientific objectives remained compatible with hardware capabilities. The project is defined to provide biological data pertinent to extended duration crewed space flight including crew health issues and development of a Controlled Ecological Life Support System (CELSS). In addition, opportunities are opened for investigations leading to commercial applications of space, such as pharmaceutical development, modeling of terrestrial diseases, and material processing.

Essential Role of the m2R-RGS6-IKACh Pathway in Controlling Intrinsic Heart Rate Variability

PubMed Central

Posokhova, Ekaterina; Ng, David; Opel, Aaisha; Masuho, Ikuo; Tinker, Andrew; Biesecker, Leslie G.; Wickman, Kevin; Martemyanov, Kirill A.

2013-01-01

Normal heart function requires generation of a regular rhythm by sinoatrial pacemaker cells and the alteration of this spontaneous heart rate by the autonomic input to match physiological demand. However, the molecular mechanisms that ensure consistent periodicity of cardiac contractions and fine tuning of this process by autonomic system are not completely understood. Here we examined the contribution of the m2R-IKACh intracellular signaling pathway, which mediates the negative chronotropic effect of parasympathetic stimulation, to the regulation of the cardiac pacemaking rhythm. Using isolated heart preparations and single-cell recordings we show that the m2R-IKACh signaling pathway controls the excitability and firing pattern of the sinoatrial cardiomyocytes and determines variability of cardiac rhythm in a manner independent from the autonomic input. Ablation of the major regulator of this pathway, Rgs6, in mice results in irregular cardiac rhythmicity and increases susceptibility to atrial fibrillation. We further identify several human subjects with variants in the RGS6 gene and show that the loss of function in RGS6 correlates with increased heart rate variability. These findings identify the essential role of the m2R-IKACh signaling pathway in the regulation of cardiac sinus rhythm and implicate RGS6 in arrhythmia pathogenesis. PMID:24204714

Wnt5a-Ror2 signaling in mesenchymal stem cells promotes proliferation of gastric cancer cells by activating CXCL16-CXCR6 axis.

PubMed

Takiguchi, Gosuke; Nishita, Michiru; Kurita, Kana; Kakeji, Yoshihiro; Minami, Yasuhiro

2016-03-01

Wnt5a-Ror2 signaling has been shown to play important roles in promoting aggressiveness of various cancer cells in a cell-autonomous manner. However, little is known about its function in cancer-associated stromal cells, including mesenchymal stem cells (MSCs). Thus, we examined the role of Wnt5a-Ror2 signaling in bone marrow-derived MSCs in regulating proliferation of undifferentiated gastric cancer cells. Coculture of a gastric cancer cell line, MKN45, with MSCs either directly or indirectly promotes proliferation of MKN45 cells, and suppressed expression of Ror2 in MSCs prior to coculture inhibits enhanced proliferation of MKN45 cells. In addition, conditioned media from MSCs, treated with control siRNA, but not siRNAs against Ror2, can enhance proliferation of MKN45 cells. Interestingly, it was found that expression of CXCL16 in MSCs is augmented by Wnt5a-Ror2 signaling, and that recombinant chemokine (C-X-C motif) ligand (CXCL)16 protein can enhance proliferation of MKN45 cells in the absence of MSCs. In fact, suppressed expression of CXCL16 in MSCs or an addition of a neutralizing antibody against CXCL16 fails to promote proliferation of MKN45 cells in either direct or indirect coculture with MSCs. Importantly, we show that MKN45 cells express chemokine (C-X-C motif) receptor (CXCR)6, a receptor for CXCL16, and that suppressed expression of CXCR6 in MKN45 cells results in a failure of its enhanced proliferation in either direct or indirect coculture with MSCs. These findings indicate that Wnt5a-Ror2 signaling enhances expression of CXCL16 in MSCs and, as a result, enhanced secretion of CXCL16 from MSCs might act on CXCR6 expressed on MKN45, leading to the promotion of its proliferation. © 2015 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Desperately seeking social approval: Adam Smith, Thorstein Veblen and the moral limits of capitalist culture.

PubMed

Watson, Matthew

2012-09-01

Adam Smith and Thorstein Veblen shared much in matters of economic ontology. Both dismissed the very notion of an autonomous economic self and instead investigated the processes through which self and other are mutually constituted under changing cultural traditions of individual aspiration. Their strikingly similar critiques of status-oriented consumption and concern for the moral basis of the market economy are established in this manner. However, the political implications of their analyses point in different directions, with Veblen being the more radical. The Smithian individual can always use spectatorial insights to assert through genuinely praiseworthy behaviour personal moral distance from social norms of status-oriented consumption. The Veblenian individual, by contrast, has no such capacity for elevating abstract moral principles above socially-situated conduct, as mind and environment co-evolve in line with changing material circumstances of life. For Veblen, the rise of status-oriented consumption itself acted as a form of moral self-education that more deeply entrenched the social norms of ownership out of which it arose, thus the impossibility of an autonomous economic self was matched by the impossibility of an autonomous moral self. To his way of thinking, moral degradation in conspicuous consumption was irredeemably inscribed into the whole cultural structure of capitalism. © London School of Economics and Political Science 2012.

Helping Your Partner with Chronic Pain: The Importance of Helping Motivation, Received Social Support, and Its Timeliness.

PubMed

Kindt, Sara; Vansteenkiste, Maarten; Josephy, Haeike; Bernardes, Sonia F; Goubert, Liesbet

2018-02-02

Like all intentional acts, social support provision varies with respect to its underlying motives. Greater autonomous or volitional motives (e.g., enjoyment, full commitment) to help individuals with chronic pain (ICPs) are associated with greater well-being benefits for the latter, as indexed by improved satisfaction of their psychological needs for autonomy, competence, and relatedness. The present study investigates the processes explaining why partners' autonomous or volitional helping motivation yields these benefits. A total of 134 couples, where at least one partner had chronic pain, completed a 14-day diary. Partners reported on their daily helping motives, whereas ICPs reported on their daily received support, timing of help, need-based experiences, and pain. On days when partners provided help for volitional motives, ICPs indicated receiving more help, which partially accounted for the effect of autonomous helping motivation on ICP need-based experiences. Timing of help moderated the effects of daily received support on ICP need-based experiences. Findings highlight the importance of ICPs of receiving support in general and the role of timing in particular, which especially matters when there is little support being received. © 2018 American Academy of Pain Medicine. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Constrained navigation for unmanned systems

NASA Astrophysics Data System (ADS)

Vasseur, Laurent; Gosset, Philippe; Carpentier, Luc; Marion, Vincent; Morillon, Joel G.; Ropars, Patrice

2005-05-01

The French Military Robotic Study Program (introduced in Aerosense 2003), sponsored by the French Defense Procurement Agency and managed by Thales as the prime contractor, focuses on about 15 robotic themes which can provide an immediate "operational add-on value". The paper details the "constrained navigation" study (named TEL2), which main goal is to identify and test a well-balanced task sharing between man and machine to accomplish a robotic task that cannot be performed autonomously at the moment because of technological limitations. The chosen function is "obstacle avoidance" on rough ground and quite high speed (40 km/h). State of the art algorithms have been implemented to perform autonomous obstacle avoidance and following of forest borders, using scanner laser sensor and standard localization functions. Such an "obstacle avoidance" function works well most of the time, BUT fails sometimes. The study analyzed how the remote operator can manage such failures so that the system remains fully operationally reliable; he can act according to two ways: a) finely adjust the vehicle current heading; b) take the control of the vehicle "on the fly" (without stopping) and bring it back to autonomous behavior when motion is secured again. The paper also presents the results got from the military acceptance tests performed on French 4x4 DARDS ATD.

Open-Loop Flight Testing of COBALT GN&C Technologies for Precise Soft Landing

NASA Technical Reports Server (NTRS)

Carson, John M., III; Amzajerdian, Farzin; Seubert, Carl R.; Restrepo, Carolina I.

2017-01-01

A terrestrial, open-loop (OL) flight test campaign of the NASA COBALT (CoOperative Blending of Autonomous Landing Technologies) platform was conducted onboard the Masten Xodiac suborbital rocket testbed, with support through the NASA Advanced Exploration Systems (AES), Game Changing Development (GCD), and Flight Opportunities (FO) Programs. The COBALT platform integrates NASA Guidance, Navigation and Control (GN&C) sensing technologies for autonomous, precise soft landing, including the Navigation Doppler Lidar (NDL) velocity and range sensor and the Lander Vision System (LVS) Terrain Relative Navigation (TRN) system. A specialized navigation filter running onboard COBALT fuzes the NDL and LVS data in real time to produce a precise navigation solution that is independent of the Global Positioning System (GPS) and suitable for future, autonomous planetary landing systems. The OL campaign tested COBALT as a passive payload, with COBALT data collection and filter execution, but with the Xodiac vehicle Guidance and Control (G&C) loops closed on a Masten GPS-based navigation solution. The OL test was performed as a risk reduction activity in preparation for an upcoming 2017 closed-loop (CL) flight campaign in which Xodiac G&C will act on the COBALT navigation solution and the GPS-based navigation will serve only as a backup monitor.

Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress

PubMed Central

Rojas, Fabiola; Cortes, Nicole; Abarzua, Sebastian; Dyrda, Agnieszka; van Zundert, Brigitte

2013-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder caused by dysfunction and degeneration of motor neurons. Multiple disease-causing mutations, including in the genes for SOD1 and TDP-43, have been identified in ALS. Astrocytes expressing mutant SOD1 are strongly implicated in the pathogenesis of ALS: we have shown that media conditioned by astrocytes carrying mutant SOD1G93A contains toxic factor(s) that kill motoneurons by activating voltage-sensitive sodium (Nav) channels. In contrast, a recent study suggests that astrocytes expressing mutated TDP43 contribute to ALS pathology, but do so via cell-autonomous processes and lack non-cell-autonomous toxicity. Here we investigate whether astrocytes that express diverse ALS-causing mutations release toxic factor(s) that induce motoneuron death, and if so, whether they do so via a common pathogenic pathway. We exposed primary cultures of wild-type spinal cord cells to conditioned medium derived from astrocytes (ACM) that express SOD1 (ACM-SOD1G93A and ACM-SOD1G86R) or TDP43 (ACM-TDP43A315T) mutants; we show that such exposure rapidly (within 30–60 min) increases dichlorofluorescein (DCF) fluorescence (indicative of nitroxidative stress) and leads to extensive motoneuron-specific death within a few days. Co-application of the diverse ACMs with anti-oxidants Trolox or esculetin (but not with resveratrol) strongly improves motoneuron survival. We also find that co-incubation of the cultures in the ACMs with Nav channel blockers (including mexiletine, spermidine, or riluzole) prevents both intracellular nitroxidative stress and motoneuron death. Together, our data document that two completely unrelated ALS models lead to the death of motoneuron via non-cell-autonomous processes, and show that astrocytes expressing mutations in SOD1 and TDP43 trigger such cell death through a common pathogenic pathway that involves nitroxidative stress, induced at least in part by Nav channel activity. PMID:24570655

Branched-chain amino acid catabolism is a conserved regulator of physiological ageing.

PubMed

Mansfeld, Johannes; Urban, Nadine; Priebe, Steffen; Groth, Marco; Frahm, Christiane; Hartmann, Nils; Gebauer, Juliane; Ravichandran, Meenakshi; Dommaschk, Anne; Schmeisser, Sebastian; Kuhlow, Doreen; Monajembashi, Shamci; Bremer-Streck, Sibylle; Hemmerich, Peter; Kiehntopf, Michael; Zamboni, Nicola; Englert, Christoph; Guthke, Reinhard; Kaleta, Christoph; Platzer, Matthias; Sühnel, Jürgen; Witte, Otto W; Zarse, Kim; Ristow, Michael

2015-12-01

Ageing has been defined as a global decline in physiological function depending on both environmental and genetic factors. Here we identify gene transcripts that are similarly regulated during physiological ageing in nematodes, zebrafish and mice. We observe the strongest extension of lifespan when impairing expression of the branched-chain amino acid transferase-1 (bcat-1) gene in C. elegans, which leads to excessive levels of branched-chain amino acids (BCAAs). We further show that BCAAs reduce a LET-363/mTOR-dependent neuro-endocrine signal, which we identify as DAF-7/TGFβ, and that impacts lifespan depending on its related receptors, DAF-1 and DAF-4, as well as ultimately on DAF-16/FoxO and HSF-1 in a cell-non-autonomous manner. The transcription factor HLH-15 controls and epistatically synergizes with BCAT-1 to modulate physiological ageing. Lastly and consistent with previous findings in rodents, nutritional supplementation of BCAAs extends nematodal lifespan. Taken together, BCAAs act as periphery-derived metabokines that induce a central neuro-endocrine response, culminating in extended healthspan.

Branched-chain amino acid catabolism is a conserved regulator of physiological ageing

PubMed Central

Mansfeld, Johannes; Urban, Nadine; Priebe, Steffen; Groth, Marco; Frahm, Christiane; Hartmann, Nils; Gebauer, Juliane; Ravichandran, Meenakshi; Dommaschk, Anne; Schmeisser, Sebastian; Kuhlow, Doreen; Monajembashi, Shamci; Bremer-Streck, Sibylle; Hemmerich, Peter; Kiehntopf, Michael; Zamboni, Nicola; Englert, Christoph; Guthke, Reinhard; Kaleta, Christoph; Platzer, Matthias; Sühnel, Jürgen; Witte, Otto W.; Zarse, Kim; Ristow, Michael

2015-01-01

Ageing has been defined as a global decline in physiological function depending on both environmental and genetic factors. Here we identify gene transcripts that are similarly regulated during physiological ageing in nematodes, zebrafish and mice. We observe the strongest extension of lifespan when impairing expression of the branched-chain amino acid transferase-1 (bcat-1) gene in C. elegans, which leads to excessive levels of branched-chain amino acids (BCAAs). We further show that BCAAs reduce a LET-363/mTOR-dependent neuro-endocrine signal, which we identify as DAF-7/TGFβ, and that impacts lifespan depending on its related receptors, DAF-1 and DAF-4, as well as ultimately on DAF-16/FoxO and HSF-1 in a cell-non-autonomous manner. The transcription factor HLH-15 controls and epistatically synergizes with BCAT-1 to modulate physiological ageing. Lastly and consistent with previous findings in rodents, nutritional supplementation of BCAAs extends nematodal lifespan. Taken together, BCAAs act as periphery-derived metabokines that induce a central neuro-endocrine response, culminating in extended healthspan. PMID:26620638

S6 Kinase Inhibits Intrinsic Axon Regeneration Capacity via AMP Kinase in Caenorhabditis elegans

PubMed Central

Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D.

2014-01-01

The ability of axons to regrow after injury is determined by the complex interplay of intrinsic growth programs and external cues. In Caenorhabditis elegans mechanosensory neuron, axons exhibit robust regenerative regrowth following laser axotomy. By surveying conserved metabolic signaling pathways, we have identified the ribosomal S6 kinase RSKS-1 as a new cell-autonomous inhibitor of axon regeneration. RSKS-1 is not required for axonal development but inhibits axon regrowth after injury in multiple neuron types. Loss of function in rsks-1 results in more rapid growth cone formation after injury and accelerates subsequent axon extension. The enhanced regrowth of rsks-1 mutants is partly dependent on the DLK-1 MAPK cascade. An essential output of RSKS-1 in axon regrowth is the metabolic sensor AMP kinase, AAK-2. We further show that the antidiabetic drug phenformin, which activates AMP kinase, can promote axon regrowth. Our data reveal a new function for an S6 kinase acting through an AMP kinase in regenerative growth of injured axons. PMID:24431434

Harnessing surface-bound enzymatic reactions to organize microcapsules in solution

PubMed Central

Shklyaev, Oleg E.; Shum, Henry; Sen, Ayusman; Balazs, Anna C.

2016-01-01

By developing new computational models, we examine how enzymatic reactions on an underlying surface can be harnessed to direct the motion and organization of reagent-laden microcapsules in a fluid-filled microchannel. In the presence of appropriate reagents, surface-bound enzymes can act as pumps, which drive large-scale fluid flows. When the reagents diffuse through the capsules’ porous shells, they can react with enzymatic sites on the bottom surface. The ensuing reaction generates fluid density variations, which result in fluid flows. These flows carry the suspended microcapsules and drive them to aggregate into “colonies” on and near the enzyme-covered sites. This aggregation continues until the reagent has been depleted and the convection stops. We show that the shape of the assembled colonies can be tailored by patterning the distribution of enzymes on the surface. This fundamental physicochemical mechanism could have played a role in the self-organization of early biological cells (protocells) and can be used to regulate the autonomous motion and targeted delivery of microcarriers in microfluidic devices. PMID:27034990

Immunosuppression after Sepsis: Systemic Inflammation and Sepsis Induce a Loss of Naïve T-Cells but No Enduring Cell-Autonomous Defects in T-Cell Function

PubMed Central

Markwart, Robby; Condotta, Stephanie A.; Requardt, Robert P.; Borken, Farina; Schubert, Katja; Weigel, Cynthia; Bauer, Michael; Griffith, Thomas S.; Förster, Martin; Brunkhorst, Frank M.; Badovinac, Vladimir P.; Rubio, Ignacio

2014-01-01

Sepsis describes the life-threatening systemic inflammatory response (SIRS) of an organism to an infection and is the leading cause of mortality on intensive care units (ICU) worldwide. An acute episode of sepsis is characterized by the extensive release of cytokines and other mediators resulting in a dysregulated immune response leading to organ damage and/or death. This initial pro-inflammatory burst often transits into a state of immune suppression characterised by loss of immune cells and T-cell dysfunction at later disease stages in sepsis survivors. However, despite these appreciations, the precise nature of the evoked defect in T-cell immunity in post-acute phases of SIRS remains unknown. Here we present an in-depth functional analysis of T-cell function in post-acute SIRS/sepsis. We document that T-cell function is not compromised on a per cell basis in experimental rodent models of infection-free SIRS (LPS or CpG) or septic peritonitis. Transgenic antigen-specific T-cells feature an unaltered cytokine response if challenged in vivo and ex vivo with cognate antigens. Isolated CD4+/CD8+ T-cells from post-acute septic animals do not exhibit defects in T-cell receptor-mediated activation at the the level of receptor-proximal signalling, activation marker upregulation or expansion. However, SIRS/sepsis induced transient lymphopenia and gave rise to an environment of immune attenuation at post acute disease stages. Thus, systemic inflammation has an acute impact on T-cell numbers and adaptive immunity, but does not cause major cell-autonomous enduring functional defects in T-cells. PMID:25541945

Hybrid power systems for autonomous MEMS

NASA Astrophysics Data System (ADS)

Bennett, Daniel M.; Selfridge, Richard H.; Humble, Paul; Harb, John N.

2001-08-01

This paper describes the design of a hybrid power system for use with autonomous MEMS and other microdevices. This hybrid power system includes energy conversion and storage along with an electronic system for managing the collection and distribution of power. It offers flexibility and longevity in a compact package. The hybrid power system couples a silicon solar cell with a microbattery specially designed for MEMS applications. We have designed a control/interface charging circuit to be compatible with a MEMS duty cycle. The design permits short pulses of 'high' power while taking care to avoid excessive charging or discharging of the battery. Charging is carefully controlled to provide a balance between acceptably small charging times and a charging profile that extends battery life. Our report describes the charging of our Ni/Zn microbatteries using solar cells. To date we have demonstrated thousands of charge/discharge cycles of a simulated MEMS duty cycle.

Segmentation of the zebrafish axial skeleton relies on notochord sheath cells and not on the segmentation clock

PubMed Central

Lleras Forero, Laura; Narayanan, Rachna; Huitema, Leonie FA; VanBergen, Maaike; Apschner, Alexander; Peterson-Maduro, Josi; Logister, Ive; Valentin, Guillaume

2018-01-01

Segmentation of the axial skeleton in amniotes depends on the segmentation clock, which patterns the paraxial mesoderm and the sclerotome. While the segmentation clock clearly operates in teleosts, the role of the sclerotome in establishing the axial skeleton is unclear. We severely disrupt zebrafish paraxial segmentation, yet observe a largely normal segmentation process of the chordacentra. We demonstrate that axial entpd5+ notochord sheath cells are responsible for chordacentrum mineralization, and serve as a marker for axial segmentation. While autonomous within the notochord sheath, entpd5 expression and centrum formation show some plasticity and can respond to myotome pattern. These observations reveal for the first time the dynamics of notochord segmentation in a teleost, and are consistent with an autonomous patterning mechanism that is influenced, but not determined by adjacent paraxial mesoderm. This behavior is not consistent with a clock-type mechanism in the notochord. PMID:29624170

Ubiquitination switches EphA2 vesicular traffic from a continuous safeguard to a finite signalling mode

PubMed Central

Sabet, Ola; Stockert, Rabea; Xouri, Georgia; Brüggemann, Yannick; Stanoev, Angel; Bastiaens, Philippe I. H.

2015-01-01

Autocatalytic phosphorylation of receptor tyrosine kinases (RTKs) enables diverse, context-dependent responses to extracellular signals but comes at the price of autonomous, ligand-independent activation. Using a conformational biosensor that reports on the kinase activity of the cell guidance ephrin receptor type-A (EphA2) in living cells, we observe that autonomous EphA2 activation is suppressed by vesicular recycling and dephosphorylation by protein tyrosine phosphatases 1B (PTP1B) near the pericentriolar recycling endosome. This spatial segregation of catalytically superior PTPs from RTKs at the plasma membrane is essential to preserve ligand responsiveness. Ligand-induced clustering, on the other hand, promotes phosphorylation of a c-Cbl docking site and ubiquitination of the receptor, thereby redirecting it to the late endosome/lysosome. We show that this switch from cyclic to unidirectional receptor trafficking converts a continuous suppressive safeguard mechanism into a transient ligand-responsive signalling mode. PMID:26292967

In serum veritas—in serum sanitas? Cell non-autonomous aging compromises differentiation and survival of mesenchymal stromal cells via the oxidative stress pathway

PubMed Central

Geißler, S; Textor, M; Schmidt-Bleek, K; Klein, O; Thiele, M; Ellinghaus, A; Jacobi, D; Ode, A; Perka, C; Dienelt, A; Klose, J; Kasper, G; Duda, G N; Strube, P

2013-01-01

Even tissues capable of complete regeneration, such as bone, show an age-related reduction in their healing capacity. Here, we hypothesized that this decline is primarily due to cell non-autonomous (extrinsic) aging mediated by the systemic environment. We demonstrate that culture of mesenchymal stromal cells (MSCs) in serum from aged Sprague–Dawley rats negatively affects their survival and differentiation ability. Proteome analysis and further cellular investigations strongly suggest that serum from aged animals not only changes expression of proteins related to mitochondria, unfolded protein binding or involved in stress responses, it also significantly enhances intracellular reactive oxygen species production and leads to the accumulation of oxidatively damaged proteins. Conversely, reduction of oxidative stress levels in vitro markedly improved MSC function. These results were validated in an in vivo model of compromised bone healing, which demonstrated significant increase regeneration in aged animals following oral antioxidant administration. These observations indicate the high impact of extrinsic aging on cellular functions and the process of endogenous (bone) regeneration. Thus, addressing the cell environment by, for example, systemic antioxidant treatment is a promising approach to enhance tissue regeneration and to regain cellular function especially in elderly patients. PMID:24357801

Autonomic responses to cold face stimulation in sickle cell disease: a time-varying model analysis.

PubMed

Chalacheva, Patjanaporn; Kato, Roberta M; Sangkatumvong, Suvimol; Detterich, Jon; Bush, Adam; Wood, John C; Meiselman, Herbert; Coates, Thomas D; Khoo, Michael C K

2015-07-14

Sickle cell disease (SCD) is characterized by sudden onset of painful vaso-occlusive crises (VOC), which occur on top of the underlying chronic blood disorder. The mechanisms that trigger VOC remain elusive, but recent work suggests that autonomic dysfunction may be an important predisposing factor. Heart-rate variability has been employed in previous studies, but the derived indices have provided only limited univariate information about autonomic cardiovascular control in SCD. To circumvent this limitation, a time-varying modeling approach was applied to investigate the functional mechanisms relating blood pressure (BP) and respiration to heart rate and peripheral vascular resistance in healthy controls, untreated SCD subjects and SCD subjects undergoing chronic transfusion therapy. Measurements of respiration, heart rate, continuous noninvasive BP and peripheral vascular resistance were made before, during and after the application of cold face stimulation (CFS), which perturbs both the parasympathetic and sympathetic nervous systems. Cardiac baroreflex sensitivity estimated from the model was found to be impaired in nontransfused SCD subjects, but partially restored in SCD subjects undergoing transfusion therapy. Respiratory-cardiac coupling gain was decreased in SCD and remained unchanged by chronic transfusion. These results are consistent with autonomic dysfunction in the form of impaired parasympathetic control and sympathetic overactivity. As well, CFS led to a significant reduction in vascular resistance baroreflex sensitivity in the nontransfused SCD subjects but not in the other groups. This blunting of the baroreflex control of peripheral vascular resistance during elevated sympathetic drive could be a potential factor contributing to the triggering of VOC in SCD. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

VGLUT1 and VGLUT2 innervation in autonomic regions of intact and transected rat spinal cord.

PubMed

Llewellyn-Smith, Ida J; Martin, Carolyn L; Fenwick, Natalie M; Dicarlo, Stephen E; Lujan, Heidi L; Schreihofer, Ann M

2007-08-20

Fast excitatory neurotransmission to sympathetic and parasympathetic preganglionic neurons (SPN and PPN) is glutamatergic. To characterize this innervation in spinal autonomic regions, we localized immunoreactivity for vesicular glutamate transporters (VGLUTs) 1 and 2 in intact cords and after upper thoracic complete transections. Preganglionic neurons were retrogradely labeled by intraperitoneal Fluoro-Gold or with cholera toxin B (CTB) from superior cervical, celiac, or major pelvic ganglia or adrenal medulla. Glutamatergic somata were localized with in situ hybridization for VGLUT mRNA. In intact cords, all autonomic areas contained abundant VGLUT2-immunoreactive axons and synapses. CTB-immunoreactive SPN and PPN received many close appositions from VGLUT2-immunoreactive axons. VGLUT2-immunoreactive synapses occurred on Fluoro-Gold-labeled SPN. Somata with VGLUT2 mRNA occurred throughout the spinal gray matter. VGLUT2 immunoreactivity was not noticeably affected caudal to a transection. In contrast, in intact cords, VGLUT1-immunoreactive axons were sparse in the intermediolateral cell column (IML) and lumbosacral parasympathetic nucleus but moderately dense above the central canal. VGLUT1-immunoreactive close appositions were rare on SPN in the IML and the central autonomic area and on PPN. Transection reduced the density of VGLUT1-immunoreactive axons in sympathetic subnuclei but increased their density in the parasympathetic nucleus. Neuronal cell bodies with VGLUT1 mRNA occurred only in Clarke's column. These data indicate that SPN and PPN are densely innervated by VGLUT2-immunoreactive axons, some of which arise from spinal neurons. In contrast, the VGLUT1-immunoreactive innervation of spinal preganglionic neurons is sparse, and some may arise from supraspinal sources. Increased VGLUT1 immunoreactivity after transection may correlate with increased glutamatergic transmission to PPN. (c) 2007 Wiley-Liss, Inc.

Fatty Acid Binding Protein FABP4 Mechanistically Links Obesity with Aggressive AML by Enhancing Aberrant DNA Methylation in AML Cells

PubMed Central

Yan, F; Shen, N; Pang, JX; Zhang, YW; Rao, EY; Bode, AM; Al-Kali, A; Zhang, DE; Litzow, MR; Li, B; Liu, SJ

2016-01-01

Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here, we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and IL-6 in sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and STAT3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15INK4B tumor suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15INK4B expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity, and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia. PMID:27885273

Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells.

PubMed

Yan, F; Shen, N; Pang, J X; Zhang, Y W; Rao, E Y; Bode, A M; Al-Kali, A; Zhang, D E; Litzow, M R; Li, B; Liu, S J

2017-06-01

Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid-binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and interleukin (IL)-6 in the sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and signal transducer and activator of transcription factor 3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15 INK4B tumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15 INK4B expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia.

Wind-driven Circulation and Freshwater Fluxes off Sri Lanka: 4D-Sampling with Autonomous Gliders

DTIC Science & Technology

2015-09-30

riverine freshwater input, precipitation and atmospheric forcing act to govern Bay of Bengal upper ocean variability, water mass formation and...fraction of the water moving through the section is going south, carrying freshwater out of the Bay of Bengal. Currents near the coast have the same...transport of freshwater from the Northern Bay of Bengal, as well of the import of salty Arabian Sea Water , are being investigated are using all the

TET Explorers: Pushing back the frontiers of Science

NASA Astrophysics Data System (ADS)

Curtis, S. A.; Clark, P. E.; Garvin, J. B.; Rilee, M. L.; Dorband, J. E.; Cheung, C. Y.; Sams, J. E.

2005-12-01

We are in the process of developing Tetrahedral Explorer Technologies (TETs) for the extreme mobility needed to explore remote, rugged terrain. TET architecture is based on the tetrahedron as building block, acting singly or interconnected, where apices act as nodes from which struts reversibly deploy. Conformable tetrahedra are the simplest space-filling form the way triangles are the simplest plane-filling facets. The tetrahedral framework acts as a simple skeletal muscular structure. Reconfigurable architecture is essential in exploration because reaching features of the greatest potential interest requires crossing a wide range of terrains. Thus, areas of interest are relatively inaccessible to permanently appendaged vehicles. For example, morphology and geochemistry of interior basins, walls, and ejecta blankets of impact structures must all be studied to understand the nature of an impact event. The crater floor might be relatively flat and navigable, while typical crater walls are variably sloping, and dominated by unconsolidated debris. To be totally functional, structures must form pseudo-appendages varying in size, rate, and manner of deployment (gait). We have already prototyped a simple robotic walker from a single reconfigurable tetrahedron capable of tumbling and are simulating and building a prototype of the more evolved 12Tetrahedral Walker (Autonomous Lunar Investigator) which has interior nodes for payload, more continuous motion, and is commandable through a user friendly interface. Our current applications consist of a more differentiated architecture to form detachable, reconfigurable, reshapable linearly extendable bodies (Class W or Worm), ranging from arms terminating in opposable digits (Class S or Spider) to act as manual assistant subsystems on rovers, to autonomous pseudo-hominid clamberers (Class M or Mammal), with extensions terminating in a wider range of sensors. We are now simulating Class W and Class S gaits and will be building a prototype rover arm. Ultimately, complex continuous n-tetrahedral structures, more advanced versions of Class A, will have deployable outer skin, and even higher degrees of freedom. Combined high and low level intelligence through an extended neural interface will allow `shape shifting' for required function, from surface-conformable lander to amorphous rover to concave surface formation for antenna function. Such architecture will consist of reusable, reconfigurable, mobile, and self-repairing structures, capable of acting as a multi-functional infrastructure. TET systems will act as robotic adjuncts to human explorers, enabling access to otherwise inaccessible resources essential to sustaining human presence.

CXCR4 receptors in the dorsal medulla: implications for autonomic dysfunction

PubMed Central

Hermann, Gerlinda E.; Van Meter, Montina J.; Rogers, Richard C.

2014-01-01

The chemokine receptor, CXCR4, plays an essential role in guiding neural development of the CNS. Its natural agonist, CXCL12 [or stromal cell-derived factor-1 (SDF-1)], normally is derived from stromal cells, but is also produced by damaged and virus-infected neurons and glia. Pathologically, this receptor is critical to the proliferation of the HIV virus and initiation of metastatic cell growth in the brain. Anorexia, nausea and failed autonomic regulation of gastrointestinal (GI) function cause morbidity and contribute to the mortality associated with these disease states. Our previous work on the peripheral cytokine, tumor necrosis factor-alpha, demonstrated that similar morbidity factors involving GI dysfunction are attributable to agonist action on neural circuit elements of the dorsal vagal complex (DVC) of the hindbrain. The DVC includes vagal afferent terminations in the solitary nucleus, neurons in the solitary nucleus (NST) and area postrema, and visceral efferent motor neurons in the dorsal motor nucleus (DMN) that are responsible for the neural regulation of digestive functions from the oral cavity to the transverse colon. Immunohistochemical techniques demonstrate a dense concentration of CXCR4 receptors on neurons throughout the DVC and the hypoglossal nucleus. CXCR4-immunoreactivity is also intense on microglia within the DVC, though not on the astrocytes. Physiological studies show that nanoinjection of SDF-1 into the DVC produces a significant reduction in gastric motility in parallel with an elevation in the numbers of cFOS-activated neurons in the NST and DMN. These results suggest that this chemokine receptor may contribute to autonomically mediated pathophysiological events associated with CNS metastasis and infection. PMID:18333961

Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature.

PubMed

Elhennawy, Karim; Reda, Seif; Finke, Christian; Graul-Neumann, Luitgard; Jost-Brinkmann, Paul-Georg; Bartzela, Theodosia

2017-08-15

Hereditary sensory and autonomic neuropathy type VIII is a rare autosomal recessive inherited disorder. Chen et al. recently identified the causative gene and characterized biallelic mutations in the PR domain-containing protein 12 gene, which plays a role in the development of pain-sensing nerve cells. Our patient's family was included in Chen and colleagues' study. We performed a literature review of the PubMed library (January 1985 to December 2016) on hereditary sensory and autonomic neuropathy type I to VIII genetic disorders and their orofacial manifestations. This case report is the first to describe the oral manifestations, and their treatment, of the recently discovered hereditary sensory and autonomic neuropathy type VIII in the medical and dental literature. We report on the oral manifestations and dental management of an 8-month-old white boy with hereditary sensory and autonomic neuropathy-VIII over a period of 16 years. Our patient was homozygous for a mutation of PR domain-containing protein 12 gene and was characterized by insensitivity to pain and thermal stimuli, self-mutilation behavior, reduced sweat and tear production, absence of corneal reflexes, and multiple skin and bone infections. Oral manifestations included premature loss of teeth, associated with dental traumata and self-mutilation, severe soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary teeth, and mandibular osteomyelitis. The lack of scientific knowledge on hereditary sensory and autonomic neuropathy due to the rarity of the disease often results in a delay in diagnosis, which is of substantial importance for the prevention of many complications and symptoms. Interdisciplinary work of specialized medical and dental teams and development of a standardized treatment protocols are essential for the management of the disease. There are many knowledge gaps concerning the management of patients with hereditary sensory and autonomic neuropathy-VIII, therefore more research on an international basis is needed.

Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and non-autonomous mechanisms.

PubMed

Gao, Xueqin; Usas, Arvydas; Lu, Aiping; Kozemchak, Adam; Tang, Ying; Poddar, Minakshi; Sun, Xuying; Cummins, James H; Huard, Johnny

2016-08-01

This study investigated the role of cyclooxygenase-2 (COX-2) expression by donor and host cells in muscle-derived stem cell (MDSC)-mediated bone regeneration utilizing a critical size calvarial defect model. We found that BMP4/green fluorescent protein (GFP)-transduced MDSCs formed significantly less bone in COX-2 knock-out (Cox-2KO) than in COX-2 wild-type (WT) mice. BMP4/GFP-transduced Cox-2KO MDSCs also formed significantly less bone than transduced WT MDSCs when transplanted into calvarial defects created in CD-1 nude mice. The impaired bone regeneration in the Cox-2KO MDSCBMP4/GFP group is associated with downregulation of BMP4-pSMAD1/5 signaling, decreased osteogenic differentiation and lowered proliferation capacity after transplantation, compared with WT MDSCBMP4/GFP cells. The Cox-2KO MDSCBMP4/GFP group demonstrated a reduction in cell survival and direct osteogenic differentiation in vitro These effects were mediated in part by the downregulation of Igf1 and Igf2. In addition, the Cox-2KO MDSCBMP4/GFP cells recruited fewer macrophages than the WT MDSC/BMP4/GFP cells in the early phase after injury. We concluded that the bone regeneration capacity of Cox-2KO MDSCs was impaired because of a reduction in cell proliferation and survival capacities, reduction in osteogenic differentiation and a decrease in the ability of the cells to recruit host cells to the injury site. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

TSPAN12 is a critical factor for cancer–fibroblast cell contact-mediated cancer invasion

PubMed Central

Otomo, Ryo; Otsubo, Chihiro; Matsushima-Hibiya, Yuko; Miyazaki, Makoto; Tashiro, Fumio; Ichikawa, Hitoshi; Kohno, Takashi; Ochiya, Takahiro; Yokota, Jun; Nakagama, Hitoshi; Taya, Yoichi; Enari, Masato

2014-01-01

Communication between cancer cells and their microenvironment controls cancer progression. Although the tumor suppressor p53 functions in a cell-autonomous manner, it has also recently been shown to function in a non–cell-autonomous fashion. Although functional defects have been reported in p53 in stromal cells surrounding cancer, including mutations in the p53 gene and decreased p53 expression, the role of p53 in stromal cells during cancer progression remains unclear. We herein show that the expression of α-smooth muscle actin (α-SMA), a marker of cancer-associated fibroblasts (CAFs), was increased by the ablation of p53 in lung fibroblasts. CAFs enhanced the invasion and proliferation of lung cancer cells when cocultured with p53-depleted fibroblasts and required contact between cancer and stromal cells. A comprehensive analysis using a DNA chip revealed that tetraspanin 12 (TSPAN12), which belongs to the tetraspanin protein family, was derepressed by p53 knockdown. TSPAN12 knockdown in p53-depleted fibroblasts inhibited cancer cell proliferation and invasion elicited by coculturing with p53-depleted fibroblasts in vitro, and inhibited tumor growth in vivo. It also decreased CXC chemokine ligand 6 (CXCL6) secretion through the β-catenin signaling pathway, suggesting that cancer cell contact with TSPAN12 in fibroblasts transduced β-catenin signaling into fibroblasts, leading to the secretion of CXCL6 to efficiently promote invasion. These results suggest that stroma-derived p53 plays a pivotal role in epithelial cancer progression and that TSPAN12 and CXCL6 are potential targets for lung cancer therapy. PMID:25512506

Enteromegaly and cardiomegaly in Chagas disease

PubMed Central

Köberle, Fritz

1963-01-01

Chagas disease due to a trypanosome infection may lead to extensive destruction of ganglion cells in the peripheral autonomic system and may result in gross enlargement of the oesophagus, colon, and heart. From studies on nerve cell counts it is concluded that the number of ganglion cells in the oesophagus must be reduced to less than half to produce functional disturbances in the oesophagus and to one tenth to produce a megaoesophagus. Problems of terminology are discussed. PMID:14084752

Tissue-autonomous promotion of palisade cell development by phototropin 2 in Arabidopsis.

PubMed

Kozuka, Toshiaki; Kong, Sam-Geun; Doi, Michio; Shimazaki, Ken-ichiro; Nagatani, Akira

2011-10-01

Light is an important environmental information source that plants use to modify their growth and development. Palisade parenchyma cells in leaves develop cylindrical shapes in response to blue light; however, the photosensory mechanism for this response has not been elucidated. In this study, we analyzed the palisade cell response in phototropin-deficient mutants. First, we found that two different light-sensing mechanisms contributed to the response in different proportions depending on the light intensity. One response observed under lower intensities of blue light was mediated exclusively by a blue light photoreceptor, phototropin 2 (PHOT2). Another response was elicited under higher intensities of light in a phototropin-independent manner. To determine the tissue in which PHOT2 perceives the light stimulus to regulate the response, green fluorescent protein (GFP)-tagged PHOT2 (P2G) was expressed under the control of tissue-specific promoters in the phot1 phot2 mutant background. The results revealed that the expression of P2G in the mesophyll, but not in the epidermis, promoted palisade cell development. Furthermore, a constitutively active C-terminal kinase fragment of PHOT2 fused to GFP (P2CG) promoted the development of cylindrical palisade cells in the proper direction without the directional cue provided by light. Hence, in response to blue light, PHOT2 promotes the development of cylindrical palisade cells along a predetermined axis in a tissue-autonomous manner.

Neuron-Glia Crosstalk in the Autonomic Nervous System and Its Possible Role in the Progression of Metabolic Syndrome: A New Hypothesis

PubMed Central

Del Rio, Rodrigo; Quintanilla, Rodrigo A.; Orellana, Juan A.; Retamal, Mauricio A.

2015-01-01

Metabolic syndrome (MS) is characterized by the following physiological alterations: increase in abdominal fat, insulin resistance, high concentration of triglycerides, low levels of HDL, high blood pressure, and a generalized inflammatory state. One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system. Indeed, enhanced sympathetic drive has been linked to the development of endothelial dysfunction, hypertension, stroke, myocardial infarct, and obstructive sleep apnea. Glial cells, the most abundant cells in the central nervous system, control synaptic transmission, and regulate neuronal function by releasing bioactive molecules called gliotransmitters. Recently, a new family of plasma membrane channels called hemichannels has been described to allow the release of gliotransmitters and modulate neuronal firing rate. Moreover, a growing amount of evidence indicates that uncontrolled hemichannel opening could impair glial cell functions, affecting synaptic transmission and neuronal survival. Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells. In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process. PMID:26648871