Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization

Critical to homeostasis of blood cell production by hematopoietic stem/progenitor (HSC/P) cells is the regulation of HSC/P retention within the bone marrow microenvironment and migration between the bone marrow and the blood. Key extracellular regulatory elements for this process have been defined (cell–cell adhesion, growth factors, chemokines), but the mechanism by which HSC/P cells reconcile multiple external signals has not been elucidated. Rac and related small GTPases are candidates for this role and were studied in HSC/P deficient in Rac2, a hematopoietic cell-specific family member. Rac2 appears to be critical for HSC/P adhesion both in vitro and in vivo, whereas a compensatory increase in Cdc42 activation regulates HSC/P migration. This genetic analysis provides physiological evidence of cross-talk between GTPase proteins and suggests that a balance of these two GTPases controls HSC/P adhesion and mobilization in vivo.

Independence of metastatic ability and extravasation: metastatic ras-transformed and control fibroblasts extravasate equally well.

Escape of cancer cells from the circulation (extravasation) is thought to be a major rate-limiting step in metastasis, with few cells being able to extravasate. Furthermore, highly metastatic cells are believed to extravasate more readily than poorly metastatic cells. We assessed in vivo the extravasation ability of highly metastatic ras-transformed NIH 3T3 cells (PAP2) versus control nontumorigenic nontransformed NIH 3T3 cells and primary mouse embryo fibroblasts. Fluorescently labeled cells were injected intravenously into chicken embryo chorioallantoic membrane and analyzed by intravital videomicroscopy. The chorioallantoic membrane is an appropriate model for studying extravasation, since, at the embryonic stage used, the microvasculature exhibits a continuous basement membrane and adult permeability properties. The kinetics of extravasation were assessed by determining whether individual cells (n = 1481) were intravascular, extravascular, or in the process of extravasation, at 3, 6, and 24 h after injection. Contrary to expectations, our results showed that all three cell types extravasated with the same kinetics. By 24 h after injection > 89% of observed cells had completed extravasation from the capillary plexus. After extravasation, individual fibroblasts of all cell types demonstrated preferential migration within the mesenchymal layer toward arterioles, not to venules or lymphatics. Thus in this model and for these cells, extravasation is independent of metastatic ability. This suggests that the ability to extravasate in vivo is not necessarily predictive of subsequent metastasis formation, and that postextravasation events may be key determinants in metastasis.

Oxygen as a key developmental regulator of Rhizobium meliloti N2-fixation gene expression within the alfalfa root nodule.

The symbiotic pattern of expression of Rhizobium meliloti N2-fixation genes is tightly coupled with the histological organization of the alfalfa root nodule and thus is under developmental control. N2-fixation gene expression is induced very sharply at a particular zone of the nodule called interzone II-III that precedes the zone where N2 fixation takes place. We show here that this coupling can be disrupted, hereby resulting in ectopic expression of N2-fixation genes in the prefixing zone II of the nodule. Uncoupling was obtained either by using a R. meliloti strain in which a mutation rendered N2-fixation gene expression constitutive with respect to oxygen in free-living bacterial cultures or by placing nodules induced by a wild-type R. meliloti strain in a microoxic environment. These results implicate oxygen as a key determinant of the symbiotic pattern of N2-fixation gene expression.

Coastal Erosion--Causes, Erosion Control Methods, Economic and Environmental Impacts, and Best Management Practices

Coastal erosion is an important and constant issue facing coastal areas all over the world today. The rate of coastal development over the years has increased, in turn requiring that action be taken to protect structures from the threat of erosion. A review of the causes of coastal erosion and the methods implemented to control it was conducted in order to determine the best course of action in response to coastal erosion issues. The potential positive and negative economic and environmental impacts are key concerns in determining whether or not to restore an eroding beach and which erosion control method(s) to implement. Results focus on providing a comparison of these concerns as well as recommendations for addressing coastal erosion issues.

Captores del fósforo: preferencias de los pacientes en hemodiálisis y su repercusión sobre el cumplimiento del tratamiento y el control del fósforo

Introducción: En la actualidad disponemos de un amplio abanico de captores del fósforo (CF), pero sabemos poco acerca de las preferencias de los pacientes y de su repercusión sobre el cumplimiento del tratamiento y el control de los niveles de fósforo. Objetivo: Estudiar las preferencias y creencias de los pacientes respecto a los CF, y su influencia sobre el cumplimiento del tratamiento y el control de los niveles de fósforo. Pacientes y métodos: Estudio observacional transversal. Se incluyeron 121 pacientes que respondieron un cuestionario genérico de cumplimiento del tratamiento (SMAQ) y a un cuestionario específico sobre cumplimiento del tratamiento con CF, tipo de CF preferido y razones de dicha preferencia. Todos los pacientes entrevistados habían probado dos o tres CF. Las consecuencias de la falta de cumplimiento del tratamiento con CF se estimaron indirectamente analizando los valores promedio de fósforo sérico. Resultados: El 40% de los pacientes era incumplidor según el cuestionario SMAQ; se encontró una asociación estadísticamente significativa entre la falta de cumplimiento en general y no alcanzar el objetivo de fósforo sérico promedio <5,5 mg/dl (OR = 4,8; IC 95%, 1,0-6,6; p = 0,02). El 21,4% de los pacientes reconocía un incumplimiento específico para los CF; estos pacientes presentaban una mayor probabilidad de tener cifras medias de fósforo >5,5 mg/dl (OR = 4,7; IC 95%, 1,1-6,5; p = 0,03). Un 43,8% de los pacientes no refirió tener preferencias entre los diferentes tipos de CF; para el resto de pacientes, el CF preferido fue Royen®, seguido de Fosrenol®, Renagel® y Pepsamar®. Las razones expresadas para el desagrado con el Renagel® fueron las siguientes: incomodidad en la toma por su gran tamaño (28,8%), necesidad de tomar muchos comprimidos y gran consumo de agua (57,7%) e intolerancia gástrica (13,3%). En el caso del Fosrenol®: incómodo de tomar (72,7%) e intolerancia gástrica (27,2%); para el Pepsamar®: mal sabor (54,5%) e intolerancia gástrica (45,4%). Sólo al 9,4% no le gustaba el Royen®. Al analizar los conocimientos de los pacientes respecto a la utilidad de los CF, un 42% sabía que servían para controlar el fósforo; un 52% no lo sabía y un 6% tenía ideas equivocadas. En cuanto a su importancia: un 47% no conocía por qué son importantes; un 2% tenía ideas erróneas; un 9% creía que era beneficioso para la salud; un 11% creía que era bueno «porque lo dice el medico»; un 26% porque controla el fósforo y un 5% lo relacionaba con el hueso. Ningún paciente relacionó los CF con la enfermedad cardiovascular. Un 24,4% no se llevaba los CF cuando salía fuera de casa o estaba con los amigos; eran pacientes más jóvenes a quienes se les habían prescrito un mayor número de comprimidos de CF y que presentaban un mayor riesgo de no cumplir el objetivo de fósforo (OR = 10,5; IC 95%, —1,8 a —16,4; p <0,001). El porcentaje de pacientes a quienes no les gustaba el CF prescrito fue del 54,5%; dichos pacientes presentaban un mayor riesgo de tener niveles séricos de fósforo >5,5 mg/dl (OR = 13.3; IC 95%, 1,1-1,5; p = 0,0001). Paradójicamente, los pacientes que no cumplían con el tratamiento demostraban un mejor conocimiento de su uso (OR = 17,3; IC 95%, 2,2-10,1; p <0.0001) e importancia (OR = 10,4; IC 95%, 1,5-6,6; p = 0,001). Conclusión: Los pacientes a los que se les habían prescrito CF que no les gustaban tenían un peor control de los niveles de fósforo sérico y se les habían recomendado dosis más altas de los fármacos. El conocimiento de las preferencias de los pacientes acerca de las medicaciones que se les prescriben puede ser un factor esencial para conseguir un mayor cumplimiento del tratamiento y, por ende, lograr mejores resultados en la consecución de los objetivos terapéuticos.

Metabolomics analysis in rats with thiamine deficiency identifies key metabolites in vulnerable brain regions and suggests neural stem progenitor cells play a role in ameliorating metabolic dysfunction

La documentation scientifique fait état de la présence, chez l’adulte, de cellules souches et progénitrices neurales (CSPN) endogènes dans les zones sous-ventriculaire et sous-granulaire du cerveau ainsi que dans le gyrus denté de l’hippocampe. De plus, un postulat selon lequel il serait également possible de retrouver ce type de cellules dans la moelle épinière et le néocortex des mammifères adultes a été énoncé. L’encéphalopathie de Wernicke, un trouble neurologique grave toutefois réversible qui entraîne un dysfonctionnement, voire une défaillance du cerveau, est causée principalement par une carence importante en thiamine (CT). Des observations récentes laissent envisager que les facteurs en cause dans la prolifération et la différenciation des CSPN pourraient également jouer un rôle important lors d’un épisode de CT. L’hypothèse, selon laquelle l’identification de nouveaux métabolites entrant dans le mécanisme ou la séquence de réactions se soldant en une CT pourraient en faciliter la compréhension, a été émise au moyen d'une démarche en cours permettant d’établir le profil des modifications métaboliques qui surviennent en de telles situations. Cette approche a été utilisée pour constater les changements métaboliques survenus au niveau du foyer cérébral dans un modèle de rats déficients en thiamine (rats DT), particulièrement au niveau du thalamus et du colliculus inférieur (CI). La greffe de CSPN a quant à elle été envisagée afin d’apporter de nouvelles informations sur la participation des CSPN lors d’un épisode de CT et de déterminer les bénéfices thérapeutiques potentiels offerts par cette intervention. Les sujets de l’étude étaient répartis en quatre groupes expérimentaux : un premier groupe constitué de rats dont la CT était induite par la pyrithiamine (rats DTiP), un deuxième groupe constitué de rats-contrôles nourris ensemble (« pair-fed control rats » ou rats PFC) ainsi que deux groupes de rats ayant subi une greffe de CSPN, soit un groupe de rats DTiP greffés et un dernier groupe constitué de rats-contrôles (rats PFC) greffés. Les échantillons de foyers cérébraux (thalamus et CI) des quatre groupes de rats ont été prélevés et soumis à des analyses métabolomiques non ciblées ainsi qu’à une analyse visuelle par microscopie à balayage électronique (SEM). Une variété de métabolites-clés a été observée chez les groupes de rats déficients en thiamine (rats DTiP) en plus de plusieurs métabolites dont la documentation ne faisait pas mention. On a notamment constaté la présence d’acides biliaires, d’acide cynurénique et d’acide 1,9— diméthylurique dans le thalamus, alors que la présence de taurine et de carnosine a été observée dans le colliculus inférieur. L’étude a de plus démontré une possible implication des CSPN endogènes dans les foyers cérébraux du thalamus et du colliculus inférieur en identifiant les métabolites-clés ciblant les CSPN. Enfin, les analyses par SEM ont montré une amélioration notable des tissus à la suite de la greffe de CSPN. Ces constatations suggèrent que l’utilisation de CSPN pourrait s’avérer une avenue thérapeutique intéressante pour soulager la dégénérescence symptomatique liée à une grave carence en thiamine chez l’humain.

North Caucasus: the Russian Gordian knot. The key problems and conflicts in the region and the effect thereof on the future of Russia; Putin after re-election: The Kremlin's policy in Vladimir Putin's second term. OSW Study 16/2004

North Caucasus: North Caucasus is the most instable part of the Russian Federation: since the early 90's, there has been going on the military conflict in Chechnya, which is gradually spilling over into the other republics of the region, terrorism seems to have occupied its regular position in the political life of Caucasus, organized crime is flourishing, the tension persists there and military incidents and attacks are breaking out every now and again. During the recent year, the destabilization of the region, which affects many fields of Russian political and social life, has grown to an alarming size. Putin after re-election: Vladimir Putin's first term as President was a period of submitting political, regional and economic lobbies to the Kremlin. The actions Putin has taken since being re-elected are aimed at consolidating the Kremlin's control over the political, economic and social spheres. Further liquidation of political and informational pluralism, an increase of the ruling group's control over state and private property, and an intensification of state propaganda aimed at generating social support for the Kremlin's initiatives have all proceeded apace. These processes reinforce authoritarian tendencies and strengthen the emerging monocentric political system, with the President's strong domination over political, economic and social life.

Temporal Control of Leaf Complexity by miRNA-Regulated Licensing of Protein Complexes

The tremendous diversity of leaf shapes has caught the attention of naturalists for centuries. In addition to interspecific and intraspecific differences, leaf morphologies may differ in single plants according to age, a phenomenon known as heteroblasty. In Arabidopsis thaliana, the progression from the juvenile to the adult phase is characterized by increased leaf serration. A similar trend is seen in species with more complex leaves, such as the A. thaliana relative Cardamine hirsuta, in which the number of leaflets per leaf increases with age. Although the genetic changes that led to the overall simpler leaf architecture in A. thaliana are increasingly well understood, less is known about the events underlying age-dependent changes within single plants, in either A. thaliana or C. hirsuta. Here, we describe a conserved miRNA transcription factor regulon responsible for an age-dependent increase in leaf complexity. In early leaves, miR319-targeted TCP transcription factors interfere with the function of miR164-dependent and miR164-independent CUC proteins, preventing the formation of serrations in A. thaliana and of leaflets in C. hirsuta. As plants age, accumulation of miR156-regulated SPLs acts as a timing cue that destabilizes TCP-CUC interactions. The destabilization licenses activation of CUC protein complexes and thereby the gradual increase of leaf complexity in the newly formed organs. These findings point to posttranslational interaction between unrelated miRNA-targeted transcription factors as a core feature of these regulatory circuits.

Lake-effect snow as the dominant control of mesic-forest distribution in Michigan, USA

1Recent studies demonstrated the sensitivity of northern forest ecosystems to changes in the amount and duration of snow cover at annual to decadal time scales. However, the consequences of snowfall variability remain uncertain for ecological variables operating at longer time scales, especially the distributions of forest communities. 2The Great Lakes region of North America offers a unique setting to examine the long-term effects of variable snowfall on forest communities. Lake-effect snow produces a three-fold gradient in annual snowfall over tens of kilometres, and dramatic edaphic variations occur among landform types resulting from Quaternary glaciations. We tested the hypothesis that these factors interact to control the distributions of mesic (dominated by Acer saccharum, Tsuga canadensis and Fagus grandifolia) and xeric forests (dominated by Pinus and Quercus spp.) in northern Lower Michigan. 3We compiled pre-European-settlement vegetation data and overlaid these data with records of climate, water balance and soil, onto Landtype Association polygons in a geographical information system. We then used multivariate adaptive regression splines to model the abundance of mesic vegetation in relation to environmental controls. 4Snowfall is the most predictive among five variables retained by our model, and it affects model performance 29% more than soil texture, the second most important variable. The abundance of mesic trees is high on fine-textured soils regardless of snowfall, but it increases with snowfall on coarse-textured substrates. Lake-effect snowfall also determines the species composition within mesic forests. The weighted importance of A. saccharum is significantly greater than of T. canadensis or F. grandifolia within the lake-effect snowbelt, whereas T. canadensis is more plentiful outside the snowbelt. These patterns are probably driven by the influence of snowfall on soil moisture, nutrient availability and fire return intervals. 5Our results imply that a key factor dictating the spatio-temporal patterns of forest communities in the vast region around the Great Lakes is how the lake-effect snowfall regime responds to global change. Snowfall reductions will probably cause a major decrease in the abundance of ecologically and economically important species, such as A. saccharum.

GAO questions key aspects of FAA's plans to acquire the multi-billion dollar advanced automation system and related programs.

"B-206887."

Remote Control Electrodeposition: Patterning on Substrates without Direct Electrical Connections

Thesis (Ph.D.)--University of Washington, 2016-06

Traffic control: p120-catenin acts as a gatekeeper to control the fate of classical cadherins in mammalian cells

Proteins of the p120 family have been implicated in the regulation of cadherin-based cell adhesion, but their relative importance in this process and their mechanism of action have remained less clear. Three papers in this issue suggest that p120 plays a key role in maintaining normal levels of cadherin in mammalian cells, and that it may do so by regulating cadherin trafficking.

Hypothalamic control of bone formation: Distinct actions of leptin and Y2 receptor pathways

Leptin and Y2 receptors on hypothalamic NPY neurons mediate leptin effects on energy homeostasis; however, their interaction in modulating osteoblast activity is not established. Here, direct testing of this possibility indicates distinct mechanisms of action for leptin anti-osteogenic and Y2(-/-) anabolic pathways in modulating bone formation. Introduction: Central enhancement of bone formation by hypothalamic neurons is observed in leptin-deficient oblob and Y2 receptor null mice. Similar elevation in central neuropeptide Y (NPY) expression and effects on osteoblast activity in these two models suggest a shared pathway between leptin and Y2 receptors in the central control of bone physiology. The aim of this study was to test whether the leptin and Y2 receptor pathways regulate bone by the same or distinct mechanisms. Materials and Methods: The interaction of concomitant leptin and Y2 receptor deficiency in controlling bone was examined in Y2(-/-) oblob double mutant mice, to determine whether leptin and Y2 receptor deficiency have additive effects. Interaction between leptin excess and Y2 receptor deletion was examined using recombinant adeno-associated viral vector overproduction of NPY (AAV-NPY) to produce weight gain and thus leptin excess in adult Y2(-/-) mice. Cancellous bone volume and bone cell function were assessed. Results: Osteoblast activity was comparably elevated in oblob, Y2(-/-), and Y2(-/-) oblob mice. However, greater bone resorption in oblob and Y2(-/-) oblob mice reduced cancellous bone volume compared with Y2(-/-). Both wildtype and Y2(-/-) AAV-NPY mice exhibited marked elevation of white adipose tissue accumulation and hence leptin expression, thereby reducing osteoblast activity. Despite this anti-osteogenic leptin effect in the obese AAV-NPY model, osteoblast activity in Y2(-/-) AAV-NPY mice remained significantly greater than in wildtype AAV-NPY mice. Conclusions: This study suggests that NPY is not a key regulator of the leptin-dependent osteoblast activity, because both the leptin-deficient stimulation of bone formation and the excess leptin inhibition of bone formation can occur in the presence of high hypothalamic NPY. The Y2(-/-) pathway acts consistently to stimulate bone formation; in contrast, leptin continues to suppress bone formation as circulating levels increase. As a result, they act increasingly in opposition as obesity becomes more marked. Thus, in the absence of leptin, the cancellous bone response to loss of Y2 receptor and leptin activity can not be distinguished. However, as leptin levels increase to physiological levels, distinct signaling pathways are revealed.

Explaining landholders' decisions about riparian zone management: The role of behavioural, normative, and control beliefs

Water quality is a key concern in the current global environment, with the need to promote practices that help to protect water quality, such as riparian zone management, being paramount. The present study used the theory of planned behaviour as a framework for understanding how beliefs influence decisions about riparian zone management. Respondents completed a survey that assessed their behavioural, normative, and control beliefs in relation to intentions to manage riparian zones on their property. The results of the study showed that, overall, landholders with strong intentions to manage their riparian zones differed significantly in terms of their beliefs compared to landholders who had weak intentions to manage their riparian zones. Strong intentions to manage riparian zones were associated with a favourable cost-benefit analysis, greater perceptions of normative support for the practice and lower perceptions of the extent to which barriers would impede management of riparian zones. It was also evident that willingness to comply with the recommendations of salient referents, beliefs about the benefits of riparian zone management and perceptions of the extent to which barriers would impede riparian zone management were most important for determining intentions to manage riparian zones. Implications for policy and extension practice are discussed. (c) 2005 Elsevier Ltd. All rights reserved.