VEGFR-2 and VEGFR-3 Specific Signaling in Lymphangiogenesis and Angiogenesis

The circulatory system consists of the blood and lymphatic vessels. While blood vessels transport oxygen, cells, and nutrients to tissues, the lymphatic vessels collect fluid, cells, and plasma proteins from tissues to return back to the blood circulation. Angiogenesis, the growth of new blood vessels from pre-existing ones, is an important process involved in several physiological conditions such as inflammation, wound healing, and embryonic development. Furthermore, angiogenesis is found in many pathological conditions such as atherosclerosis and the growth and differentiation of solid tumors. Many tumor types spread via lymphatic vessels to form lymph node metastasis. The elucidation of the molecular players coordinating development of the vascular system has provided an array of tools for further insight of the circulatory system. The discovery of the Vascular Endothelial Growth Factor (VEGF) family members and their tyrosine kinase receptors (VEGFRs) has facilitated the understanding of the vasculature in different physiological and pathological situations. The VEGFRs are expressed on endothelial cells and mediate the growth and maintenance of both the blood and lymphatic vasculatures. This study was undertaken to address the role of VEGFR-2 specific signaling in maturation of blood vessels during neoangiogenesis and in lymphangiogenesis. We also wanted to differentiate between VEGFR-2 and VEGFR-3 specific signaling in lymphangiogenesis. We found that specific VEGFR-2 stimulation alone by gene therapeutic methods is not sufficient for production of mature blood vessels. However, VEGFR-2 stimulation in combination with expression of platelet-derived growth factor D (PDGF-D), a recently identified member of the PDGF growth factor family, was capable of stabilizing these newly formed vessels. Signaling through VEGFR-3 is crucial during developmental lymphangiogenesis, but we showed that the lymphatic vasculature becomes independent of VEGFR-3 signaling after the postnatal period. We also found that VEGFR-2 specific stimulation cannot rescue the loss of lymphatic vessels when VEGFR-3 signaling is blocked and that VEGFR-2 specific signals promote lymphatic vessel enlargement, but are not involved in vessel sprouting to generate new lymphatic vessels in vivo, in contrast to the VEGFR-2 dependent sprouting observed in blood vessels. In addition, we compared the inhibitory effects of a small molecular tyrosine kinase inhibitor of VEGFR-2 vs. VEGFR-3 specific signaling in vitro and in vivo. Our results showed that the tyrosine kinase inhibitor could equally affect physiological and pathological processes dependent on VEGFR-2 and VEGFR-3 driven angiogenesis or lymphangiogenesis. These results provide new insights into the VEGFR specific pathways required for pre- and postnatal angiogenesis as well as lymphangiogenesis, which could provide important targets and therapies for treatment of diseases characterized by abnormal angiogenesis or lymphangiogenesis.

Venous thromboembolism during pregnancy and the impact of thrombophilia in pregnancy complications

Venous thromboembolism (VTE) is the greatest single cause of maternal mortality in pregnant women in developed countries. Pregnancy is a hypercoagulable state and brings about an enhanced risk of deep venous thrombosis (DVT) in otherwise healthy women. Traditionally, unfractionated heparin (UFH) has been used for treatment of DVT during pregnancy. We showed in our observational study that low molecular weight heparin (LMWH) is as effective and safe as UFH in the treatment of DVT during pregnancy. Although DVT during pregnancy is often massive, increasing the risk of developing long-term consequences, namely post-thrombotic syndrome (PTS), only 11% of all patients had confirmed PTS 3 4 years after DVT. In our studies the prevalence of PTS was not dependent on treatment (UFH vs LMWH). Low molecular weight heparin is more easily administered, few laboratory controls are required and the hospital stay is shorter, factors that lower the costs of treatment. Cervical insufficiency is defined as repeated very preterm delivery during the second or early third trimester. Infection is a well-known risk factor of preterm delivery. We found overpresentation of thrombophilic mutations (FV Leiden, prothrombin G20210A)among 42 patients with cervical insufficiency compared with controls (OR 6.7, CI 2.7 18.4). Thus, thrombophilia might be a risk factor of cervical insufficiency possibly explained by interaction of coagulation and inflammation processes. The presence of antiphospholipid (aPL) antibodies increases the risk for recurrent miscarriage (RM). Annexins are proteins which all bind to anionic phospholipids (PLs) preventing clotting on vascular phospholipid surfaces. Plasma concentrations of circulating annexin IV and V were investigated in 77 pregnancies at the beginning of pregnancy among women with a history of RM, and in connection to their aPL antibody status. Control group consisted unselected pregnant patients (n=25) without history of adverse pregnancy outcome. Plasma levels of annexin V were significantly higher at the beginning (≤5th week) of pregnancy in women with aPL antibodies compared with those without aPL antibodies (P=0.03). Levels of circulating annexin V were also higher at the 6th (P= 0.01) and 8th week of pregnancy in subjects with aPL antibodies (P=0.01). Results support the hypothesis that aPL could displace annexin from anionic phospholipid surfaces of syncytiotrophoblasts (STBs) and may exert procoagulant activities on the surfaces of STBs Recurrent miscarriage (RM) has been suggested to be caused by mutations in genes coding for various coagulation factors resulting in thrombophilia. In the last study of my thesis were investigated the prevalence of thrombomodulin (TM) and endothelial protein C receptor polymorphism EPCR among 40 couples and six women suffering RM. This study showed that mutations in the TM or EPCR genes are not a major cause of RM in Finnish patients.

Highly Luminescent Mn-Doped ZnS Nanocrystals: Gram-Scale Synthesis

Following growth doping technique highly luminescent (quantum yield >50%) Mn-doped ZnS nanocrystals are synthesized via colloidal synthetictechnique. The dopant emission has been optimized with varying reaction parameters and found the ratio of Zn and S as well as the percentage of introduced dopant in the reaction mixture are key factors for controlling the intensity. The method is simple, hassle free, and can be scalable to gram level without hindering the quality of nanocrystals. These nanocrystals retain their emission during various ligand exchange processes and aqueous dispersion.

HDL subspecies : association with low HDL-C, obesity, and metabolic syndrome

AIMS An independent, powerful coronary heart disease (CHD) predictor is a low level of high-density lipoprotein cholesterol (HDL-C). Discoidal preβ-HDL particles and large HDL2 particles are the primary cholesterol acceptors in reverse cholesterol transport, a key anti-atherogenic HDL mechanism. The quality of HDL subspecies may provide better markers of HDL functionality than does HDL-C alone. We aimed I) to study whether alterations in the HDL subspecies profile exist in low-HDL-C subjects II) to explore the relationship of any changes in HDL subspecies profile in relation to atherosclerosis and metabolic syndrome; III) to elucidate the impact of genetics and acquired obesity on HDL subspecies distribution. SUBJECTS The study consisted of 3 cohorts: A) Finnish families with low HDL-C and premature CHD (Study I: 67 subjects with familial low HDL-C and 64 controls; Study II: 83 subjects with familial low HDL-C, 65 family members with normal HDL-C, and 133 controls); B) a cohort of 113 low- and 133 high-HDL-C subjects from the Health 2000 Health Examination Survey carried out in Finland (Study III); and C) a Finnish cohort of healthy young adult twins (52 monozygotic and 89 dizygotic pairs) (Study IV). RESULTS AND CONCLUSIONS The subjects with familial low HDL-C had a lower preβ-HDL concentration than did controls, and the low-HDL-C subjects displayed a dramatic reduction (50-70%) in the proportion of large HDL2b particles. The subjects with familial low HDL-C had increased carotid atherosclerosis measured as intima-media-thickness (IMT), and HDL2b particles correlated negatively with IMT. The reduction in both key cholesterol acceptors, preβ-HDL and HDL2 particles, supports the concept of impaired reverse cholesterol transport contributing to the higher CHD risk in low-HDL-C subjects. The family members with normal HDL-C and the young adult twins with acquired obesity showed a reduction in large HDL2 particles and an increase in small HDL3 particles, which may be the first changes leading to the lowering of HDL-C. The low-HDL-C subjects had a higher serum apolipoprotein E (apoE) concentration, which correlated positively with the metabolic syndrome components (waist circumference, TG, and glucose), highlighting the need for a better understanding of apoE metabolism in human atherosclerosis. In the twin study, the increase in small HDL3b particles was associated with obesity independent of genetic effects. The heritability estimate, of 73% for HDL-C and 46 to 63% for HDL subspecies, however, demonstrated a strong genetic influence. These results suggest that the relationship between obesity and lipoproteins depends on different elements in each subject. Finally, instead of merely elevating HDL-C, large HDL2 particles and discoidal preβ-HDL particles may provide beneficial targets for HDL-targeted therapy.

Dynamical configurations and bistability of helical nanostructures under external torque

We study the motion of a ferromagnetic helical nanostructure under the action of a rotating magnetic field. A variety of dynamical configurations were observed that depended strongly on the direction of magnetization and the geometrical parameters, which were also confirmed by a theoretical model, based on the dynamics of a rigid body under Stokes flow. Although motion at low Reynolds numbers is typically deterministic, under certain experimental conditions the nanostructures showed a surprising bistable behavior, such that the dynamics switched randomly between two configurations, possibly induced by thermal fluctuations. The experimental observations and the theoretical results presented in this paper are general enough to be applicable to any system of ellipsoidal symmetry under external force or torque.

Velocity Fluctuations in Helical Propulsion: How Small Can a Propeller Be

Helical propulsion is at the heart of locomotion strategies utilized by various natural and artificial swimmers. We used experimental observations and a numerical model to study the various fluctuation mechanisms that determine the performance of an externally driven helical propeller as the size of the helix is reduced. From causality analysis, an overwhelming effect of orientational noise at low length scales is observed, which strongly affects the average velocity and direction of motion of a propeller. For length scales smaller than a few micrometers in aqueous media, the operational frequency for the propulsion system would have to increase as the inverse cube of the size, which can be the limiting factor for a helical propeller to achieve locomotion in the desired direction.

Plasmonic Interactions at Close Proximity in Chiral Geometries: Route toward Broadband Chiroptical Response and Giant Enantiomeric Sensitivity

Chiral metamaterials can have diverse technological applications, such as engineering strongly twisted local electromagnetic fields for sensitive detection of chiral molecules, negative indices of refraction, broadband circular polarization devices, and many more. These are commonly achieved by arranging a group of noble-metal nanoparticles in a chiral geometry, which, for example, can be a helix, whose chiroptical response originates in the dynamic electromagnetic interactions between the localized plasmon modes of the individual nanoparticles. A key question relevant to the chiroptical response of such materials is the role of plasmon interactions as the constituent particles are brought closer, which is investigated in this paper through theoretical and experimental studies. The results of our theoretical analysis, when the particles are brought in close proximity are dramatic, showing a large red shift and enhancement of the spectral width and a near-exponential rise in the strength of the chiroptical response. These predictions were further confirmed with experimental studies of gold and silver nanoparticles arranged on a helical template, where the role of particle separation could be investigated in a systematic manner. The ``optical chirality'' of the electromagnetic fields in the vicinity of the nanoparticles was estimated to be orders of magnitude larger than what could be achieved in all other nanoplasmonic geometries considered so far, implying the suitability of the experimental system for sensitive detection of chiral molecules.

Extremely High Near Field Enhancement in a Novel Plasmonic Nano Material used for Photovoltage Generation

Enhancement of localized electric field near metal (plasmonic) nanostructures can have various interesting applications in sensing, imaging, photovoltage generation etc., for which significant efforts are aimed towards developing plasmonic systems with well designed and large electromagnetic response. In this paper, we discuss the wafer scale fabrication and optical characterization of a unique three dimensional plasmonic material. The near field enhancement in the visible range of the electromagnetic spectrum obtained in these structures (order of 106), is close to the fundamental limit that can be obtained in this and similar EM field enhancement schemes. The large near field enhancement has been reflected in a huge Raman signal of graphene layer in close proximity to the plasmonic system, which has been validated with FEM simulations. We have integrated graphene photodetectors with this material to obtain record photovoltage generation, with responsivity as high as A/W. As far as we know, this is the highest sensitivity obtained in any plasmonic-graphene hybrid photodetection system till date.

Evaluación de tres tipos de dietas (calostro: leche) en terneras holstein friesian bajo crianza artificial

El presente trabajo se realizó en la Empresa Genética Roberto Alvarado (Chiltepe), ubicada en la península de Chiltepe, en el departamento de Managua, con el objetivo de establecer la mejor forma de suministrar dietas liquidas, establecer la asociación entre los niveles de calostro con los comportamientos productivos de terneras bajo crianza artificial. Se emplearon 18 terneras de raza Holstein F., con un promedio de 40 Kg+- 8 kg de peso vivo, las que fueron distribuidas aleatoriamente en tres grupos asignándoles los siguientes tratamientos: T15 litros de leche entera/día (testigo) ; T2: 5 Litros de mezcla de calostro y leche/día (20:80) y T3: 5 Litros de mezcla de calostro y leche/día (40:60). Adicionalmente todos los tratamientos recibieron "adibitum", alimento solido a base de forraje Taiwán picado, heno de pasto estrella, agua y concentrado iniciador. El manejo de las terneras se realizó de manera similar a la utilizada en los centros de crianza de las empresas. Se efectuaron pasajes semanales individuales y se registró el consumo de concentrado. Se realizó análisis bromatológico de las dietas liquidas según metodología A.O.A.C. (1984), así como un análisis económico de las mismas. Al realizar ANDEVA para la variable GMD28, GMD49 y GMD70, se encontró para la primera que no existen diferencias (P<0.05) y para la dos últimas si existen diferencias significativas (P<0.05). El ANDECOVA (mínimo cuadrado realizado para la variable P28, utilizando la covariable PI mostró que no existen diferencias entre las dietas, y diferencias significativas (P<0.05) para la covariable. Para la variable Cons28, utilizando como variable el PI, se encontró diferencias significativas entre las dietas y no significativas para la variable concomitante. Al analizar la variable P49 usando como variable concomitante el P28, mostró diferencias estadísticamente significativas (P<0.05) tanto para las dietas como para la covariable. Para la variable P70, utilizando como covariable P49, se encontró que existen diferencias significativas para las dietas suministradas así como para la variable concomitante. Posteriormente al realizar prueba de separación de medidas con rangos múltiples utilizando test de Duncan, para las variables GMD14, GMD28, GMD49 y GMD70 se encontró el siguiente orden de mérito para las dietas: Calostro: Leche (40:60) a; Calostro: Leche (20:80)a, y Calostro: Leche (0:100) b. El análisis económico mostro que las dietas T3 y T2 tiene costos notablemente inferiores en relación al costo del T1. Estos análisis conllevan a establecer un orden decreciente del efecto de las dietas liquidas sobre la GMD y el PF según el siguiente esquema: T3 (40:60)>T2 (20:80)>T1 (0.100). Encontrando que la dieta más efectiva es la del T3.

Familia romana e identidad femenina en época de Augusto

Resumen: Hacia el 167 a.C., un joven Polibio, se sorprendía de que Roma hubiera podido afi rmar su poderío en la península, resistir los ataques cartagineses y acabar imponiendo sus leyes en Oriente. Probablemente –explica P. Grimal– en ello también haya infl uido que las costumbres y tradiciones romanas contribuían a asegurar una superioridad sobre el resto de las culturas y hacían de Roma una ciudad única entre todas. La familia y la mujer constituyeron parte fundamental dentro de la consolidación de esa estructura socio política y de ello heredaríamos, especialmente a nivel normativo, una sólida tradición jurídico-romana. Sin embargo, la época imperial representó un grave período de crisis en el cual, tomar esposa, dar hijos a la patria y controlar los patrimonios, se convirtió en una importante reafi rmación moral, jurídica y política para la sociedad de su tiempo. En esta forma, se analizarán brevemente algunos conceptos y leyes relevantes –cuyos ecos volveremos a encontrar refl ejados a lo largo y ancho de la España cristiana medieval– los cuales nos ayudarán a adentrarnos en la cotidianidad de este singular período, sus emancipadas mujeres aristocráticas y el derecho privado.

Las mujeres mozárabes : identidades híbridas y campo de acción del colectivo femenino entre Al- Andalus y la cristianidad

Resumen: La historia de los mozárabes de la Península Ibérica ha sido abordada desde múltiples perspectivas. Sin embargo, la situación de las mujeres de este colectivo no ha sido objeto de mayores estudios. El propósito del presente trabajo será realizar un primer acercamiento a la situación de las mujeres mozárabes, sus características y sus posibilidades de actuación tanto bajo las leyes islámicas, como bajo las normas cristianas. El análisis de esta cuestión se realizará teniendo en cuenta la naturaleza plástica de la identidad mozárabe, como así también el conjunto de normas internas y externas al grupo que modelaron sus posibilidades de acción.

Actividades de las autoridades argentinas y la embajada española sobre los anarquistas antes de la Ley de Residencia

Resumen: El presente trabajo investiga la actuación de la Embajada de España con respecto a la entrada a la Argentina de inmigrantes con antecedentes anarquistas durante fines del siglo XIX y los primeros dos años del siglo XX. Registra además el interés por seguir los movimientos de dichos inmigrantes en el país. Se destaca el rol de la documentación diplomática, mediante la cual la Embajada española se mantenía en permanente contacto con el gobierno central, con las autoridades argentinas y con los consulados del interior para intercambiar información. A través de las fuentes se puede observar la labor de “inteligencia ideológica” que se realizó y el detallado conocimiento que se tenía sobre los anarquistas, sus vías de traslado hacia nuestro país, sus profesiones, paraderos, domicilios, relaciones, y las minuciosas descripciones físicas de los sospechados. En esta política se nota la coparticipación entre la Embajada de España y las instituciones argentinas para desligarse de elementos que denominaban “no deseados”. También se consideran las relaciones entre el anarquismo argentino y el español, así como la importancia de la prensa revolucionaria, aun sobre la misma España. La vigilancia que ejercía la Embajada española sobre los inmigrantes, el control sobre los anarquistas españoles en la Argentina y la influencia de éstos sobre los sucesos de la Península demuestran a las claras la preocupación del gobierno hispano en la cuestión.

Toward a new synthesis of the god of Edom and Yahweh

This article deals primarily with two things: 1) the history and nature of the Edomite deity Qos, as far as these can be determined from the known archaeological and textual evidence, and 2) the similarities between Qos and Yahweh, the god of Israel, particularly in regard to the theories concerning the origins of the deities. Through the article I will consider some of the recent suggestions concerning the origin of Qos and how this may relate to the origin of Yahweh. I will suggest that both deities originated in the northwestern portion of the Arabian Peninsula and, that ultimately, the mutual origin of the deities accounts for the fact that the Bible makes no reference to Qos as the god of Edom.

Los gitanos en la España del siglo XV y su vinculación a Hungría

Rara vez el público relaciona la llegada de los gitanos a los reinos de España con el siglo XV. Para muchos lo gitano es la esencia más española, de cuya tradición beben escritores y músicos. Esto no es así, los “egipcianos” llegaron hace seis siglos en calidad de penitentes refugiados que huían del turco, lo que en historia no es mucho tiempo atrás. Llegaron a la península cruzando Europa, entrando a ésta por el Reino de Hungría, siguiendo las rutas de peregrinación como forma de subsistencia. Su inadaptación al modelo de vasallo de la Monarquía absoluta trajo su persecución. Los vientos de la reforma y del erasmismo tampoco les favorecieron.