Células madre hepáticas: tipos, caracterización e implicaciones.

El espectacular interés generado por las células madre durante los últimos años ha conducido al descubrimiento de nuevas propiedades de estas células. El objetivo de este trabajo de revisión bibliográfica ha sido sintetizar la clasificación de los distintos tipos de células madre que participan en la homeostasis hepática, indagar en las características de cada una de ellas y exponer sus distintas aplicaciones terapéuticas. Se han revisado también los mecanismos de acción que ejercen en los distintos procesos regenerativos tras un daño, las diferentes señales de diferenciación hacia hepatocitos o células biliares y los marcadores que expresan los progenitores celulares hepáticos. Dentro de las células madre hepáticas, las células progenitoras hepáticas existen en un pequeño porcentaje en el hígado adulto sano, se dividen rápidamente pero su potencial de linaje es limitado y constituyen la progenie de células madre. Por su parte, las células madre hematopoyéticas se autorrenuevan, son multipotentes (pueden diferenciarse a muchos linajes celulares distintos) e incluso se pueden trasplantar de forma seriada

Las Julias: Princesas sirias a las riendas de Roma

RESUMEN En una sociedad patriarcal como lo era la romana, extraña era la vez en que las mujeres salían del anonimato y tenían un lugar en la vida pública. En el marco histórico del siglo II y III d.C., se encuadra la existencia de cuatro mujeres sirias, de la misma familia: la del emperador. Su influencia es iniciada mediante un programa propagandístico, destinado a garantizar la legitimidad de la dinastía de los Severos. La presencia de estas mujeres, Julia Domna, Julia Maesa, Julia Soemias y Julia Mamaea, fue haciéndose más visible con el devenir de los años. En una época en que el poder estaba sustentado por la fuerza del ejército, se hacía necesario crear un paradigma común para civiles y militares. Las Augustas ostentarán repetidamente, entre otros, los títulos de Mater Castrorum y Mater Senatus et Patriae¸ de forma que la legitimación de su poder llegaba a todos los sectores sociales. Estas emperatrices sirias intervinieron en la religión, en el campo militar, en la administración y a nivel social, llegando a ser las verdaderas dueñas del poder imperial. Palabras clave: Severos, Mater Castrorum, Mater Senatus et Patriae, emperatrices, sirias, Julia Domna, Julia Maesa, Julia Soemias, Julia Mamaea. SUMMARY In a patriarchal society such as that of the Romans, it was a strange time for woman to abandon their situation of anonymity and take their place in public life. Within the historical framework of the 3rd and 4th century A.D., we see the existence of four such Syrian women, all with common family ties: to that of the emperor. Their influence commences with a propaganda programme designed to ensure the legitimacy of the Severian dynasty. The presence of these women, Julia Domna, Julia Maesa, Julia Soemias and Julia Mamaea, became more visible over the years. In an era in which power was wielded by the armed forces, it was necessary to create a common paradigm for civilians and the military. The Augustas repeatedly held the titles of Mater Castrorum and Mater Senatus et Patriae, thus legitimising their reach of power in all social sectors. These Syrian empresses intervened in religion, in the military sector, in the administration and in general society, coming to be the true masters of the imperial power holders. Keywords: Severos, Mater Castrorum, Mater Senatus et Patriae, Syrian empresses, Julia Domna, Julia Maesa Julia Soemias, Julia Mamaea

La dinastía Julio-Claudia: problemas dinásticos.

Augusto creó un nuevo régimen, el Principado, que se consolidó bajo sus sucesores, quienes accedieron al poder en virtud de su pertenencia a la domus augusta julio-claudia y gracias a la recuperación, por parte de Augusto, de la tradición nobiliar gentilicia. En esa transmisión del poder tuvieron una enorme influencia las mujeres de la domus augusta, quienes incluso rivalizaban entre sí para conseguir un lugar prominente cerca de la púrpura imperial. Sin embargo, no hemos conservado ninguna lex de imperio de esta época, necesaria para la legitimación de la llegada al poder del nuevo príncipe, cuestión sobre la que sigue abierto un intenso debate.<br /

Improved Suzuki–Miyaura reaction conversion efficiency using magnetic nanoparticles and inductive heating

The use of magnetic nanoparticles in C–C coupling reactions enables the facile recovery of the catalyst under environmentally friendly conditions. Herein, the synthesis of Pd/Fe@Fe3O4 nanoparticles by the reduction of Pd2+ and oxidation of Fe on the surface of preformed Fe@Fe3O4 is reported. The nanoparticles were characterized using a variety of analytical techniques (transmission electron microscopy, Mössbauer spectroscopy, X-ray photoelectron spectroscopy, and X-ray diffraction) to determine their size, structure, and chemical composition. The catalytic efficiency of these nanoparticles in classical Suzuki–Miyaura coupling reactions was investigated. The nanoparticles achieved high catalytic activity with the application of local heating by an alternating magnetic field. An investigation was conducted at identical temperatures to compare global heating with the application of an external magnetic field; magnetic heating demonstrated excellent substrate conversion in lesser time and at a lower temperature. The catalyst could also be recycled and reused three times, with ~ 30% decrease in the substrate conversion, which is most likely due to the agglomeration of the Pd nanoparticles or poisoning of the Pd catalyst. This approach, which takes advantage of the catalytic activity and magnetic susceptibility of magnetic nanoparticles, can be applied to several organic transformations to improve their efficiencyWe are grateful for financial support provided by the Government of Spain through project PGC2018-095642-B-I00. In addition, A. Villacampa and L. Duque acknowledge the Community of Madrid for Predoctoral contracts PEJD-2019-PRE/IND-15356 and PEJ-2019-AI/IND-12506, respectively, co-financed by the European Social Fund through the Youth Employment Operational Program and the Youth Employment Initiative (YEI

Controlled atmosphere pallets to extend the shelf-life of Calanda peaches

Calanda peaches have achieved great prestige in European markets because of their size, firmness and sweetness. However, apart from maintaining current markets by offering a high-quality product, further research is needed to improve their shelf-life in order to reach more distant markets. Thus, the effects of controlled atmosphere (CA) pallets at O2:CO2 concentrations of, 10:10, 5:10 and 2:10%, on the quality and shelf-life of Calanda ‘Calante’ peaches were studied. Physico-chemical parameters, ethanol and acetaldehyde production, decay percentage, chilling injury development and sensory evaluation were determined four times every 2 weeks of cold storage and shelf-life. Also, gas chromatography-olfactometry was conducted to detect off-flavours. Peaches stored at ambient atmosphere at 1°C promptly developed symptoms of chilling injury that became severe on day 28. All the CA conditions delayed ripening and prevented chilling injury with the best sensory results obtained for peaches stored at 2% O2:10% CO2. Although an increase in the production of ethanol and acetaldehyde was detected from day 14 onwards, this did not affect the quality of the fruit that was excellent after 56 days at 1°C plus a shelf-life period of 1 day at 20°C

Proliferative retinopathy: study of the contribution of neuroglial alterations and development of gene therapy approaches

La retinopatía diabética es la causa más común de ceguera adquirida en los países desarrollados, con una alta prevalencia en los pacientes diabéticos. El desarrollo de nuevas terapias requiere un buen conocimiento de la patología de la enfermedad y para ello son necesarios buenos modelos animales. Dichos modelos también resultan esenciales para ensayar el potencial de las nuevas terapias. El ratón transgénic IGF-I constituye un excelente modelo de retinopatía, ya que desarrolla la mayoría de las alteraciones vasculares presentes en los pacientes diabéticos. Para completar la caracterización del fenotipo de la retina de los animales TgIGF-I, la primera parte de esta tesis se centra en el estudio de las alteraciones de las neuronas y las células de la glia en las retinas transgénicas. Los resultados obtenidos muestran que los animales transgénicos presentan una pérdida progresiva de sus respuestas electroretinográficas resultando en una disfunción neuronal grave en los animales transgénicos de avanzada edad. Se detecta gliosis y microgliosis en las retinas de animales transgénicos jóvenes. La gliosis está relacionada con la pérdida de funciones esenciales para la supervivencia de las neuronas que realizan las células de Müller. Las retinas transgénicas presentan cambios en su metabolismo, relacionados con el reciclaje del glutamato, signos de estrés oxidativo y alteraciones en la homeostasis del potasio. Estas alteraciones pueden ser la causa de la disfunción neuronal observada en las retinas transgénicas, que además puede ser agravada por el incremento en la producción de citoquinas pro-inflamatorias. La segunda parte este trabajo se dedicó al estudio de la eficacia de una aproximación de terapia génica dirigida a contrarrestar la neovascularización y la neurodegeneración en la retinopatía diabética. Los vectores adeno-asociados (12V) de tipo 2 fueron escogidos para sobreexpresar el Pigmented Epithelium Derived Factor (PEDF), una proteina con potentes propiedades antiangiogénicas y neuroprotectoras. La transferencia génica del PEDF mediante vectores 12V induce la expresión a largo plazo de esta proteína y, como consecuencia, una marcada reducción de la neovascularization intravítrea, la normalización de la densidad capilar de la retina y la prevención del desprendimiento de retina. Esta reversión del fenotipo es paralela a la reducción de los niveles intraoculares de VEGF y la regulación negativa de efectores de la angiogénesis. Estos resultados demuestran la eficacia a largo plazo del a sobreexpresión de PEDF para contrarrestar la neovascularización retinal y ofrece evidencias para el uso de esta estrategia en el tratamiento de la retinopatía diabética y otras enfermedades proliferativas de la retina.Diabetic retinopathy (DR) is the most common cause of acquired blindness in developed countries, with a high prevalence in diabetic patients. The development of new effective therapies requires further investigations on disease pathogenesis and good animal models are essential to this end and to assay the potential efficacy of new experimental therapies. The TgIGF-I mice is a good model of retinopathy, developing many of the retinal vascular alterations observed in human diabetic patients. To fully characterize the eye pathology of the TgIGF-I, the first part of this work was focused in the study of the alterations of neurons and glial cells in the retinas of these mice. We found that TgIGF-I retinas showed a progressive decline in their electroretinographic responses that resulted in significantly impaired neuronal functionality in old animals. Gliosis and microgliosis were also detected in transgenic retinas at early ages. Gliosis is associated with the loss of essential neuron-supportive functions performed by Müller cells. We found that transgenic retinas showed changes in normal retinal metabolism, such as alterations in the glutamate metabolism, signs of oxidative stress and impaired potassium buffering, that may underlie neuronal dysfunction in transgenic retinas, which could be exacerbated by the increased production of pro-inflammatory cytokines. Thus, the second part of this work was dedicated to the study of the efficacy of a gene therapy approach aimed at counteracting neovascularization and neurodegeneration. Adeno-associated (AAV) vectors of serotype 2 were chosen to overexpress Pigmented Epithelium Derived Factor (PEDF), a protein with potent antiangiogenic and neuroprotective properties. AAV2-mediated PEDF gene transfer led to long-term production of PEDF and to a striking inhibition of intravitreal neovascularization, normalization of retinal capillary density, and prevention of retinal detachment. This was parallel to a reduction in the intraocular levels of Vascular Endothelial Growth Factor (VEGF), that was consistent with a downregulation of downstream effectors of angiogenesis. These results demonstrate long-term efficacy of AAV-mediated PEDF overexpression in counteracting retinal neovascularization and provide evidence towards the use of this strategy to treat angiogenesis in DR and other chronic proliferative retinal disorders

Insulin-like growth factor I (IGF-I)-induced chronic gliosis and retinal stress lead to neurodegeneration in a mouse model of retinopathy

Insulin-like growth factor I (IGF-I) exerts multiple effects on different retinal cell types in both physiological and pathological conditions. Despite the growth factor's extensively described neuroprotective actions, transgenic mice with increased intraocular levels of IGF-I showed progressive impairment of electroretinographic amplitudes up to complete loss of response, with loss of photoreceptors and bipolar, ganglion, and amacrine neurons. Neurodegeneration was preceded by the overexpression of genes related to retinal stress, acute-phase response, and gliosis, suggesting that IGF-I altered normal retinal homeostasis. Indeed, gliosis and microgliosis were present from an early age in transgenic mice, before other alterations occurred, and were accompanied by signs of oxidative stress and impaired glutamate recycling. Older mice also showed overproduction of pro-inflammatory cytokines. Our results suggest that, when chronically increased, intraocular IGF-I is responsible for the induction of deleterious cellular processes that can lead to neurodegeneration, and they highlight the importance that this growth factor may have in the pathogenesis of conditions such as ischemic or diabetic retinopathy

Accelerated oxygen-induced retinopathy is a reliable model of ischemia-induced retinal neovascularization

Retinal ischemia and pathological angiogenesis cause severe impairment of sight. Oxygen-induced retinopathy (OIR) in young mice is widely used as a model to investigate the underlying pathological mechanisms and develop therapeutic interventions. We compared directly the conventional OIR model (exposure to 75% O-2 from postnatal day (P) 7 to P12) with an alternative, accelerated version (85% O-2 from P8 to P11). We found that accelerated OIR induces similar pre-retinal neovascularization but greater retinal vascular regression that recovers more rapidly. The extent of retinal gliosis is similar but neuroretinal function, as measured by electroretinography, is better maintained in the accelerated model. We found no systemic or maternal morbidity in either model. Accelerated OIR offers a safe, reliable and more rapid alternative model in which pre-retinal neovascularization is similar but retinal vascular regression is greater

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement

A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features

Background: perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging. Methods: patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m2 twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0). Results: ninety pts were included in arm A (44) or arm B (46). Grade 3-4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02). Conclusions: the addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies