Retinoic acid-induced differentiation sensitizes myeloid progenitors cells to ER stress

The clonal expansion of hematopoietic myeloid precursors blocked at different stages of differentiation characterizes the acute myeloid leukemia (AML) phenotype. A subtype of AML, acute promyelocytic leukemia (APL), characterized by the chimeric protein PML-RARα is considered a paradigm of differentiation therapy. In this leukemia subtype the all-trans-retinoic acid (RA)-based treatments are able to induce PML-RARα degradation and leukemic blast terminal differentiation [1-2]. Granulocytic differentiation of APL cells driven by RA triggers a physiological Unfolded Protein Response (UPR), a series of pathways emanating from the ER in case of ER stress, which ensues when higher protein folding activity is required as during differentiation. We show here that, although mild, the ER stress induced by RA is sufficient to render human APL cell lines and primary blasts very sensitive to low doses of Tunicamycin (Tm), an ER stress inducing drug, at doses that are not toxic in the absence of RA. Importantly only human progenitors cells derived from APL patients resulted sensitive to the combined treatment with RA and Tm whereas those obtained from healthy donors were not affected. We also show that the UPR pathway downstream of PERK plays a major protective role against ER stress in differentiating cells and, by using a specific PERK inhibitor, we potentiated the toxic effect of the combination of RA and Tm. In conclusion, our findings identify the ER stress-related pathways as potential targets in the search for novel therapeutic strategies in AML

Time-dependent Nonlinear Optical Susceptibility of an Out-of-Equilibrium Soft Material

We investigate the time-dependent nonlinear optical absorption of a clay dispersion (Laponite) in organic dye (Rhodamine B) water solution displaying liquid-arrested state transition. Specifically, we determine the characteristic time $\tau_D$ of the nonlinear susceptibility build-up due as to the Soret effect. By comparing $\tau_D$ with the relaxation time provided by standard dynamic light scattering measurements we report on the decoupling of the two collective diffusion times at the two very different length scales during the aging of the out-of-equilibrium system. With this demonstration experiment we also show the potentiality of nonlinear optics measurements in the study of the late stage of arrest in soft materials

Why haven't loose globular clusters collapsed yet?

We report on the discovery of a surprising observed correlation between the slope of the low-mass stellar global mass function (GMF) of globular clusters (GCs) and their central concentration parameter c=log(r_t/r_c), i.e. the logarithmic ratio of tidal and core radii. This result is based on the analysis of a sample of twenty Galactic GCs with solid GMF measurements from deep HST or VLT data. All the high-concentration clusters in the sample have a steep GMF, most likely reflecting their initial mass function. Conversely, low-concentration clusters tend to have a flatter GMF implying that they have lost many stars via evaporation or tidal stripping. No GCs are found with a flat GMF and high central concentration. This finding appears counter-intuitive, since the same two-body relaxation mechanism that causes stars to evaporate and the cluster to eventually dissolve should also lead to higher central density and possibly core-collapse. Therefore, more concentrated clusters should have lost proportionately more stars and have a shallower GMF than low concentration clusters, contrary to what is observed. It is possible that severely depleted GCs have also undergone core collapse and have already recovered a normal radial density profile. It is, however, more likely that GCs with a flat GMF have a much denser and smaller core than suggested by their surface brightness profile and may well be undergoing collapse at present. In either case, we may have so far seriously underestimated the number of post core-collapse clusters and many may be lurking in the Milky Way.Comment: Four pages, one figure, accepted for publication in ApJ Letter

Italia-España, un entramado de relaciones literarias : la "Escuela de Barcelona" /

La presente tesis de doctorado tiene como objeto de estudio demostrar la relación de la cultura literaria italiana de la posguerra con la española, y muy especialmente la influencia de Italia en el grupo catalán de la generación poética de los cincuenta, conocida como la Escuela de Barcelona. En la investigación se ha tratado principalmente del intercambio entre la Escuela de Barcelona (José Agustín Goytisolo, Jaime Gil de Biedma, Carlos Barral y Josep Maria Castellet) y el ámbito literario italiano representado por autores, poetas, hispanistas y asesores editoriales. El periodo de referencia del estudio cubre las décadas 1950 y 1960, época en que se consolidan los lazos entre los editores internacionales y los españoles. El trabajo tiene como fin presentar bajo una nueva perspectiva a la Escuela de Barcelona con el objetivo de determinar cómo la interacción con el ámbito literario italiano influye en la producción intelectual (literaria, crítica, memorialística, editorial) de José Agustín Goytisolo, Josep Maria Castellet, Carlos Barral y en menor medida, en Jaime Gil de Biedma. La tesis muestra el entramado de contactos con los principales hispanistas de la época. Carlo Bo, Vittorio Bodini, Dario Puccini, Mario Socrate, Oreste Macrí, (también importantes traductores), ya que fueron los indispensables interlocutores de los barceloneses y artífices del vínculo entre la cultura italiana de la posguerra y la España intelectual anti-franquista. Se ha llevado a cabo también un estudio de las publicaciones más significativas que ligan a ambos países, y de las polémicas que algunas de estas desataron contribuyendo a focalizar la atención en España. He considerado esencial prestar especial atención a la figura de Giulio Einaudi por su continua interacción dialéctica con los miembros de la Escuela de Barcelona. Para precisar el destacado papel de Einaudi en la cultura española me ha sido imprescindible consultar su correspondencia todavía inédita conservada en el "Archivio di Stato" de Turín, gracias a la amabilidad de Malcolm Einaudi y Pamela Giorgi. El material estudiado ilustra cómo se desarrollan las conexiones entre seixbarralianos y einaudianos desde sus primeros contactos. Los libros intercambiados y los "proyectos editoriales" permiten reconstruir el mosaico del futuro catálogo de la colección "Biblioteca Breve" de Seix Barral, y al mismo tiempo evidencian la apertura hacia nuevas literaturas por parte de las dos editoriales. Recojo en un apéndice la lista de traducciones realizadas en Italia de las obras escritas por los miembros de la Escuela de Barcelona desde entonces hasta hoy, con el fin de multiplicar las fuentes de las que disponemos de la forma más completa posible. Para de este modo, gracias al examen de la correspondencia "italiana" de nuestros autores con sus traductores y principales impulsores, entender mejor su proyección en Italia. El apéndice pretende ser también un instrumento de consulta para quienes quieran recorrer este complejo camino. En la parte final, me he centrado en especial en las traducciones del italiano realizadas por José Agustín Goytisolo, cuya imprescindible tarea de difusor y receptor de la literatura italiana contemporánea llega a constituir una de las más eficaces del siglo XX. La traducción se confirma así como un válido instrumento de estudio y de comparación en las líneas esenciales del proceso de acercamiento de los dos sistemas literarios.The key objective of the following doctoral thesis is to investigate the ties between post-war Italian literary culture and that of Spain. The thesis focuses, in particular, on the Italian influence in the 1950s on the Catalan group known as the 'School of Barcelona'. The research deals mainly with the dialogue between the School of Barcelona (José Agustín Goytisolo, Jaime Gil de Biedma, Carlos Barral and Josep Maria Castellet) and the Italian literary sphere, represented at the time by an ensemble of different individual authors, poets, Hispanicists and publishing editors. The reference period of the study covers the decades of the 1950s and the 1960s, because this was the time during which the links between the various representatives of Spanish publishing houses and their foreign counterparts were consolidated. The work proposes to present the School of Barcelona from a new perspective in order to illustrate the way in which the relationship with a foreign literary system could influence the intellectual output (literary, critical, memoirs, editorial) of José Agustín Goytisolo, Josep Maria Castellet, Carlos Barral and, to a lesser extent, of Jaime Gil de Biedma. The thesis seeks to explain the network of contacts between the principal Hispanicists of the time. Carlo Bo, Vittorio Bodini, Dario Puccini, Mario Socrate, Oreste Macrí (all first-class translators as well) would prove themselves indispensable interlocutors with respect to the Barcelona group and true instigators of the bond between post-war Italian culture and the anti-Francoist intellectuals in Spain. Furthermore, the thesis studies the most significant publications that linked the two countries together. It examines the controversies that sprang from some of these publications which contributed to focusing attention on Spain. It is deemed necessary to dedicate a certain amount of space in this work to the figure of Giulio Einaudi, renowned for his constant "dialectic" with members of the School of Barcelona. In order to award him his rightful place in Spanish culture, I sought and then benefited from direct access to the considerable nucleus of still unpublished letters in the care of the 'State Archives' of Turin, thanks to the cooperation of Malcolm Einaudi and Pamela Giorgi. The researched material illustrates how relations between the Seix Barral and Einaudi groups developed from their first tentative attempts at communication onwards. Mapping out the exchanged books and the editorial projects in this way permits the reconstruction of the mosaic of the future catalogue of 'Biblioteca Breve' of Seix Barral. It also underlines the opening up that occurred vis-à-vis "new" literature on the part of the two publishing houses. Furthermore, I assemble an appendix concerning the Italian translations of the work of the authors of the School of Barcelona up until the present day. This is to increase the available source material in the most complete manner possible. In this way, thanks to an examination of the "Italian" correspondence of these Spanish authors with their translators and main promoters, it was possible to achieve a more precise account of their Italian projection. At the same time, the appendix may serve as a useful consultative instrument for anyone interested in the further pursuit of this complex research route. In the concluding section, I dedicated myself, in particular, to the Italian translation undertaken by José Agustín Goytisolo, whose indispensable work in embracing and circulating contemporary Italian literature can be considered one of the most valuable efforts of the 20th century. Translation can be confirmed then as a valid instrument in studying and in comparing the key elements that characterise the process that drew the two literary systems in question together

Correlation between oesophageal acid exposure and dyspeptic symptoms in patients with nonerosive reflux disease.

Oesophageal acidification induces dyspeptic symptoms in healthy individuals. This study aimed to evaluate the correlation between oesophageal acid exposure and dyspeptic symptoms in patients with nonerosive reflux disease. METHODS: A total of 68 patients with dominant symptoms of heartburn, negative upper gastrointestinal endoscopy and concomitant dyspeptic symptoms participated in the study. The severity of dyspepsia and reflux-related symptoms was evaluated, and 24-h gastro-oesophageal pH-monitoring study was performed in all patients at baseline and after 4 weeks of therapy with esomeprazole 40 mg. RESULTS: Oesophageal basal acid exposure was pathological in 43 patients and normal in 25 patients, with a similar prevalence and severity of individual dyspeptic symptoms in the two groups. A significant correlation between reflux and dyspepsia scores was observed in the subgroup of patients with normal, but not in those with abnormal pHmetry (r=0.4, P=0.04 and r=0.2 P=0.07, respectively). After esomeprazole, a reduction in severity of dyspepsia (>or=50% with respect to baseline) was observed, independent of improvement of reflux-associated symptoms. Improvement in dyspepsia was, however, similar in patients with normal and abnormal basal acid exposure (14/25 vs. 33/43, respectively, P=NS). CONCLUSION: Dyspeptic symptoms coexist in a subset of nonerosive reflux disease patients, but prevalence and severity of the symptoms seems to be independent of oesophageal acid exposure

Effect of Utipro® (containing gelatin-xyloglucan) against Escherichia coli invasion of intestinal epithelial cells: results of an in vitro study

Aim: To evaluate whether Utipro(®), a natural product approved to prevent urinary tract infections, protects intestinal epithelial cells from Escherichia coli adherence/intracellular invasion in vitro. Materials & methods: Caco-2 and CacoGoblet(TM) cells were treated with Utipro (1.5 to 10 mg/ml) or untreated (controls). E. coli adherence/intracellular invasion was evaluated by Trans-Epithelial Electrical Resistance, Lucifer Yellow assay and microbial counts. Results: Utipro was noncytotoxic. Utipro 5 and 10 mg/ml protected cell tight junctions (mean ± SD Trans-Epithelial Electrical Resistance [Ω × cm(2)] 66.83 ± 0.29 and 71.33 ± 0.29, respectively), and protected cells from E. coli intracellular invasion (mean ± SD reductions in total bacteria counts [Log10] 0.9 ± 0.06 and 2.1 ± 0.56, respectively). Conclusion: Results indicate that Utipro creates a protective physical barrier on intestinal epithelial cells in vitro which reduces the settling of E. coli reservoirs. These results constitute the first step in the demonstration of the efficacy of Utipro to prevent urinary tract infections. Further research is needed in in vivo models and clinical trials

The Mass Function of Main Sequence Stars in NGC6397 from Near IR and Optical High Resolution HST Observations

We have investigated the properties of the stellar mass function in the globular cluster NGC6397 using a large set of HST observations that include WFPC2 images in V and I, obtained at ~4' and 10' radial distances, and a series of deep images in the J and H bands obtained with the NIC2 and NIC3 cameras of NICMOS pointed to regions located ~4.5' and ~3.2' from the center. These observations span the region from ~1 to ~3 times the cluster's half-light radius. All luminosity functions, derived from color magniutde diagrams, increase with decreasing luminosity up to a peak at M_I~8.5 or M_H~7 and then precipitously drop well before photometric incompleteness becomes significant. Within the observational uncertainties, at M_I~12 or M_H~10.5 (~0.09 Msun) the luminosity functions are compatible with zero. By applying the best available mass- luminosity relation appropriate to the metallicity of NGC6397 to both the optical and IR data, we obtain a mass function that shows a break in slope at \~0.3 Msun. No single exponent power-law distribution is compatible with these data, regardless of the value of the exponent. We find that a dynamical model of the cluster can simultaneously reproduce all the luminosity functions observed throughout the cluster only if the IMF rises as m**-1.6 in the range 0.8-0.3 Msun and then drops as m**0.2 below ~0.3 Msun. Adopting a more physical log-normal distribution for the IMF, all these data taken together imply a best fit distribution with characteristic mass m_c~0.3 and sigma~1.8.Comment: 18 pages, 6 figures (ps). Accepted for publication in Ap

Body mass index and age correlate with antioxidant supplementation effects on sperm quality: Post hoc analyses from a double-blind placebo-controlled trial

Spermatozoa are vulnerable to lack of energy and oxidative stress as a result of elevated levels of reactive oxygen species. Therefore, it is essential that appropriate nutrients are available during maturation. This randomised, double-blind, placebo-controlled trial investigated the effect of 6-month supplementation with carnitines and other micronutrients on sperm quality in 104 subjects with oligo- and/or astheno- and/or teratozoospermia with or without varicocele. Semen analyses were done at the beginning and end of the treatment. In addition to main analyses, post hoc analyses for age and body mass index (BMI) were carried out. Results were interpreted by dividing the population into two age and BMI classes. In 94 patients who completed the study, all sperm parameters increased in supplemented patients compared to the placebo group. A significant (p = .0272) difference in supplementation efficacy was observed for total motility on patients with varicocele and BMI < 25. In the same group, also the progressive motility was significantly superior (p = .0159). For Responder analysis, total motility results were confirmed in both the cited group (p = .0066) and in the varicocele group with BMI < 25 and age < 35 (p = .0078). This study suggests that supplementation is more effective in subjects with varicocele younger than 35 years with BMI < 25

A refined Razumov-Stroganov conjecture

We extend the Razumov-Stroganov conjecture relating the groundstate of the O(1) spin chain to alternating sign matrices, by relating the groundstate of the monodromy matrix of the O(1) model to the so-called refined alternating sign matrices, i.e. with prescribed configuration of their first row, as well as to refined fully-packed loop configurations on a square grid, keeping track both of the loop connectivity and of the configuration of their top row. We also conjecture a direct relation between this groundstate and refined totally symmetric self-complementary plane partitions, namely, in their formulation as sets of non-intersecting lattice paths, with prescribed last steps of all paths.Comment: 20 pages, 4 figures, uses epsf and harvmac macros a few typos correcte

Nonlinear graphene metamaterial

We demonstrate that the broadband nonlinear optical response of graphene can be resonantly enhanced by more than an order of magnitude through hybridization with a plasmonic metamaterial,while retaining an ultrafast nonlinear response time of ~1 ps. Transmission modulation close to ~1% is seen at a pump uence of ~0.03 mJ/cm^2 at the wavelength of ~1600 nm. This approach allows to engineer and enhance graphene's nonlinearity within a broad wavelength range enabling applications in optical switching, mode-locking and pulse shaping.Comment: The following article has been submitted to Applied Physics Letters. After it is published, it will be found at http://apl.aip.org