Membrane interaction of a new synthetic antimicrobial lipopetide sp-85 with broad spectrum activity

Antimicrobial peptides offer a new class of therapeutic agents to which bacteria may not be able todevelop genetic resistance, since their main activity is in the lipid component of the bacterial cell mem-brane. We have developed a series of synthetic cationic cyclic lipopeptides based on natural polymyxin,and in this work we explore the interaction of sp-85, an analog that contains a C12 fatty acid at theN-terminus and two residues of arginine. This analog has been selected from its broad spectrum antibac-terial activity in the micromolar range, and it has a disruptive action on the cytoplasmic membrane ofbacteria, as demonstrated by TEM. In order to obtain information on the interaction of this analog withmembrane lipids, we have obtained thermodynamic parameters from mixed monolayers prepared withPOPG and POPE/POPG (molar ratio 6:4), as models of Gram positive and Gram negative bacteria, respec-tively. LangmuirBlodgett films have been extracted on glass plates and observed by confocal microscopy,and images are consistent with a strong destabilizing effect on the membrane organization induced bysp-85. The effect of sp-85 on the membrane is confirmed with unilamelar lipid vesicles of the same com-position, where biophysical experiments based on fluorescence are indicative of membrane fusion andpermeabilization starting at very low concentrations of peptide and only if anionic lipids are present.Overall, results described here provide strong evidence that the mode of action of sp-85 is the alterationof the bacterial membrane permeability barrier.

Estudi de les alteracions en la capacitat neuroprotectora dels astròcits reactius en l'envelliment

En el periodo 2005-2008 hemos publicado tres artículos sobre las alteraciones de los astrocitos reactivos en el cerebro durante el envejecimiento. En el primer estudio, evaluamos la capacidad neuroprotectora de los astrocitos en un modelo experimental in vitro de envejecimiento. Los cambios en el estrés oxidativo, la captación del glutamato y la expresión proteica fueron evaluados en los astrocitos corticales de rata cultivados durante 10 y 90 días in vitro (DIV). Los astrocitos envejecidos tenían una capacidad reducida de mantener la supervivencia neuronal. Estos resultados indican que los astrocitos pueden perder parcialmente su capacidad neuroprotectora durante el envejecimiento. En el segundo estudio el factor neurotrófico derivado de la línea glial (GDNF) fue probado para observar sus efectos neurotróficos contra la atrofia neuronal que causa déficits cognitivos en la vejez. Las ratas envejecidas Fisher 344 con deficiencias en el laberinto de Morris recibieron inyecciones intrahippocampales de un vector lentiviral que codifica GDNF humano en los astrocitos o del mismo vector que codifica la proteína fluorescente verde humana como control. El GDNF secretado por los astrocitos mejoró la función de la neurona como se muestra por aumentos locales en la síntesis de los neurotransmisores acetilcolina, dopamina y serotonina. El aprendizaje espacial y la prueba de memoria demostraron un aumento significativo en las capacidades cognitivas debido a la exposición de GDNF, mientras que las ratas control mantuvieron sus resultados al nivel del azar. Estos resultados confirman el amplio espectro de la acción neurotrófica del GDNF y abre nuevas posibilidades de terapia génica para reducir la neurodegeneración asociada al envejecimiento. En el último estudio, examinamos cambios en la fosforilación de tau, el estrés oxidativo y la captación de glutamato en los cultivos primarios de astrocitos corticales de ratones neonatos de senescencia acelerada (SAMP8) y ratones resistentes a la senescencia (SAMR1). Nuestros resultados indican que las alteraciones en cultivos del astrocitos de los ratones SAMP8 son similares a las detectadas en cerebros enteros de los ratones SAMP8 de 1-5 meses de edad. Por otra parte, nuestros resultados sugieren que esta preparación in vitro es adecuada para estudiar en este modelo murino el envejecimiento temprano y sus procesos moleculares y celulares.

Identification of myxobacteria-derived HIV inhibitors by a high-throughput two-step infectivity assay

Drug-resistance and therapy failure due to drug-drug interactions are the main challenges in current treatment against Human Immunodeficiency Virus (HIV) infection. As such, there is a continuous need for the development of new and more potent anti-HIV drugs. Here we established a high-throughput screen based on the highly permissive TZM-bl cell line to identify novel HIV inhibitors. The assay allows discriminating compounds acting on early and/or late steps of the HIV replication cycle. The platform was used to screen a unique library of secondary metabolites derived from myxobacteria. Several hits with good anti-HIV profiles were identified. Five of the initial hits were tested for their antiviral potency. Four myxobacterial compounds, sulfangolid C, soraphen F, epothilon D and spirangien B, showed EC50 values in the nM range with SI > 15. Interestingly, we found a high amount of overlapping hits compared with a previous screen for Hepatitis C Virus (HCV) using the same library. The unique structures and mode-of-actions of these natural compounds make myxobacteria an attractive source of chemicals for the development of broad-spectrum antivirals. Further biological and structural studies of our initial hits might help recognize smaller drug-like derivatives that in turn could be synthesized and further optimized.

Efficacy and safety of tigecycline versus levofloxacin for community-acquired pneumonia.

Abstract Background: Tigecycline, an expanded broad-spectrum glycylcycline, exhibits in vitro activity against many common pathogens associated with community-acqui red pneumonia (CAP), as well as penetration into lung tissues that suggests effectiveness in ho spitalized CAP patients. The aim of the present study was to compare the efficacy and safety of intravenous (IV) tigecycline with IV levofloxacin in hospitalized adults with CAP. Methods: In this prospective, double-blin d, non-inferiority phase 3 trial, eligible patients with a clinical diagnosis of CAP supported by radiographic evidence were stratified by Fine Pneumonia Severity Index and randomized to tigecycline or levofloxacin for 7-14 days of therapy. Co-primary efficacy endpoints were clinical response in the clinically evaluable (CE) and clinical modified intent- to-treat (c-mITT) populations at te st-of-cure (Day 10-21 post-therapy). Results: Of the 428 patients who received at least on e dose of study drug, 79% had CAP of mild-moderate severity according to their Fine score. Clinical cure rates for the CE population were 88.9% for tigecycline and 85.3% for levofloxac in. Corresponding c-mITT population rates were 83.7% and 81.5%, respectively. Eradication rates for Streptococcus pneumoniae were 92% for tigecycline and 89% for levofloxac in. Nausea, vomiting, and diarrhoea were the most frequently reported adverse events. Rates of premature disc continuation of study drug or study withdrawal because of any adverse event were similar for both study drugs. Conclusion: These findings suggest that IV tigecycline is non-inferior to IV levofloxacin and is generally well-tolerated in the treatment of hospitalized adults with CAP.

Clean Development Mechanism and Sustainable Development: a discussion on the link between the CDM and Sustainable Development, an analysis of the current status of the CDM portfolio, and an multicriteria evaluation of the effects of additional incentives in order to foster broad local Sustainable Development dividends from the CDM projects

vegeu resum en el fitxer adjunt a l'inici del treball de recerca

Spectrum of some trianguled categories

In this paper, we compute the triangular spectrum (as de fined by P. Balmer) of two classes of tensor triangulated categories which are quite common in algebraic geometry. One of them is the derived category of G-equivariant sheaves on a smooth scheme X, for a fi nite group G. The other class is the derived category of split superschemes.

Engineering the thermal emission of macroporous silicon

Todos los cuerpos emiten luz espontaneamente al ser calentados. El espectro de radiacion es una funcion de la temperatura y el material. Sin embargo, la mayoria de los materiales irradia, en general, en una banda espectral amplia. Algunas matereiales, por el contrario, son capaces de concentrar la radiacion termica en una banda espectral mucho mas estrecha. Estos materiales se conocen como emisores selectivos y su uso tiene un profundo impacto en la eficiencia de sistemas sistemas tales como iluminacion y conversion de energia termofotovoltaica. De los emisores selectivos se espera que sean capaces de operar a altas temperaturas y que emitan en una banda espectral muy concisa. Uno de los metodos mas prometedores para controlar y disenar el espectro de emision termico es la utilizacion de cristales fotonicos. Los cristales fotonicos son estructuras periodicas artificiales capaces de controlar y confinar la luz de formas sin precedentes. Sin embargo, la produccion de dichas estructuras con grandes superficies y capaces de soportar altas temperaturas sigue siendo una dificil tarea. Este trabajo esta dedicada al estudio de las propiedades de emision termica de estructuras 3D de silicio macroporoso en el rango espectral mid-IR (2-30 m). En particular, este trabajo se enfoca en reducir la elevada emisividad del silicio cristalino. Las muestras estudiadas en este trabajo tienen una periodicidad de 4 m, lo que limitan los resultados obtenidos a la banda del infrarrojo medio, aunque estructuras mucho mas pequenas son tecnologicamente realizables con el metodo de fabricacion utilizado. Hemos demostrado que el silicio macroporoso 3D puede inhibir completamente la emision termica en su superficie. Mas aun, esta banda se puede ajustar en un amplio margen mediante pequenos cambios durante la formacion de los macroporos. Tambien hemos demostrado que tanto el ancho como la frecuencia de la banda de inhibicion se puede doblar mediante la aplicacion de tecnicas de postprocesado adecuadas. Finalmente hemos mostrado que es posible crear bandas de baja emisividad arbitrariamente anchas mediante estructuras macroporosas aperiodicas.

Ab initio absorption spectrum of NiO combining molecular dynamics with the embedded cluster approach in a discrete reaction field

We developed a procedure that combines three complementary computational methodologies to improve the theoretical description of the electronic structure of nickel oxide. The starting point is a Car-Parrinello molecular dynamics simulation to incorporate vibrorotational degrees of freedom into the material model. By means ofcomplete active space self-consistent field second-order perturbation theory (CASPT2) calculations on embedded clusters extracted from the resulting trajectory, we describe localized spectroscopic phenomena on NiO with an efficient treatment of electron correlation. The inclusion of thermal motion into the theoretical description allowsus to study electronic transitions that, otherwise, would be dipole forbidden in the ideal structure and results in a natural reproduction of the band broadening. Moreover, we improved the embedded cluster model by incorporating self-consistently at the complete active space self-consistent field (CASSCF) level a discrete (or direct) reaction field (DRF) in the cluster surroundings. The DRF approach offers an efficient treatment ofelectric response effects of the crystalline embedding to the electronic transitions localized in the cluster. We offer accurate theoretical estimates of the absorption spectrum and the density of states around the Fermi level of NiO, and a comprehensive explanation of the source of the broadening and the relaxation of the charge transferstates due to the adaptation of the environment

Calculation of Franck-Condon factors including anharmonicity: simulation of the C2 H4+ X̃2B 3u←C2 H4X̃1 Ag band in the photoelectron spectrum of ethylene

Our new simple method for calculating accurate Franck-Condon factors including nondiagonal (i.e., mode-mode) anharmonic coupling is used to simulate the C2H4+X2B 3u←C2H4X̃1 Ag band in the photoelectron spectrum. An improved vibrational basis set truncation algorithm, which permits very efficient computations, is employed. Because the torsional mode is highly anharmonic it is separated from the other modes and treated exactly. All other modes are treated through the second-order perturbation theory. The perturbation-theory corrections are significant and lead to a good agreement with experiment, although the separability assumption for torsion causes the C2 D4 results to be not as good as those for C2 H4. A variational formulation to overcome this circumstance, and deal with large anharmonicities in general, is suggested

Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder

Background: There is increasing evidence that impairment of mitochondrial energy metabolism plays an important role in the pathophysiology of autism spectrum disorders (ASD; OMIM number: 209850). A significant proportion of ASD cases display biochemical alterations suggestive of mitochondrial dysfunction and several studies have reported that mutations in the mitochondrial DNA (mtDNA) molecule could be involved in the disease phenotype. Methods: We analysed a cohort of 148 patients with idiopathic ASD for a number of mutations proposed in the literature as pathogenic in ASD. We also carried out a case control association study for the most common European haplogroups (hgs) and their diagnostic single nucleotide polymorphisms (SNPs) by comparing cases with 753 healthy and ethnically matched controls.Results: We did not find statistical support for an association between mtDNA mutations or polymorphisms and ASD.Conclusions: Our results are compatible with the idea that mtDNA mutations are not a relevant cause of ASD and the frequent observation of concomitant mitochondrial dysfunction and ASD could be due to nuclear factors influencing mitochondrion functions or to a more complex interplay between the nucleus and the mitochondrion/mtDNA.

Interplay of spectral efficiency, power and doppler spectrum for reference-signal-assisted wireless communication

Expressions relating spectral efficiency, power, and Doppler spectrum, are derived for Rayleigh-faded wireless channels with Gaussian signal transmission. No side information on the state of the channel is assumed at the receiver. Rather, periodic reference signals are postulated in accordance with the functioning of most wireless systems. The analysis relies on a well-established lower bound, generally tight and asymptotically exact at low SNR. In contrast with most previous studies, which relied on block-fading channel models, a continuous-fading model is adopted. This embeds the Doppler spectrum directly in the derived expressions, imbuing them with practical significance. Closed-form relationships are obtained for the popular Clarke-Jakes spectrum and informative expansions, valid for arbitrary spectra, are found for the low- and high-power regimes. While the paper focuses on scalar channels, the extension to multiantenna settings is also discussed.

The extraordinarily bright optical afterglow of GRB 991208 and its host galaxy

Observations of the extraordinarily bright optical afterglow (OA) of GRB 991208 started 2.1 d after the event. The flux decay constant of the OA in the R-band is -2.30 +/- 0.07 up to 5 d, which is very likely due to the jet effect, and after that it is followed by a much steeper decay with constant -3.2 +/- 0.2, the fastest one ever seen in a GRB OA. A negative detection in several all-sky films taken simultaneously to the event implies either a previous additional break prior to 2 d after the occurrence of the GRB (as expected from the jet effect). The existence of a second break might indicate a steepening in the electron spectrum or the superposition of two events. Once the afterglow emission vanished, contribution of a bright underlying SN is found, but the light curve is not sufficiently well sampled to rule out a dust echo explanation. Our determination of z = 0.706 indicates that GRB 991208 is at 3.7 Gpc, implying an isotropic energy release of 1.15 x 10E53 erg which may be relaxed by beaming by a factor > 100. Precise astrometry indicates that the GRB coincides within 0.2' with the host galaxy, thus given support to a massive star origin. The absolute magnitude is M_B = -18.2, well below the knee of the galaxy luminosity function and we derive a star-forming rate of 11.5 +/- 7.1 Mo/yr. The quasi-simultaneous broad-band photometric spectral energy distribution of the afterglow is determined 3.5 day after the burst (Dec 12.0) implying a cooling frequency below the optical band, i.e. supporting a jet model with p = -2.30 as the index of the power-law electron distribution.

The complete Raman spectrum of nanometric SnO2 particles

The complete Raman spectrum of SnO2 nanoparticles in presented and analyzed. In addition to the "classical" modes observed in the rutile structure, two other regions shown Raman activity for nanoparticles. The Raman bands in the low-frequency region are attributed to acoustic modes associated with the vibration of the individual nanoparticle as a whole. The high-frequency region is activated by surface disorder. A detailed analysis of these regions and the changes in the normal modes of SnO2 are presented as a function nanoparticle size.

Spectrum of transmitted light in optical bistability: Effects of phase fluctuations of the driving laser

Time-dependent correlation functions and the spectrum of the transmitted light are calculated for absorptive optical bistability taking into account phase fluctuations of the driving laser. These fluctuations are modeled by an extended phase-diffusion model which introduces non-Markovian effects. The spectrum is obtained as a superposition of Lorentzians. It shows qualitative differences with respect to the usual calculation in which phase fluctuations of the driving laser are neglected.