Elongation factor 2-diphthamide is critical for translation of two IRES-dependent protein targets, XIAP and FGF2, under oxidative stress conditions

Elongation factor-2 (eEF2) catalyzes the movement of the ribosome along the mRNA. A single histidine residue in eEF2 (H715) is modified to form diphthamide. A role for eEF2 in cellular stress responses is highlighted by the fact that eEF2 is sensitive to oxidative stress and that it must be active in order to drive the synthesis of proteins that help cells to mitigate the adverse effects of oxidative stress. Many of the latter proteins are encoded by mRNAs containing a sequence called an “internal ribosomal entry site” (IRES). Under high oxidative stress conditions diphthamide-deficient cells were significantly more sensitive to cell death. These results suggest that diphthamide may play a role in protection against the degradation of eEF2. Its protection is especially important under those situations where it is necessary for the re-programming of translation from global to IRES synthesis. Indeed, we found that the expression of X-linked inhibitor of apoptosis (XIAP) and fibroblast growth factor 2 (FGF2), two proteins synthesized from mRNAs with IRES that promote cell survival are deregulated in diphthamide-deficient cells. Our findings therefore suggest that eEF2/diphthamide controls the selective translation of IRES-dependent protein targets XIAP and FGF2, critical for cell survival under conditions of oxidative stress.España, Ministerio de Ciencia e Innovación BFU 2010-20882

Strong lensing by fermionic dark matter in galaxies

It has been shown that a self-gravitating system of massive keV fermions in thermodynamic equilibrium correctly describes the dark matter (DM) distribution in galactic halos and predicts a denser quantum core towards the center of the configuration. Such a quantum core, for a fermion mass in the range of $50$ keV $\lesssim m c^2 \lesssim 345$ keV, can be an alternative interpretation of the central compact object in Sgr A*. We present in this work the gravitational lensing properties of this novel DM model in Milky Way-like spiral galaxies. We describe the lensing effects of the pure DM component both on halo scales, where we compare them to the effects of the Navarro-Frenk-White and the Non-Singular Isothermal Sphere DM models, and near the galaxy center, where we compare them with the effects of a Schwarzschild BH. For the particle mass leading to the most compact DM core, $m c^2\approx 10^{2}$ keV, we draw the following conclusions. At distances $r\gtrsim 20$ pc from the center of the lens the effect of the central object on the lensing properties is negligible. However, we show that measurements of the deflection angle produced by the DM distribution in the outer region at a few kpc, together with rotation curve data, could help to discriminate between different DM models. We show that at distances $\sim 10^{-4}$ pc strong lensing effects, such as multiple images and Einstein rings, may occur. Large differences in the deflection angle produced by a DM central core and a central BH appear at distances $r\lesssim 10^{-6}$ pc; in this regime the weak-field formalism is no longer applicable and the exact general-relativistic formula has to be used. We find that quantum DM cores do not show a photon sphere what implies that they do not cast a shadow. Similar conclusions apply to the other DM distributions for other fermion masses in the above specified range and for other galaxy types.Comment: 10 pages, 8 figures. v2: Version published in PR

La reacción de nitrilos con compuestos organo-alumínicos

Tesis - Universidad Complutense de Madrid, 1978.Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEProQuestpu

Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal

Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970–1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010–2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are show

Síndrome de las plaquetas pegajosas, la condición de trombofilia heredada más frecuente en pacientes mexicanos

Antecedentes: el síndrome de las plaquetas pegajosas supone trastornos en la agregabilidad de las plaquetas, caracterizados por incremento anormal de las mismas y tendencia a fenómenos vasoclusivos, arteriales y venosos. El mecanismo patogénico no se conoce; su existencia sólo puede determinarse con las pruebas de agregación plaquetaria. Su prevalencia tampoco se conoce pero hay datos que sugieren que es frecuente. Algunos autores opinan que es responsable de 20% de las trombosis arteriales inexplicables y de 13% de las venosas en las que no es posible identificar una causa. Objetivos: revisar la información disponible sobre el síndrome de las plaquetas pegajosas y su trascendencia en México. Conclusiones: el síndrome de las plaquetas pegajosas es la condición de trombofi lia más frecuente en México. Existen pocos reportes de la evaluación clínica de pacientes mexicanos, lo que hace imperativo realizar estudios prospectivos rigurosos para establecer su magnitud

Stress Increases Vulnerability to Inflammation in the Rat Prefrontal Cortex

Inflammation could be involved in some neurodegenerative disorders that accompany signs of inflammation. However, because sensitivity to inflammation is not equal in all brain structures, a direct relationship is not clear. Our aim was to test whether some physiological circumstances, such as stress, could enhance susceptibility to inflammation in the prefrontal cortex (PFC), which shows a relative resistance to inflammation. PFC is important in many brain functions and is a target for some neurodegenerative diseases. We induced an inflammatory process by a single intracortical injection of 2 μg of lipopolysaccharide (LPS), a potent proinflammogen, in nonstressed and stressed rats. We evaluated the effect of our treatment on inflammatory markers, neuronal populations, BDNF expression, and behavior of several mitogen-activated protein (MAP) kinases and the transcription factor cAMP response element-binding protein. Stress strengthens the changes induced by LPS injection: microglial activation and proliferation with an increase in the levels of the proinflammatory cytokine tumor necrosis factor-α; loss of cells such as astroglia, seen as loss of glial fibrillary acidic protein immunoreactivity, and neurons, studied by neuronal-specific nuclear protein immunohistochemistry and GAD67 and NMDA receptor 1A mRNAs expression by in situ hybridization. A significant increase in the BDNF mRNA expression and modifications in the levels of MAP kinase phosphorylation were also found. In addition, we observed a protective effect from RU486 [mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], a potent inhibitor of the glucocorticoid receptor activation. All of these data show a synergistic effect between inflammation and stress, which could explain the relationship described between stress and some neurodegenerative pathologies.España,Ministerio de Educación y Ciencia Grants SAF2002-01952 and SAF2004-0660

Physical exercise and myokines

Among the types of muscles present in the body is skeletal muscle, which is the one that allows the development of physical activity thanks to the contractile activity of its muscle cells. It is known that physical exercise involves the release of plasma, by the skeletal muscle, of molecules called myokines as a result of muscle contraction. These myokines seem to be at the base of the beneficial effect of physical exercise on health. For this reason, this article reviews the characteristics and properties of the most important myokines and how they can contribute to a healthier aging

Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: 12 months results

Background: Biological agents, such as infliximab, have transformed the outcomes of patients with immune-mediated inflammatory diseases. The advent of biosimilar treatment options such as CT-P13 promises to improve the availability of biological therapy, yet real-world switching data are currently limited. Here, we assess the effectiveness and safety of switching to CT-P13 from infliximab reference product (RP) in patients with inflammatory bowel disease. Materials and methods: This was a prospective single-center observational study in patients with moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC). All patients were switched from infliximab RP (Remicade) to CT-P13 treatment and followed up for up to 12 months. The efficacy endpoint was the change in clinical response assessed at 3-monthly intervals, according to the Harvey–Bradshaw score and partial Mayo score for patients with CD and UC, respectively. C-reactive protein (CRP) was also measured. Adverse events were monitored and recorded throughout the study. Results: A total of 98 patients with inflammatory bowel disease (67 CD/31 UC) were included. A total of 83.6% (56/67) of patients with CD were in remission at the time of the switch and 62.7% were in remission at 12 months. The Harvey–Bradshaw score showed a significant change at 12 months (P =0.007) but no significant change was observed in median CRP at this timepoint (P= 0.364). A total of 80.6% (25/31) of patients with UC were in remission at the time of the switch and 65.3% (18/28) were in remission at 12 months. No significant changes in the median partial Mayo score (P=0.058) or CRP (P =0.329) were observed at 12 months. Serious adverse events related to medication were reported in 11 (11.2%) patients. Conclusion: Switching from infliximab RP to CT-P13 is efficacious and well tolerated in patients with CD or UC for up to 12 months