Study of the Bcl-2 Interactome by BiFC reveals differences in the activation mechanism of Bax and Bak

Evasion of apoptosis is one of the hallmarks of cancer cells. Proteins of the Bcl-2 family are key regulators of the intrinsic pathway of apoptosis, and alterations in some of these proteins are frequently found in cancer cells. Permeabilization of the outer mitochondrial membrane, regulated by pro- and antiapoptotic members of the Bcl-2 family of proteins, is essential for the release of apoptogenic factors leading to caspase activation, cell dismantlement, and death. Mitochondrial permeabilization depends on the formation of oligomers of the effector proteins Bax and Bak after an activation event mediated by BH3-only proteins and regulated by antiapoptotic members of the Bcl-2 family. In the present work, we have studied interactions between different members of the Bcl-2 family in living cells via the BiFC technique. Despite the limitations of this technique, present data suggest that native proteins of the Bcl-2 family acting inside living cells establish a complex network of interactions, which would fit nicely into “mixed” models recently proposed by others. Furthermore, our results point to differences in the regulation of Bax and Bak activation by proteins of the antiapoptotic and BH3-only subfamilies. We have also applied the BiFC technique to explore the different molecular models proposed for Bax and Bak oligomerization. Bax and Bak’s mutants lacking the BH3 domain were still able to associate and give BiFC signals, suggesting the existence of alternative surfaces of interaction between two Bax or Bak molecules. These results agree with the widely accepted symmetric model for the dimerization of these proteins and also suggest that other regions, different from the α6 helix, could be involved in the oligomerization of BH3-in groove dimers

Future prospects for mitosis-targeted antitumor therapies

Dysregulation of cell cycle progression is a hallmark of cancer cells. In recent years, efforts have been devoted to the development of new therapies that target proteins involved in cell cycle regulation and mitosis. Novel targeted antimitotic drugs include inhibitors of aurora kinase family, polo-like kinase 1, Mps1, Eg5, CENP-5 and the APC/cyclosome complex. While certain new inhibitors reached the clinical trial stage, most were discontinued due to negative results. However, these therapies should not be readily dismissed. Based on recent advances concerning their mechanisms of action, new strategies could be devised to increase their efficacy and promote further clinical trials. Here we discuss three main lines of action to empower these therapeutic approaches: increasing cell death signals during mitotic arrest, targeting senescent cells and facilitating antitumor immune response through immunogenic cell death (ICD). © 2021 The Author(s

Silicic Acid and Beer Consumption Reverses the Metal Imbalance and the Prooxidant Status Induced by Aluminum Nitrate in Mouse Brain

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Abstract: Background: Emerging evidence suggests that by affecting mineral balance, aluminum (Al) may enhance some events associated with neurodegenerative diseases. Aim: To examine the effect of Al(NO3)3 exposure on brain Al, cooper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), silicon (Si), and zinc (Zn) levels, and the metal-change implication in brain oxidant and inflammatory status. Methods: Four groups of six-week-old male NMRI mice were treated for three months: i) controls, administrated with deionized water; ii) Al, which received Al(NO3)3; iii) Al+silicic acid, which were given Al(NO3)3 plus silicic acid; and iv) Al+beer, which received Al(NO3)3 plus beer. Results: Brain Al and TBARS levels and TNFα and GPx expressions increased, while Cu, Mn, and Zn levels, and catalase and CuZn-SOD expression decreased (at least, p < 0.05) in Al versus control animals. Al, Si, and TBARS levels and TNFα expression decreased (p < 0.05) in Al+silicic acid and Al+beer specimens while Cu, Mn, and Zn levels and antioxidant expression increased versus the Al group. Brain Al levels correlated negatively with those of Cu, Fe, Mn, and Zn, and catalase, CuZn-SOD, and GPx enzyme expressions but positively with Si and TBARS levels and TNFα expression. Two components of the principal component analysis (PCA) explained 71.2% of total data variance (p < 0.001). PCA connected the pro-oxidant markers with brain Al content, while brain Zn and Cu levels were closer to antioxidant enzyme expression. Conclusion: Administration of Al(NO3)3 induced metal imbalance, inflammation, and antioxidant status impairment in the brain. Those effects were blocked to a significant extent by silicic acid and beer administration

Virulence Characteristics of Klebsiella and Clinical Manifestations of K. pneumoniae Bloodstream Infections

Differences in clinical manifestations are due to virulence factors expressed by the organism

Using Perfect Sampling in Parameter Estimation of a Whole Sentence Maximum Entropy Language Model

The Maximum Entropy principle (ME) is an ap- propriate framework for combining information of a diverse nature from several sources into the same language model. In order to incorporate long-distance information into the ME framework in a language model, a Whole Sentence Maximum Entropy Language Model (WSME) could be used. Until now MonteCarlo Markov Chains (MCMC) sampling techniques has been used to estimate the paramenters of the WSME model. In this paper, we propose the application of another sampling technique: the Perfect Sampling (PS). The experiment has shown a reduction of 30% in the perplexity of the WSME model over the trigram model and a reduc- tion of 2% over the WSME model trained with MCMC

Complicación intracraneal de procesos palpebrales banales: A propósito de un caso

Presentamos el caso de un paciente diagnosticado inicialmente de chalacion refractario al tratamiento. Las pruebas de imagen demostraron la existencia de pansinusitis y abceso cerebral de lóbulo frontal. El paciente fue tratado con antibioterapia sistémica y drenaje quirúrgico, siendo la evolución favorable con resolución del cuadro.We present the case of a patient that was, at the beginning, diagnosed of achalazion refractory to treatment . Scanner and MNR images let us see the existence of a pansinusitis and a frontal cerebral abscess. The patient was treatedwith systemic antibiotics and surgical drainage. The evolution was correct and the episode resolved