Ab initio determination of heavy oxide perovskite related structures from precession electron diffraction data

Two complex perovskite-related structures were solved by ab initio from precession electron diffraction intensities. Structure models were firstly derived from HREM images and than have been confirmed independently using two and three-dimensional sets of precession intensities. Patterson techniques prove to be effective for ab initio structure resolution, specially in case of projections with no overlapping atoms. Quality of precession intensity data may be suitable enough to resolve unknown heavy oxide structures.     

EDEN: An Intelligent Software Environment for Diagnosis of Discrete-Event Systems

A software environment, called EDEN, that prototypes a recent approach to model-based diagnosis of discrete-event systems, is presented. The environment integrates a specification language, called SMILE, a model base, and a diagnostic engine. SMILE enables the user to create libraries of models and systems, which are permanently stored in the model base, wherein both final and intermediate results of the diagnostic sessions are hosted as well. Given the observation of a physical system gathered during its reaction to an external event, the diagnostic engine performs the a posteriori reconstruction of all the possible evolutions of the system over time and, then, draws candidate diagnoses out of them. The diagnostic method is described using a simplified example within the domain of power transmission networks. Strong points of the method include compositional modeling, support for model update, ability to focus on any sub-system, amenability to parallel execution, management of multiple faults, and broad notions of system and observation.     

Josef Bro?ek: Friendship and History.

Presents reflections on the life and achievements of Josef Maria Bro?ek. The author notes that, in his way, Bro?ek turned psychology historiography into an international domain involving, in this construction, researchers from countries not only of Anglo Saxon languages but also those of Slavic and Latin languages, including Brazil. Quoting from Braque, he affirmed that "knowledge of the past enables the revelation of the present." However, he believed that "reality is not revealed if it is not sparkled by a poetic beam." The poetry of life illuminated Bro?ek and his actions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mechanical robustness of Pseudomonas aeruginosa biofilms

Biofilms grow on various surfaces and in many different environments, a phenomenon that constitutes major problems in industry and medicine. Despite their importance little is known about the viscoelastic properties of biofilms and how these depend on the chemical microenvironment. Here, we find that the mechanical properties of Pseudomonas aeruginosa (P.a.) biofilms are highly robust towards chemical perturbations. Specifically, we observe that P.a. biofilms are able to fully regain their initial stiffness after yielding is enforced, even in the presence of chemicals. Moreover, only trivalent ions and citric acid significantly affect the biofilm elasticity, the first of which also alter the texture of the material. Finally, our results indicate that biofilm mechanics and bacteria viability inside the biofilm are not necessarily linked which suggests that targeting bacteria alone might not be sufficient for biofilm removal strategies.     

Neutrophils Mediate Pulmonary Artery Thrombosis In Situ

Pulmonary embolism is a life-threatening condition, which can result in respiratory insufficiency and death. Blood clots occluding branches of the pulmonary artery (PA) are traditionally considered to originate from thrombi in deep veins (usually in legs). However, growing evidence suggests that occlusion of the vessels in the lungs can develop without preceding deep vein thrombosis (DVT). In this work, we used an inferior vena cava (IVC) complete ligation model of DVT in Wistar rats to explore the possibility and mechanisms of PA thrombosis under the conditions where all routes of thrombotic mass migration from peripheral veins are blocked. We demonstrate that rats both with normal and reduced neutrophil counts developed thrombi in the IVC, although, neutropenia caused a substantial decrease in thrombus size and a shift from fresh fibrin toward mature fibrin and connective tissue inside the thrombus. Massive fibrin deposition was found in the PA branches in the majority of DVT rats with normal neutrophil counts, but in none of the neutropenic animals. Neutrophil ablation also abolished macroscopic signs of lung damage. Altogether, the results demonstrate that thrombi in the lung vasculature can form in situ by mechanisms that require local neutrophil recruitment taking place in the DVT setting.     

Secure computation of hidden Markov models and secure floating-point arithmetic in the malicious model

Hidden Markov model (HMM) is a popular statistical tool with a large number of applications in pattern recognition. In some of these applications, such as speaker recognition, the computation involves personal data that can identify individuals and must be protected. We thus treat the problem of designing privacy-preserving techniques for HMM and companion Gaussian mixture model computation suitable for use in speaker recognition and other applications. We provide secure solutions for both two-party and multi-party computation models and both semi-honest and malicious settings. In the two-party setting, the server does not have access in the clear to either the user-based HMM or user input (i.e., current observations) and thus the computation is based on threshold homomorphic encryption, while the multi-party setting uses threshold linear secret sharing as the underlying data protection mechanism. All solutions use floating-point arithmetic, which allows us to achieve high accuracy and provable security guarantees, while maintaining reasonable performance. A substantial part of this work is dedicated to building secure protocols for floating-point operations in the two-party setting, which are of independent interest.     

The State of the Art of Piezo1 Channels in Skeletal Muscle Regeneration

Piezo1 channels are highly mechanically-activated cation channels that can sense and transduce the mechanical stimuli into physiological signals in different tissues including skeletal muscle. In this focused review, we summarize the emerging evidence of Piezo1 channel-mediated effects in the physiology of skeletal muscle, with a particular focus on the role of Piezo1 in controlling myogenic precursor activity and skeletal muscle regeneration and vascularization. The disclosed effects reported by pharmacological activation of Piezo1 channels with the selective agonist Yoda1 indicate a potential impact of Piezo1 channel activity in skeletal muscle regeneration, which is disrupted in various muscular pathological states. All findings reported so far agree with the idea that Piezo1 channels represent a novel, powerful molecular target to develop new therapeutic strategies for preventing or ameliorating skeletal muscle disorders characterized by an impairment of tissue regenerative potential.     

Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile,Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α- and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC₅₀^(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.     

MIL-100(Fe) Sub-Micrometric Capsules as a Dual Drug Delivery System

Nanoparticles of metal–organic frameworks (MOF NPs) are crystalline hybrid micro- or mesoporous nanomaterials that show great promise in biomedicine due to their significant drug loading ability and controlled release. Herein, we develop porous capsules from aggregate of nanoparticles of the iron carboxylate MIL-100(Fe) through a low-temperature spray-drying route. This enables the concomitant one-pot encapsulation of high loading of an antitumor drug, methotrexate, within the pores of the MOF NPs, and the collagenase enzyme (COL), inside the inter-particular mesoporous cavities, upon the formation of the capsule, enhancing tumor treatment. This association provides better control of the release of the active moieties, MTX and collagenase, in simulated body fluid conditions in comparison with the bare MOF NPs. In addition, the loaded MIL-100 capsules present, against the A-375 cancer cell line, selective toxicity nine times higher than for the normal HaCaT cells, suggesting that MTX@COL@MIL-100 capsules may have potential application in the selective treatment of cancer cells. We highlight that an appropriate level of collagenase activity remained after encapsulation using the spray dryer equipment. Therefore, this work describes a novel application of MOF-based capsules as a dual drug delivery system for cancer treatment.     

Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma

Glioblastoma (GBM) is the most common tumor in the central nervous system in adults. This neoplasia shows a high capacity of growth and spreading to the surrounding brain tissue, hindering its complete surgical resection. Therefore, the finding of new antitumor therapies for GBM treatment is a priority. We have previously described that cyclin D1-CDK4 promotes GBM dissemination through the activation of the small GTPases RalA and RalB. In this paper, we show that RalB GTPase is upregulated in primary GBM cells. We found that the downregulation of Ral GTPases, mainly RalB, prevents the proliferation of primary GBM cells and triggers a senescence-like response. Moreover, downregulation of RalA and RalB reduces the viability of GBM cells growing as tumorspheres, suggesting a possible role of these GTPases in the survival of GBM stem cells. By using mouse subcutaneous xenografts, we have corroborated the role of RalB in GBM growth in vivo. Finally, we have observed that the knockdown of RalB also inhibits cell growth in temozolomide-resistant GBM cells. Overall, our work shows that GBM cells are especially sensitive to Ral-GTPase availability. Therefore, we propose that the inactivation of Ral-GTPases may be a reliable therapeutic approach to prevent GBM progression and recurrence.