Tributyltin(Iv) butyrate: A novel epigenetic modifier with er stress-and apoptosis-inducing properties in colon cancer cells

Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H,13C and119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 µM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and-H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment

influence of piston shape and injector geometry on combustion and emission characteristics of syngas in direct injection spark ignition engine

Abstract This paper presents a numerical study of the influence of piston shape and injector geometry on combustion and emissions characteristics of a direct-injection spark-ignition engine fueled by syngas (50% by volume of hydrogen, 50% by volume of carbon monoxide) under low/medium load conditions. Three different piston cup geometries namely: High-clearance Combustion Cup (HCC), Low-clearance Combustion Cup (LCC) and Omega Combustion Cup (OCC) have been considered with a compression ratio of 14. An axial full-cone gas jet injector has been considered together with a hollow-cone gas jet injector with several included half-angles, i.e. 30°, 45°, 52.5° and 60°. Computational fluid dynamics modelling has been performed to simulate the combustion process. The results indicate that, in terms of performance, OCC shape is favorable, even if OCC generates relatively higher NOx than the other two configurations. A further analysis has been performed by simulating an engine with OCC piston shape and an included half-angle of injection of 30°, by varying the Start Of Injection (SOI). The results show that the flame propagation velocity reduces as the SOI advances, since the fuel distribution becomes more homogeneous approaching to a premixed case. However, the flame speed reduction is partially balanced by the disappearance of very lean regions thanks to fuel convection and diffusion

Pharmacological inhibition of PKCθ counteracts muscle disease in a mouse model of duchenne muscular dystrophy

Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C θ (PKCθ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease

Diplofuranones A and B, two further new 4-monosubstituted 2(3<i>H</i>)-dihydrofuranones produced by <i>Diplodia corticola</i>, a fungus pathogen of cork oak

Two new 4-monosubstituted 2(3H)-dihydrofuranones, named diplofuranones A and B, were isolated from liquid cultures of Diplodia corticola, a plant pathogenic fungus causing a canker disease of cork oak (Quercus suber L.). The same fungus also produces several metabolites such as the diplopyrone, the (3S,4R)-trans- and the (3R,4R)-cis-4-hydroxymellein, the sapinofuranone B and its (S,S)-enantiomer, the well known sphaeropsidins A-C, and the diplobifuranylones A and B. The diplofuranones A and B were characterised, using spectroscopic (essentially NMR and MS techniques) methods, as the 4-[(1E,3E)-5-hydroxyhexadienyl]butan-4-olide and its corresponding 3,4-dihydro side chain derivative. The stereochemistry of the stereogenic secondary hydroxylated carbon of the side chain of diplofuranone A was determined by application of Mosher’s method and proved to be R. Diplofuranone A tested at 0.2 mg mL-1 on non-host plant did not show phytotoxic activity

Corticolimbic catecholamines in stress: A computational model of the appraisal of controllability

Appraisal of a stressful situation and the possibility to control or avoid it is thought to involve frontal-cortical mechanisms. The precise mechanism underlying this appraisal and its translation into effective stress coping (the regulation of physiological and behavioural responses) are poorly understood. Here, we propose a computational model which involves tuning motivational arousal to the appraised stressing condition. The model provides a causal explanation of the shift from active to passive coping strategies, i.e. from a condition characterised by high motivational arousal, required to deal with a situation appraised as stressful, to a condition characterised by emotional and motivational withdrawal, required when the stressful situation is appraised as uncontrollable/unavoidable. The model is motivated by results acquired via microdialysis recordings in rats and highlights the presence of two competing circuits dominated by different areas of the ventromedial prefrontal cortex: these are shown having opposite effects on several subcortical areas, affecting dopamine outflow in the striatum, and therefore controlling motivation. We start by reviewing published data supporting structure and functioning of the neural model and present the computational model itself with its essential neural mechanisms. Finally, we show the results of a new experiment, involving the condition of repeated inescapable stress, which validate most of the model's prediction

Adaptively Secure Single Secret Leader Election from DDH

Single Secret Leader Election protocols (SSLE, for short) allow a group of users to select a random leader so that the latter remains secret until she decides to reveal herself. Thanks to this feature, SSLE can be used to build an election mechanism for proof-of-stake based blockchains. In particular, a recent work by Azouvi and Cappelletti (ACM AFT 2021) shows that in comparison to probabilistic leader election methods, SSLE-based proof-of-stake blockchains have significant security gains, both with respect to grinding attacks and with respect to the private attack. Yet, as of today, very few concrete constructions of SSLE are known. In particular, all existing protocols are only secure in a model where the adversary is supposed to corrupt participants before the protocol starts -- an assumption that clashes with the highly dynamic nature of decentralized blockchain protocols. In this paper we make progress in the study of SSLE by proposing new efficient constructions that achieve stronger security guarantees than previous work. In particular, we propose the first SSLE protocol that achieves adaptive security. Our scheme is proven secure in the universal composability model and achieves efficiency comparable to previous, less secure, realizations in the state of the art

Efficient and Universally Composable Single Secret Leader Election from Pairings

Single Secret Leader Election (SSLE) protocols allow a set of users to elect a leader among them so that the identity of the winner remains secret until she decides to reveal herself. This notion was formalized and implemented in a recent result by Boneh, et al. (ACM Advances on Financial Technology 2020) and finds important applications in the area of Proof of Stake blockchains. In this paper we put forward new SSLE solutions that advance the state of the art both from a theoretical and a practical front. On the theoretical side we propose a new definition of SSLE in the universal composability framework. We believe this to be the right way to model security in highly concurrent contexts such as those of many blockchain related applications. Next, we propose a UC-realization of SSLE from public key encryption with keyword search (PEKS) and based on the ability of distributing the PEKS key generation and encryption algorithms. Finally, we give a concrete PEKS scheme with efficient distributed algorithms for key generation and encryption and that allows us to efficiently instantiate our abstract SSLE construction. Our resulting SSLE protocol is very efficient, does not require participants to store any state information besides their secret keys and guarantees so called on-chain efficiency: the information to verify an election in the new block should be of size at most logarithmic in the number of participants. To the best of our knowledge, this is the first SSLE scheme achieving this property along with practical efficiency

Parthenolide induces caspase-independent and AIF-mediated cell death in human osteosarcoma and melanoma cells.

The mechanism of the cytotoxic effect exerted by parthenolide on tumor cells is not clearly defined today. This article shows that parthenolide stimulates in human osteosarcoma MG63 and melanoma SK-MEL-28 cells a mechanism of cell death, which is not prevented by z-VAD-fmk and other caspase inhibitors. In particular treatment with parthenolide rapidly stimulated (1-2 h) reactive oxygen species (ROS) generation by inducing activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and NADPH oxidase. This event caused depletion of thiol groups and glutathione, NF-κB inhibition, c-Jun N-terminal kinase (JNK) activation, cell detachment from the matrix, and cellular shrinkage. The increase of ROS generation together with the mitochondrial accumulation of Ca(2+) also favored dissipation of Δψm, which seemed primarily determined by permeability transition pore opening, since Δψm loss was partially prevented by the inhibitor cyclosporin A. Staining with Hoechst 33342 revealed in most cells, at 3-5 h of treatment, chromatin condensation, and fragmentation, while only few cells were propidium iodide (PI)-positive. In addition, at this stage apoptosis inducing factor (AIF) translocated to the nucleus and co-localized with areas of condensed chromatin. Prolonging the treatment (5-15 h) ATP content declined while PI-positive cells strongly augmented, denouncing the increase of necrotic effects. All these effects were prevented by N-acetylcysteine, while caspase inhibitors were ineffective. We suggest that AIF exerts a crucial role in parthenolide action. In accordance, down-regulation of AIF markedly inhibited parthenolide effect on the production of cells with apoptotic or necrotic signs. Taken together our results demonstrate that parthenolide causes in the two cell lines a caspase-independent cell death, which is mediated by AIF

Speckle statistics in adaptive optics images at visible wavelengths

Residual speckles in adaptive optics (AO) images represent a well-known limitation on the achievement of the contrast needed for faint source detection. Speckles in AO imagery can be the result of either residual atmospheric aberrations, not corrected by the AO, or slowly evolving aberrations induced by the optical system. We take advantage of the high temporal cadence (1 ms) of the data acquired by the System for Coronagraphy with High-order Adaptive Optics from R to K bands-VIS forerunner experiment at the Large Binocular Telescope to characterize the AO residual speckles at visible wavelengths. An accurate knowledge of the speckle pattern and its dynamics is of paramount importance for the application of methods aimed at their mitigation. By means of both an automatic identification software and information theory, we study the main statistical properties of AO residuals and their dynamics. We therefore provide a speckle characterization that can be incorporated into numerical simulations to increase their realism and to optimize the performances of both real-time and postprocessing techniques aimed at the reduction of the speckle noise

On the Impossibility of Algebraic Vector Commitments in Pairing-Free Groups

Vector Commitments allow one to (concisely) commit to a vector of messages so that one can later (concisely) open the commitment at selected locations. In the state of the art of vector commitments, algebraic constructions have emerged as a particularly useful class, as they enable advanced properties, such as stateless updates, subvector openings and aggregation, that are for example unknown in Merkle-tree-based schemes. In spite of their popularity, algebraic vector commitments remain poorly understood objects. In particular, no construction in standard prime order groups (without pairing) is known. In this paper, we shed light on this state of affairs by showing that a large class of concise algebraic vector commitments in pairing-free, prime order groups are impossible to realize. Our results also preclude any cryptographic primitive that implies the algebraic vector commitments we rule out, as special cases. This means that we also show the impossibility, for instance, of succinct polynomial commitments and functional commitments (for all classes of functions including linear forms) in pairing-free groups of prime order