Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage

Bilirubin toxicity to the central nervous system (CNS) is responsible for severe and permanent neurologic damage, resulting in hearing loss, cognitive, and movement impairment. Timely and effective management of severe neonatal hyperbilirubinemia by phototherapy or exchange transfusion is crucial for avoiding permanent neurological consequences, but these therapies are not always possible, particularly in low-income countries. To explore alternative options, we investigated a pharmaceutical approach focused on protecting the CNS from pigment toxicity, independently from serum bilirubin level. To this goal, we tested the ability of curcumin, a nutraceutical already used with relevant results in animal models as well as in clinics in other diseases, in the Gunn rat, the spontaneous model of neonatal hyperbilirubinemia. Curcumin treatment fully abolished the landmark cerebellar hypoplasia of Gunn rat, restoring the histological features, and reverting the behavioral abnormalities present in the hyperbilirubinemic rat. The protection was mediated by a multi-target action on the main bilirubin-induced pathological mechanism ongoing CNS damage (inflammation, redox imbalance, and glutamate neurotoxicity). If confirmed by independent studies, the result suggests the potential of curcumin as an alternative/complementary approach to bilirubin-induced brain damage in the clinical scenario.     

Synthesis and Evaluation of Voltage-Gated Sodium Channel Blocking Pyrroline Derivatives Endowed with Both Antiarrhythmic and Antioxidant Activities

Under the hypothesis that cardioprotective agents might benefit from synergism between antiarrhythmic activity and antioxidant properties, a small series of mexiletine analogues were coupled with the 2,2,5,5-tetramethylpyrroline moiety, known for its antioxidant effect, in order to obtain dual-acting drugs potentially useful in the protection of the heart against post-ischemic reperfusion injury. The pyrroline derivatives reported herein were found to be more potent as antiarrhythmic agents than mexiletine and displayed antioxidant activity. The most interesting tetramethylpyrroline congener, a tert-butyl-substituted analogue, was at least 100 times more active as an antiarrhythmic than mexiletine.     

Evidence for a Negative Correlation between Human Reactive Enamine-Imine Intermediate Deaminase A (RIDA) Activity and Cell Proliferation Rate: Role of Lysine Succinylation of RIDA

Reactive intermediate deaminase (Rid) proteins are enzymes conserved in all domains of life. UK114, a mammalian member of RidA subfamily, has been firstly identified as a component of liver perchloric acid-soluble proteins (L-PSP). Although still poorly defined, several functions have been attributed to the mammalian protein UK114/RIDA, including the reactive intermediate deamination activity. The expression of UK114/RIDA has been observed in some tumors, arousing interest in this protein as an evaluable tumor marker. However, other studies reported a negative correlation between UK114/RIDA expression, tumor differentiation degree and cell proliferation. This work addressed the question of UK114/RIDA expression in human non-tumor HEK293 cell lines and in some human tumor cell lines. Here we reported that human RIDA (hRIDA) was expressed in all the analyzed cell line and subjected to lysine (K-)succinylation. In HEK293, hRIDA K-succinylation was negatively correlated to the cell proliferation rate and was under the control of SIRT5. Moreover, K-succinylation clearly altered hRIDA quantification by immunoblotting, explaining, at least in part, some discrepancies about RIDA expression reported in previous studies. We found that hRIDA was able to deaminate reactive enamine-imine intermediates and that K-succinylation drastically reduced deaminase activity. As predicted by in silico analysis, the observed reduction of deaminase activity has been related to the drastic alterations of hRIDA structure inferred by K-succinylation. The role of hRIDA and the importance of its K-succinylation in cell metabolism, especially in cancer biology, have been discussed.     

High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.     

A low-cost real time virtual system for postural stability assessment at home

Background and objective

The degeneration of the balance control system in the elderly and in many pathologies requires measuring the equilibrium conditions very often. In clinical practice, equilibrium control is commonly evaluated by using a force platform (stabilometric platform) in a clinical environment.In this paper, we demonstrate how a simple movement analysis system, based on a 3D video camera and a 3D real time model reconstruction of the human body, can be used to collect information usually recorded by a physical stabilometric platform.

Methods

The algorithm used to reconstruct the human body model as a set of spheres is described and discussed. Moreover, experimental measurements and comparisons with data collected by a physical stabilometric platform are also reported. The measurements were collected on a set of 6 healthy subjects to whom a change in equilibrium condition was stimulated by performing an equilibrium task.

Results

The experimental results showed that more than 95% of data collected by the proposed method were not significantly different from those collected by the classic platform, thus confirming the usefulness of the proposed system.

Conclusions

The proposed virtual balance assessment system can be implemented at low cost (about 500$) and, for this reason, can be considered a home use medical device. On the contrary, astabilometric platform has a cost of about 10,000$ and requires periodical calibration. The proposed system does not require periodical calibration, as is necessary for stabilometric force platforms, and it is easy to use. In future, the proposed system with little integration can be used, besides being an emulator of a stabilometric platform, also to recognize and track, in real time, head, legs, arms and trunk, that is to collect information actually obtained by sophisticated optoelectronic systems.     

Formal verification of security protocol implementations: a survey

Automated formal verification of security protocols has been mostly focused on analyzing high-level abstract models which, however, are significantly different from real protocol implementations written in programming languages. Recently, some researchers have started investigating techniques that bring automated formal proofs closer to real implementations. This paper surveys these attempts, focusing on approaches that target the application code that implements protocol logic, rather than the libraries that implement cryptography. According to these approaches, libraries are assumed to correctly implement some models. The aim is to derive formal proofs that, under this assumption, give assurance about the application code that implements the protocol logic. The two main approaches of model extraction and code generation are presented, along with the main techniques adopted for each approach.     

The use of games to help children eyes testing

A doctor cannot perform a good diagnosis without the patient collaboration. One of the major problem for ophthalmologists with children is to capture and maintain their attention while performing their tests. Sometimes children give wrong answers, or not accurate, since they are no longer interested in the task. In this paper we use the serious game paradigm to help children eyes testing. We ask the children to perform a vision acuity and a daltonism test using our game PlayWithEyes. Children have to recognize symbols projected on a wall and point them in a touch interface which displays all the possible answers. Tests performed in a kindergarten with 65 children have shown that the use of our game helps to obtain children cooperation because they have fun, so their attention may last longer, thus improving the possibility to perform a correct diagnosis especially for very young children. This is particular important for some sight defects like amblyopia (lazy eye). Moreover, the system allows us to identify visual acuity reduction in two children. Tests also highlight some limitations of the tool which have been promptly fixed.     

Scientific workflows for process mining: building blocks,scenarios, and implementation

Over the past decade process mining has emerged as a new analytical discipline able to answer a variety of questions based on event data. Event logs have a very particular structure; events have timestamps, refer to activities and resources, and need to be correlated to form process instances. Process mining results tend to be very different from classical data mining results, e.g., process discovery may yield end-to-end process models capturing different perspectives rather than decision trees or frequent patterns. A process-mining tool like ProM provides hundreds of different process mining techniques ranging from discovery and conformance checking to filtering and prediction. Typically, a combination of techniques is needed and, for every step, there are different techniques that may be very sensitive to parameter settings. Moreover, event logs may be huge and may need to be decomposed and distributed for analysis. These aspects make it very cumbersome to analyze event logs manually. Process mining should be repeatable and automated. Therefore, we propose a framework to support the analysis of process mining workflows. Existing scientific workflow systems and data mining tools are not tailored towards process mining and the artifacts used for analysis (process models and event logs). This paper structures the basic building blocks needed for process mining and describes various analysis scenarios. Based on these requirements we implemented RapidProM, a tool supporting scientific workflows for process mining. Examples illustrating the different scenarios are provided to show the feasibility of the approach.     

Deductive verification of alternating systems

Alternating systems are models of computer programs whose behavior is governed by the actions of multiple agents with, potentially, different goals. Examples include control systems, resource schedulers, security protocols, auctions and election mechanisms. Proving properties about such systems has emerged as an important new area of study in formal verification, with the development of logical frameworks such as the alternating temporal logic ATL*. Techniques for model checking ATL* over finite-state systems have been well studied, but many important systems are infinite-state and thus their verification requires, either explicitly or implicitly, some form of deductive reasoning. This paper presents a theoretical framework for the analysis of alternating infinite-state systems. It describes models of computation, of various degrees of generality, and alternating-time logics such as ATL* and its variations. It then develops a proof system that allows to prove arbitrary ATL* properties over these infinite-state models. The proof system is shown to be complete relative to validities in the weakest possible assertion language. The paper then derives auxiliary proof rules and verification diagrams techniques and applies them to security protocols, deriving a new formal proof of fairness of a multi-party contract signing protocol where the model of the protocol and of the properties contains both game-theoretic and infinite-state (parameterized) aspects.