Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma

ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients—and classified by in silico tools as pathogenic, uncertain significance, or benign—using multiple assays evaluating ATM/pATM expression and/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum.     

A Resilient Control Strategy for Cyber-Physical Systems Subject to Denial of Service Attacks: A Leader-Follower Set-Theoretic Approach

Multi-agent systems are usually equipped with open communication infrastructures to improve interactions efficiency, reliability and sustainability. Although technologically cost-effective, this makes them vulnerable to cyber-attacks with potentially catastrophic consequences. To this end, we present a novel control architecture capable to deal with the distributed constrained regulation problem in the presence of time-delay attacks on the agents’ communication infrastructure. The basic idea consists of orchestrating the interconnected cyber-physical system as a leader-follower configuration so that adequate control actions are computed to isolate the attacked unit before it compromises the system operations. Simulations on a multi-area power system confirm that the proposed control scheme can reconfigure the leader-follower structure in response to denial of-service (DoS) attacks.      

Optimization of pump absorption in MOF lasers via multi-long-period gratings: design strategies

Different strategies for designing optical couplers, optimized to enhance the pump absorption in the rare-earth-doped core of microstructured fiber lasers, are illustrated. Three kinds/configurations of optical couplers have been designed and compared as examples of the different design strategies which can be followed. Their effectiveness to enhance the performance of an ytterbium-doped, double cladding, microstructured optical fiber laser has been accurately simulated. They consist of a suitable cascade of multiple long-period gratings (MLPGs) inscribed in the fiber core region. The characteristics of the MLPG couplers have been simulated via a homemade computer code based on both rate equations and an extended coupled mode theory. The proposed MLPG couplers seem particularly useful in the case of low rare-earth concentration but, even for a middle-high ytterbium concentration, as N(Yb)=5×10(25) ions/m(3), the slope efficiency S can be increased up to 20%, depending on the fiber length.     

Absorption of sulphur dioxide by electrosprayed droplets

This paper describes and discusses experimental results on the absorption of sulphur dioxide in electrified water sprays, either when the polluted gas is treated as is or when the gas is exposed to a corona source to ionize the sulphur dioxide. The experiments revealed that an electrified spray with a charge-to-mass ratio of 50 μC · kg⁻¹ enabled the absorption rate of droplets to double, regardless of their polarities. Corona charging gave rise to an increase in the SO₂ depletion rate over the scrubber wall, while negligible effects appeared on the actual droplets absorption rate. These findings suggested that faster absorption rates mostly, though not uniquely, depend on the modifications on the morphological and interfacial properties of the sprayed droplets induced by the free electric charge imposed on their surface. Conversely, the absorption rates were negligibly affected by the electrical interactions between droplets (either charged or uncharged) and the sulphur dioxide ions/radicals originating from the corona source.     

Drug-induced reinstatement to heroin and cocaine seeking: A rodent model of relapse in polydrug use.

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 μg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine-associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Closed-loop Live Marked Graphs under Generalized Mutual Exclusion Constraint Enforcement

Enforcing a supervisory control policy to avoid forbidden states on a discrete event system modeled by a Petri net may result in a non live system. This may happen even if the admissible states are specified by Generalized Mutual Exclusion Constraints (GMECs). This leads to the problem of synthesizing a maximally permissive control policy preserving liveness of the system under a GMEC. This problem is very interesting in practice, but difficult even for a restricted class of systems. In this paper, we focus on systems which can be modeled as live and safe Marked Graphs (MGs). On such systems, when some of the transitions are uncontrollable, a GMEC can be forced by a monitor place if a not maximally permissive policy is accepted, otherwise a more complex control has to be adopted. Anyway, liveness of the closed-loop system (plant plus control) is not guaranteed. Two sufficient conditions to verify the closed-loop liveness of a live and safe MG plant controlled by a monitor are derived. A sufficient condition for closed loop liveness of MGs where a GMEC has been enforced on is derived. In addition, a set of predicates is provided that enforces, in a maximally permissive way, a GMEC while preserving closed-loop liveness on live and safe MG systems under some restrictions.

A Pareto-based multi-objective evolutionary approach to the identification of Mamdani fuzzy systems

In the last years, the numerous successful applications of fuzzy rule-based systems (FRBSs) to several different domains have produced a considerable interest in methods to generate FRBSs from data. Most of the methods proposed in the literature, however, focus on performance maximization and omit to consider FRBS comprehensibility. Only recently, the problem of finding the right trade-off between performance and comprehensibility, in spite of the original nature of fuzzy logic, has arisen a growing interest in methods which take both the aspects into account. In this paper, we propose a Pareto-based multi-objective evolutionary approach to generate a set of Mamdani fuzzy systems from numerical data. We adopt a variant of the well-known (2+2) Pareto Archived Evolutionary Strategy ((2+2)PAES), which adopts the one-point crossover and two appropriately defined mutation operators. (2+2)PAES determines an approximation of the optimal Pareto front by concurrently minimizing the root mean squared error and the complexity. Complexity is measured as sum of the conditions which compose the antecedents of the rules included in the FRBS. Thus, low values of complexity correspond to Mamdani fuzzy systems characterized by a low number of rules and a low number of input variables really used in each rule. This ensures a high comprehensibility of the systems. We tested our version of (2+2)PAES on three well-known regression benchmarks, namely the Box and Jenkins Gas Furnace, the Mackey-Glass chaotic time series and Lorenz attractor time series datasets. To show the good characteristics of our approach, we compare the Pareto fronts produced by the (2+2)PAES with the ones obtained by applying a heuristic approach based on SVD-QR decomposition and four different multi-objective evolutionary algorithms.     

Augmentative Pharmacological Strategies in Treatment-Resistant Major Depression: A Comprehensive Review

Treatment resistant depression (TRD) is associated with poor outcomes, but a consensus is lacking in the literature regarding which compound represents the best pharmacological augmentation strategy to antidepressants (AD). In the present review, we identify the available literature regarding the pharmacological augmentation to AD in TRD. Research in the main psychiatric databases was performed (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles in English with the main topic being pharmacological augmentation in TRD and presenting a precise definition of TRD were included. Aripiprazole and lithium were the most investigated molecules, and aripiprazole presented the strongest evidence of efficacy. Moreover, olanzapine, quetiapine, cariprazine, risperidone, and ziprasidone showed positive results but to a lesser extent. Brexpiprazole and intranasal esketamine need further study in real-world practice. Intravenous ketamine presented an evincible AD effect in the short-term. The efficacy of adjunctive ADs, antiepileptic drugs, psychostimulants, pramipexole, ropinirole, acetyl-salicylic acid, metyrapone, reserpine, testosterone, T3/T4, naltrexone, SAMe, and zinc cannot be precisely estimated in light of the limited available data. Studies on lamotrigine and pindolol reported negative results. According to our results, aripiprazole and lithium may be considered by clinicians as potential effective augmentative strategies in TRD, although the data regarding lithium are somewhat controversial. Reliable conclusions about the other molecules cannot be drawn. Further controlled comparative studies, standardized in terms of design, doses, and duration of the augmentative treatments, are needed to formulate definitive conclusions.