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The chapter titled “Eight-membered Rings with two Heteroatoms 1,2” deals with heterocine rings with two heteroatoms in a 1,2 relationship, namely 1,2-diazocine, 2H-1,2-oxazocine, 2H-1,2-thiazocine, 1,2-dioxocin, 1,2-oxathiocin and 1,2-dithiocin. This article covers the literature from 2007 to 2019 and reports the chemistry of uncondensed derivatives, heterocines fused to carbocycles and heterocycles, as well as bridged heterocines. As usual, in the case that a particular section is not mentioned, it means that no chemistry has been reported. In this article, the “Biosynthesis” paragraph was additionally introduced, since in the latest years the contribution of Nature to the synthesis of diheterocines became important, especially for biologically active compounds. Following this approach, the natural sources will be analyzed, as well as the biosynthetic pathway whenever available. In this edition, as happened in the previous one, the interest in 1,2-heterocines has been driven by the pharmacological activity shown by several derivatives or some potentially important industrial applications.

Innovative, automated, and non-invasive techniques have been developed by scientific community to indirectly assess structural conditions and support the decision-making process for a worthwhile maintenance schedule. Nowadays, machine learning tools are in the spotlight because of their outstanding capabilities to deal with data coming from even heterogeneous sources and their ability to extract information from the structural systems, providing highly effective, reliable, and efficient damage classification tools. In the current study, a supervised multi-level damage classification strategy has been developed regarding Ground Penetrating Radar (GPR) profiles for the assessment of tunnel lining conditions. In previous research, the authors firstly considered a convolutional neural network (CNN), adopting the quite popular ResNet-50, initialized through transfer learning. In the present work, further enhancements have been attempted by adopting two configurations of the newest state-of-art advanced neural architectures: the neural transformers. The foremost is the original Vision Transformer (ViT), whose core is an encoder entirely based on the innovative self-attention mechanism and does not rely on convolution at all. The second is an improvement of ViT which merges convolution and self-attention, the Compact Convolution Transformer (CCT). In conclusion, a critical discussion of the different pros and cons of adopting the above-mentioned different architectures is finally provided, highlighting the actual powerfulness of these technologies in the future civil engineering paradigm nevertheless.

This paper presents a new MRAS speed observer for high performance FOC induction motor drives which employs the flux error for estimating the rotor speed, but overcomes the pure integration problems by using a novel adaptive integration method based on neural adaptive filtering. A linear neuron (the ADALINE) is employed for the estimation of both the rotor speed and the rotor flux-linkage using a recursive TLS (Total Least Squares) algorithm (the TLS EXIN neuron) for on-line training. This neural model is also used as a predictor with no feedback loops between the output of the neural network and its input. The proposed scheme has been implemented in a test setup and compared with an MRAS OLS (Ordinary Least Squares) speed estimation with low-pass filter integration and with the well- known Schauder's scheme. The experimental results show the in the high and medium speed ranges with and without load, the three algorithms give practically the same results, while in low speed ranges (i.e. below 10 rad/s ) the TLS based algorithm outperforms the other two algorithms. Experiments have also been made to test the robustness of the algorithm to load perturbations and to test its performance at zero speed operation.

Many computer vision techniques, above all for structure from motion problems, require a segmentation of the images captured by one or more cameras. This paper deals the segmentation based on the motion information, but can be easily extended to other cases (color, texture and so on). A new neural network, the EXIN Segmentation Neural Network (EXIN SNN) is here introduced. It is incremental, self-organizing and considers its task as the solution of a pattern recognition problem. This original approach overcomes the limits of the traditional segmentation techniques, namely the need of a spatial support for the image objects and the translation parallel to the image plane for the objects in the scene. Examples are given both for synthetic and real images.

A series of [1, 2, 4triazino[4,3-a]indoles was prepared in good yield by reacting 2-diazo-3-ethoxycarbonylindole with methylene active compounds. Derivatives of the title ring system were tested against a panel of 60 human tumor cell lines, and showed inhibitory activity against a wide range of cancer cell lines at micromolar concentration.

Contains fulltext : 290798.pdf (Publisher’s version ) (Open Access) BACKGROUND: Several reports have demonstrated the impact of the COVID-19 pandemic on the management and outcome of patients with ST-segment elevation myocardial infarction (STEMI). The aim of the current analysis is to investigate the potential gender difference in the effects of the COVID-19 pandemic on mechanical reperfusion and 30-day mortality for STEMI patients within the ISACS-STEMI COVID-19 Registry. METHODS: This retrospective multicenter registry was performed in high-volume primary percutaneous coronary intervention (PPCI) centers on four continents and included STEMI patients undergoing PPCIs in March-June 2019 and 2020. Patients were divided according to gender. The main outcomes were the incidence and timing of the PPCI, (ischemia time ≥ 12 h and door-to-balloon ≥ 30 min) and in-hospital or 30-day mortality. RESULTS: We included 16683 STEMI patients undergoing PPCIs in 109 centers. In 2020 during the pandemic, there was a significant reduction in PPCIs compared to 2019 (IRR 0.843 (95% CI: 0.825-0.861, p < 0.0001). We did not find a significant gender difference in the effects of the COVID-19 pandemic on the numbers of STEMI patients, which were similarly reduced from 2019 to 2020 in both groups, or in the mortality rates. Compared to prepandemia, 30-day mortality was significantly higher during the pandemic period among female (12.1% vs. 8.7%; adjusted HR [95% CI] = 1.66 [1.31-2.11], p < 0.001) but not male patients (5.8% vs. 6.7%; adjusted HR [95% CI] = 1.14 [0.96-1.34], p = 0.12). CONCLUSIONS: The COVID-19 pandemic had a significant impact on the treatment of patients with STEMI, with a 16% reduction in PPCI procedures similarly observed in both genders. Furthermore, we observed significantly increased in-hospital and 30-day mortality rates during the pandemic only among females. Trial registration number: NCT 04412655.

This review deals with 1,5-diheterocines that exhibited biological properties and covers comprehensively the literature from 2007 to the end of February 2019. Among the six possible heterocyclic systems belonging to the eight-membered rings with two heteroatoms, N, O, and S, five had derivatives showing pharmacological activities: 1,5-diazocines, 1,5-oxazocines, 1,5-thiazocines, 1,5-dioxocins, and 1,5-dithiocins. Instead, literature reported no articles dealing with 1,5-oxathiocins of interest in medicinal chemistry. In addition to uncondensed derivatives, 1,5-diheterocines fused to five- and six-membered carbocycles or heterocycles are covered. Bridged 1,5-diheterocines are covered as well.

There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.

A series of 22 derivatives of the [1,2]oxazolo[5,4-e]isoindole system were synthesized through an efficient and versatile procedure that involves the annelation of the [1,2]oxazole moiety to the isoindole ring, producing derivatives with a wide substitution pattern. The structure-activity relationship indicates that the N-4-methoxybenzyl group appears crucial for potent activity. In addition, the presence of a 6-phenyl moiety is important and the best activity is reached with a 3,4,5-trimethoxy substituent. The most active compound, bearing both the structural features, was able to inhibit tumor cell proliferation at nanomolar concentrations when tested against the full NCI human tumor cell line panel. Interestingly, this compound was effective in reducing in vitro and in vivo cell growth, impairing cell cycle progression and inducing apoptosis, as a consequence of the inhibition of tubulin polymerization, in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional therapeutic strategies.

Derivatives of the new ring systems bispyrido[4',3':4,5]pyrrolo[1,2-a:1',2'-d] pyrazine-6,13-dione and its deaza analogue pyrido[4'',3'':4',5']pyrrolo-[1',2':4,5]pyrazino [1,2-a]indole-6,13-dione were conveniently synthesized through a four-step sequence. Symmetrical derivatives of the former ring system were obtained through self condensation. On the other hand, condensation of 6-azaindole carboxylic acid with indole 2-carboxylic acid afforded the deaza analogue ring system. Derivatives of the title ring system were tested by the National Cancer Institute (Bethesda, MD, USA) and four of them exhibited modest activity against MCF7 (a breast cancer cell line) and/or UO-31 (a renal cancer cell line).

Pyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridines were synthesized as a new class of tricyclic system in which the pyridine ring is annelated to a cycloheptapyrrole scaffold, with the aim of obtaining new photosensitizing agents with improved antiproliferative activity and lower undesired toxic effects. A versatile synthetic pathway was approached, which allowed the isolation of derivatives of the title ring system with a good substitution pattern on the pyrrole moiety. Photobiological studies revealed that the majority of the new compounds showed a potent cytotoxic effect upon photoactivation with light of the proper wavelength, especially when decorated with a 2-ethoxycabonyl group and a N-benzyl substituted moiety, with EC50 values reaching the submicromolar level. The mechanism of action was evaluated.

The synthesis of a novel class of tetrahydropyrrolo[3,4-g]indazoles is reported, by annelation of the pyrazole ring on the isoindole moiety by means of 5-hydroxymethylene tetrahydroisoindole-4-ones key intermediates, with good regioselectivity. Dihydroderivatives were also obtained by oxidation with DDQ of the corresponding tetrahydropyrrolo[3,4-g]indazoles. The growth inhibitory effect was evaluated at the National Cancer Institute of Bethesda and some derivatives showed modest activity.

We have designed and synthesized isonetropsin and its one pyrrole unit analogue in which the amine and carbonyl groups have been switched in positions 2 and 4, respectively instead of 4 and 2 positions of the natural antibiotic netropsin.

This paper proposes a sensorless technique for an induction machine Flywheel Energy Storage System (FESS) based on a non-linear observer integrated with a total least-squares speed estimator taking into consideration the IM (Induction Machine) saturation effects. The nonlinear observer is based on an original formulation of the dynamic model of the IM including the magnetic saturation, rearranged in a space-state form, after assuming as state variables the stator current and the rotor magnetizing current space-vectors in the stator reference frame. The choice of the observer gain has been made by the use of Lyapunov's method. The speed signal needed by the non-linear observer for the flux estimation is provided by the Total Least Square (TLS) based speed estimator, which itself takes into consideration the magnetic saturation for the speed estimation. The proposed nonlinear observer has been tested in numerical simulation and verified experimentally on a suitably developed test set-up, demonstrating its applicability as far as FESS is concerned.

Heteroanalogues of angelicin, pyrrolo[3,2-h]quinazolines, were synthesized with the aim of obtaining new potent photochemotherapeutic agents. Many derivatives caused a significant decrease in cell proliferation in several human tumor cell lines after irradiation with UVA light (GI(50) =15.2-0.2 μM). Their phototoxicity effected apoptosis in Jurkat cells with the involvement of mitochondria (as determined by the loss of mitochondrial membrane potential and production of reactive oxygen species) and lysosomes. The phototoxicity of these compounds could be explained by lipid peroxidation.

Despite improvements in the treatment and prevention of cancer, the number of new diagnoses continues to rise; this has fuelled substantial interest in the development of new and effective chemotherapeutic agents. Compounds of the triazene class, such as dacarbazine, have been used in the clinical management of many cancer types including brain, leukemia, and melanoma. A new compound class bearing a triazenoazaindole scaffold was synthesized with the aim of identifying new antiproliferative agents. Compounds 5 a-g and 6 a-c were screened against a panel of human tumor cell lines, and two of them, 5 e and 5 f, showed cytotoxicity (GI(50) range: 2.2-8.2 μM) in all cell lines. These two compounds even maintained their cytotoxicity in some multidrug-resistant cell lines. Flow cytometry analysis demonstrated their ability to induce cell death by apoptosis with involvement of lysosomes.

Pyrrolo[3,4- h ]quinolin-2-ones were synthesized as nitrogen isosters of the angular furocoumarin angelicin, with the aim of obtaining new photochemotherapeutic agents with increased antiproliferative activity and lower undesired toxic effects. A versatile synthetic pathway was approached to allow the isolation of derivatives of the new ring system with a good substitution pattern on the pyrrole moiety. Photobiological screenings of the new compounds revealed a potent phototoxic effect and a great UVA dose dependence, reaching IC 50 values at submicromolar level. The induced cellular photocytotoxicity was related to apoptosis with the involvement of mitochondria and lysosomes, alteration of cell cycle profile and membrane lipid peroxidation.

A series of derivatives of new ring system pyrido[4’,3’:4,5]pyrrolo[2,1-d] [1,2,3,5]tetrazine was obtained from moderate to excellent yields by reaction of 2-diazo-3-ethoxycarbonyl-pyrrolo[2,3- c]pyridine with alkyl- or aryl-isocyanates in dichlorometane at room temperature or at 50 °C under microwave irradiation.

A convenient synthesis of the pyrano[2,3-e]isoindol-2-one ring system, an heteroanalogue of angelicin, is reported. Our synthetic approach consists of the annelation of the pyran ring on the isoindole moiety using 5-dialkylamino- or 5-hydroxymethylene intermediates as building blocks. The photoantiproliferative activity of the new derivatives was studied. Some of them bearing the benzyl group at the 8 position were active with IC(50) in the micromolar range. Cell cytotoxicity involves apoptosis, alteration of cell cycle profile and membrane photodamage.

Twelve derivatives of new ring system pyrido[2’,3’:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazine were prepared in good yields by reaction of 2-diazo-3-ethoxycarbonyl-pyrrolo[3,2-b]pyridine with alkyl- or aryl-isocyanates. Nine derivatives, screened by the National Cancer Institute (Bethesda, MD) for the in vitro one dose primary anticancer assay against a panel of about 60 human tumor cell lines, showed no significant activity.