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4-Membered heterocycles have been increasingly exploited in medicinal chemistry and, as small polar motifs, often show important influence on activity and physicochemical properties. Thietane dioxides similarly offer potential in both agricultural and pharmaceutical applications but are notably understudied. Here we report a divergent approach to 3,3-disubstituted thietane dioxide derivatives by forming carbocations on the 4-membered ring with catalytic Lewis or Brønsted acids. Benzylic tertiary alcohols of the thietane dioxides are coupled directly with arenes, thiols, and alcohols.

No evaluation of the quality of different carotid guidelines using validated scales has been performed to date. The present study aims to analyze 3 carotid stenosis guidelines, apprizing their quality and reporting using validated tools.

The elimination of methyl mercaptan from natural gas sources and many industrial processes remains an actively investigated issue. The discovery that acidic zeolites are efficient catalysts for the decomposition and conversion of methyl mercaptan to value-added products has prompted a better understanding of the fundamental reaction mechanisms. Periodic density functional theory calculations with empirical dispersion corrections were employed in this work to investigate the mechanism of toluene formation from benzene and methyl mercaptan over acidic chabazite (H-CHA) zeolite. The free energy surfaces along the stepwise and the concerted mechanisms of mercaptan and methanol reagents are identified and compared. Although mercaptan is the chemical analogue of methanol, we found that mercaptan conversion is possible only along the stepwise route, owing to the larger size of sulfur if coadsorbed with benzene in the H-CHA zeolite pore. Both reagents undergo their conversion via the same rate-limiting steps, which are the formation of the surface-bound methoxide (stepwise route) and C–C bond formation from the coadsorbed CH3XH (X = S, O) and C6H6molecules (concerted route). The ab initio molecular dynamics simulations at the reactive temperatures revealed intramolecular hydrogen transfer in the toluenium cation that facilitates the H-back-donation for the catalyst regeneration.

Electromagnetic Interference and Compatibility (EMI–EMC) are a serious problem in Microelectromechanical Systems (MEMS), and specially in powered by wireless energy transfer MEMS. Most MEMS have dimensions in the order of 1 mm or less, thus, most of the suitable electromagnetic radiation sources have wavelengths larger than this, making isolation of electromagnetic effects very difficult. Model‐Based Systems Engineering (MBSE) can be an excellent tool to deal with EMI—EMC in MEMS during early design phases. In this work, we present a problem‐solving procedure and integration of EMI—EMC in MEMS from a Model‐Based Systems Engineering perspective. This approach is described in detail by a real example using a procedure based on nine steps fully integrated with the proposed systems engineering methodology. For example, the use of context diagrams (IBDs) and N SQUARE charts to describe EMC interactions is explained in detail. The system is formed by a Wireless Power Transfer (WPT) subsystem working near 2.45 or 4.5 GHz coupled to an electromagnetic micromotor. This micromotor contains copper microcoils which can receive electromagnetic radiation directly at the same time that the WPT subsystem. The greatest difficulty is, then, to power the WPT while isolating the micromotor, and optimizing the coupling interface. A summary of the most important EMC concepts and tools are reviewed from the systems engineer perspective and possible problems during the design and testing phases are discussed in detail using the example.

The implementation of the cyclic cluster model (CCM) for molecular mechanics is presented in the framework of the computational chemistry program deMon2k. Because the CCM is particularly well-suited for the description of periodic systems with defects, it can be used for periodic QM/MM approaches where the non-periodic QM part is treated as a defect in a periodic MM surrounding. To this end, we present here the explicit formulae for the evaluation of the Ewald sum and its first- and second-order derivatives as implemented in deMon2k. The outlined implementation was tested in molecular dynamics (MD) simulations and periodic structure optimization calculations. MD simulations of an argon system were carried out using the Nosé-Hoover chain (NHC) thermostat and the Martyna-Tobias-Klein (MTK) barostat to control the temperature and pressure of the system, respectively. For the validation of CCM structure optimization a set of molecular crystals were optimized using the Ewald method for the evaluation of the electrostatic interactions. Two optimization procedures for the determination of the atomic positions and CCM cell parameters were tested. Our results show that the simultaneous optimization of the atomic positions and cell parameters is most efficient.

cGAMP-specific nucleases (poxins) are a recently described family of proteins dedicated to obstructing cyclic GMP-AMP synthase signaling (cGAS), an important sensor triggered by cytoplasmic viral replication that activates type I interferon (IFN) production. The B2Rgene of vaccinia viruses (VACV) codes for one of these nucleases. Here, we evaluated the effects of inactivating the VACV B2 nuclease in the context of an oncolytic VACV. VACV are widely used as anti-cancer vectors due to their capacity to activate immune responses directed against tumor antigens. We aimed to elicit robust antitumor immunity by preventing viral inactivation of the cGAS/STING/IRF3 pathway after infection of cancer cells. Activation of such a pathway is associated with a dominant T helper 1 (Th1) cell differentiation of the response, which benefits antitumor outcomes. Deletion of the B2Rgene resulted in enhanced IRF3 phosphorylation and type I IFN expression after infection of tumor cells, while effective VACV replication remained unimpaired, both in vitro and in vivo. In syngeneic mouse tumor models, the absence of the VACV cGAMP-specific nuclease translated into improved antitumor activity, which was associated with antitumor immunity directed against tumor epitopes.

Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond formation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question systematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic oxetane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radicals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acrylates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more π-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent’s rule rendering the Giese addition irreversible.

The model based systems engineering (MBSE) approach describes a system using consistent views to provide a holistic model as complete as possible. MBSE methodologies end with the physical architecture of the system, but a physical model is clearly incomplete without the study of its associated physical laws and phenomena related to the whole system or its parts. However, the computational demands could be excessive even for modest projects. Dimensional analysis (DA) is common in fluid dynamics and chemical engineering, but its application to systems engineering is still limited. We describe an engineering methodological process, which incorporates DA as a powerful tool to understand the physical constraints of the system without the burden of complex analytical or numerical calculations. A detailed example describing a microantenna is presented showing the benefits of this approach. The selected example describes a problem rarely covered in modern expositions of DA in order to show the wide benefit of these techniques. The information provided by this analysis is very useful to select the best physically realizable architectures, testing design, and conduct trade‐off studies. The complexity of modern systems and systems of systems demands new testing procedures in order to comply with increasingly demanding requirements and regulations. This can be accomplished through research in new DA methods. Finally, this article serves as a fairly comprehensive guide to the use of DA in the context of MBSE, detailing its strengths, limitations, and controversial issues.

El objetivo del estudio fue estimar el impacto presupuestario asociado a la incorporación de alemtuzumab para pacientes adultos con esclerosis múltiple recaída remisión (EMRR) en Argentina, desde la perspectiva de la seguridad social.

Approximately 170,000 people worldwide have neuromyelitis optica spectrum disorder (NMOSD), an inflammatory autoimmune disease of the central nervous system with a relatively low prevalence of 0.5–4 / 100,000. Both cardinal symptoms of NMOSD, including visual loss and myelitis, and secondary symptoms such as fatigue, pain, and mental health complications, can lead to cumulative and permanent disability for patients living with the disease. In turn, these deficits could impact adults of working age in work contexts, influencing their ability to work and earn income.

•In this real-world clinical MS setting, using icobrain for analysis of brain atrophy and our quality control criteria, we found comparable variance on brain volume changes for same-scanner and different-scanner MRI pairs.•A higher number of different-scanner MRI pairs did not pass quality control and had poorer alignment similarity.•Applying strict selection criteria for volumetric analyses in real-world settings, and longitudinal imaging within scanners, remain imperative to reduce brain atrophy variability.

The objective of this study was to determine by a conjoint analysis the preferences for a range of disease-modifying treatment attributes in patients with multiple sclerosis (MS) and treating neurologists.

This paper describes Ecoacoustic bank, a software for managing and storing passive acoustic monitoring (PAM) data. The software allows integrating audio with other commonly collected data types, such as information on acquisition systems used and spatial–temporal conditions, to encourage research in biodiversity and environmental monitoring. As part of this effort, we use docker technology to facilitate software deployment, where we integrated a user-friendly web interface with the database engine. Other features include integrating advanced search filters and audio annotation of anthropophonies, biophonies, and geophonies.

Polysaccharide methylation, especially that of pectin, is a common and important feature of land plant cell walls. Polysaccharide methylation takes place in the Golgi apparatus and therefore relies on the import of S-adenosyl methionine (SAM) from the cytosol into the Golgi. However, so far, no Golgi SAM transporter has been identified in plants. Here we studied major facilitator superfamily members in Arabidopsisthat we identified as putative Golgi SAM transporters (GoSAMTs). Knockout of the two most highly expressed GoSAMTs led to a strong reduction in Golgi-synthesized polysaccharide methylation. Furthermore, solid-state NMR experiments revealed that reduced methylation changed cell wall polysaccharide conformations, interactions and mobilities. Notably, NMR revealed the existence of pectin ‘egg-box’ structures in intact cell walls and showed that their formation is enhanced by reduced methyl esterification. These changes in wall architecture were linked to substantial growth and developmental phenotypes. In particular, anisotropic growth was strongly impaired in the double mutant. The identification of putative transporters involved in import of SAM into the Golgi lumen in plants provides new insights into the paramount importance of polysaccharide methylation for plant cell wall structure and function.

ABSTRACTThroughout recent history, Chilean society has suffered severe socio-political events, such as the advent of authoritarian regimes like Pinochet’s dictatorship (1973–1989) disseminating propaganda to defend political power and control citizens. This article critically analyzes and discusses the issue of military regimes performing authoritarian power and political repression against their citizens, which, in turn, is connected with the Chilean context of the second half of the twentieth century and the first decades of the twenty-first century. Using a discourse analysis approach, this study examines José Ricardo Morales’ play Los culpablesto critique the emergence of an authoritarian political-military system disseminating political montage against innocent citizens throughout the twentieth century. The analysis of the play reveals an avant la lettrediscourse on authoritarianism, which is relevant to shed light on a new interpretation of the current use of propaganda and violence as a form of political action by the Chilean government.

Annulations that combine diacceptors with bis-nucleophiles are uncommon. Here, we report the synthesis of 1,4-dioxanes from 3-aryloxetan-3-ols, as 1,2-bis-electrophiles and 1,2-diols. Brønsted acid Tf2NH catalyzes both the selective activation of the oxetanol, to form an oxetane carbocation that reacts with the diol, and intramolecular ring opening of the oxetane. High regio- and diastereoselectivity are achieved with unsymmetrical diols. The substituted dioxanes and fused bicyclic products present interesting motifs for drug discovery and can be further functionalized.

Bioisosteres provide valuable design elements that medicinal chemists can use to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides—extremely common pharmacophores—but are rarely examined due to the lack of available synthetic methods. Here we describe a class of reactions for sulfonyl fluorides to form amino-oxetanes by an alternative pathway to the established SuFEx (sulfonyl–fluoride exchange) click reactivity. A defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared. Kinetic and computational studies support the formation of an oxetane carbocation as the rate-determining step, followed by a chemoselective nucleophile coupling step.

Indigenous Peoples have resiliently weathered continued assaults on their sovereignty and rights throughout colonialism and its continuing effects. Indigenous Peoples’ sovereignty has been strained by the increasing effects of global environmental change within their territories, including climate change and pollution, and by threats and impositions against their land and water rights. This continuing strain against sovereignty has prompted a call to action to conceptualise the determinants of planetary health from a perspective that embodied Indigenous-specific methods of knowledge gathering from around the globe. A group of Indigenous scholars, practitioners, land and water defenders, respected Elders, and knowledge-holders came together to define the determinants of planetary health from an Indigenous perspective. Three overarching levels of interconnected determinants, in addition to ten individual-level determinants, were identified as being integral to the health and sustainability of the planet, Mother Earth.

This paper presents ALFAsim, a new commercial software tool for the simulation of transient and steady-state multiphase flows in tubes and pipelines. The main goal of this work is to show that ALFAsim's one-dimensional multiphase flow simulator models can reproduce accurately an offshore production system with isothermal and non-isothermal study cases in steady state condition considering field data extracted from the literature. The difference when simulating a case when temperature effects are present is investigated and different parameters like hold-up, void fraction and phase velocities are analysed. A discussion about these effects linking them to observations in the open literature. The software is tested with field data from the open literature and the results obtained with ALFAsim are within ±15% deviation range. [Received: July 5, 2021; Accepted: October 9, 2021]