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Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min.

The urgency of climate change forces many countries and regions to accelerate toward the goal of a carbon-neutral economy. The consequence of replacing fossil-fuel synchronous generation with inverter-based renewables, such as wind and solar, leads to a paradigm shift from power systems dominated by synchronous machines to inverter-dominated power systems. When the share of inverter-based generation increases, the behavioral differences in terms of the grid services provided to the power network by generation become more salient. Services for grid stability that were historically inherently provided by synchronous generators now must be replaced by services from these inverter-based generation resources, other grid devices, or the combination of the two to ensure stable grid operation in the future as well.

The grid's intelligence has been developing since the beginning of the electric power industry. And most customers expect to continue benefitting from an ever-smarter grid that will readily support future [...]

Dysautonomia (autonomic dysfunction) occurs in the Ehlers–Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Symptoms include palpitations, dizziness, presyncope, and syncope, especially when standing upright. Symptoms of orthostatic intolerance are usually relieved by sitting or lying and may be exacerbated by stimuli in daily life that cause vasodilatation, such as food ingestion, exertion, and heat. Neurocardiovascular dysautonomia may result in postural tachycardia syndrome (PoTS), a major cause of orthostatic intolerance. It is defined by a rise in heart rate of >30 beats per minute (bpm) in adults and >40 bpm in teenagers while upright, without a fall in blood pressure (BP; orthostatic hypotension). In some, it can be compounded by the presence of low BP. For many, there is delay in clinicians recognizing the nature of the symptoms, and recognizing EDS or HSD, leading to delays in treatment. The onset of PoTS may be linked to an event such as infection, trauma, surgery, or stress. Gastrointestinal and urinary bladder involvement may occur, along with thermoregulatory dysfunction. In some, the mast cell activation syndrome may be contributary, especially if it causes vasodilatation. This paper reviews neurocardiovascular dysautonomia with an emphasis on PoTS, its characteristics, associations, pathophysiology, investigation, and treatment.

Aeration tanks in wastewater treatment plants (WWTPs) are significant sources of bioaerosols, which contain microbial contaminants and can travel miles from the site of origin, risking the health of operators and the general public. One potential mitigation strategy is to apply free-floating carrier media (FFCM) to suppress bioaerosol emission. This article presents a multiscale study on the effects of mixing and FFCM on bioaerosol release using Bacillus globigiispores in well-defined liquid media. Bioaerosol release, defined as percentage of spores aerosolized during a 30 minute sampling period, ranged from 6.09 × 10−7% to 0.057%, depending upon the mixing mode and intensity. Bioaerosol release increased with the intensity of aeration (rotating speed in mechanical agitation and aeration rate in diffused aeration). A surface layer of polystyrene beads reduced bioaerosol released by >92% in the bench-scale studies and >74% in the pilot-scale study. This study discovered strong correlations (R2> 0.82) between bioaerosol release and superficial gas velocity, Froude number, and volumetric gas flow per unit liquid volume per minute. The Reynolds number was found to be poorly correlated with bioaerosol release (R2< 0.5). This study is a significant step toward the development of predictive models for full scale systems.

Macrocyclic peptides represent attractive scaffolds for targeting protein–protein interactions, making methods for the diversification and functional selection of these molecules highly valuable for molecular discovery purposes. Here, we report the development of a novel strategy for the generation and high-throughput screening of combinatorial libraries of macrocyclic peptides constrained by a nonreducible thioether bridge. In this system, spontaneous, posttranslational peptide cyclization by means of a cysteine-reactive noncanonical amino acid was integrated with M13 bacteriophage display, enabling the creation of genetically encoded macrocyclic peptide libraries displayed on phage particles. This platform, named MOrPH-PhD, was successfully applied to produce and screen 105- to 108-member libraries of peptide macrocycles against three different protein targets, resulting in the discovery of a high-affinity binder for streptavidin (KD: 20 nM) and potent inhibitors of the therapeutically relevant proteins Kelch-like ECH-associated protein 1 (KD: 40 nM) and Sonic Hedgehog (KD: 550 nM). This work introduces and validates an efficient and general platform for the discovery and evolution of functional, conformationally constrained macrocyclic peptides useful for targeting proteins and protein-mediated interactions.

The aftermath of the recent recession has seen calls to use transfers to poorer households as a means to enhance aggregate economic activity. The goal of this paper is to study the effects of wealth redistribution from rich to poor households on consumption and output in the short run. We first demonstrate analytically how the direction and size of the output effects of such interventions depend on labor supply decisions. We then show that in a standard incomplete‐markets model extended to allow for nominal rigidities and parametrized to match the U.S. wealth distribution, wealth redistribution does lead to a temporary boom in consumption but a far smaller increase in output. Our results suggest substantial value in empirical research uncovering the distribution of marginal propensities to work in the population.

Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1N48Kthat involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1N48K, followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure–activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1N48Kmutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.

A versatile method for orchestrating the formation of side chain-to-tail cyclic peptides from ribosomally derived polypeptide precursors is reported. Upon ribosomal incorporation into intein-containing precursor proteins, designer unnatural amino acids bearing side chain 1,3- or 1,2-aminothiol functionalities are able to promote the cyclization of a downstream target peptide sequence via a C-terminal ligation/ring contraction mechanism. Using this approach, peptide macrocycles of variable size and composition could be generated in a pH-triggered manner in vitroor directly in living bacterial cells. This methodology furnishes a new platform for the creation and screening of genetically encoded libraries of conformationally constrained peptides. This strategy was applied to identify and isolate a low-micromolar streptavidin binder (KD= 1.1 μM) from a library of cyclic peptides produced in Escherichia coli, thereby illustrating its potential toward aiding the discovery of functional peptide macrocycles.

Several letters tot the editor are presented in reponse to articles in the previous issues which include one about the Superbike race, one about Ducati 1299 Panigale motorcycle launch test, and one about Spanish motorcycle company Derbi.

Several letters to the editor are presented in response to articles published in previous issues including a letter on travelling to the opening round of the World SuperBike (WSBK) championship at Phillip Island, an article on the flouro vest mandatory for Victorian learner riders and rider Troy Bayliss's race in the opening round of the 2015 World Superbike Championship.

SunGard AvantGard conducted a Market Insight study to gain insight into how companies are implementing and managing Shared Service Centres (SSCs). Centralising payment functions can improve visibility of cash balances while reducing the fees and infrastructure costs needed to support each individual local group, while allowing subsidiaries to have independence on a specified range of operations and processes through supported workflows and controls that are standardised at the company level. The SunGard Insight Study uncovered some concerns when comparing the perceptions of the SSC service levels and capabilities from within the SSC to the businesses, with many business units unhappy with performance while the SSC expressed higher levels of satisfaction. Drivers to create an SSC have shifted – although companies still look toward cost savings and productivity gains, more strategic drivers like increased standardisation have grown in importance. Also indicative of the heightened strategic importance of the SSC is the growing trend toward creating a strategic shared service job title such as global process manager to oversee the creation and implementation of the SSC. This paper reviews the results and potential implications of the study results.

Postural tachycardia syndrome (PoTS) is a poorly understood but important cause of orthostatic intolerance resulting from cardiovascular autonomic dysfunction. PoTS is distinct from the syndromes of autonomic failure usually associated with orthostatic hypotension, such as pure autonomic failure and multiple system atrophy. Individuals affected by PoTS are mainly young (aged between 15 years and 40 years) and predominantly female. The symptoms—palpitations, dizziness and occasionally syncope—mainly occur when the patient is standing upright, and are often relieved by sitting or lying flat. Common stimuli in daily life, such as modest exertion, food ingestion and heat, are now recognized to be capable of exacerbating the symptoms. Onset of the syndrome can be linked to infection, trauma, surgery or stress. PoTS can be associated with various other disorders; in particular, joint hypermobility syndrome (also known as Ehlers–Danlos syndrome hypermobility type, formerly termed Ehlers–Danlos syndrome type III). This Review describes the characteristics and neuroepidemiology of PoTS, and outlines possible pathophysiological mechanisms of this syndrome, as well as current and investigational treatments.

A series of high-affinity GABAA agonists with good oral bioavailability in rat and dog and functional selectivity for the GABAAα2 and -α3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.

Biosynthetic cascades represent a transformative technology that is revolutionizing the way chemists approach synthetic challenges and have set new standards for what constitutes green and sustainable chemistry. Early work in this field was focused on the production of natural products and therefore relied on the use of naturally occurring enzymes. Although natural products continue to be a source of useful chemical matter, synthetic derivatives of natural products or wholly synthetic molecules are dominant drivers of pharmaceutical and fine-chemical demand. Consequently, natural enzymes are insufficient or ineffective as catalysts and often require extensive protein engineering — to alter a range of properties — before they can be useful. Here, we review the extensive progress achieved in protein engineering as applied to syntheses containing multiple concurrent or sequential enzyme-catalyzed synthetic steps both in vivoand in vitrofrom 2018 to 2020.

Attractive economics and short development timelines have often been cited as reasons for using bacteria to express eukaryotic proteins on a commercial scale. Nevertheless, routine techniques for bacterial expression of heterologous proteins are beset by a variety of technical and legal difficulties. In particular, the use of plasmids to express foreign proteins, popular promoter systems, protein fusion partners, and histidine tags and the recovery of proteins from inclusion bodies are affected by a host of issued patents. Chromosomally encoded leaderless fusions (CELF) offer a variety of technical and legal advantages over existing bacterial expression systems. In this study, we show that CELF can be used to produce a wide assortment of eukaryotic proteins at 10-liter fermentation scale.

Joint hypermobility is a common connective tissue variant. Surprisingly, people with this disorder are especially vulnerable to anxiety. Recent imaging studies suggest that non-anxious individuals with hypermobility express structural and functional differences in emotional brain regions. Autonomic dysregulation, typically postural tachycardia, is often found. Our aim was to test the hypothesis that joint hypermobility increases the expression of anxiety through aberrant central autonomic control.

Several letters to the editor are presented in response to articles in previous issues including the boxing match between Oscar De La Hoya and Floyd Mayweather, the negative comments of Rory Steele to Teddy Atlas in the July 2008 issue and William Dettloff's interview with Larry Holmes in the June 2008 issue.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.