Combating COVID-19 with charisma: Evidence on governor speeches in the United States.

Using field and laboratory data, we show that leader charisma can affect COVID-related mitigating behaviors. We coded a panel of U.S. governor speeches for charisma signaling using a deep neural network algorithm. The model explains variation in stay-at-home behavior of citizens based on their smart phone data movements, showing a robust effect of charisma signaling: stay-at-home behavior increased irrespective of state-level citizen political ideology or governor party allegiance. Republican governors with a particularly high charisma signaling score impacted the outcome more relative to Democratic governors in comparable conditions. Our results also suggest that one standard deviation higher charisma signaling in governor speeches could potentially have saved 5,350 lives during the study period (02/28/2020-05/14/2020). Next, in an incentivized laboratory experiment we found that politically conservative individuals are particularly prone to believe that their co-citizens will follow governor appeals to distance or stay at home when exposed to a speech that is high in charisma; these beliefs in turn drive their preference to engage in those behaviors. These results suggest that political leaders should consider additional "soft-power" levers like charisma-which can be learned-to complement policy interventions for pandemics or other public heath crises, especially with certain populations who may need a "nudge."

A surrogate gradient spiking baseline for speech command recognition.

Artificial neural networks (ANNs) are the basis of recent advances in artificial intelligence (AI); they typically use real valued neuron responses. By contrast, biological neurons are known to operate using spike trains. In principle, spiking neural networks (SNNs) may have a greater representational capability than ANNs, especially for time series such as speech; however their adoption has been held back by both a lack of stable training algorithms and a lack of compatible baselines. We begin with a fairly thorough review of literature around the conjunction of ANNs and SNNs. Focusing on surrogate gradient approaches, we proceed to define a simple but relevant evaluation based on recent speech command tasks. After evaluating a representative selection of architectures, we show that a combination of adaptation, recurrence and surrogate gradients can yield light spiking architectures that are not only able to compete with ANN solutions, but also retain a high degree of compatibility with them in modern deep learning frameworks. We conclude tangibly that SNNs are appropriate for future research in AI, in particular for speech processing applications, and more speculatively that they may also assist in inference about biological function.

Asymmetric Synthesis of Lysergic Acid via an Intramolecular (3+2) Dipolar Cycloaddition/Ring-Expansion Sequence.

An effective, potentially scalable asymmetric synthesis of lysergic acid, a core component of the ergot alkaloid family, is reported. The synthesis features the strategic combination of an intramolecular azomethine ylide cycloaddition and Cossy-Charette ring expansion to assemble the target's C- and D-rings. Simple functional group manipulation produced a compound that had been converted to lysergic acid in four steps, thus constituting a formal synthesis of the natural product. The strategy may be used to prepare novel ergot analogues that include unnatural antipodes and may be more amenable to analogue generation relative to prior approaches.

A Bayesian Approach to Recurrence in Neural Networks.

We begin by reiterating that common neural network activation functions have simple Bayesian origins. In this spirit, we go on to show that Bayes's theorem also implies a simple recurrence relation; this leads to a Bayesian recurrent unit with a prescribed feedback formulation. We show that introduction of a context indicator leads to a variable feedback that is similar to the forget mechanism in conventional recurrent units. A similar approach leads to a probabilistic input gate. The Bayesian formulation leads naturally to the two pass algorithm of the Kalman smoother or forward-backward algorithm, meaning that inference naturally depends upon future inputs as well as past ones. Experiments on speech recognition confirm that the resulting architecture can perform as well as a bidirectional recurrent network with the same number of parameters as a unidirectional one. Further, when configured explicitly bidirectionally, the architecture can exceed the performance of a conventional bidirectional recurrence.

Site-Specific Synthesis of Cysteine-Bridged Glycoproteins via Expressed Protein Glycoligation.

Site-specific glycosylation of a functional recombinant protein thioester is reported. The thioester functionalized protein sfGFP-Y151ThioD, prepared by genetic code expansion, underwent native chemical ligation with the cysteine-conjugated glycans H-Cys-NH-GlcNAc and H-Cys-NH-(GlcNAc)2(Man)3 to give the corresponding cysteine-bridged glycoproteins. The intact glycoproteins, which retained their fluorescence, were characterized by top-down mass spectrometry and gel electrophoresis. The bridging cysteine provided a convenient handle for affinity chromatography purification of the glycoproteins via a removable biotin tag. Given the influence that specific glycoforms can have on a protein's function, the ability to attach a homogeneous glycan to an intact protein in a functional group controlled yet sequon-independent manner could find widespread application. These preliminary results set the stage for development of the expressed protein glycoligation (EPG) concept.

Design and Synthesis of Pyrrolidine-based Fragments That Sample Three-dimensional Molecular Space.

Fragment-based drug discovery (FBDD) is a well-established technology for lead compound generation in drug discovery. As this technology has evolved, the design of fragments for screening has also evolved to engender not just an understanding of the role of modulating the physicochemical properties of fragments (Rule of Three, Ro3) but also the importance and implications of incorporating shape and, in particular, 3D characteristics into fragments. Herein, we describe the design and synthesis of pyrrolidine-based fragments with good fragment-like (Ro3) physicochemical properties that effectively sample three-dimensional molecular space.

The Impact of Superfast Broadband, Tailored Booklets for Households, and Discussions With General Practitioners on Personal Electronic Health Readiness: Cluster Factorial Quasi-Randomized Control Trial.

BACKGROUND: Electronic health (eHealth) may improve health outcomes, but many people remain digitally excluded. Personal readiness to use the internet for health may be limited by lack of internet infrastructure, personal skills, social support, service provision, and cost. The impact of interventions to reduce these barriers is unknown. From 2011, the British Government supported the implementation of "superfast" broadband (Superfast) across the rural county of Cornwall. This provided the opportunity to assess the impact of interventions at regional, practice, and household levels. OBJECTIVE: This study aimed to assess the impact of 3 interventions on personal eHealth readiness: (1) regional-level implementation of Superfast, (2) practice-level discussions with general practitioners to encourage greater internet use in health service provision, and (3) household-level tailored booklets providing information to help improve personal skills in eHealth. METHODS: This was a cluster quasi-randomized factorial controlled trial. Implementation of Superfast was monitored, and postcodes were classified as having early or late availability. An algorithm selected 78 from 16,385 eligible postcodes to minimize the possibility of overlap between general practices and ensure a balance of urban and rural areas; 1388 households were randomly selected from the 78 postcodes and allocated to the 8 (2 × 2 × 2) study arms. A modified version of the Personal eHealth Readiness Questionnaire was used to compare scores (0 to 10) and 4 components (personal, provision, support, and economic) from baseline (August 2013) to the 18-month follow-up between the 8 arms, to assess the impact of interventions. We compared SDs of scores to assess changes in eHealth inequalities. RESULTS: eHealth readiness improved over 18 months from 4.36 out of 10 to 4.59 out of 10 (t235=4.18; P<.001; CI=0.13 to 0.35), resulting from increases in personal and provision components of the score (t255=3.191; P=.002 and t258=3.410; P=.001). However, there were no significant differences between the 3 interventions, either singly or in combination using intention-to-treat analysis. The proportion of internet users did not significantly increase (79.2%, 205/259 to 81.5%, 211/259) and mobile use was significantly greater (50.5%, 101/199 to 64.8%, 129/199). There was no change in eHealth inequality. CONCLUSIONS: People in Cornwall became more ready to adopt eHealth services, increasing both their personal ability to use eHealth and their methods of access. The implementation of Superfast may have contributed to this; we are certain that our other 2 interventions did not. This increased eHealth readiness did not cause a larger digital divide. The study illustrates the complexity of conducting a randomized controlled trial to assess the impact of interventions at regional, practice, and household levels. Our method may be of use to others. TRIAL REGISTRATION: ClinicalTrials.gov NCT00102401; https://clinicaltrials.gov/ct2/show/NCT02355808 (Archived by WebCite at http://www.webcitation.org/75oEz0E1x).

Site-Specific Incorporation of a Thioester Containing Amino Acid into Proteins.

Here, we report the site-specific incorporation of a thioester containing noncanonical amino acid (ncAA) into recombinantly expressed proteins. Specifically, we genetically encoded a thioester-activated aspartic acid (ThioD) in bacteria in good yield and with high fidelity using an orthogonal nonsense suppressor tRNA/aminoacyl-tRNA synthetase (aaRS) pair. To demonstrate the utility of ThioD, we used native chemical ligation to label green fluorescent protein with a fluorophore in good yield.

A concise [C+NC+CC] coupling-enabled synthesis of kaitocephalin.

A 15-step synthesis of the iGluR antagonist kaitocephalin from aspartic acid is reported. The linchpin pyrrolidine ring of the target molecule is efficiently assembled with in a single operation via an asymmetric [C+NC+CC] reaction.

Catalytic asymmetric exo-selective [C+NC+CC] reaction.

A catalytic asymmetric version of the exo-selective [C+NC+CC] reaction is reported. This multicomponent reaction utilizes a readily prepared achiral glycyl sultam as the "NC" component and commercially available catalyst components. The method can be applied to a variety of aldehydes ("C" component) and activated alkenes ("CC" component) to provide substituted pyrrolidines in good yields and high enantioselectivities. Of particular note is the ability to employ labile enolizable aldehydes (e.g., acetaldehyde and propionaldehyde) in this reaction.

Rapid formation of N-Glycopeptides via Cu(II)-promoted glycosylative ligation.

Herein is described the chemoselective Cu(II)-HOBt promoted chemical ligation of glycosylamines and peptide thioacids to give N-glycosylated peptides. The method is distinguished from other chemical approaches to peptide N-glycosylation in that (1) it can be employed in the presence of unprotected N-terminal and Lys side chain amines; (2) it is remarkably fast, going to completion in under 30 min; and (3) it produces glycopeptides without attendant aspartimide formation.

The structure of (-)-kaitocephalin bound to the ligand binding domain of the (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/glutamate receptor, GluA2.

Glutamate receptors mediate the majority of excitatory synaptic transmission in the central nervous system, and excessive stimulation of these receptors is involved in a variety of neurological disorders and neuronal damage from stroke. The development of new subtype-specific antagonists would be of considerable therapeutic interest. Natural products can provide important new lead compounds for drug discovery. The only natural product known to inhibit glutamate receptors competitively is (-)-kaitocephalin, which was isolated from the fungus Eupenicillium shearii and found to protect CNS neurons from excitotoxicity. Previous work has shown that it is a potent antagonist of some subtypes of glutamate receptors (AMPA and NMDA, but not kainate). The structure of kaitocephalin bound to the ligand binding domain of the AMPA receptor subtype, GluA2, is reported here. The structure suggests how kaitocephalin can be used as a scaffold to develop more selective and high affinity antagonists for glutamate receptors.

[C+NC+CC] coupling-enabled synthesis of influenza neuramidase inhibitor A-315675.

An efficient synthesis of the neuramidase inhibitor A-315675 is reported. The fully functionalized pyrrolidine core of the target is assembled in one pot via an exo-selective asymmetric [C+NC+CC] coupling reaction.

Aziridine-mediated ligation and site-specific modification of unprotected peptides.

A synthesis of aziridine-containing peptides via the Cu(II)-promoted coupling of unprotected peptide thioacids and N-H aziridine-2-carbonyl peptides is reported. The unique reactivity of the resulting N-acylated aziridine-2-carbonyl peptides facilitates their subsequent regioselective and stereoselective nucleophilic ring-opening to give unprotected peptides that are specifically modified at the ligation site. The aziridine-mediated peptide ligation concept is exemplified using H(2)O as the nucleophile, producing a Xaa-Thr linkage (where Xaa can be an epimerizable and hindered amino acid). The overall process is compatible with a variety of unprotected amino acid functionality, most notably the N-terminal and Lys side chain amines.

Asymmetric [C + NC + CC] coupling entry to the naphthyridinomycin natural product family: formal total synthesis of cyanocycline A and bioxalomycin ß2.

A full account of our [C + NC + CC] coupling approach to the naphthyridinomycin family of natural products is presented, culminating in formal total syntheses of cyanocycline A and bioxalomycin ß2. The key complexity-building reaction in the synthesis involves the Ag(I)-catalyzed endo-selective [C + NC + CC] coupling of aldehyde 7, (S)-glycyl sultam 8, and methyl acrylate (9) to provide the highly functionalized pyrrolidine 6, which was carried forward to an advanced intermediate (compound 33) in Fukuyama's synthesis of cyanocycline A. Since cyanocycline A has been converted to bioxalomycin ß2, this constitutes a formal synthesis of the latter natural product as well. The multicomponent reaction-based strategy reduces the number of steps previously needed to assemble these complex molecular targets by one-third. This work highlights the utility of the asymmetric [C + NC + CC] coupling reaction in the context of a complex pyrrolidine-containing target and provides an illustrative guide for its application to other synthesis problems. The synthesis also fueled collaborative biological and biochemical research that identified a unique small molecule inhibitor of cell migration (compound 30).

Hospital--school liaison: perspectives of health and education professionals supporting children with renal transplants.

This article explores collaboration between health and education staff as a key aspect of educational provision for children with chronic medical conditions, drawing upon material from interviews with eight health professionals (paediatric nephrologists and specialist renal nurses) and 11 mainstream schoolteachers involved in the care and schooling of children with renal transplants. Notwithstanding the apparent existence of good practice, a complex interplay of attitudinal, institutional and wider political and economic factors is identified that is likely to undermine the effectiveness of collaboration between health and education professionals. The importance of hospital-school liaison - that is, of a proactive, preventative and hence systematic and strategic nature - is highlighted. Such findings have a particular relevance for policy and practice in the context of the current Every Child Matters agenda, and are likely to have wider applicability to the education of chronically-ill children at large.

Analogs of tetrahydroisoquinoline natural products that inhibit cell migration and target galectin-3 outside of its carbohydrate-binding site.

Cell migration is central to a number of normal and disease processes. Small organic molecules that inhibit cell migration have potential as both research probes and therapeutic agents. We have identified two tetrahydroisoquinoline natural product analogs with antimigratory activities on Madin-Darby canine kidney epithelial cells: a semisynthetic derivative of quinocarmycin (also known as quinocarcin), DX-52-1, and a more complex synthetic molecule, HUK-921, related to the naphthyridinomycin family. It has been assumed that the cellular effects of reactive tetrahydroisoquinolines result from the alkylation of DNA. We have reported previously that the primary target of DX-52-1 relevant to cell migration appears to be the membrane-cytoskeleton linker protein radixin. Here we extend the analysis of the protein targets of DX-52-1, reporting that the multifunctional carbohydrate-binding protein galectin-3 is a secondary target of DX-52-1 that may also be relevant to the antimigratory effects of both DX-52-1 and HUK-921. All known inhibitors of galectin-3 target its beta-galactoside-binding site in the carbohydrate recognition domain. However, we found that DX-52-1 and HUK-921 bind galectin-3 outside of its beta-galactoside-binding site. Intriguingly HUK-921, although a less potent inhibitor of cell migration than DX-52-1, had far greater selectivity for galectin-3 over radixin, exhibiting little binding to radixin, both in vitro and in cells. Overexpression of galectin-3 in cells led to a dramatic increase in cell adhesion on different extracellular matrix substrata as well as changes in cell-cell adhesion and cell motility. Galectin-3-overexpressing cells had greatly reduced sensitivity to DX-52-1 and HUK-921, and these compounds caused a change in localization of the overexpressed galectin-3 and reversion of the cells to a more normal morphology. The converse manipulation, RNA interference-based silencing of galectin-3 expression, resulted in reduced cell-matrix adhesion and cell migration. In aggregate, the data suggest that DX-52-1 and HUK-921 inhibit a carbohydrate binding-independent function of galectin-3 that is involved in cell migration.

New zinc(II)-based catalyst for asymmetric azomethine ylide cycloaddition reactions.

[reaction: see text] A new chiral aziridino alcohol ligand for zinc(II)-catalyzed azomethine ylide cycloadditions is described. In the presence of this catalyst, N-arylidene glycine methyl esters react with a variety of dipolarophiles to give substituted pyrrolidines in very good to excellent chemical yields and up to 95% ee. The absolute sense of asymmetric induction appears to be dipolarophile-dependent.

Asymmetric multicomponent [C+NC+CC] synthesis of highly functionalized pyrrolidines catalyzed by silver(I).

[reaction: see text] Highly functionalized pyrrolidines are obtained in a single chemical step via a mild, efficient, and selective Ag(I)-catalyzed asymmetric [C+NC+CC] coupling process. Oppolzer's camphorsultam enables the desired reaction cascade and provides a reliable means to control the developing stereochemistry and purify the products. This three-component reaction provides unprecedented access to structurally diverse pyrrolidines for both target- and diversity-oriented syntheses.