Enhancing public health response: a framework for topics and sentiment analysis of COVID-19 in the UK using Twitter and the embedded topic model.

Introduction: To protect citizens during the COVID-19 pandemic unprecedented public health restrictions were imposed on everyday life in the UK and around the world. In emergencies like COVID-19, it is crucial for policymakers to be able to gauge the public response and sentiment to such measures in almost real-time and establish best practices for the use of social media for emergency response. Methods: In this study, we explored Twitter as a data source for assessing public reaction to the pandemic. We conducted an analysis of sentiment by topic using 25 million UK tweets, collected from 26th May 2020 to 8th March 2021. We combined an innovative combination of sentiment analysis via a recurrent neural network and topic clustering through an embedded topic model. Results: The results demonstrated interpretable per-topic sentiment signals across time and geography in the UK that could be tied to specific public health and policy events during the pandemic. Unique to this investigation is the juxtaposition of derived sentiment trends against behavioral surveys conducted by the UK Office for National Statistics, providing a robust gauge of the public mood concurrent with policy announcements. Discussion: While much of the existing research focused on specific questions or new techniques, we developed a comprehensive framework for the assessment of public response by policymakers for COVID-19 and generalizable for future emergencies. The emergent methodology not only elucidates the public's stance on COVID-19 policies but also establishes a generalizable framework for public policymakers to monitor and assess the buy-in and acceptance of their policies almost in real-time. Further, the proposed approach is generalizable as a tool for policymakers and could be applied to further subjects of political and public interest.

Molecular mechanisms in Alzheimer's disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules.

The amyloid cascade is the most frequently accepted hypothesis of Alzheimer's Disease (AD). According to this hypothesis, the formation of plaques precedes the appearance of fibrillary tangles. Therapeutic agents able to inhibit the formation of plaques are therefore considered as potential disease-modifying treatments (DMT) that could prevent or limit the progression of AD. Plaques are deposits formed by aggregates of amyloid-ß (Aß)-peptides. These peptides are metabolites of amyloid precursor protein (APP) first mediated by two enzymes: ß-secretase 1 (BACE1) and γ-secretase. Molecular identification of these two enzymes has stimulated the development of their inhibitors. The clinical testing of these two classes of molecules has not been successful to date. The oligomerization of Aß-peptides into plaques is now targeted by immunological approaches such as antibodies and vaccines. Structural consideration of the Aß-peptide sequence led to the launch of the antibody Aducanumab. Several other antibodies are in late clinical phases. Progress in the understanding of the effects of N-truncated Aß-peptides such as pE3-42, formed by the action of recently well characterized enzymes (aminopeptidase A, dipeptidylpeptidase-4 and glutaminyl cyclase) suggests that oligomerization can be limited either by enzyme inhibitors or antibody approaches. This strategy associating two structurally interconnected mechanisms is focused in this review.

In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition.

Leishmaniasis constitutes a severe public health problem, with an estimated prevalence of 12 million cases. This potentially fatal disease has a worldwide distribution and in 2012, the fatal Visceral Leishmaniasis (VL) was declared as new emerging disease in Europe, mainly due to global warming, with expected important public health impact. The available treatments are toxic, costly or lead to parasite resistance, thus there is an urgent need for new drugs with new mechanism of action. Previously, we reported the discovery of CTN1122, a potent imidazo[1,2-a]pyrazine-based antileishmanial hit compound targeting L-CK1.2 at low micromolar ranges. Here, we described structurally related, safe and selective compounds endowed with antiparasitic properties, better than miltefosine, the reference therapy by oral route. L-CK1.2 homology model gave the first structural explanations of the role of 4-pyridyl (CTN1122) and 2-aminopyrimidin-4-yl (compound 21) moieties, at the position 3 of the central core, in the low micromolar to nanomolar L-CK1.2 inhibition, whereas N-methylpyrazole derivative 11 remained inactive against the parasite kinase.

Synthesis and Antimalarial Activity of 1,4-Disubstituted Piperidine Derivatives.

In order to prepare, at low cost, new compounds active against Plasmodium falciparum, and with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine derivatives from 4-aminopiperidine derivatives 6. The resulting compound library has been evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. The most active molecules-compounds 12d (13.64 nM (3D7)), 13b (4.19 nM (3D7) and 13.30 nM (W2)), and 12a (11.6 nM (W2))-were comparable to chloroquine (22.38 nM (3D7) and 134.12 nM (W2)).

GDP-Mannose Pyrophosphorylase: A Biologically Validated Target for Drug Development Against Leishmaniasis.

Leishmaniases are neglected tropical diseases that threaten about 350 million people in 98 countries around the world. In order to find new antileishmanial drugs, an original approach consists in reducing the pathogenic effect of the parasite by impairing the glycoconjugate biosynthesis, necessary for parasite recognition and internalization by the macrophage. Some proteins appear to be critical in this way, and one of them, the GDP-Mannose Pyrophosphorylase (GDP-MP), is an attractive target for the design of specific inhibitors as it is essential for Leishmania survival and it presents significant differences with the host counterpart. Two GDP-MP inhibitors, compounds A and B, have been identified in two distinct studies by high throughput screening and by a rational approach based on molecular modeling, respectively. Compound B was found to be the most promising as it exhibited specific competitive inhibition of leishmanial GDP-MP and antileishmanial activities at the micromolar range with interesting selectivity indexes, as opposed to compound A. Therefore, compound B can be used as a pharmacological tool for the development of new specific antileishmanial drugs.

In Silico Target Druggability Assessment: From Structural to Systemic Approaches.

This chapter will focus on today's in silico direct and indirect approaches to assess therapeutic target druggability. The direct approach tries to infer from the 3D structure the capacity of the target protein to bind small molecule in order to modulate its biological function. Algorithms to recognize and characterize the quality of the ligand interaction sites whether within buried protein cavities or within large protein-protein interface will be reviewed in the first part of the paper. In the case a ligand-binding site is already identified, indirect aspects of target druggability can be assessed. These indirect approaches focus first on target promiscuity and the potential difficulties in developing specific drugs. It is based on large-scale comparison of protein-binding sites. The second aspect concerns the capacity of the target to induce resistant pathway once it is inhibited or activated by a drug. The emergence of drug-resistant pathways can be assessed through systemic analysis of biological networks implementing metabolism and/or cell regulation signaling.

In Silico Drug-Target Profiling.

Pharmacological science is trying to establish the link between chemicals, targets, and disease-related phenotypes. A plethora of chemical proteomics and structural data have been generated, thanks to the target-based approach that has dominated drug discovery at the turn of the century. There is an invaluable source of information for in silico target profiling. Prediction is based on the principle of chemical similarity (similar drugs bind similar targets) or on first principles from the biophysics of molecular interactions. In the first case, compound comparison is made through ligand-based chemical similarity search or through classifier-based machine learning approach. The 3D techniques are based on 3D structural descriptors or energy-based scoring scheme to infer a binding affinity of a compound with its putative target. More recently, a new approach based on compound set metric has been proposed in which a query compound is compared with a whole of compounds associated with a target or a family of targets. This chapter reviews the different techniques of in silico target profiling and their main applications such as inference of unwanted targets, drug repurposing, or compound prioritization after phenotypic-based screening campaigns.

Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads.

Leishmaniases are an ensemble of diseases caused by the protozoan parasite of the genus Leishmania. Current antileishmanial treatments are limited and present main issues of toxicity and drug resistance emergence. Therefore, the generation of new inhibitors specifically directed against a leishmanial target is an attractive strategy to expand the chemotherapeutic arsenal. GDP-Mannose Pyrophosphorylase (GDP-MP) is a prominent therapeutic target involved in host-parasite recognition which has been described to be essential for parasite survival. In this work, we produced and purified GDP-MPs from L. mexicana (LmGDP-MP), L. donovani (LdGDP-MP), and human (hGDP-MP), and compared their enzymatic properties. From a rationale design of 100 potential inhibitors, four compounds were identified having a promising and specific inhibitory effect on parasite GDP-MP and antileishmanial activities, one of them exhibits a competitive inhibition on LdGDP-MP and belongs to the 2-substituted quinoline series.

Simple and efficient synthesis of 5'-aryl-5'-deoxyguanosine analogs by azide-alkyne click reaction and their antileishmanial activities.

A series of non-hydrolysable 5'-aryl substituted GDP analogs has been synthesized by reacting 5'-azido-5'-deoxyguanosine with different aryl- and benzyloxy-alkynes. Cu(I) nanoparticles in water were found to be the most efficient catalyst, producing the desired 5'-arylguanosines with good yields. The synthesized compounds were screened for in vitro antileishmanial activity against Leishmania donovani axenic amastigotes and intramacrophage amastigotes stages. The 4-(3-nitrobenzyl)-1,2,3-triazole 5'-substituted guanosine analog was found to be the most active in the series with an IC50 of 8.6 µM on axenic amastigotes. Despite a rather low in vitro antileishmanial activity on the intramacrophage amastigotes, the absence of cytotoxicity on RAW 264.7 macrophages justifies further pharmacomodulations making this antileishmanial series promising.

Comparative study of structural models of Leishmania donovani and human GDP-mannose pyrophosphorylases.

Leishmania is the parasite responsible for the neglected disease leishmaniasis. Its virulence and survival require biosynthesis of glycoconjugates, whose guanosine diphospho-d-mannose pyrophosphorylase (GDP-MP) is a key player. However, experimentally resolved structures of this enzyme are still lacking. We herein propose structural models of the GDP-MP from human and Leishmania donovani. Based on a multiple sequences alignment, the models were built with MODELLER and then carefully refined with all atom molecular dynamics simulations in explicit solvent. Their quality was evaluated against several standard criteria, including their ability to bind GDP-mannose assessed by redocking calculations. Special attention was given in this study to interactions of the catalytic site residues with the enzyme substrate and competitive inhibitors, opening the perspective of medicinal chemistry developments.

Asymmetric reduction of ß-ketoesters and chiral ß-iminoesters: impact of a α-quaternary stereocenter.

Diastereomeric reduction of nonactivated, hindered ß-keto and chiral ß-iminoesters are described. The influence of a α-stereocontrolled center on the efficiency and stereoselectivity of the reduction was studied. Reaction conditions were optimized to synthesize ß-hydroxy- and ß-aminoesters in good yields. In the case of chiral ß-iminoesters, influence of matched/mismatched diastereomeric pairs has been assessed.

Auditory-tactile speech perception in congenitally blind and sighted adults.

The present study investigated whether manual tactile information from a speaker's face modulates the intelligibility of speech when audio-tactile perception is compared with audio-only perception. Since more elaborated auditory and tactile skills have been reported in the blind, two groups of congenitally blind and sighted adults were compared. Participants performed a forced-choice syllable decision task across three conditions: audio-only and congruent/incongruent audio-tactile conditions. For the auditory modality, the syllables were embedded or not in noise while, for the tactile modality, participants felt in synchrony a mouthed syllable by placing a hand on the face of a talker. In the absence of acoustic noise, syllables were almost perfectly recognized in all conditions. On the contrary, with syllables embedded with acoustic noise, more correct responses were reported in case of congruent mouthing compared to no mouthing, and in case of no mouthing compared to incongruent mouthing. Interestingly, no perceptual differences were observed between blind and sighted adults. These findings demonstrate that manual tactile information relevant to recovering speech gestures modulates auditory speech perception in case of degraded acoustic information and that audio-tactile interactions occur similarly in blind and sighted untrained listeners.

Are eyebrow movements linked to voice variations and turn-taking in dialogue? An experimental investigation.

Following our work on the relationship between eyebrow movements and the fundamental frequency of the voice, this article presents the results of a study on this phenomenon, and also on the temporal location of rapid eyebrow movements with respect to speaking turns during dialogue. We used an automatic movement-acquisition system coupled with the simultaneous, synchronized recording of the vocal production. This procedure permits an objective analysis of eyebrow movements in relation to the vocal production. The data obtained showed that the speakers' rapid eyebrow movements were associated both with turn-taking (occurring right before or right after speaking turn onset) and with changes in the fundamental frequency. These findings suggest that rapid eyebrow movements are mainly linked to motivation and the intention to communicate, and may also act as a focus marker in speech.

Asymmetric Michael reaction involving chiral imines/secondary enamines: stereocontrolled synthesis of 2,2-disubstituted tetrahydrothiophen-3-ones.

[reaction: see text] The asymmetric Michael reaction involving a chiral imine derived from 2-methyltetrahydrothiophenone-3-one and enantiopure (R)-1-phenylethylamine with a variety of electrophilic alkenes furnished 2,2-disubstituted tetrahydrothiophenone-3-ones with good yields and excellent stereoselectivity.

Regio- and diastereocontrolled preparative oxidation of methyloctalones by a biomimetic porphyrin catalyst.

Both enantiomers of methyloctalone were oxidized by a biomimetic manganese/porphyrin/imidazole catalytic system in order to obtain sufficient amounts of various model metabolites. The double bond proved to be less sensitive than the ring methylenes. Hydroxylation occurred mainly in the allylic position (position 8) and also at positions 7 and 6. In position 8, two diastereomers were obtained while in positions 7 and 6 the reaction was diastereospecific. In the case of position 8 only the oxidation yielded a keto compound. The efficiency of this method for the preparation of functionalized chiral synthons was better than it was for biological pathways.

Stereochemical Aspects in the Asymmetric Michael Addition of Chiral Imines to Substituted Electrophilic Alkenes.

The Michael-type addition of chiral imines, derived from racemic alpha-substituted cyclanones and optically active 1-phenylethylamine, to electrophilic alkenes, in neutral conditions, constitutes one of the most efficient methods for the stereocontrolled construction of quaternary carbon centers. In order to create an additional stereogenic center at the alpha- or beta-position to the quaternary one, the behavior of a variety of alpha- and beta-substituted alkenyl acceptors was examined. In general, these additions are highly regioselective, the alkylation taking place predominantly, if not exclusively, at the more substituted alpha-side of the imine function; however, in some cases (electrophilic alkenes 28 and 49), significant amounts (10-15%) of regioisomeric adducts were obtained. With the exception of methyl propiolate 52, a remarkable control of the absolute configuration of the adducts were always observed with these Michael acceptors. According to the general rule we have previously proposed, the alkylation process takes place preferentially on the less hindered pi-face of the more substituted secondary enamine, in tautomeric equilibrium with the starting imine. An excellent diastereocontrol was always obtained by using the present alpha- and beta-substituted alkenes. These stereochemical outcomes can be interpreted by invoking that the reaction proceeds through a compact approach of the reactants, the hydrogen atom at the nitrogen center of the enamine being transferred to the alpha-vinylic carbon atom of the acceptor, concertedly with the creation of the C-C bond. In this respect the "endo-approach" 58, in which the electron-withdrawing group of the acceptor faced to the nitrogen atom of the enamine (case of acceptors 10, methyl methacrylate, 24, 28, 43, 47, and 49) largely prevails over the "exo-approach" 59 (case of acceptor 38). This predominant "endo-preference" can be reasonably interpreted in terms of a cooperative effect between steric and stereoelectronic factors.