Temperature dependent viral tropism: understanding viral seasonality and pathogenicity as applied to the avoidance and treatment of endemic viral respiratory illnesses.

This review seeks to explain three features of viral respiratory illnesses that have perplexed generations of virologists: (1) the seasonal timing of respiratory illness and the rapid response of outbreaks to weather, specifically temperature; (2) the common viruses causing respiratory illness worldwide, including year-round disease in the Tropics; (3) the rapid arrival and termination of epidemics caused by influenza and other viruses. The inadequacy of the popular explanations of seasonality is discussed, and a simple hypothesis is proposed, called temperature dependent viral tropism (TDVT), that is compatible with the above features of respiratory illness. TDVT notes that viruses can spread more effectively if they moderate their pathogenicity (thereby maintaining host mobility) and suggests that endemic respiratory viruses accomplish this by developing thermal sensitivity within a range that supports organ-specific viral tropism within the human body, whereby they replicate most rapidly at temperatures below body temperature. This can confine them to the upper respiratory tract and allow them to avoid infecting the lungs, heart, gut etc. Biochemical and tissue-culture studies show that 'wild' respiratory viruses show such natural thermal sensitivity. The typical early autumn surge of colds and the occurrence of respiratory illness in the Tropics year-round at intermediate levels are explained by the tendency for strains to adapt their thermal sensitivity to their local climate and season. TDVT has important practical implications for preventing and treating respiratory illness including Covid-19. It is testable with many options for experiments to increase our understanding of viral seasonality and pathogenicity.

A High-Affinity "Synthavidin" Receptor for Squaraine Dyes.

Strong-binding host-guest pairings in aqueous media have potential as "supramolecular glues" in biomedical techniques, complementing the widely-used (strept)avidin-biotin combination. We have previously found that squaraine dyes are bound very strongly by tetralactam macrocycles possessing anthracenyl units as cavity walls. Here we show that replacing the anthracenes with pentacyclic 5,7,12,14-tetrahydro-5,7,12,14-tetraoxapentacene (TOP) units generates receptors which bind squaraines with increased affinities (around Ka =1010  m-1 ) and improved selectivities. Binding can be followed through changes to squaraine fluorescence and absorbance. The TOP units are easy to prepare and potentially variable, while the TOP-based receptor shows improved photostability, both in itself and in complex with squaraines. The results suggest that this system could prove valuable in the further development of practical "synthavidin" chemistry.

Acute lower gastrointestinal haemorrhage: outcomes and risk factors for intervention in 949 emergency cases.

PURPOSE: Outcomes of acute lower gastrointestinal haemorrhage (ALGIH) are mostly derived from studies performed in the sub-acute/elective rather than the emergency department (ED) setting. The aims of this study were to determine the incidence and outcomes of patients presenting to a tertiary hospital ED with ALGIH and to identify associated clinicopathological risk factors. METHOD: A retrospective observational cohort study of consecutive patients presenting with ALGIH to a tertiary hospital ED was performed. Primary outcome measures included mortality and hospital (including high dependency [HDU]) admission. Secondary outcome measures included rates of (i) blood transfusion, (ii) radiological/endoscopic investigation(s) and (iii) therapeutic intervention. RESULTS: ALGIH accounted for 949 (512 M, mean age 62.3 years) of 130,262 (0.73%) ED presentations, of which 285 patients (30.1%) were on anti-platelet/coagulant therapy. There were five deaths (0.5%). Hospital admission was required in 498 patients (52.5%), of which 19 (3.8%) required HDU monitoring. Hospital admission was twice as likely in males and four times more likely in patients >75 years old and those taking multiple anti-platelet/coagulant therapy (P < 0.05). Blood product transfusion was required in 172 patients (34.5%), specialist investigations in 230 (46.2%) and therapeutic intervention in 51 (10.2%) (surgery in 24 [4.8%]; endoscopic haemostasis in 20 [4.0%] and angiographic embolisation in 9 [1.8%] patients). CONCLUSION: ALGIH accounts for 1% of all ED presentations, with half requiring hospital admission. Mortality and surgical intervention rates are low and although most patients can be managed supportively, access to interventional radiology/endoscopy is important.

Platform Synthetic Lectins for Divalent Carbohydrate Recognition in Water.

Biomimetic carbohydrate receptors ("synthetic lectins") have potential as agents for biological research and medicine. However, although effective strategies are available for "all-equatorial" carbohydrates (glucose, etc.), the recognition of other types of saccharide under natural (aqueous) conditions is less well developed. Herein we report a new approach based on a pyrene platform with polar arches extending from aryl substituents. The receptors are compatible with axially substituted carbohydrates, and also feature two identical binding sites, thus mimicking the multivalency observed for natural lectins. A variant with negative charges forms 1:2 host/guest complexes with aminosugars, with K1 >3000 m(-1) for axially substituted mannosamine, whereas a positively charged version binds the important α-sialyl unit with K1 ≈1300 m(-1) .

Membrane protein structure determination - the next generation.

The field of Membrane Protein Structural Biology has grown significantly since its first landmark in 1985 with the first three-dimensional atomic resolution structure of a membrane protein. Nearly twenty-six years later, the crystal structure of the beta2 adrenergic receptor in complex with G protein has contributed to another landmark in the field leading to the 2012 Nobel Prize in Chemistry. At present, more than 350 unique membrane protein structures solved by X-ray crystallography (http://blanco.biomol.uci.edu/mpstruc/exp/list, Stephen White Lab at UC Irvine) are available in the Protein Data Bank. The advent of genomics and proteomics initiatives combined with high-throughput technologies, such as automation, miniaturization, integration and third-generation synchrotrons, has enhanced membrane protein structure determination rate. X-ray crystallography is still the only method capable of providing detailed information on how ligands, cofactors, and ions interact with proteins, and is therefore a powerful tool in biochemistry and drug discovery. Yet the growth of membrane protein crystals suitable for X-ray diffraction studies amazingly remains a fine art and a major bottleneck in the field. It is often necessary to apply as many innovative approaches as possible. In this review we draw attention to the latest methods and strategies for the production of suitable crystals for membrane protein structure determination. In addition we also highlight the impact that third-generation synchrotron radiation has made in the field, summarizing the latest strategies used at synchrotron beamlines for screening and data collection from such demanding crystals. This article is part of a Special Issue entitled: Structural and biophysical characterisation of membrane protein-ligand binding.

Label-free identification and characterization of living human primary and secondary tumour cells.

We used three label-free minimally invasive methods to characterize individual cells derived from primary and secondary tumours from the same patient, and of the same type ­ colorectal. Raman spectroscopy distinguished cells by their biochemical 'fingerprint' in a vibrational spectrum with 100% accuracy, and revealed that the primary cell line contains more lipids and alpha-helix proteins, whereas the secondary cell line contains more porphyrins and beta-sheet proteins. Stimulated Raman scattering (SRS) microscopy distinguished cells in chemically-specific images of CH2 bonds which revealed lipid droplets in secondary tumour cells. Atomic force microscopy (AFM) was used to distinguish cells with 80% accuracy by measuring their elasticity ­ secondary tumour cells (SW620) are around 3 times softer than primary ones (SW480). As well as characterizing the physical and biochemical differences between cell lines in vitro, these techniques offer three novel methods which could potentially be used for diagnosis ­ to assign a tumour as primary or secondary.

Multidisciplinary protocol for rapid head computed tomography turnaround time in acute stroke patients.

BACKGROUND: The door-to-computed tomography (CT) head reporting time is an essential step to determining eligibility for thrombolysis in acute stroke patients, but the specific components of the process have not been reported in detail. METHODS: We performed a retrospective cross-sectional analysis of the prospectively collected Get-With-The-Guidelines database in our comprehensive stroke center to evaluate the effect of a structured multidisciplinary protocol on head CT times in acute stroke patients under consideration for thrombolysis. RESULTS: The median CT turnaround time in the first 6-month period was 27 (interquartile range [IQR], 27) and decreased in all subsequent periods after implementation of a formal protocol to 18 (IQR, 12; range, 17-20 minutes; P < .0001 for all pairwise comparisons). The median CT turnaround time was 18 (IQR, 12) versus 20 (IQR, 14) minutes for patients with admission diagnosis of stroke (n = 1123) versus nonstroke (n = 685; P < .0001), respectively. CONCLUSIONS: A structured multidisciplinary protocol for obtaining acute stroke protocol head CT scan was associated with reduced CT turnaround time over the study period. Prospective studies should be done to determine if implementation in other stroke centers confirms the effectiveness of our protocol.

Affinity enhancement by dendritic side chains in synthetic carbohydrate receptors.

Dendritic side chains have been used to modify the binding environment in anthracene-based synthetic carbohydrate receptors. Control of length, charge, and branching enabled the positioning of side-chain carboxylate groups in such a way that they assisted in binding substrates rather than blocking the cavity. Conformational degeneracy in the dendrimers resulted in effective preorganization despite the flexibility of the system. Strong binding was observed to glucosammonium ions in water, with Ka values up to 7000 M(-1) . Affinities for uncharged substrates (glucose and N-acetylglucosamine) were also enhanced, despite competition from solvent and the absence of electrostatic interactions.

Laughter and effective presidential leadership: A case study of Ronald Reagan as the 'great communicator'.

Former United States President Ronald Reagan's use of media and his charismatic connection with viewers earned him the moniker "the great communicator". One aspect of his charisma, the influence of elicited laughter, during a highly critical 5-minute news story by CBS reporter Leslie Stahl during the 1984 US presidential election is examined here. Two experiments examining the effects of audience laughter on perceptions of charismatic leadership are reported. In the first experiment the effects of audience laughter in response to Reagan's comments were investigated. Here, Reagan's perceived warmth as an effective leader significantly diminished when strong laughter is removed, whereas perceptions of competence remained unaffected. The second study carried out on an older cohort replicated and extended the first in a pre-registered design by considering the perception of trait charisma. Here, the presence or absence of audience laughter did not affect judgements of charisma. Additionally, the affective response before, and then after, the presentation of the news story was measured. Emotions associated with a positive appraisal all decreased after being shown the news story while emotions associated negative appraisal all increased. However, only participant anger was significantly increased when audience laughter was removed. Taken together the findings of both studies converge on the fact that subtle changes in media presentation of political leaders can have a significant effect on viewers. The findings show that even after 40 years in office the social psychological effects of presidential charisma can still influence observers.

Winners and losers: Emotional shifts across elections are conveyed by a politician's smile.

The human smile can convey both rewarding and affiliative social intent and thus has significant utility in politics, where the ability to bond with and reassure voters is vital to electoral success. We examine experimental evidence from the 2019 UK general election to investigate the influence of a politician's reward or affiliative smile on voter emotions. It was hypothesised that the winner's affiliative smile would engender positive affect across all partisan groups compared to the winner's reward smile display. Participants from a nationally representative sample were shown campaign footage containing both types of smiles from the leaders of the main competing political parties both before and after the election. Increases in happiness and affinity were revealed across all partisan groups when shown footage of the eventual winner's affiliative smile; at the same time, supporters of losing parties indicated a decrease in negative affect. Affinity has been shown to increase civic engagement. Thus, we conclude that affiliative smiles displayed by leading candidates during the campaign likely acted as a mechanism to align voter behaviour with the dominant political message.

The influence of President Trump's micro-expressions during his COVID-19 national address on viewers' emotional response.

This preregistered study replicates and extends studies concerning emotional response to wartime rally speeches and applies it to U.S. President Donald Trump's first national address regarding the COVID-19 pandemic on March 11, 2020. We experimentally test the effect of a micro-expression (ME) by Trump associated with appraised threat on change in participant self-reported distress, sadness, anger, affinity, and reassurance while controlling for followership. We find that polarization is perpetuated in emotional response to the address which focused on portraying the COVID-19 threat as being of Chinese provenance. We also find a significant, albeit slight, effect by Trump's ME on self-reported sadness, suggesting that this facial behavior served did not diminish his speech, instead serving as a form of nonverbal punctuation. Further exploration of participant response using the Linguistic Inventory and Word Count software reinforces and extends these findings.

Cognitive impairment following sedative overdose.

INTRODUCTION: Patients with sedative overdose may have residual cognitive impairment at the time they are deemed medically cleared for discharge. Impairment could affect the performance of high-risk activities, including driving. The Trail Making Test is an alpha-numeric assessment that can be performed at the bedside to assess cognitive function. We examined whether there were differences in cognitive function when medically cleared between patients that overdosed on sedative and non-sedative drugs. METHODS: A prospective, observational study assessed cognitive function using the Trail Making Test between 2018 and 2021. Patients (16 years and greater) completed testing upon medical clearance if they spoke English and had no previous neurological injury. Continuous covariates were compared using t-tests or Mann-Whitney U tests and multiple linear regression; binary variables were modelled using logistic regression. RESULTS: Of 171 patients enrolled, 111 (65 per cent) had sedative overdose; they were older (median 32.1 versus 22.2 years) and more likely to be male (58.6 per cent versus 36.7 per cent). Benzodiazepines and paracetamol were the commonest drug overdoses. Patients with sedative overdose performed worse on Trail Making Test part A (37.0 versus 33.1 seconds, P = 0.017) and Trail Making Test part B (112.4 versus 81.5 seconds, P = 0.004). Multiple linear regression analysis indicated that patient age (P < 0.001, 1.7 seconds slower per year, 95 per cent confidence interval: 0.9-2.6 seconds) and perception of recovery (P = 0.006, 36.4 seconds slower if perceived not recovered, 95 per cent confidence interval: 10.8-62.0 seconds) were also associated with Trail Making Test part B times. Patients with sedative overdose were more likely to be admitted to the intensive care unit (Odds Ratio: 4.9, 95 percent confidence interval: 1.1-22.0; P = 0.04). DISCUSSION: Our results are broadly in keeping with previously published work, but include a wider range of drug overdose scenarios (polypharmacy and recreational drugs). While patients demonstrated some perception of their cognitive impairment, our model could not reliably be used to provide individual discharge advice. The study design did not allow us to prove causation of cognitive impairment, or to make comparison between the strength of an overdose to the trail making test time. CONCLUSIONS: Trail Making Test results suggested that patients who had sedative drug overdoses may have significant cognitive deficits even when medically cleared. Risk of harm may be minimised with advice to avoid high-risk activities such as driving. More profound impacts seen on the Trail Making Test part B than A may mean higher-order thinking is more affected than simple cognitive function.

Using Electronic Health Records and Linked Claims Data to Assess New Medication Use and Primary Nonadherence in Rheumatology Patients.

OBJECTIVE: The objective of this study was to determine the proportion of new medication prescriptions observed in electronic health records (EHR) that represent true incident medication use, accounting for undocumented previous prescriptions (prevalent medication use) and failure to initiate treatment (primary nonadherence) with linked administrative claims data as the reference standard. METHODS: Using single-specialty rheumatology EHR data from more than 700 community practices in the United States linked to administrative claims data, we identified first (index) EHR prescriptions and assessed the positive predictive value (PPV) of different EHR-derived new user definitions to identify true incident use (no prior claims). We then assessed how often index EHR prescriptions that met a definition of new use resulted in primary nonadherence (no subsequent claims). RESULTS: Overall, 12,405 index EHR prescriptions were identified with PPVs of 0.59 to 0.67 for true incident use. PPVs increased to 0.76 to 0.85 by excluding medications listed during the EHR medication reconciliation process and further increased to 0.87 to 0.93 by requiring ≥12 elapsed months since the first rheumatology office visit. Primary nonadherence at three months was observed in 33% to 38% overall and varied substantially by medication class, ranging from 15% to 23% for conventional synthetic disease-modifying antirheumatic drugs (DMARDs) to 54% to 64% for targeted synthetic DMARDs. CONCLUSION: New DMARD use was accurately distinguished from prevalent use with EHR prescriptions and simple new user definitions that include current medications collected during medication reconciliation. Primary nonadherence was frequent and varied by DMARD class. This has important implications for epidemiologic studies using EHR data and for optimal delivery of clinical care.

COVID-19 Vaccine Uptake, Hesitancy, and Flare in a Large Rheumatology Practice Network.

OBJECTIVE: The goal of this study was to ascertain COVID-19 vaccine uptake, reasons for hesitancy, and self-reported flare in a large rheumatology practice-based network. METHODS: A tablet-based survey was deployed by 108 rheumatology practices from December 2021 to December 2022. Patients were asked about COVID-19 vaccine status and why they might not receive a vaccine or booster. We used descriptive statistics to explore the differences between vaccination status and vaccine and booster hesitancy, comparing patients with and without autoimmune and inflammatory rheumatic diseases (AIIRDs). We used multivariable logistic regression to examine the association between vaccine uptake and AIIRD status and self-reported flare and AIIRD status. We reported adjusted odds ratios (aORs). RESULTS: Of the 61,158 patients, 89% reported at least one dose of vaccine; of the vaccinated, 68% reported at least one booster. Vaccinated patients were less likely to have AIIRDs (44% vs 56%). A greater proportion of patients with AIIRDs were vaccine hesitant (14% vs 10%) and booster hesitant (21% vs 16%) compared to patients without AIIRDs. Safety concerns (28%) and side effects (23%) were the main reasons for vaccine hesitancy, whereas a lack of recommendation from the physician was the primary factor for booster hesitancy (23%). Patients with AIIRD did not have increased odds of self-reported flare or worsening disease compared to patients without with AIIRD (aOR 0.99, 95% confidence interval [CI] 0.94-1.05). Among the patients who were vaccine hesitant and booster hesitant, 12% and 39% later reported receiving a respective dose. Patients with AIIRD were 32% less likely to receive a vaccine (aOR 0.68, 95% CI 0.65-0.72) versus patients without AIIRD. CONCLUSION: Some patients who are vaccine and booster hesitant eventually receive a vaccine dose, and future interventions tailored to patients with AIIRD may be fruitful.

Droplet microfluidics for time-resolved serial crystallography.

Serial crystallography requires large numbers of microcrystals and robust strategies to rapidly apply substrates to initiate reactions in time-resolved studies. Here, we report the use of droplet miniaturization for the controlled production of uniform crystals, providing an avenue for controlled substrate addition and synchronous reaction initiation. The approach was evaluated using two enzymatic systems, yielding 3 µm crystals of lysozyme and 2 µm crystals of Pdx1, an Arabidopsis enzyme involved in vitamin B6 biosynthesis. A seeding strategy was used to overcome the improbability of Pdx1 nucleation occurring with diminishing droplet volumes. Convection within droplets was exploited for rapid crystal mixing with ligands. Mixing times of <2 ms were achieved. Droplet microfluidics for crystal size engineering and rapid micromixing can be utilized to advance time-resolved serial crystallography.

Structure of arylamine N-acetyltransferase from Mycobacterium tuberculosis determined by cross-seeding with the homologous protein from M. marinum: triumph over adversity.

Arylamine N-acetyltransferase from Mycobacterium tuberculosis (TBNAT) plays an important role in the intracellular survival of the microorganism inside macrophages. Medicinal chemistry efforts to optimize inhibitors of the TBNAT enzyme have been hampered by the lack of a three-dimensional structure of the enzyme. In this paper, the first structure of TBNAT, determined using a lone crystal produced using cross-seeding with the homologous protein from M. marinum, is reported. Despite the similarity between the two enzymes (74% sequence identity), they show distinct physical and biochemical characteristics. The structure elegantly reveals the characteristic features of the protein surface as well as details of the active site of TBNAT relevant to drug-discovery efforts. The crystallographic analysis of the diffraction data presented many challenges, since the crystal was twinned and the habit possessed pseudo-translational symmetry.

Measuring Protein Aggregation and Stability Using High-Throughput Biophysical Approaches.

Structure-function relationships of biological macromolecules, in particular proteins, provide crucial insights for fundamental biochemistry, medical research and early drug discovery. However, production of recombinant proteins, either for structure determination, functional studies, or to be used as biopharmaceutical products, is often hampered by their instability and propensity to aggregate in solution in vitro. Protein samples of poor quality are often associated with reduced reproducibility as well as high research and production expenses. Several biophysical methods are available for measuring protein aggregation and stability. Yet, discovering and developing means to improve protein behaviour and structure-function integrity remains a demanding task. Here, we discuss workflows that are made possible by adapting established biophysical methods to high-throughput screening approaches. Rapid identification and optimisation of conditions that promote protein stability and reduce aggregation will support researchers and industry to maximise sample quality, stability and reproducibility, thereby reducing research and development time and costs.

The effect of electrode placement and pulsewidth on asystole and bradycardia during the electroconvulsive therapy stimulus.

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, and different forms are increasingly used in clinical practice. This study investigated the acute cardiac effects of different forms of ECT: bitemporal and bifrontal (1.5 times seizure threshold), and right unilateral (RUL) (five times seizure threshold). For RUL ECT, the effect of stimulus pulsewidth (1.0 or 0.3 ms) was also examined. Electrocardiograms recorded just prior to and during the ECT stimulus in 476 ECT treatments in 114 patients were examined. The degree of bradycardia (any slowing of heart rate) and incidence of asystole (absence of heart beats for ≥5 s) during the ECT stimulus were measured from these traces. Regression analyses estimated the contribution of patient and ECT treatment factors to the risk of bradycardia and asystole. Bifrontal ECT was associated with less severe bradycardia than bitemporal or RUL ECT (p<0.001). Modelling showed, for a mean pre-ECT heart rate of 85 beats per minute (bpm), expected heart rates during the stimulus were 78 bpm (bifrontal), 46 bpm (bitemporal) and 35 bpm (RUL). Bifrontal ECT was also associated with a lower incidence of asystole than RUL ECT (corrected odds ratio 1:207) and bitemporal ECT (corrected odds ratio 1:24). Ultrabrief pulsewidth stimulation resulted in lesser bradycardia and asystole than standard pulsewidth stimulation for RUL ECT. Modelling showed, for a mean pre-ECT heart rate of 86 bpm, expected heart rates were 43 bpm (ultrabrief RUL) and 26 bpm (RUL). Bradycardia and asystole were relatively common side-effects during the ECT stimulus. Bifrontal ECT was associated with the lowest risk of bradycardia and asystole during ECT and should be considered for patients at risk of arrhythmias and prolonged asystole during ECT.

Micro-Expressions of Fear During the 2016 Presidential Campaign Trail: Their Influence on Trait Perceptions of Donald Trump.

The 2016 United States presidential election was exceptional for many reasons; most notably the extreme division between supporters of Donald Trump and Hillary Clinton. In an election that turned more upon the character traits of the candidates than their policy positions, there is reason to believe that the non-verbal performances of the candidates influenced attitudes toward the candidates. Two studies, before Election Day, experimentally tested the influence of Trump's micro-expressions of fear during his Republican National Convention nomination acceptance speech on how viewers evaluated his key leadership traits of competence and trustworthiness. Results from Study 1, conducted 3 weeks prior to the election, indicated generally positive effects of Trump's fear micro-expressions on his trait evaluations, particularly when viewers were first exposed to his opponent, Clinton. In contrast, Study 2, conducted 4 days before Election Day, suggests participants had at that point largely established their trait perceptions and were unaffected by the micro-expressions.

Psychophysiology, cognition, and political differences: Guest editors' introduction to the special issue.

We introduce the Politics and the Life Sciences special issue on Psychophysiology, Cognition, and Political Differences. This issue represents the second special issue funded by the Association for Politics and the Life Sciences that adheres to the Open Science Framework for registered reports (RR). Here pre-analysis plans (PAPs) are peer-reviewed and given in-principle acceptance (IPA) prior to data being collected and/or analyzed, and are published contingent upon the preregistration of the study being followed as proposed. Bound by a common theme of the importance of incorporating psychophysiological perspectives into the study of politics, broadly defined, the articles in this special issue feature a unique set of research questions and methodologies. In the following, we summarize the findings, discuss the innovations produced by this research, and highlight the importance of open science for the future of political science research.