Abstract
Motivation
Protein-protein interactions are vital for protein function with the average protein having between three and ten interacting partners. Knowledge of precise protein-protein ...interfaces comes from crystal structures deposited in the Protein Data Bank (PDB), but only 50% of structures in the PDB are complexes. There is therefore a need to predict protein-protein interfaces in silico and various methods for this purpose. Here we explore the use of a predictor based on structural features and which exploits random forest machine learning, comparing its performance with a number of popular established methods.
Results
On an independent test set of obligate and transient complexes, our IntPred predictor performs well (MCC = 0.370, ACC = 0.811, SPEC = 0.916, SENS = 0.411) and compares favourably with other methods. Overall, IntPred ranks second of six methods tested with SPPIDER having slightly better overall performance (MCC = 0.410, ACC = 0.759, SPEC = 0.783, SENS = 0.676), but considerably worse specificity than IntPred. As with SPPIDER, using an independent test set of obligate complexes enhanced performance (MCC = 0.381) while performance is somewhat reduced on a dataset of transient complexes (MCC = 0.303). The trade-off between sensitivity and specificity compared with SPPIDER suggests that the choice of the appropriate tool is application-dependent.
Availability and implementation
IntPred is implemented in Perl and may be downloaded for local use or run via a web server at www.bioinf.org.uk/intpred/.
Supplementary information
Supplementary data are available at Bioinformatics online.
Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in ...SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)-2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.
Dual luminescence,
i.e.
intense, simultaneous, room temperature phosphorescence (RTP) and thermally activated delayed fluorescence (TADF) is observed in a series of donor–acceptor–donor (D–A–D) ...molecules. This dual luminescence is stronger in the “angular” isomers, compared to their “linear” regioisomers, which is consistent with an enhanced intersystem crossing (ISC) in the former. Herein, we demonstrate that the small energy gap between the triplet levels, T
1
–T
n
, below the lowest singlet state, S
1
, in the “angular” regioisomers, enhances the coupling between S
1
and T
1
states and favors ISC and reverse ISC (rISC). This is consistent with a spin–vibronic mechanism. In the absence of this “triplet ladder”, due to the larger energy difference between T
1
and T
n
in the “linear” regioisomers, the ISC and rISC are not efficient. Remarkably, the enhancement of the ISC rate in the “angular” regioisomers is accompanied by an increase of the rate of internal conversion (IC). These results highlight the contributions of higher triplet excited states and molecular vibronic coupling to the harvest of triplet states in organic compounds, and cast the TADF and RTP mechanisms into a common conceptual framework.
Integrating knowledge from across the natural and social sciences is necessary to effectively address societal tradeoffs between human use of biological diversity and its preservation. Collaborative ...processes can change the ways decision makers think about scientific evidence, enhance levels of mutual trust and credibility, and advance the conservation policy discourse. Canada has responsibility for a large fraction of some major ecosystems, such as boreal forests, Arctic tundra, wetlands, and temperate and Arctic oceans. Stressors to biological diversity within these ecosystems arise from activities of the country's resource-based economy, as well as external drivers of environmental change. Effective management is complicated by incongruence between ecological and political boundaries and conflicting perspectives on social and economic goals. Many knowledge gaps about stressors and their management might be reduced through targeted, timely research. We identify 40 questions that, if addressed or answered, would advance research that has a high probability of supporting development of effective policies and management strategies for species, ecosystems, and ecological processes in Canada. A total of 396 candidate questions drawn from natural and social science disciplines were contributed by individuals with diverse organizational affiliations. These were collaboratively winnowed to 40 by our team of collaborators. The questions emphasize understanding ecosystems, the effects and mitigation of climate change, coordinating governance and management efforts across multiple jurisdictions, and examining relations between conservation policy and the social and economic well-being of Aboriginal peoples. The questions we identified provide potential links between evidence from the conservation sciences and formulation of policies for conservation and resource management. Our collaborative process of communication and engagement between scientists and decision makers for generating and prioritizing research questions at a national level could be a model for similar efforts beyond Canada. La integración del conocimiento proveniente de las ciencias sociales y naturales es necesaria para atender efectivamente los pros y contras sociales de la utilización de la biodiversidad por humanos y su preservación. Los procesos de colaboración pueden cambiar la forma en que los tomadores de decisiones piensan sobre la evidencia científica, incrementar los niveles de confianza y credibilidad mutua y avanzar en el discurso político de la conservación. Canadá tiene responsabilidad por una gran proporción de algunos de los principales ecosistemas, como bosques boreales, tundra Ártica, humedales y océanos templados y Ártico. Factores estresantes para la diversidad biológica en esos ecosistemas se originan de actividades de la economía del país basada en recursos, así como de factores externos causantes del cambio ambiental. El manejo efectivo es complicado por la incongruencia entre los límites ecológicos y políticos y por perspectivas conflictivas de las metas sociales y económicas. Muchos vacíos de información sobre los factores estresantes y su manejo podrían reducirse por medio de investigaciones dirigidas y oportunas. Identificamos 40 preguntas que, sí son atendidas o respondidas, harían avanzar a la investigación que tiene una alta probabilidad de soportar el desarrollo de políticas y estrategias de manejo efectivas para especies, ecosistemas y procesos ecológicos en Canadá. Un total de 396 preguntas propuestas, derivadas de disciplinas naturales y sociales, fueron aportadas por individuos de afiliaciones organizacionales diferentes y fueron reducidas a 40 por nuestro equipo de colaboradores. Estas preguntas enfatizan el entendimiento de los ecosistemas, los efectos y mitigación del cambio climático, la coordinación de esfuerzos de gobernanza y manejo en jurisdicciones múltiples y el examen de las relaciones entre las políticas de conservación y el bienestar social y económico de los pueblos aborígenes. Las preguntas que identificamos proporcionan posibles vínculos entre la evidencia aportada por las ciencias de la conservación y la formulación de políticas para la conservación y el manejo de los recursos. Nuestro proceso colaborativo de comunicación y compromiso entre científicos y tomadores de decisiones para generar y priorizar preguntas de investigación a nivel nacional podría ser un modelo para esfuerzos similares fuera de Canadá.
Background. Campylobacter species is a leading cause of bacterial gastroenteritis worldwide. Quinolone resistance has emerged as an increasing problem among persons with Campylobacter infection over ...the past decade, but the clinical consequences are unclear. Methods. A case-comparison study of patients infected with ciprofloxacin-resistant or ciprofloxacin-susceptible Campylobacter species was conducted in Wales during the period 2003–2004. Campylobacter isolates were classified as resistant or susceptible to ciprofloxacin on the basis of standardized disk diffusion methods. Participants were interviewed by telephone at the time of illness, 3 months later, and 6 months later to compare disease severity, duration of illness, and medium-term clinical outcomes. Results. There was no difference between 145 persons with ciprofloxacin-resistant infection and 411 with ciprofloxacin-susceptible infection with regard to the severity or duration of acute illness. Mean duration of diarrhea was similar in patients with ciprofloxacin-resistant versus ciprofloxacin-susceptible infection (8.2 vs. 8.6 days; P=.57) and did not alter significantly after adjustment for potential covariates, including age, underlying disease, foreign travel, use of antidiarrheal medication, and use of antimicrobials in a multiple linear regression model. There was no difference between case patients and comparison patients in the frequency of reported symptoms or in general practitioner consultation rates at either the 3-month or the 6-month follow-up interview. Conclusions. In this study, there was no evidence of more-severe or prolonged illness in participants with quinolone-resistant Campylobacter infection, nor was there evidence of any adverse medium-term consequences. This suggests that the clinical significance of quinolone resistance in Campylobacter infection may have been overestimated.
Objectives To identify risk factors for ciprofloxacin resistance in both travel-related and domestically acquired Campylobacter infection. Methods Case–comparison study of patients with ...ciprofloxacin-resistant and ciprofloxacin-susceptible Campylobacter infection conducted in Wales during 2003 and 2004. Results Foreign travel was the major risk factor for ciprofloxacin-resistant infection adjusted odds ratio (adjOR) 24.0, 95% confidence interval (95% CI) 12.6–45.9. Among travellers, case patients were five times more likely to drink still bottled water (adjOR 4.7, 95% CI 1.0–21.7), whilst among non-travellers, case patients were three times more likely to drink sparkling bottled water (adjOR 3.3, 95% CI 1.5–7.4). There was no increased risk associated with eating poultry or prior quinolone use. Conclusions Foreign travel remains the most important risk factor for ciprofloxacin-resistant Campylobacter infection. The possible association of both domestic- and travel-related ciprofloxacin-resistant Campylobacter infection with bottled water needs to be further explored.
Dual luminescence,
i.e.
intense, simultaneous, room temperature phosphorescence (RTP) and thermally activated delayed fluorescence (TADF) is observed in a series of donor-acceptor-donor (D-A-D) ...molecules. This dual luminescence is stronger in the "angular" isomers, compared to their "linear" regioisomers, which is consistent with an enhanced intersystem crossing (ISC) in the former. Herein, we demonstrate that the small energy gap between the triplet levels, T
1
-T
n
, below the lowest singlet state, S
1
, in the "angular" regioisomers, enhances the coupling between S
1
and T
1
states and favors ISC and reverse ISC (rISC). This is consistent with a spin-vibronic mechanism. In the absence of this "triplet ladder", due to the larger energy difference between T
1
and T
n
in the "linear" regioisomers, the ISC and rISC are not efficient. Remarkably, the enhancement of the ISC rate in the "angular" regioisomers is accompanied by an increase of the rate of internal conversion (IC). These results highlight the contributions of higher triplet excited states and molecular vibronic coupling to the harvest of triplet states in organic compounds, and cast the TADF and RTP mechanisms into a common conceptual framework.
Dual luminescence (RTP and TADF) is observed in a series of donor-acceptor-donor molecules.
Integrating knowledge from across the natural and social sciences is necessary to effectively address societal tradeoffs between human use of biological diversity and its preservation. Collaborative ...processes can change the ways decision makers think about scientific evidence, enhance levels of mutual trust and credibility, and advance the conservation policy discourse. Canada has responsibility for a large fraction of some major ecosystems, such as boreal forests, Arctic tundra, wetlands, and temperate and Arctic oceans. Stressors to biological diversity within these ecosystems arise from activities of the country's resource-based economy, as well as external drivers of environmental change. Effective management is complicated by incongruence between ecological and political boundaries and conflicting perspectives on social and economic goals. Many knowledge gaps about stressors and their management might be reduced through targeted, timely research. We identify 40 questions that, if addressed or answered, would advance research that has a high probability of supporting development of effective policies and management strategies for species, ecosystems, and ecological processes in Canada. A total of 396 candidate questions drawn from natural and social science disciplines were contributed by individuals with diverse organizational affiliations. These were collaboratively winnowed to 40 by our team of collaborators. The questions emphasize understanding ecosystems, the effects and mitigation of climate change, coordinating governance and management efforts across multiple jurisdictions, and examining relations between conservation policy and the social and economic well-being of Aboriginal peoples. The questions we identified provide potential links between evidence from the conservation sciences and formulation of policies for conservation and resource management. Our collaborative process of communication and engagement between scientists and decision makers for generating and prioritizing research questions at a national level could be a model for similar efforts beyond Canada.
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