Evolutionary Multi-Objective Design of SARS-CoV-2 Protease Inhibitor Candidates

Computational drug design based on artificial intelligence is an emerging research area. At the time of writing this paper, the world suffers from an outbreak of the coronavirus SARS-CoV-2. A promising way to stop the virus replication is via protease inhibition. We propose an evolutionary multi-objective algorithm (EMOA) to design potential protease inhibitors for SARS-CoV-2's main protease. Based on the SELFIES representation the EMOA maximizes the binding of candidate ligands to the protein using the docking tool QuickVina 2, while at the same time taking into account further objectives like drug-likeliness or the fulfillment of filter constraints. The experimental part analyzes the evolutionary process and discusses the inhibitor candidates.Comment: 15 pages, 7 figures, submitted to PPSN 202

A machine learning system to optimise triage in an adult ophthalmic emergency department: a model development and validation study

BACKGROUND: A substantial proportion of attendances to ophthalmic emergency departments are for non-urgent presentations. We developed and evaluated a machine learning system (DemDx Ophthalmology Triage System: DOTS) to optimise triage, with the aim of reducing inappropriate emergency attendances and streamlining case referral when necessary. METHODS: DOTS was built using retrospective tabular data from 11,315 attendances between July 1st, 2021, to June 15th, 2022 at Moorfields Eye Hospital Emergency Department (MEH) in London, UK. Demographic and clinical features were used as inputs and a triage recommendation was given (“see immediately”, “see within a week”, or “see electively”). DOTS was validated temporally and compared with triage nurses’ performance (1269 attendances at MEH) and validated externally (761 attendances at the Federal University of Minas Gerais - UFMG, Brazil). It was also tested for biases and robustness to variations in disease incidences. All attendances from patients aged at least 18 years with at least one confirmed diagnosis were included in the study. FINDINGS: For identifying ophthalmic emergency attendances, on temporal validation, DOTS had a sensitivity of 94.5% [95% CI 92.3–96.1] and a specificity of 42.4% [38.8–46.1]. For comparison within the same dataset, triage nurses had a sensitivity of 96.4% [94.5–97.7] and a specificity of 25.1% [22.0–28.5]. On external validation at UFMG, DOTS had a sensitivity of 95.2% [92.5–97.0] and a specificity of 32.2% [27.4–37.0]. In simulated scenarios with varying disease incidences, the sensitivity was ≥92.2% and the specificity was ≥36.8%. No differences in sensitivity were found in subgroups of index of multiple deprivation, but the specificity was higher for Q2 when compared to Q4 (Q4 is less deprived than Q2). INTERPRETATION: At MEH, DOTS had similar sensitivity to triage nurses in determining attendance priority; however, with a specificity of 17.3% higher, DOTS resulted in lower rates of patients triaged to be seen immediately at emergency. DOTS showed consistent performance in temporal and external validation, in social-demographic subgroups and was robust to varying relative disease incidences. Further trials are necessary to validate these findings. This system will be prospectively evaluated, considering human-computer interaction, in a clinical trial. FUNDING: The Artificial Intelligence in Health and Care Award (AI_AWARD01671) of the NHS AI Lab under National Institute for Health and Care Research (NIHR) and the Accelerated Access Collaborative (AAC)

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

Socio-cultural determinants of adiposity and physical activity in preschool children: A cross-sectional study

BACKGROUND: Both individual socio-cultural determinants such as selected parental characteristics (migrant background, low educational level and workload) as well as the regional environment are related to childhood overweight and physical activity (PA). The purpose of the study was to compare the impact of distinct socio-cultural determinants such as the regional environment and selected parental characteristics on adiposity, PA and motor skills in preschool children. METHODS: Forty preschools (N = 542 children) of two culturally different urban regions (German and French speaking part of Switzerland) participated in the study (Ballabeina Study). Outcome measures included adiposity (BMI and skinfold thickness), objectively measured sedentary activities and PA (accelerometers) and agility performance (obstacle course). Parental characteristics (migrant status, educational level and workload) were assessed by questionnaire. RESULTS: Children from the French speaking areas had higher adiposity, lower levels of total and of more intense PA, were more sedentary and less agile than children from the German speaking regions (percent differences for all outcome parameters except for BMI ≥10%; all p ≤ 0.04). Differences in skinfold thickness, sedentary activities and agility, but not in PA, were also found between children of Swiss and migrant parents, though they were ≤8% (p ≤ 0.02). While paternal workload had no effect, maternal workload and parental education resulted in differences in some PA measures and/or agility performance (percent differences in both: ≤9%, p ≤ 0.008), but not in adiposity or sedentary activities (p = NS). Regional differences in skinfold thickness, PA, sedentary activities and agility performance persisted after adjustment for parental socio-cultural characteristics, parental BMI and, where applicable, children's skinfolds (all p ≤ 0.01). CONCLUSIONS: The regional environment, especially the broader social environment, plays a prominent role in determining adiposity, PA and motor skills of young children and should be implicated in the prevention of obesity and promotion of PA in children

Nursing and sexuality: integrative review of papers published by the Latin-American Journal of Nursing and Brazilian Journal of Nursing

This study departs from the assumption that studies addressing sexuality in the field of nursing present changes and broaden the scope of discussion to include gender and sexual rights, although a strong tendency to link sexuality to its biological aspects is still observed. This study identifies the state-of-the-art of studies addressing sexuality published by two international journals: Latin American Journal of Nursing and The Brazilian Journal of Nursing. The sources were papers published in both periodicals over a period of ten years (from 1998 to 2007). In a universe of 1,894 searched abstracts, 29 mentioned the word ‘sexuality’. The results confirm this study’s assumption showing that the studies addressing sexuality from the perspective of nursing published by these two journals broaden the understanding on the subject as they incorporate categories such as gender, but also excessively link sexuality to its biological aspects.Esta investigación partió del supuesto de que los estudios sobre sexualidad realizados por la Enfermería presentan cambios y amplían la perspectiva sobre la realidad al incluir género y derechos sexuales, a pesar de que permanezca una fuerte tendencia en la vinculación de la sexualidad a sus aspectos biológicos. El objetivo del estudio fue identificar el estado del arte de las publicaciones sobre sexualidad en dos periódicos de circulación internacional: Revista Latino Americana de Enfermería/RLAE y Revista Brasileña de Enfermería/REBEn. Las fuentes fueron artículos publicados en ambos periódicos en el período de diez años (1998 a 2007). En un universo de 1894 resúmenes consultados fueron identificados 29 que contenían en el título, palabras clave o el resumen de la palabra sexualidad. Los resultados confirman el supuesto del estudio demostrando que la producción sobre sexualidad por la Enfermería divulgada en esos dos periódicos, al mismo tiempo en que amplía la comprensión sobre la temática al incorporar categorías como género, mantiene la vinculación excesiva de la sexualidad a sus aspectos biológicos.Esta pesquisa partiu do pressuposto de que os estudos sobre sexualidade, realizados pela Enfermagem, apresentam mudanças e ampliam o olhar sobre a realidade ao incluir gênero e direitos sexuais, embora permaneça forte tendência para a vinculação da sexualidade aos seus aspectos biológicos. O objetivo do estudo foi identificar o estado da arte das publicações sobre sexualidade em dois periódicos de circulação internacional: Revista Latino-Americana de Enfermagem/RLAE e Revista Brasileira de Enfermagem/REBEn. As fontes foram artigos publicados em ambos os periódicos, no período de dez anos (1998 a 2007). Em um universo de 1894 resumos consultados, foram identificados 29 que traziam no título, palavras-chave, ou resumo a palavra sexualidade. Os resultados confirmam o pressuposto do estudo, demonstrando que a produção sobre sexualidade pela Enfermagem, divulgada nesses dois periódicos, ao mesmo tempo em que amplia a compreensão sobre a temática ao incorporar categorias, como gênero, mantém vinculação excessiva da sexualidade aos seus aspectos biológicos

Expression of P. falciparum var Genes Involves Exchange of the Histone Variant H2A.Z at the Promoter

Plasmodium falciparum employs antigenic variation to evade the human immune response by switching the expression of different variant surface antigens encoded by the var gene family. Epigenetic mechanisms including histone modifications and sub-nuclear compartmentalization contribute to transcriptional regulation in the malaria parasite, in particular to control antigenic variation. Another mechanism of epigenetic control is the exchange of canonical histones with alternative variants to generate functionally specialized chromatin domains. Here we demonstrate that the alternative histone PfH2A.Z is associated with the epigenetic regulation of var genes. In many eukaryotic organisms the histone variant H2A.Z mediates an open chromatin structure at promoters and facilitates diverse levels of regulation, including transcriptional activation. Throughout the asexual, intraerythrocytic lifecycle of P. falciparum we found that the P. falciparum ortholog of H2A.Z (PfH2A.Z) colocalizes with histone modifications that are characteristic of transcriptionally-permissive euchromatin, but not with markers of heterochromatin. Consistent with this finding, antibodies to PfH2A.Z co-precipitate the permissive modification H3K4me3. By chromatin-immunoprecipitation we show that PfH2A.Z is enriched in nucleosomes around the transcription start site (TSS) in both transcriptionally active and silent stage-specific genes. In var genes, however, PfH2A.Z is enriched at the TSS only during active transcription in ring stage parasites. Thus, in contrast to other genes, temporal var gene regulation involves histone variant exchange at promoter nucleosomes. Sir2 histone deacetylases are important for var gene silencing and their yeast ortholog antagonises H2A.Z function in subtelomeric yeast genes. In immature P. falciparum parasites lacking Sir2A or Sir2B high var transcription levels correlate with enrichment of PfH2A.Z at the TSS. As Sir2A knock out parasites mature the var genes are silenced, but PfH2A.Z remains enriched at the TSS of var genes; in contrast, PfH2A.Z is lost from the TSS of de-repressed var genes in mature Sir2B knock out parasites. This result indicates that PfH2A.Z occupancy at the active var promoter is antagonized by PfSir2A during the intraerythrocytic life cycle. We conclude that PfH2A.Z contributes to the nucleosome architecture at promoters and is regulated dynamically in active var genes