SARS-CoV-2 introductions to the island of Ireland: a phylogenetic and geospatiotemporal study of infection dynamics.

Background: Ireland's COVID-19 response combined extensive SARS-CoV-2 testing to estimate incidence, with whole genome sequencing (WGS) for genome surveillance. As an island with two political jurisdictions-Northern Ireland (NI) and Republic of Ireland (RoI)-and access to detailed passenger travel data, Ireland provides a unique setting to study virus introductions and evaluate public health measures. Using a substantial Irish genomic dataset alongside global data from GISAID, this study aimed to trace the introduction and spread of SARS-CoV-2 across the island.

Low-voltage electrical injuries and the electrocardiogram: is a 'normal' electrocardiogram sufficient for safe discharge from care? A systematic review.

Introduction: The current Joint Royal Colleges Ambulance Liaison Committee guidelines in the United Kingdom provide clear national guidance for low-voltage electrical injury patients. While patients can be considered safe to discharge with an apparently 'normal' initial electrocardiogram (ECG), some evidence questions the safety profile of these patients with a risk of a 'delayed arrhythmia'. This review aims to examine this as well as identifying the frequency and common arrhythmias that require patients to be conveyed to hospital for further monitoring post electrical injury.

Transcription factor expression levels and environmental signals constrain transcription factor innovation.

Evolutionary innovation of transcription factors frequently drives phenotypic diversification and adaptation to environmental change. Transcription factors can gain or lose connections to target genes, resulting in novel regulatory responses and phenotypes. However the frequency of functional adaptation varies between different regulators, even when they are closely related.

Causes and Consequences of Purifying Selection on SARS-CoV-2.

Owing to a lag between a deleterious mutation's appearance and its selective removal, gold-standard methods for mutation rate estimation assume no meaningful loss of mutations between parents and offspring. Indeed, from analysis of closely related lineages, in SARS-CoV-2, the Ka/Ks ratio was previously estimated as 1.008, suggesting no within-host selection.

Transcription, mRNA Export, and Immune Evasion Shape the Codon Usage of Viruses.

The nucleotide composition, dinucleotide composition, and codon usage of many viruses differ from their hosts. These differences arise because viruses are subject to unique mutation and selection pressures that do not apply to host genomes; however, the molecular mechanisms that underlie these evolutionary forces are unclear. Here, we analyzed the patterns of codon usage in 1,520 vertebrate-infecting viruses, focusing on parameters known to be under selection and associated with gene regulation.

Evidence for Strong Mutation Bias toward, and Selection against, U Content in SARS-CoV-2: Implications for Vaccine Design.

Large-scale re-engineering of synonymous sites is a promising strategy to generate vaccines either through synthesis of attenuated viruses or via codon-optimized genes in DNA vaccines. Attenuation typically relies on deoptimization of codon pairs and maximization of CpG dinucleotide frequencies. So as to formulate evolutionarily informed attenuation strategies that aim to force nucleotide usage against the direction favored by selection, here, we examine available whole-genome sequences of SARS-CoV-2 to infer patterns of mutation and selection on synonymous sites.

Deficient pregnenolone synthesis associated with congenital adrenal hyperplasia and organelle dysfunction.

Steroid hormones are essential for the survival of all mammals. In adrenal glands and gonads, cytochrome P450 side chain cleavage enzyme (SCC or CYP11A1), catalyzes conversion of cholesterol to pregnenolone. We studied a patient with ambiguous genitalia by the absence of Müllerian ducts and the presence of an incompletely formed vagina, who had extremely high adrenocorticotropic hormone (ACTH) and reduced pregnenolone levels with enlarged adrenal glands.

A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities.

The polycomb repressive complex 2 (PRC2) consists of core subunits SUZ12, EED, RBBP4/7, and EZH1/2 and is responsible for mono-, di-, and tri-methylation of lysine 27 on histone H3. Whereas two distinct forms exist, PRC2.1 (containing one polycomb-like protein) and PRC2.

Dosage-sensitive genes in evolution and disease.

For a subset of genes in our genome a change in gene dosage, by duplication or deletion, causes a phenotypic effect. These dosage-sensitive genes may confer an advantage upon copy number change, but more typically they are associated with disease, including heart disease, cancers and neuropsychiatric disorders. This gene copy number sensitivity creates characteristic evolutionary constraints that can serve as a diagnostic to identify dosage-sensitive genes.

disruption of promoter and exon 1 of STAR gene reveals essential role for gonadal development.

Summary: Cholesterol transport into the mitochondria is required for synthesis of the first steroid, pregnenolone. Cholesterol is transported by the steroidogenic acute regulatory protein (STAR), which acts at the outer mitochondrial membrane prior to its import. Mutations in the STAR protein result in lipoid congenital adrenal hyperplasia (CAH).

Dosage sensitivity is a major determinant of human copy number variant pathogenicity.

Human copy number variants (CNVs) account for genome variation an order of magnitude larger than single-nucleotide polymorphisms. Although much of this variation has no phenotypic consequences, some variants have been associated with disease, in particular neurodevelopmental disorders. Pathogenic CNVs are typically very large and contain multiple genes, and understanding the cause of the pathogenicity remains a major challenge.

Novel SCC mutation in a patient of Mexican descent with sex reversal, salt-losing crisis and adrenal failure.

Unlabelled: Congenital adrenal hyperplasia (CAH) is caused by mutations in cytochrome P450 side chain cleavage enzyme (CYP11A1 and old name, SCC). Errors in cholesterol side chain cleavage by the mitochondrial resident CYP11A1 results in an inadequate amount of pregnenolone production. This study was performed to evaluate the cause of salt-losing crisis and possible adrenal failure in a pediatric patient whose mother had a history of two previous stillbirths and loss of another baby within a week of birth.

A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence.

Polycomb-like proteins 1-3 (PCL1-3) are substoichiometric components of the Polycomb-repressive complex 2 (PRC2) that are essential for association of the complex with chromatin. However, it remains unclear why three proteins with such apparent functional redundancy exist in mammals. Here we characterize their divergent roles in both positively and negatively regulating cellular proliferation.

Virtual patients in a virtual world: Training paramedic students for practice.

Collaborative learning through case-based or problem-based learning (PBL) scenarios is an excellent way for students to acquire knowledge and develop decision-making skills. However, the process is threatened by the movement towards more self-directed learning and the migration of students from campus-based to workplace-based learning. Paper-based PBL cases can only proceed in a single direction which can prevent learners from exploring the impact of their decisions.

Insulin pump therapy in toddlers and preschool children with type 1 diabetes mellitus.

Objective: To test whether glycemic control in young children could be achieved more effectively and safely by using continuous insulin infusions administered by insulin pumps.

Study Design: We analyzed the effects of pump therapy in nine toddlers in whom type 1 diabetes developed between the ages of 10 and 40 months. After a mean of 13.