Genomic reconstruction of the SARS-CoV-2 epidemic in England.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021

Molecular Characterization of Tyrosinase (Dopa Oxidase Activity, Abundance, and Synthesis) In Lethal Yellow Mice - A Mutation That Affects Pigmentation, Fertility, and Obesity

How does the information in a given gene translate into a given function? Or simply, how do genes work? How do genes influence other genes? What makes gene interaction so complex? How does one begin to understand the coordinated functions of all the genes in a genome? The answers to these questions are largely unknown, but we have made impressive advances. A functional understanding of gene interaction may be found in the study of melanogenesis. A number of genes regulating melanogenesis have been identified, studied, and functionally characterized. Mutations of genes that control melanogenesis are present in animals (including humans) with different coat colors. Some aberrations are spontaneous while some are induced. The important thing is they are readily identified. Over 50 genetic loci and over 140 different mutations have been identified and characterized (Silvers, 1979). These mutations affecting melanogenesis provide a comprehensive body of knowledge concerning the genes that control melanogenesis. This system of interacting genes provides a productive model to study genetic interaction of two or more genes. This body of knowledge gives one a powerful tool to dissect the relationships of certain genes that are fundamental to melanogenesis. For example, a mutation at a certain locus can cause a total lack of pigment. Mutations at other loci can affect the type of melanin produced. A most intriguing situation exists when an animal can produce one type of melanin and then switch to produce another and then switch back to the first type. Such is the case in the system we studied, the agouti switch. In our study we used agouti locus mutations to characterize genetic interactions of melanogenesis. The mice in this study were genetically identical except for one allele. The locus and different alleles investigated are found at the agouti locus on chromosome 2. The agouti locus allele (A), the wild type, causes the hairbulb melanocyte to produce first black then yellow then black pigment. The nonagouti black allele (a), causes the mouse to produce only black melanin (eumelanin), while the lethal yellow (Ay) allele (lethal only when homozygous) causes the mouse to produce exclusively yellow melanin (phaeomelanin). These alleles seem to affect tyrosinase, the gene product of the albino locus on chromosome 7. Tyrosinase is a fundamental enzyme during both eu- and phaeomelanogenesis. Mutations at the albino locus can result in the total absence of tyrosinase or the production of a non-functional tyrosinase. In either case no pigment can be produced, and the resultant animal is termed an albino. Alleles at the agouti and albino locui plus other pigmentation loci work together to produce the color combinations or lack of color found in nature. The wild-type agouti allele (A) allows the switching back and forth while a/a and Ay/a mice seem to be stuck in their respective stages of pigment production. Since all the mice used in this study are genetically identical except for alleles at the agouti locus (congenic mice), differences in the type of pigment produced can be attributed to the effect of one different allele at the agouti locus. This system provides a tool to monitor the actions of the agouti locus alleles on the albino locus product-tyrosinase. These effects of the agouti locus on tyrosinase may vary from a post-translational processing difference to a reduction in the synthesis of the protein. It\u27s conceivable that the agouti locus could modulate the following components of tyrosinase: transcription, translation, glycosylation and other posttranslational processes, deployment of tyrosinase through the cell\u27s endomembrane system to the tyrosinase - containing coated Golgi Vesicle, migration of the Golgi vesicle to premelanosomes, incorporation into melanosomes, parameters of tyrosinase - matrix protein interaction, and others. Some of these effects of the agouti locus on tyrosinase activity were studied in this research. It is important to keep in mind that knowledge gained from the study of genes that regulate melanogenesis may help in revealing the function of genes that cause cancer, obesity, infertility, and other abnormalities. Because the mouse is a mammal, the modus operandi of gene expression and regulation may be closely related to that of Homo sapiens. Because genetic regulation is fundamental not only to embryogenesis and development but also to homeostasis, studies which lead to an understanding of the regulation of mammalian genes are highly meritorious

Variability of recurrence interval and single-event slip for surface-rupturing earthquakes in New Zealand

<p>Recurrence interval (RI) and single-event slip (SES) for large-magnitude earthquakes that ruptured the ground surface (<i>M</i>_w > 6–7.2) can vary by more than an order of magnitude on individual faults. Frequency histograms, probability density functions (PDFs) and coefficient of variation (<i>C</i>_v, standard deviation/arithmetic mean) values for geological and simulated earthquakes on over 100 New Zealand active faults have been used to quantify RI and SES variability. Histograms of RI and SES for geological paleoearthquakes were constructed using a Monte Carlo method which accounts for the observations and their uncertainties. For the best of the geological PDFs (i.e. ≥7 surface-rupturing events) and earthquake simulations, RI are positively skewed with long recurrence tails (c. three times the mean) which are approximately described by log-normal and Weibull distributions. The geometric mean and coefficient of variation (<i>C</i>_vln) calculated for these log-normal distributions may be up to a factor of two lower and higher, respectively, than those determined assuming a normal distribution. By contrast, SES for geological and simulated earthquakes is often approximately normally distributed and appears to be less variable than RI (RI <i>C</i>_v 0.6 ± 0.2 geological and 0.6 ± 0.3 simulations; SES <i>C</i>_v 0.4 ± 0.2 geological). Variations in earthquake RI and to a lesser extent SES produce order-of-magnitude changes in slip rate over time intervals up to five times the arithmetic mean RI. Quantifying variability of RI, SES and slip rates is important when producing estimates of seismic hazard for surface-rupturing earthquakes, and could be estimated for active faults with poorly constrained paleoearthquake histories using the PDFs presented here.</p

Crowning glory: public law, power and the monarchy

‘New public law’ has a keen interest in the deployment of power and the shifting nature of the public and private. In this article, we argue that the historical legacy of the Crown has hindered the ability of public lawyers to respond to changes in modes of governance in the UK. The constitutional law textbook tradition has played a key role in limiting critiques of the Crown because of the obfuscation that surrounds the legal and political status of the Monarch. However, instead of discounting the significance of the monarchy, we use it as a resource for exploring governing power, the blurring of boundaries and constitutional renewal. Our starting point is the life, death and, most importantly, the funeral of Diana, Princess of Wales. The latter event exposed the political relevance of the ‘personal’ in a most dramatic way, generating claims about the ‘feminisation of the government’ and ‘emotions augmenting democracy’. We follow through on these claims in order to focus on the effects of adopting private, intimate-sphere norms in the public sphere, in particular public-sphere decision making. While aware of the risks associated with this ‘transformation’ of democracy, we conclude that the increasing centrality of the intimate merits onsideration in new public law’s search for progressive tools of modern governance

Whole egg consumption increases gene expression within the glutathione pathway in the liver of Zucker Diabetic Fatty rats.

Nutrigenomic evidence supports the idea that Type 2 Diabetes Mellitus (T2DM) arises due to the interactions between the transcriptome, individual genetic profiles, lifestyle, and diet. Since eggs are a nutrient dense food containing bioactive ingredients that modify gene expression, our goal was to examine the role of whole egg consumption on the transcriptome during T2DM. We analyzed whether whole egg consumption in Zucker Diabetic Fatty (ZDF) rats alters microRNA and mRNA expression across the adipose, liver, kidney, and prefrontal cortex tissue. Male ZDF (fa/fa) rats (n = 12) and their lean controls (fa/+) (n = 12) were obtained at 6 wk of age. Rats had ad libitum access to water and were randomly assigned to a modified semi-purified AIN93G casein-based diet or a whole egg-based diet, both providing 20% protein (w/w). TotalRNA libraries were prepared using QuantSeq 3' mRNA-Seq and Lexogen smallRNA library prep kits and were further sequenced on an Illumina HighSeq3000. Differential gene expression was conducted using DESeq2 in R and Benjamini-Hochberg adjusted P-values controlling for false discovery rate at 5%. We identified 9 microRNAs and 583 genes that were differentially expressed in response to 8 wk of consuming whole egg-based diets. Kyto Encyclopedia of Genes and Genomes/Gene ontology pathway analyses demonstrated that 12 genes in the glutathione metabolism pathway were upregulated in the liver and kidney of ZDF rats fed whole egg. Whole egg consumption primarily altered glutathione pathways such as conjugation, methylation, glucuronidation, and detoxification of reactive oxygen species. These pathways are often negatively affected during T2DM, therefore this data provides unique insight into the nutrigenomic response of dietary whole egg consumption during the progression of T2DM