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Abstract Objectives As mismatch repair status confers differential prognosis in colorectal cancers, this study aimed to determine associations of α–smooth muscle actin (α-SMA) protein expression in mismatch repair–proficient (pMMR) and mismatch repair–deficient (dMMR) colorectal tumors with clinicopathologic and prognostic features. Methods Tissue microarrays from patients with colorectal cancer, immunostained with α-SMA, were assessed through digital image analysis. Total (n = 962), pMMR (n = 782), and dMMR (n = 156) stromal H-scores were assessed for associations with clinicopathologic and survival data. Results Higher α-SMA expression was correlated with pMMR status (P = 5.2223 × 10–8). In the pMMR subgroup, higher α-SMA stromal expression at the tumor periphery was correlated with higher T stage (P = .002), perineural invasion (P = .038), infiltrative tumor edge (P = .01), involved nodal status (P = .036), metastases (P = .013), synchronous metastases (P = .007), recurrence (P = .004), and both 3-year and 5-year survival (P = .018). dMMR tumors showed no significant correlations with α-SMA staining. Conclusions The findings highlight that immunostaining with α-SMA in pMMR colorectal tumors, especially at the tumor periphery, has the potential to identify patients with adverse prognostic features. Digital assessment of α-SMA may offer improved objectivity, accuracy, economy of time, and risk stratification for management.

Objectives: As mismatch repair status confers differential prognosis in colorectal cancers, this study aimed to determine associations of a-smooth muscle actin ([alpha]-SMA) protein expression in mismatch repair-proficient (pMMR) and mismatch repair–deficient (dMMR) colorectal tumors with clinicopathologic and prognostic features. Methods: Tissue microarrays from patients with colorectal cancer, immunostained with [alpha]-SMA, were assessed through digital image analysis. Total (n = 962), pMMR (n = 782), and dMMR (n = 156) stromal H-scores were assessed for associations with clinicopathologic and survival data. Results: Higher [alpha]-SMA expression was correlated with pMMR status (P = 5.2223 x [10.sup.-8]). In the pMMR subgroup, higher [alpha]-SMA stromal expression at the tumor periphery was correlated with higher T stage (P = .002), perineural invasion (P = .038), infiltrative tumor edge (P = .01), involved nodal status (P = .036), metastases (P = .013), synchronous metastases (P = .007), recurrence (P = .004), and both 3-year and 5-year survival (P = .018). dMMR tumors showed no significant correlations with [alpha]-SMA staining. Conclusions: The findings highlight that immunostaining with [alpha]-SMA in pMMR colorectal tumors, especially at the tumor periphery, has the potential to identify patients with adverse prognostic features. Digital assessment of [alpha]-SMA may offer improved objectivity, accuracy, economy of time, and risk stratification for management. KEY WORDS colorectal cancer; biomarker analysis; immunohistochemistry; DNA mismatch repair; [alpha]-SMA; digital image analysis

Mobile element dynamics in seven alleles of the chalcone synthase D locus (CHS-D) of the common morning glory (Ipomoea purpurea) are analyzed in the context of synonymous nucleotide sequence distances for CHS-D exons. By using a nucleotide sequence of CHS-D from the sister species Ipomoea nil (Japanese morning glory [Johzuka-Hisatomi, Y., Hoshino, A., Mori, T., Habu, Y. & Iida, S. (1999) Genes Genet. Syst. 74, 141-147], it is also possible to determine the relative frequency of insertion and loss of elements within the CHS-D locus between these two species. At least four different types of transposable elements exist upstream of the coding region, or within the single intron of the CHS-D locus in I. purpurea. There are three distinct families of miniature inverted-repeat transposable elements (MITES), and some recent transpositions of Activator/Dissociation (Ac/Ds)-like elements (Tip100), of some short interspersed repetitive elements (SINEs), and of an insertion sequence (InslpCHSD) found in the neighborhood of this locus. The data provide no compelling evidence of the transposition of the mites since the separation of I. nil and I. purpurea roughly 8 million years ago. Finally, it is shown that the number and frequency of mobile elements are highly heterogeneous among different duplicate CHS loci, suggesting that the dynamics observed at CHS-D are locus-specific.

Reference genomes from representative species across families provide the critical infrastructure for research and conservation. The Cetacean Genomes Project (CGP) began in early 2020 to facilitate the generation of near error-free, chromosome-resolved reference genomes for all cetacean species. Towards that goal, and using the methods, goals and genome assembly quality standards of the Vertebrate Genomes Project (VGP), we generated 13 new reference genomes across eight of the 14 cetacean families. Additionally, we summarize the genome assembly characteristics for 18 species, including these newly-generated and five published genome assemblies that meet the completeness and quality standards. We infer ancestral linkage groups (ALG) for cetaceans, showing that the ancestral karyotype of 22 ALGs is largely conserved in extant species, except for Ziphiidae, and for Balaenidae and Kogiidae, which exhibit similar independent fusions. Gene annotation, characterization of historical demography, heterozygosity and runs of homozygosity (ROH) reveal important information for conservation applications. By comparing the new reference genomes to previous draft assemblies, we show that the reference genomes have enhanced characteristics that will support and promote scientific research. Specifically, the genomes improve resolution and characterization of repetitive elements, provide validation (or exclusion) of genes linked to complex traits, and allow more complete characterization of gene regions such as the highly complex Major Histocompatibility Complex (MHC) Class I and II gene clusters that are important for population health.

Reference genomes from representative species across families provide the critical infrastructure for research and conservation. The Cetacean Genomes Project (CGP) began in early 2020 to facilitate the generation of near error-free, chromosome-resolved reference genomes for all cetacean species. Towards that goal, and using the methods, goals and genome assembly quality standards of the Vertebrate Genomes Project (VGP), we generated 13 new reference genomes across eight of the 14 cetacean families. Additionally, we summarize the genome assembly characteristics for 18 species, including these newly-generated and five published genome assemblies that meet the completeness and quality standards. We infer ancestral linkage groups (ALG) for cetaceans, showing that the ancestral karyotype of 22 ALGs is largely conserved in extant species, except for Ziphiidae, and for Balaenidae and Kogiidae, which exhibit similar independent fusions. Gene annotation, characterization of historical demography, heterozygosity and runs of homozygosity (ROH) reveal important information for conservation applications. By comparing the new reference genomes to previous draft assemblies, we show that the reference genomes have enhanced characteristics that will support and promote scientific research. Specifically, the genomes improve resolution and characterization of repetitive elements, provide validation (or exclusion) of genes linked to complex traits, and allow more complete characterization of gene regions such as the highly complex Major Histocompatibility Complex (MHC) Class I and II gene clusters that are important for population health.

Notothenioids are a well characterised species flock endemic to the Antarctic and an important model group for the study of genome adaptation to extreme cold. We used a new reference assembly and clade-wide comparative genomic analysis to investigate cryonotothenioid evolution and the appearance of novel functionalities linked to cold adaptation. A new phased assembly of a model notothenioid, demonstrated low levels of haplotypic variability across the genome. Nevertheless, numerous insertions from multiple LINE-L2 clades were found, suggesting ongoing transposition with potential contribution to speciation. Contrary to expectations the locus was highly similar between haplotypes, except for large length allelic variants of genes. Analysis suggests a model for the locus expansion in through segmental tandem duplications involving two pairs of genes at time. Syntenic reconstruction of genomes from across the clade demonstrates conserved macrosyntenic relationships and group specific chromosomal fusions of notothenioids. Quantification of genome gain and transposition rates during cryonotothenioid diversification showed a first ancestral slow genome expansion concurrent with historic temperature drops. This was followed by lineage-specific massive peaks of genomic gain and transposition activity. Finally, we identified a set of genes that underwent ancestral diversifying selection and acquired novel conserved non-coding elements during the cryonotothenioid emergence. These were related to antioxidants and proteostasis, which may have facilitated the notothenioid Antarctic radiation. Diversifying selection and genomic gain linked to transposon activity are primary contributors to lineage-specific evolutionary dynamics through the clade which facilitated adaptation to life in the cold.

The energy change (ΔH) was determined for cation exchange in montmorillonite clay using solution calorimetry to quantify accepted qualitative trends of cation exchange. Five clays were obtained from the Source Clays Repository and included SAz-1, SCa-3, SHCa-1, STx-1, and SWy–2. All clays were exchanged with sodium, potassium, magnesium, calcium, aluminum, and iron. Each heat exchange was measured in calories per gram (cal/g) and average values were determined. The energy change was plotted against known cation exchange capacities (CEC) for each type of clay. Based on these trends, a linear relationship between cation exchange capacity and energy was expected. However, only the potassium clay showed any linearity. Unusual behavior resulted from all other cations and led to consideration of charge origination, solvation properties, pH, surface area, and entropy in order to improve understanding of exchange processes.

Since its inception in 2019, the Tree of Life programme at the Wellcome Sanger Institute has released high-quality, chromosomally-resolved reference genome assemblies for over 2000 species. Tree of Life has at its core multiple teams, each of which are responsible for key components of the ′genome engine′. One of these teams is the Tree of Life core laboratory, which is responsible for processing tissues across a wide range of species into high quality, high molecular weight DNA and intact RNA, and preparing tissues for Hi-C. Here, we detail the different workflows we have developed to successfully process a wide variety of species, covering plants, fungi, chordates, protists, arthropods, meiofauna and other metazoa. We summarise our success rates and describe how to best apply and combine the suite of current protocols, which are all publicly available at protocols.io.

Protein-coding nuclear genes remain an underexplored source of molecular data for phylogeny estimation in plants. Nuclear genes often occur in multigene families which limits their utility in phylogenetic studies due to the difficulties involved in assessing orthology and detecting concerted evolution. Low rates of nucleotide substitution in many nuclear genes has limited their ability to resolve evolutionary relationships at lower taxonomic levels. In addition, natural phenomena such as introgression and lineage sorting (differential transmission of alleles from a polymorphic ancestor) can complicate species-level phylogenetic analysis. A major goal of this dissertation research was to develop rapidly-evolving intron sequences in a single-copy nuclear gene (RPB2, the second-largest subunit of RNA polymerase II), for phylogenetic analysis of closely related plant taxa. The research described here involved the design of a PCR-based approach to recovering RPB2 sequences from species within the angiosperm family Ericaceae. These primers were used to PCR-amplify a 2.2 kb section of RPB2 from 37 ericaceous taxa. Nucleotide sequences from a 600 nt intron located within this region of RPB2 were used to investigate several questions pertaining to the evolutionary history of the genus Rhododendron Phylogenetic analyses of these intron sequences revealed that Ledum and Menziesia are derived from within Rhododendron. The monophyly of the lepidote rhododendrons and their close relationship to Ledum, and the multiple origins of the lateral-flowered azaleas also were demonstrated. The orthologous nature of the RPB2 sequences isolated from all taxa was proven by Southern blot, restriction fragment analysis and a genetic test cross. To critically test the phylogenetic utility of RPB2 introns at the species level, sequence variation was examined within and among Rhododendron macrophyllum populations from British Columbia to California. Trans-species polymorphism was discovered within R. macrophyllum RPB2 alleles. An RPB2 gene genealogy was generated and used to infer an evolutionary hypothesis for R. macrophyllum that incorporates Pleistocene glacial history and includes introgression of RPB2 alleles from outside the group broadly defined as elepidote rhododendrons.

Coronary computed tomography angiography (CCTA) is the first line investigation for chest pain, and it is used to guide revascularisation. However, the widespread adoption of CCTA has revealed a large group of individuals without obstructive coronary artery disease (CAD), with unclear prognosis and management. Measurement of coronary inflammation from CCTA using the perivascular fat attenuation index (FAI) Score could enable cardiovascular risk prediction and guide the management of individuals without obstructive CAD. The Oxford Risk Factors And Non-invasive imaging (ORFAN) study aimed to evaluate the risk profile and event rates among patients undergoing CCTA as part of routine clinical care in the UK National Health Service (NHS); to test the hypothesis that coronary arterial inflammation drives cardiac mortality or major adverse cardiac events (MACE) in patients with or without CAD; and to externally validate the performance of the previously trained artificial intelligence (AI)-Risk prognostic algorithm and the related AI-Risk classification system in a UK population. This multicentre, longitudinal cohort study included 40 091 consecutive patients undergoing clinically indicated CCTA in eight UK hospitals, who were followed up for MACE (ie, myocardial infarction, new onset heart failure, or cardiac death) for a median of 2·7 years (IQR 1·4–5·3). The prognostic value of FAI Score in the presence and absence of obstructive CAD was evaluated in 3393 consecutive patients from the two hospitals with the longest follow-up (7·7 years [6·4–9·1]). An AI-enhanced cardiac risk prediction algorithm, which integrates FAI Score, coronary plaque metrics, and clinical risk factors, was then evaluated in this population. In the 2·7 year median follow-up period, patients without obstructive CAD (32 533 [81·1%] of 40 091) accounted for 2857 (66·3%) of the 4307 total MACE and 1118 (63·7%) of the 1754 total cardiac deaths in the whole of Cohort A. Increased FAI Score in all the three coronary arteries had an additive impact on the risk for cardiac mortality (hazard ratio [HR] 29·8 [95% CI 13·9–63·9], p<0·001) or MACE (12·6 [8·5–18·6], p<0·001) comparing three vessels with an FAI Score in the top versus bottom quartile for each artery. FAI Score in any coronary artery predicted cardiac mortality and MACE independently from cardiovascular risk factors and the presence or extent of CAD. The AI-Risk classification was positively associated with cardiac mortality (6·75 [5·17–8·82], p<0·001, for very high risk vs low or medium risk) and MACE (4·68 [3·93–5·57], p<0·001 for very high risk vs low or medium risk). Finally, the AI-Risk model was well calibrated against true events. The FAI Score captures inflammatory risk beyond the current clinical risk stratification and CCTA interpretation, particularly among patients without obstructive CAD. The AI-Risk integrates this information in a prognostic algorithm, which could be used as an alternative to traditional risk factor-based risk calculators. British Heart Foundation, NHS-AI award, Innovate UK, National Institute for Health and Care Research, and the Oxford Biomedical Research Centre.