Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis

Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.</p

Pelvis morphology suggests that early Mesozoic birds were too heavy to contact incubate their egg

Numerous new fossils have driven an interest in reproduction of early birds, but direct evidence remains elusive. No Mesozoic avian eggs can be unambiguously assigned to a species, which hampers our understanding of the evolution of contact incubation, which is a defining feature of extant birds. Compared to living species, eggs of Mesozoic birds are relatively small, but whether the eggs of Mesozoic birds could actually have borne the weight of a breeding adult has not yet been investigated. We estimated maximal egg breadth for a range of Mesozoic avian taxa from the width of the pelvic canal defined by the pubic symphysis. Known elongation ratios of Mesozoic bird eggs allowed us to predict egg mass and hence the load mass an egg could endure before cracking. These values were compared to the predicted body masses of the adult birds based on skeletal remains. Based on 21 fossil species, we show that for nonornithothoracine birds body mass was 187% of the load mass of the eggs. For Enantiornithes, body mass was 127% greater than the egg load mass, but some early Cretaceous ornithuromorphs were 179% heavier than their eggs could support. Our indirect approach provides the best evidence yet that early birds could not have sat on their eggs without running the risk of causing damage. We suggest that contact incubation evolved comparatively late in birds

Size Doesn't Matter: Towards a More Inclusive Philosophy of Biology

notes: As the primary author, O’Malley drafted the paper, and gathered and analysed data (scientific papers and talks). Conceptual analysis was conducted by both authors.publication-status: Publishedtypes: ArticlePhilosophers of biology, along with everyone else, generally perceive life to fall into two broad categories, the microbes and macrobes, and then pay most of their attention to the latter. ‘Macrobe’ is the word we propose for larger life forms, and we use it as part of an argument for microbial equality. We suggest that taking more notice of microbes – the dominant life form on the planet, both now and throughout evolutionary history – will transform some of the philosophy of biology’s standard ideas on ontology, evolution, taxonomy and biodiversity. We set out a number of recent developments in microbiology – including biofilm formation, chemotaxis, quorum sensing and gene transfer – that highlight microbial capacities for cooperation and communication and break down conventional thinking that microbes are solely or primarily single-celled organisms. These insights also bring new perspectives to the levels of selection debate, as well as to discussions of the evolution and nature of multicellularity, and to neo-Darwinian understandings of evolutionary mechanisms. We show how these revisions lead to further complications for microbial classification and the philosophies of systematics and biodiversity. Incorporating microbial insights into the philosophy of biology will challenge many of its assumptions, but also give greater scope and depth to its investigations

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy

Evidence for Parapatric Speciation in the Mormyrid Fish, Pollimyrus castelnaui (Boulenger, 1911), from the Okavango–Upper Zambezi River Systems: P. marianne sp. nov., Defined by Electric Organ Discharges, Morphology and Genetics

We report on parapatric speciation in the mormyrid fish,Pollimyrus castelnaui (Boulenger, 1911), from the Okavango and the Upper Zambezi River systems. We recognise samples from the Zambezi River as a distinct species, P. marianne, displaying an eastern phenotype of electric organ discharge (EOD) waveform (Type 3) that is distinct from the western EOD phenotype (Type 1) observed in P. castelnaui samples from the neighbouring Okavango. Samples from the geographically intermediate Kwando/Linyanti River (a tributary of the Zambezi that is also intermittently connected to the Okavango) presented a more variable third EOD phenotype (Type 2). In 13 out of 14 morphological characters studied, the Zambezi River samples differed significantly from P. castelnaui. Morphologically and in EOD characters, the Kwando/Linyanti fish are distinct from both P. castelnaui and P. marianne. Sequence analysis of the mitochondrial cytochrome b gene unambiguously reveals that specimens from the Zambezi River System form a well supported taxon which clearly differs from P. castelnaui from the Okavango (1.5–2.5% sequence divergence).Within specimens from theKwando–Zambezi System some geographic differentiation can be detected (nucleotide substitutions up to 0.6%); but groups cannot be resolved with certainty. Significant allozyme differences were found between the Okavango and all other EOD types from the Upper Zambezi System, and, within the Zambezi System, between the Kwando (Type 2) and Zambezi (Type 3) individuals. The low Wright’s fixation index values, the lack of fixed allele differences, and small genetic distances provide little evidence for speciation between groups within the Zambezi System, but moderate to great fixation index values and significant allele frequency differences were observed between the Okavango and the other fishes. It is concluded that within the Zambezi System, differentiation between Kwando/Linyanti and Zambezi populations (as revealed by morphology and EOD waveform comparisons) is so recent that substantial genetic (allozyme and mitochondrial sequence) differences could not have evolved, or were not detected