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Structural color is poorly known in plants relative to animals. In fruits, only a handful of cases have been described, including in Viburnum tinus where the blue color results from a disordered multilayered reflector made of lipid droplets. Here, we examine the broader evolutionary context of fruit structural color across the genus Viburnum. We obtained fresh and herbarium fruit material from 30 Viburnum species spanning the phylogeny and used transmission electron microscopy, optical simulations, and ancestral state reconstruction to identify the presence/absence of photonic structures in each species, understand the mechanism producing structural color in newly identified species, relate the development of cell wall structure to reflectance in Viburnum dentatum, and describe the evolution of cell wall architecture across Viburnum. We identify at least two (possibly three) origins of blue fruit color in Viburnum in species which produce large photonic structures made of lipid droplets embedded in the cell wall and which reflect blue light. Examining the full spectrum of mechanisms producing color in pl, including structural color as well as pigments, will yield further insights into the diversity, ecology, and evolution of fruit color.

Neurotrophic Tyrosine Receptor Kinase (NTRK) genes undergo chromosomal translocations to create novel open reading frames coding for oncogenic fusion proteins; the N-terminal portion, donated by various partner genes, becomes fused to the tyrosine kinase domain of either NTRK1, NTRK2, or NTRK3. NTRK fusion proteins have been identified as driver oncogenes in a wide variety of tumors over the past three decades, including Pediatric Gliomas, Papillary Thyroid Carcinoma, Spitzoid Neoplasms, Glioblastoma, and additional tumors. Importantly, NTRK fusions function as drivers of pediatric sarcomas, accounting for approximately 15% of childhood cancers including Infantile Fibrosarcoma (IFS), a subset of pediatric soft tissue sarcoma (STS). While tyrosine kinase inhibitors (TKIs), such as larotrectinib and entrectinib, have demonstrated profound results against NTRK fusion-positive cancers, acquired resistance to these TKIs has resulted in the formation of gatekeeper, solvent-front, and compound mutations. We present a comprehensive compilation of oncogenic fusions involving NTRKs focusing specifically on pediatric STS, examining their biological signaling pathways and mechanisms of activation. The importance of an obligatory dimerization or multimerization domain, invariably donated by the N-terminal fusion partner, is discussed using characteristic fusions that occur in pediatric sarcomas. In addition, examples are presented of oncogenic fusion proteins in which the N-terminal partners may contribute additional biological activities beyond an oligomerization domain. Lastly, therapeutic approaches to the treatment of pediatric sarcoma will be presented, using first generation and second-generation agents such as selitrectinib and repotrectinib.

Paired fins are a major innovation that evolved within the jawed vertebrate lineage after divergence from the living jawless vertebrates. Extinct jawless armored stem-gnathostomes exhibit a diversity of paired bodywall extensions, from skeletal processes to simple flaps. However, osteostracans (sister to jawed vertebrates) are interpreted to manifest the first true paired appendages in a pectoral position, with pelvic appendages evolving later in association with jaws. Here we show, based on articulated remains of Tujiaaspis vividus from the Silurian of China, that galeaspids (sister to osteostracans and jawed vertebrates) possessed three unpaired dorsal fins, an approximately symmetrical hypochordal tail and a pair of continuous, branchial to caudal ventro-lateral fins. The ventro-lateral fins compare to paired fin flaps in other stem-gnathostomes but specifically to the ventro-lateral ridges of cephalaspid osteostracans which also possess differentiated pectoral fins. The ventro-lateral fins as compatible with aspects of the fin-fold hypothesis for the origin of vertebrate paired appendages. Galeaspids manifest a precursor condition to osteostracans and jawed vertebrates where paired fins arose initially as continuous pectoral-pelvic lateral fins that our Computed Fluid Dynamic experiments demonstrate passively generate lift. Only later in the stem-lineage to osteostracans and jawed vertebrates did pectoral fins differentiate anteriorly. This was followed by restriction of the remaining field of fin competence to a pelvic position, facilitating active propulsion and steering.

The early history of deuterostomes, the group composed of the chordates, echinoderms and hemichordates, is still controversial, not least because of a paucity of stem-representatives to these clades. The early Cambrian microscopic animal Saccorhytus coronarius was interpreted as an early deuterostome on the basis of purported pharyngeal openings, providing evidence for a meiofaunal ancestry and an explanation for the temporal mismatch between palaeontological and molecular clock timescales of animal evolution. Here we report new material of Saccorhytus coronarius, which is reconstructed as a millimetric and ellipsoidal meiobenthic animal with spinose armor and a terminal mouth but no anus. Purported pharyngeal openings in support of the deuterostome hypothesis are shown to be taphonomic artifacts. Phylogenetic analyses indicate that Saccorhytus coronarius belongs to total-group Ecdysozoa, expanding the morphological disparity and ecological diversity of early Cambrian ecdysozoans.

Translocation of Fibroblast Growth Factor Receptors (FGFRs) often leads to aberrant cell proliferation and cancer. The BCR-FGFR1 fusion protein, created by chromosomal translocation t(8;22)(p11;q11), contains Breakpoint Cluster Region (BCR) joined to Fibroblast Growth Factor Receptor 1 (FGFR1). BCR-FGFR1 represents a significant driver of 8p11 myeloproliferative syndrome, or stem cell leukemia/lymphoma, which progresses to acute myeloid leukemia or T-cell lymphoblastic leukemia/lymphoma. Mutations were introduced at Y177F, the binding site for adapter protein Grb2 within BCR; and at Y766F, the binding site for the membrane associated enzyme PLCγ1 within FGFR1. We examined anchorage-independent cell growth, overall cell proliferation using hematopoietic cells, and activation of downstream signaling pathways. BCR-FGFR1-induced changes in protein phosphorylation, binding partners, and signaling pathways were dissected using quantitative proteomics to interrogate the protein interactome, the phosphoproteome, and the interactome of BCR-FGFR1. The effects on BCR-FGFR1-stimulated cell proliferation were examined using the PLCγ1 inhibitor U73122, and the irreversible FGFR inhibitor futibatinib (TAS-120), both of which demonstrated efficacy. An absolute requirement is demonstrated for the dual binding partners Grb2 and PLCγ1 in BCR-FGFR1-driven cell proliferation, and new proteins such as ECSIT, USP15, GPR89, GAB1, and PTPN11 are identified as key effectors for hematopoietic transformation by BCR-FGFR1.

The endosymbiotic origin of mitochondria during eukaryogenesis has long been viewed as an adaptive response to the oxygenation of Earth’s surface environment, presuming a fundamentally aerobic lifestyle for the free-living bacterial ancestors of mitochondria. This oxygen-centric view has been robustly challenged by recent advances in the Earth and life sciences. While the permanent oxygenation of the atmosphere above trace concentrations is now thought to have occurred 2.22 billion years ago, large parts of the deep ocean remained anoxic until less than 0.5 billion years ago. Neither fossils nor molecular clocks correlate the origin of mitochondria, or eukaryogenesis more broadly, to either of these planetary redox transitions. Instead, mitochondria-bearing eukaryotes are consistently dated to between these two oxygenation events, during an interval of pervasive deep-sea anoxia and variable surface water oxygenation. The discovery and cultivation of the Asgard archaea has reinforced metabolic evidence that eukaryogenesis was initially mediated by syntrophic H2 exchange between an archaeal host and an ⍺-proteobacterial symbiont living under anoxia. Together, these results temporally, spatially, and metabolically decouple the earliest stages of eukaryogenesis from the oxygen content of the surface ocean and atmosphere. Rather than reflecting the ancestral metabolic state, obligate aerobiosis in eukaryotes is most likely derived, having only become globally widespread over the past half billion years or so as atmospheric oxygen reached modern levels.

Procedural sedation (PS) is commonly performed in emergency departments (EDs) by nonanesthesiologists. Although adverse events (AEs) are rare, providers must possess the clinical skills to react in a timely manner. We previously described residents' experience and confidence in PS as part of a needs assessment. We found that their ability to perform important clinical tasks as a result of the usual training experience demonstrates educational needs. We developed an educational intervention to address the deficiencies uncovered during our needs assessment.To evaluate the effectiveness of an educational intervention on pediatric residents' clinical performance and confidence when faced with an AE during a simulated PS.This was a prospective observational cohort study of residents at a tertiary care children's hospital. All ED attending physicians and fellows were trained in uniform delivery of the educational intervention, which was delivered extemporaneously at the bedside ("Just-in-Time" [JIT]) to all residents performing PS on actual patients in the pediatric ED, over the course of 1 year. Subjects completed the following both before and after the educational intervention: a survey pertaining to confidence in PS, followed by a standardized, video-recorded simulated PS complicated by apnea and desaturation. Clinical performance was evaluated and assessed both in real time and by a video-rater blinded to participants' year of training. We summarized baseline resident characteristics, confidence questionnaire item rankings and success in both the preparation and AE tasks. We compared successful task completion and time to task completion before and after intervention.Forty residents completed both the PRE and POST phases of the study. There was significant improvement in the proportion of residents who completed both preparation and AE tasks after the JIT training. Specifically, there was a significant improvement in the proportion of residents who performed positive-pressure ventilation to treat an apneic event associated with desaturation during the PS (P = 0.007). Residents' confidence scores also significantly improved after the training.A brief JIT training in the pediatric ED improves resident clinical performance and confidence when faced with an AE during a simulated PS. Future direction includes correlating this improved performance with patient outcomes in PS.

The timing of early cellular evolution from the divergence of Archaea and Bacteria to the origin of eukaryotes remains poorly constrained. The ATP synthase complex is thought to have originated prior to the Last Universal Common Ancestor (LUCA) and analyses of ATP synthase genes, together with ribosomes, have played a key role in inferring and rooting the tree of life. Here we reconstruct the evolutionary history of ATP synthases using an expanded sampling of Archaea, Bacteria, and eukaryotes. We developed a phylogenetic cross-bracing approach making use of endosymbioses and ancient gene duplications of the major ATP synthase subunits to infer a highly resolved, dated species tree and establish an absolute timeline for ATP synthase evolution. Our analyses show that the divergence of the ATP synthase into F- and A/V-type lineages, was a very early event in cellular evolution dating back to more than 4Ga potentially predating the diversification of Archaea and Bacteria. Our cross-braced, dated tree of life also provides insight into more recent evolutionary transitions including eukaryogenesis, showing that the eukaryotic nuclear and mitochondrial lineages diverged from their closest archaeal (2.67-2.19Ga) and bacterial (2.58-2.12Ga) relatives at roughly the same time, with the nuclear stem being moderately longer.

Whole genome duplications (WGDs) are major events that drastically reshape genome architecture and are causally associated with organismal innovations and radiations1. The 2R Hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution2,3. However, the veracity and timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved4-6 and whether these WGD events underlie vertebrate phenotypic diversification remains elusive7. Here we present the genome of the inshore hagfish, Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and the 2R event occurred in the gnathostome stem-lineage in the late Cambrian after its divergence from cyclostomes. We find that the genome of stem-cyclostomes experienced two additional, independent genome duplications (herein CR1 and CR2). Functional genomic and morphospace analyses demonstrate that WGD events generally contribute to developmental evolution with similar changes in the regulatory genome of both vertebrate groups. However, appreciable morphological diversification occurred only after the 2R event, questioning the general expectation that WGDs lead to leaps of morphological complexity7.

Galeaspids are extinct jawless relatives of living jawed vertebrates whose contribution to understanding the evolutionary assembly of the gnathostome bodyplan has been limited by absence of postcranial remains. Here, we describe Foxaspis novemura gen. et sp. nov., based on complete articulated remains from a newly discovered Konservat-Lagerstätte in the Early Devonian (Pragian, ∼410 Ma) of Guangxi, South China. F. novemura had a broad, circular dorso-ventrally compressed headshield, slender trunk and strongly asymmetrical hypochordal tail fin comprised of nine ray-like scale-covered digitations. This tail morphology contrasts with the symmetrical hypochordal tail fin of Tujiaaspis vividus, evidencing disparity in galeaspid postcranial anatomy. Analysis of swimming speed reveals galeaspids as moderately fast swimmers, capable of achieving greater cruising swimming speeds than their more derived jawless and jawed relatives. Our analyses reject the hypothesis of a driven trend towards increasingly active food acquisition which has been invoked to characterize early vertebrate evolution.

FGFR3-TACC3 represents an oncogenic fusion protein frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Various exon breakpoints of FGFR3-TACC3 have been identified in cancers; these were analyzed to determine the minimum contribution of TACC3 for activation of the FGFR3-TACC3 fusion protein. While TACC3 exons 11 and 12 are dispensable for activity, our results show that FGFR3-TACC3 requires exons 13-16 for biological activity. A detailed analysis of exon 13, which consists of 8 heptads forming a coiled coil, further defined the minimal region for biological activity as consisting of 5 heptads from exon 13, in addition to exons 14-16. These conclusions were supported by transformation assays of biological activity, examination of MAPK pathway activation, analysis of disulfide-bonded FGFR3-TACC3, and by examination of the Endoglycosidase H-resistant portion of FGFR3-TACC3. These results demonstrate that clinically identified FGFR3-TACC3 fusion proteins differ in their biological activity, depending upon the specific breakpoint. This study further suggests the TACC3 dimerization domain of FGFR3-TACC3 as a novel target in treating FGFR translocation driven cancers.

Embryo-like fossils from the early Ediacaran Weng’an biota provide a window of exceptional fossil preservation onto the period of life history in which molecular clocks estimate the fundamental animal lineages to have diverged. However, their diversity and biological affinities have proven controversial, because they are morphologically simple and, consequently, their interpretation lacks phylogenetic constraint. The subcellular structures preserved in these embryo-like fossils might help to understand their cytology, biology, and diversity, but the potential of these structures has not been fully realized, because detailed microscale physical and chemical investigations are lacking. Here, to remedy this deficiency, we performed a comprehensive study to characterize their micro- and ultra-structures as well as in-situ chemical components. Our results reveal three types of subcellular structure that differ in size, shape, and mineral components: (1) relatively small and spheroidal granules in embryo-like fossils with equal cell division pattern; (2) relatively large, spheroidal, or polygonal granules in embryo-like fossils with unequal and asynchronous cell division pattern; and (3) irregular multi-layered rim-bounded granules in embryo-like fossils with unequal and asynchronous cell division pattern. We propose that the three types may be rationalized to a single taphonomic pathway of preferential mineralization of the cell cytoplasm, preserving an external mould of subcellular granules. We followed the previous interpretation that the spheroidal and polygonal granules should be fossilized lipid droplets or yolk platelets. The distinction between these subcellular structures are largely the result of postmortem degradation processes such as autolysis. The widely preserved lipid droplets or yolk platelets within these Ediacaran embryo-like fossils are compatible with the interpretion of large yolky embryos with maternal nourishment and direct development.

Premise of research. Many angiosperms produce floral displays with morphologically distinct flower types that together operate in pollinator attraction. In Viburnum, nine species in four widely sep...

— All Viburnum species produce drupes with a hardened endocarp surrounding a single seed. Endocarp form varies greatly within Viburnum, and differences in shape have long been used to distinguish major subclades. Here we trace the evolution of Viburnum endocarp shape using morphometric analyses and phylogenies for 115 Viburnum species. Endocarp measurements were obtained from fruits sampled from herbarium specimens and from field collections, and shapes were analyzed using elliptical Fourier analysis. We infer that the first viburnums had flattened and grooved endocarps. Subsequently, there were multiple losses of grooving in conjunction with shifts to both highly flattened and nearly round endocarps. In several clades the parallel evolution of a derived endocarp shape was accompanied by changes in a suite of other fruit traits, yielding distinctive fruit syndromes likely related to bird dispersal. However, in other clades endocarp shapes similar to the ancestral form have been retained while other fruit traits (color, amount of flesh, nutritional content) have diverged. We quantify cases of parallel evolution in endocarp shape that cut across recognized fruit syndromes such as red, carbohydrate-rich fruits with flattened endocarps or blue, lipid-rich fruits with round endocarps. Our analyses now invite studies of function and the selective factors that have yielded the distinctive suites of fruit and seed traits that distinguish the major Viburnum lineages.

Cladistic character matrices are routinely repurposed in analyses of morphological disparity. Unfortunately, the sampling of taxa and characters within such datasets reflects their intended application - to resolve phylogeny, rather than distinguish between phenotypes - resulting in tree shapes that often misrepresent broader taxonomic and morphological diversity. Here we use tree shape as a proxy to explore how sampling can affect perceptions of evolving morphological disparity. Through analyses of simulated and empirical data, we demonstrate that sampling can introduce biases in morphospace occupation between clades that are predicted by differences in tree symmetry and branch length distribution. Symmetrical trees with relatively long internal branches predict more expansive patterns of morphospace occupation. Conversely, asymmetrical trees with relatively short internal branches predict more compact distributions. Additionally, we find that long external branches predict greater phenotypic divergence by peripheral morphotypes. Taken together, our results caution against the uncritical repurposing of cladistic datasets in disparity analyses. However, they also demonstrate that when morphological diversity is proportionately sampled, differences in tree shape between clades can speak to genuine differences in morphospace occupation. While cladistic datasets may serve as a useful starting point, disparity datasets must attempt to achieve uniformity of lineage sampling across time and topology. Only when all potential sources of bias are accounted for can genuine evolutionary phenomena be distinguished from artefactual signals. It must be accepted that the non-uniformity of the fossil record may preclude representative sampling and, therefore, a faithful characterization of the evolution of morphological disparity.

The Wangcun fossil Lagerstätte in Hunan, South China, has yielded hundreds of fossilized embryos of Markuelia hunanensis representing different developmental stages. Internal tissues have only rarely been observed, impeding further understanding of the soft tissue anatomy, phylogenetic affinity and evolutionary significance of Markuelia . In this study, we used synchrotron radiation X-ray tomographic microscopy (SRXTM) to study a new collection of fossil embryos from the Wangcun fossil Lagerstätte. We describe specimens exhibiting a spectrum of preservation states, the best of which preserves palisade structures underneath the cuticle of the head and tail, distinct from patterns of centripetal mineralization of the cuticle and centrifugal mineralization of hypha-like structures, seen elsewhere in this specimen and other fossils within the same assemblage. Our computed tomographic reconstruction of these mineralization phases preserves the gross morphology of (i) longitudinal structures associated with the tail spines, which we interpret as the proximal ends of longitudinal muscles, and (ii) a ring-shaped structure internal to the introvert, which we interpret as a ring-shaped brain, as anticipated of the cycloneuralian affinity of Markuelia . This is the first record of a fossilized nervous system in a scalidophoran, and the first instance in Orsten-style preservation, opening the potential for further such records within this widespread mode of high-fidelity three-dimensional preservation.

The colours of fleshy fruits play a critical role in plant dispersal by advertising ripe fruits to consumers. Fruit colours have long been classified into syndromes attributed to selection by animal dispersers, despite weak evidence for this hypothesis. Here, we test the relative importance of biotic (bird and mammal frugivory) and abiotic (wet season temperatures, growing season length and UV-B radiation) factors in determining fruit colour syndrome in 3163 species of fleshy-fruited plants. We find that both dispersers and environment are important, and they interact. In warm areas, contrastive, bird-associated fruit colours increase with relative bird frugivore prevalence, whereas in cold places these colours dominate even where mammalian dispersers are prevalent. We present near-global maps of predicted fruit colour syndrome based on our species-level model and our newly developed characterisations of relative importance of bird and mammal frugivores.

Premise The Ocotea complex contains the greatest diversity of Lauraceae in the Neotropics. However, the traditional taxonomy of the group has relied on only three main floral characters, and previous molecular analyses have used only a few markers and provided limited support for relationships among the major clades. This lack of useful data has hindered the development of a comprehensive classification, as well as studies of character evolution. Methods We used RAD-seq data to infer the phylogenetic relationships of 149 species in the Ocotea complex, generating a reference-based assembly using the Persea americana genome. The results provide the basis for a phylogenetic classification that reflects our current molecular knowledge and for analyses of the evolution of breeding system, stamen number, and number of anther locules. Results We recovered a well-supported tree that demonstrates the paraphyly of Licaria, Aniba, and Ocotea and clarifies the relationships of Umbellularia, Phyllostemonodaphne, and the Old World species. To begin the development of a new classification and to facilitate precise communication, we also provide phylogenetic definitions for seven major clades. Our ancestral reconstructions show multiple origins for the three floral characters that have routinely been used in Lauraceae systematics, suggesting that these be used with caution in the future. Conclusions This study advances our understanding of phylogenetic relationships and character evolution in a taxonomically difficult group using RAD-seq data. Our new phylogenetic names will facilitate unambiguous communication as studies of the Ocotea complex progress.

Nongenomic effects of estrogen receptor α (ERα) signaling have been described for decades. Several distinct animal models have been generated previously to analyze the nongenomic ERα signaling (eg, membrane-only ER, and ERαC451A). However, the mechanisms and physiological processes resulting solely from nongenomic signaling are still poorly understood. Herein, we describe a novel mouse model for analyzing nongenomic ERα actions named H2NES knock-in (KI). H2NES ERα possesses a nuclear export signal (NES) in the hinge region of ERα protein resulting in exclusive cytoplasmic localization that involves only the nongenomic action but not nuclear genomic actions. We generated H2NESKI mice by homologous recombination method and have characterized the phenotypes. H2NESKI homozygote mice possess almost identical phenotypes with ERα null mice except for the vascular activity on reendothelialization. We conclude that ERα-mediated nongenomic estrogenic signaling alone is insufficient to control most estrogen-mediated endocrine physiological responses; however, there could be some physiological responses that are nongenomic action dominant. H2NESKI mice have been deposited in the repository at Jax (stock no. 032176). These mice should be useful for analyzing nongenomic estrogenic responses and could expand analysis along with other ERα mutant mice lacking membrane-bound ERα. We expect the H2NESKI mouse model to aid our understanding of ERα-mediated nongenomic physiological responses and serve as an in vivo model for evaluating the nongenomic action of various estrogenic agents.

Fleas (Siphonaptera) are medically important blood-feeding insects responsible for spreading pathogens such as plague, murine typhus, and myxomatosis. The peculiar morphology of fleas resulting from their specialised ectoparasitic lifestyle has meant that the phylogenetic position of this diverse and medically important group has remained one of the most persistent problems in insect evolution. Here we test competing hypotheses on the contentious evolutionary relationships of fleas and antliophoran insects using the largest molecular dataset available to date consisting of over 1,400 protein-coding genes, and a smaller mitogenome and Sanger sequence alignment of 16 genes. By removing ambiguously aligned sequence regions and using site-heterogeneous models, we consistently recover fleas nested within scorpionflies (Mecoptera) as sister to the relictual southern hemisphere family Nannochoristidae. Topology tests accounting for compositional heterogeneity strongly favour the proposed topology over previous hypotheses of antliophoran relationships. This clade is diagnosed by shared morphological characters of the head and sperm pump. Fleas may no longer be regarded as a separate insect order and we propose that Siphonaptera should be treated as an infraorder within Mecoptera, reducing the number of extant holometabolan insect orders to ten.

Premise Plant genome size ranges widely, providing many opportunities to examine how genome size variation affects plant form and function. We analyzed trends in chromosome number, genome size, and leaf traits for the woody angiosperm clade Viburnum to examine the evolutionary associations, functional implications, and possible drivers of genome size. Methods Chromosome counts and genome size estimates were mapped onto a Viburnum phylogeny to infer the location and frequency of polyploidization events and trends in genome size evolution. Genome size was analyzed with leaf anatomical and physiological data to evaluate the influence of genome size on plant function. Results We discovered nine independent polyploidization events, two reductions in base chromosome number, and substantial variation in genome size with a slight trend toward genome size reduction in polyploids. We did not find strong relationships between genome size and the functional and morphological traits that have been highlighted at broader phylogenetic scales. Conclusions Polyploidization events were sometimes associated with rapid radiations, demonstrating that polyploid lineages can be highly successful. Relationships between genome size and plant physiological function observed at broad phylogenetic scales may be largely irrelevant to the evolutionary dynamics of genome size at smaller scales. The view that plants readily tolerate changes in ploidy and genome size, and often do so, appears to apply to Viburnum.

The spatial distribution of biomes has changed considerably over deep time, so the geographical opportunity for an evolutionary lineage to shift into a new biome may depend on how the availability and connectivity of biomes has varied temporally. To better understand how lineages shift between biomes in space and time, we developed a phylogenetic biome shift model in which each lineage shifts between biomes and disperses between regions at rates that depend on the lineage’s biome affinity and location relative to the spatial distribution of biomes at any given time. To study the behavior of the biome shift model in an empirical setting, we developed a literature-based representation of paleobiome structure for three mesic forest biomes, six regions, and eight time strata, ranging from the Late Cretaceous (100 Ma) through the present. We then fitted the model to a time-calibrated phylogeny of 119 Viburnum species to compare how the results responded to various realistic or unrealistic assumptions about paleobiome structure. Ancestral biome estimates that account for paleobiome dynamics reconstructed a warm temperate (or tropical) origin of Viburnum, which is consistent with previous fossil-based estimates of ancestral biomes. Imposing unrealistic paleobiome distributions led to ancestral biome estimates that eliminated support for tropical origins, and instead inflated support for cold temperate ancestry throughout the warmer Paleocene and Eocene. The biome shift model we describe is applicable to the study of evolutionary systems beyond Viburnum, and the core mechanisms of our model are extensible to the design of richer phylogenetic models of historical biogeography and/or lineage diversification. We conclude that biome shift models that account for dynamic geographical opportunities are important for inferring ancestral biomes that are compatible with our understanding of Earth history.[Ancestral states; biome shifts; historical biogeography; niche conservatism; phylogenetics]

Cholangiocarcinoma, originating from the biliary duct, represents a subset of liver cancer. With about 8000 new cases of cholangiocarcinoma diagnosed annually in the U.S., these fall into three categories: intrahepatic, peri-hilar, and extrahepatic cholangiocarcinoma. Arising from the epithelium of the bile duct, intrahepatic cholangiocarcinoma (ICC) is a universally fatal malignancy with very few treatment options. The poor prognosis and lack of molecular targeted therapies highlights ICC as a critical unmet medical need. With advances in sequencing technology, numerous chromosomal translocations have been discovered as drivers in cancer initiation and progression. Particularly in ICC, chromosomal translocations involving Fibroblast Growth Factor Receptor 2 (FGFR2) have been frequently identified, resulting in the creation of oncogenic fusion proteins. At the N-terminus, these fusion proteins share a nearly-identical FGFR2 moiety retaining an intact kinase domain and, at the C-terminus, a dimerization/oligomerization domain provided by different partner genes, including: Periphilin 1 (PPHLN1), Bicaudal family RNA binding protein 1 (BICC1), Adenosylhomocysteinase Like 1 (AHCYL1), and Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3). A number of pre-clinical and clinical trials have shown the effectiveness of FGFR inhibitors in treating FGFR2 fusion-positive ICC patients. However, the efficacy of these inhibitors may be short-lived due to acquired resistance. In this review, we provide an overview of FGFR2 fusions, comparing their structures and mechanism of dimerization, examining the importance of FGFR2 as a partner gene, as well as highlighting the significance of alternative splicing of FGFR2 in these fusion proteins. In addition, we discuss various therapeutic options and their associated potencies in targeting these translocation-induced ICCs.

Glioblastoma (GBM) is characterized by a particularly invasive phenotype, supported by oncogenic signals from the fibroblast growth factor (FGF)/ FGF receptor (FGFR) network. However, a possible role of FGFR4 remained elusive so far. Several transcriptomic glioma datasets were analyzed. An extended panel of primary surgical specimen-derived and immortalized GBM (stem)cell models and original tumor tissues were screened for FGFR4 expression. GBM models engineered for wild-type and dominant-negative FGFR4 overexpression were investigated regarding aggressiveness and xenograft formation. Gene set enrichment analyses of FGFR4-modulated GBM models were compared to patient-derived datasets. Despite widely absent in adult brain, FGFR4 mRNA was distinctly expressed in embryonic neural stem cells and significantly upregulated in glioblastoma. Pronounced FGFR4 overexpression defined a distinct GBM patient subgroup with dismal prognosis. Expression levels of FGFR4 and its specific ligands FGF19/FGF23 correlated both in vitro and in vivo and were progressively upregulated in the vast majority of recurrent tumors. Based on overexpression/blockade experiments in respective GBM models, a central pro-oncogenic function of FGFR4 concerning viability, adhesion, migration, and clonogenicity was identified. Expression of dominant-negative FGFR4 resulted in diminished (subcutaneous) or blocked (orthotopic) GBM xenograft formation in the mouse and reduced invasiveness in zebrafish xenotransplantation models. In vitro and in vivo data consistently revealed distinct FGFR4 and integrin/extracellular matrix interactions. Accordingly, FGFR4 blockade profoundly sensitized FGFR4-overexpressing GBM models towards integrin/focal adhesion kinase inhibitors. Collectively, FGFR4 overexpression contributes to the malignant phenotype of a highly aggressive GBM subgroup and is associated with integrin-related therapeutic vulnerabilities.

Significance Geography molds how species evolve in space. Strong geographical barriers to movement, for instance, both inhibit dispersal between regions and allow isolated populations to diverge as new species. Weak barriers, by contrast, permit species range expansion and persistence. These factors present a conundrum: How strong must a barrier be before between-region speciation outpaces dispersal? We designed a phylogenetic model of dispersal, extinction, and speciation that allows regional features to influence rates of biogeographic change and applied it to the neotropical radiation of Anolis lizards. Separation by water induces a threefold steeper barrier to movement than equivalent distances over land. Our model will help biologists detect relationships between evolutionary processes and the spatial contexts in which they operate.

The Wangcun fossil Lagerstätte in Hunan, South China, has yielded hundreds of fossilized embryos of

Ecdysozoans (Phyla Arthropoda, Kinorhyncha, Loricifera, Nematoda, Nematomorpha, Onychophora, Priapulida, Tardigrada) are invertebrates bearing a tough, periodically moulted cuticle that predisposes them to exceptional preservation. Ecdysozoans dominate the oldest exceptionally preserved bilaterian animal biotas in the early to mid-Cambrian (c. 520–508 Ma), with possible trace fossils in the latest Ediacaran (, The NERC GW4 + Doctoral Training Partnership provided stipend and research expenditure to R.J.H. D.P. and M.G. were supported by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 764840. D.P. and P.C.J.D. were funded by Natural Environment Research Council (NERC) grant NE/P013678/1, part of the Biosphere Evolution, Transitions and Resilience (BETR) programme, which is co-funded by the Natural Science Foundation of China (NSFC). P.C.J.D. is funded by Biotechnology and Biological Sciences Research Council (BBSRC) grants BB/N000919/1 and BB/T012773/1. R.M.K. was funded by the Danish Natural Science Research Council (grant FNU 272-08-0576) and Carlsberg Foundation (grants CF 970345/30-488, CF 2009_01_0063, CF 2012_01_0123 and CF 16-0236). J.O. was supported by a grant from the Danish Agency for Science, Technology and Innovation (0601-12345B). M.A.W acknowledges BBSRC grant BB/K006754/1 and JTF Grant 61408. NERC Independent Research Fellowship (Grant 680 NE/L011751/1) provided salary and research expenditure for X.-Y.M. J.F.F was funded by Royal Society–Japan Society for the Promotion of Science KAKENHI grant 18F18788.

To identify a biological signal in the distribution of homoplasy, it is first necessary to isolate non-biological factors affecting its measurement. The number of states per character in a phylogenetic data matrix may indicate evolutionary flexibility and, consequently, the likelihood of recurrent evolution. However, we show here that the number of states per character limits the maximum number of steps that may be inferred using parsimony. A formula is provided for the maximum number of steps that may be taken by a character with a given number of states and taxa. We show that as more character states are included the maximum proportion of steps that can be attributed to homoplasy falls, and the greatest amount of homoplasy measurable with the consistency index declines. © The Willi Hennig Society 2009.

The ecological context of early vertebrate evolution is envisaged as a long-term trend towards increasingly active food acquisition and enhanced locomotory capabilities culminating in the emergence of jawed vertebrates. However, support for this hypothesis has been anecdotal and drawn almost exclusively from the ecology of living taxa, despite knowledge of extinct phylogenetic intermediates that can inform our understanding of this formative episode. Here we analyse the evolution of swimming speed in early vertebrates based on caudal fin morphology using ancestral state reconstruction and evolutionary model fitting. We predict the lowest and highest ancestral swimming speeds in jawed vertebrates and microsquamous jawless vertebrates, respectively, and find complex patterns of swimming speed evolution with no support for a trend towards more active lifestyles in the lineage leading to jawed groups. Our results challenge the hypothesis of an escalation of Palaeozoic marine ecosystems and shed light into the factors that determined the disparate palaeobiogeographic patterns of microsquamous versus macrosquamous armoured Palaeozoic jawless vertebrates. Ultimately, our results offer a new enriched perspective on the ecological context that underpinned the assembly of vertebrate and gnathostome body plans, supporting a more complex scenario characterized by diverse evolutionary locomotory capabilities reflecting their equally diverse ecologies.

The origin of plants and their colonization of land fundamentally transformed the terrestrial environment. Here we elucidate the basis of this formative episode in Earth history through patterns of lineage, gene and genome evolution. We use new fossil calibrations, a relative clade age calibration (informed by horizontal gene transfer) and new phylogenomic methods for mapping gene family origins. Distinct rooting strategies resolve tracheophytes (vascular plants) and bryophytes (non-vascular plants) as monophyletic sister groups that diverged during the Cambrian, 515-494 million years ago. The embryophyte stem is characterized by a burst of gene innovation, while bryophytes subsequently experienced an equally dramatic episode of reductive genome evolution in which they lost genes associated with the elaboration of vasculature and the stomatal complex. Overall, our analyses reveal that extant tracheophytes and bryophytes are both highly derived from a more complex ancestral land plant. Understanding the origin of land plants requires tracing character evolution across a diversity of modern lineages.

The endosymbiotic origin of mitochondria during eukaryogenesis has long been viewed as an adaptive response to the oxygenation of Earth's surface environment, presuming a fundamentally aerobic lifestyle for the free-living bacterial ancestors of mitochondria. This oxygen-centric view has been robustly challenged by recent advances in the Earth and life sciences. While the permanent oxygenation of the atmosphere above trace concentrations is now thought to have occurred 2.2 billion years ago, large parts of the deep ocean remained anoxic until less than 0.5 billion years ago. Neither fossils nor molecular clocks correlate the origin of mitochondria, or eukaryogenesis more broadly, to either of these planetary redox transitions. Instead, mitochondria-bearing eukaryotes are consistently dated to between these two oxygenation events, during an interval of pervasive deep-sea anoxia and variable surface-water oxygenation. The discovery and cultivation of the Asgard archaea has reinforced metabolic evidence that eukaryogenesis was initially mediated by syntrophic H

Summary There can be no doubt that early land plant evolution transformed the planet but, until recently, how and when this was achieved was unclear. Coincidence in the first appearance of land plant fossils and formative shifts in atmospheric oxygen and CO2 are an artefact of the paucity of earlier terrestrial rocks. Disentangling the timing of land plant bodyplan assembly and its impact on global biogeochemical cycles has been precluded by uncertainty concerning the relationships of bryophytes to one another and to the tracheophytes, as well as the timescale over which these events unfolded. New genome and transcriptome sequencing projects, combined with the application of sophisticated phylogenomic modelling methods, have yielded increasing support for the Setaphyta clade of liverworts and mosses, within monophyletic bryophytes. We consider the evolution of anatomy, genes, genomes and of development within this phylogenetic context, concluding that many vascular plant (tracheophytes) novelties were already present in a comparatively complex last common ancestor of living land plants (embryophytes). Molecular clock analyses indicate that embryophytes emerged in a mid-Cambrian to early Ordovician interval, compatible with hypotheses on their role as geoengineers, precipitating early Palaeozoic glaciations.

Replicated radiations, in which sets of similar forms evolve repeatedly within different regions, can provide powerful insights into parallel evolution and the assembly of functional diversity within communities. Several cases have been described in animals, but in plants we lack well-documented cases of replicated radiation that combine comprehensive phylogenetic and biogeographic analyses, the delimitation of geographic areas within which a set of 'ecomorphs' evolved independently and the identification of potential underlying mechanisms. Here we document the repeated evolution of a set of leaf ecomorphs in a group of neotropical plants. The Oreinotinus lineage within the angiosperm clade Viburnum spread from Mexico to Argentina through disjunct cloud forest environments. In 9 of 11 areas of endemism, species with similar sets of leaf forms evolved in parallel. We reject gene-flow-mediated evolution of similar leaves and show, instead, that species with disparate leaf forms differ in their climatic niches, supporting ecological adaptation as the driver of parallelism. Our identification of a case of replicated radiation in plants sets the stage for comparative analyses of such phenomena across the tree of life.

The evolution of wings propelled insects to their present mega-diversity. However, interordinal relationships of early-diverging winged insects and the timescale of their evolution are difficult to resolve, in part due to uncertainties in the placement of the enigmatic and species-poor order Zoraptera. The ‘Zoraptera problem’ has remained a contentious issue in insect evolution since its discovery more than a century ago. This is a key issue because different placements of Zoraptera imply dramatically different scenarios of diversification and character evolution among polyneopteran. Here, we investigate the systematic placement of Zoraptera using the largest protein-coding gene dataset available to date, deploying methods to mitigate common sources of error in phylogenomic inference, and testing historically proposed hypotheses of zorapteran evolution. We recover Zoraptera as the earliest-diverging polyneopteran order, while earwigs (Dermaptera) and stoneflies (Plecoptera) form a monophyletic clade (Dermoplectopterida) sister to the remainder of Polyneoptera. The morphology and palaeobiology of stem-zorapterans are informed by Mesozoic fossils. The gut content and mouthparts of a male specimen of Zorotypus nascimbenei from Kachin amber (Cretaceous) reveal a fungivorous diet of Mesozoic zorapterans, akin to extant species. Based on a set of 42 justified fossil and stratigraphic calibrations, we recover a Devonian origin of winged insects and Polyneoptera, suggesting that these groups coincided with the rise of arborescence during the diversification of early terrestrial plants, fungi, and animals. Our results provide a robust framework for understanding the pattern and timescale of early winged insect diversification.

SUMMARY High-quality protein feeds are needed in ecological and organic poultry production. Feeds that are rich in methionine (MET) are particularly important because synthetic amino acids are generally prohibited in organic livestock production. Bigheaded carp present an opportunity as feed because they are an invasive fish species that are high in protein and MET. A carp-based meal (CBM) was prepared using innovative dry extrusion, and proximate analysis and nutritional analyses were conducted. The digestible amino acids and true metabolizable energy (TMEn) of the CBM were determined using a colony of cecetomized adult roosters. Starter and grower diets were formulated with CBM and tested in a broiler feeding trial. Diets were high overall in protein, but formulated without synthetic MET. Day-old chicks were randomly assigned to pens of 30 chicks belonging to 1 of 2 treatments (CBM or control containing synthetic MET), with 8 replications. Body weights, feed intake, and feed conversion ratio (FCR) for starter (0–21 d), grower (22–42 d), and overall periods (0–42 d) were analyzed using 1-way ANOVA. The weight gains, feed intake, and FCR did not differ between treatments (P > 0.05) for the overall period (0–42 d). The results indicate that invasive bigheaded carp can be harvested and dry extruded into a novel meal, providing not only a natural and sustainable source of MET, but also an environmental service for damaged aquatic ecosystems in the U.S.

Micro-CT provides a means of nondestructively investigating the internal structure of organisms with high spatial resolution and it has been applied to address a number of palaeontological problems that would be undesirable by destructive means. This approach has been applied successfully to characterize the cranial anatomy of Shuyu, a 428 million-year-old galeaspid (jawless stem-gnathostome) from the Silurian of Changxing, Zhejiang Province, China. Here, we use the synchrotron X-ray tomographic microscopy (SRXTM) to further describe the circulatory system of the head of Shuyu. Our results indicate that the circulatory system of galeaspids exhibits a mosaic of primitive vertebrate and derived gnathostome characters, including a number of derived gnathostome characters that are absent from osteostracans — the group conventionally interpreted as the sister lineage of jawed vertebrates. Our study provides a rich source of information that can be used to infer and reconstruct the early evolutionary history of the vertebrate cardiovascular system.

Two new studies that consider the timing of origin of angiosperms are poles apart in their estimates. However, their partisan molecular and palaeontological perspectives may hold the key to establishing a unified evolutionary timescale for flowering plants.

Teeth and jaws have been widely perceived as key innovations underpinning the adaptive radiation and the evolutionary success of jawed vertebrates. However, the origin, evolution, and developmental evolution of teeth are all the subject of controversy. There are three competing hypotheses that are more or less well supported by the available data: (i) the ‘outside-in’ hypothesis which contends that odontogenic competence spread from the external dermis to the oro-pharynx – the traditional hypothesis based on the observation that teeth and scales exhibit common patterns of development that extend to the molecular genetic level, combined with evidence that scales appear before teeth within phylogeny; (ii) the ‘inside-out’ hypothesis that teeth and scales evolved independently, based on the observation that some jawless scale-covered vertebrates also possess oro-pharyngeal scales, and (iii) the ‘inside-outside’ hypothesis which is effectively agnostic on the question. The available evidence supports an origin of teeth through extension of odontogenic competence from the external dermis to the oro-pharynx.

We reconstruct the apparatus architecture of the gondollelid conodont Nicoraella kockeli based on fused clusters from the early Middle Triassic (middle Anisian, Pelsonian) of Luoping County, east Yunnan Province, southwest China. These materials were characterized non-invasively using Synchrotron X-Ray Tomographic Microscopy and the ensuing data analysed using computed tomography, allowing us to infer the composition, homologies and architectural arrangement of elements within the apparatus. Much of the original three-dimensional architecture of the apparatus is preserved and our apparatus reconstruction is the best characterized of any taxon within the superfamily Gondolelloidea. This allows us to test architectural models for gondolelloids and prioniodinins, more generally, as well as the functional interpretations based upon them. In particular, we reject a recent functional interpretation of the conodont feeding apparatus which was based on a biomechanically-optimised inference of apparatus architecture in a close gondolelloid relative of Nicoraella. Nevertheless, our architectural model provides a foundation for future functional interpretations of gondolleloids and prioniodinins, more generally.

Considerable advances have been made in our understanding of the molecular basis of hematopoietic cancers. The discovery of the BCR-ABL fusion protein over 50 years ago has brought about a new era of therapeutic progress and overall improvement in patient care, mainly due to the development and use of personalized medicine and tyrosine kinase inhibitors (TKIs). However, since the detection of BCR-ABL, BCR has been identified as a commonly occurring fusion partner in hematopoietic disorders. BCR has been discovered fused to additional tyrosine kinases, including: Fibroblast Growth Factor Receptor 1 (FGFR1), Platelet-derived Growth Factor Receptor Alpha (PDGFRA), Ret Proto-Oncogene (RET), and Janus Kinase 2 (JAK2). While BCR translocations are infrequent in hematopoietic malignancies, clinical evidence suggests that patients who harbor these mutations benefit from TKIs and additional personalized therapies. The improvement of further methodologies for characterization of these fusions is crucial to determine a patient's treatment regimen, and optimal outcome. However, potential relapse and drug resistance among patients' highlights the need for additional treatment options and further understanding of these oncogenic fusion proteins. This review explores the mechanisms behind cancer progression of these BCR oncogenic fusion proteins, comparing their similarities and differences, examining the significance of BCR as a partner gene, and discussing current treatment options for these translocation-induced hematopoietic malignancies.