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BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations.
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Proteína BRCA1 , Replicação do DNA , Síndrome Hereditária de Câncer de Mama e Ovário , Mutação , Transcrição Gênica , Humanos , Proteína BRCA1/deficiência , Proteína BRCA1/genética , Replicação do DNA/genética , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Síndrome Hereditária de Câncer de Mama e Ovário/fisiopatologia , RNA Polimerase II/metabolismo , Transcrição Gênica/genética , Regiões Promotoras Genéticas , Metiltransferases/deficiência , Metiltransferases/genética , Estruturas R-Loop , Morte CelularRESUMO
Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.
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Proteína BRCA1 , Neoplasias da Mama , Animais , Feminino , Humanos , Camundongos , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Neoplasias da Mama/genética , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Exorribonucleases/metabolismo , Instabilidade Genômica , Recidiva Local de Neoplasia , Estruturas R-Loop , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on five individuals with mutations in SMARCD1; the individuals present with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. Trio exome sequencing proved the mutations to be de novo in four of the five individuals. Mutations in other SWI/SNF components cause Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack their typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog Bap60 in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom-body-specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify an NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in the regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development when neuronal circuits that are required for learning and memory are formed.
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Proteínas Cromossômicas não Histona/genética , Memória , Transtornos do Neurodesenvolvimento/genética , Neurônios/metabolismo , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Regulação da Expressão Gênica , Humanos , Deficiência Intelectual/genética , Aprendizagem , Masculino , Mitose , Hipotonia Muscular/genética , Corpos Pedunculados , Mutação , Síndrome , Fatores de Transcrição/genéticaRESUMO
PREMISE: Altingiaceae is a small family with a bimodal Northern Hemisphere distribution in eastern North America and eastern Asia, and a rich Cenozoic fossil record. The charcoalified fossil infructescence Paleoaltingia gen. nov. from Turonian (Late Cretaceous) deposits of New Jersey, provides new evidence of early Altingiaceae reproductive structures and has biogeographical implications in understanding modern distribution. METHODS: Fossils were prepared using standard methods for obtaining and processing mesofossils. The fossils were examined with light microscopy, and scanning electron microscopy for observing structural and anatomical details. Phylogenetic analyses were performed using a combined matrix of molecular and morphological data. RESULTS: Based on morphological features of the fossil and the phylogenetic analyses, the new genus, Paleoaltingia, with two species (Paleoaltingia ovum-dinosauri and P. polyodonta) is erected. The phylogenetic position of Paleoaltingia confirms affinities with living Altingiaceae. CONCLUSIONS: The combination of characters-simple capitate infructescence, syncarpous bicarpellate, and bilocular ovary, unique sterile phyllome structures-indicates that the fossil taxa have close affinities to modern Altingiaceae. The unique characters of the phyllomes provide new information on the floral diversity of Altingiaceae. The emergence of Paleoaltingia in Late Cretaceous sediments of Northeastern North America represents the earliest fossil record of Altingiaceae and provides new insights into its biogeography.
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Fósseis , Ásia Oriental , Microscopia Eletrônica de Varredura , New Jersey , FilogeniaRESUMO
Proteinase-activated receptors (PARs) are a four-member family of G-protein-coupled receptors that are activated via proteolysis. PAR4 is a member of this family that is cleaved and activated by serine proteinases such as thrombin, trypsin, and cathepsin-G. PAR4 is expressed in a variety of tissues and cell types, including platelets, vascular smooth muscle cells, and neuronal cells. In studying PAR4 signaling and trafficking, we observed dynamic changes in the cell membrane, with spherical membrane protrusions that resemble plasma membrane blebbing. Since nonapoptotic membrane blebbing is now recognized as an important regulator of cell migration, cancer cell invasion, and vesicular content release, we sought to elucidate the signaling pathway downstream of PAR4 activation that leads to such events. Using a combination of pharmacological inhibition and CRISPR/CRISPR-associated protein 9 (Cas9)-mediated gene editing approaches, we establish that PAR4-dependent membrane blebbing occurs independently of the Gα q/11- and Gα i-signaling pathways and is dependent on signaling via the ß-arrestin-1/2 and Ras homolog family member A (RhoA) signaling pathways. Together these studies provide further mechanistic insight into PAR4 regulation of cellular function. SIGNIFICANCE STATEMENT: We find that the thrombin receptor PAR4 triggers cell membrane blebbing in a RhoA-and ß-arrestin-dependent manner. In addition to identifying novel cellular responses mediated by PAR4, these data provide further evidence for biased signaling in PAR4 since membrane blebbing was dependent on some, but not all, signaling pathways activated by PAR4.
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Membrana Celular/metabolismo , Membrana Celular/patologia , Receptores de Trombina/metabolismo , beta-Arrestinas/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Sistemas CRISPR-Cas , Forma Celular , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Músculo Liso Vascular/metabolismo , Ratos , Ratos Endogâmicos WKY , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Trombina/agonistas , Transdução de SinaisRESUMO
PREMISE: Fossils provide fundamental evidence of the evolutionary processes that crafted today's biodiversity and consequently for understanding life on Earth. We report the finding of Myrtaceidites eucalyptoides pollen grains preserved within the anthers of a 52-million-year-old Eucalyptus flower collected at Laguna del Hunco locality of Argentinean Patagonia and discuss its implications in understanding the evolutionary history of the iconic Australian genus Eucalyptus. METHODS: Pollen grains were extracted from the flower's anthers and were then observed under light microscopy and scanning electron microscopy. The phylogenetic position of the fossil was investigated by adding pollen data to a previously published total-evidence matrix and analyzing it using parsimony. RESULTS: We erect the species Eucalyptus xoshemium for the fossil flower. Pollen extracted from E. xoshemium belongs to the species Myrtaceidites eucalyptoides, which, until now, was only known as dispersed pollen. The numerous pollen grains recovered from the single flower allowed estimation of M. eucalyptoides' variability. Results of the phylogenetic analysis reinforce the position of this fossil within crown group Eucalyptus. CONCLUSIONS: The discovery of these pollen grains within a Patagonian Eucalyptus fossil flower confirms the hypothesis that Myrtaceidites eucalyptoides represents fossil pollen in the Eucalyptus lineage, extends the geographic and stratigraphic fossil pollen record, and supports an earlier age for crown-group eucalypts.
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Eucalyptus , Austrália , Eucalyptus/genética , Flores , Fósseis , Filogenia , PólenRESUMO
Defects in neuronal migration cause brain malformations, which are associated with intellectual disability (ID) and epilepsy. Using exome sequencing, we identified compound heterozygous variants (p.Arg71His and p. Leu729ThrfsTer6) in TMTC3, encoding transmembrane and tetratricopeptide repeat containing 3, in four siblings with nocturnal seizures and ID. Three of the four siblings have periventricular nodular heterotopia (PVNH), a common brain malformation caused by failure of neurons to migrate from the ventricular zone to the cortex. Expression analysis using patient-derived cells confirmed reduced TMTC3 transcript levels and loss of the TMTC3 protein compared to parental and control cells. As TMTC3 function is currently unexplored in the brain, we gathered support for a neurobiological role for TMTC3 by generating flies with post-mitotic neuron-specific knockdown of the highly conserved Drosophila melanogaster TMTC3 ortholog, CG4050/tmtc3. Neuron-specific knockdown of tmtc3 in flies resulted in increased susceptibility to induced seizures. Importantly, this phenotype was rescued by neuron-specific expression of human TMTC3, suggesting a role for TMTC3 in seizure biology. In addition, we observed co-localization of TMTC3 in the rat brain with vesicular GABA transporter (VGAT), a presynaptic marker for inhibitory synapses. TMTC3 is localized at VGAT positive pre-synaptic terminals and boutons in the rat hypothalamus and piriform cortex, suggesting a role for TMTC3 in the regulation of GABAergic inhibitory synapses. TMTC3 did not co-localize with Vglut2, a presynaptic marker for excitatory neurons. Our data identified TMTC3 as a synaptic protein that is involved in PVNH with ID and epilepsy, in addition to its previously described association with cobblestone lissencephaly.
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Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Heterotopia Nodular Periventricular/metabolismo , Adulto , Animais , Encéfalo/anormalidades , Córtex Cerebral/metabolismo , Drosophila melanogaster , Epilepsia/genética , Epilepsia/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Heterozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Masculino , Malformações do Sistema Nervoso/metabolismo , Neurônios/metabolismo , Linhagem , Heterotopia Nodular Periventricular/genética , Terminações Pré-Sinápticas , Ratos , Convulsões/metabolismo , Sinapses/metabolismo , Sequenciamento do ExomaRESUMO
PREMISE OF THE STUDY: Numerous fossils from the Upper Cretaceous have been confidently placed within modern crown groups. Many 95-75 Myr-old taxa, however, including the taxon described herein, do not fit well with known extant crown or stem groups. Understanding such fossils and their possible affinities would certainly enhance our understanding of the circumstances involved in a major eudicot radiation. METHODS: Bulk samples from the Old Crossman Clay Pit were prepared using standard methodology, which includes several washing and sieving steps, and a treatment with hydrofluoric acid. The fossil taxon was coded into a matrix built from the combination of two previously published morphological matrices and was analyzed using the parsimony criterion with the computer program TNT. KEY RESULTS: The fossils have a unique combination of characters relative to living and fossil Ericales taxa, and therefore, a new genus, Teuschestanthes, is erected. Mosaic evolution and rapid parallel changes in such groups blur taxonomic distinctions, and these issues are exacerbated by limited numbers of characters available in fossils. Teuschestanthes flowers are slightly bilaterally symmetrical and somewhat variable with regard to petal disposition, suggesting an early stage in transition to bilaterality from radial symmetry early in eudicot history under pollinator selective pressure. CONCLUSIONS: While Teuschestanthes shares characters with modern Ericales and Sapindales, there are significant non-overlapping differences between Teuschestanthes and modern Sapindales (notably, among others, ovule number). Based on available evidence, however, the position of Teuschestanthes is likely as an early offshoot of the stem clade of core Ericales (Ericales sensu stricto). Its relatively unstable floral plan may presage subsequent bilaterality associated with growing selective pressure by advanced pollinators.
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Evolução Biológica , Ericales/genética , Flores/anatomia & histologia , Fósseis/anatomia & histologia , Ericales/anatomia & histologia , New JerseyRESUMO
PREMISE OF THE STUDY: An inflorescence with three pistillate flowers in amber from the early Upper Cretaceous (Turonian, ~90-94 million years ago) of central New Jersey represents the oldest known flowers with features present in an early stem complex of the Fagales. The inflorescence has characteristics of Nothofagaceae, but also has strikingly distinct characters that suggest it is intermediate between Nothofagus and other Fagales. This intermediacy is consistent with its northern hemisphere distribution. METHODS: We investigated this new fossil by comparing it with extant and fossil members of the Fagales using light microscopy and nano-computed tomography. In addition, for exploring its relationships, we mapped the morphological characters onto a widely accepted molecular-based tree of modern basal Fagales using standard methods of character optimization. KEY RESULTS: The phylogenetic position of the fossil inflorescence can be unequivocally determined by the presence of unique features, singly and in combination, that are found only in "basal" members of Fagales. The fossil adds critical information on the features of the early stem Fagales, evolution of the cupule in Nothofagaceae and Fagaceae, and a reasonable biogeographic hypothesis for the differentiation of southern (e.g., Nothofagaceae) and northern hemisphere Fagales. CONCLUSIONS: This new fossil provides insight into the early evolution of Fagales and suggests that early stem Fagales that had not yet differentiated into modern families were present in the Late Cretaceous of North America. Based on available evidence, the fossil is best interpreted as an early stem member of the Fagales, with features that suggest a transition from a more generalized Nothofagus-like fagalean ancestor with some unique presumably plesiomorphic features. The presence of an enlarged perianth and flexuous styles also suggests the possibility of insect pollination, which has been lost in all Fagales with the exception of some members of subfamily Castaneoideae in Fagaceae sensu stricto (which otherwise are very different from this fossil). The poorly developed, bract-like cupule valves of the fossil can be interpreted as primitive (i.e., incipient) or as reduced from more developed cupules that are found in most modern Fagaceae and Nothofagaceae.
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Fagales/anatomia & histologia , Fósseis , Inflorescência/anatomia & histologia , Âmbar , New JerseyRESUMO
PREMISE OF THE STUDY: The floral history of early angiosperms is far from complete. The fossil discussed here has the potential to expand our knowledge of timing, reproductive biology, and paleobiogeography in early angiosperms. METHODS: Cutting-edge methodologies in CT scanning in conjunction with tomography software have opened new possibilities for discovering details in amber-preserved fossils that were inaccessible for meaningful study in the past. KEY RESULTS: The fossil is small and complex, cupulate, with numerous stamens and a suite of characters distributed in the modern families of Laurales. The most parsimonious placement of the fossil based on morphology is as a sister taxon of Atherospermataceae + Gomortega (Gomortegaceae). CONCLUSIONS: This fossil taxon, a Laurasian Lauralean from the mid-Cretaceous, is an important example of fossil Laurales with implications for biogeography and timing in the radiation and extinction in this group.
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Evolução Biológica , Fósseis/anatomia & histologia , Magnoliopsida/anatomia & histologia , Filogenia , Dispersão Vegetal , Flores/anatomia & histologia , Mianmar , ReproduçãoRESUMO
UNLABELLED: ⢠PREMISE OF THE STUDY: Plant distributions have long been understood to be correlated with the environmental conditions to which species are adapted. Climate is one of the major components driving species distributions. Therefore, it is expected that the plants coexisting in a community are reflective of the local environment, particularly climate.⢠METHODS: Presented here is a method for the estimation of climate from local plant species coexistence data. The method, Climate Reconstruction Analysis using Coexistence Likelihood Estimation (CRACLE), is a likelihood-based method that employs specimen collection data at a global scale for the inference of species climate tolerance. CRACLE calculates the maximum joint likelihood of coexistence given individual species climate tolerance characterization to estimate the expected climate.⢠KEY RESULTS: Plant distribution data for more than 4000 species were used to show that this method accurately infers expected climate profiles for 165 sites with diverse climatic conditions. Estimates differ from the WorldClim global climate model by less than 1.5°C on average for mean annual temperature and less than â¼250 mm for mean annual precipitation. This is a significant improvement upon other plant-based climate-proxy methods.⢠CONCLUSIONS: CRACLE validates long hypothesized interactions between climate and local associations of plant species. Furthermore, CRACLE successfully estimates climate that is consistent with the widely used WorldClim model and therefore may be applied to the quantitative estimation of paleoclimate in future studies.
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Clima , Meteorologia/métodos , Dispersão Vegetal , Funções Verossimilhança , Modelos BiológicosRESUMO
The coacervation and complexation of oppositely charged polyelectrolytes are dependent on numerous environmental and preparatory factors, but temperature is often overlooked. Temperature effects remain unclear because the temperature dependence of both the dielectric constant and polymer-solvent interaction parameter can yield lower and/or upper critical solution phase behaviors for PECs. Further, secondary interactions, such as hydrogen bonding, can affect the temperature response of a PEC. That is, mixtures of oppositely charged polyelectrolytes can exhibit phase separation upon lowering and/or increasing the mixture's temperature. Here, the phase behavior of poly(diallylmethylammonium)/poly(acrylic acid) (PDADMA/PAA) complexes under varying KBr ionic strengths, mixing ratios, and temperatures at a fixed pH (in which PAA hydrogen bonding can occur) is examined. At room temperature, the PDADMA/PAA PECs exhibit four different phase states: precipitate, coexisting precipitate and coacervate, solid-like gel, and coacervate. Variable-temperature optical microscopy reveals the upper critical solution temperature (UCST) at which each phase transitioned to a solution state. Interestingly, the UCST value is highly dependent on the original phase of the PEC, in which solid-like precipitates exhibit higher UCST values. Large-scale all-atom molecular dynamics (MD) simulations support that precipitates exhibit kinetic trapping, which may contribute to the higher UCST values observed in the experiment. Taken together, this study highlights the significance of temperature on the phase behavior of PECs, which may play a larger role in stimuli-responsive materials, membraneless organelles, and separations applications.
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PURPOSE: Small cell lung cancer (SCLC) is an aggressive and lethal form of lung cancer and the overall 5-year survival (OS) for patients is a dismal 7%. Radiation therapy (RT) provides some benefit for selected patients with SCLC but could be improved with radiosensitizing agents. In this study, we identified novel radiosensitizers for SCLC by a CRISPR-Cas9 screen and evaluated the efficacy of ATM inhibitor AZD1390 as a radiosensitizer of SCLC. METHODS AND MATERIALS: We transduced the SCLC cell line SBC5 with a custom CRISPR sgRNA library focused on druggable gene targets and treated cells with RT. Cells collected at multiple timepoints were subjected to next-generation sequencing. We determined radiosensitization both in vitro with cell lines assessed by short-term viability and clonogenic assays, and in vivo mouse models by tumor growth delay. Pharmacodynamic effects of AZD1390 were quantified by ATM-Ser1981 phosphorylation, and RT-induced DNA damage by comet assay. RESULTS: Using a CRISPR dropout screen, we identified multiple radiosensitizing genes for SCLC at various timepoints with ATM as a top determinant gene for radiosensitivity. Validation by ATM knockout (KO) demonstrated increased radiosensitivity by short-term viability assay (dose modification factor [DMF]50 = 3.25-3.73 in SBC5 ATM-KO) and clonogenic assays (DMF37 1.25-1.65 in SBC5 ATM-KO). ATM inhibition by AZD1390 effectively abrogated ATM Ser1981 phosphorylation in SCLC cell lines and increased RT-induced DNA damage. AZD1390 synergistically increased the radiosensitivity of SCLC cell lines (cell viability assay: SBC5 DMF37 = 2.19, SHP77 DMF37 = 1.56, H446 DMF37 = 3.27, KP1 DMF37 = 1.65 at 100nM; clonogenic assay: SBC5 DMF37 = 4.23, H1048 DMF37 = 1.91), and in vivo murine syngeneic, KP1, and patient-derived xenograft (PDX) models, JHU-LX108 and JHU-LX33. CONCLUSIONS: In this study, we demonstrated that genetically and pharmacologically (AZD1390) inhibiting ATM markedly enhanced RT against SCLC, providing a novel pharmacologically tractable radiosensitizing strategy for patients with SCLC.
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Neoplasias Pulmonares , Piridinas , Quinolonas , Radiossensibilizantes , Carcinoma de Pequenas Células do Pulmão , Humanos , Animais , Camundongos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/radioterapia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , RNA Guia de Sistemas CRISPR-Cas , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Linhagem Celular Tumoral , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
Breast cancer (BC) prognosis and outcome are adversely affected by obesity. Hyperinsulinemia, common in the obese state, is associated with higher risk of death and recurrence in BC. Up to 80% of BCs overexpress the insulin receptor (INSR), which correlates with worse prognosis. INSR's role in mammary tumorigenesis was tested by generating MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC mouse models, respectively, with coordinate mammary epithelium-restricted deletion of INSR. In both models, deletion of either one or both copies of INSR leads to a marked delay in tumor onset and burden. Longitudinal phenotypic characterization of mouse tumors and cells reveals that INSR deletion affects tumor initiation, not progression and metastasis. INSR upholds a bioenergetic phenotype in non-transformed mammary epithelial cells, independent of its kinase activity. Similarity of phenotypes elicited by deletion of one or both copies of INSR suggest a dose-dependent threshold for INSR impact on mammary tumorigenesis.
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Neoplasias Mamárias Experimentais , Receptor de Insulina , Camundongos , Animais , Receptor de Insulina/genética , Recidiva Local de Neoplasia , Transformação Celular Neoplásica/genética , Células Epiteliais/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos TransgênicosRESUMO
Homology in cladistics is reviewed. The definition of important terms is explicated in historical context. Homology is not synonymous with synapomorphy: it includes symplesiomorphy, and Hennig clearly included both plesiomorphy and synapomorphy as types of homology. Homoplasy is error, in coding, and is analogous to residual error in simple regression. If parallelism and convergence are to be distinguished, homoplasy would be evidence of the former and analogy evidence of the latter. We discuss whether there is a difference between molecular homology and morphological homology, character state homology, nested homology (additive characters), and serial homology. We conclude by proposing a global definition of homology. ©The Will Henning Society 2011.
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Pan-cancer analysis of TCGA and CPTAC (proteomics) data shows that SULF1 and SULF2 are oncogenic in a number of human malignancies and associated with poor survival outcomes. Our studies document a consistent upregulation of SULF1 and SULF2 in HNSC which is associated with poor survival outcomes. These heparan sulfate editing enzymes were considered largely functional redundant but single-cell RNAseq (scRNAseq) shows that SULF1 is secreted by cancer-associated fibroblasts in contrast to the SULF2 derived from tumor cells. Our RNAScope and patient-derived xenograft (PDX) analysis of the HNSC tissues fully confirm the stromal source of SULF1 and explain the uniform impact of this enzyme on the biology of multiple malignancies. In summary, SULF2 expression increases in multiple malignancies but less consistently than SULF1, which uniformly increases in the tumor tissues and negatively impacts survival in several types of cancer even though its expression in cancer cells is low. This paradigm is common to multiple malignancies and suggests a potential for diagnostic and therapeutic targeting of the heparan sulfatases in cancer diseases.
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PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with an overall 5-year survival rate of less than 10%. Treatment for SCLC with cisplatin/etoposide chemotherapy (C/E) ± radiotherapy has changed modestly over several decades. The ubiquitin-proteasome system is an underexplored therapeutic target for SCLC. We preclinically evaluated TAK-243, a first-in-class small molecule E1 inhibitor against UBA1. EXPERIMENTAL DESIGN: We assessed TAK-243 in 26 SCLC cell-lines as monotherapy and combined with C/E, the PARP-inhibitor, olaparib, and with radiation using cell viability assays. We interrogated TAK-243 response with gene expression to identify candidate biomarkers. We evaluated TAK-243 alone and in combination with olaparib or radiotherapy with SCLC patient-derived xenografts (PDX). RESULTS: Most SCLC cell lines were sensitive to TAK-243 monotherapy (EC50 median 15.8 nmol/L; range 10.2 nmol/L-367.3 nmol/L). TAK-243 sensitivity was associated with gene-sets involving the cell cycle, DNA and chromatin organization, and DNA damage repair, while resistance associated with cellular respiration, translation, and neurodevelopment. These associations were also observed in SCLC PDXs. TAK-243 synergized with C/E and olaparib in vitro across sensitive and resistant SCLC cell lines. Considerable TAK-243-olaparib synergy was observed in an SCLC PDX resistant to both drugs individually. TAK-243 radiosensitization was also observed in an SCLC PDX. CONCLUSIONS: TAK-243 displays efficacy in SCLC preclinical models. Enrichment of gene sets is associated with TAK-243 sensitivity and resistance. TAK-243 exhibits synergy when combined with genotoxic therapies in cell lines and PDXs. TAK-243 is a potential therapeutic strategy to improve SCLC patient outcomes, both as a single agent and in combination with existing therapies.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Complexo de Endopeptidases do Proteassoma , Pirazóis , Pirimidinas , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Sulfetos , Sulfonamidas , Ubiquitina , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Field photographs of plant species are crucial for research and conservation, but the lack of a centralized database makes them difficult to locate. We surveyed 25 online databases of field photographs and found that they harboured only about 53% of the approximately 125,000 vascular plant species of the Americas. These results reflect the urgent need for a centralized database that can both integrate and complete the photographic record of the world's flora.
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Biodiversidade , Bases de Dados Factuais/estatística & dados numéricos , Geografia/estatística & dados numéricos , Fotografação/estatística & dados numéricos , Plantas , AméricaRESUMO
Studies examining the diversity of plant specialized metabolites suggest that biotic and abiotic pressures greatly influence the qualitative and quantitative diversity found in a species. Large geographic distributions expose a species to a great variety of environmental pressures, thus providing an enormous opportunity for expression of environmental plasticity. Pilocarpus, a neotropical genus of Rutaceae, is rich in alkaloids, terpenoids, and coumarins, and is the only commercial source of the alkaloid pilocarpine for the treatment of glaucoma. Overharvesting of species in this genus for pilocarpine, has threatened natural populations of the species. The aim of this research was to understand how adaptation to environmental variation shapes the metabolome in multiple populations of the widespread species Pilocarpus pennatifolius. LCMS data from alkaloid and phenolic extracts of leaf tissue were analyzed with environmental predictors using unimodal unconstrained and constrained ordination methods for an untargeted metabolomics analysis. PLS-DA was used to further confirm the chemoecotypes of each site. The most important variables contributing to the alkaloid variation between the sites: mean temperature of wettest quarter, as well as the soil content of phosphorus, magnesium, and base saturation (V%). The most important contributing to the phenolic variation between the sites: mean temperature of the wettest quarter, temperature seasonality, calcium and soil electrical conductivity. This research will have broad implications in a variety of areas including biocontrol for pests, environmental and ecological plant physiology, and strategies for species conservation maximizing phytochemical diversity.
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The beech-oak family Fagaceae dominates forests from the northern temperate zone to tropical Asia and Malesia, where it reaches its southern limit. We report early Eocene infructescences of Castanopsis, a diverse and abundant fagaceous genus of Southeast Asia, and co-occurring leaves from the 52-million-year-old Laguna del Hunco flora of southern Argentina. The fossil assemblage notably includes many plant taxa that associate with Castanopsis today. The discovery reveals novel Gondwanan history in Fagaceae and the characteristic tree communities of Southeast Asian lower-montane rainforests. The living diaspora associations persisted through Cenozoic climate change and plate movements as the constituent lineages tracked post-Gondwanan mesic biomes over thousands of kilometers, underscoring their current vulnerability to rapid climate change and habitat loss.