Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression

The DNA damage response comprises DNA repair, cell-cycle checkpoint control, and DNA damage-induced apoptosis that collectively promote genomic integrity and suppress tumorigenesis. Previously, we have shown that the Chk2 kinase functions independently of the Mre11 complex (Mre11, Rad50, and Nbs1) and ATM in apoptosis and suppresses tumorigenesis resulting from hypomorphic alleles of Mre11 or Nbs1. Based on this work, we have proposed that Chk2 limits the oncogenic potential of replication-associated DNA damage. Here we further address the role of Chk2 and damage-induced apoptosis in suppressing the oncogenic potential of chromosome breaks. We show that loss of Chk2 or a mutation in p53 (R172P), which selectively impairs its function in apoptosis, rescued the lethality of mice lacking Lig4, a ligase required for nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks in G0/G1. In contrast to Lig4(−/−)p53(−/−) mice, Lig4(−/−)Chk2(−/−) and Lig4(−/−)p53(R172P/R172P) mice were not prone to organ-specific, rapid tumorigenesis. Although the severe NHEJ deficiency of Lig4(−/−) was a less potent initiator of tumorigenesis in the p53(R172P/R172P) and Chk2(−/−) backgrounds, where p53 cell-cycle functions are largely intact, even mild defects in the intra-S and G2/M checkpoints caused by mutations in Nbs1 are sufficient to influence malignancy in p53(R172P/R172P) mice. We conclude that the oncogenic potential of double-strand breaks resulting from NHEJ deficiency is highly restricted by nonapoptotic functions of p53, such as the G1/S checkpoint or senescence, suggesting that the particular facets of the DNA damage response required for tumor suppression are dictated by the proliferative status of the tumor-initiating cell

Spatially Resolved Outflows in a Seyfert Galaxy at z = 2.39

We present the first spatially resolved analysis of rest-frame optical and UV imaging and spectroscopy for a lensed galaxy at z = 2.39 hosting a Seyfert active galactic nucleus (AGN). Proximity to a natural guide star has enabled high signal-to-noise VLT SINFONI + adaptive optics observations of rest-frame optical diagnostic emission lines, which exhibit an underlying broad component with FWHM ~ 700 km/s in both the Balmer and forbidden lines. Measured line ratios place the outflow robustly in the region of the ionization diagnostic diagrams associated with AGN. This unique opportunity - combining gravitational lensing, AO guiding, redshift, and AGN activity - allows for a magnified view of two main tracers of the physical conditions and structure of the interstellar medium in a star-forming galaxy hosting a weak AGN at cosmic noon. By analyzing the spatial extent and morphology of the Ly-alpha and dust-corrected H-alpha emission, disentangling the effects of star formation and AGN ionization on each tracer, and comparing the AGN induced mass outflow rate to the host star formation rate, we find that the AGN does not significantly impact the star formation within its host galaxy.Comment: 16 pages, 5 figures, accepted for publication in Ap

Development of the US3D Code for Advanced Compressible and Reacting Flow Simulations

Aerothermodynamics and hypersonic flows involve complex multi-disciplinary physics, including finite-rate gas-phase kinetics, finite-rate internal energy relaxation, gas-surface interactions with finite-rate oxidation and sublimation, transition to turbulence, large-scale unsteadiness, shock-boundary layer interactions, fluid-structure interactions, and thermal protection system ablation and thermal response. Many of the flows have a large range of length and time scales, requiring large computational grids, implicit time integration, and large solution run times. The University of Minnesota NASA US3D code was designed for the simulation of these complex, highly-coupled flows. It has many of the features of the well-established DPLR code, but uses unstructured grids and has many advanced numerical capabilities and physical models for multi-physics problems. The main capabilities of the code are described, the physical modeling approaches are discussed, the different types of numerical flux functions and time integration approaches are outlined, and the parallelization strategy is overviewed. Comparisons between US3D and the NASA DPLR code are presented, and several advanced simulations are presented to illustrate some of novel features of the code

The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung

IntroductionBecause small-cell lung carcinomas (SCLC) are seldom resected, human materials for study are limited. Thus, genetically engineered mouse models (GEMMs) for SCLC and other high-grade lung neuroendocrine (NE) carcinomas are crucial for translational research.MethodsThe pathologies of five GEMMs were studied in detail and consensus diagnoses reached by four lung cancer pathology experts. Hematoxylin and Eosin and immunostained slides of over 100 mice were obtained from the originating and other laboratories and digitalized. The GEMMs included the original Rb/p53 double knockout (Berns Laboratory) and triple knockouts from the Sage, MacPherson, and Jacks laboratories (double knockout model plus loss of p130 [Sage laboratory] or loss of Pten [MacPherson and Jacks laboratories]). In addition, a GEMM with constitutive co-expression of SV40 large T antigen and Ascl1 under the Scgb1a1 promoter from the Linnoila laboratory were included.ResultsThe lung tumors in all of the models had common as well as distinct pathological features. All three conditional knockout models resulted in multiple pulmonary tumors arising mainly from the central compartment (large bronchi) with foci of in situ carcinoma and NE cell hyperplasia. They consisted of inter- and intra-tumor mixtures of SCLC and large-cell NE cell carcinoma in varying proportions. Occasional adeno- or large-cell carcinomas were also seen. Extensive vascular and lymphatic invasion and metastases to the mediastinum and liver were noted, mainly of SCLC histology. In the Rb/p53/Pten triple knockout model from the MacPherson and Jacks laboratories and in the constitutive SV40/T antigen model many peripherally arising non–small-cell lung carcinoma tumors having varying degrees of NE marker expression were present (non–small-cell lung carcinoma-NE tumors). The resultant histological phenotypes were influenced by the introduction of specific genetic alterations, by inactivation of one or both alleles of specific genes, by time from Cre activation and by targeting of lung cells or NE cell subpopulations.ConclusionThe five GEMM models studied are representative for the entire spectrum of human high-grade NE carcinomas and are also useful for the study of multistage pathogenesis and the metastatic properties of these tumors. They represent one of the most advanced forms of currently available GEMM models for the study of human cancer

The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung

Introduction: Because small-cell lung carcinomas (SCLC) are seldom resected, human materials for study are limited. Thus, genetically engineered mouse models (GEMMs) for SCLC and other high-grade lung neuroendocrine (NE) carcinomas are crucial for translational research. Methods: The pathologies of five GEMMs were studied in detail and consensus diagnoses reached by four lung cancer pathology experts. Hematoxylin and Eosin and immunostained slides of over 100 mice were obtained from the originating and other laboratories and digitalized. The GEMMs included the original Rb/p53 double knockout (Berns Laboratory) and triple knockouts from the Sage, MacPherson, and Jacks laboratories (double knockout model plus loss of p130 [Sage laboratory] or loss of Pten [MacPherson and Jacks laboratories]). In addition, a GEMM with constitutive co-expression of SV40 large T antigen and Ascl1 under the Scgb1a1 promoter from the Linnoila laboratory were included. Results: The lung tumors in all of the models had common as well as distinct pathological features. All three conditional knockout models resulted in multiple pulmonary tumors arising mainly from the central compartment (large bronchi) with foci of in situ carcinoma and NE cell hyperplasia. They consisted of inter- and intra-tumor mixtures of SCLC and large-cell NE cell carcinoma in varying proportions. Occasional adeno- or large-cell carcinomas were also seen. Extensive vascular and lymphatic invasion and metastases to the mediastinum and liver were noted, mainly of SCLC histology. In the Rb/p53/Pten triple knockout model from the MacPherson and Jacks laboratories and in the constitutive SV40/T antigen model many peripherally arising non-small-cell lung carcinoma tumors having varying degrees of NE marker expression were present (non-small-cell lung carcinoma-NE tumors). The resultant histological phenotypes were influenced by the introduction of specific genetic alterations, by inactivation of one or both alleles of specific genes, by time from Cre activation and by targeting of lung cells or NE cell subpopulations. Conclusion: The five GEMM models studied are representative for the entire spectrum of human high-grade NE carcinomas and are also useful for the study of multistage pathogenesis and the metastatic properties of these tumors. They represent one of the most advanced forms of currently available GEMM models for the study of human cancer. Key Words: Neuroendocrine carcinomas; Small-cell lung carcinoma; Lung carcinoma; Non–small-cell lung cancer; Genetically engineered mouse models; Patholog

Spatially Resolved Outflows in a Seyfert Galaxy at z=2.39

We present the first spatially resolved analysis of rest-frame optical and UV (UltraViolet) imaging and spectroscopy for a lensed galaxy at z equals 2.39 hosting a Seyfert active galactic nucleus (AGN). Proximity to a natural guide star has enabled observations with high signal-to-noise ratio using Very Large Telescope SINFONI (Spectrograph for INtegral Field Observations in the Near Infrared) plus adaptive optics (AO) of rest-frame optical diagnostic emission lines, which exhibit an underlying broad component with full width at half maximum approximately 700 kilometers per second in both the Balmer and forbidden lines. Measured line ratios place the outflow robustly in the region of the ionization diagnostic diagrams associated with AGNs. This unique opportunity - combining gravitational lensing, AO guiding, redshift, and AGN activity - allows for a magnified view of two main tracers of the physical conditions and structure of the interstellar medium in a star-forming galaxy hosting a weak AGN at Cosmic Noon. By analyzing the spatial extent and morphology of the Lyman alpha spectral line and dust-corrected Hydrogen spectral line emission, disentangling the effects of star formation and AGN ionization on each tracer, and comparing the AGN-induced mass outflow rate to the host star formation rate, we find that the AGN does not significantly impact the star formation within its host galaxy

Accommodating 'others'?: housing dispersed, forced migrants in the UK

Utilising insights from a qualitative study in the city of Leeds (UK), this paper considers issues related to the housing of dispersed forced migrants. The term 'dispersed forced migrants' is used here as a general label to include four groups of international migrants (i.e. refugees, asylum seekers, those with humanitarian protection status and failed asylum seekers) who have previously been dispersed, on a no choice basis, to a variety of locations across the UK under the requirements of the Immigration and Asylum Act (1999). The tiering of housing entitlement that exists within the generic population of dispersed forced migrants (a consequence of the particular socio-legal status assigned to individuals), and its role in rendering migrants susceptible to homelessness is outlined. The adequacy/standard of accommodation made available to forced migrants is also discussed. It is concluded that current arrangements fail to meet the basic housing needs of many forced migrants. Any future improvement in this situation will require a significant shift in government policy

Recruitment Strategies and Lessons Learned from the Children's Healthy Living Program Prevalence Survey

The US Affiliated Pacific region's childhood obesity prevalence has reached epidemic proportions. To guide program and policy development, a multi-site study was initiated, in collaboration with partners from across the region, to gather comprehensive information on the regional childhood obesity prevalence. The environmental and cultural diversity of the region presented challenges to recruiting for and implementing a shared community-based, public health research program. This paper presents the strategies used to recruit families with young children (n = 5775 for children 2 - 8 years old) for obesity-related measurement across eleven jurisdictions in the US Affiliated Pacific Region. Data were generated by site teams that provided summaries of their recruitment strategies and lessons learned. Conducting this large multi-site prevalence study required considerable coordination, time and flexibility. In every location, local staff knowledgeable of the community was hired to lead recruitment, and participant compensation reflected jurisdictional appropriateness (e.g., gift cards, vouchers, or cash). Although recruitment approaches were site-specific, they were predominantly school-based or a combination of school- and community-based. Lessons learned included the importance of organization buy-in; communication, and advance planning; local travel and site peculiarities; and flexibility. Future monitoring of childhood obesity prevalence in the region should consider ways to integrate measurement activities into existing organizational infrastructures for sustainability and cost-effectiveness, while meeting programmatic (e.g. study) goals

Harnessing the NEON data revolution to advance open environmental science with a diverse and data-capable community

It is a critical time to reflect on the National Ecological Observatory Network (NEON) science to date as well as envision what research can be done right now with NEON (and other) data and what training is needed to enable a diverse user community. NEON became fully operational in May 2019 and has pivoted from planning and construction to operation and maintenance. In this overview, the history of and foundational thinking around NEON are discussed. A framework of open science is described with a discussion of how NEON can be situated as part of a larger data constellation—across existing networks and different suites of ecological measurements and sensors. Next, a synthesis of early NEON science, based on \u3e100 existing publications, funded proposal efforts, and emergent science at the very first NEON Science Summit (hosted by Earth Lab at the University of Colorado Boulder in October 2019) is provided. Key questions that the ecology community will address with NEON data in the next 10 yr are outlined, from understanding drivers of biodiversity across spatial and temporal scales to defining complex feedback mechanisms in human–environmental systems. Last, the essential elements needed to engage and support a diverse and inclusive NEON user community are highlighted: training resources and tools that are openly available, funding for broad community engagement initiatives, and a mechanism to share and advertise those opportunities. NEON users require both the skills to work with NEON data and the ecological or environmental science domain knowledge to understand and interpret them. This paper synthesizes early directions in the community’s use of NEON data, and opportunities for the next 10 yr of NEON operations in emergent science themes, open science best practices, education and training, and community building