Confinement of the Sun's interior magnetic field: some exact boundary-layer solutions

High-latitude laminar confinement of the Sun's interior magnetic field is shown to be possible, as originally proposed by Gough and McIntyre (1998) but contrary to a recent claim by Brun and Zahn (A&A 2006). Mean downwelling as weak as 2x10^-6cm/s -- gyroscopically pumped by turbulent stresses in the overlying convection zone and/or tachocline -- can hold the field in advective-diffusive balance within a confinement layer of thickness scale ~ 1.5Mm ~ 0.002 x (solar radius) while transmitting a retrograde torque to the Ferraro-constrained interior. The confinement layer sits at the base of the high-latitude tachocline, near the top of the radiative envelope and just above the `tachopause' marking the top of the helium settling layer. A family of exact, laminar, frictionless, axisymmetric confinement-layer solutions is obtained for uniform downwelling in the limit of strong rotation and stratification. A scale analysis shows that the flow is dynamically stable and the assumption of laminar flow realistic. The solution remains valid for downwelling values of the order of 10^-5cm/s but not much larger. This suggests that the confinement layer may be unable to accept a much larger mass throughput. Such a restriction would imply an upper limit on possible internal field strengths, perhaps of the order of hundreds of gauss, and would have implications also for ventilation and lithium burning. The solutions have interesting chirality properties not mentioned in the paper owing to space restrictions, but described at http://www.atmos-dynamics.damtp.cam.ac.uk/people/mem/papers/SQBO/solarfigure.htmlComment: 6 pages, 3 figures, to appear in conference proceedings: Unsolved Problems in Stellar Physic

Mouse models of colorectal cancer as preclinical models.

In this review, we discuss the application of mouse models to the identification and pre-clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large-scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross-species comparative 'omics-based approaches to this problem. We highlight recent progress in modelling late-stage disease using mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection.REM, SJAB, MJA and DJA are funded by Cancer Research UK.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/bies.20150003

A high-throughput in vivo micronucleus assay for genome instability screening in mice.

We describe a sensitive, robust, high-throughput method for quantifying the formation of micronuclei, markers of genome instability, in mouse erythrocytes. Micronuclei are whole chromosomes or chromosome segments that have been separated from the nucleus. Other methods of detection rely on labor-intensive, microscopy-based techniques. Here we describe a 2-d, 96-well plate-based flow cytometric method of micronucleus scoring that is simple enough for a research technician experienced in flow cytometry to perform. The assay detects low levels of genome instability that cannot be readily identified by classic phenotyping, using 25 μl of blood. By using this assay, we have screened >10,000 blood samples and discovered novel genes that contribute to vertebrate genome maintenance, as well as novel disease models and mechanisms of genome instability disorders. We discuss experimental design considerations, including statistical power calculation, we provide troubleshooting tips and we discuss factors that contribute to a false-positive increase in the number of micronucleated red blood cells and to experimental variability.Acknowledgments We thank M. Hitcham and N. Harman for assistance with blood collections, W. Cheng for assistance with flow cytometry during high-throughput screening and K. Dry for comments on the manuscript. R.E.M. is supported by Cancer Research UK (CRUK; project grant C20510/A12401). D.J.A. is supported by CRUK. D.J.A. and B.L.N. are supported by the Wellcome Trust. Research in the Jackson Laboratory is funded by CRUK program grant no. C6/A11224, the European Research Council and the European Community Seventh Framework Programme grant agreement no. HEALTH-F2-2010-259893 (DDResponse). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, UK, supplemented by CRUK. G.B. is funded by CRUK program grant no. C6/A11224.This is the accepted manuscript for a paper published in Nature Protocols 10, 205–215 (2015) doi:10.1038/nprot.2015.010, Published online 31 December 201

Quantitative diffusion tensor imaging detects dopaminergic neuronal degeneration in a murine model of Parkinson\u27s disease.

Early diagnosis of Parkinson\u27s disease (PD) is required to improve therapeutic responses. Indeed, a clinical diagnosis of resting tremor, rigidity, movement and postural deficiencies usually reflect \u3e50% loss of the nigrostriatal system in disease. In a step to address this, quantitative diffusion tensor magnetic resonance imaging (DTI) was used to assess nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication model of dopaminergic nigral degeneration. We now demonstrate increased average diffusion (p\u3c0.005) and decreased fractional anisotropy (p\u3c0.03) in the substantia nigra (SN) of 5- to 7-day MPTP-treated animals when compared to saline controls. Transverse diffusivity demonstrated the most significant differences (p \u3c or = 0.002) and correlated with the numbers of SN dopaminergic neurons (r=-0.75, p=0.012). No differences were found in the striatum, corpus callosum, cerebral cortex, or ventricles. These results demonstrate that DTI may be used as a surrogate biomarker of nigral dopaminergic neuronal degeneration

A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice.

In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate <5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males.This work was supported by Cancer Research UK and the Wellcome Trust.This is the final version of the article. It first appeared from the Genetics Society of America via http://dx.doi.org/10.1534/g3.116.03076

Increased tumorigenesis associated with loss of the tumor suppressor gene Cadm1

<p>Abstract</p> <p>Background</p> <p><it>CADM1</it> encodes an immunoglobulin superfamily (IGSF) cell adhesion molecule. Inactivation of <it>CADM1</it>, either by promoter hypermethylation or loss of heterozygosity, has been reported in a wide variety of tumor types, thus it has been postulated as a tumor suppressor gene.</p> <p>Findings</p> <p>We show for the first time that <it>Cadm1</it> homozygous null mice die significantly faster than wildtype controls due to the spontaneous development of tumors at an earlier age and an increased tumor incidence of predominantly lymphomas, but also some solid tumors. Tumorigenesis was accelerated after irradiation of <it>Cadm1</it> mice, with the reduced latency in tumor formation suggesting there are genes that collaborate with loss of <it>Cadm1</it> in tumorigenesis. To identify these co-operating genetic events, we performed a <it>Sleeping Beauty</it> transposon-mediated insertional mutagenesis screen in <it>Cadm1</it> mice, and identified several common insertion sites (CIS) found specifically on a <it>Cadm1</it>-null background (and not wildtype background).</p> <p>Conclusion</p> <p>We confirm that <it>Cadm1</it> is indeed a bona fide tumor suppressor gene and provide new insights into genetic partners that co-operate in tumorigenesis when <it>Cadm1</it>-expression is lost.</p

Navigating Social and Emotional Learning from the Inside Out: ?????????????????????Looking Inside and Across 33 leading SEL Programs: A Practical Resource for Schools and OST Providers

The field of social and emotional learning (SEL) is rapidly expanding, as educators bring a sharper focus to helping children build skills beyond academic knowledge. School climate initiatives, anti-bullying work, positive behavior supports and other SEL efforts are now steering programs in schools and out-of-school-time (OST) settings across the country. Building children's SEL skills has taken on even more urgency in the wake of the COVID-19 pandemic.This updated and expanded guide to evidence-based SEL programs offers detailed information on 33 pre-K through elementary school programs, encompassing curricular content and program highlights. Practitioners from schools, early childhood education (ECE) providers and out-of-school time (OST) can use this resource to look "inside and across" programs to better understand program content and assess program fit with their district or community needs.New chapters in the 2021 edition include recommendations for achieving equitable SEL (including common barriers and best practices) and guidance on trauma-informed or trauma-sensitive approaches to SEL, which includes principles, practices and recommendations for integrating SEL into regular practice

Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation.

Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages. We show that Nrbp1 interacts with key components of the ubiquitination machinery and that loss of Nrbp1 in the intestine results in the accumulation of Sall4, a key mediator of stem cell fate, and of Tsc22d2. We also reveal that somatic loss of Nrbp1 results in tumourigenesis, with haematological and intestinal tumours predominating, and that nuclear receptor binding protein 1 (NRBP1) is downregulated in a range of human tumours, where low expression correlates with a poor prognosis. Thus NRBP1 is a conserved regulator of cell fate, that plays an important role in tumour suppression

Somatic Evolution in Non-neoplastic IBD-Affected Colon.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis

A globally relevant change taxonomy and evidence-based change framework for land monitoring

A globally relevant and standardized taxonomy and framework for consistently describing land cover change based on evidence is presented, which makes use of structured land cover taxonomies and is underpinned by the Driver-Pressure-State-Impact-Response (DPSIR) framework. The Global Change Taxonomy currently lists 246 classes based on the notation 'impact (pressure)', with this encompassing the consequence of observed change and associated reason(s), and uses scale-independent terms that factor in time. Evidence for different impacts is gathered through temporal comparison (e.g., days, decades apart) of land cover classes constructed and described from Environmental Descriptors (EDs; state indicators) with pre-defined measurement units (e.g., m, %) or categories (e.g., species type). Evidence for pressures, whether abiotic, biotic or human-influenced, is similarly accumulated, but EDs often differ from those used to determine impacts. Each impact and pressure term is defined separately, allowing flexible combination into 'impact (pressure)' categories, and all are listed in an openly accessible glossary to ensure consistent use and common understanding. The taxonomy and framework are globally relevant and can reference EDs quantified on the ground, retrieved/classified remotely (from ground-based, airborne or spaceborne sensors) or predicted through modelling. By providing capacity to more consistently describe change processes-including land degradation, desertification and ecosystem restoration-the overall framework addresses a wide and diverse range of local to international needs including those relevant to policy, socioeconomics and land management. Actions in response to impacts and pressures and monitoring towards targets are also supported to assist future planning, including impact mitigation actions