Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells

The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell of origin of these tumors, c-KIT-positive luminal progenitors. Here, we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1 mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms-uncoupling from upstream signals and splice isoform ratios-drive the activity of LYN in aggressive breast cancers

Suburban watershed nitrogen retention : estimating the effectiveness of stormwater management structures

Excess nitrogen (N) is a primary driver of freshwater and coastal eutrophication globally, and urban stormwater is a rapidly growing source of N pollution. Stormwater best management practices (BMPs) are used widely to remove excess N from runoff in urban and suburban areas, and are expected to perform under a wide variety of environmental conditions. Yet the capacity of BMPs to retain excess N varies; and both the variation and the drivers thereof are largely unknown, hindering the ability of water resource managers to meet water quality targets in a cost-effective way. Here, we use structured expert judgment (SEJ), a performance-weighted method of expert elicitation, to quantify the uncertainty in BMP performance under a range of site-specific environmental conditions and to estimate the extent to which key environmental factors influence variation in BMP performance. We hypothesized that rain event frequency and magnitude, BMP type and size, and physiographic province would significantly influence the experts’ estimates of N retention by BMPs common to suburban Piedmont and Coastal Plain watersheds of the Chesapeake Bay region. Expert knowledge indicated wide uncertainty in BMP performance, with N removal efficiencies ranging from 40%. Experts believed that the amount of rain was the primary identifiable source of variability in BMP efficiency, which is relevant given climate projections of more frequent heavy rain events in the mid-Atlantic. To assess the extent to which those projected changes might alter N export from suburban BMPs and watersheds, we combined downscaled estimates of rainfall with distributions of N loads for different-sized rain events derived from our elicitation. The model predicted higher and more variable N loads under a projected future climate regime, suggesting that current BMP regulations for reducing nutrients may be inadequate in the future

Students as co-creators of teaching approaches, course design and curricula: implications for academic developers

Within higher education, students’ voices are frequently overlooked in the design of teaching approaches, courses and curricula. In this paper we outline the theoretical background to arguments for including students as partners in pedagogical planning processes. We present examples where students have worked collaboratively in design processes along with the beneficial outcomes of these examples. Finally we focus on some of the implications and opportunities for academic developers of proposing collaborative approaches to pedagogical planning

Carbon-Enhanced Metal-Poor Stars in the Inner and Outer Halo Components of the Milky Way

(Abridged) Carbon-enhanced metal-poor (CEMP) stars in the halo components of the Milky Way are explored, based on accurate determinations of the carbon-to-iron ([C/Fe]) abundance ratios and kinematic quantities for over 30000 calibration stars from the Sloan Digital Sky Survey (SDSS). Using our present criterion that low-metallicity stars exhibiting [C/Fe] ratios ("carbonicity") in excess of [C/Fe]$= +0.7$ are considered CEMP stars, the global frequency of CEMP stars in the halo system for \feh\ $< -1.5$ is 8%; for \feh\ $< -2.0$ it is 12%; for \feh\ $<-2.5$ it is 20%. We also confirm a significant increase in the level of carbon enrichment with declining metallicity, growing from $\sim +1.0$ at \feh\ $= -1.5$ to $\sim +1.7$ at \feh\ $= -2.7$. The nature of the carbonicity distribution function (CarDF) changes dramatically with increasing distance above the Galactic plane, $|$Z$|$. For $|$Z$|$ $< 5$ kpc, relatively few CEMP stars are identified. For distances $|$Z$|$ $> 5$ kpc, the CarDF exhibits a strong tail towards high values, up to [C/Fe] $>$ +3.0. We also find a clear increase in the CEMP frequency with $|$Z$|$. For stars with $-2.0 <$ [Fe/H] $< -$1.5, the frequency grows from 5% at $|$Z$|$ $\sim 2$ kpc to 10% at $|$Z$|$ $\sim 10$ kpc. For stars with [Fe/H] $< -$2.0, the frequency grows from 8% at $|$Z$|$ $\sim 2$ kpc to 25% at $|$Z$|$ $\sim 10$ kpc. For stars with $-2.0 <$ [Fe/H] $\sim +1.0$ for 0 kpc $<$ $|$Z$|$ $<$ 10 kpc, with little dependence on $|$Z$|$; for [Fe/H] $< -$2.0, $\sim +1.5$, again roughly independent of $|$Z$|$.Comment: Accepted for publication in the Astrophysical Journal, 32 pages, 15 figure

Soot and smoke aerosol may not warm climate

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94810/1/jgrd10551.pd

Diverse perspectives on interdisciplinarity from Members of the College of the Royal Society of Canada

Various multiple-disciplinary terms and concepts (although most commonly interdisciplinarity, which is used herein) are used to frame education, scholarship, research, and interactions within and outside academia. In principle, the premise of interdisciplinarity may appear to have many strengths; yet, the extent to which interdisciplinarity is embraced by the current generation of academics, the benefits and risks for doing so, and the barriers and facilitators to achieving interdisciplinarity, represent inherent challenges. Much has been written on the topic of interdisciplinarity, but to our knowledge there have been few attempts to consider and present diverse perspectives from scholars, artists, and scientists in a cohesive manner. As a team of 57 members from the Canadian College of New Scholars, Artists, and Scientists of the Royal Society of Canada (the College) who self-identify as being engaged or interested in interdisciplinarity, we provide diverse intellectual, cultural, and social perspectives. The goal of this paper is to share our collective wisdom on this topic with the broader community and to stimulate discourse and debate on the merits and challenges associated with interdisciplinarity. Perhaps the clearest message emerging from this exercise is that working across established boundaries of scholarly communities is rewarding, necessary, and is more likely to result in impact. However, there are barriers that limit the ease with which this can occur (e.g., lack of institutional structures and funding to facilitate cross-disciplinary exploration). Occasionally, there can be significant risk associated with doing interdisciplinary work (e.g., lack of adequate measurement or recognition of work by disciplinary peers). Solving many of the world\u27s complex and pressing problems (e.g., climate change, sustainable agriculture, the burden of chronic disease, and aging populations) demands thinking and working across long-standing, but in some ways restrictive, academic boundaries. Academic institutions and key support structures, especially funding bodies, will play an important role in helping to realize what is readily apparent to all who contributed to this paper-that interdisciplinarity is essential for solving complex problems; it is the new norm. Failure to empower and encourage those doing this research will serve as a great impediment to training, knowledge, and addressing societal issues

Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development.

Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life

Estrogen pathway polymorphisms in relation to primary open angle glaucoma: An analysis accounting for gender from the United States

Purpose Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender. Methods: We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22 mmHg (high-pressure glaucoma [HPG]) or IOP 0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01). Conclusions: The estrogen SNP pathway was associated with POAG among women

Principles and Practices Fostering Inclusive Excellence: Lessons from the Howard Hughes Medical Institute’s Capstone Institutions

Best-practices pedagogy in science, technology, engineering, and mathematics (STEM) aims for inclusive excellence that fosters student persistence. This paper describes principles of inclusivity across 11 primarily undergraduate institutions designated as Capstone Awardees in Howard Hughes Medical Institute’s (HHMI) 2012 competition. The Capstones represent a range of institutional missions, student profiles, and geographical locations. Each successfully directed activities toward persistence of STEM students, especially those from traditionally underrepresented groups, through a set of common elements: mentoring programs to build community; research experiences to strengthen scientific skill/ identity; attention to quantitative skills; and outreach/bridge programs to broaden the student pool. This paper grounds these program elements in learning theory, emphasizing their essential principles with examples of how they were implemented within institutional contexts. We also describe common assessment approaches that in many cases informed programming and created traction for stakeholder buy-in. The lessons learned from our shared experiences in pursuit of inclusive excellence, including the resources housed on our companion website, can inform others’ efforts to increase access to and persistence in STEM in higher education

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo