Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease

Effective treatment options for advanced colorectal cancer (CRC) are limited, survival rates are poor and this disease continues to be a leading cause of cancer-related deaths worldwide. Despite being a highly heterogeneous disease, a large subset of individuals with sporadic CRC typically harbor relatively few established ‘driver’ lesions. Here, we describe a collection of genetically engineered mouse models (GEMMs) of sporadic CRC that combine lesions frequently altered in human patients, including well-characterized tumor suppressors and activators of MAPK signaling. Primary tumors from these models were profiled, and individual GEMM tumors segregated into groups based on their genotypes. Unique allelic and genotypic expression signatures were generated from these GEMMs and applied to clinically annotated human CRC patient samples. We provide evidence that a Kras signature derived from these GEMMs is capable of distinguishing human tumors harboring KRAS mutation, and tracks with poor prognosis in two independent human patient cohorts. Furthermore, the analysis of a panel of human CRC cell lines suggests that high expression of the GEMM Kras signature correlates with sensitivity to targeted pathway inhibitors. Together, these findings implicate GEMMs as powerful preclinical tools with the capacity to recapitulate relevant human disease biology, and support the use of genetic signatures generated in these models to facilitate future drug discovery and validation efforts

Impacts of Climate Change on Multiple Use Management of Bureau of Land Management Land in the Intermountain West, USA

Although natural resource managers are concerned about climate change, many are unable to adequately incorporate climate change science into their adaptation strategies or management plans, and are not always aware of or do not employ the most current scientific knowledge. One of the most prominent natural resource management agencies in the United States is the Bureau of Land Management (BLM), which is tasked with managing over 248 million acres (\u3e1 million km2) of public lands for multiple, often conflicting, uses. Climate change will affect the sustainability of many of these land uses and could further increase conflicts between them. As such, the purpose of our study was to determine the extent to which climate change will affect public land uses, and whether the BLM is managing for such predicted effects. To do so, we first conducted a systematic review of peer-reviewed literature that discussed potential impacts of climate change on the multiple land uses the BLM manages in the Intermountain West, USA, and then expanded these results with a synthesis of projected vegetation changes. Finally, we conducted a content analysis of BLM Resource Management Plans in order to determine how climate change is explicitly addressed by BLM managers, and whether such plans reflect changes predicted by the scientific literature. We found that active resource use generally threatens intrinsic values such as conservation and ecosystem services on BLM land, and climate change is expected to exacerbate these threats in numerous ways. Additionally, our synthesis of vegetation modeling suggests substantial changes in vegetation due to climate change. However, BLM plans rarely referred to climate change explicitly and did not reflect the results of the literature review or vegetation model synthesis. Our results suggest there is a disconnect between management of BLM lands and the best available science on climate change. We recommend that the BLM actively integrates such research into on-the-ground management plans and activities, and that researchers studying the effects of climate change make a more robust effort to understand the practices and policies of public land management in order to effectively communicate the management significance of their findings

Manfaat Retribusi TPI Terhadap Pendapatan Nelayan Di PPN Pekalongan : Sebuah Tinjauan Kebijakan

Pekalongan Archipelagic Fishing Port is one of many ports which it has not executed appeal wipping out of fisheries retribution include fish auction fee. Objectives of this research are analysis implementation of auction fee policy and its benefit for fishermen income on Pekalongan Archipelagic Fishing Port. Methods that it used on this research were study case. This research used analysis of both qualitative and quantitative approach. Results of this research explained that fish auction fee referred to Perda No 12 in 2009. Fish auction fee is allocated both routine and incidental every year. Each fishermen who landed fish felt receiving benefit, but it were not equal which they were pay. If fish auction fee is stopped, operation of fish auction will be depend on both local government budget and particular alocation fund from center government.Key word : benefit, income, fish auction fe

The Power of Environmental Observatories for Advancing Multidisciplinary Research, Outreach, and Decision Support: The Case of the Minnesota River Basin

Observatory‐scale data collection efforts allow unprecedented opportunities for integrative, multidisciplinary investigations in large, complex watersheds, which can affect management decisions and policy. Through the National Science Foundation‐funded REACH (REsilience under Accelerated CHange) project, in collaboration with the Intensively Managed Landscapes‐Critical Zone Observatory, we have collected a series of multidisciplinary data sets throughout the Minnesota River Basin in south‐central Minnesota, USA, a 43,400‐km2 tributary to the Upper Mississippi River. Postglacial incision within the Minnesota River valley created an erosional landscape highly responsive to hydrologic change, allowing for transdisciplinary research into the complex cascade of environmental changes that occur due to hydrology and land use alterations from intensive agricultural management and climate change. Data sets collected include water chemistry and biogeochemical data, geochemical fingerprinting of major sediment sources, high‐resolution monitoring of river bluff erosion, and repeat channel cross‐sectional and bathymetry data following major floods. The data collection efforts led to development of a series of integrative reduced complexity models that provide deeper insight into how water, sediment, and nutrients route and transform through a large channel network and respond to change. These models represent the culmination of efforts to integrate interdisciplinary data sets and science to gain new insights into watershed‐scale processes in order to advance management and decision making. The purpose of this paper is to present a synthesis of the data sets and models, disseminate them to the community for further research, and identify mechanisms used to expand the temporal and spatial extent of short‐term observatory‐scale data collection efforts

Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer

PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer. Keywords: PI3K; MEK; KRAS; Colorectal cancer; Mouse model of cance

The 4D Nucleome Project [preprint]

The spatial organization of the genome and its dynamics contribute to gene expression and cellular function in normal development as well as in disease. Although we are increasingly well equipped to determine a genome\u27s sequence and linear chromatin composition, studying the three-dimensional organization of the genome with high spatial and temporal resolution remains challenging. The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and mouse genomes in space and time with the long term goal of gaining deeper mechanistic understanding of how the nucleus is organized. The project will develop and benchmark experimental and computational approaches for measuring genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other genome functions. Further efforts will be directed at applying validated experimental approaches combined with biophysical modeling to generate integrated maps and quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells

Nuclear matter effects on J/ψJ/\psi production in asymmetric Cu+Au collisions at sNN\sqrt{s_{_{NN}}} = 200 GeV

We report on $J/\psi$ production from asymmetric Cu+Au heavy-ion collisions at $\sqrt{s_{_{NN}}}$=200 GeV at the Relativistic Heavy Ion Collider at both forward (Cu-going direction) and backward (Au-going direction) rapidities. The nuclear modification of $J/\psi$ yields in Cu$+$Au collisions in the Au-going direction is found to be comparable to that in Au$+$Au collisions when plotted as a function of the number of participating nucleons. In the Cu-going direction, $J/\psi$ production shows a stronger suppression. This difference is comparable in magnitude and has the same sign as the difference expected from shadowing effects due to stronger low-$x$ gluon suppression in the larger Au nucleus. The relative suppression is opposite to that expected from hot nuclear matter dissociation, since a higher energy density is expected in the Au-going direction.Comment: 349 authors, 10 pages, 4 figures, and 4 tables. Submitted to Phys. Rev. C. For v2, fixed LaTeX error in 3rd-to-last sentence. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Transverse-Momentum Dependence of the J/psi Nuclear Modification in d+Au Collisions at sqrt(s_NN)=200 GeV

We present measured J/psi production rates in d+Au collisions at sqrt(s_NN) = 200 GeV over a broad range of transverse momentum (p_T=0-14 GeV/c) and rapidity (-2.2<y<2.2). We construct the nuclear-modification factor R_dAu for these kinematics and as a function of collision centrality (related to impact parameter for the R_dAu collision). We find that the modification is largest for collisions with small impact parameters, and observe a suppression (R_dAu<1) for p_T<4 GeV/c at positive rapidities. At negative rapidity we observe a suppression for p_T1) for p_T>2 GeV/c. The observed enhancement at negative rapidity has implications for the observed modification in heavy-ion collisions at high p_T.Comment: 384 authors, 24 pages, 19 figures, 13 tables. Submitted to Phys. Rev. C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/phenix/WWW/info/data/ppg123_data.htm

Condensed Mitotic Chromosome Structure at Nanometer Resolution Using PALM and EGFP- Histones

Photoactivated localization microscopy (PALM) and related fluorescent biological imaging methods are capable of providing very high spatial resolutions (up to 20 nm). Two major demands limit its widespread use on biological samples: requirements for photoactivatable/photoconvertible fluorescent molecules, which are sometimes difficult to incorporate, and high background signals from autofluorescence or fluorophores in adjacent focal planes in three-dimensional imaging which reduces PALM resolution significantly. We present here a high-resolution PALM method utilizing conventional EGFP as the photoconvertible fluorophore, improved algorithms to deal with high levels of biological background noise, and apply this to imaging higher order chromatin structure. We found that the emission wavelength of EGFP is efficiently converted from green to red when exposed to blue light in the presence of reduced riboflavin. The photon yield of red-converted EGFP using riboflavin is comparable to other bright photoconvertible fluorescent proteins that allow <20 nm resolution. We further found that image pre-processing using a combination of denoising and deconvolution of the raw PALM images substantially improved the spatial resolution of the reconstruction from noisy images. Performing PALM on Drosophila mitotic chromosomes labeled with H2AvD-EGFP, a histone H2A variant, revealed filamentous components of ∼70 nm. This is the first observation of fine chromatin filaments specific for one histone variant at a resolution approximating that of conventional electron microscope images (10–30 nm). As demonstrated by modeling and experiments on a challenging specimen, the techniques described here facilitate super-resolution fluorescent imaging with common biological samples