This handbook focuses on the enormous literature applying statistical methodology and modelling to environmental and ecological processes. The 21st century statistics community has become ...increasingly interdisciplinary, bringing a large collection of modern tools to all areas of application in environmental processes. In addition, the environmental community has substantially increased its scope of data collection including observational data, satellite-derived data, and computer model output. The resultant impact in this latter community has been substantial; no longer are simple regression and analysis of variance methods adequate. The contribution of this handbook is to assemble a state-of-the-art view of this interface.
Features:
An internationally regarded editorial team.
A distinguished collection of contributors.
A thoroughly contemporary treatment of a substantial interdisciplinary interface.
Written to engage both statisticians as well as quantitative environmental researchers.
34 chapters covering methodology, ecological processes, environmental exposure, and statistical methods in climate science.
Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the ...therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy.
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•MITF is a driver of a reversible non-mutational drug-tolerance phase in melanoma•Drug repositioning identifies nelfinavir mesylate as a suppressor of MITF expression•Nelfinavir sensitizes BRAF and NRAS mutant melanoma to MAPK inhibitor treatment•A nelfinavir combination therapy overcomes NRAS-driven acquired resistance
Smith et al. discover PAX3-mediated overexpression of MITF as a reversible resistance mechanism to MAPK-pathway inhibition in BRAF mutant melanomas and identify nelfinavir, which inhibits this mechanism and sensitizes not only BRAF mutant but also BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Supplementary feeding, the intentional provision of food to wild birds is a common activity in developed nations during the winter. The energy inputs represented by supplementary feeding are vast, ...and thus it is likely an important mechanism shaping bird communities in urban areas. However, research in this regard has mainly occurred in temperate and non-urban settings. Moreover, few studies have been informed by supplementary feeding habits of local community members limiting their inference. We evaluated the effects of two commonly provided wild bird foods on the abundance and species diversity of birds in yards over two winters in San Antonio, Texas, United States, a city located in a subtropical region. We used a reversed Before-After-Control-Impact experimental design in which yards were randomly allocated either mixed seed, Nyjer, or no food (control) between November 2019 and March 2020 (Year One). Between November 2020 and March 2021 (Year Two) supplementary food was not provided in any yards. Point counts conducted during both years of the study revealed that overall bird abundance was consistent between years in control yards and yards provided with Nyjer. In contrast, overall bird abundance was statistically significantly higher when supplementary food was present in mixed seed yards, driven by an increase in granivorous and omnivorous species. In contrast, supplementary feeding had no statistically significant effect on the abundance of insectivorous species or on species diversity, although species diversity tended to be higher in the presence of mixed seed. Our study demonstrates that wild bird food commonly provided by community members influences measures of avian community structure during the winter in urban yards in a subtropical city. However, these results depend on the type of bird food provided. Our results provide insight into the processes underlying the effects of urbanization on bird communities, and thus have implications for the management of urban birds more broadly.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Plasmon-coupled circular dichroism has emerged as a promising approach for ultrasensitive detection of biomolecular conformations through coupling between molecular chirality and surface plasmons. ...Chiral nanoparticle assemblies without chiral molecules present also have large optical activities. We apply single-particle circular differential scattering spectroscopy coupled with electron imaging and simulations to identify both structural chirality of plasmonic aggregates and plasmon-coupled circular dichroism induced by chiral proteins. We establish that both chiral aggregates and just a few proteins in interparticle gaps of achiral assemblies are responsible for the ensemble signal, but single nanoparticles do not contribute. We furthermore find that the protein plays two roles: It transfers chirality to both chiral and achiral plasmonic substrates, and it is also responsible for the chiral three-dimensional assembly of nanorods. Understanding these underlying factors paves the way toward sensing the chirality of single biomolecules.
•Results support a causal association between interleukin-6 signaling and depression.•SNPs in the IL6R gene can affect multiple IL-6 receptor types and signaling pathways.•The direction of these ...results suggests involvement of the trans signaling pathway.
A large body of research has reported associations between depression and elevated interleukin-6 (IL-6), a cytokine with several roles including pro-inflammatory signaling. The nature and directionality of this relationship are not yet clear. In this study we use Mendelian Randomization to examine the possibility of a causal relationship between IL-6 and depressive symptoms, and to explore multiple signaling pathways that could serve as mechanisms for this relationship.
This study uses a two-sample Mendelian Randomization design. Data come from the UK Biobank (n = 89,119) and published summary statistics from six existing GWAS analyses. The primary analysis focuses on the soluble interleukin-6 receptor (sIL-6R), which is involved in multiple signaling pathways. Exploratory analyses use C-reactive protein (CRP) and soluble glycoprotein 130 (sgp130) to further examine potential underlying mechanisms.
Results are consistent with a causal effect of sIL-6R on depression (PCA-IVW Odds Ratio: 1.023 (95% Confidence Interval: 1.006–1.039), p = 0.006). Exploratory analyses demonstrate that the relationship could be consistent with either decreased classical signaling or increased trans signaling as the underlying mechanism.
These results strengthen the body evidence implicating IL-6 signaling in depression. When compared with existing observational and animal findings, the direction of these results suggests involvement of IL-6 trans signaling. Further study is needed to examine whether IL6R genetic variants might influence IL-6 trans signaling in the brain, as well as to explore other potential pathways linking depression and inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The data and analysis methodology used for the SDSS/APOGEE Data Releases 13 and 14 are described, highlighting differences from the DR12 analysis presented in Holtzman et al. Some improvement in the ...handling of telluric absorption and persistence is demonstrated. The derivation and calibration of stellar parameters, chemical abundances, and respective uncertainties are described, along with the ranges over which calibration was performed. Some known issues with the public data related to the calibration of the effective temperatures (DR13), surface gravity (DR13 and DR14), and C and N abundances for dwarfs (DR13 and DR14) are highlighted. We discuss how results from a data-driven technique, The Cannon, are included in DR14 and compare those with results from the APOGEE Stellar Parameters and Chemical Abundances Pipeline. We describe how using The Cannon in a mode that restricts the abundance analysis of each element to regions of the spectrum with known features from that element leads to Cannon abundances can lead to significantly different results for some elements than when all regions of the spectrum are used to derive abundances.
Gene silencing through sequence-specific targeting of mRNAs by RNAi has enabled genome-wide functional screens in cultured cells and in vivo in model organisms. These screens have resulted in the ...identification of new cellular pathways and potential drug targets. Considerable progress has been made to improve the quality of RNAi screen data through the development of new experimental and bioinformatics approaches. The recent availability of genome-editing strategies, such as the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system, when combined with RNAi, could lead to further improvements in screen data quality and follow-up experiments, thus promoting our understanding of gene function and gene regulatory networks.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genome-wide association studies (GWASs) have identified many SNPs associated with various common diseases. Understanding the biological functions of these identified SNP associations requires ...identifying disease/trait relevant tissues or cell types. Here, we develop a network method, CoCoNet, to facilitate the identification of trait-relevant tissues or cell types. Different from existing approaches, CoCoNet incorporates tissue-specific gene co-expression networks constructed from either bulk or single cell RNA sequencing (RNAseq) studies with GWAS data for trait-tissue inference. In particular, CoCoNet relies on a covariance regression network model to express gene-level effect measurements for the given GWAS trait as a function of the tissue-specific co-expression adjacency matrix. With a composite likelihood-based inference algorithm, CoCoNet is scalable to tens of thousands of genes. We validate the performance of CoCoNet through extensive simulations. We apply CoCoNet for an in-depth analysis of four neurological disorders and four autoimmune diseases, where we integrate the corresponding GWASs with bulk RNAseq data from 38 tissues and single cell RNAseq data from 10 cell types. In the real data applications, we show how CoCoNet can help identify specific glial cell types relevant for neurological disorders and identify disease-targeted colon tissues as relevant for autoimmune diseases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The nutritional sins of the mother…
Prenatal exposures of a mother can affect the health of her offspring, but how? Radford
et al.
found that the male progeny of undernourished pregnant mice had ...altered DNA chemistry in their sperm. In addition, the offspring displayed compromised metabolic health. The specific affected genes not only lost DNA methylation but also lacked the normal sperm DNA packaging factors (protamines) and instead were enriched in nucleosomes. Thus, when subjected to a suboptimal prenatal environment, offspring feel the effects of the maternal assault.
Science
, this issue p.
10.1126/science.1255903
Prenatal assaults change DNA methylation and chromatin structure in sperm and affect offspring.
Also see Perspective by
Susiarjo and Bartolomei
Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F
2
mouse metabolism, we demonstrate that the in utero nutritional environment of F
1
embryos alters the germline DNA methylome of F
1
adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F
2
development. Differential methylation is not maintained in F
2
tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring.
Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) ...dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.
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