Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we ...performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the
gene that conferred risk for CD (N2081D variant,
= 9.5 × 10
) or protection from CD (N551K variant, tagging R1398H-associated haplotype,
= 3.3 × 10
). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated
in CD pathogenesis. Analysis of the extended
locus in 24,570 CD cases, patients with Parkinson's disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The
N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared
alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.
Forests of eastern North America have been negatively impacted by excessive white-tailed deer browsing for decades. Previous studies have shown how deer-driven changes to forest structure, plant ...species composition, and microhabitat negatively impact forest birds. However, most experimental studies used relatively small plot sizes with few replications, limiting the transferability of findings to operational-scale timber harvests and landscape-scale management. We studied the influence of white-tailed deer browsing on breeding bird communities in ten pairs of operational-sized fenced and unfenced regeneration timber harvests in northcentral Pennsylvania. Based on a previous study that examined correlations between bird and deer abundance in Pennsylvania, we developed species-specific predictions about how density would vary between fenced and unfenced harvests. We predicted six species would show a negative response to deer and three would show a neutral response. Overall, diversity and composition of breeding bird communities did not differ between fenced and unfenced harvests. However, four species showed a negative response to deer, four showed a neutral response to deer, and one showed a positive response to deer. Thus, six of nine focal species aligned with our predictions: negative (n = 4) and neutral (n = 2). Densities of two remaining focal species were associated with vegetative features that also were consistent with our predictions. Our final focal species showed a strong positive association with unfenced harvests, contrary to our prediction. Our findings demonstrate that deer-induced impacts on vegetation in operational-scale timber harvests can have considerable influence on densities of some avian species. We conclude that the use of deer-exclusion fencing after timber harvests is an effective and sometimes necessary management tool to achieve maximum forestry and wildlife benefits.
Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard ...classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests.
models built using existing data facilitate rapid acute toxicity predictions without using animals.
The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop
models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (
value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals
(
), and nontoxic chemicals (
).
An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches.
The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with
results.
CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for
rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495.
Removal of pesticide residues from fresh produce is important to reduce pesticide exposure to humans. This study investigated the effectiveness of commercial and homemade washing agents in the ...removal of surface and internalized pesticide residues from apples. Surface-enhanced Raman scattering (SERS) mapping and liquid chromatography tandem mass spectrometry (LC–MS/MS) methods were used to determine the effectiveness of different washing agents in removing pesticide residues. Surface pesticide residues were most effectively removed by sodium bicarbonate (baking soda, NaHCO3) solution when compared to either tap water or Clorox bleach. Using a 10 mg/mL NaHCO3 washing solution, it took 12 and 15 min to completely remove thiabendazole or phosmet surface residues, respectively, following a 24 h exposure to these pesticides, which were applied at a concentration of 125 ng/cm2. LC–MS/MS results showed, however, that 20% of applied thiabendazole and 4.4% of applied phosmet had penetrated into the apples following the 24 h exposure. Thiabendazole, a systemic pesticide, penetrated 4-fold deeper into the apple peel than did phosmet, a non-systemic pesticide, which led to more thiabendazole residues inside the apples, which could not be washed away using the NaHCO3 washing solution. This study gives us the information that the standard postharvest washing method using Clorox bleach solution for 2 min is not an effective means to completely remove pesticide residues on the surface of apples. The NaHCO3 method is more effective in removing surface pesticide residues on apples. In the presence of NaHCO3, thiabendazole and phosmet can degrade, which assists the physical removal force of washing. However, the NaHCO3 method was not completely effective in removing residues that have penetrated into the apple peel. The overall effectiveness of the method to remove all pesticide residues diminished as pesticides penetrated deeper into the fruit. In practical application, washing apples with NaHCO3 solution can reduce pesticides mostly from the surface. Peeling is more effective to remove the penetrated pesticides; however, bioactive compounds in the peels will become lost too.
Objective:
Genome‐wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility.
Methods:
A ...2‐stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta‐analyzed. Second, 768 single‐nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls).
Results:
Genome‐wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio OR = 1.37; p = 9.3 × 10−21), MAPT (rs242559; C: OR = 0.78; p = 1.5 × 10−10), GAK/DGKQ (rs11248051; T: OR = 1.35; p = 8.2 × 10−9/rs11248060; T: OR = 1.35; p = 2.0 × 10−9), and the human leukocyte antigen (HLA) region (rs3129882; A: OR = 0.83; p = 1.2 × 10−8), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR = 1.71; p = 5 × 10−8 Combined Sample) (N370; OR = 3.08; p = 7 × 10−5 Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p = 5 × 10−5 Discovery Sample; p = 1.52 × 10−7 Replication sample; p = 2 × 10−10 Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes.
Interpretation:
We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.ANN NEUROL 2012;
Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial ...expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.
This chapter conducts social network analysis on two case studies from the late prehispanic US Southwest. It takes a diachronic perspective in order to look at network dynamics over a 200-year period ...(ad 1200 to 1400). The case studies chosen are areas where, through independent data, extensive migration has been demonstrated and is widely accepted. The analyses pertain to three specific topics of archaeological interest: (1) first-comer advantage within a social landscape of migration; (2) the relationship of spatial to social centrality; and (3) node persistence or resilience over time. The chapter focuses on two geographically circumscribed areas of central and south-eastern Arizona — the San Pedro Valley and the Tonto Basin — which have been intensively studied by archaeologists over the past two decades. Although both areas saw periods of migration, the outcomes were very different. Because of the temporal control allowed by decades of archaeological research in the south-west, including tree-ring dating, the 200-year time span could be divided into 50-year ‘snapshots’ to look at changes over time.
The challenge facing the anthropologist is one of reconciling the problem of order with the problem of change (Gosden 1999: 167). In this chapter we examine the ways in which individual, household, ...and supra-household mobility both forms and transforms communities of small scale agriculturalists. The importance of mobility in agricultural societies has not been addressed adequately in many models of social organization, including the ‘tribal model’. In evolutionary constructs, agriculturalists are differentiated from foraging groupsbecauseof their reduced mobility. However, in the farming communities of the prehispanic American Southwest (see Fig. 1) , mobility was an essential aspect of
While several recent reports have described the toxicity of water-soluble C60 fullerene nanoparticles, none have reported the toxicity resulting from the inhalation exposures to C60 fullerene ...nanoparticles or microparticles. To address this knowledge gap, we exposed male rats to C60 fullerene nanoparticles (2.22 mg/m3, 55 nm diameter) and microparticles (2.35 mg/m3, 0.93 μm diameter) for 3 h a day, for 10 consecutive days using a nose-only exposure system. Nanoparticles were created utilizing an aerosol vaporization and condensation process. Nanoparticles and microparticles were subjected to high-pressure liquid chromatography (HPLC), XRD, and scanning laser Raman spectroscopy, which cumulatively indicated no chemical modification of the C60 fullerenes occurred during the aerosol generation. At necropsy, no gross or microscopic lesions were observed in either group of C60 fullerene exposures rats. Hematology and serum chemistry results found statistically significant differences, although small in magnitude, in both exposure groups. Comparisons of bronchoalveolar (BAL) lavage fluid parameters identified a significant increase in protein concentration in rats exposed to C60 fullerene nanoparticles. BAL fluid macrophages from both exposure groups contained brown pigments, consistent with C60 fullerenes. C60 lung particle burdens were greater in nanoparticle-exposed rats than in microparticle-exposed rats. The calculated lung deposition rate and deposition fraction were 41 and 50% greater, respectively, in C60 fullerene nanoparticle–exposed group than the C60 fullerene microparticle–exposed group. Lung half-lives for C60 fullerene nanoparticles and microparticles were 26 and 29 days, respectively. In summary, this first in vivo assessment of the toxicity resulting from inhalation exposures to C60 fullerene nanoparticles and microparticles found minimal changes in the toxicological endpoints examined. Additional toxicological assessments involving longer duration inhalation exposures are needed to develop a better and more conclusive understanding of the potential toxicity of inhaled C60 fullerenes whether in nanoparticle or microparticle form.
Estrogen signaling through estrogen receptor alpha (ER) plays a major role in endometrial cancer risk and progression, however, the molecular mechanisms underlying ER's regulatory role in endometrial ...cancer are poorly understood. In breast cancer cells, ER genomic binding is enabled by FOXA1 and GATA3, but the transcription factors that control ER genomic binding in endometrial cancer cells remain unknown. We previously identified ETV4 as a candidate factor controlling ER genomic binding in endometrial cancer cells, and here we explore the functional importance of ETV4. Homozygous deletion of ETV4, using CRISPR/Cas9, led to greatly reduced ER binding at the majority of loci normally bound by ER. Consistent with the dramatic loss of ER binding, the gene expression response to estradiol was dampened for most genes. ETV4 contributes to estrogen signaling in two distinct ways. ETV4 loss affects chromatin accessibility at some ER bound loci and impairs ER nuclear translocation. The diminished estrogen signaling upon ETV4 deletion led to decreased growth, particularly in 3D culture, where hollow organoids were formed and
in the context of estrogen-dependent growth. These results show that ETV4 plays an important role in estrogen signaling in endometrial cancer cells. SIGNIFICANCE: Estrogen receptor alpha (ER) is a key oncogene in endometrial cancer. This study uncovers ETV4 as an important factor in controlling the activity of ER and the growth of endometrial cancer cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/6/1234/F1.large.jpg.
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