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1
Phillips, John D., Colin P. Farrell, Jessica Overbey, Hetanshi Naik, Gordon D. McLaren, Christine E. McLaren, Luming Zhou, and Charles J. Parker. "Identification of Polymorphic Gnpat As a Risk Factor for Porphyria Cutanea Tarda." Blood 126, no. 23 (December 3, 2015): 3353. http://dx.doi.org/10.1182/blood.v126.23.3353.3353.
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Abstract Symptoms of porphyria cutanea tarda (PCT) resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y) that increases iron absorption by reducing hepcidin expression is a risk factor for PCT. These observations suggest that PCT is an iron dependent disease and that factors that affect iron homeostasis influence the risk of developing the PCT. Recently, a polymorphic variant (D519G) of GNPAT was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype [McLaren CE, et al. Hepatology Aug;62(2):429-39 2015]. Available evidence suggests that like HFE C282Y, GNPAT D519G increases iron absorption by reducing expression of hepcidin. Therefore, we investigated the prevalence GNPAT D519G in patients with PCT. The study population consisted of 247 patients with PCT. High-resolution DNA melting analysis and Taqman SNP assays were used to identify HFE (C282Y) and GNPAT (D519G) allelic variants, respectively and mutations in uroporphyrinogen decarboxylase (UROD) were identified by nucleotide sequencing. Patients with mutant UROD were categorized as familial PCT (F-PCT) (n=87, 36.0%) and those with wild-type UROD were categorized as sporadic PCT (S-PCT) (n=155, 64.0%). GNPAT D519G was significantly enriched in the patient population (prevalence 22.1%, p<0.001) compared to the general population (prevalence 13.6%) as was HFE C282Y (prevalence of 19.2% in the study population compared to 1.5% in the general population, p<0.001). The relative risk of GNPAT D519G was significantly increased in patients with F-PCT compared to those with S-PCT (odds ratio 1.81, CI 1.06-3.08) whereas the relative risk of HFE C282Y in the F-PCT was lower than in the S-PCT population (odds ratio 0.82, CI 0.46-1.47). Together, these observations suggest that GNPAT D519G, is more likely to require a cofactor (e. g., mutant UROD) to produce PCT whereas HFE C282Y functions as an independent PCT risk factor. This difference may be a consequence of the relative potency of GNPAT D519G (weak) and HFE C282Y (strong) with respect to effects on iron homeostasis. Our studies have identified a new risk factor (polymorphic GNPAT) for PCT that adds support for the involvement of aberrant iron metabolism in the pathobiology of PCT. Disclosures No relevant conflicts of interest to declare.
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McLaren, Gordon D., Mary J. Emond, V. Nathan Subramaniam, Pradyumna D. Phatak, James C. Barton, Paul C. Adams, Justin B. Goh, et al. "Exome Sequencing Identifies a GNPAT Variant Associated with Severe Iron Overload in HFE C282Y Homozygous Men with Extreme Phenotypes; Possible Role in Regulation of Hepcidin Expression." Blood 124, no. 21 (December 6, 2014): 745. http://dx.doi.org/10.1182/blood.v124.21.745.745.
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Abstract Variability in the severity of iron overload among homozygotes for the HFE C282Y polymorphism is one of the major unsolved problems in our understanding of hereditary hemochromatosis (HH). We previously conducted exome sequencing of DNA from 35 HFE C282Y male homozygotes with either markedly increased iron stores (n=22; cases) or normal to mildly increased iron stores (n=13; controls) to identify rare and common causal variants associated with variability of disease expression in HH. The 35 participants, residents of the U.S., Canada, and Australia, reported little or no alcohol consumption. Criteria for HFE C282Y homozygotes with increased iron stores included serum ferritin >1000 µg/L at diagnosis and either (a) hepatic iron concentration >236 µmol/g dry weight (reference range 0-36 µmol/g) or (b) mobilized body iron >10 g by quantitative phlebotomy. Criteria for HFE C282Y homozygotes with normal or mildly elevated iron stores included (a) serum ferritin <300 µg/L or either (a) age ≥40 y with ≤2.5 g iron removed by phlebotomy to achieve serum ferritin <50 µg/L, or (b) age ≥50 y with ≤3.0 g iron removed by phlebotomy. After quality control filtering, sequencing data included 82,068 single nucleotide variants and 1,403 insertions/deletions (indels); 10,337 genes were tested for a difference between cases and controls. We identified the polymorphism GNPAT p.D519G (1556A>G; exon 11; chromosome 1q42; rs11558492) as the most significantly different variant between cases and controls (p=0.033 by the likelihood ratio test after correction for multiple comparisons). In a principal components analysis of ancestry, all 35 study participants were clustered closely together within a larger group of Europeans. Mean (SD) ages at presentation were 53 (11.5) y and 57 (10.0) y for cases and controls, respectively. Median serum ferritin was 2391 µg/L in cases and 302 μg/L in controls. The median transferrin saturation (96%) was greater in cases than controls (70%). Sixteen of 22 case participants had polymorphism GNPAT p.D519G (rs11558492) (15 heterozygotes, 1 homozygote); no control participant had this polymorphism. The homozygous case presented at age 26 y with severe iron overload but no cirrhosis. One GNPAT p.D519G heterozygote presented at age 36 y with severe iron overload and cirrhosis. GNPAT p.D519G is common among people of European descent (allele frequency 20.6%) and might interact with aberrant HFE to increase the risk of hepatic iron overload. More recently, we compared the allele frequencies of GNPAT p.D519G in the present 22 cases and 13 controls with that of 4300 European Americans in the NHLBI Exome Sequencing Project Exome Variant Server. The allele frequency in cases was greater than that of European Americans (38.6% vs. 20.6%, respectively; p = 0.0076). The allele frequency in controls was significantly lower (0% vs. 20.6%, p = 0.0054). Next, to determine whether other known mutations influenced iron phenotypes, the exome data were used to screen for mutations in HAMP, HJV, TFR2, FPN1, and TMPRSS6. One case participant was heterozygous for HJV p.G320V; he was among the six case participants who did not have GNPAT p.D519G. No other known or probable mutation that would possibly explain differences in expression between cases and controls was found. To examine functional consequences of GNPAT deficiency, we now have performed siRNA-based knockdown of GNPAT in the human liver cell line HepG2/C3A. GNPAT was efficiently knocked down by its siRNA by ~85% compared to control siRNA as assayed by qPCR. This knockdown resulted in a >17-fold decrease in HAMP mRNA expression. mRNA expression of two genes coordinately regulated with HAMP, ID1 (inhibitor of DNA binding protein 1) and SMAD7 (SMAD family member 7), was similarly decreased, as was expression of phospho-SMAD 1/5/8, suggesting that GNPAT knockdown affects the baseline activity of the bone morphogenetic protein 6 (BMP6)-SMAD pathway. Our data indicate that GNPAT p.D519G is associated with a high-iron phenotype in male HFE C282Y homozygotes and may participate in hepcidin regulation, thereby modifying severity of iron overload. The results identify GNPAT as a candidate gene for expanded studies to examine its function in regulating iron absorption and metabolism and to identify newly-diagnosed C282Y homozygotes whose risk for development of severe iron overload is great. Disclosures No relevant conflicts of interest to declare.
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Azad, Abul Kalam, Abdullah Md Sheikh, Md Ahsanul Haque, Harumi Osago, Hiromichi Sakai, Abu Zaffar Shibly, Shozo Yano, et al. "Time-Dependent Analysis of Plasmalogens in the Hippocampus of an Alzheimer’s Disease Mouse Model: A Role of Ethanolamine Plasmalogen." Brain Sciences 11, no. 12 (December 2, 2021): 1603. http://dx.doi.org/10.3390/brainsci11121603.
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Plasmalogens are alkenyl-acyl glycerophospholipids and decreased in post-mortem Alzheimer’s disease (AD) brains. The aim of this study is to investigate the time-dependent changes of plasmalogens in the hippocampus of an AD model mouse (J20). Plasmalogen levels at 3, 6, 9, 12 and 15 months were analyzed by liquid-chromatography-targeted-multiplexed-selected-reaction-monitoring-tandem-mass-spectrometry (LC-SRM/MS). Reactive oxygen species (ROS) levels were evaluated using dichlorofluorescein diacetate (DCF-DA). Plasmalogen synthesizing enzyme glycerone-phosphate O-acyltransferase (GNPAT) and late endosome marker Rab7 levels were quantified by Western blotting. GNPAT localization, changes of neuronal and glial cell numbers were evaluated by immunostaining. Compared to wild-type mice (WT), total plasmalogen-ethanolamine, but not plasmalogen-choline levels, were increased at 9 months and subsequently decreased at 15 months in J20 mice. A principal component analysis of plasmalogen-ethanolamine species could separate WT and J20 mice both at 9 and 15 months. Both GNPAT and Rab7 protein were increased in J20 mice at 9 months, whereas GNPAT was decreased at 15 months. ROS levels were increased in J20 mice except for 9 months. Our results suggest that increased plasmalogen-ethanolamine could counteract ROS levels and contribute to the phagocytosis process in J20 mice at 9 months. Such results might indicate a transient protective response of plasmalogen-ethanolamine in AD conditions.
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Tachon, Gaelle, Marie-Paule Roth, Fabienne Calcoen, Celine Besson-Fournier, Michael Bismuth, and Patricia Aguilar-Martinez. "Phenotypic Variability in Genetic Hemochromatosis: Study of Five SNPs in a Cohort of 342 Compound Heterozygotes for the HFE Cys282Tyr / His63Asp Mutations." Blood 126, no. 23 (December 3, 2015): 3361. http://dx.doi.org/10.1182/blood.v126.23.3361.3361.
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Abstract The HFE p.Cys282Tyr (C282Y) mutation is the disease-causing defect in most cases of genetic hemochromatosis, but involvement of the p.His63Asp (H63D) variant in the pathogenesis of the illness is still a matter of debate. Some authors consider C282Y/H63D (YD) subjects as at risk of developing hemochromatosis, whereas others argue that iron overload, seen in some of these subjects, is related to external factors. As for the C282Y homozygotes, genetic modifiers might contribute to the phenotypic variability of hemochromatosis in YD subjects. This work was thus aimed at assessing the possible influence of Single Nucleotide Polymorphism (SNPs) suspected to play a role in iron metabolism on disease expression in compound heterozygotes. We genotyped five SNPs in 342 YD unrelated Caucasian patients (208 males, 134 females) from South France. Information on demographics, clinical manifestations, laboratory tests, viral status and alcohol consumption was obtained from the medical records of the participants. The selected SNPs were already described as modifiers of iron overload by previous studies. They are located in the TMPRSS6 (rs855791 and rs4820268), TF (rs3811647), CYBRD1 (rs884409) and GNPAT (rs11558492) genes. The role of GNPAT in iron metabolism is unknown but it has been recently associated with the severity of the clinical expression in C282Y homozygous subjects1. Analysis of the SNPs was performed using Endpoint TaqMan Genotyping technology. For each SNP, the additive effect of the minor allele on the logarithm of serum ferritin (SF) was first assessed through a linear regression, controlling for age, sex, alcohol consumption, and patient's referral motive. We found a marginally significant association between rs884409 allele G of CYBRD1 and SF (p = 0.014). In a second step, we restricted our analysis to the 77 most severe males (SF > 500 µg/l and no past or current history of alcohol consumption > 20g/day), and found that the GNPAT rs11558492 allele G was significantly enriched in this subset. Indeed, 8 subjects were homozygous for allele G and 40 were heterozygous AG. G allele frequency in these 77 males was 36%, which is higher than the 19% found in the individuals from Northwest Europe (CEU) used for the HapMap project (p<0.0001) and the 21% reported in 4300 European Americans from the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (p <0.0001). It is also higher than in the 26% found in the rest of the YD cohort (p=0.0029) which includes a large number of younger subjects recruited because of family history of hemochromatosis and of premenopausal women whose severity on the long term is difficult to assess. In conclusion, our study draws attention to two SNPs (rs884409 and rs11558492) in genes DCYTB and GNPAT, respectively, that are appear to worsen the phenotypic expression of YD patients. These results also support the hypothesis that GNPAT plays a still undiscovered role in iron homeostasis. 1. McLaren, C. E. et al. Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload. Hepatol. Baltim. Md (2015). doi:10.1002/hep.27851 The authors are grateful to the members of the "Centre de competence" on rare iron disorders of CHU de Montpellier Disclosures No relevant conflicts of interest to declare.
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Dorninger, Fabian, Attila Kiss, Peter Rothauer, Alexander Stiglbauer-Tscholakoff, Stefan Kummer, Wedad Fallatah, Mireia Perera-Gonzalez, et al. "Overlapping and Distinct Features of Cardiac Pathology in Inherited Human and Murine Ether Lipid Deficiency." International Journal of Molecular Sciences 24, no. 3 (January 18, 2023): 1884. http://dx.doi.org/10.3390/ijms24031884.
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Inherited deficiency in ether lipids, a subgroup of glycerophospholipids with unique biochemical and biophysical properties, evokes severe symptoms in humans resulting in a multi-organ syndrome. Mouse models with defects in ether lipid biosynthesis have widely been used to understand the pathophysiology of human disease and to study the roles of ether lipids in various cell types and tissues. However, little is known about the function of these lipids in cardiac tissue. Previous studies included case reports of cardiac defects in ether-lipid-deficient patients, but a systematic analysis of the impact of ether lipid deficiency on the mammalian heart is still missing. Here, we utilize a mouse model of complete ether lipid deficiency (Gnpat KO) to accomplish this task. Similar to a subgroup of human patients with rhizomelic chondrodysplasia punctata (RCDP), a fraction of Gnpat KO fetuses present with defects in ventricular septation, presumably evoked by a developmental delay. We did not detect any signs of cardiomyopathy but identified increased left ventricular end-systolic and end-diastolic pressure in middle-aged ether-lipid-deficient mice. By comprehensive electrocardiographic characterization, we consistently found reduced ventricular conduction velocity, as indicated by a prolonged QRS complex, as well as increased QRS and QT dispersion in the Gnpat KO group. Furthermore, a shift of the Wenckebach point to longer cycle lengths indicated depressed atrioventricular nodal function. To complement our findings in mice, we analyzed medical records and performed electrocardiography in ether-lipid-deficient human patients, which, in contrast to the murine phenotype, indicated a trend towards shortened QT intervals. Taken together, our findings demonstrate that the cardiac phenotype upon ether lipid deficiency is highly heterogeneous, and although the manifestations in the mouse model only partially match the abnormalities in human patients, the results add to our understanding of the physiological role of ether lipids and emphasize their importance for proper cardiac development and function.
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Secondes, Eriza S., Daniel F. Wallace, Gautam Rishi, Gordon D. McLaren, Christine E. McLaren, Wen-Pin Chen, Louise Ramm, et al. "Increased Allele Frequency of GNPAT p.D519G in Compound HFE p.C282Y/p.H63D Heterozygotes with Elevated Serum Ferritin Levels." Blood 134, Supplement_1 (November 13, 2019): 4807. http://dx.doi.org/10.1182/blood-2019-128240.
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In hemochromatosis, iron overload is due to increased intestinal iron absorption attributable to mutations in several genes involved in the regulation of iron absorption and metabolism. The most common type of hemochromatosis is caused by mutations in the HFE gene, and homozygosity for the HFE p.C282Y mutation is associated with a risk of iron overload. Approximately 1:200 people of Caucasian origin are homozygous for p.C282Y, but only a minority of p.C282Y homozygotes develop significant iron overload. This is attributed in part to the presence of putative genetic modifiers of iron absorption. Recently, we identified GNPAT, encoding glyceronephosphate O-acyltransferase, as a potential modifier of HFE hemochromatosis in a whole-exome sequencing study of p.C282Y homozygotes with extreme iron overload phenotypes. A GNPAT polymorphism (p.D519G, rs11558492) was associated with severe iron overload among p.C282Y homozygous men (Hepatology 2015;62:429-39). Other studies have either substantiated or contradicted the importance of GNPAT p.D519G as a genetic modifier of iron phenotypes in HFE p.C282Y homozygotes. p.D519G is also a risk factor for familial (but not sporadic) porphyria cutanea tarda (Plos One 2016;11:e0163322). Some patients with hemochromatosis phenotypes are heterozygous for p.C282Y and a different HFE polymorphism, p.H63D (which is also common but usually not itself associated with clinically significant iron overload). Many p.C282Y/p.H63D compound heterozygotes have milder iron overload phenotypes than p.C282Y homozygotes. Herein, we report studies of the prevalence of p.D519G in a cohort of compound heterozygous p.C282Y/p.H63D Australian patients, with or without elevated serum ferritin (SF) levels. We also compared p.D519G allele frequency of the present p.C282Y/p.H63D compound heterozygotes with those of large population cohorts. We identified 72 HFE p.C282Y/p.H63D compound heterozygotes with DNA available for analysis. Of these, 9 had missing SF data and were excluded. GNPAT p.D519G was assessed in the remaining 63 subjects. Compound heterozygotes with elevated SF levels ≥300 µg/mL (males) and ≥200 µg/mL (females) were selected as cases (n=28), and participants with SF levels below these cut-offs were classified as controls (n=35). The mean age at the time of testing was 31 y (males 31, females 31) in the control group and 48 y (males 47, females 51) in subjects with elevated SF levels. Among cases, mean SF was 612 µg/L (median 557 µg/L, IQR 361- 821 µg/L). Mean SF in the control group was 85 µg/L (median 58 µg/L, IQR 38 - 121 µg/L). All samples were genotyped for GNPAT p.D519G. We compared the p.D519G allele frequency of the present subjects, with and without elevated SF, to the p.D519G frequency in publically available datasets. p.D519G allele frequency was greater in the elevated SF group (37.5%) than the control group (24.3%), but this difference was not significant (p=0.1285). p.D519G was more prevalent in our cohort of p.C282Y/p.H63D compound heterozygotes with elevated SF (37.5%) than in European populations reported in public datasets: ExAC 19.7%, 1000G 21.3%, gnomAD 20.4%, and ESP 20.6%. There was a significant association between allele count and case/control status among men (type 3 analysis of effects; p = 0.049) but not women. For a male case, the odds of having either 1 or 2 alleles versus having 0 alleles was 5.08 (95% CI, 1.01, 25.66) times higher than that of a male control. In conclusion, our results demonstrate that GNPAT p.D519G is associated with elevated SF levels in Australian HFE p.C282Y/p.H63D compound heterozygotes and that the p.D519G allele frequency is greater in p.C282Y/p.H63D compound heterozygotes with elevated SF than in several large European population cohorts. We found a statistically significant association between the allele count and the case/control status among men. The small number of subjects with elevated SF in our study may have limited our ability to demonstrate significant differences in some comparisons. Some subjects with p.D519G do not have elevated SF, suggesting that there are other factors, genetic or environmental, which also affect iron absorption in p.C282Y/p.H63D compound heterozygotes. Disclosures No relevant conflicts of interest to declare.
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Valcárcel, Luis Vitores V., Raquel Ordoñez, Iñigo Apaolaza, Ana Valcárcel, Leire Garate, Cem Meydan, Bruno Paiva, et al. "Computational Systems Biology Models for the Identification of Metabolic Vulnerabilities in Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 3084. http://dx.doi.org/10.1182/blood-2019-123970.
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Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal accumulation of clonal plasma cells in the bone marrow. MM heterogeneity is associated to the presence of different genomic and transcriptomic profiles that have a clear impact on the prognosis of the disease. Metabolism has been deeply studied in cancer research, unveiling several vulnerabilities in different tumors. However, information regarding the role of metabolism in the pathogenesis of MM has not been explored in detail. Previous studies from our group using Systems Biology approach, explained the essentiality of metabolic gene RRM1 in several MM cell lines. The aim of our current study was to identify metabolic vulnerabilities in MM based on the application of a system biology approach focus on metabolic networks and trascriptomic data from MM patients. Our hypothesis being that changes in the metabolic landscape of MM could be exploited to uncover novel targets for prognosis and treatment in MM patients. We have analyzed the strand specific RNA-seq data from 35 samples from different subpopulations of B cells (Naïve, Centroblast, Centrocyte, Memory, Tonsilar and Bone Marrow Plasma cells (PCs)) and PCs of 37 MM patient samples. Using only the expression of 3287 metabolic genes included in Recon3D, the latest human metabolic reconstruction, we identified metabolic transcription patterns that clearly differentiate the different B cells from MM plasma cells (Figure 1A). MM samples were more similar to the normal PCs than to other B cells, which suggest that they maintain part of the metabolic pattern of the PCs, but in turn showed significant differences in the expression of metabolic genes. Interestingly, differential expression analysis of metabolic genes in MM PCs revealed a decrease in the expression of genes involved in mitochondrial activity and an increase in those that participate in metabolic proliferation, indicating that these alterations could probably play an important role in the development of this tumor. Using our novel systems biology approach, based on Recon3D and transcriptomic profiles, we predicted essential genes and synthetic lethals (involving two or more genes) that were specific for MM patients and not for the rest of the B cell subpopulations. Our approach makes use of the concept of genetic Minimal Cut Sets, previously introduced by our group in cancer research, which defines subsets of genes that if knocked out at the same time, induce a blockage of cellular proliferation. A metabolic vulnerability is found when only one gene is highly expressed in one of these gMCSs. We also analyzed the essentiality of these genes in more than 500 MM patients samples included in CoMMpass project and MM cell lines analyzed in Cancer Cell Line encyclopedia (CCLE). Using this computational strategy, we detected 8 essential genes involved in 42 gMCS specific for MM patients. From those candidates, GNPAT was our most promising target gene, as it was predicted to be essential for more than 40% of MM patients in our group, approximately 10% of patients of CoMMpass and in the majority of MM cell lines (Figure 1B). Validation of GNPAT expression and other 18 genes involved in the GNPAT gMCS was carried out by RT-qPCR showing similar results that were obtained with our RNA-seq data. Interestingly, the expression of the partner genes included in the GNPAT gMCS, such as DGK gene family, could also be indicators of the effectiveness of knocking-out, where their high expression is an indicator of resistance and their low expression an indicator of sensitivity. In conclusion, our findings suggest that our systems biology computational approach, driven by RNA-seq data, identifies metabolic vulnerabilities (defined as essential genes or synthetic lethal genes) providing pairs of new targets (essential gene) and their associated biomarkers (gMCS) in patients with MM. Figure 1: Metabolic genes expression analysis in human humoral immune response and MM patient samples. A) Standardized PCA result using the expression of metabolic genes included in Recon3D, in distinct subpopulations of B cells and MM samples. B) GNPAT gMCS showing the expression (in TPM) of GNPAT and associated 18 genes in MM cell lines. Figure 1 Disclosures Paiva: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Melnick:Epizyme: Consultancy; KDAc Therapeutics: Membership on an entity's Board of Directors or advisory committees; Constellation Pharmaceuticals: Consultancy; Janssenn: Research Funding. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.
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McLaren, Christine E., Mary J. Emond, Pradyumna D. Phatak, Paul C. Adams, V. Nathan Subramaniam, James C. Barton, Lawrie W. Powell, et al. "Exome Sequencing Identifies Genes and Variant Alleles Associated With Severity Of Iron Overload In Hemochromatosis HFE C282Y Homozygotes." Blood 122, no. 21 (November 15, 2013): 179. http://dx.doi.org/10.1182/blood.v122.21.179.179.
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Abstract Variability in the severity of iron overload among homozygotes for the HFE C282Y polymorphism is one of the major problems extant in our understanding of hereditary hemochromatosis (HH). We conducted exome sequencing of DNA from C282Y homozygotes with markedly increased iron stores (cases) and C282Y homozygotes with normal or mildly increased iron stores (controls) to identify rare and common causal variants associated with variability of disease expression in HH. Criteria for cases included serum ferritin >1000 µg/L at diagnosis, and (a) mobilized body iron >10 g by quantitative phlebotomy, and/or (b) hepatic iron concentration >236 µmol/g dry weight. Criteria for controls included (a) serum ferritin <300 µg/L, or (b) age ≥50 y with ≤3.0 g iron removed by phlebotomy or age ≥40 y with ≤2.5 g iron removed by phlebotomy to achieve serum ferritin <50 µg/L. Deep sequencing of the full exome was performed in 33 cases and 14 controls. After quality control filtering, the dataset included 82,068 SNPs and 1,403 insertions/deletions (indels). Our initial analysis tested for differences in the distribution of variants between groups for each gene separately using the Sequence Kernel Association Test (SKAT) that includes rare and common variants but downweights the contribution of common variants to the test statistic. Only non-synonymous variants were included in the by-gene tests. Principal components were constructed from the exome variants to adjust for possible confounding by ancestry and to confirm no ancestral outliers. All study participants were male, and all clustered closely together within a larger group of Europeans in a principal components analysis of ancestry. Mean (SD) ages at presentation were 54 (11.0) y and 56 (9.4) y for cases and controls, respectively. Median serum ferritin was 2788 µg/L in those with increased iron stores and 309 μg/L in those with normal or mildly increased iron stores. The median transferrin saturation (94%) was greater in cases than in the comparison group (70%). In a preliminary analysis, we found 9 genes associated with case-control status. To separate effects of alcohol use and/or alcohol addiction variants, an analysis was conducted to compare the 13 controls and 22 cases who reported never using alcohol or only very light use. The two most significant genes identified in this comparison were GNPAT (p=7.4x10-6) and CDHR2 (p=2.8x10-4). A quantile-quantile (QQ) plot is shown in the Figure, comparing the observed distribution of –(log10p-values) from 10,337 genes to the expected uniform distribution if there were no variants modifying severity of expression, and gives evidence of the effect of the GNPAT gene.Figure 1Figure 1. Inspection of the two variants contributing to the GNPAT by-gene p-value revealed one missense variant (rs11558492) for which 0/13 controls had a polymorphism, while 16/22 cases had at least one missense variant, and one case was homozygous for this missense variant. The latter case presented at the early age of 26 with a serum ferritin of 1762 µg/L, 4+ hepatocellular iron and hepatic iron concentration of 284.4 µmol/g dry weight. GNPAT (aka DHAPAT) mutations/deletions have been found in peroxisomal disease, a class of diseases in which increased hepatic iron is observed (Biochim Biophys Acta 1801:272-280, 2010). GNPAT rs11558492 is common among people of European descent but might interact with aberrant HFE to increase risk of hepatic iron overload. Three rare variants in CDHR2 accounted for its low p-value, having a cumulative frequency of 4/13 among controls and 0/22 among cases: rs115050587, rs752138, rs143224505 with minor allele frequencies, MAF = 1.4%, 4.7% and 0.06%, respectively. The first two polymorphisms are predicted to be highly damaging by PolyPhen2 and the third probably damaging. Expression levels of CDHR2 recently have been associated with increased hepatocyte iron and elevated serum ferritin in liver allograft patients (J Clin Invest 122:368-382, 2012). These data indicate associations between iron status in HFE C282Y homozygotes and genes with previous links to iron overload that may modify severity of disease expression. Of note, the data suggest that more than one modifier gene may be involved in determining severity of disease in HFE C282Y homozygotes. Our results identify candidate genes for expanded studies that would examine their functional significance for iron absorption and metabolism. Disclosures: No relevant conflicts of interest to declare.
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Rametta, Raffaela, Paola Dongiovanni, Silvia Fargion, and Luca Valenti. "GNPAT p.D519G variant and iron metabolism during oral iron tolerance test." Hepatology 65, no. 1 (August 24, 2016): 384–85. http://dx.doi.org/10.1002/hep.28745.
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Dorninger, Fabian, Anna Gundacker, Gerhard Zeitler, Daniela D. Pollak, and Johannes Berger. "Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders." International Journal of Molecular Sciences 20, no. 16 (August 13, 2019): 3929. http://dx.doi.org/10.3390/ijms20163929.
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Ether lipids form a specialized subgroup of phospholipids that requires peroxisomes to be synthesized. We have previously detected that deficiency in these lipids leads to a severe disturbance of neurotransmitter homeostasis and release as well as behavioral abnormalities, such as hyperactivity, in a mouse model. Here, we focused on a more detailed examination of the behavioral phenotype of ether lipid-deficient mice (Gnpat KO) and describe a set of features related to human psychiatric disorders. Gnpat KO mice show strongly impaired social interaction as well as nestlet shredding and marble burying, indicating disturbed execution of inborn behavioral patterns. Also, compromised contextual and cued fear conditioning in these animals suggests a considerable memory deficit, thus potentially forming a connection to the previously determined ether lipid deficit in human patients with Alzheimer’s disease. Nesting behavior and the preference for social novelty proved normal in ether lipid-deficient mice. In addition, we detected task-specific alterations in paradigms assessing depression- and anxiety-related behavior. The reported behavioral changes may be used as easy readout for the success of novel treatment strategies against ether lipid deficiency in ameliorating nervous system-associated symptoms. Furthermore, our findings underline that ether lipids are paramount for brain function and demonstrate their relevance for cognitive, social, and emotional behavior. We hereby substantially extend previous observations suggesting a link between deficiency in ether lipids and human mental illnesses, particularly autism and attention-deficit hyperactivity disorder.
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Sanjana, Puppala, Triveni ., Bushra ., and Vijaya Prasanna Boyeni. "A rare case of proximal short limb dwarfism-rhizomelic chondrodysplasia punctata type-2." International Journal of Contemporary Pediatrics 8, no. 10 (September 23, 2021): 1750. http://dx.doi.org/10.18203/2349-3291.ijcp20213743.
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Rhizomelic chondrodysplasia punctata (RCDP) is one of the rare peroxisomal disorder (autosomal recessive inheritance) due to altered phytanic acid alpha oxidation and plasmalogen synthesis. RCDP 1 is the most frequent form of RCDP. It is a peroxisomal biosynthesis disorder. RCDP 2 and RCDP 3 are disorders of individual peroxisome enzyme. Authors described a case of RCDP type 2 in a 13 months old girl with characteristic features of typical chondrodysplastic facies, bilateral cataract, rhizomelic shortening of limbs, growth and global developmental delay; radiological features showed epiphyseal stippling. Genetic analysis showed apparent homozygous deletion of c.1848delC after full sequencing of her GNPAT genes.
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Tobiasch, Moritz, Benedikt Schaefer, André Viveiros, Herbert Tilg, Ivo Graziadei, and Heinz Zoller. "Survival in HFE hemochromatosis: influence of polymorphisms in HSD17B13, GNPAT, and PCSK7." Journal of Hepatology 73 (August 2020): S551—S552. http://dx.doi.org/10.1016/s0168-8278(20)31575-0.
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Gu, Li, Yahui Zhu, Xi Lin, Xingyu Tan, Bingjun Lu, and Youjun Li. "Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis." Oncogene 39, no. 11 (January 23, 2020): 2437–49. http://dx.doi.org/10.1038/s41388-020-1156-0.
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Ryan, Eleanor, Jennifer Russell, John D. Ryan, John Crowe, and Stephen Stewart. "GNPAT variant is not associated with severe iron overload in Irish C282Y homozygotes." Hepatology 63, no. 6 (October 28, 2015): 2055–56. http://dx.doi.org/10.1002/hep.28258.
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Barton, James C., Wen-Pin Chen, Mary J. Emond, Pradyumna D. Phatak, V. Nathan Subramaniam, Paul C. Adams, Lyle C. Gurrin, et al. "GNPAT p.D519G is Independently Associated with Markedly Increased Iron Stores in HFE p.C282Y Homozygotes." Blood 128, no. 22 (December 2, 2016): 3617. http://dx.doi.org/10.1182/blood.v128.22.3617.3617.
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Abstract GNPAT (chromosome 1q42.2) encodes the peroxisomal enzyme glyceronephosphate O-acyltransferase. In a previous study, DNA of men with hemochromatosis and HFE p.C282Y homozygosity and either markedly increased iron stores or normal or mildly increased iron stores were evaluated with exome sequencing. Positivity for the GNPAT polymorphism p.D519G (rs11558492) was significantly greater in men with markedly increased iron stores (McLaren CE et al., Hepatology 2015;62:429-39). This result suggests that the p.D519G is a candidate modifier of iron phenotypes in p.C282Y homozygotes. To learn more, we examined associations of p.D519G, age, iron-related variables, and daily alcohol consumption with iron stores in p.C282Y homozygotes classified by extremes of iron overload phenotypes. We defined markedly increased iron stores as serum ferritin >1000 µg/L and either hepatic iron >236 µmol/g dry weight or mobilizable iron >10 g by induction phlebotomy (men and women). Normal or mildly elevated iron stores were defined as serum ferritin <300 µg/L and either age ≥40 y with ≤2.5 g iron removed by induction phlebotomy or age ≥50 y with ≤3.0 g iron removed by induction phlebotomy (men only). We first compared general characteristics of participant subgroups using univariate methods. Then, using multivariable logistic regression, we evaluated associations of markedly increased iron stores with the following six variables observed at diagnosis of hemochromatosis that might account for markedly increased iron stores: age; iron supplement use (dichotomous); number of whole blood units donated; number of erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity). There were 56 participants (53 men, 3 women), of whom 41 (38 men, 3 women) had markedly increased iron stores and 15 others had normal or mildly increased iron stores (all men). The mean age of the 56 participants was 55 ± 10 (SD) y. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated serum levels of aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis proven by biopsy. Odds ratios of having markedly increased iron stores for each of the six variables, as determined by univariate logistic regression, are displayed in Table 1. In the multivariable analysis, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p = 0.0126). Area under the curve for the multivariable logistic regression analysis was 0.82. We conclude that GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and daily alcohol consumption. It remains unknown whether p.D519G directly enhances iron transport into the blood by absorptive enterocytes, indirectly augments iron absorption by suppressing hepcidin, or is linked to a putative iron absorption promoter on chromosome 1q. Disclosures No relevant conflicts of interest to declare.
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An, Peng, Jiaming Wang, Hao Wang, Li Jiang, Jia Wang, Junxia Min, and Fudi Wang. "Gnpat does not play an essential role in systemic iron homeostasis in murine model." Journal of Cellular and Molecular Medicine 24, no. 7 (February 28, 2020): 4118–26. http://dx.doi.org/10.1111/jcmm.15068.
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Barton, James C., Wen-pin Chen, Mary J. Emond, Pradyumna D. Phatak, V. Nathan Subramaniam, Paul C. Adams, Lyle C. Gurrin, et al. "GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes." Blood Cells, Molecules, and Diseases 63 (March 2017): 15–20. http://dx.doi.org/10.1016/j.bcmd.2016.11.009.
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Besson-Fournier, Céline, Maria Martinez, Jean-Pierre Vinel, Patricia Aguilar-Martinez, Hélène Coppin, and Marie-Paule Roth. "Further support for the association of GNPAT variant rs11558492 with severe iron overload in hemochromatosis." Hepatology 63, no. 6 (October 30, 2015): 2054–55. http://dx.doi.org/10.1002/hep.28259.
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Secondes, Eriza S., Daniel F. Wallace, Gautam Rishi, Gordon D. McLaren, Christine E. McLaren, Wen-Pin Chen, Louise E. Ramm, et al. "Increased frequency of GNPAT p.D519G in compound HFE p.C282Y/p.H63D heterozygotes with elevated serum ferritin levels." Blood Cells, Molecules, and Diseases 85 (November 2020): 102463. http://dx.doi.org/10.1016/j.bcmd.2020.102463.
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Tobiasch, M., H. Zoller, A. Finkenstedt, and H. Tilg. "Association between GNPAT genotypes and serum iron parameters in C282Y homozygous and C282Y/H63D compound heterozygous patients." Journal of Hepatology 66, no. 1 (2017): S180. http://dx.doi.org/10.1016/s0168-8278(17)30646-3.
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Greni, Federico, Luca Valenti, Raffaella Mariani, Irene Pelloni, Raffaela Rametta, Fabiana Busti, Giulia Ravasi, et al. "GNPAT rs11558492 is not a Major Modifier of Iron Status: Study of Italian Hemochromatosis Patients and Blood Donors." Annals of Hepatology 16, no. 3 (May 2017): 451–56. http://dx.doi.org/10.5604/01.3001.0009.8601.
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Itzkovitz, Brandon, Sarn Jiralerspong, Graeme Nimmo, Melissa Loscalzo, Dafne D. G. Horovitz, Ann Snowden, Ann Moser, Steve Steinberg, and Nancy Braverman. "Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3." Human Mutation 33, no. 1 (October 31, 2011): 189–97. http://dx.doi.org/10.1002/humu.21623.
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Bizeau, Jean-Baptiste, Mayssa Albouery, Stéphane Grégoire, Bénédicte Buteau, Lucy Martine, Marine Crépin, Alain M. Bron, et al. "Dietary Inulin Supplementation Affects Specific Plasmalogen Species in the Brain." Nutrients 14, no. 15 (July 28, 2022): 3097. http://dx.doi.org/10.3390/nu14153097.
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Plasmalogens (Pls) are glycerophospholipids that play critical roles in the brain. Evidence supports the role of diet and that of the gut microbiota in regulating brain lipids. We investigated the impact of dietary intake of inulin—a soluble fiber used as prebiotic—on the Pl content of the cortex in mice. No global modification in the Pl amounts was observed when evaluated by gas chromatographic analysis of dimethyl acetals (DMAs). However, the analysis of individual molecular species of Pls by liquid chromatography revealed a reduced abundance of major species of ethanolamine Pls (PlsEtn)―PE(P-18:0/22:6) and PE(P-34:1)―in the cortex of mice fed a diet supplemented with inulin. DMA and expression levels of genes (Far-1, Gnpat, Agps, Pla2g6 and Tmem86b) encoding key enzymes of Pl biosynthesis or degradation were not altered in the liver and in the cortex of mice exposed to inulin. In addition, the fatty acid profile and the amount of lyso forms derived from PlsEtn were not modified in the cortex by inulin consumption. To conclude, inulin affects the brain levels of major PlsEtn and further investigation is needed to determine the exact molecular mechanisms involved.
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Fernandes, Anna Maria A. P., Marcia C. F. Messias, Gustavo H. B. Duarte, Gabrielle K. D. de Santis, Giovana C. Mecatti, Andreia M. Porcari, Michael Murgu, et al. "Plasma Lipid Profile Reveals Plasmalogens as Potential Biomarkers for Colon Cancer Screening." Metabolites 10, no. 6 (June 25, 2020): 262. http://dx.doi.org/10.3390/metabo10060262.
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In this era of precision medicine, there is an increasingly urgent need for highly sensitive tests for detecting tumors such as colon cancer (CC), a silent disease where the first symptoms may take 10–15 years to appear. Mass spectrometry-based lipidomics is an emerging tool for such clinical diagnosis. We used ultra-performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry operating in high energy collision spectral acquisition mode (MSE) mode (UPLC-QTOF-MSE) and gas chromatography (GC) to investigate differences between the plasmatic lipidic composition of CC patients and control (CTR) subjects. Key enzymes in lipidic metabolism were investigated using immuno-based detection assays. Our partial least squares discriminant analysis (PLS-DA) resulted in a suitable discrimination between CTR and CC plasma samples. Forty-two statistically significant discriminating lipids were putatively identified. Ether lipids showed a prominent presence and accordingly, a decrease in glyceronephosphate O-acyltransferase (GNPAT) enzyme activity was found. A receiver operating characteristic (ROC) curve built for three plasmalogens of phosphatidylserine (PS), named PS(P-36:1), PS(P-38:3) and PS(P-40:5), presented an area under the curve (AUC) of 0.998, and sensitivity and specificity of 100 and 85.7% respectively. These results show significant differences in CC patients’ plasma lipid composition that may be useful in discriminating them from CTR individuals with a special role for plasmalogens.
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Mishra, Bhabani. "AN ANALYSIS OF NON PERFORMING ASSETS OF INDIAN SCHEDULED COMMERCIAL BANKS." International Journal of Advanced Research 9, no. 11 (November 30, 2021): 476–85. http://dx.doi.org/10.21474/ijar01/13766.
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Non-performing Asset breaks the recycling procedure of deposit and investment as it does not generate substantial income and blocks the cash flow. The motive of the paper is to conduct comparative analysis among Gross NPA, Net NPA, and Net Profit by adopting correlation, ANOVA, the average for selected bank groups which are analyzed in MS-EXCEL and SPSS. The aggregate data of 16 years from 2004-05 to 2019-20 is taken from the RBI website. Public Sector banks acquire more GNPA and NNPA and less Net Profit as compared to other two due to various reasons explained in this paper. Pearson correlation in SPSS shows that there is strongly negative and significant correlation between net profit and GNPA of public sector bank group which reflects that rising bad assets can reduce the banks’ profitability. But in case of foreign banks group, a strong but positive association between net profit and GNPA is observed. The Private bank group shows no significant association between these two variables. ANOVA test result shows there is a significant difference in the movement of GNPAs and NNPAs (in amounts) for different groups of banks during the study period. But in the case of Net profit, no significant difference was observed for these bank groups.
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Liu, Yu-Li, Cathy Shen-Jang Fann, Chih-Min Liu, Wei J. Chen, Jer-Yuarn Wu, Shuen-Iu Hung, Chun-Houh Chen, et al. "A Single Nucleotide Polymorphism Fine Mapping Study of Chromosome 1q42.1 Reveals the Vulnerability Genes for Schizophrenia, GNPAT and DISC1: Association with Impairment of Sustained Attention." Biological Psychiatry 60, no. 6 (September 2006): 554–62. http://dx.doi.org/10.1016/j.biopsych.2006.04.024.
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Ofman, Rob, Shahin Lajmir, and Ronald J. A. Wanders. "Etherphospholipid Biosynthesis and Dihydroxyactetone-Phosphate Acyltransferase: Resolution of the Genomic Organization of the Human GNPAT Gene and Its Use in the Identification of Novel Mutations." Biochemical and Biophysical Research Communications 281, no. 3 (March 2001): 754–60. http://dx.doi.org/10.1006/bbrc.2001.4407.
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Deng, Yi, Ziyi Mao, Jinling Huang, Faling Yan, Shenghai Han, and Anqi Li. "Spatial Patterns of Natural Protected Areas and Construction of Protected Area Groups in Guangdong Province." International Journal of Environmental Research and Public Health 19, no. 22 (November 11, 2022): 14874. http://dx.doi.org/10.3390/ijerph192214874.
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The fragmentation of protected areas is a common issue in global conservation, which means a new approach to planning and management needs to be explored. In this paper, we proposed the concept of a group of natural protected areas (GNPA) and studied the construction of GNPAs. Firstly, the spatial distribution characteristics of 1363 natural protected areas (NPAs) in Guangdong Province were qualitatively studied. The overall spatial pattern among NPAs and the spatial distribution characteristics of mountain ranges, river basins, urbanization level and economic density were analyzed, and the relationship between the distribution of NPAs and physical geography and social development was clarified. Then, the geographical concentration index, nearest index and Gini coefficient were used for quantitative analysis. The geographical concentration index was 24.6, and the nearest neighbor index was 0.8. The Gini coefficients of the spatial distribution of NPAs in Guangdong Province were Gini = 0.956 and C = 0.044. These indices proved that the overall spatial patterns of NPAs in Guangdong Province had the tendency and characteristics of agglomeration. On this basis, 29 agglomeration areas were constructed using kernel density analysis and the natural break point classification method. According to the requirements of spatial connectivity and management feasibility, combined with the characteristics of physical geography, ecosystems and biodiversity, 32 GNPAs were constructed based on the reasonable adjustment of 29 agglomeration areas. Using Geodetector statistics to analyze the spatial stratified heterogeneity of the GNPAs, the results showed that mountain range, water system, population density, economic density and urbanization level were all factors that could explain the clustering distribution of the natural protected areas. The most important factor was mountain range (p = 0.190), followed by population density (p = 0.162). The 32 GNPAs covered the most representative natural ecosystems in the province and had compact spatial organization, a close ecological relationship and feasible unified management, which means they could aid in resolving the fragmentation of protected areas and improving management efficiency.
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Guan, Ning-Nan, Qiong Zhou, Tian Lan, Lai-Fang Zhou, Bo-Wen Zhao, Wei-Min Wang, and Ze-Xia Gao. "Is the Nutritional Value of Fish Fillet Related to Fish Maturation or Fish Age? Integrated Analysis of Transcriptomics and Metabolomics in Blunt Snout Bream (Megalobrama amblycephala)." Cellular Physiology and Biochemistry 49, no. 1 (2018): 17–39. http://dx.doi.org/10.1159/000492837.
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Background/Aims: Fish is a protein-rich food and is increasingly favored by consumers. It has been well recognized that the flesh composition of fish is closely related to its maturation and growth stage, but few studies have explored these differences. Additionally, hormone residues in fish after artificial induction of reproduction also attract consumer concern. In this study, we attempt to address these concerns by using a combination of transcriptomics and metabolomics analyses to identify key regulated pathways, genes, and metabolites that may affect the flesh nutrition of one typical aquaculture species in China, blunt snout bream (Megalobrama amblycephala). Methods: The four groups of fish were used for transcriptomics and metabolomics analyses, including one-year-old immature (group I), two-year-old immature (group II), two-year-old mature (group III) and successfully spawned (group IV) female M. amblycephala after artificial induction of reproduction. Results: We identified a total of 1460 differential compounds and 1107 differentially expressed unigenes in muscle among the different groups. Differential metabolites related to fish age (group II vs group I, group III vs group I) were largely enriched in “Glycerophospholipid metabolism”, “Linoleic acid metabolism”, “α-Linolenic acid metabolism”, and “Biosynthesis of unsaturated fatty acids”. Between these two pairwise comparisons, metabolites that are beneficial to human health, such as docosapentaenoic acid, α-Linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid were found to be significantly decreased in two-year-old (group II, group III) compared with one-year-old (group I) M. amblycephala. Only one differential metabolite related to fish maturation, a triglyceride, was detected between groups III and II. Transcriptomics data showed that differently expressed genes (between group III vs group II, group III vs group I) related to maturation were highly enriched in “Cell adhesion molecules (CAMs)”, “Sphingolipid metabolism” and “Phagosome”. DEGs (between group II vs group I, group III vs group I) relating to fish age were enriched in the “cGMP-PKG signaling pathway”, “FoxO signaling pathway”, and “AMPK signaling pathway”. The gene-metabolite interaction network showed pivotal genes, including fumarate hydratase and GNPAT, which played a major role in the regulation of glycerphospholipid metabolism. The nutritional components were also measured, which verified the metabolomics results. Moreover, the metabolomics results showed that after 24 hours of artificial hormone injection, the drug was completely metabolized. Conclusion: Integrated analysis demonstrated that the nutrition value of fish fillet was much more related to fish age compared with maturation status in M. amblycephala females.
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Gordon Lish. "Gnat." Antioch Review 70, no. 1 (2012): 89. http://dx.doi.org/10.7723/antiochreview.70.1.0089.
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Edwards, Karen. "GNAT." Milton Quarterly 40, no. 4 (December 2006): 263–66. http://dx.doi.org/10.1111/j.1094-348x.2006.00151_1.x.
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Miranda, Javier, and Edmond Schonberg. "GNAT." ACM SIGAda Ada Letters XXIV, no. 4 (December 2004): 51–60. http://dx.doi.org/10.1145/1046191.1032307.
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Lish, Gordon. "Gnat." Antioch Review 70, no. 1 (2012): 89. http://dx.doi.org/10.7723/antioch.70.1.0089.
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Krtenic, Bojan, Adrian Drazic, Thomas Arnesen, and Nathalie Reuter. "Classification and phylogeny for the annotation of novel eukaryotic GNAT acetyltransferases." PLOS Computational Biology 16, no. 12 (December 23, 2020): e1007988. http://dx.doi.org/10.1371/journal.pcbi.1007988.
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The enzymes of the GCN5-related N-acetyltransferase (GNAT) superfamily count more than 870 000 members through all kingdoms of life and share the same structural fold. GNAT enzymes transfer an acyl moiety from acyl coenzyme A to a wide range of substrates including aminoglycosides, serotonin, glucosamine-6-phosphate, protein N-termini and lysine residues of histones and other proteins. The GNAT subtype of protein N-terminal acetyltransferases (NATs) alone targets a majority of all eukaryotic proteins stressing the omnipresence of the GNAT enzymes. Despite the highly conserved GNAT fold, sequence similarity is quite low between members of this superfamily even when substrates are similar. Furthermore, this superfamily is phylogenetically not well characterized. Thus functional annotation based on sequence similarity is unreliable and strongly hampered for thousands of GNAT members that remain biochemically uncharacterized. Here we used sequence similarity networks to map the sequence space and propose a new classification for eukaryotic GNAT acetyltransferases. Using the new classification, we built a phylogenetic tree, representing the entire GNAT acetyltransferase superfamily. Our results show that protein NATs have evolved more than once on the GNAT acetylation scaffold. We use our classification to predict the function of uncharacterized sequences and verify by in vitro protein assays that two fungal genes encode NAT enzymes targeting specific protein N-terminal sequences, showing that even slight changes on the GNAT fold can lead to change in substrate specificity. In addition to providing a new map of the relationship between eukaryotic acetyltransferases the classification proposed constitutes a tool to improve functional annotation of GNAT acetyltransferases.
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Gicca, Greg, and Ben Brosgol. "GNAT BoF." ACM SIGAda Ada Letters 28, no. 3 (December 2008): 139–40. http://dx.doi.org/10.1145/1454497.1454496.
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Herrick, Nathan J., and Raymond A. Cloyd. "Effects of Growing Medium Type and Predator:Prey Ratio on Rove Beetle, Dalotia coriaria (Coleoptera: Staphylinidae), Adult Predation on Fungus Gnat, Bradysia sp. nr. coprophila (Diptera: Sciaridae), Larvae." HortScience 53, no. 10 (October 2018): 1441–46. http://dx.doi.org/10.21273/hortsci13268-18.
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Fungus gnats, Bradysia spp. (Diptera: Sciaridae), are major insect pests because the larvae can directly damage plants grown in greenhouse production systems. In general, insecticides are commonly used to suppress fungus gnat larval populations. However, the rove beetle, Dalotia coriaria (Kraatz) (Coleoptera: Staphylinidae), a commercially available predator of insect pests, including fungus gnat larvae, may be an alternative to using insecticides. Growing medium selection used for growing plants can influence insect pest and predator interactions in greenhouse production systems; however, quantitative information is limited. Therefore, we conducted greenhouse experiments and a laboratory experiment to determine the effects of growing medium type on D. coriaria adult predation and fungus gnat, Bradysia. sp. nr. coprophila (Lintner) (Diptera: Sciaridae), larval survival when feeding on the roots of coleus, Solenostemon scutellarioides (L.) Codd, plants. In addition, experiments were conducted to determine the number of rove beetle adults, based on predator:prey ratios, needed to regulate fungus gnat larval populations. In all three experiments, fewer fungus gnat larvae survived in Pro-Mix BX than the Berger BM1 growing medium, and rove beetles reduced the number of fungus gnat larvae in both growing media in the greenhouse experiments. Although predator:prey ratio was not significant, we found that 10 rove beetle adults per 15.2-cm diameter container (1834.82 cm3 with 2.0 L of growing medium) regulated fungus gnat larval populations at the densities investigated. Therefore, greenhouse producers should consider the effects of production practices, such as growing medium type, when using rove beetles to regulate fungus gnat larval populations.
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Cloyd, Raymond A., Amy Dickinson, Richard A. Larson, and Karen A. Marley. "Phototaxis of Fungus Gnat, Bradysia sp. nr coprophila (Lintner) (Diptera: Sciaridae), Adults to Different Light Intensities." HortScience 42, no. 5 (August 2007): 1217–20. http://dx.doi.org/10.21273/hortsci.42.5.1217.
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Multiple-choice experimental arenas, with sample compartments, were used to assess the response of fungus gnat, Bradysia sp. nr. coprophila (Lintner) (Diptera: Sciaridae), adults to varying light intensities in environmentally controlled walk-in chambers. Each sample compartment contained a yellow sticky card (2.5 × 2.5 cm) to capture fungus gnat adults. Under conditions of darkness, fungus gnat adults migrated randomly with no significant differences among the six sample compartments. Fungus gnat adults were observed to positively respond to light intensities less than 0.08374 μmol·m−2·s−1. In addition, adults responded to light intensities that were below the detection threshold of a photosynthetically active radiation light sensor. A higher percentage of fungus gnat adults (22% to 39%) were captured on yellow sticky cards in the sample compartments that were closest to a directional light source compared with sample compartments that were located further away from the light source (2% to 9%). Fungus gnat adults exhibited a significant response when exposed to two distinct ranges of light intensities (0.12 to 0.26 versus 0.87 to 1.02 μmol·m−2·s−1) with adults significantly more attracted to the highest light intensities (0.87 to 1.02 μmol·m−2·s−1). The results obtained in this study indicate that fungus gnat adults are positively phototactic, and as light intensity increases, they display a preference for those higher light intensities. It is possible that modifications in light intensity may be a feasible management strategy for alleviating problems with fungus gnats in greenhouses.
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Russi, Calice, Ruggieri, Laurino, Rocca, Amendola, Lapadula, et al. "Gastric Normal Adjacent Mucosa Versus Healthy and Cancer Tissues: Distinctive Transcriptomic Profiles and Biological Features." Cancers 11, no. 9 (August 26, 2019): 1248. http://dx.doi.org/10.3390/cancers11091248.
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Gastric cancer (GC) is a leading cause of cancer-related deaths in the world. Molecular heterogeneity is a major determinant for the clinical outcomes and an exhaustive tumor classification is currently missing. Histologically normal tissue adjacent to the tumor (NAT) is commonly used as a control in cancer studies, nevertheless a recently published paper described the unique characteristics of the NAT in several tumor types. Little is known about the global gene expression profile of gastric NAT (gNAT) which could be an effective tool for a more realistic definition of GC molecular signature. Here, we integrated data of 512 samples from the Genotype-Tissue Expression project (GETx) and The Cancer Genome Atlas (TCGA) to analyze the transcriptome of healthy gastric tissues, gNAT, and GC samples. We validated TCGA-GETx data mining through inHouse gNAT and GC expression dataset. Differential gene expression together with pathway enrichment analyses, indeed, led to different results when using the gNAT or the healthy tissue as control. Based on our analyses, gNAT showed a peculiar gene signature and biological features, like the estrogen receptor pathways activation, suggesting a molecular behavior partially different from both healthy and GC tissues. Therefore, using gNAT as healthy control tissue in the characterization of tumor associated biological processes and pathways could lead to suboptimal results.
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Cloyd, Raymond A., and Amy Dickinson. "Procedure to Enhance the Recovery Rate of Fungus Gnat, Bradysia sp. nr. coprophila Lintner (Diptera: Sciaridae) Adults from Growing Medium." HortScience 43, no. 5 (August 2008): 1528–30. http://dx.doi.org/10.21273/hortsci.43.5.1528.
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Fungus gnats, Bradysia spp., are major insect pests in greenhouses and interiorscapes. Management typically involves the use of either insecticides or biological control agents such as entomopathogenic nematodes. Efficacy trials provide information to greenhouse producers on the effectiveness of these management options. However, a simple procedure that rapidly evaluates the performance of control products against fungus gnat larvae is needed. Because fungus gnat larvae inhabit the growing medium, excess or deficient growing medium moisture may reduce adult fungus gnat emergence, thus confounding effects from efficacy trial treatments. Therefore, it is important to determine the amount of moisture and moisture content that results in the highest recovery of fungus gnat adults. We conducted two replicated experiments in a completely randomized design using a range of initial water volumes (treatments) and two larval stages (second and third) of the fungus gnat, Bradysia sp. nr. coprophila. The success of the procedure was based on the number of fungus gnat adults that emerged per treatment. In the first experiment, initial water volumes of 0, 25, 50, 75, 100, 150, and 200 mL were applied to 300 mL of a soilless growing medium consisting of 50% composted pine bark, 20% Canadian sphagnum peatmoss, 10% perlite, and 20% medium coarse vermiculite (SB300 Universal Mix). In general, the highest mean numbers (range, 11.2 to 14.6) of fungus gnat adults were recovered from growing medium treated with 50, 75, and 100 mL of water. In the second experiment, initial water volumes (treatments) of 50, 55, 60, 65, 70, and 75 mL were applied to 300 mL of the soilless growing medium (SB300 Universal Mix). There were no significant differences in the mean number of fungus gnat adults recovered regardless of the larval instar (second instar: 15.8 to 17.7; third instar: 14.4 to 17.4). The final percent moisture content ranged from 65% to 68% for the second instars and 56% to 66% for third instars. This study demonstrates that the highest number of fungus gnat adults may be recovered from soilless growing medium (SB300 Universal Mix) treated with between 50 and 75 mL of water, thus enhancing the confidence in any data set generated when evaluating insecticides or biological control agents for control of fungus gnats.
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Cloyd, Raymond A., Karen A. Marley, Richard A. Larson, and Bari Arieli. "Attractiveness of Parboiled Rice Hulls to the Fungus Gnat, Bradysia sp. nr coprophila (Diptera: Sciaridae), Adult Relative to Standard Growing Medium Components." HortScience 44, no. 5 (August 2009): 1366–69. http://dx.doi.org/10.21273/hortsci.44.5.1366.
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This study was conducted to assess the attractiveness of growing media containing parboiled rice hulls (PBH) to fungus gnat, Bradysia sp. nr. coprophila (Diptera: Sciaridae), adults. In comparing commercially prepared PBH with peatmoss (LC1) and pine bark (SB200)-based growing media, it was established that the fungus gnat adults were not specifically attracted to any of the growing media, even those containing PBH, with the mean proportion of fungus gnat adults recovered in the sample compartments ranging from 0.16 to 0.23. Moisture content was more important in terms of fungus gnat adult attractiveness to the growing media. In addition, the volatile constituents of the various growing media were determined using a steam distillation procedure. The component that was present in the highest concentration (39.2%) in the dried PBH as determined by gas chromatography analysis was palmitic acid, a straight-chain C16 fatty acid. S8 (cyclo-octasulfur), a well-known odoriferous component of degraded waste materials, was present at a higher concentration (6.2%) in the RH1 growing medium (80% peatmoss) compared with the other growing media evaluated. The data indicate that PBH, when incorporated in certain growing media, do not attract fungus gnat adults, and as such, greenhouse producers can use PBH as an amendment to growing medium without having to be concerned with the prospect of luring fungus gnat adults and sustaining plant damage.
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Herrick, Nathan J., and Raymond A. Cloyd. "Effect of Plant-growing Media on Western Flower Thrips, Frankliniella occidentalis, Pupae and Fungus Gnat, Bradysia sp. nr. coprophila, Larvae under Laboratory Conditions." HortScience 55, no. 8 (August 2020): 1323–26. http://dx.doi.org/10.21273/hortsci15139-20.
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Western flower thrips, Frankliniella occidentalis, and fungus gnats (Bradysia spp.) are major insect pests of greenhouse production systems. Both insect pests have life stages that reside in the soil or plant-growing medium: prepupae and pupae of western flower thrips and fungus gnat larvae. There are unsubstantiated allegations made by a manufacturer that certain plant-growing media that contain a bacterium, Bacillus pumilus, and arbuscular mycorrhizal fungus, Glomus intraradices, negatively affect the survival of western flower thrips pupae and fungus gnat larvae. Therefore, we conducted a study involving laboratory experiments replicated over time (2019 and 2020) to investigate the influence of the plant-growing media Pro-Mix BX + Mycorrhizae and Pro-Mix BX + Biofungicide + Mycorrhizae on western flower thrips pupae and fungus gnat larvae. All experiments involved placing western flower thrips pupae or fungus gnat larvae (second and third instar) into 473-mL deli containers with the different treatments (plant-growing media). A 5 × 4-cm section of a yellow sticky card was affixed to the lid of each deli container. After 21 days, the number of western flower thrips or fungus gnat adults that emerged from the growing media and were captured on the yellow sticky cards was recorded. The use of the yellow sticky card was an indirect assessment of western flower thrips pupal or fungus gnat larval mortality. We found none of the plant-growing media tested that contained a bacterium and/or arbuscular mycorrhizal fungus affected the survival of western flower thrips pupae or fungus gnat larvae. Therefore, greenhouse producers should be leery of information provided by manufacturers that does not contain valid, scientifically based data.
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Eberlein-Braun, Katharina, and Torben Stamer. "Introduction: Bamberg GNPT." International Journal of Public Theology 16, no. 1 (March 22, 2022): 3–5. http://dx.doi.org/10.1163/15697320-01540035.
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Rybin, Sergey, Alfred Strohmeier, and Eugene Zueff. "ASIS for GNAT." ACM SIGAda Ada Letters XVI, no. 2 (March 1996): 39–49. http://dx.doi.org/10.1145/230509.230512.
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Boldero, Jennifer M., David Rawlings, and Nick Haslam. "Convergence between GNAT‐assessed implicit and explicit personality." European Journal of Personality 21, no. 3 (May 2007): 341–58. http://dx.doi.org/10.1002/per.622.
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Two studies investigated the characteristics and correlates of implicit personality measures provided by the Go/No‐Go Association Task (GNAT), a variant of the Implicit Association Test (IAT). Extraversion was assessed in Study 1, and all Big‐Five factors in Study 2. Of interest were the convergent validity of the measures with explicit personality and their reliability. The results demonstrate that the GNAT metric (d') is reliable, and has convergent validity, only when systematic variance in the GNAT indices is controlled. We also provide preliminary evidence for the predictive utility of GNAT indices of implicit extraversion and neuroticism by examining their ability to predict reaction times. The results suggest that this task provides a promising method for assessing implicit personality. Copyright © 2007 John Wiley & Sons, Ltd.
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Raudenbush, Amy L., Raymond A. Cloyd, and Erik R. Echegaray. "Effect of a Physical Barrier on Adult Emergence and Egg Survival Associated with the Fungus Gnat, Bradysia sp. nr. coprophila (Diptera: Sciaridae), under Laboratory Conditions." HortScience 49, no. 7 (July 2014): 905–10. http://dx.doi.org/10.21273/hortsci.49.7.905.
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This study was conducted to assess the direct and indirect effects of Growstones™ aggregates, which are made from recycled glass, on fungus gnat, Bradysia sp. nr. coprophila (Diptera: Sciaridae), adult emergence, female egg-laying capacity, and egg survival. A series of experiments were performed under laboratory conditions to evaluate the effect of different sizes (2.0 to 10.0 mm) of Growstones™ aggregates, layer thicknesses (0.63 to 3.18 cm), and the use of the biological control agent, the rove beetle, Dalotia coriaria, along with different thicknesses (1.27 and 3.18 cm) of small Growstones™ aggregates on fungus gnat adult emergence. For each experiment, Growstones™ aggregates were applied to the surface of the growing medium in 473-mL polypropylene deli containers. This study demonstrated that the thickest (3.18 cm) layer of small (2.0 mm) Growstones™ aggregates significantly reduced or delayed the emergence of fungus gnat adults. In addition, the thickest layer of small Growstones™ aggregates may have indirectly affected egg survival. However, the use of Growstones™ along with rove beetle adults did not significantly reduce fungus gnat adult emergence.
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Fiodorova, O. A., and E. I. Sivkova. "Blood-sucking midges ecology in pastures and cattle farms of the Tyumen Region." Ukrainian Journal of Ecology 10, no. 4 (August 10, 2020): 43–47. http://dx.doi.org/10.15421/2020_165.
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The article presents materials on the seasonal dynamics of the population of gnat on pasture and farm, shows the feasibility of protecting cattle from these insects both when grazing, and zero grazing, comparative harmfulness in conditional units, and presumed loss of animal productivity. The purpose of the study is to determine the parasitological situation on insects of the gnat complex, the terms of protection depending on the technology of cattle management. One of the topical tasks for the successful development of livestock in the Tyumen region is to eliminate the harm caused by blood-sucking dipterous insects as hematophages and vectors pathogens of a number of dangerous diseases for humans and animals. When zero grazing indoor there is a mass attack of mosquitoes and black gnats on animals from mid-June to the middle of the first decade of July. The main gnat component in the specified time interval is mosquitoes, which have averaged 2.1 cu. The malicious population of gnat as a whole during this period amounted to 2.216 cu, and the estimated loss of productivity of animals — 8.2%.
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Braun, S. E., J. P. Sanderson, E. B. Nelson, M. L. Daughtrey, and S. P. Wraight. "Fungus Gnat Feeding and Mechanical Wounding Inhibit Pythium aphanidermatum Infection of Geranium Seedlings." Phytopathology® 99, no. 12 (December 2009): 1421–28. http://dx.doi.org/10.1094/phyto-99-12-1421.
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A series of laboratory tests were conducted to investigate potential effects of fungus gnat (Bradysia impatiens) feeding damage on susceptibility of geranium seedlings (Pelargonium × hortorum) to infection by the root rot pathogen Pythium aphanidermatum. Effects were compared with those from similar tests in which the seedlings were mechanically wounded by severing the root tip with a scalpel. Assays of geranium seedlings in petri dishes revealed a pronounced negative fungus gnat–Pythium interaction, with exposure to fungus gnat larvae 24 h prior to inoculation with P. aphanidermatum zoospores resulting in up to 47% fewer seedling deaths than would have been expected if the two agents had acted independently. Similar results were observed when seedlings were subjected to mechanical wounding 24 h prior to zoospore inoculation. In contrast, no interaction occurred when seedlings were mechanically wounded immediately prior to inoculation. The degree of plant damage inflicted by the feeding activities of the larval fungus gnats had no significant effect on the combined damage from fungus gnats and Pythium in petri dishes. Ancillary studies showed that Pythium development on V8 agar was not inhibited by the presence of fungus gnat-associated microorganisms, nor were seedlings inoculated with these microbes less susceptible to Pythium infection. The precise mechaism or mechanisms underlying the observed interactions were not elucidated; however, the results strongly suggest that both fungus gnat feeding and mechanical wounding activated systemic defenses that made the seedlings more resistant to Pythium infection.
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Williams, El. "Elegy for the Gnat." Ploughshares 47, no. 4 (2021): 167–68. http://dx.doi.org/10.1353/plo.2021.0132.
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Olson, Denise L., Ronald D. Oetting, and Marc W. van Iersel. "Effect of Soilless Potting Media and Water Management on Development of Fungus Gnats (Diptera: Sciaridae) and Plant Growth." HortScience 37, no. 6 (October 2002): 919–23. http://dx.doi.org/10.21273/hortsci.37.6.919.
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Coconut coir dust is being marketed as a soilless medium substitute for sphagnum peat moss that inhibits fungus gnat (Bradysia sp.) development. However, little information is available on the effects of coconut coir dust on Bradysia sp. In a laboratory study we examined the effect of substituting coconut coir dust for peat moss, with or without a food source, on the development of fungus gnats. An average of less than one adult emerged when 20 fungus gnat eggs were provided with pure or sterilized peat moss or coconut coir. A significantly higher number of adults (11.5-13) emerged when a food source of 1 g of yeast was added to either soilless potting medium type. The adults required up to 10 fewer days to emerge when food was provided, compared to sterilized and pure media, except for the pure peat moss. In a greenhouse study examining the effects of coir and peat at different textures and different moisture levels on fungus gnat survival, there were significant differences at the different levels of moisture. There was a higher population of larvae in the coarse medium containing peat. In the coir-based media, the fine-textured medium had the highest population level of fungus gnats. There were no significant effects on fungus gnat populations among the different levels of moisture within a medium type. However, there was a tendency for lower populations in the most moist and the driest media and the highest survival in the media that were maintained at 52.5% moisture. Plant growth was best in the media with the lowest number of fungus gnats (coarse coconut coir dust-based and fine and medium peat-based media). These results suggest that it is possible to select growing media that minimize fungus gnat populations, while optimizing plant growth. However, contrary to claims made by growing media producers, coconut coir dust does not necessarily inhibit fungus gnat development.
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Evans, Michael R., James N. Smith, and Raymond A. Cloyd. "Fungus Gnat Population Development in Coconut Coir and Sphagnum peat-based Substrates." HortTechnology 8, no. 3 (July 1998): 406–9. http://dx.doi.org/10.21273/horttech.8.3.406.
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Coir and peat-based substrates were tested for their effectiveness in inhibiting the development of fungus gnat populations. The first experiment was conducted in July under relatively high temperatures (20 to 35 °C) and a second experiment was conducted in April under relatively low temperatures (20 °C). Euphorbia pulcherrima Willd. ex Klotzch `Freedom' plants were planted into 18-cm-diameter containers filled with substrates containing 80% sphagnum peat or coir, with the remainder being perlite. Half of the containers of each substrate were inoculated with fungus gnat larvae and sealed with either cheesecloth or thrips screen for Expts. 1 and 2, respectively. After 6 and 8 weeks for Expts. 1 and 2, respectively, fungus gnat adult and larval populations were sampled. Adults and larvae were recovered from coir and peat-based substrates in both experiments. In Expt. 1, significantly more adults and larvae were recovered from coir-based than peat-based substrates. In Expt. 2, significantly more adults and larvae were recovered from the peat-based than coir-based substrates. In a third experiment, the peat- and coir-based substrates used in Expts. 1 and 2 were used as well as the Iowa State greenhouse substrate, which contained 40% Sphagnum peat, 40% perlite, and 20% loam (v/v). Helianthus annuus L. `Pacino' seeds were sown into 18-cm-diameter containers filled with the test substrates. Natural infestation was allowed to occur for 6 weeks, after which time potato disks were used to sample the fungus gnat larvae population. Larvae were recovered from all substrates, and there was no significant difference in the number of larvae collected from the three substrates. Based on the results of these experiments, we concluded that coir does not inhibit the development of fungus gnat larvae populations and, when presented with options, fungus gnats will infest coir-based substrates as readily as peat-based substrates.