Histones and their posttranslational modifications influence the regulation of many DNA-dependent processes. Although an essential role for histone-modifying enzymes in these processes is well ...established, defining the specific contribution of individual histone residues remains a challenge because many histone-modifying enzymes have nonhistone targets. This challenge is exacerbated by the paucity of suitable approaches to genetically engineer histone genes in metazoans. Here, we describe a platform in Drosophila for generating and analyzing any desired histone genotype, and we use it to test the in vivo function of three histone residues. We demonstrate that H4K20 is neither essential for DNA replication nor for completion of development, unlike inferences drawn from analyses of H4K20 methyltransferases. We also show that H3K36 is required for viability and H3K27 is essential for maintenance of cellular identity but not for gene activation. These findings highlight the power of engineering histones to interrogate genome structure and function in animals.
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•Specific histone genotypes can be engineered in Drosophila using BAC transgenes•Histone gene expression is controlled by an active dosage compensation mechanism•Posttranslational modification of H4K20 is not required to complete development•H3K27 is required for Polycomb target gene repression but not for gene activation
McKay et al. describe a platform for histone gene engineering in Drosophila that allows direct genetic assessment of histone residue function in vivo. Using the system, they demonstrate that, contrary to inferences based on analysis of H4K20 methyltransferases, H4K20 is not essential for DNA replication or completion of development.
Significant endeavor has been applied to identify functional therapeutic targets in glioblastoma (GBM) to halt the growth of this aggressive cancer. We show that the receptor tyrosine kinase EphA3 is ...frequently overexpressed in GBM and, in particular, in the most aggressive mesenchymal subtype. Importantly, EphA3 is highly expressed on the tumor-initiating cell population in glioma and appears critically involved in maintaining tumor cells in a less differentiated state by modulating mitogen-activated protein kinase signaling. EphA3 knockdown or depletion of EphA3-positive tumor cells reduced tumorigenic potential to a degree comparable to treatment with a therapeutic radiolabelled EphA3-specific monoclonal antibody. These results identify EphA3 as a functional, targetable receptor in GBM.
► EphA3 is overexpressed on mesenchymal GBM and inhibits terminal differentiation ► EphA3 maintains the tumor-forming cell population in GBM ► EphA3 negatively regulates mitogen-activated protein kinase signaling in GBM ► EphA3 is a targetable tumor antigen for the treatment of GBM
Women have a consistently higher prevalence of major depressive disorder (MDD) than men. Hypotheses implicating hypothalamic-pituitary -adrenal, -gonadal, and -thyroid axes, immune response, genetic ...factors, and neurotransmitters have emerged to explain this difference. However, more evidence for these hypotheses is needed and new explanations must be explored. Here, we investigated sex differences in MDD markers using multiplex immunoassay measurements of 171 serum molecules in individuals enrolled in the Netherlands Study of Depression and Anxiety (NMDD = 231; Ncontrol = 365). We found 28 sex-dependent markers of MDD, as quantified by a significant interaction between sex and log2-transformed analyte concentration in a logistic regression with diagnosis (MDD/control) as the outcome variable (p<0.05; q<0.30). Among these were a number of male-specific associations between MDD and elevated levels of proteins involved in immune response, including C-reactive protein, trefoil factor 3, cystatin-C, fetuin-A, β2-microglobulin, CD5L, FASLG receptor, and tumor necrosis factor receptor 2. Furthermore, only male MDD could be classified with an accuracy greater than chance using the measured serum analytes (area under the ROC curve = 0.63). These findings may have consequences for the generalization of inflammatory hypotheses of depression to males and females and have important implications for the development of diagnostic biomarker tests for MDD. More studies are needed to validate these results, investigate a broader range of biological pathways, and integrate this data with brain imaging, genetic, and other relevant data.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In a previous paper we have shown that, when DNA samples for cases and controls are prepared in different laboratories prior to high-throughput genotyping, scoring inaccuracies can lead to ...differential misclassification and, consequently, to increased false-positive rates. Different DNA sourcing is often unavoidable in large-scale disease association studies of multiple case and control sets. Here, we describe methodological improvements to minimise such biases. These fall into two categories: improvements to the basic clustering methods for identifying genotypes from fluorescence intensities, and use of "fuzzy" calls in association tests in order to make appropriate allowance for call uncertainty. We find that the main improvement is a modification of the calling algorithm that links the clustering of cases and controls while allowing for different DNA sourcing. We also find that, in the presence of different DNA sourcing, biases associated with missing data can increase the false-positive rate. Therefore, we propose the use of "fuzzy" calls to deal with uncertain genotypes that would otherwise be labeled as missing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We ...obtained further support for 4q27 (IL2-IL21, P = 1.9 x 10(-8)) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously unknown and distinct risk loci in chromosome regions 6q15 (BACH2, P = 4.7 x 10(-12)), 10p15 (PRKCQ, P = 3.7 x 10(-9)), 15q24 (CTSH, P = 3.2 x 10(-15)) and 22q13 (C1QTNF6, P = 2.0 x 10(-8)).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Type 1 diabetes and celiac disease, both of which are associated with HLA class II genes, cosegregate in populations, suggesting a common genetic origin. In this article, the authors tested whether ...any non-HLA loci are shared. They report susceptibility alleles shared by both diseases, indicating that common biologic mechanisms underlie these immune-mediated disorders.
Type 1 diabetes and celiac disease cosegregate in populations, suggesting a common genetic origin. These authors report susceptibility alleles shared by both diseases, indicating that common biologic mechanisms underlie these immune-mediated disorders.
Type 1 diabetes is caused by autoimmune destruction of the insulin-producing beta cells in the pancreatic islets. The disease affects approximately 0.4% of persons of European origin and is strongly clustered in families. The major susceptibility genes — the HLA class II loci, HLA-DQB1 and HLA-DRB1 on chromosome 6p21 — act in combination with many other non-HLA loci across the genome,
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Celiac disease, which results from an immune, inflammatory reaction in the small intestine to proteins in ingested barley, wheat, and rye gluten, occurs in approximately 0.1% of persons of . . .
There is an increasing interest in the use of dried blood spot (DBS) sampling and multiple reaction monitoring in proteomics. Although several groups have explored the utility of DBS by focusing on ...protein detection, the reproducibility of the approach and whether it can be used for biomarker discovery in high throughput studies is yet to be determined. We assessed the reproducibility of multiplexed targeted protein measurements in DBS compared to serum. Eighty-two medium to high abundance proteins were monitored in a number of technical and biological replicates. Importantly, as part of the data analysis, several statistical quality control approaches were evaluated to detect inaccurate transitions. After implementing statistical quality control measures, the median CV on the original scale for all detected peptides in DBS was 13.2% and in Serum 8.8%. We also found a strong correlation (r = 0.72) between relative peptide abundance measured in DBS and serum. The combination of minimally invasive sample collection with a highly specific and sensitive mass spectrometry (MS) technique allows for targeted quantification of multiple proteins in a single MS run. This approach has the potential to fundamentally change clinical proteomics and personalized medicine by facilitating large-scale studies.
To impact carbon emissions, new materials for carbon capture must be inexpensive, robust, and able to adsorb CO2 specifically from a mixture of other gases. In particular, materials must be tolerant ...to the water vapor and to the acidic impurities that are present in gas streams produced by using fossil fuels to generate electricity. We show that a porous organic polymer has excellent CO2 capacity and high CO2 selectivity under conditions relevant to precombustion CO2 capture. Unlike polar adsorbents, such as zeolite 13x and the metal–organic framework, HKUST-1, the CO2 adsorption capacity for the hydrophobic polymer is hardly affected by the adsorption of water vapor. The polymer is even stable to boiling in concentrated acid for extended periods, a property that is matched by few microporous adsorbents. The polymer adsorbs CO2 in a different way from rigid materials by physical swelling, much as a sponge adsorbs water. This gives rise to a higher CO2 capacities and much better CO2 selectivity than for other water-tolerant, nonswellable frameworks, such as activated carbon and ZIF-8. The polymer has superior function as a selective gas adsorbent, even though its constituent monomers are very simple organic feedstocks, as would be required for materials preparation on the large industrial scales required for carbon capture.
In this study we report convincing statistical support for a sixth type 1 diabetes (T1D) locus in the innate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard) on ...chromosome 2q24.3. We found the association in an interim analysis of a genome-wide nonsynonymous SNP (nsSNP) scan, and we validated it in a case-control collection and replicated it in an independent family collection. In 4,253 cases, 5,842 controls and 2,134 parent-child trio genotypes, the risk ratio for the minor allele of the nsSNP rs1990760 A → G (A946T) was 0.86 (95% confidence interval = 0.82-0.90) at P = 1.42 × 10−10.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genome-wide association studies are now identifying disease-associated chromosome regions. However, even after convincing replication, the localization of the causal variant(s) requires comprehensive ...resequencing, extensive genotyping and statistical analyses in large sample sets leading to targeted functional studies. Here, we have localized the type 1 diabetes (T1D) association in the interleukin 2 receptor alpha (IL2RA) gene region to two independent groups of SNPs, spanning overlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5' regions of IL2RA and RBM17 (odds ratio = 2.04, 95% confidence interval = 1.70-2.45; P = 1.92 x 10(-28); control frequency = 0.635). Furthermore, we have associated IL2RA T1D susceptibility genotypes with lower circulating levels of the biomarker, soluble IL-2RA (P = 6.28 x 10(-28)), suggesting that an inherited lower immune responsiveness predisposes to T1D.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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