hSSB1 (NABP2/OBFC2B) is regulated by oxidative stress

The maintenance of genome stability is an essential cellular process to prevent the development of diseases including cancer. hSSB1 (NABP2/ OBFC2A) is a critical component of the DNA damage response where it participates in the repair of double-strand DNA breaks and in base excision repair of oxidized guanine residues (8-oxoguanine) by aiding the localization of the human 8-oxoguanine glycosylase (hOGG1) to damaged DNA. Here we demonstrate that following oxidative stress, hSSB1 is stabilized as an oligomer which is required for hSSB1 to function in the removal of 8-oxoguanine. Monomeric hSSB1 shows a decreased affinity for oxidized DNA resulting in a cellular 8-oxoguanine-repair defect and in the absence of ATM signaling initiation. While hSSB1 oligomerization is important for the removal of 8-oxoguanine from the genome, it is not required for the repair of double-strand DNA-breaks by homologous recombination. These findings demonstrate a novel hSSB1 regulatory mechanism for the repair of damaged DNA.Publisher PDFPeer reviewe

Plasma transferrin and hemopexin are associated with altered Aβ uptake and cognitive decline in Alzheimer’s disease pathology

Background:Heme and iron homeostasis is perturbed in Alzheimer’s disease (AD); therefore, the aim of the studywas to examine the levels and association of heme with iron-binding plasma proteins in cognitively normal (CN),mild cognitive impairment (MCI), and AD individuals from the Australian Imaging, Biomarker and Lifestyle FlagshipStudy of Ageing (AIBL) and Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohorts.Methods:Non-targeted proteomic analysis by high-resolution mass spectrometry was performed to quantify relativeprotein abundances in plasma samples from 144 CN individuals from the AIBL and 94 CN from KARVIAH cohorts and21 MCI and 25 AD from AIBL cohort. ANCOVA models were utilized to assess the differences in plasma proteinsimplicated in heme/iron metabolism, while multiple regression modeling (and partial correlation) was performed toexamine the association between heme and iron proteins, structural neuroimaging, and cognitive measures.Results:Of the plasma proteins implicated in iron and heme metabolism, hemoglobin subunitβ(p= 0.001) was significantlyincreased in AD compared to CN individuals. Multiple regression modeling adjusted for age, sex, APOEε4 genotype, anddisease status in the AIBL cohort revealed lower levels of transferrin but higher levels of hemopexin associated with augmentedbrain amyloid deposition. Meanwhile, transferrin was positively associated with hippocampal volume and MMSE performance,and hemopexin was negatively associated with CDR scores. Partial correlation analysis revealed lack of significant associationsbetween heme/iron proteins in the CN individuals progressing to cognitive impairment.Conclusions:In conclusion, heme and iron dyshomeostasis appears to be a feature of AD. The causal relationship betweenheme/iron metabolism and AD warrants further investigation

COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks

Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks.</p

Plasma neurofilament light chain and amyloid-β are associated with the kynurenine pathway metabolites in preclinical Alzheimer\u27s disease

BACKGROUND: Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer\u27s disease amyloid pathology (amyloid-β; Aβ), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aβ correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation. METHODS: Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aβ concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65-90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. RESULTS: A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed (r = .451, p \u3c .0001). Positive correlations were also observed between NFL and kynurenine (r = .364, p \u3c .0005), kynurenic acid (r = .384, p \u3c .0001), 3-hydroxykynurenine (r = .246, p = .014), anthranilic acid (r = .311, p = .002), and quinolinic acid (r = .296, p = .003). Further, significant associations were observed between plasma Aβ40 and the K/T (r = .375, p \u3c .0005), kynurenine (r = .374, p \u3c .0005), kynurenic acid (r = .352, p \u3c .0005), anthranilic acid (r = .381, p \u3c .0005), and quinolinic acid (r = .352, p \u3c .0005). Significant associations were also observed between plasma Aβ42 and the K/T ratio (r = .215, p = .034), kynurenic acid (r = .214, p = .035), anthranilic acid (r = .278, p = .006), and quinolinic acid (r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aβ load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma Aβ and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent. CONCLUSIONS: The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aβ seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential

Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result

Background: Blood biomarkers may aid in recruitment to clinical trials of Alzheimer's disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) A\u3b2 and tau tests. Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/A\u3b242 (n = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF A\u3b242 measurements (n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/A\u3b242 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen \u3b2 chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/A\u3b242. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF A\u3b242 (P 48 0.05), while both A1AT and clusterin were nominally significantly associated with CSF A\u3b242 (both P < 0.05). Conclusion: Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Rapid draft sequencing and real-time nanopore sequencing in a hospital outbreak of Salmonella

Background: Foodborne outbreaks of Salmonella remain a pressing public health concern. We recently detected a large outbreak of Salmonella enterica serovar Enteritidis phage type 14b affecting more than 30 patients in our hospital. This outbreak was linked to community, national and European-wide cases. Hospital patients with Salmonella are at high risk, and require a rapid response. We initially investigated this outbreak by whole-genome sequencing using a novel rapid protocol on the Illumina MiSeq; we then integrated these data with whole-genome data from surveillance sequencing, thereby placing the outbreak in a national context. Additionally, we investigated the potential of a newly released sequencing technology, the MinION from Oxford Nanopore Technologies, in the management of a hospital outbreak of Salmonella. Results: We demonstrate that rapid MiSeq sequencing can reduce the time to answer compared to the standard sequencing protocol with no impact on the results. We show, for the first time, that the MinION can acquire clinically relevant information in real time and within minutes of a DNA library being loaded. MinION sequencing permits confident assignment to species level within 20 min. Using a novel streaming phylogenetic placement method samples can be assigned to a serotype in 40 min and determined to be part of the outbreak in less than 2 h. Conclusions: Both approaches yielded reliable and actionable clinical information on the Salmonella outbreak in less than half a day. The rapid availability of such information may facilitate more informed epidemiological investigations and influence infection control practices

Labeling poststorm coastal imagery for machine learning: measurement of interrater agreement

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Goldstein, E. B., Buscombe, D., Lazarus, E. D., Mohanty, S. D., Rafique, S. N., Anarde, K. A., Ashton, A. D., Beuzen, T., Castagno, K. A., Cohn, N., Conlin, M. P., Ellenson, A., Gillen, M., Hovenga, P. A., Over, J.-S. R., Palermo, R., Ratliff, K. M., Reeves, I. R. B., Sanborn, L. H., Straub, J. A., Taylor, L. A., Wallace E. J., Warrick, J., Wernette, P., Williams, H. E. Labeling poststorm coastal imagery for machine learning: measurement of interrater agreement. Earth and Space Science, 8(9), (2021): e2021EA001896, https://doi.org/10.1029/2021EA001896.Classifying images using supervised machine learning (ML) relies on labeled training data—classes or text descriptions, for example, associated with each image. Data-driven models are only as good as the data used for training, and this points to the importance of high-quality labeled data for developing a ML model that has predictive skill. Labeling data is typically a time-consuming, manual process. Here, we investigate the process of labeling data, with a specific focus on coastal aerial imagery captured in the wake of hurricanes that affected the Atlantic and Gulf Coasts of the United States. The imagery data set is a rich observational record of storm impacts and coastal change, but the imagery requires labeling to render that information accessible. We created an online interface that served labelers a stream of images and a fixed set of questions. A total of 1,600 images were labeled by at least two or as many as seven coastal scientists. We used the resulting data set to investigate interrater agreement: the extent to which labelers labeled each image similarly. Interrater agreement scores, assessed with percent agreement and Krippendorff's alpha, are higher when the questions posed to labelers are relatively simple, when the labelers are provided with a user manual, and when images are smaller. Experiments in interrater agreement point toward the benefit of multiple labelers for understanding the uncertainty in labeling data for machine learning research.The authors gratefully acknowledge support from the U.S. Geological Survey (G20AC00403 to EBG and SDM), NSF (1953412 to EBG and SDM; 1939954 to EBG), Microsoft AI for Earth (to EBG and SDM), The Leverhulme Trust (RPG-2018-282 to EDL and EBG), and an Early Career Research Fellowship from the Gulf Research Program of the National Academies of Sciences, Engineering, and Medicine (to EBG). U.S. Geological Survey researchers (DB, J-SRO, JW, and PW) were supported by the U.S. Geological Survey Coastal and Marine Hazards and Resources Program as part of the response and recovery efforts under congressional appropriations through the Additional Supplemental Appropriations for Disaster Relief Act, 2019 (Public Law 116-20; 133 Stat. 871)