Scalable Analysis of Untargeted LC-HRMS Data by Means of SQL Database Archiving

Liquid chromatography-high-resolution mass spectrometry (LC-HRMS) is widely used to detect chemicals with a broad range of physiochemical properties in complex biological samples. However, the current data analysis strategies are not sufficiently scalable because of data complexity and amplitude. In this article, we report a novel data analysis strategy for HRMS data founded on structured query language database archiving. A database called ScreenDB was populated with parsed untargeted LC-HRMS data after peak deconvolution from forensic drug screening data. The data were acquired using the same analytical method over 8 years. ScreenDB currently holds data from around 40,000 data files, including forensic cases and quality control samples that can be readily sliced and diced across data layers. Long-term monitoring of system performance, retrospective data analysis for new targets, and identification of alternative analytical targets for poorly ionized analytes are examples of ScreenDB applications. These examples demonstrate that ScreenDB makes a significant improvement to forensic services and that the concept has potential for broad applications for all large-scale biomonitoring projects that rely on untargeted LC-HRMS data

Future management of arable perennials - an introduction to the project AC/DC-weeds

Mehrjährige Wurzelunkräuter beeinträchtigen die ackerbauliche Produktion. Verbreitete Bekämpfungspraktiken sind intensive wendende Bodenbearbeitung und chemisch-synthetische Herbizide. Diese gebräuchlichen Methoden haben allerdings unerwünschte Effekte auf Nicht-Ziel-Organismen und die Umwelt. Ziel des SusCrop-ERA-NET geförderten Europäischen Projekts ‘AC/DC-weeds’ ist es, agrarökologisch basiertes Management von mehrjährigen Wurzelunkräutern zu etablieren. Beiträge zur Reduktion von wendender Bodenbearbeitung in ökologischen und konventionellen Ackerbau und dem Ersatz von Glyphosat in letzterem zu liefern, sind die übergeordneten Aufgaben. Getragen von sieben Partnern aus fünf europäischen Ländern läuft das Projekt von 2019 bis 2022. Drei wichtige mehrjährige Arten in Nord- und Zentral-Europa werden fokussiert (Sonchus arvensis, Cirsium arvense und Elymus repens). Zu diesen Arten erfasst AC/DC-weeds Ökologie und Wirkungen des agronomischen Managements mit Experimenten und einer systematischen Literatur-Recherche. Neues agrar-ökologisches Managements der Arten wird in Feldversuchen und Semi-Feld Versuchen untersucht. Für die Erfassung werden innovative Technologien eingesetzt, um der nesterweisen Verteilung im Feld gerecht zu werden. Qualitative Modelle nutzen Wissen zu den Einflussfaktoren auf das Vorkommen von mehrjährigen Unkräutern, um sie für Entscheidungen nutzbar zu machen. Das Wachstum der Arten und die Effekte des Managements werden einfach und grafisch in einer Web-Anwendung visualisiert. Die Versuche und Modellierungen werden begleitet durch eine Umweltbewertung- und ökonomische Kalkulationen.Creeping perennial weeds have strong negative impacts on arable production. The common control practices are intensive inversion tillage and chemical herbicides. However, these traditional methods negatively affect non-target species and the environment. The objective of the SusCrop-ERA-NET funded European project ‘AC/DC-weeds’ is to implement agro-ecological management for creeping perennials in arable farming. The overall aim of this project is to reduce plough-tillage in organic and conventional farming, and to replace glyphosate in the latter system. From 2019 to 2022, this project involves seven partners from five European countries. Focusing on three important perennial species in central and northern Europe (Sonchus arvensis, Cirsium arvense and Elymus repens), AC/DC-weeds will thoroughly study the ecology and agronomical management of these species through systematic literature reviews and experiments. Novel agro-ecological management of these species is examined in field experiments and semi-field approaches. Innovative technology will be used to identify and monitor the distribution of these weeds on fields. Qualitative models are developed to make use of existing knowledge and expertise of the influences on perennial infestations in management decisions. A graphic web tool will enable visualization of the growth of the species and the effects of weed management. Environmental and economic evaluations on different weed management accompany the experimental and modelling work

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM

Diet-associated vertically transferred metabolites and risk of asthma, allergy, eczema, and infections in early childhood

BackgroundEvidence suggests maternal pregnancy dietary intake and nutrition in the early postnatal period to be of importance for the newborn child's health. However, studies investigating diet-related metabolites transferred from mother to child on disease risk in childhood are lacking. We sought to investigate the influence of vertically transferred metabolites on risk of atopic diseases and infections during preschool age. MethodsIn the Danish population-based COPSAC(2010) mother-child cohort, information on 10 diet-related vertically transferred metabolites from metabolomics profiles of dried blood spots (DBS) at age 2-3 days was analyzed in relation to the risk of childhood asthma, allergy, eczema, and infections using principal component and single metabolite analyses. ResultsIn 678 children with DBS measurements, a coffee-related metabolite profile reflected by principal component 1 was inversely associated with risk of asthma (odds ratio (95% CI) 0.78 (0.64; 0.95), p = .014) and eczema at age 6 years (0.79 (0.65; 0.97), p = .022). Furthermore, increasing stachydrine (fruit-related), 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (fish-related), and ergothioneine (fruit-, green vegetables-, and fish-related) levels were all significantly associated with reduced risks of infections at age 0-3 years (p < .05). ConclusionThis study demonstrates associations between pregnancy diet-related vertically transferred metabolites measured in children in early life and risk of atopic diseases and infections in childhood. The specific metabolites associated with a reduced disease risk in children may contribute to the characterization of a healthy nutritional profile in pregnancy using a metabolomics-based unbiased tool for predicting childhood health

Effects of Thyroxine Exposure on Osteogenesis in Mouse Calvarial Pre-Osteoblasts

The incidence of craniosynostosis is one in every 1,800-2500 births. The gene-environment model proposes that if a genetic predisposition is coupled with environmental exposures, the effects can be multiplicative resulting in severely abnormal phenotypes. At present, very little is known about the role of gene-environment interactions in modulating craniosynostosis phenotypes, but prior evidence suggests a role for endocrine factors. Here we provide a report of the effects of thyroid hormone exposure on murine calvaria cells. Murine derived calvaria cells were exposed to critical doses of pharmaceutical thyroxine and analyzed after 3 and 7 days of treatment. Endpoint assays were designed to determine the effects of the hormone exposure on markers of osteogenesis and included, proliferation assay, quantitative ALP activity assay, targeted qPCR for mRNA expression of Runx2, Alp, Ocn, and Twist1, genechip array for 28,853 targets, and targeted osteogenic microarray with qPCR confirmations. Exposure to thyroxine stimulated the cells to express ALP in a dose dependent manner. There were no patterns of difference observed for proliferation. Targeted RNA expression data confirmed expression increases for Alp and Ocn at 7 days in culture. The genechip array suggests substantive expression differences for 46 gene targets and the targeted osteogenesis microarray indicated 23 targets with substantive differences. 11 gene targets were chosen for qPCR confirmation because of their known association with bone or craniosynostosis (Col2a1, Dmp1, Fgf1, 2, Igf1, Mmp9, Phex, Tnf, Htra1, Por, and Dcn). We confirmed substantive increases in mRNA for Phex, FGF1, 2, Tnf, Dmp1, Htra1, Por, Igf1 and Mmp9, and substantive decreases for Dcn. It appears thyroid hormone may exert its effects through increasing osteogenesis. Targets isolated suggest a possible interaction for those gene products associated with calvarial suture growth and homeostasis as well as craniosynostosis. © 2013 Cray et al

Mechanisms for reducing low back pain: a mediation analysis of a multifaceted intervention in workers in elderly care

Purpose A multifaceted workplace intervention consisting of participatory ergonomics, physical training, and cognitive–behavioural training (CBT) has shown effectiveness for reducing low back pain (LBP). However, the mechanisms of action underlying these intervention components are not well understood. Methods This was a mediation analysis of a cluster-randomised controlled trial of a multifaceted intervention in 420 workers in elderly care. Mediation analysis was carried out via structural equation modelling. Potential mediators investigated were: fear-avoidance beliefs, perceived muscle strength, use of assistive devices at work and perceived physical exertion at work. LBP outcomes assessed were: days with LBP, LBP intensity and days with bothersome LBP. Results There were no significant indirect effects of the intervention on LBP outcomes. There were significant effects of the intervention on both fear-avoidance measures [β = − 0.63, 95% CI (1.23, 0.03); β = − 1.03, 95% CI (− 1.70, − 0.34)] and the use of assistive devices [β = − 0.55, 95% CI (− 1.04, − 0.05)], but not on perceived muscle strength [β = − 0.18, 95% CI (− 0.50, 0.13)] or physical exertion [β = − 0.05, 95% CI (− 0.40, 0.31)]. The only potential mediator with a significant effect on LBP outcomes was physical exertion, which had a significant effect on LBP intensity [β = 0.14, 95% CI (0.04, 0.23)]. Conclusions A multifaceted intervention consisting of participatory ergonomics, physical training, and CBT was able to decrease fear-avoidance beliefs and increase use of assistive devices in the workplace. However, these changes did not explain the effect of any of the intervention components on days with LBP, LBP intensity and days with bothersome LBP

Fraction of Inspired Oxygen During General Anesthesia for Non-Cardiac Surgery:Systematic Review and Meta-Analysis

BACKGROUND: Controversy exists regarding the effects of a high versus a low intraoperative fraction of inspired oxygen (FiO(2)) in adults undergoing general anesthesia. This systematic review and meta‐analysis investigated the effect of a high versus a low FiO(2) on postoperative outcomes. METHODS: PubMed and Embase were searched on March 22, 2022 for randomized clinical trials investigating the effect of different FiO(2) levels in adults undergoing general anesthesia for non‐cardiac surgery. Two investigators independently reviewed studies for relevance, extracted data, and assessed risk of bias. Meta‐analyses were performed for relevant outcomes, and potential effect measure modification was assessed in subgroup analyses and meta‐regression. The evidence certainty was evaluated using GRADE. RESULTS: This review included 25 original trials investigating the effect of a high (mostly 80%) versus a low (mostly 30%) FiO(2). Risk of bias was intermediate for all trials. A high FiO(2) did not result in a significant reduction in surgical site infections (OR: 0.91, 95% CI 0.81–1.02 [p = .10]). No effect was found for all other included outcomes, including mortality (OR = 1.27, 95% CI: 0.90–1.79 [p = .18]) and hospital length of stay (mean difference = 0.03 days, 95% CI −0.25 to 0.30 [p = .84). Results from subgroup analyses and meta‐regression did not identify any clear effect modifiers across outcomes. The certainty of evidence (GRADE) was rated as low for most outcomes. CONCLUSIONS: In adults undergoing general anesthesia for non‐cardiac surgery, a high FiO(2) did not improve outcomes including surgical site infections, length of stay, or mortality. However, the certainty of the evidence was assessed as low