Insight into the atomic scale structure of CaF₂-CaO-SiO₂ glasses using a combination of neutron diffraction, ²⁹Si solid state NMR, high energy X-ray diffraction, FTIR, and XPS

Bioactive glasses are important for biomedical and dental applications. The controlled release of key ions, which elicit favourable biological responses, is known to be the first key step in the bioactivity of these materials. Properties such as bioactivity and solubility can be tailored for specific applications. The addition of fluoride ions is particularly interesting for dental applications as it promotes the formation of fluoro-apatite. To date there have been mixed reports in the literature on how fluorine is structurally incorporated into bioactive glasses. To optimize the design and subsequent bioactivity of these glasses, it is important to understand the connections between the glass composition, structure and relevant macroscopic properties such as apatite formation and glass degradation in aqueous media. Using neutron diffraction, high energy X-ray diffraction, ²⁹Si NMR, FTIR and XPS we have investigated the atomic scale structure of mixed calcium oxide / calcium fluoride silicate based bioactive glasses. No evidence of direct Si-F bonding was observed, instead fluorine was found to bond directly to calcium resulting in mixed oxygen/fluoride polyhedra. It was therefore concluded that the addition of fluorine does not depolymerise the silicate network and that the widely used network connectivity models are valid in these oxyfluoride systems

A machine learning case–control classifier for schizophrenia based on DNA methylation in blood

Epigenetic dysregulation is thought to contribute to the etiology of schizophrenia (SZ), but the cell type-specificity of DNA methylation makes population-based epigenetic studies of SZ challenging. To train an SZ case–control classifier based on DNA methylation in blood, therefore, we focused on human genomic regions of systemic interindividual epigenetic variation (CoRSIVs), a subset of which are represented on the Illumina Human Methylation 450K (HM450) array. HM450 DNA methylation data on whole blood of 414 SZ cases and 433 non-psychiatric controls were used as training data for a classification algorithm with built-in feature selection, sparse partial least squares discriminate analysis (SPLS-DA); application of SPLS-DA to HM450 data has not been previously reported. Using the first two SPLS-DA dimensions we calculated a “risk distance” to identify individuals with the highest probability of SZ. The model was then evaluated on an independent HM450 data set on 353 SZ cases and 322 non-psychiatric controls. Our CoRSIV-based model classified 303 individuals as cases with a positive predictive value (PPV) of 80%, far surpassing the performance of a model based on polygenic risk score (PRS). Importantly, risk distance (based on CoRSIV methylation) was not associated with medication use, arguing against reverse causality. Risk distance and PRS were positively correlated (Pearson r = 0.28, P = 1.28 × 10−12), and mediational analysis suggested that genetic effects on SZ are partially mediated by altered methylation at CoRSIVs. Our results indicate two innate dimensions of SZ risk: one based on genetic, and the other on systemic epigenetic variants

Ruthenium polypyridyl complexes and their modes of interaction with DNA : is there a correlation between these interactions and the antitumor activity of the compounds?

Various interaction modes between a group of six ruthenium polypyridyl complexes and DNA have been studied using a number of spectroscopic techniques. Five mononuclear species were selected with formula [Ru(tpy) L1L2](2-n)?, and one closely related dinuclear cation of formula [{Ru(apy)(tpy)}2{l-H2N(CH2)6NH2}]4?. The ligand tpy is 2,20:60,200-terpyridine and the ligand L1 is a bidentate ligand, namely, apy (2,20-azobispyridine), 2-phenylazopyridine, or 2-phenylpyridinylmethylene amine. The ligand L2 is a labile monodentate ligand, being Cl-, H2O, or CH3CN. All six species containing a labile L2 were found to be able to coordinate to the DNA model base 9-ethylguanine by 1H NMR and mass spectrometry. The dinuclear cationic species, which has no positions available for coordination to a DNA base, was studied for comparison purposes. The interactions between a selection of four representative complexes and calf-thymus DNA were studied by circular and linear dichroism. To explore a possible relation between DNA-binding ability and toxicity, all compounds were screened for anticancer activity in a variety of cancer cell lines, showing in some cases an activity which is comparable to that of cisplatin. Comparison of the details of the compound structures, their DNA binding, and their toxicity allows the exploration of structure–activity relationships that might be used to guide optimization of the activity of agents of this class of compounds

Genetic architecture of epigenetic cortical clock age in brain tissue from older individuals: alterations in <em>CD46</em> and other loci

\ua9 2024 The Author(s). Published by Informa UK Limited, trading as Taylor &amp; Francis Group. The cortical epigenetic clock was developed in brain tissue as a biomarker of brain aging. As one way to identify mechanisms underlying aging, we conducted a GWAS of cortical age. We leveraged postmortem cortex tissue and genotyping array data from 694 participants of the Rush Memory and Aging Project and Religious Orders Study (ROSMAP; 11000,000 SNPs), and meta-analysed ROSMAP with 522 participants of Brains for Dementia Research (5,000,000 overlapping SNPs). We confirmed results using eQTL (cortical bulk and single nucleus gene expression), cortical protein levels (ROSMAP), and phenome-wide association studies (clinical/neuropathologic phenotypes, ROSMAP). In the meta-analysis, the strongest association was rs4244620 (p = 1.29 7 10−7), which also exhibited FDR-significant cis-eQTL effects for CD46 in bulk and single nucleus (microglia, astrocyte, oligodendrocyte, neuron) cortical gene expression. Additionally, rs4244620 was nominally associated with lower cognition, faster slopes of cognitive decline, and greater Parkinsonian signs (n ~ 1700 ROSMAP with SNP/phenotypic data; all p ≤ 0.04). In ROSMAP alone, the top SNP was rs4721030 (p = 8.64 7 10−8) annotated to TMEM106B and THSD7A. Further, in ROSMAP (n = 849), TMEM106B and THSD7A protein levels in cortex were related to many phenotypes, including greater AD pathology and lower cognition (all p ≤ 0.0007). Overall, we identified converging evidence of CD46 and possibly TMEM106B/THSD7A for potential roles in cortical epigenetic clock age

Prospective memory functioning among ecstasy/polydrug users: evidence from the Cambridge Prospective Memory Test (CAMPROMPT)

Rationale: Prospective memory (PM) deficits in recreational drug users have been documented in recent years. However, the assessment of PM has largely been restricted to self-reported measures that fail to capture the distinction between event-based and time-based PM. The aim of the present study is to address this limitation. Objectives: Extending our previous research, we augmented the range laboratory measures of PM by employing the CAMPROMPT test battery to investigate the impact of illicit drug use on prospective remembering in a sample of cannabis only, ecstasy/polydrug and non-users of illicit drugs, separating event and time-based PM performance. We also administered measures of executive function and retrospective memory in order to establish whether ecstasy/polydrug deficits in PM were mediated by group differences in these processes. Results: Ecstasy/polydrug users performed significantly worse on both event and time-based prospective memory tasks in comparison to both cannabis only and non-user groups. Furthermore, it was found that across the whole sample, better retrospective memory and executive functioning was associated with superior PM performance. Nevertheless, this association did not mediate the drug-related effects that were observed. Consistent with our previous study, recreational use of cocaine was linked to PM deficits. Conclusions: PM deficits have again been found among ecstasy/polydrug users, which appear to be unrelated to group differences in executive function and retrospective memory. However, the possibility that these are attributable to cocaine use cannot be excluded

Gene silencing in tick cell lines using small interfering or long double-stranded RNA

Gene silencing by RNA interference (RNAi) is an important research tool in many areas of biology. To effectively harness the power of this technique in order to explore tick functional genomics and tick-microorganism interactions, optimised parameters for RNAi-mediated gene silencing in tick cells need to be established. Ten cell lines from four economically important ixodid tick genera (Amblyomma, Hyalomma, Ixodes and Rhipicephalus including the sub-species Boophilus) were used to examine key parameters including small interfering RNA (siRNA), double stranded RNA (dsRNA), transfection reagent and incubation time for silencing virus reporter and endogenous tick genes. Transfection reagents were essential for the uptake of siRNA whereas long dsRNA alone was taken up by most tick cell lines. Significant virus reporter protein knockdown was achieved using either siRNA or dsRNA in all the cell lines tested. Optimum conditions varied according to the cell line. Consistency between replicates and duration of incubation with dsRNA were addressed for two Ixodes scapularis cell lines; IDE8 supported more consistent and effective silencing of the endogenous gene subolesin than ISE6, and highly significant knockdown of the endogenous gene 2I1F6 in IDE8 cells was achieved within 48 h incubation with dsRNA. In summary, this study shows that gene silencing by RNAi in tick cell lines is generally more efficient with dsRNA than with siRNA but results vary between cell lines and optimal parameters need to be determined for each experimental system

Quantifying the proportion of different cell types in the human cortex using DNA methylation profiles

This is the final version. Available from BMC via the DOI in this record. Availability of data and materials: All data generated or analysed during this study are included in this published article, its supplementary information files and publicly available repositories. Data generated for this project are available at NCBI Gene Express Omnibus (GEO) under accession number GSE234520 [64]. We also reanalysed data previously made available via GEO (via accession numbers GSE74193 [65], GSE59685 [66], GSE80970 [67], GSE88890 [68], GSE43414 [69]) and the synapse platform (syn7072866 [70], syn8263588 [71]). Code for the analyses presented here can be found on GitHub and Zenodo https://github.com/ejh243/BrainFANS/tree/master/array/DNAm/preprocessing (https://doi.org/https://doi.org/10.5281/zenodo.10402167). Specifically, code for the quality control of the DNAm data can be found at https://github.com/ejh243/BrainFANS/tree/master/array/DNAm/preprocessing and the code for the statistical analyses can be found at https://github.com/ejh243/BrainFANS/tree/master/array/DNAm/analysis/neuralCellComposition. Our new trained deconvolution models for brain are made available to the wider research community via our R package CETYGO available on GitHub (https://github.com/ds420/CETYGO; https://doi.org/10.5281/zenodo.10418430).Background: Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the proportion of different cell types using DNA methylation data. Here, we validate and profile the use of an expanded reference DNA methylation dataset incorporating two neuronal and three glial cell subtypes for quantifying the cellular composition of the human cortex. Results: We tested eight reference panels containing different combinations of neuronal- and glial cell types and characterised their performance in deconvoluting cell proportions from computationally reconstructed or empirically derived human cortex DNA methylation data. Our analyses demonstrate that while these novel brain deconvolution models produce accurate estimates of cellular proportions from profiles generated on postnatal human cortex samples, they are not appropriate for the use in prenatal cortex or cerebellum tissue samples. Applying our models to an extensive collection of empirical datasets, we show that glial cells are twice as abundant as neuronal cells in the human cortex and identify significant associations between increased Alzheimer’s disease neuropathology and the proportion of specific cell types including a decrease in NeuNNeg/SOX10Neg nuclei and an increase of NeuNNeg/SOX10Pos nuclei. Conclusions: Our novel deconvolution models produce accurate estimates for cell proportions in the human cortex. These models are available as a resource to the community enabling the control of cellular heterogeneity in epigenetic studies of brain disorders performed on bulk cortex tissue.Engineering and Physical Sciences Research CouncilMedical Research CouncilAlzheimer's Research UKMedical Research Counci

Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas

Syncopation and the Score

The first and second authors were supported by an EPSRC DTA (www.epsrc.ac.uk) studentship