The "missing" heritability of complex traits may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. We propose a ...new kernel-based method called Latent Interaction Testing (LIT) to screen for genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Using simulated data, we demonstrate that LIT increases power to detect latent genetic interactions compared to univariate methods. We then apply LIT to obesity-related traits in the UK Biobank and detect variants with interactive effects near known obesity-related genes (URL: https://CRAN.R-project.org/package=lit ).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Practical algorithms predicting the probability of amyloid pathology among patients with subjective cognitive decline or mild cognitive impairment may help clinical decisions regarding confirmatory ...biomarker testing for Alzheimer's disease.
Algorithm feature selection was conducted with Alzheimer's Disease Neuroimaging Initiative and Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing data. Probability algorithms were developed in Alzheimer's Disease Neuroimaging Initiative using nested cross-validation accompanied by stratified subsampling to obtain 1000 internally validated decision trees. Semi-independent validation was conducted using Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. Independent external validation was conducted in the population-based Mayo Clinic Study of Aging.
Two algorithms were developed using age and normalized immediate recall z-scores, with or without apolipoprotein E ε4 carrier status. Both algorithms had robust performance across data sets and when substituting different recall memory tests.
The statistical framework resulted in robust probability estimation. Application of these algorithms may assist in clinical decision-making for further testing to diagnose amyloid pathology.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The presence of brain amyloid-beta positivity is associated with cognitive impairment and dementia, but whether there are specific aspects of cognition that are most linked to amyloid-beta is ...unclear. Analysis of neuropsychological test data presents challenges since a single test often requires drawing upon multiple cognitive functions to perform well. It can thus be imprecise to link performance on a given test to a specific cognitive function. Our objective was to provide insight into how cognitive functions are associated with brain amyloid-beta positivity among samples consisting of cognitively normal and mild cognitively impaired (MCI) subjects, by using partially ordered set models (POSETs).
We used POSET classification models of neuropsychological test data to classify samples to detailed cognitive profiles using ADNI2 and AIBL data. We considered 3 gradations of episodic memory, cognitive flexibility, verbal fluency, attention and perceptual motor speed, and performed group comparisons of cognitive functioning stratified by amyloid positivity (yes/no) and age (<70, 70-80, 81-90 years). We also employed random forest methods stratified by age to assess the effectiveness of cognitive testing in predicting amyloid positivity, in addition to demographic variables, and
4 allele count.
In ADNI2, differences in episodic memory and attention by amyloid were found for <70, and 70-80 years groups. In AIBL, episodic memory differences were found in the 70-80 years age group. In both studies, no cognitive differences were found in the 81-90 years group. The random forest analysis indicates that variable importance in classification depends on age. Cognitive testing that targets an intermediate level of episodic memory and delayed recall, in addition to
4 allele count, are the most important variables in both studies.
In the ADNI2 and AIBL samples, the associations between specific cognitive abilities and brain amyloid-beta positivity depended on age, but in general episodic memory was most consistently predictive of brain amyloid-beta positivity. Random forest methods and OOB error rates establish the feasibility of predicting the presence of brain beta-amyloid using cognitive testing,
4 genotyping and demographic variables.
This cohort study assesses the utility of restricted mean survival time as a method for quantifying time to nursing home placement among patients with dementia.
Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-& beta;(A & beta;) peptide into plaques and the ...microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of A & beta;plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with A & beta;plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than A & beta;and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with A & beta;and tau. Proteomic analysis of cerebrospinal fluid from individuals with autosomal dominant Alzheimer's disease reveals how this complex and chronic disease evolves over many decades.
The naturally tight entanglement of fibers in bacterial cellulose (BC) results in low printability when BC is used as a bioink for printing scaffolds. In this study, neat BC was treated by ...TEMPO-mediated oxidation (TO-BC) and maleic acid (MA-BC) to prepare homogeneous BC dispersions to fabricate scaffolds for bone regeneration. Results showed that the treatments released individual fibrils in the corresponding uniform dispersions without impairing inherent crystalline properties. Compared with TO-BC, MA-BC hybridized with gelatin could endow the gel with improved rheological properties and compression modulus for 3D printing. Both TO-BC and MA-BC dispersions showed good osteoblast viability. However, MA-BC possessed more pronounced ability to express osteogenic marker genes and formation of mineralized nodules in vitro. Compared with TO-BC-based gelatin scaffolds, MA-BC-based gelatin scaffolds showed a better ability to stimulate the regeneration of rat calvaria, demonstrating a higher bone mineral density of newly formed bone and trabecular thickness in vivo.
•TEMPO and MA treatments can liberate individual fibrils in BC dispersion.•MA treated BC endows gelatin with better compression modulus for 3D printing.•MA treated BC shows best performance for bone regeneration in vitro and in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this study, localized surface plasmon-enhanced electrochemiluminescence (LSP-ECL) biosensor, a new ECL enhancement way for S2O82−/O2 system, was constructed based on urchin-like Au and Ag ...nanoparticles (AgNPs) for fast, one-step, and label-free detection of broad-spectrum bacteria. We found plasmonic metals with small diameters contributed to the ECL enhancement. Moreover, relying entirely on the physical puncture of urchin-like Au, the bacteria could be captured to the electrode surface without the need for target recognition agents. The single-step LSP-ECL biosensor exhibited high sensitivity in the range of 102–108 CFU/mL bacteria with the detection limit as low as 52 CFU/mL, meanwhile possessing a short detection time of 30 min. What’s more, the LSP-ECL biosensing strategy achieved detection of S.aureus present in plasma samples without involving bacterial culture and nucleic acid extraction. Considering the merits of label-free, short assay time, and one-step operation, the developed LSP-ECL strategy provides a versatile and culture-free platform for pathogenic bacteria detection.
•The LSP-ECL biosensor was developed for rapid, label-free, and single-step bacterial detection.•The urchin-like Au effectively capture broad-spectrum bacteria without target recognition agents.•A new ECL enhancement way for S2O82−/O2 system was explored to analyze bacteria.•The strategy achieved label-free and single-step quantification of bacteria within 30 min.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A novel non-enzyme electrochemical biosensor for the rapid detection of Gram-positive bacteria has been constructed that relys on a stable and efficient combination between the peptidoglycan layer ...and platinum-nickel-copper nanocubes (Pt-Ni-Cu NCs). Briefly, bacteria were first captured by a specific antibody. Then, the electrochemical signal materials (Pt-Ni-Cu NCs) were bound to the bacteria peptidoglycan layer using specific structural and surface features. The rapid and sensitive bacterial detection was then achieved using intrinsic electrochemical characteristics and superoxidase-like activity of the Pt-Ni-Cu NCs. Moreover, the nature of peptidoglycan covering the whole bacteria provided the premise for signal amplification. Under optimal conditions, the electrochemical signal variation was proportional to the concentration of bacteria ranging from 1.5 × 10
2
to 1.5 × 10
8
CFU/mL with a detection limit of 42 CFU/mL using a working potential of − 0.4 V. This electrochemical biosensor has been successfully applied to detect bacteria concentrations in urine samples, and the recoveries range from 90.4 to 107%. The proposed biosensor could be applied for broad-spectrum detection of Gram-positive bacteria since most Gram-positive bacteria possess a thick peptidoglycan layer. The developed electrochemical biosensing strategy might be used as a potential tool for clinical pathogenic bacteria detection and point-of-care testing (POCT).
Pogostemon cablin
(patchouli) cultivation is challenged by serious soil sickness, of which autotoxins accumulation is a major cause. p-hydroxybenzoic acid (p-HBA) is one of the main autotoxins of ...patchouli. However, the molecular mechanism underlying the response of patchouli to p-HBA remains unclear. In this study, RNA-sequencing combined with physiological analysis was used to monitor the dynamic transcriptomic and physiological changes in patchouli seedlings 0, 6, 12, 24, 48, and 96 h after p-HBA treatment. p-HBA stress inhibited root biomass accumulation, induced excessive hydrogen peroxide accumulation and lipid peroxidation, and activated most antioxidant enzymes. Compared with that of the control, the osmotic adjustment substance content was elevated with treatment. Subsequently, 15,532, 8,217, 8,946, 2,489, and 5,843 differentially expressed genes (DEGs) at 6, 12, 24, 48, and 96 h after p-HBA treatment, respectively, were identified in patchouli roots. GO functional enrichment analysis showed that the DEGs were enriched mainly in plasma membrane, defense response, response to chitin, DNA-binding transcription factor activity and abscisic acid-activated signaling pathway. The upregulated genes were involved in glycolysis/gluconeogenesis, cysteine and methionine metabolism, starch and sucrose metabolism, biosynthesis of unsaturated fatty acids, and linoleic acid metabolism. Genes associated with MAPK signaling pathway-plant, plant-pathogen interaction, plant hormone signal transduction were downregulated with p-HBA treatment. These pathways are related to root browning and rotting, leading to plant death.
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