Biology subjects

Jackson, T.

Publications and source records attributed to Jackson, T..

29 records · Page 2Linked to original sources

bioRxiv2023

A novel framework to build saliva-based DNA methylation biomarkers: quantifying systemic chronic inflammation as a case study

Accessible and non-invasive biomarkers that measure human ageing processes and the risk of developing age-related disease are paramount in preventative healthcare. In this study, we describe a novel framework to train saliva-based DNA methylation (DNAm) biomarkers that are reproducible and biologically interpretable. By leveraging a reliability dataset with replicates across tissues, we demonstrate that it is possible to transfer knowledge from blood DNAm data to saliva DNAm data using DNAm proxies of blood proteins (EpiScores). We then apply these methods to create a new saliva-based epigenetic clock (InflammAge) that quantifies systemic chronic inflammation (SCI) in humans. Using a large blood DNAm human cohort with linked electronic health records and over 18,000 individuals (Generation Scotland), we demonstrate that InflammAge significantly associates with all-cause mortality, disease outcomes, lifestyle factors and immunosenescence; in many cases outperforming the widely used SCI biomarker C-reactive protein (CRP). We propose that our biomarker discovery framework and InflammAge will be useful to improve our understanding of the molecular mechanisms underpinning human ageing and to assess the impact of gero-protective interventions.

bioinformatics↗

bioRxiv2023

Clec12a tempers inflammation while restricting expansion of a colitogenic commensal

SUMMARYRegulation of the microbiota is critical to intestinal health yet the mechanisms employed by innate immunity remain unclear. Here we show that mice deficient in the C-Type-lectin receptor, Clec12a developed severe colitis, which was dependent on the microbiota. Fecal-microbiota-transplantation (FMT) studies into germfree mice revealed a colitogenic microbiota formed within Clec12a-/- mice that was marked by expansion of the gram-positive organism, Faecalibaculum rodentium. Treatment with F. rodentium was sufficient to worsen colitis in wild-type mice. Macrophages within the gut express the highest levels of Clec12a. Cytokine and sequencing analysis in Clec12a-/- macrophages revealed heighten inflammation but marked reduction in genes associated with phagocytosis. Indeed, Clec12a-/- macrophages are impaired in their ability to uptake F. rodentium. Purified Clec12a had higher binding to gram-positive organisms such as F. rodentium. Thus, our data identifies Clec12a as an innate immune surveillance mechanism to control expansion of potentially harmful commensals without overt inflammation.

immunology↗

bioRxiv2022

Circadian reprogramming of adipose progenitor cells regulates intermittent fasting-mediated adipose tissue remodeling and metabolic improvement

White adipose tissue (WAT) fibrosis is a hallmark of dysfunctional WAT that is directly linked to metabolic abnormalities. Recent studies have highlighted the role of dysfunctional adipose progenitor cells (APCs) in WAT fibrosis and impaired adaptive tissue plasticity, leading to systemic insulin resistance. However, therapeutic options for WAT fibrosis are limited. Intermittent fasting (IF) is an effective dietary regimen for weight control and metabolic improvement through various mechanisms, including healthy remodeling of WAT. However, whether IF is effective in improving age-associated WAT fibrosis and metabolic homeostasis is unknown. Here, we show that IF confers therapeutic benefits in aged and obese mice through reduction of WAT fibrosis. Single-cell analyses revealed that IF significantly reduces pro-fibrotic signatures within APCs along with upregulation of the circadian pathways, suggesting that the circadian clock of APCs mediates IF-induced WAT remodeling. Importantly, mice lacking core circadian gene exhibited increased fibrotic signatures in WAT and diminished beneficial response to IF, further supporting the importance of circadian rhythm in IF-mediated metabolic benefits. Lastly, insulin resistance in humans also presented with dysregulated circadian rhythm signatures in APC populations. Collectively, our findings highlight the novel role of the APC circadian rhythm in plasticity of WAT and metabolic response to IF.

molecular biology↗

bioRxiv2022

Aging Fly Cell Atlas Identifies Exhaustive Aging Features at Cellular Resolution

Aging is characterized by a decline in tissue function, but the underlying changes at cellular resolution across the organism remain unclear. Here, we present the Aging Fly Cell Atlas, a single-nucleus transcriptomic map of the whole aging Drosophila. We characterize 163 distinct cell types and perform an in-depth analysis of changes in tissue cell composition, gene expression, and cell identities. We further develop aging clock models to predict the fly age and show that ribosomal gene expression is a conserved predictive factor for age. Combining all aging features, we find unique cell type-specific aging patterns. This atlas provides a valuable resource for studying fundamental principles of aging in complex organisms.

developmental biology↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part III: 2D Shape Recognition by Log-Scaling

Human vision has a remarkable ability to recognize complex 3D objects such as faces that appear with any size and 3D orientations at any 3D location. If we initially memorize a face only with a normalized size and viewed from directly head on, the direct comparison between the one-sized memory and a new incoming image would demand tremendous mental frame translations in 7D. How can we perform such a demanding task so promptly and reliably as we experience the objects in the world around us? Intriguingly, our primary visual cortex exhibits a 2D retinotopy with a log-polar coordinate system, where scaling up/down of shape is converted to linear frame translation. As a result, mental scaling can be performed by linearly translating the memory or the perceptual image until they overlap with each other. According to our new model of NHT (Neural Holography Tomography), alpha brainwaves traveling at a constant speed can conduct this linear translation. With this scheme, every scaling up/down by a factor of two should take the same amount of extra mental time to recognize a smaller/larger face. To test this hypothesis, we designed a reaction time (RT) experiment, where participants were first asked to memorize sets of unfamiliar faces with a given specific size (4{degrees} or 8{degrees}). Following the memorization phase, similar stimuli with a wide range of sizes (from 1{degrees} to 32{degrees}) were presented, and RTs were recorded. As predicted, the increase in RT was proportional to the scaling factor in the log scale. Furthermore, we observed that RTs were fastest for 8{degrees} faces even if the memorized face was 4{degrees}. This supports our hypothesis that we always memorize faces at the exact size of ~8 {degrees}. To our surprise, the increases in RT were also consistent with the mentally-estimated depth sensation, which indicates that the apparent size of the recognized face can create a proper depth sensation.

neuroscience↗

bioRxiv2021

A Transparent Ultrasound Array for Real-time Optical, Ultrasound and Photoacoustic Imaging

Objective and Impact StatementSimultaneous imaging of ultrasound and optical contrasts can help map structural, functional and molecular biomarkers inside living subjects with high spatial resolution. There is a need to develop a platform to facilitate this multimodal imaging capability to improve diagnostic sensitivity and specificity. IntroductionCurrently, combining ultrasound, photoacoustic and optical imaging modalities is challenging because con-ventional ultrasound transducer arrays are optically opaque. As a result, complex geometries are used to co-align both optical and ultrasound waves in the same field of view. MethodsOne elegant solution is to make the ultrasound transducer transparent to light. Here, we demonstrate a novel transparent ultrasound transducer (TUT) liner array fabricated using a transparent lithium niobate piezoelectric material for real-time multimodal imaging. ResultsThe TUT array consisted of 64 elements and centered at [~] 6 MHz frequency. We demonstrate a quad-mode ultrasound, Doppler ultrasound, photoacoustic and fluorescence imaging in real-time using the TUT array directly coupled to the tissue mimicking phantoms. ConclusionThe TUT array successfully showed a multimodal imaging capability, and has potential applications in diagnosing cancer, neuro and vascular diseases, including image-guided endoscopy and wearable imaging.

bioengineering↗

bioRxiv2021

Mutagenesis Mapping of RNA Structures within the Foot-and-Mouth Disease Virus Genome Reveals Functional Elements Localised in the Polymerase (3Dpol) Encoding Region.

AbstractRNA structure plays a crucial role in the replication of positive sense RNA viruses and can form functional elements within the untranslated regions (UTRs) and the protein coding sequences (or open reading frames (ORFs)). While RNA structures in the UTRs of several picornaviruses have been functionally characterised, the roles of putative RNA structures predicted for the ORF remain largely undefined. Here we have undertaken a bioinformatic analysis of the foot-and-mouth disease virus (FMDV) genome and predicted the existence of 53 evolutionarily conserved RNA structures within the ORF. Forty-five (45) of these structures were located in the regions encoding the non-structural proteins (nsps). To investigate if the structures in the regions encoding the nsps are required for FMDV replication we used a mutagenesis method, CDLR mapping, where sequential coding segments were shuffled to minimise RNA secondary structures while preserving protein coding, native dinucleotide frequencies and codon usage. To examine the impact of these changes on replicative fitness, mutated sequences were inserted into an FMDV sub-genomic replicon. We found that three of the RNA structures, all at the 3 termini of the FMDV ORF, were critical for replicon replication. Contrastingly, disruption of the other 42 conserved RNA structures that lie within the regions encoding the nsps had no effect on replicon replication, suggesting that these structures are not required for initiating translation or replication of viral RNA. Conserved RNA structures that are not essential for virus replication could provide ideal targets for the rational attenuation of a wide range of FMDV strains. ImportanceSome RNA structures formed by the genomes of RNA viruses are critical for viral replication. Our study shows that of 45 conserved RNA structures located within the regions of the foot-and-mouth disease virus (FMDV) genome that encode the non-structural proteins, only three are essential for replication of an FMDV sub-genomic replicon. Replicons replication is dependent on RNA translation and synthesis; thus, our results suggest that the three RNA structures are critical for either initiation of viral RNA translation and/or viral RNA synthesis. Although further studies are required to identify if the remaining 42 RNA structures have other roles in virus replication, they may provide targets for the rational large-scale attenuation of a wide range of FMDV strains. FMDV causes a highly contagious disease posing a constant threat to global livestock industries. Such weakened FMDV strains could be investigated as live-attenuated vaccines or could enhance biosecurity of conventional inactivated vaccine production.

evolutionary biology↗

bioRxiv2020

A novel human fetal liver-derived model reveals that MLL-AF4 drives a distinct fetal gene expression program in infant ALL

Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured1, the prognosis of infant-ALL (diagnosis within the first year of life) remains dismal2. Infant-ALL is usually caused by a single genetic hit that arises in utero: rearrangement of the MLL/KMT2A gene (MLL-r). This is sufficient to give rise to a uniquely aggressive and treatment-refractory leukemia compared to older children with the same MLL-r3-5. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. This paper addresses the hypothesis that fetal-specific gene expression programs co-operate with MLL-AF4 to initiate and maintain infant-ALL. Using direct comparison of fetal and adult HSC and progenitor transcriptomes we identify fetal-specific gene expression programs in primary human cells. We show that MLL-AF4-driven infant-ALL, but not MLL-AF4 childhood-ALL, displays expression of fetal-specific genes. In a direct test of this observation, we find that CRISPR-Cas9 gene editing of primary human fetal liver cells to produce a t(4;11)/MLL-AF4 translocation replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data strongly support the hypothesis that fetal-specific gene expression programs co-operate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL.

cancer biology↗

bioRxiv2020

Cancer cells are uniquely susceptible to accumulation of MMBIR mutations

Microhomology-mediated break-induced replication (MMBIR) is a mechanism of polymerase template switching at microhomology, which can produce complex genomic rearrangements (CGRs), underlies neurological and metabolic diseases, and contributes to cancer development. Yet, the extent of MMBIR activity in genomes is poorly understood due to difficulty in directly identifying MMBIR events by whole genome sequencing (WGS). Here, by using our newly developed MMBSearch software, we directly detect MMBIR events in human genomes and report substantial differences in frequency and complexity of MMBIR events between normal and cancer cells. MMBIR events appear only as germline variants in normal human fibroblast cells but readily accumulate de novo across several cancer types. Detailed analysis of MMBIR mutations in lung adenocarcinomas revealed MMBIR-initiated chromosome fusions that disrupted potential tumor suppressor genes and induced CGRs. Our findings document MMBIR as a trigger for widespread genomic instability and highlight MMBIR as a potential driver of tumor evolution.

genetics↗

bioRxiv2020

Resource availability and availability and disturbance shape maximum tree height across the Amazon

The factors shaping the distribution of giant tropical trees are poorly understood, despite its importance as a link between evolutionary biology and ecosystem biogeochemistry. The recent discovery of clusters of trees over 80 metres tall in the Guiana Shield region of the Amazon rainforest challenges the current understanding of the factors controlling the growth and survival of giant trees. The new discovery led us to revisit the question: what determines the distribution of the tallest trees of the Amazon? Here, we used high-resolution airborne LiDAR (Light Detection and Ranging) surveys to measure canopy height across 282,750 ha of primary old-growth and secondary forests throughout the entire Brazilian Amazon to investigate the relationship between the occurrence of giant trees and the environmental factors that influence their growth and survival. Our results suggest that the factors controlling where trees grow extremely tall are distinct from those controlling their longevity. Trees grow taller in areas with high soil clay content (> 42%), lower radiation (< 130 clear days per year) and wind speeds, avoiding alluvial areas (elevations higher than 40 m a.s.l), and with an optimal precipitation range of 1,500 to 2,500 mm yr-1. We then used an envelope model to determine the environmental conditions that support the very tallest trees (i.e. over 70 m height). We found that, as opposed to the myriad of interacting factors that control the maximum height at a large scale, wind speed had by far the largest influence on the distribution of these sentinel trees, and explained 67% of the probability of finding trees over 70 m in the Brazilian Amazon forest. The high-resolution pan-Amazon LiDAR data showed that environmental variables that drive growth in height are fundamentally different from environmental variables that support their survival. While precipitation and temperature seem to have lower importance for their survival than expected from previous studies, changes in wind and radiation regimes could reshape our forested biomes. This should be carefully considered by policy-makers when identifying important hotspots for the conservation of biodiversity in the Amazon.

ecology↗

bioRxiv2017

Delirium, frailty and mortality: interactions in a prospective study of hospitalized older people

BackgroundIt is unknown if the association between delirium and mortality is consistent for individuals across the whole range of health states. A bimodal relationship has been proposed, where delirium is particularly adverse for those with underlying frailty, but may have a smaller effect (perhaps even protective) if it is an early indicator of acute illness in fitter people. We investigated the impact of delirium on mortality in a cohort simultaneously evaluated for frailty.\n\nMethodsWe undertook an exploratory analysis of a cohort of consecutive acute medical admissions aged [≥]70. Delirium on admission was ascertained by psychiatrists. A Frailty Index (FI) was derived according to a standard approach. Deaths were notified from linked national mortality statistics. Cox regression was used to estimate associations between delirium, frailty and their interactions on mortality.\n\nResultsThe sample consisted of 710 individuals. Both delirium and frailty were independently associated with increased mortality rates (delirium: HR 2.4, 95%CI 1.8-3.3, p<0.01; frailty (per SD): HR 3.5, 95%CI 1.2-9.9, p=0.02). Estimating the effect of delirium in tertiles of FI, mortality was greatest in the lowest tertile: tertile 1 HR 3.4 (95%CI 2.1-5.6); tertile 2 HR 2.7 (95%CI 1.5-4.6); tertile 3 HR 1.9 (95% CI 1.2-3.0).\n\nConclusionWhile delirium and frailty contribute to mortality, the overall impact of delirium on admission appears to be greater at lower levels of frailty. In contrast to the hypothesis that there is a bimodal distribution for mortality, delirium appears to be particularly adverse when precipitated in fitter individuals.

epidemiology↗