Biology subjects

Jones, H.

Publications and source records attributed to Jones, H..

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bioRxiv2021

Characterization of methylation signatures in spontaneous preterm birth

Preterm birth is a global public health crisis which results in significant neonatal and maternal mortality. Yet little is known regarding the molecular mechanisms of idiopathic spontaneous preterm birth, and we have few diagnostic markers for adequate assessment of placental development and function. Previous studies of placental pathology and our transcriptomics studies suggest a role for placental maturity in idiopathic spontaneous preterm birth. It is known that placental DNA methylation changes over gestation. We hypothesized that if placental hypermaturity is present in our samples, we would observe a unique idiopathic spontaneous preterm birth DNA methylation profile potentially driving the gene expression differences we previously identified in our placental samples. Our results indicate the idiopathic spontaneous preterm birth DNA methylation pattern mimics the term birth methylation pattern suggesting hypermaturity. Only seven significant differentially methylated regions fitting the idiopathic spontaneous preterm birth specific (relative to the controls) profile were identified, indicating unusually high similarity in DNA methylation between idiopathic spontaneous preterm birth and term birth samples. We identified an additional 1,718 significantly methylated regions in our gestational age matched controls were the idiopathic spontaneous preterm birth DNA methylation pattern mimics the term birth methylation pattern, again indicating a striking level of similarity between the idiopathic spontaneous preterm birth and term birth samples. Pathway analysis of these regions revealed differences in genes within the WNT and Cadherin signaling pathways, both of which are essential in placental development and maturation. Taken together, these data demonstrate that the idiopathic spontaneous preterm birth samples are molecularly more mature than expected given their respective gestational age which likely impacts birth timing.

physiology↗

bioRxiv2020

ABPP-HT - high-throughput activity-based profiling of deubiquitylating enzyme inhibitors in a cellular context

The potency and selectivity of a small molecule inhibitor are key parameters to assess during the early stages of drug discovery. In particular, it is very informative for characterizing compounds in a relevant cellular context in order to reveal potential off-target effects and drug efficacy. Activity-based probes (ABPs) are valuable tools for that purpose, however, obtaining cellular target engagement data in a high-throughput format has been particularly challenging. Here, we describe a new methodology named ABPP-HT (high-throughput-compatible activity-based protein profiling), implementing a semi-automated proteomic sample preparation workflow that increases the throughput capabilities of the classical ABPP workflow approximately ten times while preserving its enzyme profiling characteristics. Using a panel of deubiquitylating enzyme (DUB) inhibitors, we demonstrate the feasibility of ABPP-HT to provide compound selectivity profiles of endogenous DUBs in a cellular context at a fraction of time as compared to previous methodologies.

biochemistry↗

bioRxiv2020

Strengthening The Organizing and Reporting of Microbiome Studies (STORMS)

BackgroundHuman microbiome research is a growing field with the potential for improving our understanding and treatment of diseases and other conditions. The field is interdisciplinary, making concise organization and reporting of results across different styles of epidemiology, biology, bioinformatics, translational medicine, and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. MethodsA multidisciplinary group of microbiome epidemiology researchers reviewed elements of available reporting guidelines for observational and genetic studies and adapted these for application to culture-independent human microbiome studies. New reporting elements were developed for laboratory, bioinformatic, and statistical analyses tailored to microbiome studies, and other parts of these checklists were streamlined to keep reporting manageable. ResultsSTORMS is a 17-item checklist for reporting on human microbiome studies, organized into six sections covering typical sections of a scientific publication, presented as a table with space for author-provided details and intended for inclusion in supplementary materials. ConclusionsSTORMS provides guidance for authors and standardization for interdisciplinary microbiome studies, facilitating complete and concise reporting and augments information extraction for downstream applications. AvailabilityThe STORMS checklist is available as a versioned spreadsheet from https://www.stormsmicrobiome.org/.

genomics↗

bioRxiv2020

Test Agreement Between Roche Cobas 6800 and Cepheid GeneXpert Xpress SARS-CoV-2 Assays at High Cycle Threshold Ranges

The SARS-CoV-2 pandemic has changed the face of the globe and upended the daily lives of billions. In an effort to bring mass-testing to as many as possible, multiple diagnostic tests including molecular, antigen detection and serological assays have been rapidly developed. However, there is very little information on positive test agreement across modalities, especially for lower viral loads. Thirty-five nasopharyngeal samples that had cycle threshold (Ct) values greater than 30.0 from the Roche cobas 6800 assay were run on the Cepheid GeneXpert Xpress SARS-CoV-2 assay. Ct values ranged from 30.1 to 37.9 (mean 36.7 {+/-} 1.9) on the Roche cobas 6800 assay and 24.6 to 42.4 (mean 32.8{+/-}4.1) on the Cepheid assay. There was a bias of 0.33 {+/-} 3.21, (mean difference -1.59, 95% limits of agreement -5.97, 6.63) signifying close agreement between the 2 instruments with a high standard deviation. The close test agreement between the cobas 6800 and GeneXpert at high Ct values allows for utilization of both assays interchangeable in accordance with testing algorithms.

microbiology↗

bioRxiv2020

Monoclonal antibody stability can be usefully monitored using the excitation-energy-dependent fluorescence edge-shift

Among the major challenges in the development of biopharmaceuticals are structural heterogeneity and aggregation. The development of a successful therapeutic monoclonal antibody (mAb) requires both a highly active and also stable molecule. Whilst a range of experimental (biophysical) approaches exist to track changes in stability of proteins, routine prediction of stability remains challenging. The fluorescence red edge excitation shift (REES) phenomenon is sensitive to a range of changes in protein structure. Based on recent work, we have found that quantifying the REES effect is extremely sensitive to changes in protein conformational state and dynamics. Given the extreme sensitivity, potentially this tool could provide a fingerprint of the structure and stability of a protein. Such a tool would be useful in the discovery and development of biopharamceuticals and so we have explored our hypothesis with a panel of therapeutic mAbs. We demonstrate that the quantified REES data show remarkable sensitivity, being able to discern between structurally identical antibodies and showing sensitivity to unfolding and aggregation. The approach works across a broad concentration range (g-mg/ml) and is highly consistent. We show that the approach can be applied alongside traditional characterisation testing within the context of a forced degradation study (FDS). Most importantly, we demonstrate the approach is able to predict the stability of mAbs both in the short (hours), medium (days) and long-term (months). The quantified REES data will find immediate use in the biopharmaceutical industry in quality assurance, formulation and development. The approach benefits from low technical complexity, is rapid and uses instrumentation which exists in most biochemistry laboratories without modification.

biochemistry↗

bioRxiv2020

Effects of breeding history and crop management on the root architecture of wheat

AimsSelection for optimal root system architecture (RSA) is important to ensure genetic gains in the sustainable production of wheat (Triticum aestivum L.). Here we examine the idea that past wheat breeding has led to changes in RSA and that future breeding efforts can focus directly on root traits to improve adaptation to a target environment. MethodsWe conducted three field trials using diverse wheat varieties, including modern and historic UK varieties and non-UK landraces, tested under contrasting tillage regimes (non-inversion tillage versus conventional ploughing) or different seeding rates (standard rate versus high rate). We used field excavation, washing and measurement of root crowns ( shovelomics) to characterise RSA traits, including: numbers of seminal, crown and nodal roots per plant, and crown root growth angle. ResultsWe found large differences among genotypes for all root traits. Modern varieties generally had fewer roots per plant than historic varieties. There were fewer crown roots and root angles were wider, on average, under shallow non-inversion tillage compared with conventional ploughing. Crown root numbers per plant also tended to be smaller at a high seeding rate compared with the standard rate. There were significant genotype-by-year, genotype-by-tillage and genotype-by-seeding-rate interactions for many root traits. ConclusionsSmaller root systems is likely to be a result of past selection and may have facilitated historical yield increases by reducing below-ground competition within the crop. The effects of crop management practices on RSA depend on genotype, suggesting that future breeding could select for improved RSA traits in resource-efficient farming systems.

plant biology↗

bioRxiv2020

Ketamine blocks the correlation between morphine-induced conditioned place preference and anxiety-like behaviors in mice.

Patients suffering from opioid use disorder often relapse during periods of abstinence, which is posited to be caused by negative affective states that drive motivated behaviors. Here, we explored whether conditioning mice with morphine in a CPP training paradigm evoked anxietylike behavior during morphine abstinence. To do this, mice were conditioned with morphine (10 mg/kg, i.p.) for five days. 24 h following conditioning, anxiety levels were tested by measuring time in the open arms of the elevated plus maze. The next day, mice were placed in the three compartment chamber to measure morphine-induced conditioned place preference (CPP). Our results show that following morphine conditioning, mice spent significantly less time in the open arm of the elevated plus maze and expressed robust morphine CPP on CPP test day. Furthermore, we found that an acute treatment with (R,S)-ketamine (10 mg/kg, i.p.), a medication demonstrating promise for preventing anxiety-related phenotypes, 30 min. prior to testing on post conditioning day 1, increased time spent in the open arm of the elevated plus maze in saline- and morphine-conditioned mice. Additionally, we found that a second injection of ketamine 30 min. prior to CPP tests on post conditioning day 2 prevented morphine-induced CPP, which lasted for up to 28 d post conditioning. Furthermore, we found that conditioning mice with 10% (w/v) sucrose using an oral self-administration procedure did not evoke anxietylike behavior, but elicited robust CPP, which was attenuated by ketamine treatment 30 min. prior to CPP tests. Overall, our results suggest that the ketamine-induced block of morphine CPP may not be attributed solely to alleviating negative affective states, but potentially through impaired memory of morphine-context associations.

neuroscience↗

bioRxiv2019

Natural selection towards wild-type in composite cross populations of winter wheat

Most of our crops are grown in monoculture with single genotypes grown over wide acreage. An alternative approach, where segregating populations are used as crops is an exciting possibility, but outcomes of natural selection upon this type of crop are not well understood. We tracked allelic frequency changes in evolving composite cross populations (CCPs) of wheat grown over ten generations under organic and conventional farming. At three generations, each population was genotyped with 19 SSR and 8 SNP markers. The latter were diagnostic for major functional genes. Gene diversity was constant at SSR markers but decreased over time for genic markers. Population differentiation between the four locations could not be detected, suggesting that organic vs. non-organic crop management did not drive allele frequency changes. However, we did see changes for genes controlling plant height and phenology in all populations independently and consistently. We interpret these changes as the result of a consistent natural selection towards wild-type. Independent selection for alleles that are associated with plant height suggests that competition for light was central, resulting in the predominance of stronger intraspecific competitors, and highlighting a potential trade-off between individual and population performance.

genetics↗

bioRxiv2019

Polygenic risk score for Alzheimer’s disease and trajectories of cardiometabolic risk factors in children

INTRODUCTIONCardiometabolic factors are implicated in the aetiology of Alzheimers disease and may lie on the pathways linking genetic variants to Alzheimers disease across the life course. We examined whether polygenic risk scores (PRS) were associated with cardiometabolic health indicators through childhood and adolescence.\n\nMETHODSIn 7,977 participants from the Avon Longitudinal Study of Parents and Children, we tested whether a PRS for Alzheimers disease was associated with trajectories of cardiometabolic risk factors. We examined trajectories for height 1-18 years; lean and fat mass 9-18 years; systolic and diastolic blood pressure 7-18 years; glucose and C-reactive protein 9-18 years; insulin 10-18 years; high and low-density lipoproteins and triglycerides birth-18 years. We also examined birthweight, interleukin-6 (IL-6) at age 9 years and physical activity at ages 11, 12, and 15 years.\n\nRESULTSNo consistent associations were observed between the PRS excluding genetic variants in the apolipoprotein E (ApoE) gene region and cardiometabolic factors trajectories across childhood and adolescence.\n\nCONCLUSIONWe did not detect evidence to suggest that the PRS for Alzheimers disease acts through childhood and adolescent cardiometabolic risk factors. Further studies should examine whether these associations emerge later in adulthood when variation in cardiometabolic risk factors is likely to be greater.

epidemiology↗

bioRxiv2019

Differences in Genetic Liability for Insomnia and Hypersomnia in Bipolar Disorder Subtypes

BackgroundInsomnia and hypersomnia are common in bipolar disorder (BD) but it is unclear whether genetic factors influence this association. Stratifying by bipolar subtypes could elucidate the nature of this association and inform research on sleep and BD. We therefore aimed to determine whether polygenic risk scores (PRS) for insomnia, daytime sleepiness and sleep duration differ according to bipolar subtypes (bipolar I disorder, BD-I or bipolar II disorder, BD-II).\n\nMethodsIn this case-control study, we used multinomial regression to determine whether PRS for insomnia, daytime sleepiness, and sleep duration were associated with risk of BD-I or BD-II when compared to each other and to controls. Cases (n=4672) were recruited within the United Kingdom from the Bipolar Disorder Research Network. Controls (n=5714) were recruited from the 1958 British Birth Cohort and UK Blood Service. All participants were of European ancestry. Clinical subtypes of BD were determined by semi-structured psychiatric interview (the Schedules for Clinical Assessment in Neuropsychiatry) and case notes.\n\nResultsWithin cases, 3404 and 1268 met DSM-IV criteria for BD-I and BD-II, respectively. Insomnia PRS was associated with increased risk of BD-II (RR = 1.14, 95% CI = 1.07-1.21, P = 8.26 x 10-5) but not BD-I (RR = 0.98, 95% CI = 0.94-1.03, P = .409) relative to controls. In contrast, sleep duration PRS was associated with increased relative risk of BD-I (RR = 1.10, 95% CI = 1.06-1.15, P = 1.13 x 10-5), but not BD-II (RR = 0.99, 95% CI = 0.93-1.06, P = .818). Daytime sleepiness PRS was associated with an increased risk of BD-I (RR = 1.07, 95% CI = 1.02-1.11, P = .005) and BD-II (RR = 1.14, 95% CI = 1.07-1.22, P = 3.22 x 10-5) compared to controls, but did not distinguish subtypes from each other.\n\nConclusionsBipolar subtypes differ in genetic liability to insomnia and sleep duration. Our findings provide further evidence that the distinction between BD-I and BD-II has biological and genetic validity. This distinction will be critical in the selection of participants for future research on the role of sleep disturbance in BD.

genomics↗

bioRxiv2019

Curriculum-based outdoor learning for children aged 9-11: A qualitative analysis of pupils' and teachers' views.

The relationship between child health, wellbeing and education demonstrates that healthier and happier children achieve higher educational attainment. An engaging curriculum that facilitates children in achieving their academic potential has strong implications for educational outcomes, future employment prospects and health and wellbeing during adulthood. Outdoor learning is a pedagogical approach used to enrich learning, enhance school engagement and improve pupil health and wellbeing. However, its non-traditional means of achieving curricular aims are not yet recognised beyond the early years by education inspectorates. This requires evidence into its acceptability from those at the forefront of delivery. This study aimed to explore headteachers, teachers and pupils views and experiences of an outdoor learning programme within the key stage two curriculum (ages 9-11). We examine the process of implementation to offer case study evidence through 1:1 interviews with headteachers (n=3) and teachers (n=10) and focus groups with pupils aged 9-11 (n=10) from three primary schools. Interviews and focus groups were conducted at baseline and six months into implementation. Schools introduced regular outdoor learning within the curriculum. This study found a variety of perceived benefits for pupils and schools. Pupils and teachers noticed improvements in pupils engagement with learning, concentration and behaviour, as well as positive impacts on health and wellbeing and teachers job satisfaction. Curriculum demands including testing and evidencing work were barriers to implementation, in addition to safety concerns, resources and teacher confidence. Participants supported outdoor learning as a curriculum-based programme for older primary school pupils. However, embedding outdoor learning within the curriculum requires education inspectorates to place higher value on this approach in achieving curricular aims, alongside greater acknowledgment of the wider benefits to children which current measurements do not capture.

scientific communication and education↗

bioRxiv2019

Smoking and the risk for bipolar disorder: causal evidence from a bidirectional Mendelian randomization study

ImportanceThere is increasing evidence that smoking is a risk factor for severe mental illness, including bipolar disorder. Conversely, patients with bipolar disorder might smoke more (often) as a result of the psychiatric disorder. Research that investigates causality and the direction of the relationship between smoking and bipolar disorder has been lacking.\n\nObjectiveTo investigate the direction and causal nature of the relationship between smoking and bipolar disorder we conducted a bidirectional Mendelian randomization (MR) study.\n\nData sourcesPublicly available summary statistics from genome-wide association studies on bipolar disorder, smoking initiation, smoking heaviness, smoking cessation and lifetime smoking (i.e., a compound measure of heaviness, duration and cessation). We applied multiple analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger or Egger SIMEX, weighted median, weighted mode, and Steiger filtered analyses.\n\nResultsAcross different methods of MR, consistent evidence was found for a positive effect of smoking on the odds of bipolar disorder (smoking initiation ORIVW=1.46, 95% CI=1.28-1.66, P=1.44x10-8, lifetime smoking ORIVW=1.72, 95% CI=1.29-2.28, P=1.8x10-4). The MR analyses of the liability of bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking initiation betaIVW= -0.008, 95% CI= -0.026-0.009, P=0.35; P=0.94; smoking heaviness betaIVW=0.028, 95% CI= 0.003-0.053, P=2.9x10-2; smoking cessation ORIVW= 0.997, 95% CI= 0.981-1.014, P=0.74; lifetime smoking betaIVW= -0.001, 95%CI=-0.022-0.020, P=0.95).\n\nConclusionsThese findings suggest that smoking initiation and lifetime smoking are likely to be a causal risk factor for developing bipolar disorder. We found some evidence that liability to smoking increased smoking heaviness. Given that smoking is a modifiable risk factor, these findings further support investment into smoking prevention and treatment in order to reduce mental health problems in future generations.

neuroscience↗

bioRxiv2018

Biodiversity trends are stronger in marine than terrestrial assemblages

Human activities have fundamentally altered biodiversity. Extinction rates are elevated and model projections suggest drastic biodiversity declines. Yet, observed temporal trends in recent decades are highly variable, despite consistent change in species composition. Here, we uncover clear spatial patterns within this variation. We estimated trends in the richness and composition of assemblages in over 50,000 time-series, to provide the most comprehensive assessment of temporal change in biodiversity across the planet to date. The strongest, most consistent pattern shows compositional change dominated by species turnover, with marine taxa experiencing up to fourfold the variation in rates of change of terrestrial taxa. Richness change ranged from no change to richness gains or losses of ~10% per year, with tropical marine biomes experiencing the most extreme changes. Earth is undergoing a process of spatial reorganisation of species and, while few areas are unaffected, biodiversity change is consistently strongest in the oceans.

ecology↗

bioRxiv2018

The geography of the Anthropocene differs between the land and the sea

O_LIClimate change and other anthropogenic drivers of biodiversity change are unequally distributed across the world. The geographic patterns of different drivers, and the spatial overlap among these drivers, have important implications for the direction and pace of biodiversity change, yet are not well documented. Moreover, it is unknown if the geographic patterns of drivers differ between the terrestrial and marine realm, as expected due to marked differences in how humans interact with the land and ocean. C_LIO_LIWe compiled global gridded datasets on climate change, land-use, resource exploitation, pollution, species invasions, and human population density. We used multivariate statistics to examine the spatial relationships among the datasets and to characterize the typical combinations of drivers experienced by different parts of the world. C_LIO_LIWe found stronger positive correlations among drivers in the terrestrial than in the marine realm, leading to areas of high intensities of multiple drivers on land. Climate change tended to be negatively correlated with other drivers in the terrestrial realm (e.g., in the tundra and boreal forest with high climate change but low human use and pollution) whereas the opposite was true in the marine realm (e.g., in the Indo-Pacific with high climate change and high fishing). C_LIO_LIWe show that different regions of the world can be defined by anthropogenic threat complexes (ATCs), distinguished by different sets of drivers with varying intensities. The ATCs can be used to test hypothesis about the pattern of biodiversity change, especially the joint effects of multiple drivers. More generally, our global analysis highlights the broad conservation priorities needed to mitigate the effects of anthropogenic change on biodiversity responses, with different priorities emerging on land and in the ocean, and in different parts of the world. C_LI

ecology↗

bioRxiv2017

The molecular genetics of participation in the Avon Longitudinal Study of Parents and Children

BackgroundIt is often assumed that selection (including participation and dropout) does not represent an important source of bias in genetic studies. However, there is little evidence to date on the effect of genetic factors on participation.\n\nMethodsUsing data on mothers (N=7,486) and children (N=7,508) from the Avon Longitudinal Study of Parents and Children, we 1) examined the association of polygenic risk scores for a range of socio-demographic, lifestyle characteristics and health conditions related to continued participation, 2) investigated whether associations of polygenic scores with body mass index (BMI; derived from self-reported weight and height) and self-reported smoking differed in the largest sample with genetic data and a sub-sample who participated in a recent follow-up and 3) determined the proportion of variation in participation explained by common genetic variants using genome-wide data.\n\nResultsWe found evidence that polygenic scores for higher education, agreeableness and openness were associated with higher participation and polygenic scores for smoking initiation, higher BMI, neuroticism, schizophrenia, ADHD and depression were associated with lower participation. Associations between the polygenic score for education and self-reported smoking differed between the largest sample with genetic data (OR for ever smoking per SD increase in polygenic score:0.85, 95% CI:0.81,0.89) and sub-sample (OR:0.95, 95% CI:0.88,1.02). In genome-wide analysis, single nucleotide polymorphism based heritability explained 17-31% of variability in participation.\n\nConclusionsGenetic association studies, including Mendelian randomization, can be biased by selection, including loss to follow-up. Genetic risk for dropout should be considered in all analyses of studies with selective participation.

genetics↗