Biology subjects

Taylor, A.

Publications and source records attributed to Taylor, A..

At least 73 records · Page 4Linked to original sources

bioRxiv2021

Mycena species can be opportunist-generalist plant root invaders

Recently, several saprotrophic genera have been found to invade/interact with plant roots in laboratory growth experiments, and this coincides with reports of abundant saprotrophic fungal sequences in plant roots. However, it is uncertain if this reflects field phenomena, and if reports on coincidentally amplified saprotrophs are simply coincidental. We investigated root invasion by presumed saprotrophic fungi by focusing on the large genus Mycena in 1) a systematic analysis of the occurrence of saprotrophic fungi in new and previously published ITS1/ITS2 datasets generated from roots of 10 mycorrhizal plant species, and 2) we analysed natural abundances of 13C/15N stable isotope signatures of fungal/plant communities from five comparable field locations to examine the trophic status of Mycena species. Mycena was the only saprotrophic genus consistently found in 9 of 10 plant host roots, with high within-host variation in Mycena sequence proportions (0-80%) recovered. Mycena carpophores displayed isotopic signatures consistent with published 13C/15N profiles of both saprotrophic or mutualistic lifestyles, with considerable intraspecific variation, resembling the patterns seen in growth experiments. These results indicate that multiple Mycena species opportunistically invade the roots of a range of plant species, possibly forming a spectrum of interactions. This potentially challenges our general understanding of fungal ecology. Originality significance statementThis is the first study to apply a dual approach of systematic metabarcoding of plant roots and stable isotope signatures on dried field material to the large and common saprotrophic fungal genus Mycena. This is significant as it shows that members of this genus, normally not expected to be found inside plant roots at all, are in fact associated eith multiple plant hosts. The study furthermore shows that species in this genus may occupy different ecological roles in the field besides being saprotrophic. That a large and common fungal genus known to be a quantitatively important litter decayer can be an opportunistic root invader and interact with host plants is of interest to all mycologists and ecologists working on plant-fungus/microb symbiosis.

ecology↗

bioRxiv2020

The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

We examined a novel function of mammalian Choline-Transporter-Like proteins CTL1/SLC44A1 and CTL2/SLC44A2 in ethanolamine transport. We established two distinct ethanolamine transport systems of a high affinity (K1 = 55.6 - 66.5 M), mediated by CTL1, and of a low affinity (K2 = 275 - 299 M), mediated by CTL2. Both types of transport are Na+-independent and mediated in a pH dependent manner, as expected for ethanolamine/H+ antiporters. Primary human fibroblasts with separate frameshift mutations (M1= SLC44A1 {Delta}Asp517 and M2= SLC44A1 {Delta}Ser126) are devoid of CTL1 ethanolamine transport but maintain unaffected CTL2 transport. The lack of CTL1 or CTL2 reduced the ethanolamine transport, the flux by the CDP-ethanolamine Kennedy pathway and PE synthesis. Overexpression of CTL1 in SLC44A1 {Delta}Ser126 (M2) cells improved the ethanolamine transport and PE synthesis. The SLC44A1 {Delta}Ser126 cells are reliant on CTL2 function and CTL2 siRNA almost completely abolished ethanolamine transport in the whole cells and mitochondria. Overexpression of CTL1 and CTL2 cDNAs increased ethanolamine transport in control and SLC44A1{Delta}Ser126 cells. CTL1 and CTL2 facilitated mitochondrial ethanolamine uptake, but the transport mediated by CTL1 is predominant in the whole cells and mitochondria. These data firmly established that CTL1 and CTL2 are the first identified ethanolamine transporters in the whole cells and mitochondria, with intrinsic roles in de novo PE synthesis by the CDP-Etn Kennedy pathway and compartmentation of intracellular ethanolamine. SignificanceThe lack of Choline Transporter Like 1 (SLC44A1/CTL1) is the primary cause of a new neurodegenerative disorder with elements of childhood-onset parkinsonism and mitochondrial dysfunction. SLC44A2/CTL2 encodes the human neutrophil antigen 3, causes autoimmune hearing loss and Menieres disease, and has been recently identified as the main risk factor for thrombosis-the major cause of death in Covid-19 patients. Our investigation provides insights into the novel functions of CTL1 and CTL2 as intrinsic ethanolamine transporters. CTL1 and CTL2 are high and low affinity transporters, with direct roles in the membrane phospholipid synthesis. The work contributes to new knowledge for CTL1 and CTL2 independent transport functions and the optimization of prevention and treatment strategies in those various diseases.

physiology↗

bioRxiv2020

A novel single-domain Na+-selective voltage-gated channel in photosynthetic eukaryotes

The evolution of Na+-selective four-domain voltage-gated channels (4D-Navs) in animals allowed rapid Na+-dependent electrical excitability, and enabled the development of sophisticated systems for rapid and long-range signalling. Whilst bacteria encode single-domain Na+-selective voltage-gated channels (BacNav), they typically exhibit much slower kinetics than 4D-Navs, and are not thought to have crossed the prokaryote-eukaryote boundary. As such, the capacity for rapid Na+-selective signalling is considered to be confined to certain animal taxa, and absent from photosynthetic eukaryotes. Certainly, in land plants, such as the Venus Flytrap where fast electrical excitability has been described, this is most likely based on fast anion channels. Here, we report a unique class of eukaryotic Na+-selective single-domain channels (EukCatBs) that are present primarily in haptophyte algae, including the ecologically important calcifying coccolithophores. The EukCatB channels exhibit very rapid voltage-dependent activation and inactivation kinetics, and sensitivity to the highly selective 4D-Nav blocker tetrodotoxin. The results demonstrate that the capacity for rapid Na+-based signalling in eukaryotes is not restricted to animals or to the presence of 4D-Navs. The EukCatB channels therefore represent an independent evolution of fast Na+-based electrical signalling in eukaryotes that likely contribute to sophisticated cellular control mechanisms operating on very short time scales in unicellular algae. One Sentence SummaryThe capacity for rapid Na+-based signalling has evolved in ecologically important coccolithophore species via a novel class of voltage-gated Na+ channels, EukCatBs.

microbiology↗

bioRxiv2020

RNA-seq of Human T-Cells After Hematopoietic Stem Cell Transplantation Identifies Linc00402 as a Novel Regulator of T-Cell Alloimmunity

Mechanisms governing allogeneic T-cell responses after allogeneic hematopoietic stem cell (HSC) and solid organ transplantation are incompletely understood. Long non-coding RNAs (lncRNA) do not code for, but control gene expression with tissue specificity. However, their role in T-cell alloimmunity is unknown. We performed RNA-seq on donor T-cells from HSCT patients and found that increasing strength of allogeneic stimulation caused greater differential expression of lncRNAs. The differential expression was validated in an independent patient cohort, and also following ex vivo allogeneic stimulation of healthy human T-cells. Linc00402, a novel, conserved lncRNA, was identified as the most differentially expressed and was enriched 88 fold in human T-cells. Mechanistically, it was mainly located in the cytoplasm, and its expression was rapidly reduced following T-cell activation. Consistent with this, tacrolimus preserved the expression of Linc00402 following T-cell activation, and lower levels of Linc00402 were found in patients who subsequently went on to develop acute graft versus host disease (GVHD). The dysregulated expression of Linc00402 was also validated in murine T-cells, both in vitro and in vivo. Functional studies using multiple modalities to deplete Linc00402 in both mouse and human T-cells, demonstrated a critical role for Linc00402 in the T-cell proliferative response to an allogeneic stimulus but not a non-specific anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a novel, conserved regulator of allogeneic T-cell function. Because of its T-cell specific expression and its impact on allogeneic T-cell responses, targeting Linc00402 may improve outcomes after allogeneic HSC and solid organ transplantation. One sentence summaryLncRNAs are differentially expressed by allogeneic antigen-stimulated T-cells, and the novel lncRNA, Linc00402, is a specific regulator of mouse and human allogeneic T-cells.

immunology↗

bioRxiv2020

Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis

Fibroblastic foci (FF) represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for dysregulated extracellular matrix deposition in multiple fibrotic conditions. The aim of this study was to define the major transcriptional programmes involved in fibrogenesis in IPF by profiling un-manipulated myo/fibroblasts within FF in situ by laser capture microdissection. The challenges associated with deriving gene calls from low amounts of RNA and the absence of a meaningful comparator cell type were overcome by adopting novel data mining strategies and by using weighted gene co-expression network analysis (WGCNA), as well as an eigengene-based approach to identify transcriptional signatures which correlate with fibrillar collagen gene expression. WGCNA identified prominent clusters of genes associated with cell cycle, inflammation/differentiation, translation and cytoskeleton/cell adhesion. Collagen eigengene analysis revealed that TGF-{beta}1, RhoA kinase and the TSC2/RHEB axis formed major signalling clusters associated with collagen gene expression. Functional studies using CRISPR-Cas9 gene edited cells demonstrated a key role for the TSC2/RHEB axis in regulating TGF-{beta}1-induced mTORC1 activation and collagen I deposition in mesenchymal cells reflecting IPF and other disease settings, including cancer-associated fibroblasts. These data provide strong support for the human tissue-based and bioinformatics approaches adopted to identify critical transcriptional nodes associated with the key pathogenic cell responsible for fibrogenesis in situ and further identifies the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions. What is the key question?Can we identify a transcriptional signature associated with collagen gene expression in the fibrotic focus, the cardinal fibrotic lesion in IPF? What is the bottom line?We herein define the major transcriptional programmes involved in fibrogenesis in IPF by profiling myo/fibroblasts within FF in situ by laser capture microdissection. Why read on?The data provide strong support for a human tissue-based approach to identify critical transcriptional nodes associated with fibrogenesis in situ and further identifies the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.

cell biology↗

bioRxiv2020

The role of CAPG in molecular communication between the embryo and the uterine endometrium: Is its function conserved in species with different implantation strategies?

During the pre-implantation period of pregnancy in eutherian mammals, changes to the uterine endometrium are required (both at the transcriptional and protein level) to facilitate the endometrium becoming receptive to an implanting embryo. We know that the developing conceptus (embryo and extraembryonic membranes) produces proteins during this developmental stage. We hypothesised that this common process in early pregnancy in eutheria may be facilitated by highly conserved conceptus-derived proteins such as macrophage capping protein CAPG. More specifically, we propose that CAPG may share functionality in modifying the transcriptome of the endometrial epithelial cells to facilitate receptivity to implantation in species with different implantation strategies, such as human and bovine. A recombinant bovine form of CAPG (91% sequence identity between bovine and human) was produced and bovine endometrial epithelial (bEECs) and stromal (bESCs) cells and human endometrial epithelial cells (hEECs) were cultured for 24 h with or without rbCAPG. RNA sequencing and quantitative real-time PCR analysis was used to assess the transcriptional response to rbCAPG (Control, vehicle, CAPG 10, 100, 1000 ng/ml: n=3 biological replicates per treatment per species). Treatment of bEECs with CAPG resulted in changes to 1052 transcripts (629 increased and 423 decreased) compared to vehicle controls, including those previously only identified as regulated by interferon-tau, the pregnancy recognition signal in cattle. Treatment of hEECs with bovine CAPG increased expression of transcripts previously known to interact with CAPG in different systems (CAPZB, CAPZA2, ADD1 and ADK) compared with vehicle controls (P<0.05). In conclusion, we have demonstrated that CAPG, a highly conserved protein in eutherian mammals elicits a transcriptional response in the endometrial epithelium in two species with different implantation strategies that may facilitate uterine receptivity.

physiology↗

bioRxiv2020

Generation of twenty four induced pluripotent stem cell lines from twenty four members of the Lothian Birth Cohort 1936

Cognitive decline is among the most feared aspects of ageing. We have generated induced pluripotent stem cells (iPSCs) from 24 people from the Lothian Birth Cohort 1936, whose cognitive ability was tested in childhood and in older age. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using non-integrating oriP/EBNA1 backbone plasmids expressing six iPSC reprogramming factors (OCT3/4 (POU5F1), SOX2, KLF4, L-Myc, shp53, Lin28, SV40LT). All lines demonstrated STR matched karyotype and pluripotency was validated by multiple methods. These iPSC lines are a valuable resource to study molecular mechanisms underlying individual differences in cognitive ageing and resilience to age-related neurodegenerative diseases.

cell biology↗

bioRxiv2019

Mendelian randomisation for mediation analysis: current methods and challenges for implementation

Mediation analysis seeks to explain the pathway(s) through which an exposure affects an outcome. Mediation analysis experiences a number of methodological difficulties, including bias due to confounding and measurement error. Mendelian randomisation (MR) can be used to improve causal inference for mediation analysis. We describe two approaches that can be used for estimating mediation analysis with MR: multivariable Mendelian randomisation (MVMR) and two-step Mendelian randomisation. We outline the approaches and provide code to demonstrate how they can be used in mediation analysis. We review issues that can affect analyses, including confounding, measurement error, weak instrument bias, and analysis of multiple mediators. Description of the methods is supplemented by simulated and real data examples. Although Mendelian randomisation relies on large sample sizes and strong assumptions, such as having strong instruments and no horizontally pleiotropic pathways, our examples demonstrate that it is unlikely to be affected by confounders of the exposure or mediator and the outcome, reverse causality and non-differential measurement error of the exposure or mediator. Both MVMR and two-step MR can be implemented in both individual-level MR and summary data MR, and can improve causal inference in mediation analysis.

genetics↗

bioRxiv2019

Quantitative Measurements of Enlarged Perivascular Spaces in the Brain are Associated with Retinal Microvascular Parameters in Older Community-Dwelling Subjects

BackgroundPerivascular Spaces (PVS) become increasingly visible with advancing age on brain MRI, yet their relationship to morphological changes in the underlying microvessels remains poorly understood. Retinal and cerebral microvessels share morphological and physiological properties. We compared computationally-derived PVS morphologies with retinal vessel morphologies in older people. MethodsWe analysed data from community-dwelling individuals who underwent multimodal brain MRI and retinal fundus camera imaging at mean age 72.55 years (SD=0.71). We assessed centrum semiovale PVS computationally to determine PVS total volume and count, and mean per-subject individual PVS length, width and size. We analysed retinal images using the VAMPIRE software suite, obtaining the Central Retinal Artery and Vein Equivalents (CRVE and CRAE), Arteriole-to-Venule ratio (AVR), and fractal dimension (FD) of both eyes. We investigated associations using general linear models, adjusted for age, gender, and major vascular risk factors. ResultsIn 381 subjects with all measures, increasing total PVS volume and count were associated with decreased CRAE in the left eye (volume {beta}=-0.170, count {beta}=-0.184, p<0.001). No associations of PVS with CRVE were found. The PVS total volume, individual width and size increased with decreasing FD of the arterioles (a) and venules (v) of the left eye (total volume: FDa {beta}=-0.137, FDv {beta}=-0.139, p<0.01; width: FDa {beta}=-0.144, FDv {beta}=-0.158, p<0.01; size: FDa {beta}=-0.157, FDv {beta}=-0.162, p<0.01). ConclusionsIncrease in PVS number and size visible on MRI reflect arteriolar narrowing and lower retinal arteriole and venule branching complexity, both markers of impaired microvascular health. Computationally-derived PVS metrics may be an early indicator of failing vascular health and should be tested in longitudinal studies.

neuroscience↗

bioRxiv2019

CD99 regulates cancer cell transendothelial migration and endothelial cell function via CDC42 and actin remodelling

Metastasis requires tumour cells to cross endothelial cell (EC) barriers and this occurs using mechanisms similar to those used by extravasating leucocytes during inflammation. The cell surface receptor CD99 is expressed by leucocytes and EC and participates in inflammatory transendothelial migration (TEM). CD99 is also expressed by tumour cells and we have analysed its role in tumour progression and cancer cell TEM. In a xenograft model, CD99 expression inhibited the metastatic progression of human breast cancer. In vitro, tumour cell CD99 was required for adhesion to ECs. However, tumour cell CD99 inhibited the invasion of the endothelial barrier by breast and prostate cancer cells and TEM itself. Furthermore, tumour cell CD99 depletion was associated with cytoskeletal remodelling. Loss of EC CD99 enhanced endothelial barrier function and reduced tumour cell TEM. Mechanistically, CD99 loss enhanced the expression and activity of CDC42, a known cytoskeletal organiser. CDC42 positively regulates EC angiogenic activity and the enhanced CDC42 activity resulting from loss of EC CD99 increased angiogenesis. As a signal transduction hub, CDC42 activity impacts upon many of the hallmarks of cancer. The functional link between CD99 and CDC42 identified here implicates CD99 in regulating these diverse pathways by modulation of CDC42 activity.

cell biology↗

bioRxiv2019

Context-dependent decision making in a premotor circuit

Cognitive capacities afford contingent associations between sensory information and behavioral responses. We studied this problem using an olfactory delayed match to sample task whereby a sample odor specifies the association between a subsequent test odor and rewarding action. Multi-neuron recordings revealed representations of the sample and test odors in olfactory sensory and association cortex, which were sufficient to identify the test odor as match/non-match. Yet, inactivation of a downstream premotor area (ALM), but not orbitofrontal cortex, confined to the epoch preceding the test odor, led to gross impairment. Olfactory decisions that were not context dependent were unimpaired. Therefore, ALM may not receive the outcome of a match/non-match decision from upstream areas but contextual information--the identity of the sample--to establish the mapping between test odor and action. A novel population of pyramidal neurons in ALM layer 2 may mediate this process.

neuroscience↗

bioRxiv2019

ALS Motor Neurons Exhibit Hallmark Metabolic Defects That Are Rescued by Nicotinamide and SIRT3 Activation

Motor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in Amyotrophic Lateral Sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells (iPSCs) from healthy controls, familial ALS and sporadic ALS patients were differentiated towards spinal MNs, cortical neurons and cardiomyocytes. Metabolic flux analyses reveal a MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, SIRT3 functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.

neuroscience↗

bioRxiv2019

Extent and context dependence of pleiotropy revealed by high-throughput single-cell phenotyping

Pleiotropy - when a single mutation affects multiple traits - is a controversial topic with far-reaching implications. Pleiotropy plays a central role in debates about how complex traits evolve and whether biological systems are modular or are organized such that every gene has the potential to affect many traits. Pleiotropy is also critical to initiatives in evolutionary medicine that seek to trap infectious microbes or tumors by selecting for mutations that encourage growth in some conditions at the expense of others. Research in these fields, and others, would benefit from understanding the extent to which pleiotropy reflects inherent relationships among phenotypes that correlate no matter the perturbation (vertical pleiotropy). Alternatively, pleiotropy may result from genetic changes that impose correlations between otherwise independent traits (horizontal pleiotropy). We distinguish these possibilities by using clonal populations of yeast cells to quantify the inherent relationships between single-cell morphological features. Then, we demonstrate how often these relationships underlie vertical pleiotropy and how often these relationships are modified by genetic variants (QTL) acting via horizontal pleiotropy. Our comprehensive screen measures thousands of pairwise trait correlations across hundreds of thousands of yeast cells and reveals ample evidence of both vertical and horizontal pleiotropy. Additionally, we observe that the correlations between traits can change with the environment, genetic background and cell-cycle position. These changing dependencies suggest a nuanced view of pleiotropy: biological systems demonstrate limited pleiotropy in any given context, but across contexts (e.g., across diverse environments and genetic backgrounds) each genetic change has the potential to influence a larger number of traits. Our method suggests that exploiting pleiotropy for applications in evolutionary medicine would benefit from focusing on traits with correlations that are less dependent on context.

evolutionary biology↗

bioRxiv2019

11β-Hydroxysteroid Dehydrogenase Type 1 inhibition in Idiopathic Intracranial Hypertension: a double-blind randomized controlled trial.

Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11{beta}-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability, and investigate indicators of in vivo efficacy of the 11{beta}-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared to placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-weeks treatment with AZD4017 or placebo was conducted. Women aged 18 to 55 years with active idiopathic intracranial hypertension (>25cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400mg twice daily of oral AZD4017 compared to matching placebo over 12-weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropological measures. In vivo efficacy was evaluated in the central nervous system and systemically. 31 subjects (mean age 31.2 (SD=6.9) years and BMI 39.2 (SD=12.6) kg/m2) were randomized to AZD4017 (n=17) or placebo (n=14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: -2.8, 95% confidence interval: -7.1-1.5; p=0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group (mean change: -4.3 cmH2O (SD=5.7); p=0.009) but not in the placebo group (mean change: -0.3 cmH2O (SD=5.9); p=0.8). AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11{beta}-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation and CSF cortisone to cortisol ratios) demonstrated significant enzyme inhibition. This is the first phase 2 randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe, well-tolerated and inhibited 11{beta}-hydroxysteroid dehydrogenase type 1 activity in vivo. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

clinical trials↗

bioRxiv2019

Dopamine deficiency is associated with risk aversion but not loss aversion in Parkinson’s disease

IntroductionClinical evidence suggests that Parkinsons Disease (PD) patients are risk averse. Dopaminergic therapy has been reported to increase risk tolerance, but the underlying mechanisms are unclear. Some studies have suggested an amplification of subjective reward value, consistent with the role of dopamine in reward value coding. Others have reported value-independent risk enhancement. We evaluated the value-dependence of the effects of PD and its therapy on risk using tasks designed to sensitively measure risk over a wide range of expected values.\n\nMethod36 patients with idiopathic PD receiving levodopa monotherapy and 36 healthy matched controls performed two behavioural economic tasks aimed at quantifying 1) risk tolerance/ aversion in the gain frame and 2) valuation of potential gains relative to losses. PD patients performed the tasks on and off their usual dose of levodopa in randomized order; controls performed the same tasks twice.\n\nResultsRelative to the controls, unmedicated PD patients showed significant value-independent risk aversion in the gain frame, which was normalized by levodopa. PD patients did not differ from controls in their valuation of gains relative to losses. However, across both tasks and regardless of medication, choices of the patients were more determined by expected values of the prospects than those of controls.\n\nConclusionDopamine deficiency in PD was associated with risk aversion, and levodopa promoted riskier choice in a value-independent manner. PD patients also showed an increased sensitivity to expected value, which was independent of levodopa and does not appear to result directly from dopamine deficiency.

neuroscience↗

bioRxiv2019

Disharmony of the world’s island floras

Disharmony is a key concept in island biology that describes the biased representation of higher taxa on islands compared to their mainland source regions. Although differential colonization success of taxa is predicted by selective dispersal, environmental and biotic filtering, the empirical evidence for disharmony remains largely anecdotal. Here, we develop a novel method for delineating island source regions and present the first global quantitative assessment of island disharmony. We analyzed the overall compositional bias of 320 island floras and examined the over- or under-representation on islands for 450 plant families. We found that the compositional bias of island floras is strongly predicted by geographical and climatic island characteristics (isolation, area, geologic origin, temperature, precipitation), whereas the representation of individual families is only weakly related to family-specific characteristics (family size, family age, taxonomic group, functional traits), indicating that the taxonomic scope of the disharmony concept has historically limited its wider applicability. Our results provide a strong foundation for integrating disharmony with quantitative functional and phylogenetic approaches in order to gain a deeper understanding of assembly processes on islands.

ecology↗

bioRxiv2018

In vivo fate of free and encapsulated iron oxide nanoparticles after injection of labelled stem cells

Nanoparticle contrast agents are useful tools to label stem cells and monitor the in vivo bio-distribution of labeled cells in pre-clinical models of disease. In this context, understanding the in vivo fate of the particles after injection of labelled cells is important for their eventual clinical use as well as for the interpretation of imaging results. We examined how the formulation of superparamagnetic iron oxide nanoparticles (SPIONs) impacts the labelling efficiency, magnetic characteristics and fate of the particles by comparing individual SPIONs with polyelectrolyte multilayer capsules containing SPIONs. At low labelling concentration, encapsulated SPIONs served as an efficient labelling agent for stem cells. The bio-distribution after intra-cardiac injection of labelled cells was monitored longitudinally by MRI and as an endpoint by inductively coupled plasma-optical emission spectrometry. The results suggest that, after being released from labelled cells after cell death, both formulations of particles are initially stored in liver and spleen and are not completely cleared from these organs 2 weeks post-injection.

biochemistry↗

bioRxiv2018

The effect of body mass index on smoking behaviour and nicotine metabolism: a Mendelian randomization study

BackgroundGiven clear evidence that smoking lowers weight, it is possible that individuals with higher body mass index (BMI) smoke in order to lose or maintain their weight.\n\nMethods and FindingsWe undertook Mendelian randomization analyses using 97 genetic variants associated with BMI. We performed two sample Mendelian randomization analyses of the effects of BMI on smoking behaviour in UK Biobank (N=335,921) and the Tobacco and Genetics consortium genomewide association study (GWAS) (N[≤]74,035) respectively, and two sample Mendelian randomization analyses of the effects of BMI on cotinine levels (N[≤]4,548) and nicotine metabolite ratio (N[≤]1,518) in published GWAS, and smoking-related DNA methylation in the Avon Longitudinal Study of Parents and Children (N[≤]846).\n\nIn inverse variance weighted Mendelian randomization analysis, there was evidence that higher BMI was causally associated with smoking initiation (OR for ever vs never smoking per one SD increase in BMI: 1.19, 95% CI: 1.11 to 1.27) and smoking heaviness (1.45 additional cigarettes smoked per day per SD increase in BMI, 95% CI: 1.03 to 1.86), but little evidence for a causal effect with smoking cessation. Results were broadly similar using pleiotropy robust methods (MR-Egger, median and weighted mode regression). These results were supported by evidence for a causal effect of BMI on DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus. There was no strong evidence that BMI was causally associated with cotinine, but suggestive evidence for a causal negative association with the nicotine metabolite ratio.\n\nConclusionsThere is a causal bidirectional association between BMI and smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism. It may be useful to consider BMI and smoking together when designing prevention strategies to minimise the effects of these risk factors on health outcomes.

epidemiology↗