Biology subjects

Jones, S.

Publications and source records attributed to Jones, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Secretoglobin family 1D member 2 (SCGB1D2) protein inhibits growth of Borrelia burgdorferi and affects susceptibility to Lyme disease

Lyme disease is a tick-borne disease caused by bacteria of the genus Borrelia. The disease can initially manifest as an erythema migrans rash and, if able to evade the host immune defenses, can progress into a secondary stage chronic disease with debilitating physical or neurological manifestations1,2. The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Here we show a novel host defense mechanism against Lyme disease in humans. Using epidemiological and genetic data from FinnGen, we identify a common missense variant at the gene encoding for Secretoglobin family 1D member 2 (SCGB1D2) protein that increases the susceptibility for Lyme disease. The genetic variant changes proline at position 53 to leucine and is predicted as deleterious. Consequently, we validate the dysfunction of this protein variant using live Borrelia burgdorferi (Bb). Recombinant reference SCGB1D2 protein inhibits the growth of Bb twice as effectively as the recombinant SCGB1D2 P53L deleterious missense variant. Together, these data suggest that SCGB1D2 is a host defense factor present in the skin, sweat, and other secretions which protects against Bb infection. This finding provides a novel therapeutic avenue for drug development to prevent and treat Lyme disease.

genetics↗

bioRxiv2022

Conformational flexibility, lipid binding, and regulatory domains in CelTOS

CelTOS is an essential Plasmodium traversal protein and conserved in apicomplexan parasites. We showed that CelTOS forms pores in cell membranes to enable traversal of parasites through cells (Jimah et al., 2016). Here, we establish roles for the distinct regions of CelTOS, examine the mechanism of pore formation and evaluate the immunogenicity of engineered CelTOS variants. CelTOS dimer dissociation is required for pore formation as disulfide bridging between monomers inhibits pore formation and this inhibition is rescued by disulfide-bridge reduction. A helix destabilizing Pro127 allows CelTOS to undergo significant conformational changes to assemble into pores. The flexible C-terminus of CelTOS is a negative regulator that limits pore formation. Lipid binding is a pre-requisite for pore assembly as mutation of a phospholipid binding site in CelTOS resulted in loss of lipid binding and abrogated pore formation. The disulfide-locked and N-terminal deletion mutants showed improved immunogenicity relative to wild-type CelTOS in mice. These findings have implications for pore-forming proteins that are essential for diverse functions, identify critical regions in CelTOS, and will guide the design of effective CelTOS-targeting vaccines to combat infection and transmission of malaria and apicomplexan parasites.

microbiology↗

bioRxiv2022

Rapid identification of mosquito species, sex and age by mass spectrometric analysis

BackgroundA rapid, accurate method to identify and to age grade mosquito populations would be a major advance in predicting the risk of pathogen transmission and evaluating the public health impact of vector control interventions. Whilst other chemometric methods show promise, current approaches rely on challenging morphological techniques or simple binary classifications that cannot identify the subset of the population old enough to be infectious. In this study, the ability of Rapid Evaporative Ionisation Mass Spectrometry (REIMS) to identify the species, sex and age of mosquitoes reared in the laboratory and derived from the wild was investigated. ResultsThe accuracy of REIMS in identifying morphologically identical species of the Anopheles gambiae complex exceeded 97 % using principal component/linear discriminant analysis (PC-LDA) and 84 % based on random forest analysis. Age separation into 3 different age categories (1 d, 5-6 d, 14-15 d.) was achieved with 99 % (PC-LDA) and 94 % (random forest) accuracy, after including three species and storing samples at room temperature for up to 11 days. When tested on wild mosquitoes from the UK, REIMS data could determine the species and age of the specimens with accuracies of 91 and 90 % respectively. ConclusionsThe accuracy of REIMS to resolve the species and age of Anopheles mosquitoes is comparable to that achieved by chemometric approaches. The processing time and ease of use represent significant advantages over current, dissection-based methods. Importantly the accuracy was maintained when using wild mosquitoes reared under differing environmental conditions, and when mosquitoes were stored frozen or desiccated. This high throughput approach thus has potential to conduct rapid, real- time monitoring of vector populations, providing entomological evidence of the impact of alternative interventions.

ecology↗

bioRxiv2022

Relapse-like behavior and nAChR sensitization following intermittent access nicotine self-administration

ABSTRACTMany tobacco smokers consume nicotine intermittently, but the underlying mechanisms and neurobiological changes associated with intermittent nicotine intake are unclear. Understanding intermittent nicotine intake is a high priority, as it could promote therapeutic strategies to attenuate tobacco consumption. We examined nicotine intake behavior and neurobiological changes in male rats that were trained to self-administer nicotine during brief (5 min) trials interspersed with longer (15 min) drug-free periods. Rats readily adapted to intermittent access (IntA) SA following acquisition on a continuous access (ContA) schedule. Probabilistic analysis of IntA nicotine SA suggested reduced nicotine loading behavior compared to ContA, and nicotine pharmacokinetic modeling revealed that rats taking nicotine intermittently may have increased intake to maintain blood levels of nicotine that are comparable to ContA SA. After IntA nicotine SA, rats exhibited an increase in unreinforced responses for nicotine-associated cues (incubation of craving) and specific alterations in the striatal proteome after 7 days without nicotine. IntA nicotine SA also induced nAChR functional upregulation in the interpeduncular nucleus (IPN), and it enhanced nicotine binding in the brain as determined via [11C]nicotine positron emission tomography. Reducing the saliency of the cue conditions during the 5 min access periods attenuated nicotine intake, but incubation of craving was preserved. Together, these results indicate that IntA conditions promote nicotine SA and nicotine seeking after a nicotine-free period.

neuroscience↗

bioRxiv2021

cSurvival: a web resource for biomarker interactions in cancer outcomes

Survival analysis is a technique to identify prognostic biomarkers and genetic vulnerabilities in cancer studies. Large-scale consortium-based projects have profiled >11,000 adult and >4,000 paediatric tumor cases with clinical outcomes and multi-omics approaches. This provides a resource for investigating molecular-level cancer etiologies using clinical correlations. Although cancers often arise from multiple genetic vulnerabilities and have deregulated gene sets (GSs), existing survival analysis protocols can report only on individual genes. Additionally, there is no systematic method to connect clinical outcomes with experimental (cell line) data. To address these gaps, we developed cSurvival (https://tau.cmmt.ubc.ca/cSurvival). cSurvival provides a user-adjustable analytical pipeline with a curated, integrated database, and offers three main advances: (a) joint analysis with two genomic predictors to identify interacting biomarkers, including new algorithms to identify optimal cutoffs for two continuous predictors; (b) survival analysis not only at the gene, but also the GS level; and (c) integration of clinical and experimental cell line studies to generate synergistic biological insights. To demonstrate these advances, we report three case studies. We confirmed findings of autophagy-dependent survival in colorectal cancers and of synergistic negative effects between high expression of SLC7A11 and SLC2A1 on outcomes in several cancers. We further used cSurvival to identify high expression of the Nrf2-antioxidant response element pathway as a main indicator for lung cancer prognosis and for cellular resistance to oxidative stress-inducing drugs. Together, these analyses demonstrate cSurvivals ability to support biomarker prognosis and interaction analysis via gene- and GS-level approaches and to integrate clinical and experimental biomedical studies. Key pointsO_LIWe developed cSurvival, an advanced framework using clinical correlations to study biomarker interactions in cancers, with source code and curated datasets freely available for all C_LIO_LIcSurvival includes new algorithms to identify optimal cutoffs for two continuous predictors to stratify patients into risk groups, enabling for the first time joint analysis with two genomic predictors; C_LIO_LIcSurvival allows survival analysis at the gene set (GS) level with comprehensive and up-to-date GS libraries C_LIO_LIThe cSurvival pipeline integrates clinical outcomes and experimental cancer cell line data to generate synergistic biological insights and to mine for appropriate preclinical cell line tools C_LIO_LIcSurvival is built on a manually curated cancer outcomes database C_LI

genomics↗

bioRxiv2021

A Rapid Bead-Based Assay For Screening Of SARS-CoV-2 Neutralising Antibodies

Quantitative determination of neutralizing antibodies against Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) is paramount in immunodiagnostics, vaccine efficacy testing, and immune response profiling among the vaccinated population. Cost-effective, rapid, easy-to-perform assays are essential to support the vaccine development process and immunosurveillance studies. Here, we describe a bead-based screening assay for S1-neutralization using recombinant fluorescent proteins of hACE2 and SARS-CoV2-S1, immobilized on solid beads employing nanobodies /metal-affinity tags. Nanobody-mediated capture of SARS-CoV-2 - Spike (S1) on agarose beads served as the trap for soluble recombinant ACE2-GFPSpark, inhibited by neutralizing antibody. The first approach demonstrates single-color fluorescent imaging of ACE2-GFPspark binding to His-tagged S1-Receptor Binding Domain (RBD-His) immobilized beads. The second approach is dual-color imaging of soluble ACE2-GFPSpark to S1-Orange Fluorescent Protein (S1-OFPSpark) beads. Both methods showed a good correlation with the gold standard pseudovirion assay and can be adapted to any fluorescent platforms for screening. Life-time imaging of the ACE2-GFPSpark confirmed the interaction of ACE2 and S1-OFPSpark on beads. The self-renewable source of secreted recombinant proteins from stable cells and its direct use without necessitating purification renders the platform a cost-effective and rapid one than the popular pseudovirion assay and live virus-based assays. Any laboratory with minimum expertise can rapidly perform this bead assay for neutralizing antibody detection using stable engineered cells.

molecular biology↗

bioRxiv2021

A Multi-proxy assessment of the impact of climate change on Late Holocene (ca 4500-3800 BP) Native American villages of the Georgia coast

Circular shell rings along the Atlantic Coast of southeastern North America are the remnants of some of the earliest villages that emerged during the Late Archaic Period (5000 - 3000 BP). Many of these villages, however, were abandoned during the Terminal Late Archaic Period (ca 3800 - 3000 BP). Here, we combine Bayesian chronological modeling with multiple environmental proxies to understand the nature and timing of environmental change associated with the emergence and abandonment of shell ring villages on Sapleo Island, Georgia. Our Bayesian models indicate that Native Americans occupied the three Sapelo shell rings at varying times with some generational overlap. By the end of the complexs occupation, only Ring III was occupied before abandonment ca. 3845 BP. Ring III also consists of statistically smaller oysters (Crassostrea virginica) that people harvested from less saline estuaries compared to earlier occupations. These data, when integrated with recent tree ring analyses, show a clear pattern of environmental instability throughout the period in which the rings were occupied. We argue that as the climate became unstable around 4300 BP, aggregation at shell ring villages provided a way to effectively manage fisheries that are highly sensitive to environmental change. However, with the eventual collapse of oyster fisheries and subsequent rebound in environmental conditions ca. 3800 BP, people dispersed from shell rings, and shifted to non-marine subsistence economies and other types of settlements. This study provides the most comprehensive evidence correlations between large-scale environmental change and societal transformations on the Georgia coast during the Late Archaic period.

ecology↗

bioRxiv2021

INF2-mediated actin filament reorganization confers intrinsic resilience to neuronal ischemic injury

During early stages of ischemic brain injury, glutamate receptor hyperactivation mediates neuronal death via osmotic cell swelling. Here we show that ischemia and excess NMDA receptor activation - conditions that trigger neuronal swelling -- cause actin filaments to undergo a rapid and extensive reorganization within the somatodendritic compartment. Normally, F-actin is concentrated within dendritic spines, with relatively little F-actin in the dendrite shaft. However, beginning <5 min after incubation of neurons with NMDA, F-actin depolymerizes within dendritic spines and polymerizes into long, stable filament bundles within the dendrite shaft and soma. A similar "actinification" of the somatodendritic compartment occurs after oxygen/glucose deprivation in vitro, and in mouse brain after photothrombotic stroke in vivo. Following transient, sub-lethal NMDA exposure these actin changes spontaneously reverse within 1-2 hours. A combination of Na+, Cl-, water, and Ca2+ entry are all necessary, but not individually sufficient, for induction of actinification. Spine F-actin depolymerization is also required. Actinification is driven by activation of the F-actin polymerization factor inverted formin-2 (INF2). Silencing of INF2 renders neurons more vulnerable to NMDA-induced membrane leakage and cell death, and formin inhibition markedly increases ischemic infarct severity in vivo. These results show that ischemia-induced actin filament reorganization within the dendritic compartment is an intrinsic pro-survival response that protects neurons from death induced by swelling.

cell biology↗

bioRxiv2021

S-acylation is a positive regulator of FLS2-mediated plant immunity

Plant receptor kinases are key transducers of extracellular stimuli, such as the presence of beneficial or pathogenic microbes or secreted signalling molecules. Receptor kinases are regulated by numerous post-translational modifications. Here, using the immune receptor kinases FLS2 and EFR, we show that S-acylation at a cysteine conserved in all plant receptor kinases is crucial for function. S-acylation involves the addition of long-chain fatty acids to cysteine residues within proteins, altering their biophysical properties and behaviour within the membrane environment. We observe S-acylation of FLS2 at C-terminal kinase domain cysteine residues within minutes following perception of its ligand flg22, in a BAK1 co-receptor dependent manner. We demonstrate that S-acylation is essential for FLS2-mediated immune signalling and resistance to bacterial infection. Similarly, mutating the corresponding conserved cysteine residue in EFR supressed elf18 triggered signalling. Analysis of unstimulated and activated FLS2-containing complexes using microscopy, detergents and native membrane DIBMA nanodiscs indicates that S-acylation stabilises and promotes retention of activated receptor kinase complexes at the plasma membrane to increase signalling efficiency.

plant biology↗

bioRxiv2021

Expression of soluble methane monooxygenase in Escherichia coli enables methane conversion

Natural gas and biogas provide an opportunity to harness methane as an industrial feedstock. Bioconversion is a promising alternative to chemical catalysis, which requires extreme operating conditions and exhibits poor specificities. Though methanotrophs natively utilize methane, efforts have been focused on engineering platform organisms like Escherichia coli for synthetic methanotrophy. Here, a synthetic E. coli methanotroph was developed by engineering functional expression of the Methylococcus capsulatus soluble methane monooxygenase in vivo via expression of its cognate GroESL chaperone. Additional overexpression of E. coli GroESL further improved activity. Incorporation of an acetone formation pathway then enabled the conversion of methane to acetone in vivo, as validated via 13C tracing. This work provides the first reported demonstration of methane bioconversion to liquid chemicals in a synthetic methanotroph.

bioengineering↗

bioRxiv2021

Interrogation of genome-wide, experimentally dissected gene regulatory networks reveals mechanisms underlying dynamic cellular state control

Pooled CRISPRi-mediated silencing of >1,000 transcriptional regulators expressed in single colorectal adenocarcinoma cells, followed by single-cell RNA-seq profiling at two timepoints, 1 day and 4 days, allowed reverse engineering the underlying tumor context-specific, causal regulatory network. Furthermore, the availability of experimentally derived, highly multiplexed gene reporter assays for each regulator, as identified by this analysis, allowed accurate assessment of differential protein activity following silencing of each regulator, thus providing proof-of-concept for generating comprehensive, tissue-specific networks of transcriptional and post-translational interactions. Analysis of this causal network allowed elucidation of complex autoregulatory mechanisms that have eluded previous computational approaches and supported systematic elucidation of cooperative mechanisms, where one regulatory protein can modulate the activity of another regulatory protein, as well as transcriptional mimicry, where one regulatory protein can phenocopy others.

systems biology↗

bioRxiv2021

Imprecise recombinant viruses evolve via a fitness-driven, iterative process of polymerase template-switching events.

Recombination is a common feature of many positive-strand RNA viruses, playing an important role in virus evolution. However, to date, there is limited understanding of the mechanisms behind the process. Utilising in vitro assays, we have previously shown that the template-switching event of recombination is a random and ubiquitous process that often leads to recombinant viruses with imprecise genomes containing sequence duplications. Subsequently, a process termed resolution, that has yet to be mechanistically studied, removes these duplicated sequences resulting in a virus population of wild type length genomes. Using defined imprecise recombinant viruses together with Oxford Nanopore and Illumina high throughput next generation sequencing technologies we have investigated the process of resolution. We show that genome resolution involves subsequent rounds of template-switching recombination with viral fitness resulting in the survival of a small subset of recombinant genomes. This alters our previously held understanding that recombination and resolution are independent steps of the process, and instead demonstrates that viruses undergo frequent and continuous recombination events over a prolonged period until the fittest viruses, predominantly those with wild type length genomes, dominate the population. Author SummaryViruses with positive-sense RNA genomes, such as poliovirus, have several mechanisms by which they evolve. One of these is the process of recombination involving the large-scale exchange of genetic information. Recombination occurs during replication when the viral polymerase switches from copying one genome to another. However, the polymerase does not always accurately switch between the two, resulting in sequence duplications or deletions, and genomes that are referred to as imprecise. Over multiple rounds of replication sequence duplications are lost and genomes are resolved to wild type length, but it is unclear how this occurs. Here we used synthetic polioviruses containing defined sequence duplications to determine that the genome population undergoes repeated rounds of recombination until sequence duplications are lost and viruses with precise, wild type length genomes are selected for. This selection is based on the overall fitness of the virus population, with less fit imprecise viruses evolving more quickly. Our study suggests that recombination is a continual process where virus fitness drives the selection of a small subset of recombinant variants. These data are important for understanding how novel viruses evolve via recombination and how this process can be blocked to prevent novel and dangerous pathogens from arising.

microbiology↗

bioRxiv2021

Experimental infection of specific-pathogen-free domestic lambs with Mycoplasma ovipneumoniae causes asymptomatic colonization of the upper airways that is resistant to antibiotic treatment

Mycoplasma ovipneumoniae (M. ovipneumoniae) is a respiratory pathogen associated with the development of mild to moderate respiratory disease in domestic lambs and severe pneumonia outbreaks in wild ruminants such as bighorn sheep. However, whether M. ovipneumoniae by itself causes clinical respiratory disease in domestic sheep in the absence of secondary bacterial pathogens is still a matter of debate. The goal of our study was to better understand the role of M. ovipneumoniae as a respiratory pathogen in domestic sheep and to explore potential antibiotic treatment approaches. Therefore, we inoculated four-month-old, specific-pathogen-free lambs with field isolates of M. ovipneumoniae and monitored the lambs for eight weeks for colonization with the bacteria, M. ovipneumoniae-specific antibodies, clinical symptoms, and cellular and molecular correlates of lung inflammation. After eight weeks, lambs were treated with the macrolide antibiotic gamithromycin and observed for an additional four weeks. Stable colonization of the upper respiratory tract with M. ovipneumoniae was established in all four M. ovipneumoniae-inoculated, but in none of the four mock-infected lambs. All M. ovipneumoniae-infected lambs developed a robust antibody response to M. ovipneumoniae within 2 weeks. However, we did not observe significant clinical symptoms or evidence of lung damage or inflammation in any of the infected lambs. Interestingly, treatment with gamithromycin failed to reduce M. ovipneumoniae colonization. These observations indicate that, in the absence of co-factors, M. ovipneumoniae causes asymptomatic colonization of the upper respiratory tract of that is resistant to clearance by the host immune response as well as by gamithromycin treatment in domestic lambs.

microbiology↗

bioRxiv2021

Should deep-sequenced amplicons become the new gold-standard for analysing malaria drug clinical trials?

BackgroundRegulatory clinical trials are required to ensure the continued supply and deployment of effective antimalarial drugs. Patient follow-up in such trials typically lasts several weeks as the drugs have long half-lives and new infections often occur during this period. "Molecular correction" is therefore used to distinguish drug failures from new infections. The current WHO-recommend method for molecular correction uses length-polymorphic alleles at highly diverse loci but is inherently poor at detecting low density clones in polyclonal infections. This likely leads to substantial underestimates of failure rates, delaying the replacement of failing drugs with potentially lethal consequences. Deep sequenced amplicons (AmpSeq) substantially increase the detectability of low-density clones and may offer a new "gold standard" for molecular correction. MethodsPharmacological simulation of clinical trials was used to evaluate the suitability of AmpSeq for molecular correction. We investigated the impact of factors such as the number of amplicon loci analysed, the informatics criteria used to distinguish genotyping noise from real low density signals, the local epidemiology of malaria transmission, and the potential impact of genetic signals from gametocytes. ResultsAmpSeq greatly improved molecular correction and provided accurate drug failure rate estimates. The use of 3 to 5 amplicons was sufficient, and simple, non-statistical, criteria could be used to classify recurrent infections as drug failures or new infections. ConclusionsThese results strongly endorse the deployment of AmpSeq as the standard for molecular correction in regulatory trials, with its potential extension into routine surveillance once the requisite technical support becomes established.

microbiology↗

bioRxiv2021

macroH2A2 shapes chromatin accessibility at enhancer elements in glioblastoma to modulate a targetable self-renewal epigenetic network

Self-renewal is a crucial property of glioblastoma cells and is enabled by the choreographed function of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could represent an important step toward developing new and effective treatments for this universally lethal cancer. Here we uncover a targetable epigenetic axis of self-renewal mediated by the histone variant macroH2A2. Using patient-derived in vitro and in vivo models, we show that macroH2A2 has a direct role in shaping chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. Pharmaceutical inhibition of the chromatin remodeler Menin increased macroH2A2 levels and repressed self- renewal. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest new treatment approaches for glioblastoma patients. SIGNIFICANCEGlioblastoma is an incurable brain cancer. Malignant self-renewing cells have been shown to drive tumor growth, to be refractory to current treatment approaches and to seed relapses, which ultimately prove lethal. Identifying new and targetable mechanisms associated with self-renewal could be a fundamental first step in designing effective therapies that slow or prevent glioblastoma relapses. Using patient-derived models of glioblastoma, we deployed epigenomic approaches and functional assays to define the role of the histone variant macroH2A2 in repressing self-renewal. We identified compounds that increase macroH2A2 levels and repress self-renewal, including a Menin inhibitor. As Menin inhibitors are being tested in clinical trials, these compounds could be used in new therapeutic paradigms to target self-renewing cell populations in glioblastoma.

cancer biology↗

bioRxiv2020

TET2 drives 5hmc marking of GATA6 and epigenetically defines pancreatic ductal adenocarcinoma transcriptional subtypes

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterised by advanced disease stage at presentation, aggressive disease biology and resistance to therapy resulting in extremely poor five-year survival <10%. PDAC is classified into transcriptional subtypes with distinct survival characteristics, although how these arise is not known. Epigenetic deregulation, rather than genetics, has been proposed to underpin progression but exactly why is unclear and hindered by analysis of clinical samples. MethodsGenome-wide epigenetic mapping of DNA modifications 5-hydroxymethylcytosine (5mc) and 5-hydroxymethylcytosine (5hmc) using oxidative bisulphite sequencing (oxBS). Bioinformatics using iCluster and mutational profiling to identify overlap with transcriptional signatures in FFPE from resected patients and confirmation in vivo. ResultsWe find that more aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci including GATA6 that promote differentiated classical-pancreatic subtypes. We show that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5mc-hydroxylase TET2. Furthermore, we find that SMAD4 directly supports TET2 levels in the pancreas and classical-pancreatic tumors and loss of SMAD4 expression is associated reduced 5hmc, GATA6 and squamous-like tumors. Importantly, enhancing TET2 stability using Metformin and VitaminC/ascorbic acid (AA) restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo. ConclusionsWe identify epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data shows that restoring epigenetic control increases biomarkers of classical-pancreatic tumors and raises the possibility that combination of Vitamin C and Metformin may prolong survival in patients with squamous-like pancreatic cancer.

cancer biology↗

bioRxiv2020

Oxylipin metabolism is controlled by mitochondrial b-oxidation during bacterial inflammation.

Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial {beta}-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin {beta}-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-{gamma}. Last, dampening oxylipin levels by {beta}-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial {beta}-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.

biochemistry↗

bioRxiv2020

Predicting range shifts of African apes under global change scenarios

AimModelling African great ape distribution has until now focused on current or past conditions, whilst future scenarios remain scarcely explored. Using an ensemble forecasting approach, we predicted changes in taxon-specific distribution under future scenarios of climate, land-use and human population changes. LocationSub-Saharan Africa MethodsWe compiled occurrence data on African ape populations from the IUCN A.P.E.S. database and extracted relevant human-, climate- and habitat-related predictors representing current and future (2050) conditions to predict taxon-specific distribution under a best- and a worst-case scenario, using ensemble forecasting. Given the large effect on model predictions, we further tested algorithm sensitivity by considering default and non-default modelling options. The latter included interactions between predictors and polynomial terms in correlative algorithms. ResultsThe future distributions of gorilla and bonobo populations are likely to be directly determined by climate-related variables. In contrast, future chimpanzee distribution is influenced mostly by anthropogenic variables. Both our modelling approaches produced similar model accuracy, although a slight difference in the magnitude of range change was found for Gorilla beringei beringei, G. gorilla diehli, and Pan troglodytes schweinfurthii. On average, a decline of 50% of the geographic range (non-default; or 55% default) is expected under the best scenario if no dispersal occurs (57% non-default or 58% default in worst scenario). However, new areas of suitable habitat are predicted to become available for most taxa if dispersal occurs (81% or 103% best, 93% or 91% worst, non-default and default, respectively), except for G. b. beringei. Main ConclusionsDespite the uncertainty in predicting the precise proportion of suitable habitat by 2050, both modelling approaches predict large range losses for all African apes. Thus, conservation planners urgently need to integrate land-use planning and simultaneously support conservation and climate change mitigation measures at all decision-making levels both in range countries and abroad.

ecology↗