Biology subjects

Jones, G.

Publications and source records attributed to Jones, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Hepatic γδ NKT cells modulate liver-resident CD8+ T cells to attenuated malaria parasite vaccines

Plasmodium parasites develop in the liver and egress to infect red blood cells, causing malaria. Vaccines that generate hepatic CD8+ T cells eliminate liver-stage parasites and prevent disease, yet how these T cells are induced is incompletely understood. We report that in mice vaccinated with replication-competent genetically attenuated Plasmodium parasites, antagonism of {gamma}{delta} T cell function curtails protection. Vaccination expands hepatic IFN{gamma}+ {gamma}{delta} NKT cells, and depletion of these cells abrogates hepatic CD8+ T cell responses. IFN{gamma}+ {gamma}{delta} NKT cells are nearly undetectable in the blood at steady state but their frequencies in the periphery are significantly increased following vaccination, hinting at their utility as biomarkers of protection. To assess the relevance of these results in humans, we performed secondary analyses of peripheral blood samples from human clinical trial participants immunized with attenuated Plasmodium parasites (Trial registration: ClinicalTrials.gov NCT01994525). Flow cytometric and single cell transcriptomic characterization of {gamma}{delta} T cells in these samples unveil for the first time, increased frequency of activated V{delta}2- {gamma}{delta} T cells and gene expression in cytotoxic, tissue-homing V{delta}1+ {gamma}{delta} T cells as correlates of protection. Together, these data identify hepatic {gamma}{delta} T cells as targets for the improvement of tissue-resident CD8+ T cell responses against hepatotropic pathogens.

immunology↗

bioRxiv2026

Early-life telomere length variation under changing developmental conditions in long-lived bats

Early-life conditions can shape molecular ageing processes, yet to what extent developmental variation in telomere length (TL) influences ageing trajectories remains unclear, particularly in long-lived mammals. We investigated how early-life environmental conditions and maternal age relate to juvenile TL and short-term survival in two long-lived bat species, Myotis myotis and Rhinolophus ferrumequinum. Using novel long-term datasets spanning ten years in M. myotis and five years in R. ferrumequinum, we measured relative telomere length (rTL) in juvenile wing tissue and applied sliding window analysis to identify sensitive climatic periods during development. In both species, early-life rTL varied significantly among years and was associated with short-term climatic conditions, with rainfall predicting rTL in both species and temperature acting in opposing directions: longer rTL with warmer conditions in M. myotis, and longer rTL at intermediate temperatures in R. ferrumequinum. Maternal age at conception showed little association with offspring TL in either species, although a weak positive sex-specific longitudinal effect was detected in R. ferrumequinum. Despite clear environmental influences on early-life rTL, we found no evidence that early-life rTL or early-life telomere change predicted short-term survival. Together, these results indicate that early-life telomere variation in bats reflects climatic conditions during development, providing novel insights into how early-life exposures could contribute to inter-individual differences in ageing trajectories in long-lived mammals.

molecular biology↗

bioRxiv2026

Genomic instability and biofilm determinants in Streptococcus mutans: insights from a sequence-defined arrayed transposon library

Streptococcus mutans is a primary architect of dental caries, utilizing complex genetic networks to build resilient, acid-producing biofilms. While pooled screens (Tn-seq) have identified important fitness factors, they often fail to capture extracellular or moderate-effect determinants due to community-level masking. Therefore, to study biofilm phenotypes, we constructed a comprehensive arrayed library of 9,216 mutants and used Cartesian Pooling-Coordinate Sequencing (CP-CSeq) to establish a sequence-defined resource covering 51% of non-essential genes. By screening the entire collection in isolation, we identified several novel biofilm determinants, including the putative metal transporter SMU_635 and the glycosylation-associated protein SMU_2160. However, systematic whole-genome sequencing (WGS) of our hits revealed an interesting level of genomic instability: 25% of biofilm-defective mutants had undergone spontaneous recombination at the gtfBC locus, while 7% had lost the TnSmu1 element, an excision rate 1,000-fold higher than previously reported. While targeted mutagenesis confirmed that TnSmu1 loss does not impact biofilm integrity, the gtfBC deletions directly accounted for the most severe phenotypes, highlighting a systemic risk of misattributing gene functions to primary transposon insertions. Our findings provide a powerful new genetic resource for the S. mutans community while establishing a critical new standard: an arrayed library is only as defined as its underlying genome, making systematic genomic verification an essential prerequisite for accurate functional genomics. ImportanceStreptococcus mutans is a major human pathogen responsible for dental caries, a global public health challenge driven in part by the organisms ability to form resilient, acidogenic biofilms. While traditional pooled genetic screens have identified many fitness factors, they often fail to capture extracellular or moderate-effect determinants because neighboring healthy bacteria can mask these defects. This work provides the scientific community with a sequence-defined arrayed mutant library, an essential resource for dissecting the individual contributions of genes to biofilm integrity in isolation. Beyond identifying well-known machinery, this study uncovers novel determinants, including the putative metal transporter SMU_635 and the putative glycosylation-associated protein SMU_2160. Crucially, the discovery of pervasive genomic instability within the library, specifically at the gtfBC and TnSmu1 loci, reveals a systemic risk in functional genomics: the potential to misattribute phenotypes to primary mutations when the underlying background has undergone large-scale rearrangements. By establishing systematic whole-genome verification as a necessary standard, this research ensures that the identification of future therapeutic targets is built upon a verified genetic foundation.

microbiology↗

bioRxiv2024

In vivo contribution of Cyp24a1 promoter vitamin D response elements

CYP24A1 is a multifunctional, P450 mitochondrial 24-hydroxylase enzyme that is responsible for catabolism of the most active vitamin D hormone (calcitriol, 1,25(OH)2D3), its precursor (calcifediol, 25(OH)D3), and numerous other vitamin D metabolites at the 23- and 24-carbon positions. In the kidney, Cyp24a1 is induced by 1,25(OH)2D3, induced by FGF23, and potently suppressed by PTH to tightly control the circulating blood levels of 1,25(OH)2D3. This gene is believed to be under the control of a pair of classic promoter proximal (PRO) vitamin D response elements (VDREs) that are aided by distal, downstream (DS) containing enhancers that we identified more recently. The DS1 enhancer cluster was found to respond to PTH and FGF23 actions in a kidney-specific manner. The DS2 enhancer cluster was found to assist in the response of 1,25(OH)2D3 in kidney, as well as other target tissues. Despite this knowledge, the in vivo contribution of the PRO VDREs to gene expression, what drives Cyp24a1 basal expression in the kidney, how FGF23 activates Cyp24a1, and importantly, how PTH suppresses Cyp24a1, all remain unknown. Here in this study, we utilize homology directed CRISPR to mutate one or both VDREs in the PRO region of the Cyp24a1 gene in vivo in the mouse to address these questions. We found that the VDRE (VDRE1) more proximal to the to the transcriptional start site (TSS) is the dominant VDRE of the pair and mutation of both VDREs leads to a dramatic loss of VDR, a reduction of Cyp24a1 gene expression in the kidney, and a near elimination of 1,25(OH)2D3 induction in the intestine. FGF23 induction of Cyp24a1 was reduced with mutation of the PRO VDREs, however, co-treatment of 1,25(OH)2D3 and FGF23 synergistically increased Cyp24a1 expression even with the loss of the PRO VDREs. PTH suppression of Cyp24a1 gene expression was unchanged with PRO VDRE mutations, despite a minor reduction in total pCREB occupancy. Finally, VDR occupancy was dramatically reduced across the DS enhancers in the Cyp24a1 locus after the PRO VDREs mutation. Taken together, our data suggest a cooperative relationship between the DS and PRO enhancers in the regulation of Cyp24a1 by 1,25(OH)2D3 and FGF23, and despite the overall reduction of CREB on the genome it appeared that suppression either does not rely on CREB or that the PRO VDREs are unconnected to PTH suppression altogether. These studies point to the DS1 region as a basal switch for Cyp24a1 expression and help further define the interconnected genomic control of these hormones on vitamin D catabolism.

genomics↗

bioRxiv2024

Nanoscale analysis of functionally diverse glutamatergic synapses in the neocortex reveals input and layer-specific organization

Discovery of synaptic nanostructures suggests a molecular logic for the flexibility of synaptic function. We still have little understanding of how functionally diverse synapses in the brain organize their nanoarchitecture due to challenges associated with super-resolution imaging in complex brain tissue. Here, we characterized single-domain camelid nanobodies for the 3D quantitative multiplex imaging of synaptic nano-organization in 6 {micro}m brain cryosections using STED nanoscopy. We focused on thalamocortical (TC) and corticocortical (CC) synapses along the apical-basal axis of layer 5 pyramidal neurons as models of functionally diverse glutamatergic synapses in the brain. Spines receiving TC input were larger than CC spines in all layers examined. However, TC synapses on apical and basal dendrites conformed to different organizational principles. TC afferents on apical dendrites frequently contacted spines with multiple aligned PSD-95/Bassoon nanomodules, which are larger. TC spines on basal dendrites contained mostly one aligned PSD-95/Bassoon nanocluster. However, PSD-95 nanoclusters were larger and scaled with spine volume. The nano-organization of CC synapses did not change across cortical layers. These results highlight striking nanoscale diversity of functionally distinct glutamatergic synapses, relying on afferent input and sub-cellular localization of individual synaptic connections.

neuroscience↗

bioRxiv2024

Ongoing hybridisation among clownfishes: the genomic architecture of the Kimbe Bay hybrid zone

Hybrid zones - locations where genetically distinct lineages interact and reproduce - are remarkable resources for exploring the evolutionary trajectory of species. Not only can we learn from hybrid zones about the mechanisms of speciation and how reproductive isolation is maintained, but we can also study their impact on evolutionary processes. Thanks to the advent of next-generation sequencing, we are now able to gain new insight into the structure of hybrid genomes and the factors influencing the outcome of hybridisation. Here, we focus on the Kimbe Bay hybrid zone, a narrow region in the Pacific Ocean where two species of clownfish - Amphiprion chrysopterus and A. sandaracinos - hybridise and give rise to the hybrid A. leucokranos. Based on whole-genome sequencing, we found that the hybrid zone is mainly composed of first-generation hybrids, the first evidence of F2 hybrids in the wild and early backcrosses with A. sandaracinos. The recurrent backcrossing with one of the parental species might lead to adaptive introgression, with few adaptive introgressed loci from A. chrysopterus integrated into the A. sandaracinos genomic background. This study builds upon the growing literature body relative to the evolutionary outcomes of hybridisation and its importance in the evolution of many species.

evolutionary biology↗

bioRxiv2024

Resolved Genomes of Wastewater ESBL-Producing Escherichia coli and Metagenomic Analysis of Source Wastewater Samples

Extended-spectrum beta-lactamase (ESBL) producing Escherichia coli pose a serious threat to human health because of their resistance to the most commonly prescribed antibiotics: penicillins and cephalosporins. In this study, we provide a genomic and metagenomic context for the determinant ESBL genes of E. coli isolated from various wastewater treatment utilities in Oregon, USA. Class A beta-lactamase genes on chromosomes (blaCTX-M, blaTEM) were clustered with antibiotic resistance genes associated with other classes of antibiotics (sulfonamides and aminoglycosides) along with insertional elements. ESBL genes such as blaCTX-M, blaTEM, and blaSHV were also detected on conjugable plasmids of IncF and IncI incompatibility types. One novel IncF plasmid (pSHV2A_ESBLF) was identified in which carried a multi-drug resistance genotype (blaSHV-2A, aadA22, aac(3), aph(6), tetA, and sul1) in addition to a mer (mercury resistance) operon, colicin, and aerobactin genes. Shotgun metagenomic analysis of the E. coli-originating wastewater samples showed the presence of class A beta-lactamases; however, the ESBL genes identified in the E. coli genomes were below the detection limits. Other ESBL-associated genes (i.e., blaOXA.11, blaFOX.7, and blaGES.17) were identified in the wastewater samples and their occurrences were correlated with the core microbial genera (e.g., Paraprevotella). In both the E. coli genomes and the wastewater samples, tetracycline, aminoglycoside, and beta-lactam resistance determinants frequently co-occurred. The unique combination of whole-genome and metagenomic analysis provides a holistic description of ESBL-producing organisms and genes in the Oregonian wastewater system.

microbiology↗

bioRxiv2024

Host response during unresolved urinary tract infection alters mammary tissue homeostasis through collagen deposition and TIMP1

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explored how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell RNA sequencing and flow cytometry, we identified that mammary tissue from UTI-bearing mice display collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells were absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue were mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolved the infection and restored mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlated with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix (ECM) remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, or broad-spectrum antibiotic, prevented mammary collagen deposition, thus providing evidence for an unexpected link between the systemic host response during UTI and mammary alterations. SummaryThe systemic response during urinary tract infection induces TIMP1-driven collagen deposition specifically into the mammary gland.

developmental biology↗

bioRxiv2023

MHC-Fine: Fine-tuned AlphaFold for Precise MHC-Peptide Complex Prediction

The precise prediction of Major Histocompatibility Complex (MHC)-peptide complex structures is pivotal for understanding cellular immune responses and advancing vaccine design. In this study, we enhanced AlphaFolds capabilities by fine-tuning it with a specialized dataset comprised by exclusively high-resolution MHC-peptide crystal structures. This tailored approach aimed to address the generalist nature of AlphaFolds original training, which, while broad-ranging, lacked the granularity necessary for the high-precision demands of MHC-peptide interaction prediction. A comparative analysis was conducted against the homology-modeling-based method Pandora [13], as well as the AlphaFold multimer model [8]. Our results demonstrate that our fine-tuned model outperforms both in terms of RMSD (median value is 0.65 [A]) but also provides enhanced predicted lDDT scores, offering a more reliable assessment of the predicted structures. These advances have substantial implications for computational immunology, potentially accelerating the development of novel therapeutics and vaccines by providing a more precise computational lens through which to view MHC-peptide interactions.

bioinformatics↗

bioRxiv2023

A shared spatial topography links the functional connectome correlates of cocaine use disorder and dopamine D2/3 receptor densities

BackgroundThe biological mechanisms that contribute to cocaine and other substance use disorders involve an array of cortical and subcortical systems. Prior work on the development and maintenance of substance use has largely focused on cortico-striatal circuits, with relatively less attention on alterations within and across large-scale functional brain networks, and associated aspects of the dopamine system. The brain-wide pattern of temporal co-activation between distinct brain regions, referred to as the functional connectome, underpins individual differences in behavior. Critically, the functional connectome correlates of substance use and their specificity to dopamine receptor densities relative to other metabotropic receptors classes remains to be established. MethodsWe comprehensively characterized brain-wide differences in functional connectivity across multiple scales, including individual connections, regions, and networks in participants with cocaine use disorder (CUD; n=69) and healthy matched controls (n=62), Further, we studied the relationship between the observed functional connectivity signatures of CUD and the spatial distribution of a broad range of normative neurotransmitter receptor and transporter bindings as assessed through 18 different normative positron emission tomography (PET) maps. ResultsOur analyses identified a widespread profile of functional connectivity differences between individuals with CUD and matched healthy comparison participants (8.8% of total edges; 8,185 edges; pFWE=0.025). We largely find lower connectivity preferentially linking default network and subcortical regions, and higher within-network connectivity in the default network in participants with CUD. Furthermore, we find consistent and replicable associations between signatures of CUD and normative spatial density of dopamine D2/3 receptors. ConclusionsOur analyses revealed a widespread profile of altered connectivity in individuals with CUD that extends across the functional connectome and implicates multiple circuits. This profile is robustly coupled with normative dopamine D2/3 receptors densities. Underscoring the translational potential of connectomic approaches for the study of in vivo brain functions, CUD- linked aspects of brain function were spatially coupled to disorder relevant neurotransmitter systems. Key PointsO_ST_ABSQuestionC_ST_ABSAre there group differences in whole brain functional connectivity between individuals with and without cocaine use disorder, and to what extent do these connectivity patterns relate to the spatial distribution of dopamine (D2/3) receptor densities? FindingsThe presence of cocaine use disorder is associated with brain-wide functional connectivity alterations that are spatially coupled to the density of dopamine (D2/3) receptors. MeaningA preferential and replicable link exists between the functional connectome correlates of cocaine use disorder and dopamine receptor densities across the brain.

neuroscience↗

bioRxiv2023

Genomic fingerprints of the world's soil ecosystems

Despite the explosion of soil metagenomic data, we lack a synthesized understanding of patterns in the distribution and functions of soil microorganisms. These patterns are critical to predictions of soil microbiome responses to climate change and resulting feedbacks that regulate greenhouse gas release from soils. To address this gap, we assay 1512 manually-curated soil metagenomes using complementary annotation databases, read-based taxonomy, and machine learning to extract multidimensional genomic fingerprints of global soil microbiomes. Our objective is to uncover novel biogeographical patterns of soil microbiomes across environmental factors and ecological biomes with high molecular resolution. We reveal shifts in the potential for (1) microbial nutrient acquisition across pH gradients; (2) stress, transport, and redox-based processes across changes in soil bulk density; and (3) greenhouse gas emissions across biomes. We also use an unsupervised approach to reveal a collection of soils with distinct genomic signatures, characterized by coordinated changes in soil organic carbon, nitrogen, and cation exchange capacity and in bulk density and clay content that may ultimately reflect soil environments with high microbial activity. Genomic fingerprints for these soils highlight the importance of resource scavenging, plant-microbe interactions, fungi, and heterotrophic metabolisms. Across all analyses, we observed phylogenetic coherence in soil microbiomes -- more closely related microorganisms tended to move congruently in response to soil factors. Collectively, the genomic fingerprints uncovered here present a basis for global patterns in the microbial mechanisms underlying soil biogeochemistry and help beget tractable microbial reaction networks for incorporation into process-based models of soil carbon and nutrient cycling. ImportanceWe address a critical gap in our understanding of soil microorganisms and their functions, which have a profound impact on our environment. We analyzed 1512 global soils with advanced analytics to create detailed genetic profiles (fingerprints) of soil microbiomes. This reveals novel patterns in how microorganisms are distributed across different soil environments. For instance, we discovered shifts in microbial potential to acquire nutrients in relation to soil acidity, as well as changes in stress responses and potential greenhouse gas emissions linked to soil structure. We also identified soils with putative high activity that had unique genomic characteristics surrounding resource acquisition, plant-microbe interactions, and fungal activity. Finally, we observed that closely related microorganisms tend to respond in similar ways to changes in their surroundings. Our work is a significant step towards comprehending the intricate world of soil microorganisms and its role in the global climate.

ecology↗

bioRxiv2023

Standardisation of cell-free DNA measurements: An International Study on Comparability of Low Concentration DNA Measurements using cancer variants

For the impact of genomic testing from liquid biopsies to be maximized, mechanisms to ensure reproducible and comparable test performance will be required. This can be established and maintained through reference measurement procedures and materials with property values that are internationally comparable through traceability to a common standard. To achieve this objective, an interlaboratory study was organised to explore digital PCR (dPCR) for standardisation of cell-free DNA (cfDNA) quantification. Blinded samples of wild-type/variant mixtures of two DNA sequences (BRAF p.V600E single nucleotide variant or EGFR exon 19 deletion) were provided to 12 laboratories. Laboratories independently designed and applied dPCR assays to determine absolute and relative quantities, with no guidance provided to harmonise the approach. The mean and coefficient of variation (CV) of copy number concentrations for variant sequences were 18 copies/L (CV 7.2%) (BRAF variant sample) and 9 copies/L (CV 25%) (EGFR variant sample) while the mean variant allele frequencies (vAF) were 8.0% (CV 5.3%) and 0.080% (CV 29%) respectively. This study demonstrated that dPCR was capable of exceptional technical accuracy for variant copy number concentration and vAF, even when different assays and platforms were used. This implies that dPCR offers a unique analytical methodology that can be deployed globally in supporting comparability for cfDNA testing based on the existing framework of the International System of units of measurement.

genetics↗

bioRxiv2023

Applying genomic approaches to identify historic population declines in European forest bats

O_LIAnthropogenically-driven environmental changes over the past two centuries have led to severe biodiversity loss, most prominently in the form of loss of populations and individuals. Better tools are needed to assess the magnitude of these wildlife population declines. Anecdotal evidence suggests European bat populations have suffered substantial declines in the past few centuries. However, there is little empirical evidence of these declines that can be used to put more recent population changes into historic context and set appropriate targets for species recovery. C_LIO_LIThis study is a collaboration between academics and conservation practitioners to develop molecular approaches capable of providing quantitative evidence of historic population changes and their drivers that can inform the assessment of conservation status and conservation management. We generated a genomic dataset for the Western barbastelle, Barbastella barbastellus, a globally Near Threatened and regionally Vulnerable bat species, including colonies from across the species British and Iberian ranges. We used a combination of landscape genetics and approximate Bayesian computation model-based inference of demographic history to identify both evidence of population size changes and possible drivers of these changes. C_LIO_LIWe found that levels of genetic diversity increased and inbreeding decreased with increasing broadleaf woodland cover around the colony location. Genetic connectivity was impeded by artificial lights and facilitated by the combination of rivers and broadleaf woodland cover. C_LIO_LIThe demographic history analysis showed that both the northern and southern British barbastelle populations have declined by 99% over the past 330-548 years. These declines may have been triggered by loss of large oak trees and native woodlands due to shipbuilding during the early colonial period. C_LIO_LISynthesis and applications. Genomic approaches can be applied to provide a better understanding of the conservation status of threatened species, within historic and contemporary context, and inform their conservation management. This study shows how we can bridge the implementation gap and promote the application of genomics in conservation management through co-designing studies with conservation practitioners and co-developing applied management targets and recommendations. C_LI

genomics↗

bioRxiv2021

A two-step metagenomics approach for prey identification from the blood meals of common vampire bats (Desmodus rotundus)

The feeding behaviour of the sanguivorous common vampire bat (Desmodus rotundus) facilitates the transmission of pathogens that can impact both human and animal health. To formulate effective strategies in controlling the spread of diseases, there is a need to obtain information on which animals they feed on. One DNA-based approach, shotgun sequencing, can be used to obtain such information. Even though it is costly, shotgun sequencing can be used to simultaneously retrieve prey and vampire bat mitochondrial DNA for population studies within one round of sequencing. However, due to the challenges of analysing shotgun sequenced metagenomic data such as false negatives/positives and typically low proportion of reads mapped to diet items, shotgun sequencing has not been used for the identification of prey from common vampire bat blood meals. To overcome these challenges and generate longer mitochondrial contigs which could be useful for prey population studies, we shotgun sequenced common vampire bat blood meal samples (n=8) and utilised a two-step metagenomic approach based on combining existing bioinformatic workflows (alignment and de novo mtDNA assembly) to identify prey. Further, we validated our results to detections made through metabarcoding. We accurately identified the common vampire bats prey in seven out of eight samples without any false positives. We also generated prey mitochondrial contig lengths between 138bp to 3231bp (mean=985bp, SD=981bp). As we develop more computationally efficient bioinformatics pipelines and reduce sequencing costs, we can expect an uptake in metagenomics dietary studies in the near future.

molecular biology↗

bioRxiv2021

Improved Docking of Protein Models by a Combination of Alphafold2 and ClusPro

It has been demonstrated earlier that the neural network based program AlphaFold2 can be used to dock proteins given the two sequences separated by a gap as the input. The protocol presented here combines AlphaFold2 with the physics based docking program ClusPro. The monomers of the model generated by AlphaFold2 are separated, re-docked using ClusPro, and the resulting 10 models are refined by AlphaFold2. Finally, the five original AlphaFold2 models are added to the 10 AlphaFold2 refined ClusPro models, and the 15 models are ranked by their predicted aligned error (PAE) values obtained by AlphaFold2. The protocol is applied to two benchmark sets of complexes, the first based on the established protein-protein docking benchmark, and the second consisting of only structures released after May 2018, the cut-off date for training AlphaFold2. It is shown that the quality of the initial AlphaFold2 models improves with each additional step of the protocol. In particular, adding the AlphaFold2 refined ClusPro models to the AlphaFold2 models increases the success rate by 23% in the top 5 predictions, whereas considering the 10 models obtained by the combined protocol increases the success rate to close to 40%. The improvement is similar for the second benchmark that includes only complexes distinct from the proteins used for training the neural network.

bioinformatics↗

bioRxiv2021

Genetic diversity, distribution and domestication history of the neglected GGAtAt genepool of wheat

Wheat yields are stagnating around the world and new sources of genes for resistance or tolerances to abiotic traits are required. In this context, the tetraploid wheat wild relatives are among the key candidates for wheat improvement. Despite of its potential huge value for wheat breeding, the tetraploid GGAtAt genepool is largely neglected. Understanding the population structure, native distribution range, intraspecific variation of the entire tetraploid GGAtAt genepool and its domestication history would further its use for wheat improvement. We report the first comprehensive survey of genomic and cytogenetic diversity sampling the full breadth and depth of the tetraploid GGAtAt genepool. We show that the extant GGAtAt genepool consists of three distinct lineages. We provide detailed insights into the cytogenetic composition of GGAtAt wheats, revealed group-, and population-specific markers and show that chromosomal rearrangements play an important role in intraspecific diversity of T. araraticum. We discuss the origin and domestication history of the GGAtAt lineages in the context of state-of-the-art archaeobotanical finds. We shed new light on the complex evolutionary history of the GGAtAt wheat genepool. We provide the basis for an increased use of the GGAtAt wheat genepool for wheat improvement. The findings have implications for our understanding of the origins of agriculture in southwest Asia.

evolutionary biology↗

bioRxiv2020

Matrix stiffness and blood pressure together regulate vascular smooth muscle cell phenotype switching and cofilin dependent podosome formation

Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. In pre-atherosclerotic lesions, VSMCs switch from a contractile to a synthetic phenotype and subsequently remodel the microenvironment, leading to further disease progression. Ageing and associated mechanical changes of the extracellular matrix as well as hypertension are major risk of atherosclerosis. Consequently, we sought here to systematically study the impact of mechanical stimulations on VSMC phenotypic switching, by modulating both stiffness and hydrodynamic pressure. Thereby we find that hemodynamic pressure and matrix stiffness individually affect the VSMC phenotype. However, only the combination of hypertensive pressure and matrix compliance, and as such mechanical stimuli that are prevalent during atherosclerosis, lead to a full phenotypic switch including the formation of matrix degrading podosomes. We further analyse the molecular mechanism in stiffness and pressure sensing and identify a regulation through different, but overlapping pathways, culminating in the regulation of the actin cytoskeleton through cofilin. Altogether, our data shows how different pathological mechanical signals combined, but through distinct pathways accelerate a phenotypic switch that will ultimately contribute to atherosclerotic disease progression.

cell biology↗

bioRxiv2020

Genome Methylation Predicts Age and Longevity of Bats

Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.

genomics↗