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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 84,901 bioRxiv papers from 365,191 authors.

Most downloaded bioRxiv papers, since beginning of last month

82,752 results found. For more information, click each entry to expand.

59881: The ERA-related GTPase AtERG2 associated with mitochondria 18S RNA is essential for early embryo development in Arabidopsis
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Posted to bioRxiv 18 Sep 2017

The ERA-related GTPase AtERG2 associated with mitochondria 18S RNA is essential for early embryo development in Arabidopsis
7 downloads plant biology

Pengyu Cheng, Hongjuan Li, Linlin Yuan, Huiyong Li, Lele Xi, Junjie Zhang, Jin Liu, Yingdian Wang, Heping Zhao, Huixin Zhao, Shengcheng Han

The ERA (E. coli RAS-like protein)-related GTPase (ERG) is a nuclear-encoded GTPase with two conserved domains: a GTPase domain and a K Homology domain. ERG plays a vital role in early seed development in Antirrhinum majus. However, the mechanism that regulates seed development remains unclear. Blasting the genome sequence revealed two homologies of ERG, AtERG1, and AtERG2 in Arabidopsis. In this study, we found that AtERG2 is localised in the mitochondria and binds mitochondrial 18S RNA. Promoter and transcript analyses indicated that AtERG2 was mainly expressed in the leaf vein, trichome, mature pollen, and ovule. The mutants of AtERG2 showed recessive lethal, gametophytic maternal effects, silique shortage, and early seed abortion, in which some seeds arrested in the zygotic stage at 1.5 days after pollination (DAP) and aborted at 2.0 DAP in aterg2-1 +/-. Reactive oxygen species (ROS) accumulated at 1.5 DAP in the arrested seeds, and the transcription of several ROS-responsible genes, WRKY40, ANAC017, and AOX1a, was up-regulated in the aterg2-1 +/- seeds which were arrested 1.5 and 2.0 DAP but not in wild-type (WT) and aterg2-1 +/- seeds. The cell death-related gene BAG6 was also transcriptionally activated in aterg2-1 +/- seeds arrested at 2.0 DAP. Chloramphenicol treatment during pollination induced a similar phenotype and gene expression pattern but showed no transcriptional changes of ANAC017 in WT. These results suggested that AtERG2 promotes early seed development by affecting the maturation of the mitochondria ribosome small subunit and mitochondrial protein translation in Arabidopsis.

59882: The closed-loop pathways of signaling molecules
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Posted to bioRxiv 23 Apr 2017

The closed-loop pathways of signaling molecules
7 downloads bioinformatics

Yang Liu

The pathways of signaling molecules are important to understanding how signaling molecules regulate physiological function and also in predicting the pathological development which is important to therapeutic strategy, however the thorough knowledge of these pathways is still lack. In this paper, we used the big data concept to analyze the pathways of signaling molecules and categorize these molecules into five groups according to their origin and effect on the five organs of heart-spleen-lung-kidney-liver. Heart group includes IGF, Ang and Mg; spleen group includes ANP, aldosterone, retinoic acid and ghrelin; lung group includes FGF7, VEGF, ascorbic acid and HIF; kidney group includes calcitonin, PTHrP, Wnt and NO; and liver group includes EPO, renin, SOD, AKR and GSH. We found that each group of molecules have assisting effect on the other organ in the order of heart-spleen-lung-kidney-liver-heart, and have regulating effect on the other organ in the order of heart-lung-liver-spleen-kidney-heart. Moreover, the pathways of molecules of each group also follow these two arrangements, in which the pathways of molecules form a closed-loop that may lead to new therapeutic strategies.

59883: Synthesis of oxyfunctionalized NSAID metabolites by microbial biocatalysts
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Posted to bioRxiv 07 May 2018

Synthesis of oxyfunctionalized NSAID metabolites by microbial biocatalysts
7 downloads biochemistry

Jan M. Klenk, Lisa Kontny, Bernd A Nebel, Bernhard Hauer

The synthesis of valuable metabolites and degradation intermediates of drugs, like non-steroidal anti-inflammatory drugs (NSAIDs), are substantially for toxicological and environmental studies, but efficient synthesis strategies and the metabolite availability are still challenging aspects. To overcome these bottlenecks filamentous fungi as microbial biocatalysts were applied. Different NSAIDs like diclofenac, ibuprofen, naproxen and mefenamic acid could be oxyfunctionalized to produce human metabolites in isolated yields of up to 99% using 1 g L-1 of substrate. Thereby the biotransformations using Beauveria bassiana, Clitocybe nebularis or Mucor hiemalis surpass previous reported chemical, microbial and P450-based routes in terms of efficiency. In addition to different hydroxylated compounds of diclofenac, a novel metabolite, 3',4'-dihydroxydiclofenac, has been catalyzed by B. bassiana and the responsible P450s were identified by proteome analysis. The applied filamentous fungi present an interesting alternative, microbial biocatalysts platform for the production of valuable oxyfunctionalized drug metabolites.

59884: Genome-wide association analysis of excessive daytime sleepiness identifies 42 loci that suggest phenotypic subgroups
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Posted to bioRxiv 26 Oct 2018

Genome-wide association analysis of excessive daytime sleepiness identifies 42 loci that suggest phenotypic subgroups
7 downloads genomics

Heming Wang, Jacqueline M. Lane, Samuel E Jones, Hassan S Dashti, Hanna Ollila, Andrew R. Wood, Vincent T. van Hees, Ben Brumpton, Bendik S Winsvold, Katri Kantojärvi, Brian E. Cade, Tamar Sofer, Yanwei Song, Krunal Patel, Simon G Anderson, David A Bechtold, Jack Bowden, Richard Emsley, Simon D Kyle, Max A Little, Andrew S Loudon, Frank AJL Scheer, Shaun M. Purcell, Rebecca C Richmond, Kai Spiegelhalder, Jessica Tyrrell, Xiaofeng Zhu, Kati Kristiansson, Sonja Sulkava, Tiina Paunio, Kristian Hveem, Jonas B. Nielsen, Cristen J. Willer, John-Anker Zwart, Linn B. Strand, Timothy M Frayling, David W Ray, Deborah A. Lawlor, Martin K Rutter, Michael N Weedon, Susan Redline, Richa Saxena

Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. We identified 42 loci for self-reported EDS in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirmed the aggregate effect of a genetic risk score of 42 SNPs on EDS in independent Scandinavian cohorts and on other sleep disorders (restless leg syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). Strong genetic correlations were also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing. EDS variants clustered into two predominant composite phenotypes - sleep propensity and sleep fragmentation - with the former showing stronger evidence for enriched expression in central nervous system tissues, suggesting two unique mechanistic pathways. Mendelian randomization analysis indicated that higher BMI is causally associated with EDS risk, but EDS does not appear to causally influence BMI.

59885: Growth-Environment Dependent Modulation of Staphylococcus aureus Branched-Chain to Straight-Chain Fatty Acid Ratio and Incorporation of Unsaturated Fatty Acids
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Posted to bioRxiv 05 Apr 2016

Growth-Environment Dependent Modulation of Staphylococcus aureus Branched-Chain to Straight-Chain Fatty Acid Ratio and Incorporation of Unsaturated Fatty Acids
7 downloads microbiology

Suranjana Sen, Seth R Johnson, Yang Song, Sirisha Sirobhushanam, Ryan Tefft, Craig Gatto, Brian J Wilkinson

The fatty acid composition of membrane glycerolipids is a major determinant of Staphylococcus aureus membrane biophysical properties that impacts key factors in cell physiology including susceptibility to membrane active antimicrobials, pathogenesis, and response to environmental stress. The fatty acids of S. aureus are considered to be a mixture of branched-chain fatty acids (BCFAs), which increase membrane fluidity, and straight-chain fatty acids (SCFAs) that decrease it. The balance of BCFAs and SCFAs in strains USA300 and SH1000 was affected considerably by differences in the conventional laboratory medium in which the strains were grown with media such as Mueller-Hinton broth and Luria broth resulting in high BCFAs and low SCFAs, whereas growth in Tryptic Soy Broth and Brain-Heart Infusion broth led to reduction in BCFAs and an increase in SCFAs. Straight-chain unsaturated fatty acids (SCUFAs) were not detected. However, when the organism was grown ex vivo in serum, the fatty acid composition was radically different with SCUFAs, which increase membrane fluidity, making up a substantial proportion of the total (<25%) with SCFAs (>37%) and BCFAs (>36%) making up the rest. Staphyloxanthin, an additional major membrane lipid component unique to S. aureus, tended to be greater in content in cells with high BCFAs or SCUFAs. Cells with high staphyloxanthin content had a lower membrane fluidity that was attributed to increased production of staphyloxanthin. S. aureus saves energy and carbon by utilizing host fatty acids for part of its total fatty acids when growing in serum. The fatty acid composition of in vitro grown S. aureus is likely to be a poor reflection of the fatty acid composition and biophysical properties of the membrane when the organism is growing in an infection in view of the role of SCUFAs in staphylococcal membrane composition and virulence.

59886: Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia
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Posted to bioRxiv 26 Dec 2019

Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia
7 downloads pathology

Petra Popovics, Wisam N. Awadallah, Sarah Kohrt, Thomas C. Case, Nicole L. Miller, Emily Ricke, Wei Huang, Marisol Ramirez-Solano, Qi Liu, Chad M. Vezina, Robert J. Matusik, William A Ricke, Magdalena M. Grabowska

Background: Male lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often use LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a pro-inflammatory and pro-fibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to pro-inflammatory stimuli and identified downstream targets of OPN in prostate stromal cells. Methods: Immunohistochemistry was performed on prostate sections obtained from the transition zone (TZ) of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS i.e. surgical BPH (S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging system and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by ELISA. qPCR was used to measure gene expression changes in these cells in response to OPN. Results: OPN immunostaining (p=0.0107) and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2 and IL6 in BHPrS-1, but not in epithelial cell lines. Conclusions: OPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by pro-inflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of pro-inflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.

59887: NAT/NCS2-hound: A webserver for the detection and evolutionary classification of prokaryotic and eukaryotic nucleobase-cation symporters of the NAT/NCS2 family.
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Posted to bioRxiv 28 May 2018

NAT/NCS2-hound: A webserver for the detection and evolutionary classification of prokaryotic and eukaryotic nucleobase-cation symporters of the NAT/NCS2 family.
7 downloads bioinformatics

A Chaliotis, P Vlastaridis, C Ntountoumi, M Botou, V Yalelis, P Lazou, E Tatsaki, D Mossialos, S Frillingos, GD Amoutzias

Nucleobase transporters are important for supplying the cell with purines and/or pyrimidines, for controlling the intracellular pool of nucleotides and for obtaining exogenous nitrogen/carbon sources for the metabolism. Nucleobase transporters are also evaluated as potential targets for antimicrobial therapies, since several pathogenic microorganisms rely on purine/pyrimidine salvage from their hosts. The majority of known nucleobase transporters belong to the evolutionarily conserved and ubiquitous NAT/NCS2 protein family. Based on a large-scale phylogenetic analysis that we performed on thousands of prokaryotic proteomes, we have developed a webserver that can detect and distinguish this family of transporters from other homologous families that recognize different substrates. We can further categorize these transporters to certain evolutionary groups with distinct substrate preferences. The webserver scans whole proteomes and graphically displays which proteins are identified as NAT/NCS2, to which evolutionary groups and subgroups they belong to and which conserved motifs they have. For key subgroups and motifs, the server displays annotated information from published crystal-structures and mutational studies pointing to key functional amino acids that may help experts assess the transport capability of the target sequences. The server is 100% accurate in detecting NAT/NCS2 family members. We also used the server to analyze 9109 prokaryotic proteomes and identified Clostridia, Bacilli, beta- and gamma-Proteobacteria, Actinobacteria and Fusobacteria as the taxa with the largest number of NAT/NCS2 transporters per proteome. An analysis of 120 representative eukaryotic proteomes also demonstrates the server's capability of correctly analyzing this major lineage, with plants emerging as the group with the highest number of NAT/NCS2 members per proteome.

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Posted to bioRxiv 09 May 2018

7 downloads biophysics

Sadie Piatt, Allen C. Price

The Generalized Method of Moments (GMM) is a statistical method for the analysis of samples from random processes. First developed for the analysis of econometric data, the method is here formulated to extract hidden kinetic parameters from measurements of single molecule dwell times. Our method is based on the analysis of cumulants of the measured dwell times. We develop a general form of an objective function whose minimization can return estimates of decay parameters for any number of intermediates directly from the data. We test the performance of our technique using both simulated and experimental data. We also compare the performance of our method to nonlinear least-squares minimization (NL-LSQM), a commonly-used technique for analysis of single molecule dwell times. Our findings indicate that the GMM performs comparably to NL-LSQM over most of the parameter range we explore. It offers some benefits compared with NL-LSQM in that it does not require binning, exhibits slightly lower bias and variance with small sample sizes (N

59889: Improved motion correction of submillimetre 7T fMRI time series with boundary-based registration (BBR)
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Posted to bioRxiv 28 Aug 2019

Improved motion correction of submillimetre 7T fMRI time series with boundary-based registration (BBR)
7 downloads neuroscience

Pei Huang, Johan D. Carlin, Richard N Henson, Marta M Correia

Ultra-high field functional magnetic resonance imaging (fMRI) has allowed us to acquire images with submillimetre voxels. However, in order to interpret the data clearly, we need to accurately correct head motion and the resultant distortions. Here, we present a novel application of Boundary Based Registration (BBR) to realign functional Magnetic Resonance Imaging (fMRI) data and evaluate its effectiveness on a set of 7T submillimetre data, as well as millimetre 3T data for comparison. BBR utilizes the boundary information from high contrast present in structural data to drive registration of functional data to the structural data. In our application, we realign each functional volume individually to the structural data, effectively realigning them to each other. In addition, this realignment method removes the need for a secondary aligning of functional data to structural data for purposes such as laminar segmentation or registration to data from other scanners. We demonstrate that BBR realignment outperforms standard realignment methods across a variety of data analysis methods. Further analysis shows that this benefit is an inherent property of the BBR cost function and not due to the difference in target volume. Our results show that BBR realignment is able to accurately correct head motion in 7T data and can be utilized in preprocessing pipelines to improve the quality of 7T data.

59890: High antibody titres induced by protein subunit vaccines against Buruli ulcer using Mycobacterium ulcerans antigens Hsp18 and MUL_3720
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Posted to bioRxiv 17 Feb 2020

High antibody titres induced by protein subunit vaccines against Buruli ulcer using Mycobacterium ulcerans antigens Hsp18 and MUL_3720
7 downloads microbiology

Kirstie M. Mangas, Nicholas Tobias, Estelle Marion, Jérémie Babonneau, Laurent Marsollier, Jessica L. Porter, Sacha J. Pidot, Chinn Yi Wong, David C. Jackson, Brendon Y. Chua, Timothy P. Stinear

Background: Mycobacterium ulcerans is the causative agent of a debilitating skin and soft tissue infection known as Buruli ulcer (BU). There is no vaccine against BU. The purpose of this study was to investigate the vaccine potential of two previously described immunogenic M. ulcerans proteins, MUL\_3720 and Hsp18, using a mouse tail infection model of BU. Methods: Recombinant versions of the two proteins were each electrostatically coupled with a previously described lipopeptide adjuvant. Seven C57BL/6 and seven BALB/c mice were vaccinated and boosted with each of the formulations. Vaccinated mice were then challenged with M. ulcerans via subcutaneous tail inoculation. Vaccine performance was assessed by time-to-ulceration compared to unvaccinated mice. Results: The MUL\_3720 and Hsp18 vaccines induced high titres of antigen-specific antibodies that were predominately subtype IgG1. However, all mice developed ulcers by day-40 post-M. ulcerans challenge. No significant difference was observed in the time-to-onset of ulceration between the experimental vaccine groups and unvaccinated animals. Conclusions: These data align with previous vaccine experiments using Hsp18 and MUL_3720 that indicated these proteins may not be appropriate vaccine antigens. This work highlights the need to explore alternative vaccine targets and different approaches to understand the role antibodies might play in controlling BU.

59891: Antenatal microbial colonisation of mammalian gut
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Posted to bioRxiv 18 Dec 2017

Antenatal microbial colonisation of mammalian gut
7 downloads microbiology

Elisa Borghi, Valentina Massa, Marco Severgnini, Grazia Fazio, Laura Avagliano, Elena Menegola, Gaetano Bulfamante, Giulia Morace, Francesca Borgo

The widely accepted dogma of intrauterine sterility and initial colonisation of the newborn during birth has been blurred by recent observations of microbial presence in meconium, placenta and amniotic fluid. Given the importance of a maternal-derived in utero infant seeding, it is crucial to exclude potential environmental or procedural contaminations, and to assess foetal colonisation before parturition. To ascertain antenatal microbial colonisation in mammals, we analysed sterilely collected intestinal tissues from rodent foetuses in parallel with experimental controls, and tissues from autoptic human foetuses. Next generation sequencing (NGS) showed the presence of pioneer microbes in both rat and human intestines, as well as in rodent placentas and amniotic fluids. Live microbes were isolated from culture-dependent analyses from homogenized rat foetal intestines. Microbial communities showed foetus- and dam-dependent clustering, confirming the high inter-individual variability of microbiota even in the antenatal period. Fluorescent in situ hybridisation analysis confirmed the microbes existence in the lumen of the developing gut. These findings have vast implications for an emerging field of enhancing the management of healthy pregnancies, and for understanding how the infant microbiome starts and it is thus shaped.

59892: Apical progenitors remain multipotent throughout cortical neurogenesis
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Posted to bioRxiv 27 Nov 2018

Apical progenitors remain multipotent throughout cortical neurogenesis
7 downloads neuroscience

Polina Oberst, Sabine Fièvre, Natalia Baumann, Cristina Concetti, Denis Jabaudon

The diverse subtypes of excitatory neurons that populate the neocortex are born from progenitors located in the ventricular zone (apical progenitors, APs). During corticogenesis, APs progress through successive temporal states to sequentially generate deep- followed by superficial-layer neurons directly or via the generation of intermediate progenitors (IPs). Yet little is known about the plasticity of AP temporal identity and whether individual progenitor subtypes remain multipotent throughout corticogenesis. To address this question, we used FlashTag (FT), a method to pulse-label and isolate APs in the mouse neocortex with high temporal resolution to fate-map neuronal progeny following heterochronic transplantation of APs into younger embryos. We find that unlike daughter IPs, which lose the ability to generate deep layer neurons when transplanted into a younger host, APs are temporally uncommitted and become molecularly respecified to generate normally earlier-born neuron types. These results indicate that APs are multipotent cells that are able to revert their temporal identity and re-enter past molecular and neurogenic states. AP fate progression thus occurs without detectable fate restriction during the neurogenic period of corticogenesis. These findings identify unforeseen cell-type specific differences in cortical progenitor fate plasticity, which could be exploited for neuroregenerative purposes.

59893: Trypanosomes have divergent kinesin-2 proteins that function differentially in IFT, cell division, and motility
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Posted to bioRxiv 13 Apr 2018

Trypanosomes have divergent kinesin-2 proteins that function differentially in IFT, cell division, and motility
7 downloads cell biology

Robert L Douglas, Brett M Haltiwanger, Haiming Wu, Robert L Jeng, Joel Mancuso, W Zacheus Cande, Matthew D. Welch

Trypanosoma brucei, the causative agent of African sleeping sickness, has a flagellum that is crucial for motility, pathogenicity, and viability. In most eukaryotes, the intraflagellar transport (IFT) machinery drives flagellum biogenesis, and anterograde IFT requires kinesin-2 motor proteins. In this study, we investigated the function of the two T. brucei kinesin-2 proteins, TbKin2a and TbKin2b, in bloodstream form trypanosomes. We found that compared to other kinesin-2 proteins, TbKin2a and TbKin2b show greater variation in neck, stalk, and tail domain sequences. Both kinesins contributed additively to flagellar lengthening. Surprisingly, silencing TbKin2a inhibited cell proliferation, cytokinesis and motility, whereas silencing TbKin2b did not. TbKin2a was localized on the flagellum and colocalized with IFT components near the basal body, consistent with it performing a role in IFT. TbKin2a was also detected on the flagellar attachment zone, a specialized structure in trypanosome cells that connects the flagellum to the cell body. Our results indicate that kinesin-2 proteins in trypanosomes play conserved roles in IFT and exhibit a specialized localization, emphasizing the evolutionary flexibility of motor protein function in an organism with a large complement of kinesins.

59894: The Fisher-Wright model with deterministic seed bank and selection
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Posted to bioRxiv 24 Dec 2015

The Fisher-Wright model with deterministic seed bank and selection
7 downloads evolutionary biology

Bendix Koopmann, Johannes Müeller, Aurélien Tellier, Daniel Živković

Seed banks are a common characteristics to many plant species, which allow storage of genetic diversity in the soil as dormant seeds for various periods of time. We investigate an above-ground population following a Fisher-Wright model with selection coupled with a deterministic seed bank assuming the length of the seed bank is kept constant and the number of seeds is large. To assess the combined impact of seed banks and selection on genetic diversity, we derive a general diffusion model. We compute the equilibrium solution of the site-frequency spectrum and derive the times to fixation of an allele with and without selection. Finally, it is demonstrated that seed banks enhance the effect of selection onto the site-frequency spectrum while slowing down the time until the mutation-selection equilibrium is reached.

59895: From modules to networks: A systems-level analysis of the bacitracin stress response in Bacillus subtilis
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Posted to bioRxiv 03 Nov 2019

From modules to networks: A systems-level analysis of the bacitracin stress response in Bacillus subtilis
7 downloads systems biology

Hannah Piepenbreier, Andre Sim, Carolin M. Kobras, Jara Radeck, Thorsten Mascher, Susanne Gebhard, Georg Fritz

Bacterial resistance against antibiotics often involves multiple mechanisms that are interconnected to ensure robust protection. So far, the knowledge about underlying regulatory features of those resistance networks is sparse, since they can hardly be determined by experimentation alone. Here, we present the first computational approach to elucidate the interplay between multiple resistance modules against a single antibiotic, and how regulatory network structure allows the cell to respond to and compensate for perturbations of resistance. Based on the response of B. subtilis towards the cell wall synthesis-inhibiting antibiotic bacitracin, we developed a mathematical model that comprehensively describes the protective effect of two well-studied resistance modules (BceAB and BcrC) on the progression of the lipid II cycle. By integrating experimental measurements of expression levels, the model accurately predicts the efficacy of bacitracin against the B. subtilis wild-type as well as mutant strains lacking one or both of the resistance modules. Our study reveals that bacitracin-induced changes in the properties of the lipid II cycle itself control the interplay between the two resistance modules. In particular, variations in the concentrations of UPP, the lipid II cycle intermediate that is targeted by bacitracin, connect the effect of the BceAB transporter and the homeostatic response via BcrC to an overall resistance response. We propose that monitoring changes in pathway properties caused by a stressor allows the cell to fine-tune deployment of multiple resistance systems and may serve as a cost-beneficial strategy to control the overall response towards this stressor.

59896: A New Technique and Device for Controlled and Continuous Drug Delivery into the Brain – A Proof of Concept Study
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Posted to bioRxiv 28 Aug 2019

A New Technique and Device for Controlled and Continuous Drug Delivery into the Brain – A Proof of Concept Study
7 downloads neuroscience

U.R. Anoop, Kavita Verma

Background Drug delivery into the brain has been a challenge for the past 100 years because of the blood brain barrier. The existing non-invasive techniques cannot provide controlled and continuous drug delivery into the brain and the invasive techniques make the brain prone to infection from external agents. Hence a new technique which can provide controlled and continuous drug delivery without the need for any surgical intervention in the brain holds immense potential. Objective The objective of this study is to deliver drugs into the brain using a novel oral and maxillofacial technique and device. Method Drug delivery into the brain from the oral and maxillofacial region was tested using a novel technique and device in an in vivo rabbit model and an ex vivo goat head model. A control animal and an experimental animal were used in each study. Drugs which do not cross the blood brain barrier normally were tested. Dopamine was delivered in vivo from the maxillo-facial region. Anti-glial fibrillary acidic protein antibody was delivered ex vivo from the oral region. Samples were collected from different sites including the brain and the optic nerve. Results The in vivo model showed a significant increase of dopamine at the pons (51.89%), midbrain (27%), medulla (48.5%) and cortex (72.637%). On including samples from other regions in the t-test, the increase was not statistically significant ( p =0.538), suggestive of a central feedback mechanism for brain and peripheral dopamine. A decrease in plasma dopamine during drug delivery further supported a central control for dopamine. In the ex vivo model, a statistically significant ( p =0.047) delivery of antibodies occurred at multiple sites including pons (86.7%), cortex (256.5%), and the optic nerve (128.8%). Conclusion This technique and device can deliver drugs into the brain without detectable increase in systemic circulation. Therefore it may be used for delivering drugs in Parkinson’s disease, Alzheimer’s disease, Pain management, Brain tumors especially pontine tumors, infections like neuro-AIDS, Basal meningitis etc. Retinal drug delivery may also be possible.

59897: Characterization Of The Stoichiometry Of The Complex Formed By Staphylococcal LukSF And Human C5aR Receptor In Living Cells
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Posted to bioRxiv 14 Apr 2017

Characterization Of The Stoichiometry Of The Complex Formed By Staphylococcal LukSF And Human C5aR Receptor In Living Cells
7 downloads biophysics

Karita Haapasalo, Adam JM Wollman, Carla de Haas, Kok van Kessel, Jos van Strijp, Mark C. Leake

Staphylococcus aureus Panton Valentine Leukocidin (PVL) is a pore-forming toxin comprising protein subunits LukS and LukF. Binding of LukS to human C5a receptor (hC5aR) on leukocytes induces secondary binding of LukF and assembly of lytic complexes. Previous analysis suggests that PVL consists of 4-plus-4 LukS/LukF subunits but the exact stoichiometry between LukS, LukF and hC5aR is not yet known. In this study we determine the stoichiometry and spatiotemporal dynamics of functional LukS/LukF- hC5aR complexes in living eukaryotic cells. By using rapid total internal reflection fluorescence (TIRF) and single-molecule photobleaching analysis we found that tetrameric LukS-hC5aR complexes are formed within a cluster of receptors. Upon binding to hC5aR each LukS subunit binds LukF leading to lytic pore formation and simultaneous dissociation of receptors from the complex. Our findings corroborate a hetero-octamer model but provide a new view on the kinetics of crucial virulence factor assembly on integrated host cell membrane receptors.

59898: Epigenetic Reprogramming of Tissue-Specific Transcription Promotes Metastasis
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Posted to bioRxiv 26 Apr 2017

Epigenetic Reprogramming of Tissue-Specific Transcription Promotes Metastasis
7 downloads cancer biology

Shuaishuai Teng, Yang Li, Ming Yang, Rui Qi, Yiming Huang, Qianyu Wang, Shasha Li, Kequan Lin, Yujing Cheng, Zhi John Lu, Dong Wang

Tumor metastasis is the cause of death for 90% of cancer patients, and no currently-available therapies target this multi-step process in which cancer cells spread from the local tissue of a primary tumor to distant organs where they establish secondary tumors. Although epithelial-to-mesenchymal transition, tumor-secreted exosomes, epigenetic regulators as well as other genes have been implicated in metastasis, little is known about how cells adapt to and colonize new tissue environments. Here, we show that the epigenetics-mediated reprogramming of tissue-specific gene transcription in cancer cells promotes metastasis. Using colorectal cancer (CRC) as a model, we found in both clinical and cell line studies that metastatic CRC cells lose their colon-specific gene transcription program and gain a liver-specific gene transcription program as they metastasize in the liver. Further, we found this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical and super-enhancers. Chemical inhibition of enhancer activity disrupts the ability of cells to execute altered transcription programs and consequently inhibits metastasis. Binding motif analysis of the enhancers in liver metastatic CRC cells identified the liver-specific transcription factor FOXA2 as a key regulator, and knocking down of FOXA2 expression prevents the colonization of metastatic CRC cells in the liver of a mice xenograft model. These results, together with additional observations of similar reprogramming in several cohorts of clinical CRC tumor samples and in multiple other forms of metastatic cancers, indicate that this reprogramming may be a common feature of metastasis in multiple cancers and suggest the targeted disruption of this epigenetic reprogramming as a strategy for the development of therapies to treat metastasis, the leading cause of cancer-related mortality.

59899: Dynamic network properties of the interictal brain determine whether seizures appear focal or generalised
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Posted to bioRxiv 14 Mar 2019

Dynamic network properties of the interictal brain determine whether seizures appear focal or generalised
7 downloads neuroscience

Wessel Woldman, Helmut Schmidt, Eugenio Abela, Fahmida A. Chowdhury, Adam D. Pawley, Sharon Jewell, Mark P Richardson, John R. Terry

Objective: Current explanatory concepts suggest seizures emerge from ongoing dynamics of brain networks. It is unclear how brain network properties determine focal or generalised seizure onset, or how network properties can be described in a clinically-useful manner. Understanding network properties would cast light on seizure-generating mechanisms and allow to quantify in the clinic the extent to which a seizure is focal or generalised. Methods: 68 people with epilepsy and 38 healthy controls underwent 19 channel scalp EEG recording. Functional brain networks were estimated in each subject using phase-locking between EEG channels in the 6-9Hz band from segments of 20s without interictal discharges. Simplified brain dynamics were simulated using a computer model. We introduce three concepts: Critical Coupling (Cc), the ability of a network to generate seizures; Onset Index (OI), the tendency of a region to generate seizures; and Participation Index (PI), the tendency of a region to become involved in seizures. Results: Cc was lower in both patient groups compared with controls. OI and PI were more variable in focal-onset than generalised-onset cases. No regions showed higher OI and PI in generalised-onset cases than in healthy controls; in focal cases, the regions with highest OI and PI corresponded to the side of seizure onset. Conclusions: Properties of interictal functional networks from scalp EEG can be estimated using a computer model and used to predict seizure likelihood and onset patterns. Our framework, consisting of three clinically-meaningful measures, could be implemented in the clinic to quantify the diagnosis and seizure onset pattern.

59900: Sclerostin Deficiency Alters Peripheral B Lymphocyte Responses in Mice
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Posted to bioRxiv 28 Jun 2018

Sclerostin Deficiency Alters Peripheral B Lymphocyte Responses in Mice
7 downloads immunology

Arthur Chow, Jourdan Mason, Larrisha Coney, Jamila Bajwa, Cameron Carlisle, Anna Zaslavsky, Yvette Pellman, Marcos E. García-Ojeda, Aris Economides, Gabriela G. Loots, Jennifer O Manilay

Understanding how changes in bone physiology and homeostasis affect immune responses will inform how to retain strong immunity in patients with bone disease and in aged individuals. We previously identified sclerostin (Sost) as a mediator of cell communication between the skeletal and the immune system. Elevated bone mineral density in Sost-knockout (Sost-/-) mice contributes to an altered bone marrow microenvironment and adversely affects B cell development. B cells originate from hematopoietic stem cells within the bone marrow and mature in peripheral lymphoid organs to produce antibodies in response to infection and/or vaccination. In this study, we investigated whether the aberrant B cell development observed in the bone marrow of Sost-/- mice extends to peripheral B cells in the spleen during immune challenge, and if these changes were age-dependent. Concomitant with more severe changes in bone architecture, B cell development in the bone marrow and in the spleen worsened with age in Sost-/- mice. B cell responses to T-independent antigens were enhanced in young Sost-/- mice, whereas responses to T-dependent antigens were impaired. Our results support the hypothesis that the adverse effects of B cell development in the Sost-deficient bone marrow microenvironment extends to the peripheral B cell immune response to protein antigens, and suggest that the B cell response to routine vaccinations should be monitored regularly in patients being treated with sclerostin antibody therapy. In addition, our results open the possibility that Sost regulates the T-independent B cell response, which might be applicable to the improvement of vaccines towards non-protein antigens.

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