bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coexistence withPseudomonas aeruginosaaltersStaphylococcus aureustranscriptome, antibiotic resistance and internalization into epithelial cells
Authors: Briaud Paul , Camus Laura , Bastien Sylvère , Doléans-Jordheim Anne , Vandenesch François , Moreau Karen 
Published: September 2019

ABSTRACTCystic fibrosis (CF) is the most common life-threatening genetic disease among Caucasians. CF patients suffer from chronic lung infections due to the presence of thick mucus, caused bycftrgene dysfunction. The two most commonly found bacteria in the mucus of CF patients areStaphylococcus aureusandPseudomonas aeruginosa. It is well known that early-infectingP. aeruginosastrains produce anti-staphylococcal compounds and inhibitS. aureusgrowth. More recently, it has been shown that late-infectingP. aeruginosastrains develop commensal-like/coexistence interaction withS. aureus. The aim of this study was to decipher the impact ofP. aeruginosastrains onS. aureus. RNA sequencing analysis showed 77 genes were specifically dysregulated in the context of competition and 140 genes in the context of coexistence in the presence ofP. aeruginosa. In coexistence, genes encoding virulence factors and proteins involved in carbohydrates, lipids, nucleotides and amino acids metabolism were downregulated. On the contrary, several transporter family encoding genes were upregulated. In particular, several antibiotic pumps belonging to the Nor family were upregulated:tet38,norAandnorC, leading to an increase in antibiotic resistance ofS. aureuswhen exposed to tetracycline and ciprofloxacin and an enhanced internalization rate within epithelial pulmonary cells. This study shows that coexistence withP. aeruginosaaffects theS. aureustranscriptome and virulence.
A histone methyltransferase inhibitor can reverse epigenetically acquired drug resistance in the malaria parasitePlasmodium falciparum
Authors: Chan Amanda , Dziedziech Alexis , Kirkman Laura A , Deitsch Kirk W , Ankarklev Johan 
Published: September 2019

AbstractMalaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencingclag3gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in bothclag3gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance inP. falciparum.ImportanceDrug resistance is a major concern for the treatment of infectious diseases throughout the world. For malaria, a novel mechanism of resistance was recently described in which epigenetic modifications led to a resistance phenotype that is rapidly reversible, thus reducing the fitness cost that is often associated with genetic mutations that lead to resistance. The possibility of this type of resistance arising in a natural setting is particularly troubling since parasites could rapidly switch to and from a resistant phenotype, thus making it especially difficult to combat. Here we show that application of a histone methyltransferase inhibitor can rapidly reverse the epigenetic changes that lead to drug resistance, thereby causing parasites to revert to a drug sensitive phenotype. This is a novel application of drugs that target epigenetic modifiers and lends additional support for ongoing efforts to develop drugs against malaria that target the histone modifiers of the parasite.
Chagas disease awareness and socioeconomic characteristics of Bolivian immigrants living in São Paulo, Brazil
Authors: da Silva Rubens Antonio , Wanderley Dalva Marli Valério , Forsyth Colin , Leite Ruth Moreira , de Albuquerque Luna Expedito José , Júnior Nivaldo Carneiro , Shikanai-Yasuda Maria Aparecida ,   Grupo de Pesquisa em Doença de Chagas: atenção primária e imigração (Chagas Disease Research Group: Primary Care and Immigration)
Published: September 2019

AbstractIn this study, part of a research project on Chagas disease among residents of Bolivia in São Paulo, we describe socioeconomic characteristics, knowledge about the disease and access to health services. A structured questionnaire was applied to a sample of 472 Bolivian adults (> 18 years) living in São Paulo enrolled in the Barra Funda School Health Center. The median age of participants was 28.5 years, 75.0% from the Bolivian department of La Paz, who were living in São Paulo for an average of 5.8 years. Regarding knowledge about the disease and exposure to certain risk factors, 47.7% indicated familiarity with the vector, 23.9% had seen vinchuca in their homes in Bolivia and 6.4% reported having been bitten by a triatomine. The conditions of living in rural areas in Bolivia or in other department than La Paz, have a relative with illness, high school graduation and have seen or been bitten by a vinchuca were significantly associated with the knowledge of the vector. This study provides a view on migration that has important implications for the distribution of Chagas’ disease and access to health care by providing subsidies for proposing public health policies.Author summaryThis article expresses part of the results of a research project called “Chagas disease in a population of Bolivian immigrants in São Paulo: an analysis of the prevalence ofTrypanosoma cruziinfection and morbidity of Chagas disease, knowledge of the population about the disease and access to different levels of health care”. The problem of chronic Chagas disease occurs in many countries, including those not considered endemic, as a result of population movements, mainly by immigration due to urbanization which has led to its globalization. It is now considered an emerging disease with significant potential for transmission via blood transfusions, organ transplants and congenital via, in the absence of appropriate strategies in terms of public health, as well as reactivation of chronic disease in urban centers. It’s no different this phenomenon to the city of Sao Paulo. This study analyzed the sociodemographic inserts, labor, migration and knowledge about Chagas disease and its impact on personal, family and professional life of Bolivian immigrants living in São Paulo.
Is Mycetoma a Vector-Borne Disease: The First Report on the Detection of Madurella mycetomatis in Ticks
Authors: Azrag RS , Bakhiet SM , Almalik AM , Mohamed AH , Fahal AH 
Published: September 2019

AbstractCurrently, there is a massive gap the mycetoma knowledge in particular in its epidemiological characteristics, the infection route, the predisposing factors and the host susceptibility. With this background, the present cross-sectional descriptive entomological study was conducted to determine the possible role of arthropod vectors in the transmission of eumycetoma as well as the knowledge, attitude and practice (KAP) among the villagers towards that in a mycetoma endemic village at Sennar State, Sudan.The study showed an abundance of indoors and outdoors arthropod vectors, and that included ticks, mosquitoes, sandflies, cockroaches and houseflies in the studied area. Ticks were more frequent, and they belonged to three genera and four species, and the later included Hyalomma (H.) anatolicum (11.03%), Hyalomma (H.) rufipes (0.67%), Rhipicephalus (R.) everts (73.1%) and Amblyoma (A.) lepidium (15.2%). The different types of the collected arthropod vectors were pooled in groups, and each group was screened for the presence of the Madurella (M.) mycetomatis DNA, the most frequent causative agents of eumycetoma in the studied area. The DNA was extracted, and amplification of the genomic rRNA genes was done by using universal pan fungal primers and specific M. mycetomatis primers. One pool containing R. evertsi DNA samples and one sample of H. Rufipes DNA gave positive results following PCR amplification of the universal fungal positive primers while H. rufipes sample gave positive results for M. mycetomatis using a specific primer. An association between the animals’ dungs, ticks and mycetoma transmission can be suggested from this study. However, further in-depth studies are needed to verify that.Author summaryMycetoma is a severely neglected tropical disease characterised by painless subcutaneous tumour-like swellings frequently noted in the extremities. There is a massive knowledge gap in transmission, infection route, and historically, it is believed to be associated with minor trauma caused by thorn pricks. This study was designed to determine the possible role of arthropods in mycetoma transmission in an endemic area in Sudan during the cold dry season. Pools of medically important arthropods were screened for mycetoma causative agents using DNA based method. The villagers’ habits and knowledge on arthropod vectors were examined using a pre-designed questionnaire. The results showed various presences of many arthropod vectors. Ticks were found in high prevalence, and densities in domestic animals found inside houses and the villagers had high contact level with the ticks in comparison to other vectors. The study reports for the first time, the detection of the causative agents of mycetoma in a pool of ticks. More studies on the possible role of ticks in the transmission of mycetoma diseases are badly needed to delineate the possible role of ticks on transmission of mycetoma.
Mechano-responsiveness of fibrillar adhesions on stiffness-gradient gels
Authors: Barber-Pérez Nuria , Georgiadou Maria , Guzmán Camilo , Isomursu Aleksi , Hamidi Hellyeh , Ivaska Johanna 
Published: September 2019

AbstractFibrillar adhesions are important structural and adhesive components in fibroblasts that are critical for fibronectin fibrillogenesis. While nascent and focal adhesions are known to respond to mechanical cues, the mechanoresponsive nature of fibrillar adhesions remains unclear. Here, we used ratiometric analysis of paired adhesion components to determine an appropriate fibrillar adhesion marker. We found that active α5β1-integrin exhibits the most definitive fibrillar adhesion localisation compared to other proteins, such as tensin-1, reported to be in fibrillar adhesions. To elucidate the mechanoresponsiveness of fibrillar adhesions, we designed and fabricated thin polyacrylamide (PA) hydrogels, embedded with fluorescently labelled beads, with physiologically relevant stiffness gradients using a cost-effective and reproducible technique. We generated a correlation curve between bead density and hydrogel stiffness, thus allowing the use of bead density as a readout of stiffness, eliminating the need for specialised knowhow including atomic force microscopy (AFM). We find that stiffness promotes the growth of fibrillar adhesions in a tensin-dependent manner. Thus, the formation of these extracellular matrix-depositing structures is coupled to the mechanical parameters of the cell environment and may enable cells to fine-tune their matrix environment in response to alternating physical conditions.
Dynamic analysis of pulsed cisplatin identifies effectors of resistance in lung adenocarcinoma
Authors: Hastings Jordan F. , Gonzalez-Rajal Alvaro , Han Jeremy Z.R. , McCloy Rachael A. , O’Donnell Yolande E.I. , Phimmachanh Monica , Murphy Alexander D. , Nagrial Adnan , Daneshvar Dariush , Chin Venessa , Watkins D. Neil , Burgess Andrew , Croucher David R. 
Published: September 2019

AbstractIdentification of clinically viable strategies for overcoming resistance to platinum chemotherapy in lung adenocarcinoma has been hampered by inappropriately tailoredin vitroassays of drug response. Therefore, using a pulse model that closely recapitulates thein vivopharmacokinetics of platinum therapy, we profiled cisplatin-induced signalling, DNA damage and apoptotic responses across a panel of lung adenocarcinoma cell lines. By coupling this data with real-time, single cell imaging of cell cycle and apoptosis, we show thatTP53mutation status influenced the mode of cisplatin induced cell cycle arrest, but could not predict cisplatin sensitivity. In contrast, P70S6K-mediated signalling promoted resistance by increasing p53/p63 and p21 expression, reducing double-stranded DNA breaks and apoptosis. Targeting P70S6K sensitised bothTP53wildtype and null lines to cisplatin, but notTP53mutant lines. In summary, usingin vitroassays that mimicin vivopharmacokinetics identified P70S6K as a robust mediator of cisplatin resistance and highlighted the importance of considering somatic mutation status when designing patient-specific combination therapies.
DJ-1 (Park7) affects the gut microbiome, metabolites and development of Innate Lymphoid cells (ILCs)
Authors: Singh Yogesh , Trautwein Christoph , Dhariwal Achal , Salker Madhuri S , Alauddin Mohammed , Zigmare Laimdota , Pelzl Lisan , Feger Martina , Matthes Jakob , Casadei Nicolas , Föller Michael , Pachauri Vivek , Park David S , Mak Tak W , Frick Julia S , Wallwiener Diethelm , Brucker Sara Y , Lang Florian , Riess Olaf 
Published: September 2019

AbstractThe proper communication between gut and brain is pivotal for maintenance of health and dysregulation of the gut-brain axis can lead to several clinical disorders. Also, in Parkinson’s disease (PD) 85% of all patients experienced constipation long before showing any signs of motor phenotypes. For differential diagnosis and when it comes to preventive treatment there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperon protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 modifies the PD risk remains incompletely understood. In the present study we provide evidence that DJ-1 is implicated in shaping the gut microbiome including their metabolite production or innate immune cells (ILCs) development. We revealed that in 4 months old mice genetic deficiency of DJ-1 leads to significantly decrease in several bacterial genera and significantly increase in two specific genera, namelyAlistipesandRikenella. DJ-1 deficient mice have a higher production of calprotectin/MCP-1 inflammatory protein - a known protein involved in colonic inflammation – and significantly higher expression of glial fibrillary acidic protein (GFAP) than control littermates. Expression of a-Synuclein, a key protein in Lewy bodies, in the colon was not significantly different between genotypes. Metabolic profiles of feces extracts analysed by H1-NMR spectroscopy showed increased short chain fatty acids (SCFAs) and decreased amino acid levels, suggesting a general switch from protein towards fibre degrading strains in DJ-1 deficient mice. We observed that Malonate - which is known to influence the immune system – has significantly higher concentrations in DJ-1 deficient mice. Moreover, DJ-1 deficient mice have high levels of the phenol derivate 3-(3-Hydroxyphenyl) propanoic acid (3-HPPA) which is a breakdown product of aromatic substrates like tyrosine, phenylalanine and polyphenols. DJ-1 deficient mice also showed significantly reduced percentage of ILCs. Thus, our data suggests that absence of DJ-1 leads to increase in gut inflammatory bacteria composition, deregulated metabolites and dysregulated innate immunity which could be a key factor in the initiation of PD disease in the gut, and potentially also in brain during disease progression.
OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis
Authors: Verboom Lien , Martens Arne , Priem Dario , Hoste Esther , Sze Mozes , Vikkula Hanna , Voet Sofie , Bongiovanni Laura , de Bruin Alain , Scott Charlotte L. , Pasparakis Manolis , Bertrand Mathieu JM , van Loo Geert 
Published: September 2019

AbstractInflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of inflammatory pathologies. OTULIN is a deubiquitinating enzyme that specifically cleaves linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC), and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. OTULIN was shown to negatively control NF-κB signaling in response to various stimuli, but also to protect cells from tumor necrosis factor (TNF)-induced apoptosis. To investigate the importance of OTULIN in liver homeostasis and pathology, we developed a novel mouse line specifically lacking OTULIN in liver parenchymal cells. These mice spontaneously develop a severe liver disease, characterized by liver inflammation, hepatocyte apoptosis and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues the severe liver pathology, and knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects from developing liver disease, demonstrating that death receptor-mediated apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease pathogenesis in hepatocyte-specific OTULIN deficient mice. Together, our study reveals the critical importance of OTULIN in protecting hepatocytes from death, and thereby avoid development of chronic liver inflammation and HCC in mice.
Disrupted gene networks in subfertile hybrid house mice
Authors: Morgan Katy , Harr Bettina , White Michael A. , Payseur Bret A. , Turner Leslie M. 
Published: September 2019

AbstractThe Dobzhansky-Muller model provides a widely accepted mechanism for the evolution of reproductive isolation: incompatible substitutions disrupt interactions between genes. To date, few candidate incompatibility genes have been identified, leaving the genes driving speciation mostly uncharacterized. The importance of interactions in the Dobzhansky-Muller model suggests that gene coexpression networks provide a powerful framework to understand disrupted pathways associated with postzygotic isolation. Here, we perform Weighted Gene Coexpression Network Analysis (WGCNA) to infer gene interactions in hybrids of two recently diverged European house mouse subspecies, Mus mus domesticus and M. m. musculus, which commonly show hybrid male sterility or subfertility. We use genome-wide testis expression data from 467 hybrid mice from two mapping populations: F2s from a laboratory cross between wild-derived pure subspecies strains and offspring of natural hybrids captured in the Central Europe hybrid zone. This large data set enabled us to build a robust consensus network using hybrid males with fertile phenotypes. We identify several expression modules, or groups of coexpressed genes, that are disrupted in subfertile hybrids, including modules functionally enriched for spermatogenesis, cilium and sperm flagellum organization, chromosome organization and DNA repair, and including genes expressed in spermatogonia, spermatocytes and spermatids. Our network-based approach enabled us to hone in on specific hub genes likely to be influencing module-wide gene expression and hence potentially driving Dobzhansky-Muller incompatibilities. A total of 69 (24.6%) of these genes lie in sterility loci identified previously in these mapping populations, and represent promising candidate barrier genes and targets for future functional analysis.
Free fatty acid receptor 4 is a nutrient sensor that resolves inflammation to maintain cardiac homeostasis
Authors: Murphy Katherine A. , Harsch Brian A. , Healy Chastity L. , Joshi Sonal S. , Huang Shue , Walker Rachel E. , Wagner Brandon M. , Ernste Katherine M. , Huang Wei , Block Robert , Wright Casey D. , Tintle Nathan , Jensen Brian C. , Shearer Gregory C , O’Connell Timothy D. 
Published: September 2019

AbstractBackgroundNon-­resolving activation of immune responses is central to the pathogenesis of heart failure (HF). Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor (GPR) for medium-and long-chain fatty acids (FA) that regulates metabolism and attenuates inflammation in diabetes and obesity. Here, we tested the hypothesis that Ffar4 functions as a cardioprotective nutrient sensor that resolves inflammation to maintain cardiac homeostasis.MethodsMice with systemic deletion of Ffar4 (Ffar4KO) were subjected to pressure overload by transverse aortic constriction (TAC). Transcriptome analysis of cardiac myocytes was performed three days post-TAC. Additionally, Ffar4-mediated effects on inflammatory oxylipin production in cardiac myocytes and oxylipin composition in plasma lipoproteins were evaluated.ResultsIn Ffar4KO mice, TAC induced more severe remodeling, identifying an entirely novel cardioprotective role for Ffar4 in the heart. Transcriptome analysis 3-days post-TAC indicated a failure to induce cell death and inflammatory genes in Ffar4KO cardiac myocytes, as well as a specific failure to induce cytoplasmic phospholipase A2α (cPLA2α) signaling genes. In cardiac myocytes, Ffar4 signaling through cPLA2α-cytochrome p450 ω/ω-1 hydroxylase induced production of the EPA-derived anti-inflammatory oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Systemically, loss of Ffar4 altered oxylipin content in circulating plasma lipoproteins consistent with a loss of anti-inflammatory oxylipins at baseline, and inability to produce both pro-inflammatory and pro-resolving oxylipins following TAC. Finally, we confirmed that Ffar4 is expressed in human heart and down-regulated in HF.ConclusionsOur results identify a novel function for Ffar4 in the heart as a FA nutrient sensor that resolves inflammation to maintain cardiac homeostasis.