657 research outputs found
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The sex-specific effects of diet quality versus quantity on morphology in Drosophila melanogaster
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publication.Variation in the quality and quantity of nutrition is a major contributor to phenotypic variation in animal populations. Although we know much of how dietary restriction impacts phenotype, and of the molecular-genetic and physiological mechanisms that underlie this response, we know much less of the effects of dietary imbalance. Specifically, although dietary imbalance and restriction both reduce overall body size, it is unclear whether both have the same effect on the size of individual traits. Here, we use the fruit fly Drosophila melanogaster to explore the effect of dietary food versus protein-to-carbohydrate ratio on body proportion and trait size. Our results indicate that body proportion and trait size respond differently to changes in diet quantity (food concentration) versus diet quality (protein-to-carbohydrate ratio), and that these effects are sex specific. While these differences suggest that Drosophila use at least partially distinct developmental mechanisms to respond to diet quality versus quantity, further analysis indicates that the responses can be largely explained by the independent and contrasting effects of protein and carbohydrate concentration on trait size. Our data highlight the importance of considering macronutrient composition when elucidating the effect of nutrition on trait size, at the levels of both morphology and developmental physiology.National Science Foundation grants: (IOS-1557638, IOS-0919855); Lake Forest College.info:eu-repo/semantics/publishedVersio
HGF Secreted by Activated Kupffer Cells Induces Apoptosis of Plasmodium-Infected Hepatocytes
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publicationMalaria liver stage infection is an obligatory parasite development step and represents a population bottleneck in Plasmodium infections, providing an advantageous target for blocking parasite cycle progression. Parasite development inside hepatocytes implies a gross cellular insult evoking innate host responses to counteract intra-hepatocytic infection. Using primary hepatocyte cultures, we investigated the role of Kupffer cell-derived hepatocyte growth factor (HGF) in malaria liver stage infection. We found that Kupffer cells from Plasmodium-infected livers produced high levels of HGF, which trigger apoptosis of infected hepatocytes through a mitochondrial-independent apoptosis pathway. HGF action in infected hepatocyte primary cultures results in a potent reduction of parasite yield by specifically sensitizing hepatocytes carrying established parasite exo-erythrocytic forms to undergo apoptosis. This apoptosis mechanism is distinct from cell death that is spontaneously induced in infected cultures and is governed by Fas signaling modulation through a mitochondrial-dependent apoptosis pathway. This work indicates that HGF and Fas signaling pathways are part of an orchestrated host apoptosis response that occurs during malaria liver stage infection, decreasing the success of infection of individual hepatocytes. Our results raise the hypothesis that paracrine signals derived from Kupffer cell activation are implicated in directing death of hepatocytes infected with the malaria parasite.info:eu-repo/semantics/publishedVersio
Multidrug-resistant bacteria compensate for the epistasis between resistances
Full text linkMutations conferring resistance to antibiotics are typically costly in the absence of the drug, but bacteria can reduce this cost by acquiring compensatory mutations. Thus, the rate of acquisition of compensatory mutations and their effects are key for the maintenance and dissemination of antibiotic resistances. While compensation for single resistances has been extensively studied, compensatory evolution of multiresistant bacteria remains unexplored. Importantly, since resistance mutations often interact epistatically, compensation of multiresistant bacteria may significantly differ from that of single-resistant strains. We used experimental evolution, next-generation sequencing, in silico simulations, and genome editing to compare the compensatory process of a streptomycin and rifampicin double-resistant Escherichia coli with those of single-resistant clones. We demonstrate that low-fitness double-resistant bacteria compensate faster than single-resistant strains due to the acquisition of compensatory mutations with larger effects. Strikingly, we identified mutations that only compensate for double resistance, being neutral or deleterious in sensitive or single-resistant backgrounds. Moreover, we show that their beneficial effects strongly decrease or disappear in conditions where the epistatic interaction between resistance alleles is absent, demonstrating that these mutations compensate for the epistasis. In summary, our data indicate that epistatic interactions between antibiotic resistances, leading to large fitness costs, possibly open alternative paths for rapid compensatory evolution, thereby potentially stabilizing costly multiple resistances in bacterial populations.Fundação para a Ciência e a Tecnologia, European Research Council.info:eu-repo/semantics/publishedVersio
IL-22 controls iron-dependent nutritional immunity against systemic bacterial infections
Full text linkThis publication hasn't any creative commons license associated.This publication has a exclusive licensee of the American Association for the Advancement of Science.The deposited article contains attached the supplementary materials.Host immunity limits iron availability to pathogenic bacteria, but whether immunity limits pathogenic bacteria from accessing host heme, the major source of iron in the body, remains unclear. Using Citrobacter rodentium, a mouse enteric pathogen and Escherichia coli, a major cause of sepsis in humans as models, we find that interleukin-22, a cytokine best known for its ability to promote epithelial barrier function, also suppresses the systemic growth of bacteria by limiting iron availability to the pathogen. Using an unbiased proteomic approach to understand the mechanistic basis of IL-22 dependent iron retention in the host, we have identified that IL-22 induces the production of the plasma hemoglobin scavenger haptoglobin and heme scavenger hemopexin. Moreover, the anti-microbial effect of IL-22 depends on the induction of hemopexin expression, while haptogloblin is dispensable. Impaired pathogen clearance in infected Il22(-/-) mice was restored by administration and hemopexin-deficient mice had increased pathogen loads after infection. These studies reveal a previously unrecognized host defense mechanism regulated by IL-22 that relies on the induction of hemopexin to limit heme availability to bacteria leading to suppression of bacterial growth during systemic infections.Japan Society for the Promotion of Science fellowship; Kanae Foundation for the Promotion of Medical Science; Mishima Kaiun Memorial Foundation; Consejo Nacional de Ciencia y Tecnología of Mexico post-doctoral fellowship: (454848); NIH grants: (DK091191, DK095782); Fundação Calouste Gulbenkian;info:eu-repo/semantics/publishedVersio
Myocardial aging as a T-cell–mediated phenomenon
Full text linkIn recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissue-resident leukocytes and with an accumulation of activated CD4+ Foxp3- (forkhead box P3) IFN-γ+ T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population.info:eu-repo/semantics/publishedVersio
The regulator LdhR and the d-lactate dehydrogenase LdhA of Burkholderia multivorans play a role in carbon overflow and in planktonic cellular aggregates formation
Full text linkThis paper version is the accepted manuscript posted online 21 July 2017. It has peer-review. This publication hasn't any creative commons license associated. The deposited article version contains attached the supplementary materials within the pdf.LysR-type transcriptional regulators (LTTR) are the most commonly found regulators in Burkholderia cepacia complex, comprising opportunistic pathogens causing chronic respiratory infections in cystic fibrosis (CF) patients. Despite LTTRs being global regulators of pathogenicity in several bacteria, few have been characterized in Burkholderia Here, we showed that gene ldhR of B. multivorans encoding a LTTR is co-transcribed with ldhA encoding a d-lactate dehydrogenase, and evaluate their implication in virulence traits like exopolysaccharide (EPS) synthesis and biofilm formation. Comparison of wild-type (WT) and its isogenic ΔldhR mutant grown in medium with 2% d-glucose revealed a negative impact on EPS biosynthesis and on cells' viability in the presence of LdhR. Loss of viability in WT cells was caused by intracellular acidification as consequence of cumulative organic acids secretion including d-lactate, this last one absent from the ΔldhR mutant supernatant. Furthermore, LdhR is implicated in the formation of planktonic cellular aggregates. WT cell aggregates reached 1000 μm after 24 hours in liquid cultures; in contrast to ΔldhR mutant aggregates that never grew more than 60 μm. Overexpression of d-lactate dehydrogenase LdhA in the ΔldhR mutant partially restored formed aggregates size, suggesting a role for fermentation inside aggregates. Similar results were obtained for surface-attached biofilms, with WT cells producing more biofilm. A systematic evaluation of planktonic aggregates in Burkholderia CF clinical isolates showed aggregates in 40 out of 74. As CF patients' lung environment is microaerophilic and bacteria are found as free aggregates/biofilms, LdhR and LdhA might have central roles in adaptation to this environment.IMPORTANCE Cystic fibrosis patients often suffer from chronic respiratory infections caused by several microorganisms. Among them are the Burkholderia cepacia complex bacteria which cause progressive deterioration of lung function and, in some patients, might develop into fatal necrotizing pneumoniae with bacteremia, known as "cepacia syndrome". Burkholderia pathogenesis is multifactorial since they express several virulence factors, form biofilms, and are highly resistant to antimicrobial compounds, making their eradication from the CF patients' airways very difficult. As Burkholderia is commonly found in the CF lungs in the form of cell aggregates and biofilms, the need to investigate the mechanisms of cellular aggregation is obvious. In this study we demonstrate the importance of a d-lactate dehydrogenase and a regulator, in regulating carbon overflow, cellular aggregates and surface-attached biofilm formation. This not only enhances our understanding of Burkholderia pathogenesis, but can also lead to the development of drugs against these proteins to circumvent biofilm formation.Instituto Gulbenkian de Ciência (Gene Expression Unit); Programa Operacional 833 Regional de Lisboa 2020 grant: (LISBOA-01-0145-FEDER-007317); Fundação para a Ciência e a Tecnologia grants: (PTDC/QUI-BIQ/118260/2010, UID/BIO/04565/2013, SFRH/BPD/86475/2012).info:eu-repo/semantics/acceptedVersio
Heterologous expression of the yeast Tpo1p or Pdr5p membrane transporters in Arabidopsis confers plant xenobiotic tolerance
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publication.Soil contamination is a major hindrance for plant growth and development. The lack of effective strategies to remove chemicals released into the environment has raised the need to increase plant resilience to soil pollutants. Here, we investigated the ability of two Saccharomyces cerevisiae plasma-membrane transporters, the Major Facilitator Superfamily (MFS) member Tpo1p and the ATP-Binding Cassette (ABC) protein Pdr5p, to confer Multiple Drug Resistance (MDR) in Arabidopsis thaliana. Transgenic plants expressing either of the yeast transporters were undistinguishable from the wild type under control conditions, but displayed tolerance when challenged with the herbicides 2,4-D and barban. Plants expressing ScTPO1 were also more resistant to the herbicides alachlor and metolachlor as well as to the fungicide mancozeb and the Co(2+), Cu(2+), Ni(2+), Al(3+) and Cd(2+) cations, while ScPDR5-expressing plants exhibited tolerance to cycloheximide. Yeast mutants lacking Tpo1p or Pdr5p showed increased sensitivity to most of the agents tested in plants. Our results demonstrate that the S. cerevisiae Tpo1p and Pdr5p transporters are able to mediate resistance to a broad range of compounds of agricultural interest in yeast as well as in Arabidopsis, underscoring their potential in future biotechnological applications.Fundação para a Ciência e a Tecnologia grants: (EXPL/AGR-PRO/1013/2013, PTDC/BIA-PLA/1084/2014, SFRH/BPD/44640/2008, SFRH/BPD/81221/2011, PD/BD/105735/2014, PD/00133/2012, SFRH/BD/92552/2013, UID/BIO/04565/2013, UID/Multi/04551/2013). Programa Operacional Regional de Lisboa 2020 grant: (Project N. 007317).info:eu-repo/semantics/publishedVersio
KIF13A mediates influenza a virus ribonucleoproteins trafficking
Full text linkThe deposited article version contains attached the supplementary materials within the pdf. This publication hasn't any creative commons license associated. The deposited article version is a "JCS Advance Online Article" provided by The Company of Biologists, and it is the "Accepted manuscript" posted online on 23 October 2017.Influenza A is a rapid evolving virus, successful in provoking periodic epidemics and occasional pandemics in humans. Viral assembly is complex as the virus incorporates an eight-partite segmented genome of RNA (in the form of viral ribonucleoproteins, vRNPs). Genome assembly, with implications to public health, is not completely understood. It was reported that vRNPs are transported to the cell surface on Rab11 vesicles using microtubules, but no molecular motor has been assigned to the process. Here, we have identified KIF13A, a member of the kinesin-3 family, as the first molecular motor efficiently transporting vRNP-Rab11 vesicles during IAV infection. Depletion of KIF13A resulted in reduced viral titres and less accumulation of vRNPs at the cell surface, without interfering with the levels of other viral proteins at sites of viral assembly. In addition, in overexpression conditions and using two artificial methods able to displace vRNP-Rab11 vesicles, KIF13A augmented vRNP levels at the plasma membrane. Together our results show that KIF13A is an important host factor promoting influenza A vRNP transport, which is a crucial step for viral assembly.Fundação para a Ciência e a Tecnologia grants: (PTDC/IMI-MIC/1142/2012, IF/00899/2013, SFRH/BPD/62982/2009, SFRH/BPD/94204/2013); Instituto Calouste Gulbenkian; Fundação Calouste Gulbenkian; Fondation pour la Recherche Médicale grant: (Equipe FRM DEQ20140329491 Team label); Fondation ARC pour la Recherche sur le Cancer grant: (PJA20161204965); CNRS; INSERM; Institut Curie.info:eu-repo/semantics/acceptedVersio
A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly
Full text linkThe deposited article is a post-print version and has peer review. The deposited article version contains attached the supplementary materials within the pdf. This publication hasn't any creative commons license associated.Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell-cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, that mediated specific inhibitory phosphorylation. Simultaneous expression of mutant proteins lacking these residues results in complete uncoupling from the cell cycle. Consequently, CENP-A assembly is fully recapitulated under high Cdk activities, indistinguishable from G1 assembly. We find that Cdk-mediated inhibition is exerted by sequestering active factors away from the centromere. Finally, we show that displacement of M18BP1 from the centromere is critical for the assembly mechanism of CENP-A.Fundação para a Ciência e a Tecnologia grants: (SFRH/BD/51878/2012, SFRH/BD/74284/2010, BIA-BCM/100557/2008); NIH/National Institute of General Medical Sciences grants: (R01-GM082989; T32-GM008275); NIH/NCI grant: (F30-CA186430); NIH grants (GM 037537, GM 110174); EMBO installation grant: (1818); ERC-consolidator grant: (ERC-2013-CoG-615638).info:eu-repo/semantics/publishedVersio
A systematic review of East African-Indian family of Mycobacterium tuberculosis in Brazil
No full textThis deposit is composed by a publication in which the IGC's authors have had the role of collaboration (it's a collaboration publication). This type of deposit in ARCA is in restrictedAccess (it can't be in open access to the public), and can only be accessed by two ways: either by requesting a legal copy from the author (the email contact present in this deposit) or by visiting the following link: https://www.sciencedirect.com/science/article/pii/S1413867016305475?via%3DihubFurther funders are not indicated in the document.The Mycobacterium tuberculosis East African-Indian (EAI) spoligotyping family (belonging to lineage 1, Indo-Oceanic, defined by the region of deletion RD239) is distributed worldwide, but is more prevalent in Southeast Asia, India, and East Africa. Studies in Latin America have rarely identified EAI. In this study, we describe the occurrence of the EAI family in Brazil.Conselho Nacional de Desenvolvimento Científico e Tecnológico grant: (Edital MCT-CNPq/MS-SCTIE-DECIT – N° 25/2006)info:eu-repo/semantics/publishedVersio