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SNP typing reveals similarity in Mycobacterium tuberculosis genetic diversity between Portugal and Northeast Brazil
No full textThis deposit is composed by the main article plus the supplementary materials of the publication.Human tuberculosis is an infectious disease caused by bacteria from the Mycobacterium tuberculosis complex (MTBC). Although spoligotyping and MIRU-VNTR are standard methodologies in MTBC genetic epidemiology, recent studies suggest that Single Nucleotide Polymorphisms (SNP) are advantageous in phylogenetics and strain group/lineages identification. In this work we use a set of 79 SNPs to characterize 1987 MTBC isolates from Portugal and 141 from Northeast Brazil. All Brazilian samples were further characterized using spolygotyping. Phylogenetic analysis against a reference set revealed that about 95% of the isolates in both populations are singly attributed to bacterial lineage 4. Within this lineage, the most frequent strain groups in both Portugal and Brazil are LAM, followed by Haarlem and X. Contrary to these groups, strain group T showed a very different prevalence between Portugal (10%) and Brazil (1.5%). Spoligotype identification shows about 10% of mis-matches compared to the use of SNPs and a little more than 1% of strains unidentifiability. The mis-matches are observed in the most represented groups of our sample set (i.e., LAM and Haarlem) in almost the same proportion. Besides being more accurate in identifying strain groups/lineages, SNP-typing can also provide phylogenetic relationships between strain groups/lineages and, thus, indicate cases showing phylogenetic incongruence. Overall, the use of SNP-typing revealed striking similarities between MTBC populations from Portugal and Brazil.FCT; National Counsel of Technological and Scientific Development (CNPQ) project number: (410498/2006-8); Coordination of Improvement of Higher Education Personnel (CAPES) project number: (23038.005107/2011-83)
THE OPPORTUNITY FOR BALANCING SELECTION IN EXPERIMENTAL POPULATIONS OFCAENORHABDITIS ELEGANS
Get PDFThe deposited article is a Post-print version and has been submitted to peer reviewing. This publication hasn't any creative commons license associated. This deposit is composed by the main article plus the supplementary materials of the publication.The role of balancing selection in maintaining diversity during the evolution of sexual populations to novel environments is poorly understood. To address this issue, we studied the impact of two mating systems, androdioecy and dioecy, on genotype distributions during the experimental evolution of Caenorhabditis elegans. We analyzed the temporal trajectories of 334 single nucleotide polymorphisms, covering 1/3 of the genome, and found extensive allele frequency changes and little loss of heterozygosities after 100 generations. As modeled with numerical simulations, SNP differentiation was consistent with genetic drift and average fitness effects of 2%, assuming that selection acted independently at each locus. Remarkably, inbreeding by self-fertilization was of little consequence to SNP differentiation. Modeling selection on deleterious recessive alleles suggests that the initial evolutionary dynamics can be explained by associative overdominance, but not the later stages because much lower heterozygosities would be maintained during experimental evolution. By contrast, models with selection on true overdominant loci can explain the heterozygote excess observed at all periods, particularly when negative epistasis or independent fitness effects were considered. Overall, these findings indicate that selection at single loci, including purging of recessive alleles, underlies most of the genetic differentiation accomplished during the experiment. Nonetheless, they also imply that maintenance of genetic diversity may in large part be due to balancing selection at multiple loci.European Research Council grant: (stERC/2009-243285).info:eu-repo/semantics/publishedVersio
Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant
Get PDFThe deposited article is a post-print version and has peer review. This deposit is composed by the main article, and it hasn't any supplementary materials associated. There is no public supplementary material available.The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres.Wellcome Trust grants: ( 073915, 095021, 077707, 092076); NIH grants: (R01-GM082989, R37 GM32238, GM088313, GM074150, R01GM088371, 5R01GM61169, GM083988, R01GM088716, R37GM024364, R01GM074728, R01 GM063045, R01 GM098500, GM059618, GM69429, GM083988, Core Grant CA06927); Government of Japan- Funding Program for Next Generation World-Leading Researchers grant: (LS122); EMBO Installation Grant; ERC grants: (241548 [MitoSys], 258068 [Systems Microscopy], 281198, BioSynCen, KINSIGN, PRECISE); Cancer Research UK; NIH/NIGMS grant: (R01-50412, R01-50412); Oklahoma Center for Advancement of Science and Technology; McCasland Foundation; Japanese Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science and Technology in Japan (MEXT); FCT grants: (BIA-BCM/100557/2008, BIAPRO/100537/2008, PTDC/SAU-GMG/099704/2008, PTDC/SAU-ONC/112917/2009, COMPETE-FEDER, ON2); Netherlands Organisation for Scientific Research grants: (NWO-Vici-016.130.661, NWO-Vici-91812610); Dutch Cancer Society grants: (UU2009-4311, UU2011-5134); Spanish Ministry of Economy grants: (CSD2007-015, SAF2010-25157); EU grant: (Marie Curie ITN “Nucleosome 4D”); BBSRC grant: (BB/I021353/1, BB/H013024); Kazusa DNA Research Institute Foundation; CCSRI grant: (700824), NSF grant: (award number 1024973); Swiss National Foundation; University of Geneva; Foundation Louis-Jeantet; March of Dimes grant: (6-FY10-294); Science Foundation Ireland grant: (12/IA/1370); Commonwealth of Pennsylvania.info:eu-repo/semantics/publishedVersio
Human Cytomegalovirus Gene UL76 Induces IL-8 Expression through Activation of the DNA Damage Response
Get PDFHuman cytomegalovirus (HCMV), a β-herpesvirus, has evolved many strategies to subvert both innate and adaptive host immunity in order to ensure its survival and propagation within the host. Induction of IL-8 is particularly important during HCMV infection as neutrophils, primarily attracted by IL-8, play a key role in virus dissemination. Moreover, IL-8 has a positive effect in the replication of HCMV. This work has identified an HCMV gene (UL76), with the relevant property of inducing IL-8 expression at both transcriptional and protein levels. Up-regulation of IL-8 by UL76 results from activation of the NF-kB pathway as inhibition of both IKK-β activity or degradation of Ikβα abolishes the IL-8 induction and, concomitantly, expression of UL76 is associated with the translocation of p65 to the nucleus where it binds to the IL-8 promoter. Furthermore, the UL76-mediated induction of IL-8 requires ATM and is correlated with the phosphorylation of NEMO on serine 85, indicating that UL76 activates NF-kB pathway by the DNA Damage response, similar to the impact of genotoxic drugs. More importantly, a UL76 deletion mutant virus was significantly less efficient in stimulating IL-8 production than the wild type virus. In addition, there was a significant reduction of IL-8 secretion when ATM -/- cells were infected with wild type HCMV, thus, indicating that ATM is also involved in the induction of IL-8 by HCMV. In conclusion, we demonstrate that expression of UL76 gene induces IL-8 expression as a result of the DNA damage response and that both UL76 and ATM have a role in the mechanism of IL-8 induction during HCMV infection. Hence, this work characterizes a new role of the activation of DNA Damage response in the context of host-pathogen interactions.FCT fellowship: (SFRH/BD/27677/2006)
Neurocysticercosis: HP10 antigen detection is useful for the follow-up of the severe patients
Get PDFThe most severe clinical form of neurocysticercosis (NC) occurs when cysticerci are located in the subarachnoid space at the base of the brain (SaB). The diagnosis, monitoring and treatment of NC-SaB, constitutes a severe clinical challenge. Herein we evaluate the potential of the HP10 antigen detection enzyme-linked immunosorbent assay (HP10 Ag-ELISA) in the long term follow-up of NC-SaB cases. Assay performance was compared with that of Magnetic Resonance Imaging (MRI). In addition, the robustness of the HP10 Ag-ELISA was evaluated independently at two different institutions
Amniotic fluid deficiency and congenital abnormalities both influence fluctuating asymmetry in developing limbs of human deceased fetuses
Get PDFFluctuating asymmetry (FA), as an indirect measure of developmental instability (DI), has been intensively studied for associations with stress and fitness. Patterns, however, appear heterogeneous and the underlying causes remain largely unknown. One aspect that has received relatively little attention in the literature is the consequence of direct mechanical effects on asymmetries. The crucial prerequisite for FA to reflect DI is that environmental conditions on both sides should be identical. This condition may be violated during early human development if amniotic fluid volume is deficient, as the resulting mechanical pressures may increase asymmetries. Indeed, we showed that limb bones of deceased human fetuses exhibited increased asymmetry, when there was not sufficient amniotic fluid (and, thus, space) in the uterine cavity. As amniotic fluid deficiency is known to cause substantial asymmetries and abnormal limb development, these subtle asymmetries are probably at least in part caused by the mechanical pressures. On the other hand, deficiencies in amniotic fluid volume are known to be associated with other congenital abnormalities that may disturb DI. More specifically, urogenital abnormalities can directly affect/reduce amniotic fluid volume. We disentangled the direct mechanical effects on FA from the indirect effects of urogenital abnormalities, the latter presumably representing DI. We discovered that both factors contributed significantly to the increase in FA. However, the direct mechanical effect of uterine pressure, albeit statistically significant, appeared less important than the effects of urogenital abnormalities, with an effect size only two-third as large. We, thus, conclude that correcting for the relevant direct factors allowed for a representative test of the association between DI and stress, and confirmed that fetuses form a suitable model system to increase our understanding in patterns of FA and symmetry development.Research Fund of the University of Antwerp, mobility grant from the Research Foundation – Flanders (FWO)
Aurora at the pole and equator: overlapping functions of Aurora kinases in the mitotic spindle
Get PDFThe correct assembly and timely disassembly of the mitotic spindle is crucial for the propagation of the genome during cell division. Aurora kinases play a central role in orchestrating bipolar spindle establishment, chromosome alignment and segregation. In most eukaryotes, ranging from amoebas to humans, Aurora activity appears to be required both at the spindle pole and the kinetochore, and these activities are often split between two different Aurora paralogues, termed Aurora A and B. Polar and equatorial functions of Aurora kinases have generally been considered separately, with Aurora A being mostly involved in centrosome dynamics, whereas Aurora B coordinates kinetochore attachment and cytokinesis. However, double inactivation of both Aurora A and B results in a dramatic synergy that abolishes chromosome segregation. This suggests that these two activities jointly coordinate mitotic progression. Accordingly, recent evidence suggests that Aurora A and B work together in both spindle assembly in metaphase and disassembly in anaphase. Here, we provide an outlook on these shared functions of the Auroras, discuss the evolution of this family of mitotic kinases and speculate why Aurora kinase activity may be required at both ends of the spindle microtubules
Host Adaptation Is Contingent upon the Infection Route Taken by Pathogens
Get PDFEvolution of pathogen virulence is affected by the route of infection. Also, alternate infection routes trigger different physiological responses on hosts, impinging on host adaptation and on its interaction with pathogens. Yet, how route of infection may shape adaptation to pathogens has not received much attention at the experimental level. We addressed this question through the experimental evolution of an outbred Drosophila melanogaster population infected by two different routes (oral and systemic) with Pseudomonas entomophila. The two selection regimes led to markedly different evolutionary trajectories. Adaptation to infection through one route did not protect from infection through the alternate route, indicating distinct genetic bases. Finally, relatively to the control population, evolved flies were not more resistant to bacteria other than Pseudomonas and showed higher susceptibility to viral infections. These specificities and trade-offs may contribute to the maintenance of genetic variation for resistance in natural populations. Our data shows that the infection route affects host adaptation and thus, must be considered in studies of host-pathogen interaction.FCT fellowships: (#SFRH/BPD/62964/2009, #SFRH/BD/82299/2011), Instituto Gulbenkian de Ciência/Fundação Calouste Gulbenkian
MAPfastR: Quantitative Trait Loci Mapping in Outbred Line Crosses
Get PDFMAPfastR is a software package developed to analyze quantitative trait loci data from inbred and outbred line-crosses. The package includes a number of modules for fast and accurate quantitative trait loci analyses. It has been developed in the R language for fast and comprehensive analyses of large datasets. MAPfastR is freely available at: http://www.computationalgenetics.se/?page_id=7.Swedish Foundation for Strategic Research (Future Research Leader program), European Science Foundation (EURYI Award)
Atherogenesis May Involve the Prooxidant and Proinflammatory Effects of Ferryl Hemoglobin
Get PDFOxidized cell-free hemoglobin (Hb), including covalently cross-linked Hb multimers, is present in advanced atherosclerotic lesions. Oxidation of Hb produces methemoglobin (Fe(3+)) and ferryl hemoglobin (Fe(4+) = O(2-)). Ferryl iron is unstable and can return to the Fe(3+) state by reacting with specific amino acids of the globin chains. In these reactions globin radicals are produced followed by termination reactions yielding covalently cross-linked Hb multimers. Despite the evanescent nature of the ferryl state, herein we refer to this oxidized Hb as "ferryl Hb." Our aim in this work was to study formation and biological effects of ferrylHb. We demonstrate that ferrylHb, like metHb, can release its heme group, leading to sensitization of endothelial cells (ECs) to oxidant-mediated killing and to oxidation of low-density lipoprotein (LDL). Furthermore, we observed that both oxidized LDL and lipids derived from human atherosclerotic lesions trigger Hb oxidation and subsequent production of covalently cross-linked ferrylHb multimers. Previously we showed that ferrylHb disrupts EC monolayer integrity and induces expression of inflammatory cell adhesion molecules. Here we show that when exposed to ferrylHb, EC monolayers exhibit increased permeability and enhanced monocyte adhesion. Taken together, interactions between cell-free Hb and atheroma lipids engage in a vicious cycle, amplifying oxidation of plaque lipids and Hb. These processes trigger EC activation and cytotoxicity.Hungarian Academy of Sciences, Hungarian Government Grants: (OTKA-K75883, OTKAK83478, OTKA- PD83435), European Union and the European Social Fund: (T´AMOP-4.2.2.A-11/1/KONV-2012-0045 and T´AMOP-4.2.2/B-10/1-2010-0024)