Publications by authors named "Maria M Costa"

32 Publications

The internal structure and geodynamics of Mars inferred from a 4.2-Gyr zircon record.

Proc Natl Acad Sci U S A 2020 12 16;117(49):30973-30979. Epub 2020 Nov 16.

Centre for Star and Planet Formation, Globe Institute, University of Copenhagen, 1350 Copenhagen, Denmark;

Combining U-Pb ages with Lu-Hf data in zircon provides insights into the magmatic history of rocky planets. The Northwest Africa (NWA) 7034/7533 meteorites are samples of the southern highlands of Mars containing zircon with ages as old as 4476.3 ± 0.9 Ma, interpreted to reflect reworking of the primordial Martian crust by impacts. We extracted a statistically significant zircon population ( = 57) from NWA 7533 that defines a temporal record spanning 4.2 Gyr. Ancient zircons record ages from 4485.5 ± 2.2 Ma to 4331.0 ± 1.4 Ma, defining a bimodal distribution with groupings at 4474 ± 10 Ma and 4442 ± 17 Ma. We interpret these to represent intense bombardment episodes at the planet's surface, possibly triggered by the early migration of gas giant planets. The unradiogenic initial Hf-isotope composition of these zircons establishes that Mars's igneous activity prior to ∼4.3 Ga was limited to impact-related reworking of a chemically enriched, primordial crust. A group of younger detrital zircons record ages from 1548.0 ± 8.8 Ma to 299.5 ± 0.6 Ma. The only plausible sources for these grains are the temporally associated Elysium and Tharsis volcanic provinces that are the expressions of deep-seated mantle plumes. The chondritic-like Hf-isotope compositions of these zircons require the existence of a primitive and convecting mantle reservoir, indicating that Mars has been in a stagnant-lid tectonic regime for most of its history. Our results imply that zircon is ubiquitous on the Martian surface, providing a faithful record of the planet's magmatic history.
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http://dx.doi.org/10.1073/pnas.2016326117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733809PMC
December 2020

flower types: from the wild to crop plants.

PeerJ 2019 11;7:e7879. Epub 2019 Nov 11.

Linking Landscape, Environment, Agriculture and Food (LEAF), Instituto Superior de Agronomia, Universidade de Lisboa, Lisboa, Portugal.

can be divided into two subspecies, subsp. , one of the most important agricultural crops in the world, and its wild ancestor, subsp. . Three flower types can be observed: hermaphrodite and female (on some varieties) in , and male or female flowers in . It is assumed that the different flower types in the wild ancestor arose through specific floral patterns of organ abortion. A considerable amount of data about the diversity of sexual systems in grapevines has been collected over the past century. Several grapevine breeding studies led to the hypothesis that dioecy in is derived from a hermaphrodite ancestor and could be controlled by either, one or two linked genetic determinants following Mendelian inherence. More recently, experiments using molecular approaches suggested that these were located in a specific region of the chromosome 2 of . Based on the works published so far, its seems evident that a putative sex is present in chromosome 2. However, it is still not fully elucidated whether flower types are regulated by two linked or by one with three alleles. Nevertheless, several genes could contribute to sex determination in grapevine. This review presents the results from early studies, combined with the recent molecular approaches, which may contribute to the design of new experiments towards a better understanding of the sex inheritance in grapevine.
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http://dx.doi.org/10.7717/peerj.7879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855205PMC
November 2019

Carney complex due to a novel pathogenic variant in the PRKAR1A gene - a case report.

J Pediatr Endocrinol Metab 2019 Feb;32(2):197-202

Department of Pediatrics of Centro Hospitalar de São João, Porto, Portugal.

Background Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing's syndrome (CS). It may occur sporadically or as part of a familial syndrome called Carney complex (CC). It is a rare entity, with fewer than 750 cases reported. Case presentation We describe the case of a 16-year-old otherwise healthy female referred to our endocrinology department for progressive weight gain. During investigation, an adrenocorticotropic hormone (ACTH) independent CS was identified and the possibility of an adrenocortical tumor was suggested. The histological exam of the left adrenal gland was compatible with PPNAD. Genetic study identified a novel pathogenic variant in the PRKAR1A gene. Her family history was then reviewed and her father had died prematurely due to a cardiac myxoma. Besides abnormal skin pigmentation, the girl presented no other features of CC. Conclusions Careful follow-up of these patients is important to detect other manifestations of CC and to prevent life-threatening comorbidities, like cardiac myxomas or malignant diseases. Genetic counseling of the patients and their siblings is also very important.
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http://dx.doi.org/10.1515/jpem-2018-0199DOI Listing
February 2019

β-glucan administration induces metabolic changes and differential survival rates after bacterial or viral infection in turbot (Scophthalmus maximus).

Fish Shellfish Immunol 2018 Nov 3;82:173-182. Epub 2018 Aug 3.

Instituto de Investigaciones Marinas (IIM), CSIC, Eduardo Cabello 6, 36208, Vigo, Spain. Electronic address:

The innate immune response is able to ward off pathogens and remember previous infections using different mechanisms; this kind of immune reaction has been called "trained immunity". Changes in cellular metabolism (aerobic glycolysis) have been observed during training with some immunostimulants like β-glucans or during viral and bacterial infections. We hypothesize that β-glucans can induce metabolic changes used by the host to fight pathogens. Accordingly, we evaluated changes in metabolic parameters in turbot that could affect their survival after a previous intraperitoneal treatment with β-glucans and subsequent administration of Viral Hemorrhagic Septicemia Virus (VHSV) or bacteria (Aeromonas salmonicida subsp. salmonicida). The results obtained support that β-glucans, VHSV and A. salmonicida induce changes in lactate, glucose and ATP levels in plasma, head kidney and liver and in the mRNA expression of enzymes related to glucose and fatty acid metabolism in head kidney. Additionally, the metabolic changes induced by β-glucans are beneficial for VHSV replication, but they are harmful to A. salmonicida, resulting in reduced mortality. β-glucans appear to have great therapeutic potential and can induce trained immunity against bacterial disease but not against viral disease, which seems to take advantage of β-glucan metabolic alterations.
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http://dx.doi.org/10.1016/j.fsi.2018.08.005DOI Listing
November 2018

Flower Sex Specification Acts Downstream and Independently of the ABCDE Model Genes.

Front Plant Sci 2018 16;9:1029. Epub 2018 Jul 16.

Linking Landscape, Environment, Agriculture and Food (LEAF), School of Agriculture, University of Lisbon, Lisbon, Portugal.

The most discriminating characteristic between the cultivated subsp. and the wild-form subsp. is their sexual system. Flowers of cultivars are mainly hermaphroditic, whereas wild plants have female and male individuals whose flowers follow a hermaphroditic pattern during early stages of development and later develop non-functional reproductive organs. In angiosperms, the basic developmental system for floral organ identity is explained by the ABCDE model. This model postulates that regulatory gene functions work in a combinatorial way to confer organ identity in each whorl. In wild nothing is known about the function and expression profile of these genes. Here we show an overall view of the temporal and spatial expression pattern of the ABCDE genes as well as the pattern of that establishes a boundary between the stamen and the carpel whorls, in the male, female and complete flower types. The results show a similar pattern in species suggesting that the pathway leading to unisexuality acts independently and/or downstream of B- and C- function genes.
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http://dx.doi.org/10.3389/fpls.2018.01029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055017PMC
July 2018

Evidence for extremely rapid magma ocean crystallization and crust formation on Mars.

Nature 2018 06 27;558(7711):586-589. Epub 2018 Jun 27.

Centre for Star and Planet Formation and Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.

The formation of a primordial crust is a critical step in the evolution of terrestrial planets but the timing of this process is poorly understood. The mineral zircon is a powerful tool for constraining crust formation because it can be accurately dated with the uranium-to-lead (U-Pb) isotopic decay system and is resistant to subsequent alteration. Moreover, given the high concentration of hafnium in zircon, the lutetium-to-hafnium (Lu-Hf) isotopic decay system can be used to determine the nature and formation timescale of its source reservoir. Ancient igneous zircons with crystallization ages of around 4,430 million years (Myr) have been reported in Martian meteorites that are believed to represent regolith breccias from the southern highlands of Mars. These zircons are present in evolved lithologies interpreted to reflect re-melted primary Martian crust , thereby potentially providing insight into early crustal evolution on Mars. Here, we report concomitant high-precision U-Pb ages and Hf-isotope compositions of ancient zircons from the NWA 7034 Martian regolith breccia. Seven zircons with mostly concordant U-Pb ages define Pb/Pb dates ranging from 4,476.3 ± 0.9 Myr ago to 4,429.7 ± 1.0 Myr ago, including the oldest directly dated material from Mars. All zircons record unradiogenic initial Hf-isotope compositions inherited from an enriched, andesitic-like crust extracted from a primitive mantle no later than 4,547 Myr ago. Thus, a primordial crust existed on Mars by this time and survived for around 100 Myr before it was reworked, possibly by impacts, to produce magmas from which the zircons crystallized. Given that formation of a stable primordial crust is the end product of planetary differentiation, our data require that the accretion, core formation and magma ocean crystallization on Mars were completed less than 20 Myr after the formation of the Solar System. These timescales support models that suggest extremely rapid magma ocean crystallization leading to a gravitationally unstable stratified mantle, which subsequently overturns, resulting in decompression melting of rising cumulates and production of a primordial basaltic to andesitic crust.
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http://dx.doi.org/10.1038/s41586-018-0222-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107064PMC
June 2018

Transcriptional mechanisms underlying life-history responses to climate change in the three-spined stickleback.

Evol Appl 2017 08 15;10(7):718-730. Epub 2017 May 15.

Departamento de Ecoloxía e Bioloxía Animal Universidade de Vigo Vigo Spain.

Phenotypic plasticity, the ability of an organism to express different phenotypes depending on the environment, provides an important mechanism by which an animal population can persist under rapid climate change. We experimentally tested both life-history and transcriptional responses of an ecological model species, the three-spined stickleback, to warm acclimation at the southern edge of its European range. We explored cross-environment genetic correlations of key life-history traits in male sticklebacks exposed to long-term temperature changes to examine whether the plasticity pattern was variable among genotypes by using a character-state approach. We also studied gene expression plasticity by analysing both whole-transcriptome and candidate gene expression in brain and liver. Male sticklebacks that developed under warmer conditions during winter were smaller in size and invested less in nuptial coloration at the beginning of the breeding season, showing similar responses across different genotypes. The lack of genetic variation in life-history responses may limit any future evolution of the thermal reaction norm in the study population. After long-term exposure to increased winter temperatures, genes responsible for several metabolic and oxidation-reduction processes were upregulated, and some hormone genes involved in growth and reproduction were downregulated in the brain. In the liver, there was no significantly represented gene ontology by the differentially expressed genes. Since a higher temperature leads to a higher resting metabolic rate, living in warmer environments may incur higher energetic costs for ectotherms to maintain cellular homoeostasis, resulting in negative consequences for life-history traits. The expression of genes related to metabolism, cellular homoeostasis and regulatory signalling may underlie temperature-induced changes in life history.
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http://dx.doi.org/10.1111/eva.12487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511362PMC
August 2017

and : Two Genes Involved in Sex Specification Able to Distinguish Different Flower Types in .

Front Plant Sci 2017 31;8:98. Epub 2017 Jan 31.

Linking Landscape, Environment, Agriculture and Food, Instituto Superior de Agronomia, Universidade de Lisboa Lisboa, Portugal.

is a hermaphrodite subspecies, while its ancestor, , is dioecious. We have identified two genes that together allow the discrimination between male, female and hermaphrodite plants. The sex locus region on chromosome 2 was screened resulting in the discovery of a new gene, . The same screening revealed another gene, , located in the sex region, that be used as a sex marker. Both genes are good candidates to be involved in flower sex differentiation in grapevine. To assess their role in sex specification, spatial and temporal expression analysis was performed. The expression of is detected in petals, stamens and carpel primordia of all flower types, making its putative function unclear; however, female plants display a single allele for this gene, while male and hermaphrodites display two alleles. On the other hand, the specific expression of in the carpel primordial of male plants suggests a possible role in the abortion of pistil structures. We propose a model to explain the carpel abortion in male flowers and the absence of stamen viability in female flowers. In addition, this work reinforces the presence of a sex locus on chromosome 2.
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http://dx.doi.org/10.3389/fpls.2017.00098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5281589PMC
January 2017

Antiviral Activity of Myticin C Peptide from Mussel: an Ancient Defense against Herpesviruses.

J Virol 2016 09 12;90(17):7692-702. Epub 2016 Aug 12.

Instituto de Investigaciones Marinas (IIM), Consejo Superior de Investigaciones Científicas (CSIC), Vigo, Spain.

Unlabelled: Little is known about the antiviral response in mollusks. As in other invertebrates, the interferon signaling pathways have not been identified, and in fact, there is a debate about whether invertebrates possess antiviral immunity similar to that of vertebrates. In marine bivalves, due to their filtering activity, interaction with putative pathogens, including viruses, is very high, suggesting that they should have mechanisms to address these infections. In this study, we confirmed that constitutively expressed molecules in naive mussels confer resistance in oysters to ostreid herpesvirus 1 (OsHV-1) when oyster hemocytes are incubated with mussel hemolymph. Using a proteomic approach, myticin C peptides were identified in both mussel hemolymph and hemocytes. Myticins, antimicrobial peptides that have been previously characterized, were constitutively expressed in a fraction of mussel hemocytes and showed antiviral activity against OsHV-1, suggesting that these molecules could be responsible for the antiviral activity of mussel hemolymph. For the first time, a molecule from a bivalve has shown antiviral activity against a virus affecting mollusks. Moreover, myticin C peptides showed antiviral activity against human herpes simplex viruses 1 (HSV-1) and 2 (HSV-2). In summary, our work sheds light on the invertebrate antiviral immune response with the identification of a molecule with potential biotechnological applications.

Importance: Several bioactive molecules that have potential pharmaceutical or industrial applications have been identified and isolated from marine invertebrates. Myticin C, an antimicrobial peptide from the Mediterranean mussel (Mytilus galloprovincialis) that was identified by proteomic techniques in both mussel hemolymph and hemocytes, showed potential as an antiviral agent against ostreid herpesvirus 1 (OsHV-1), which represents a major threat to the oyster-farming sector. Both hemolymph from mussels and a myticin C peptide inhibited OsHV-1 replication in oyster hemocytes. Additionally, a modified peptide derived from myticin C or the nanoencapsulated normal peptide also showed antiviral activity against the human herpesviruses HSV-1 and HSV-2. Therefore, myticin C is an example of the biotechnological and therapeutic potential of mollusks.
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http://dx.doi.org/10.1128/JVI.00591-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988142PMC
September 2016

The Quest for Molecular Regulation Underlying Unisexual Flower Development.

Front Plant Sci 2016 19;7:160. Epub 2016 Feb 19.

Biosystems and Integrative Sciences Institute, Plant Functional Biology Centre, University of Minho Braga, Portugal.

The understanding of the molecular mechanisms responsible for the making of a unisexual flower has been a long-standing quest in plant biology. Plants with male and female flowers can be divided mainly into two categories: dioecious and monoecious, and both sexual systems co-exist in nature in ca of 10% of the angiosperms. The establishment of male and female traits has been extensively described in a hermaphroditic flower and requires the interplay of networks, directly and indirectly related to the floral organ identity genes including hormonal regulators, transcription factors, microRNAs, and chromatin-modifying proteins. Recent transcriptomic studies have been uncovering the molecular processes underlying the establishment of unisexual flowers and there are many parallelisms between monoecious, dioecious, and hermaphroditic individuals. Here, we review the paper entitled "Comparative transcriptomic analysis of male and female flowers of monoecious Quercus suber" published in 2014 in the Frontiers of Plant Science (volume 5 |Article 599) and discussed it in the context of recent studies with other dioecious and monoecious plants that utilized high-throughput platforms to obtain transcriptomic profiles of male and female unisexual flowers. In some unisexual flowers, the developmental programs that control organ initiation fail and male or female organs do not form, whereas in other species, organ initiation and development occur but they abort or arrest during different species-specific stages of differentiation. Therefore, a direct comparison of the pathways responsible for the establishment of unisexual flowers in different species are likely to reveal conserved modules of gene regulatory hubs involved in stamen or carpel development, as well as differences that reflect the different stages of development in which male and/or female organ arrest or loss-of-function occurs.
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http://dx.doi.org/10.3389/fpls.2016.00160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759290PMC
February 2016

First in-depth analysis of the novel Th2-type cytokines in salmonid fish reveals distinct patterns of expression and modulation but overlapping bioactivities.

Oncotarget 2016 Mar;7(10):10917-46

Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, UK.

IL-4 and IL-13 are closely related canonical type-2 cytokines in mammals and have overlapping bioactivities via shared receptors. They are frequently activated together as part of the same immune response and are the signature cytokines produced by T-helper (Th)2 cells and type-2 innate lymphoid cells (ILC2), mediating immunity against extracellular pathogens. Little is known about the origin of type-2 responses, and whether they were an essential component of the early adaptive immune system that gave a fitness advantage by limiting collateral damage caused by metazoan parasites. Two evolutionary related type-2 cytokines, IL-4/13A and IL-4/13B, have been identified recently in several teleost fish that likely arose by duplication of an ancestral IL-4/13 gene as a consequence of a whole genome duplication event that occurred at the base of this lineage. However, studies of their comparative expression levels are largely missing and bioactivity analysis has been limited to IL-4/13A in zebrafish. Through interrogation of the recently released salmonid genomes, species in which an additional whole genome duplication event has occurred, four genomic IL-4/13 loci have been identified leading to the cloning of three active genes, IL-4/13A, IL-4/13B1 and IL-4/13B2, in both rainbow trout and Atlantic salmon. Comparative expression analysis by real-time PCR in rainbow trout revealed that the IL-4/13A expression is broad and high constitutively but less responsive to pathogen-associated molecular patterns (PAMPs) and pathogen challenge. In contrast, the expression of IL-4/13B1 and IL-4/13B2 is low constitutively but is highly induced by viral haemorrhagic septicaemia virus (VHSH) infection and during proliferative kidney disease (PKD) in vivo, and by formalin-killed bacteria, PAMPs, the T cell mitogen PHA, and the T-cell cytokines IL-2 and IL-21 in vitro. Moreover, bioactive recombinant cytokines of both IL-4/13A and B were produced and found to have shared but also distinct bioactivities. Both cytokines rapidly induce the gene expression of antimicrobial peptides and acute phase proteins, providing an effector mechanism of fish type-2 cytokines in immunity. They are anti-inflammatory via up-regulation of IL-10 and down-regulation of IL-1β and IFN-γ. They modulate the expression of cellular markers of T cells, macrophages and B cells, the receptors of IFN-γ, the IL-6 cytokine family and their own potential receptors, suggesting multiple target cells and important roles of fish type-2 cytokines in the piscine cytokine network. Furthermore both cytokines increased the number of IgM secreting B cells but had no effects on the proliferation of IgM+ B cells in vitro. Taken as a whole, fish IL-4/13A may provide a basal level of type-2 immunity whilst IL-4/13B, when activated, provides an enhanced type-2 immunity, which may have an important role in specific cell-mediated immunity. To our knowledge this is the first in-depth analysis of the expression, modulation and bioactivities of type-2 cytokines in the same fish species, and in any early vertebrate. It contributes to a broader understanding of the evolution of type-2 immunity in vertebrates, and establishes a framework for further studies and manipulation of type-2 cytokines in fish.
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http://dx.doi.org/10.18632/oncotarget.7295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905449PMC
March 2016

The Effect of Bariatric Surgery Type on Lipid Profile: An Age, Sex, Body Mass Index and Excess Weight Loss Matched Study.

Obes Surg 2016 May;26(5):1041-7

Serviço de Endocrinologia, Diabetes e Metabolismo do Centro Hospitalar de São João, Alameda Professor Hernâni Monteiro, 4202-451, Porto, Portugal.

Background: Bariatric surgery improves lipid profile. A still unanswered question is whether this improvement is merely weight-dependent or also results from factors inherent to specificities of the bariatric procedure. We aimed to study lipid profile 1 year after bariatric surgery and compare its changes between the different procedures in patients matched for initial weight and weight loss.

Methods: We retrospectively analysed patients submitted to Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB) or sleeve gastrectomy (SG) between 2010 and 2013. Patients were matched for age (±5 years), sex, pre-surgery body mass index (BMI) (±2 Kg/m(2)) and excess weight loss (EWL) (±5%). Baseline and 1-year lipid profile, its variation and percentage of variation was compared between surgeries.

Results: We analysed 229 patients: 72 pairs RYGB-AGB, 47 pairs RYGB-SG and 33 pairs AGB-SG. The median age was 41 (35-52) years and 11.8% were male. Pre-operative BMI was 44.0 ± 4.6 and 32.1 ± 4.4 Kg/m(2) at 1 year. EWL at 1 year was 64.2 ± 18.9%. There were no differences in baseline lipid profile between patients submitted to different types of bariatric surgery. At 1 year, high-density lipoprotein cholesterol (HDL) and triglycerides (TG) improved similarly with all surgeries. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) at 1 year decreased significantly more in patients submitted to RYGB than in weight-matched patients undergoing AGB or SG.

Conclusions: RYGB is the only bariatric surgery that reduces TC and LDL in age-, sex-, BMI- and EWL-matched patients. All three procedures improved TG and HDL similarly when the confounding effect of weight loss is eliminated.
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http://dx.doi.org/10.1007/s11695-015-1825-1DOI Listing
May 2016

Comparative transcriptomic analysis of male and female flowers of monoecious Quercus suber.

Front Plant Sci 2014 6;5:599. Epub 2014 Nov 6.

Centre for Biodiversity, Functional & Integrative Genomics, Plant Functional Biology Centre, University of Minho Braga, Portugal.

Monoecious species provide a comprehensive system to study the developmental programs underlying the establishment of female and male organs in unisexual flowers. However, molecular resources for most monoecious non-model species are limited, hampering our ability to study the molecular mechanisms involved in flower development of these species. The objective of this study was to identify differentially expressed genes during the development of male and female flowers of the monoecious species Quercus suber, an economically important Mediterranean tree. Total RNA was extracted from different developmental stages of Q. suber flowers. Non-normalized cDNA libraries of male and female flowers were generated using 454 pyrosequencing technology producing a total of 962,172 high-quality reads with an average length of 264 nucleotides. The assembly of the reads resulted in 14,488 contigs for female libraries and 10,438 contigs for male libraries. Comparative analysis of the transcriptomes revealed genes differentially expressed in early and late stages of development of female and male flowers, some of which have been shown to be involved in pollen development, in ovule formation and in flower development of other species with a monoecious, dioecious, or hermaphroditic sexual system. Moreover, we found differentially expressed genes that have not yet been characterized and others that have not been previously shown to be implicated in flower development. This transcriptomic analysis constitutes a major step toward the characterization of the molecular mechanisms involved in flower development in a monoecious tree with a potential contribution toward the knowledge of conserved developmental mechanisms in other species.
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http://dx.doi.org/10.3389/fpls.2014.00599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222140PMC
November 2014

The involvement of cholesterol in sepsis and tolerance to lipopolysaccharide highlighted by the transcriptome analysis of zebrafish (Danio rerio).

Zebrafish 2014 Oct 2;11(5):421-33. Epub 2014 Sep 2.

1 Instituto de Investigaciones Marinas (IIM)-Consejo Superior de Investigaciones Científicas (CSIC) , Vigo, Spain .

Septic shock is the most common cause of death in intensive care units due to an aggressive inflammatory response that leads to multiple organ failure. However, a lipopolysaccharide (LPS) tolerance phenomenon (a nonreaction to LPS), is also often described. Neither the inflammatory response nor the tolerance is completely understood. In this work, both of these responses were analyzed using microarrays in zebrafish. Fish that were 4 or 6 days postfertilization (dpf) and received a lethal dose (LD) of LPS exhibited 100% mortality in a few days. Their transcriptome profile, even at 4 dpf, resembled the profile in humans with severe sepsis. Moreover, we selected 4-dpf fish to set up a tolerance protocol: fish treated with a nonlethal concentration of Escherichia coli LPS exhibited complete protection against the LD of LPS. Most of the main inflammatory molecules described in mammals were represented in the zebrafish microarray experiments. Additionally and focusing on this tolerance response, the use of cyclodextrins may mobilize cholesterol reservoirs to decrease mortality after a LD dose of LPS. Therefore, it is possible that the use of the whole animal could provide some clues to enhance the understanding of the inflammatory/tolerance response and to guide drug discovery.
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http://dx.doi.org/10.1089/zeb.2014.0995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172467PMC
October 2014

Interferon-induced genes of the expanded IFIT family show conserved antiviral activities in non-mammalian species.

PLoS One 2014 20;9(6):e100015. Epub 2014 Jun 20.

Instituto de Investigaciones Marinas (IIM), CSIC, Vigo, Spain.

Interferon-induced proteins with tetratricopeptide repeats (IFITs) are involved in the protective response to viral infection, although the precise mechanism of IFITs for reducing viral proliferation is currently unknown. The interaction with the translation initiation factor eIF-3 or viral proteins and the sequestering of viral RNA have been proposed as potential antiviral functions for these proteins. In humans, four members of this family have been characterized. Nevertheless, information about these proteins in fish is almost non-existent. Exploiting the conservation of synteny between human and zebrafish genomes, we have identified ten members of the IFIT family located on four different chromosomes. The induction of these genes was examined both in vitro and in vivo after interferon (IFN) administration and rhabdovirus challenge. Whereas an induction of IFIT genes was observed after interferon treatments (IFNΦ1, IFNΦ2 and IFNΦ3), the viral infection did not affect these IFN-induced genes in vitro, and even reduced the IFN-induced expression of these genes. The response was largely different in vivo, with a broad up-regulation of IFIT genes after viral challenge. In addition, three selected IFITs were cloned in an expression vector and microinjected into zebrafish larvae to examine the protective effect of IFITs upon viral infection. Reduction in the mortality rate was observed confirming a conserved antiviral function in non-mammalian species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100015PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065003PMC
February 2015

Pachydermoperiostosis in an African patient caused by a Chinese/Japanese SLCO2A1 mutation-case report and review of literature.

Semin Arthritis Rheum 2014 Feb 5;43(4):566-9. Epub 2013 Sep 5.

Genomed, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.

Objectives: Pachydermoperiostosis is a rare clinical entity characterized by skin thickening of the forehead, eyelids, and hands, digital clubbing, and periostosis. Two genes have been associated, HPGD and recently SLCO2A1. We present a detailed clinical and genetic description of an African pachydermoperiostosis patient with a SLCO2A1 mutation.

Methods: Standard clinical and laboratory evaluation was carried out. Genetic screening was done with PCR followed by direct sequencing. We discuss the clinical features and known mutations of previously reported cases identified through a PubMed literature review.

Results: The clinical findings showed special features, including exuberant knee effusions and an extraordinary good response on surgery of the blepharoptosis. We found a splice site mutation in the SLCO2A1 gene in homozygous form: c.940+1G>A. This mutation was previously reported only in 1 Chinese and 3 Japanese cases and was considered as a founder mutation in Japan. Beside our case, only one other patient in the literature carried this mutation in homozygous condition, but with different main clinical symptoms.

Conclusions: Our case demonstrates phenotypic heterogeneity of PDP even between homozygous carriers of the same mutation, suggesting further modifiers. Besides, it shows that this rare SLCO2A1 mutation is not exclusively present in East-Asia, but can occur in various ethnicities, with different origin, thus the incidence is probably underestimated.
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http://dx.doi.org/10.1016/j.semarthrit.2013.07.015DOI Listing
February 2014

IL-22 is a key player in the regulation of inflammation in fish and involves innate immune cells and PI3K signaling.

Dev Comp Immunol 2013 Dec 30;41(4):746-55. Epub 2013 Aug 30.

Instituto de Investigaciones Marinas (IIM), CSIC, Eduardo Cabello 6, 36208 Vigo, Spain. Electronic address:

IL-22 plays a role in various disorders in mammals, including mucosal-associated infections and inflammatory diseases. No functional IL-22 studies have been conducted on non-mammals to date. In this study, recombinant IL-22 (rIL-22) from turbot was produced to investigate its effects as a bioactive molecule. The expression of several pro-inflammatory cytokines was increased after rIL-22 treatment and reduced by pre-treatment with a JAK/STAT inhibitor. The involvement of the PI3K pathway in IL-22 induction was demonstrated. rIL-22 reduced the mortality in Aeromonas salmonicida-infected turbot, while higher Aeromonas hydrophila- or LPS-induced mortality was observed when IL-22 was blocked in zebrafish embryos. IL-22 knockdown increased pro-inflammatory cytokine expression in bacteria-stimulated fish. In zebrafish, IL-22 expression was detected primarily in the myeloid innate linage. It was found during early developmental stages when the adaptive immune response is not yet functional and in rag1(-)/(-) fish that lack an adaptive immune system. Our results clarify the conserved role of IL-22 in lower vertebrates. We suggest for the first time that IL-22 constitutes a key regulator of inflammatory homeostasis even in distant species such as teleosts, which diverged from mammals more than 350 million years ago.
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http://dx.doi.org/10.1016/j.dci.2013.08.021DOI Listing
December 2013

Transforming growth factor-β1b: a second TGF-β1 paralogue in the rainbow trout (Oncorhynchus mykiss) that has a lower constitutive expression but is more responsive to immune stimulation.

Fish Shellfish Immunol 2013 Feb 23;34(2):420-32. Epub 2012 Nov 23.

Scottish Fish Immunology Research Centre, Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.

The rainbow trout (Oncorhynchus mykiss) TGF-β1 sequence was one of the first fish cytokines described. Studies of its expression suggest it is constitutively expressed but displays refractory inducibility. Here we describe a second TGF-β1 (TGF-β1b) gene that is novel in several respects. TGF-β1b possesses typical TGF-β features, including a CXC motif and an integrin binding site, a tetrabasic cut site and a mature peptide of 112 amino acids (aa) containing nine conserved cysteine residues. The mature peptide is 83% identical to the first TGF-β1 sequence described in rainbow trout, that we designate TGF-β1a, and relative to TGF-β1a shows higher homology to Atlantic salmon TGF-β1b, zebrafish TGF-β1a, and sea bass and seabream TGF-β1. The gene organisation of salmonid TGF-β1b genes, as inferred from Atlantic salmon whole genome shotgun contigs, is a 6 exon/5 intron structure with exons 3 and 4 of salmonid TGF-β1a genes apparently fused together. The two trout TGF-β1 genes have a wide distribution in vivo, with highest expression found in immune tissues for both isoforms indicating that TGF-β1 has a predominant role in immunity of fish. Expression of both genes was also seen during the ontogeny of trout, with TGF-β1a relatively constant in expression level but TGF-β1b increasing over time. Immune responses in head kidney (HK) macrophages induced by pathogen associated molecular patterns (PAMPs), pro-inflammatory cytokines, mitogens and pathway activators highly elevated the expression level of TGF-β1b but not that of TGF-β1a. TGF-β1b expression was also increased by polyinosinic:polycytidylic acid (poly(I:C)) and/or lipopolysaccharide (LPS) stimulation in three different trout cell lines studied. Finally we show that TGF-β1b is potentially involved in defense against infection with viral haemorrhagic septicemia virus (VHSV), which had no effect on TGF-β1a expression. Thus, it is likely the TGF-β1b gene represents a copy which fulfils the major immune orchestrating functions of TGF-β1 as seen in other vertebrates.
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http://dx.doi.org/10.1016/j.fsi.2012.11.011DOI Listing
February 2013

Identification of IL-34 in teleost fish: differential expression of rainbow trout IL-34, MCSF1 and MCSF2, ligands of the MCSF receptor.

Mol Immunol 2013 Apr 23;53(4):398-409. Epub 2012 Oct 23.

Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen AB24 2TZ, UK.

The mononuclear phagocyte system is composed of monocytes, macrophages and dendritic cells and has crucial roles in inflammation, autoimmunity, infection, cancer, organ transplantation and in maintaining organismal homeostasis. Interleukin-34 (IL-34) and macrophage colony stimulating factor (MCSF), both signalling through the MCSF receptor, regulate the mononuclear phagocyte system. A single IL-34 and MCSF gene are present in tetrapods. Two types of MCSF exist in teleost fish which is resulted from teleost-wide whole genome duplication. In this report, we first identified and sequence analysed six IL-34 genes in five teleost fish, rainbow trout, fugu, Atlantic salmon, catfish and zebrafish. The fish IL-34 molecules had a higher identity within fish group but low identities to IL-34s from birds (27.2-33.8%) and mammals (22.2-31.4%). However, they grouped with tetrapod IL-34 molecules in phylogenetic tree analysis, had a similar 7 exon/6 intron gene organisation, and genes in the IL-34 loci were syntenically conserved. In addition, the regions of the four main helices, along with a critical N-glycosylation site were well conserved. Taken together these data suggest that the teleost IL-34 genes described in this report are orthologues of tetrapod IL-34. Comparative expression study of the three trout MCSFR ligands revealed that IL-34, MCSF1 and MCSF2 are differentially expressed in tissues and cell lines. The expression of MCSF1 and MCSF2 showed great variance in different tissues and cell lines, suggesting a role in the differentiation and maintenance of specific macrophage lineages in specific locations. The relatively high levels of IL-34 expression across different tissues suggests a homeostatic role of IL-34 for the macrophage lineage in fish. One striking observation in the present study was the lack of induction of MCSF1 and MCSF2 expression but the quick induction of IL-34 expression by PAMPs and inflammatory cytokines in cell lines and primary head kidney macrophages in rainbow trout. In a parasitic proliferative kidney disease (PKD) model, the expression of IL-34 but not the dominant MCSF2 was affected by PKD, suggesting an involvement of macrophage function in this disease model. Thus IL-34 expression is sensitive to inflammatory stimuli and may regulate macrophage biology once up-regulated.
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http://dx.doi.org/10.1016/j.molimm.2012.09.008DOI Listing
April 2013

Cloning and expression analysis of two ROR-γ homologues (ROR-γa1 and ROR-γa2) in rainbow trout Oncorhynchus mykiss.

Fish Shellfish Immunol 2012 Aug 24;33(2):365-74. Epub 2012 May 24.

Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, Scotland, UK.

This paper describes the cloning and characterisation of two retinoid-related orphan receptor (ROR)-γ homologues (ROR-γa1 and -γa2) in rainbow trout (Oncorhynchus mykiss). The coding region predicted for both homologues consists of 1410 base pairs (bp), which translate into two 469 amino acid (aa) proteins. The trout ROR-γs revealed a high conservation of both DNA- and ligand-binding domains (functional regions of the nuclear receptor family), and shared a high homology to mammalian ROR-γt. A phylogenetic tree containing ROR family members confirmed that both trout homologues clustered within the ROR-γ group. Both results suggested that these molecules are likely to be ROR-γ homologues, more similar to the mammalian splice variant ROR-γt than the full length ROR-γ. Expression analysis of tissues obtained from healthy fish revealed highest constitutive expression of trout ROR-γ in muscle, followed by the brain, heart and skin. This suggests that these genes may play an important role in such tissues. In vitro studies, using trout cell lines, demonstrated that ROR-γ is induced significantly by LPS and down-regulated by the presence of PolyI:C and recombinant interferon (IFN)-γ. Moreover, analysis of this gene in head kidney macrophages and mixed primary leucocyte cultures indicated that differences were apparent between the different cell types/sources used, indicating that its expression may be cell-type dependent. Additional studies to investigate the regulation of this gene in vivo demonstrated that its expression was significantly higher in vaccinated vs unvaccinated fish following bacterial (Yersinia ruckeri) challenge but it was down-regulated after a viral (VHSV) infection. This suggests a potential role of trout ROR-γ, a putative T(H)17 transcription factor, in protection against extracellular bacteria.
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http://dx.doi.org/10.1016/j.fsi.2012.05.023DOI Listing
August 2012

Molecular characterization and expression analysis of the putative interleukin 6 receptor (IL-6Rα and glycoprotein-130) in rainbow trout (Oncorhynchus mykiss): salmonid IL-6Rα possesses a polymorphic N-terminal Ig domain with variable numbers of two repeats.

Immunogenetics 2012 Mar 29;64(3):229-44. Epub 2011 Oct 29.

Scottish Fish Immunology Research Centre, University of Aberdeen, Aberdeen, AB24 2TZ, UK.

Interleukin (IL)-6, the founding member of IL-6 family cytokines, plays non-redundant roles in hematopoiesis and acute phase responses. IL-6 signals via a specific private IL-6Rα and a common beta chain gp130. In this study, we have cloned both the IL-6Rα and gp130 in rainbow trout. The trout gp130 cDNA encodes 906 aa and is similar in size, extracellular domain structure (D1-D6) and presence of intracellular motifs important for signal transduction to tetrapod gp130s. The trout IL-6Rα cDNA encodes for 834 aa and is larger compared to tetrapod IL-6Rαs, as are other fish IL-6Rα molecules due to a large D1 domain. However, the cytokine-binding domain is well conserved across vertebrates, with four conserved cysteine residues in the N-terminal FNIII domain and a WSXWS motif in the C-terminal FNIII domain. Furthermore, a phylogenetic tree analysis confirmed that the reported fish IL-6Rα and gp130 molecules are orthologues to their tetrapod counterparts. The extra large D1 domain of the salmonid IL-6Rα molecules results partially from the insertions of two repetitive sequences of [TS]-[TF]-VSTTT-[ND]-TTSNG and TTVS-[AT]-IKD-[DG]-S-[KD]-N-[GR], respectively. Furthermore the numbers of repetitions of the two motifs were variable in different individuals and cell lines, and even in the same fish allelic polymorphism exists. Trout IL-6Rα was expressed at higher levels than gp130 in a number of tissues examined and the expression of both IL-6Rα and gp130 could be modulated by LPS and Poly I:C in the cell lines studied. The expression patterns of the receptors suggest that high level expression of IL-6Rα is critical for IL-6 responsiveness.
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http://dx.doi.org/10.1007/s00251-011-0581-1DOI Listing
March 2012

Bioactivity studies of rainbow trout (Oncorhynchus mykiss) interleukin-6: effects on macrophage growth and antimicrobial peptide gene expression.

Mol Immunol 2011 Sep 24;48(15-16):1903-16. Epub 2011 Jun 24.

Scottish Fish Immunology Research Centre, University of Aberdeen, Aberdeen AB24 2TZ, UK.

Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates hematopoiesis, inflammation, immune responses and bone homeostasis in mammals. Fish IL-6 has been cloned in recent years but to date no functional studies have been reported. Thus, in this paper we present for the first time in fish the functional characterisation of IL-6, using rainbow trout (Oncorhynchus mykiss) as the fish model and with a focus on macrophage effects. Trout IL-6 (tIL-6) expression in macrophages could be induced by proinflammatory agents (LPS, polyI:C, and IL-1β) and recombinant tIL-6 (rtIL-6) rapidly induced STAT3 phosphorylation and expression of SOCS-1 to -3, CISH and IRF-1, as seen in mammals. However, three findings in this study suggest a novel role of tIL-6 in fish. Firstly, macrophage growth was enhanced by rtIL-6 in vitro, suggesting that IL-6 produced during inflammatory events may promote macrophage proliferation locally. Secondly, rtIL-6 induced the expression of cathelicidin-2, an antimicrobial peptide with immune-modulatory function, but down-regulated the expression of IL-1β and TNF-α, indicating a role of IL-6 in host defence and also in limiting inflammation. Thirdly, rtIL-6 induced the expression of hepcidin in macrophages. In mammals hepcidin is antimicrobial but also regulates iron homeostasis by inhibiting iron absorption, and its expression is induced by IL-6 only in hepatocytes but not macrophages. Thus, in fish if IL-6 is induced in patrolling macrophages during sepsis this may act to reduce iron availability by induction of hepcidin expression and lead to iron deficiency, as a means to limit the spread of infection.
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http://dx.doi.org/10.1016/j.molimm.2011.05.027DOI Listing
September 2011

The gamma-chain cytokine/receptor system in fish: more ligands and receptors.

Fish Shellfish Immunol 2011 Nov 2;31(5):673-87. Epub 2011 Jun 2.

Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen AB242TZ, UK.

The mammalian gamma-chain (γC) cytokine family consists of interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21. They signal through a receptor complex containing the common γC and a private alpha chain, and in the case of IL-2 and IL-15 an additional common IL-2/15Rβ chain. Deficiency of γC signalling in mammals prevents CD4+ T cells from developing effector functions and CD8+ T cells from developing immunological memory. Thus γC cytokines are critical for the generation and peripheral homeostasis of naïve and memory T cells. This review will give an update on the γC ligands and receptor subunits in fish, and also present some new data on the cloning and expression of a second γC and two IL-2Rβ chains in rainbow trout Oncorhynchus mykiss. In recent years, aided by the availability of sequenced fish genomes and expressed sequence tag databases, five of the six mammalian γC cytokines and their cognate receptors have been discovered in fish, with only the IL-9/IL-9R homologues apparently absent. Paralogues have been discovered in diploid fish and all the receptors described in the tetraploid rainbow trout, including γC itself, IL-2Rβ, IL-4Rα, IL-13Rα1, IL-13Rα2 and IL-2/15Rα, have duplicates. As a consequence of the teleost and salmonid whole genome duplications, even more paralogues may yet be discovered. Some of the paralogues have changes in domain structures and show differential expression and modulation, suggesting the potential for a change in function. Functional characterisation of fish γC cytokines is beginning but made more difficult by the co-existence of so many paralogues of the ligands and their receptors. Initial functional studies have shown that fish γC cytokines can modulate the expression of key cytokines (e.g. interferon-γ, IL-10 and IL-22) of the adaptive immune response, and may thus have promise as adjuvants to improve vaccination efficiency in fish.
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http://dx.doi.org/10.1016/j.fsi.2011.05.016DOI Listing
November 2011

Sequencing of a second interleukin-10 gene in rainbow trout Oncorhynchus mykiss and comparative investigation of the expression and modulation of the paralogues in vitro and in vivo.

Fish Shellfish Immunol 2011 Jul 27;31(1):107-17. Epub 2011 Apr 27.

Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen AB242TZ, UK.

Interleukin-10 (IL-10) is a multifaceted cytokine that is produced by and effects a variety of cell populations, including macrophages, T, B and NK cells. The gene encoding for IL-10 has been isolated in mammals, birds, amphibians and recently in fish, with only single copy identified in each species. We report here a second IL-10 gene (tIL-10b) in rainbow trout that showed 92% identity in the coding region but only 50% identity in the 5'- and 3'-UTR to the known trout IL-10 paralogue, which we have now called tIL-10a. There is a short upstream open reading frame (uORF) within the 5'-untranslated region (UTR) of tIL-10a that may inhibit its translation, whilst in tIL-10b multiple mRNA instability motifs exist in the 3'-UTR, suggesting that the two IL-10 paralogues may have different mechanisms to regulate their expression post-transcriptionally. The expression of tIL-10a is generally higher than that of tIL-10b in most of the fourteen tissues examined and in the RTS-11, RTL and RTGill cell lines. However, the expression level of tIL-10b can exceed that of tIL-10a, as seen in vivo in the ovary of healthy fish and in the gills of Yersinia ruckeri challenged fish, and in vitro in head kidney (HK) leucocytes cultured for ≥ 8 h. The expression of the trout IL-10 paralogues can be up-regulated by LPS and polyIC in RTS-11 cells and by LPS, polyIC, PHA, PMA, calcium ionophore (CI) and IL-21 in head kidney leucocytes, as well as by Y. ruckeri infection, and can be modulated positively or negatively by IFN-γ. Synergistic effects on up-regulation of IL-10 expression were also seen between PHA and IL-21, as well as between PMA and CI. The expression kinetics of the IL-10 paralogues was also found to be different, suggesting that rainbow trout has evolved different pathways to regulate the expression of the two IL-10 paralogues at the transcriptional level.
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http://dx.doi.org/10.1016/j.fsi.2011.04.010DOI Listing
July 2011

Two copies of the genes encoding the subunits of putative interleukin (IL)-4/IL-13 receptors, IL-4Rα, IL-13Rα1 and IL-13Rα2, have been identified in rainbow trout (Oncorhynchus mykiss) and have complex patterns of expression and modulation.

Immunogenetics 2011 Apr 6;63(4):235-53. Epub 2011 Jan 6.

Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, UK.

Mammalian interleukin-4 (IL-4) and IL-13 are T helper type 2 (Th2) cytokines with pleiotropic functions in immunity. They signal through receptors containing IL-4Rα and IL-2Rγ or IL-13Rα1. In addition, a decoy receptor, IL-13Rα2, is known to exist and modulates the function of IL-13. The existence of fish orthologues to mammalian IL-4 and IL-13 is still under debate. However, the receptor chains have been predicted in zebrafish, and we have previously cloned IL-2Rγ and IL-13Rα2 in rainbow trout. In this study, we have cloned a further five novel trout IL-4/13 receptors. Thus, each of the IL-4Rα, IL-13Rα1 and IL-13Rα2 chains has two copies. The identities of the receptors is supported by homology analysis, characteristic domain structure, phylogenetic tree analysis and synteny analysis in zebrafish. However, the characteristic WSXWS motif of structural importance in mammalian type I cytokine receptors is missing in all fish IL-4Rα and IL-13Rα1 molecules. All the receptors have a characteristic domain structure that is similar to their mammalian counterparts except for IL-13Rα1b that has the N-terminal Ig domain missing. Since this Ig domain is a specific and critical binding unit for IL-13 but not for IL-4 signalling, its absence potentially converts the IL-13Rα1b into a receptor that can only signal via IL-4 ligation. The existence of duplicated receptor genes perhaps suggests that more ligands still remain to be discovered that will bind these receptors. The duplicated receptors are differentially expressed in most tissues and cell lines examined, and their expression can be modulated by LPS, polyIC and IFN-γ in cell lines. In contrast, the T-cell stimulant phytohaemagglutinin increased the expression of IL-4Rα1 and IL-4Rα2, but not IL-13Rα1/2, suggesting a role of an IL-4-like molecule in T-cell growth/activation in fish.
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http://dx.doi.org/10.1007/s00251-010-0508-2DOI Listing
April 2011

Functional characterization of a nonmammalian IL-21: rainbow trout Oncorhynchus mykiss IL-21 upregulates the expression of the Th cell signature cytokines IFN-gamma, IL-10, and IL-22.

J Immunol 2011 Jan 15;186(2):708-21. Epub 2010 Dec 15.

Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen AB24 2TZ, United Kingdom.

In mammals, IL-21 is a common γ chain cytokine produced by activated CD4(+) T cells and NKT cells that acts on multiple lineages of cells. Although IL-21 has also been discovered in birds, amphibians, and fish, to date, no functional studies have been reported for any nonmammalian IL-21 molecule. We have sequenced an IL-21 gene (tIL-21) in rainbow trout, which has a six-exon/five-intron structure, is expressed in immune tissues, and is induced by bacterial and viral infection and the T cell stimulant PHA. In contrast to mammals, calcium ionophore and PMA act synergistically to induce tIL-21. Recombinant tIL-21 (rtIL-21) induced a rapid and long-lasting (4-72 h) induction of expression of IFN-γ, IL-10, and IL-22, signature cytokines for Th1-, Th2-, and Th17-type responses, respectively, in head kidney leukocytes. However, rtIL-21 had little effects on the expression of other cytokines studied. rtIL-21 maintained the expression of CD8α, CD8β, and IgM at a late stage of stimulation when their expression was significantly decreased in controls and increased the expression of the Th cell markers CD4, T-bet, and GATA3. Intraperitoneal injection of rtIL-21 confirmed the in vitro bioactivity and increased the expression of IFN-γ, IL-10, IL-21, IL-22, CD8, and IgM. Inhibition experiments revealed that the activation of JAK/STAT3, Akt1/2, and PI3K pathways were responsible for rtIL-21 action. This study helps to clarify the role of IL-21 in lower vertebrates for the first time, to our knowledge, and suggests IL-21 is a likely key regulator of T and B cell function in fish.
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http://dx.doi.org/10.4049/jimmunol.1001203DOI Listing
January 2011

Individual sequence variability and functional activities of fibrinogen-related proteins (FREPs) in the Mediterranean mussel (Mytilus galloprovincialis) suggest ancient and complex immune recognition models in invertebrates.

Dev Comp Immunol 2011 Mar 19;35(3):334-44. Epub 2010 Nov 19.

Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (CSIC), Eduardo Cabello 6, 36208, Vigo, Spain.

In this paper, we describe sequences of fibrinogen-related proteins (FREPs) in the Mediterranean mussel Mytilus galloprovincialis (MuFREPs) with the fibrinogen domain probably involved in the antigen recognition, but without the additional collagen-like domain of ficolins, molecules responsible for complement activation by the lectin pathway. Although they do not seem to be true or primive ficolins since the phylogenetic analysis are not conclusive enough, their expression is increased after bacterial infection or PAMPs treatment and they present opsonic activities similar to mammalian ficolins. The most remarkable aspect of these sequences was the existence of a very diverse set of FREP sequences among and within individuals (different mussels do not share any identical sequence) which parallels the extraordinary complexity of the immune system, suggesting the existence of a primitive system with a potential capacity to recognize and eliminate different kind of pathogens.
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http://dx.doi.org/10.1016/j.dci.2010.10.007DOI Listing
March 2011

Effect of diaphragm and lubricant gel provision on human papillomavirus infection among women provided with condoms: a randomized controlled trial.

Obstet Gynecol 2008 11;112(5):990-7

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94118, USA.

Objective: To estimate the effect of providing women with a latex diaphragm, lubricant gel, and male condoms (intervention) compared with condoms alone (control) on human papillomavirus (HPV) incidence and clearance.

Methods: Participants were 2,040 human immunodeficiency virus (HIV)-negative Zimbabwean women enrolled in a randomized trial estimating the effect of the intervention on HIV acquisition. Clinicians collected cervical samples for HPV testing at baseline, 12 months, and exit. L1 consensus polymerase chain reaction primers were used to determine HPV presence and type.

Results: We found no differences in the following outcomes: HPV prevalence at the time of the first postenrollment HPV test (intention-to-treat analysis, relative risk [RR] 1.02, 95% confidence interval [CI] 0.90-1.16); HPV incidence at 12 months among women HPV-negative at baseline (RR 0.95, 95% CI 0.80-1.14); and HPV clearance at 12 months among women HPV-positive at baseline (RR 0.80, 95% CI 0.61-1.05). Clearance of HPV type 58 was lower in the intervention group at 12 months (RR 0.67, 95% CI 0.48-0.92), but not at exit (RR 0.93, 95% CI 0.75-1.16); clearance of HPV type 18 was lower in the intervention group at exit (RR 0.55, 95% CI 0.33-0.89), but not at 12 months (RR 0.55, 95% CI 0.29-1.05). Women reporting diaphragm/gel use at 100% of prior sex acts had a lower likelihood of having one or more new HPV types detected at 12 months (RR 0.75, 95% CI 0.58-0.96) and exit (RR 0.77, 95% CI 0.59-0.99).

Conclusion: Among women receiving risk reduction counseling and condoms in an HIV prevention program, diaphragm plus lubricant gel provision did not affect HPV incidence or clearance.

Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00121459

Level Of Evidence: I.
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http://dx.doi.org/10.1097/AOG.0b013e318189a8a4DOI Listing
November 2008

Crystal structure of the MYB domain of the RAD transcription factor from Antirrhinum majus.

Proteins 2006 Dec;65(4):1041-5

Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, United Kingdom.

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http://dx.doi.org/10.1002/prot.21136DOI Listing
December 2006

Effect of Replens gel used with a diaphragm on tests for human papillomavirus and other lower genital tract infections.

J Low Genit Tract Dis 2006 Oct;10(4):213-8

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143-0128, USA.

Objective: Little is known about effects of vaginal lubricants with barrier contraceptives on detection of sexually transmissible infections. We hypothesized that Replens gel used with a diaphragm would neither inhibit human papillomavirus (HPV) detection in cervical samples and chlamydia (CT) and gonorrhea (GC) detection in urine samples, nor affect cervical cytology quality.

Materials And Methods: After a clinician-collected cervical sample and a self-collected vaginal sample for HPV detection ("pregel" specimens), women placed a diaphragm containing Replens gel into the vagina. Participants (n = 77) removed the diaphragm after 6 hours and performed vaginal HPV self-sampling at several time points thereafter. Clinicians performed cervical cytology sampling and HPV testing ("postgel" specimens) 24 hours after diaphragm removal. Pregel and postgel specimens were analyzed with and without added SiHa cells (source of defined numbers of HPV16 genomes). HPV was detected by polymerase chain reaction using MY09/11 primers. Urine samples were obtained for CT and GC testing. Proportions of samples testing positive were compared using relative risk (RR) regression models.

Results: Proportions with detectable HPV in the clinician-collected cervical pregel and postgel samples were not statistically different for samples with added SiHa cells (88.3% vs 93.2%, RR = 1.06, 95% confidence interval = 0.96-1.14) or for native HPV infection (32.9% vs 28.2%, RR = 0.87, 95% confidence interval = 0.71-1.06). In self-collected vaginal postgel samples, there was no trend for decreased HPV detection after gel exposure. Gel affected neither urine tests for CT and GC nor cytological quality.

Conclusions: Recent Replens gel use with a diaphragm does not inhibit cervical HPV testing, urine testing for CT and GC, or cervical cytology quality.
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http://dx.doi.org/10.1097/01.lgt.0000225889.13916.c6DOI Listing
October 2006