Occurrence of two distinct urotensin II-related peptides in zebrafish provides new insight into the evolutionary history of the urotensin II gene family

The urotensin II (UII) family is currently known to consist of two paralogous peptides, namely UII and UII-related peptide (URP). In contrast to UII, which has been identified in all vertebrate classes so far, URP has only been characterized in tetrapods. We report here the occurrence of two distinct URP genes in teleosts, which we have named URP1 and URP2. Synteny analysis revealed that teleost URP1 and URP2 genes and tetrapod URP genes represent three distinct paralog genes that, together with the UII gene, probably arose from the two rounds of tetraploidization, which took place early in vertebrate evolution. The absence of URP in fish indicates that the corresponding gene has been lost in the teleost lineage, whereas it is likely that both the URP1 and URP2 genes have been lost in the tetrapod lineage. Quantitative RT-PCR analysis revealed that the URP2 gene is mainly expressed in the spinal cord and the brain in adult zebrafish. In situ hybridization experiments showed that in zebrafish embryos, URP2 mRNA-containing cells are located in the floor plate of the neural tube. In adult, URP2-expressing cells occur in close contact with the ventral side of the ependymal canal along the whole spinal cord, whereas in the brain, they are located below the fourth ventricle. These URP-expressing cells may correspond to cerebrospinal fluid-contacting neurons. In conclusion, our study reveals the occurrence of four distinct UII paralogous systems in vertebrates that may exert distinct functions, both in tetrapods and teleosts.     

Comparative genomics provides insights into the aquatic adaptations of mammals

The ancestors of marine mammals once roamed the land and independently committed to an aquatic lifestyle. These macroevolutionary transitions have intrigued scientists for centuries. Here, we generated high-quality genome assemblies of 17 marine mammals (11 cetaceans and six pinnipeds), including eight assemblies at the chromosome level. Incorporating previously published data, we reconstructed the marine mammal phylogeny and population histories and identified numerous idiosyncratic and convergent genomic variations that possibly contributed to the transition from land to water in marine mammal lineages. Genes associated with the formation of blubber (NFIA), vascular development (SEMA3E), and heat production by brown adipose tissue (UCP1) had unique changes that may contribute to marine mammal thermoregulation. We also observed many lineage-specific changes in the marine mammals, including genes associated with deep diving and navigation. Our study advances understanding of the timing, pattern, and molecular changes associated with the evolution of mammalian lineages adapting to aquatic life.

Species invasions into novel habitats mark major transitions in the evolution of life on Earth. Some of these are relatively ancient, such as the vertebrate transition from the oceans to life on land (∼375 Mya) or the evolution of arboreal vertebrate species (∼160 Mya). When divergent lineages transition to the same novel habitat, it provides an opportunity to investigate the mechanisms that permit these adaptations and the relationship between similar phenotypes among lineages and the underlying genetic basis. Convergent processes may utilize homologous genomic regions in different lineages to achieve similar phenotypes (1). Alternatively, distinct, genomic processes may be possible (2), or genetic drift may lead to different options for divergent lineages. Relatively recent transitions may be the most informative, on the assumption that extended periods of evolution may obscure the relationship between genomic differences and the original adaptations. A system well suited to this investigation is the adaptation of divergent, terrestrial mammalian lineages to life in aquatic environments.Marine mammals, broadly defined as mammals whose terrestrial predecessors entered the sea and who obtain all or most of their food from a marine environment, comprise at least 129 extant species divided into three orders (3). Cetartiodactyla includes cetaceans (whales, dolphins, and porpoises); Carnivora includes pinnipeds (walruses, sea lions, and seals), sea otters, and polar bears; and Sirenia includes sea cows (now extinct), manatees, and dugongs (3). Of these, cetaceans, pinnipeds, and sirenians are considered the oldest groups of marine mammals (3). In contrast, sea otters and the polar bear emerged relatively recently so much so that the polar bear can still hybridize with terrestrial sister taxa (3–5). The most species-rich group of marine mammals is Cetacea, which comprises ∼90 species (3). Cetaceans, pinnipeds, and sirenians represent an exceptional case of convergent evolution—the emergence of similar phenotypic traits in species separated by millions of years of evolution (6). In these separate lineages of marine mammals, phenotypic convergence is observed in all major physiological systems (7, 8). The degree to which convergence is reflected at the molecular level can now be partially answered using genomics. However, the interpretation of such results has hitherto been restricted by the limited number of high-quality genomes from marine mammals (6, 9). Remaining uncertainties include the phylogenetic relationships between and within marine mammal groups and their demographic history. To address these questions, we assembled and annotated 17 marine mammal genomes (11 cetaceans and six pinnipeds). Based on more comprehensive genomic data, we identified many putative genetic innovations for the aquatic adaptation of mammals, including those associated with thermoregulation and skeletal systems.     

A candidate gene study in low HDL-cholesterol families provides evidence for the involvement of the APOA2 gene and the APOA1C3A4 gene cluster

In patients with premature coronary heart disease, the most common lipoprotein abnormality is high-density lipoprotein (HDL) deficiency. To assess the genetic background of the low HDL-cholesterol trait, we performed a candidate gene study in 25 families with low HDL, collected from the genetically isolated population of Finland. We studied 21 genes encoding essential proteins involved in the HDL metabolism by genotyping intragenic and flanking markers for these genes. We found suggestive evidence for linkage in two candidate regions: Marker D1S2844, in the apolipoprotein A-II (APOA2) region, yielded a LOD score of 2.14 and marker D11S939 flanking the apolipoprotein A-I/C-III/A-IV gene cluster (APOA1C3A4) produced a LOD score of 1.69. Interestingly, we identified potential shared haplotypes in these two regions in a subset of low HDL families. These families also contributed to the obtained positive LOD scores, whereas the rest of the families produced negative LOD scores. None of the remaining candidate regions provided any evidence for linkage. Since only a limited number of loci were tested in this candidate gene study, these LOD scores suggest significant involvement of the APOA2 gene and the APOA1C3A4 gene cluster, or loci in their immediate vicinity, in the pathogenesis of low HDL.     

Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord

Urotensin II (UII) is a cyclic peptide initially isolated from the caudal neurosecretory system of teleost fish. Subsequently, UII has been characterized from a frog brain extract, indicating that a gene encoding a UII precursor is also present in the genome of a tetrapod. Here, we report the characterization of the cDNAs encoding frog and human UII precursors and the localization of the corresponding mRNAs. In both frog and human, the UII sequence is located at the C-terminal position of the precursor. Human UII is composed of only 11 amino acid residues, while fish and frog UII possess 12 and 13 amino acid residues, respectively. The cyclic region of UII, which is responsible for the biological activity of the peptide, has been fully conserved from fish to human. Northern blot and dot blot analysis revealed that UII precursor mRNAs are found predominantly in the frog and human spinal cord. In situ hybridization studies showed that the UII precursor gene is actively expressed in motoneurons. The present study demonstrates that UII, which has long been regarded as a peptide exclusively produced by the urophysis of teleost fish, is actually present in the brain of amphibians and mammals. The fact that evolutionary pressure has acted to conserve fully the biologically active sequence of UII suggests that the peptide may exert important physiological functions in humans.     

Expressions of irisin and urotensin II and their relationships with blood pressure in patients with preeclampsia

The aims of this study are to observe irisin and urotensin II (UII) levels in serum and placenta in normal pregnant and preeclamptic women and investigate the relationship between expressions irisin and UII, and their association with blood pressure. A total of 67 pregnant subjects were recruited, including 31 healthy and 36 preeclamptic pregnant women. Serum irisin and UII concentrations were measured. Expressions of fibronectin type III domain-containing protein 5 (FNDC5) (irisin precursor) and UII in placenta specimens were performed. There was no significant difference of serum irisin levels between severe preeclamptic (SPE)) patients, mild preeclamptic (MPE) patients and normal controls, while serum UII was significantly higher in preeclamptic women than normal pregnancy. There was no relationship between serum UII and irisin levels. In patients with preeclampsia, serum irisin was negatively associated with systolic and diastolic blood pressure(r = ?0.350, P = 0.004, r = ?0.307, P = 0.011), while serum UII was positively associated with systolic blood pressure (r = 0.291, P = 0.031). Serum irisin, UII, urinary protein level, BMI and serum creatinine were the independent determinants of blood pressure in preeclampsia by multiple regression analysis. Protein expression of FNDC5 and UII was upregulated in placenta of patients with SPE and positively correlated with systolic blood pressure and urinary protein level. We firstly verify that serum irisin and placental irisin precursor expressions have differently correlated with blood pressure. Expressions of irisin and urotensin II have relationships with blood pressure in patients with preeclampsia     

A genome-wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

OBJECTIVE: Juvenile rheumatoid arthritis (JRA) represents a heterogeneous group of disorders with a complex genetic component. A genome scan was performed to detect linkage to JRA in 121 families containing 247 affected children in North America (the JRA Affected Sibpair [ASP] Registry). METHODS: Genotype data collected for HLA-DR and 386 microsatellite markers were subjected to multipoint nonparametric linkage analysis. Following analysis of the entire set of families, additional analyses were performed after a priori stratification by disease onset type, age at onset, disease course, and selected HLA-DRB1 alleles. RESULTS: Linkage of JRA to the HLA region was confirmed (logarithm of odds [LOD] score 2.26). Additional evidence supporting linkage of JRA was observed at 1p36 (D1S214; LOD 1.65), 19p13 (D19S216; LOD 1.72), and 20q13 (D20S100; LOD 1.75). For early-onset polyarticular disease, evidence of linkage was found at chromosome 7q11 (D7S502; LOD 3.47). For pauciarticular disease, evidence supporting linkage was observed on chromosome 19p13 (D19S216; LOD 2.98), the same marker that supported linkage to the "JRA" phenotype. Other regions supporting linkage with JRA disease subtype included 20q13, 4q24, 12q24, and Xp11. Stratification of families based on the presence of the HLA-DR8 allele in affected siblings resulted in significant linkage observed at 2p25 (D2S162/D2S305; LOD 6.0). CONCLUSION: These data support the hypothesis that multiple genes, including at least 1 in the HLA region, influence susceptibility to JRA. These findings for JRA are consistent with findings for other autoimmune diseases and support the notion that common genetic regions contribute to an autoimmune phenotype.     

In vitro effects of somatostatin and urotensin II on prolactin and growth hormone secretion in tilapia, Oreochromis mossambicus

The control of release of two recently characterized forms of prolactin (PRL) of molecular mass 24 and 20 kDa was investigated. The rostral pars distalis of male tilapia was incubated singly in a hypotonic modified Krebs-Ringer bicarbonate medium in order to stimulate PRL release; for comparison, the proximal pars distalis containing growth hormone (GH) cells was incubated in isotonic medium with or without 1 microgram/ml cortisol to stimulate GH release. The release of both PRLs and GH into the medium was measured by sodium dodecyl sulfate (SDS)--polyacrylamide gel electrophoresis followed by densitometry. Both somatostatin and synthetic (Gillichthys) urotensin II, a partial somatostatin homolog and analog from the teleost caudal neurosecretory system, significantly inhibited the release of both PRLs. Somatostatin significantly inhibited GH release, but urotensin II had no significant effect.     

Effects of somatostatin and urotensin II on tilapia pituitary prolactin release and interactions between somatostatin, osmotic pressure Ca++, and adenosine 3',5'-monophosphate in prolactin release in vitro

Both somatostatin (SRIF) and urotensin II, a dodecapeptide from the teleost caudal neurosecretory system, inhibit PRL release from the organ-cultured rostral pars distalis of the tilapia, Sarotherodon mossambicus, in a dose-related manner. The inhibitory action of SRIF on PRL release was completely prevented by the presence of the calcium ionophore A23187. PRL release was also blocked when Ca++ was excluded from the incubation medium, even in the presence of the ionophore. Both dibutyryl cAMP (dbcAMP) and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, alone or in combination, stimulated PRL release during incubation in high osmotic pressure medium. The effect of dbcAMP appeared to be dose related. Together, dbcAMP and 3-isobutyl-1-methylxanthine were also effective in preventing the inhibition of PRL release by SRIF. These results are consistent with the notion that Ca++, and possibly cAMP, may be important mediators of PRL secretion, and it is likely that SRIF may inhibit PRL release by blocking a Ca++- or cAMP-mediated mechanism.     

Structural, functional, and evolutionary relationships between λ-exonuclease and the type II restriction endonucleases

λ-exonuclease participates in DNA recombination and repair. It binds a free end of double-stranded DNA and degrades one strand in the 5′ to 3′ direction. The primary sequence does not appear to be related to any other protein, but the crystal structure shows part of λ-exonuclease to be similar to the type II restriction endonucleases PvuII and EcoRV. There is also a weaker correspondence with EcoRI, BamHI, and Cfr10I. The structure comparisons not only suggest that these enzymes all share a similar catalytic mechanism and a common structural ancestor but also provide strong evidence that the toroidal structure of λ-exonuclease encircles its DNA substrate during hydrolysis.     

Comparative genomics uncovers the evolutionary history,demography, and molecular adaptations of South American canids

The remarkable radiation of South American (SA) canids produced 10 extant species distributed across diverse habitats, including disparate forms such as the short-legged, hypercarnivorous bush dog and the long-legged, largely frugivorous maned wolf. Despite considerable research spanning nearly two centuries, many aspects of their evolutionary history remain unknown. Here, we analyzed 31 whole genomes encompassing all extant SA canid species to assess phylogenetic relationships, interspecific hybridization, historical demography, current genetic diversity, and the molecular bases of adaptations in the bush dog and maned wolf. We found that SA canids originated from a single ancestor that colonized South America 3.9 to 3.5 Mya, followed by diversification east of the Andes and then a single colonization event and radiation of Lycalopex species west of the Andes. We detected extensive historical gene flow between recently diverged lineages and observed distinct patterns of genomic diversity and demographic history in SA canids, likely induced by past climatic cycles compounded by human-induced population declines. Genome-wide scans of selection showed that disparate limb proportions in the bush dog and maned wolf may derive from mutations in genes regulating chondrocyte proliferation and enlargement. Further, frugivory in the maned wolf may have been enabled by variants in genes associated with energy intake from short-chain fatty acids. In contrast, unique genetic variants detected in the bush dog may underlie interdigital webbing and dental adaptations for hypercarnivory. Our analyses shed light on the evolution of a unique carnivoran radiation and how it was shaped by South American topography and climate change.

The arrival and diversification of mammals in South America during the 66-My history of the Cenozoic has long interested paleontologists and evolutionary biologists (1). The immigration of carnivorous mammals such as canids, felids, procyonids, and ursids from North America into South America during the Great American Biotic Interchange in the Pliocene was especially noteworthy and led to the turnover and extinction of many endemic species, facilitating the diversification of the colonizing lineages. As a primary example, South America harbors the most diverse extant canid community, with 10 currently recognized species (2), including disparate forms such as the squat bush dog and the long-legged maned wolf (Fig. 1). Due to their rapid and relatively recent diversification, three fundamental aspects of their evolutionary history remain uncertain.Open in a separate windowFig. 1.Species tree and ancestral area reconstruction of SA canids. The species tree was estimated by applying ASTRAL-III (45) to 6,716 genomic windows (25 kb each). A total of 31 genomes were included in the analysis (SI Appendix, Table S1), but only the clade containing SA canids is shown here (see complete tree in SI Appendix, Fig. S1). All nodes had 100% bootstrap support based on 100 replicates. The best-fitting BioGeoBEARS (46) model was DIVALIKE (dispersal vicariance) with the parameter “J” that represents a founder event (SI Appendix, Fig. S2 and Table S2). Colored boxes on each node indicate estimated ancestral ranges, while boxes at terminal branches indicate current species distribution (“e,” east of the Andes; “c,” central region of the Andes; and “w,” west of the Andes). The probabilities of these ancestral regions are shown in the pie charts below each node. Purple-colored pie charts indicate a distribution on the west and east of the Andes. The maps on the Right represent the distribution of species within three major clades. The colored distributions on the map match the colors underlining species names. Canid illustrations from ref. 2 are used with permission from Princeton University Press.First, the pattern of invasion and dispersion of canids into South America is poorly defined. Although it is widely agreed that the first canids migrated into South America using the Panama land bridge, when this migration event occurred is uncertain. Molecular, fossil, and geological data suggest that several terrestrial dispersal events may have occurred prior to the generally cited estimate of approximately 3 Mya for the complete formation of the land bridge (3–5). There is also uncertainty about the number of ancestral lineages that entered South America and the antiquity of their diverse adaptations (6–13). The Andes were close to their present-day elevation 6 Mya in the Late Miocene (14). Therefore, when canids arrived in South America, the Andes formed a distinct geographic barrier that extended along the length of the continent (9, 13, 15–19). Although canids are found on both sides of the Andes, the ancestral canid lineage could have entered the east or west side of the Andes or both sides simultaneously and subsequently diversified. Knowing the number of invasions and dispersion of canid lineages in South America is critical to understanding the timing, interrelationships, and environmental correlates underlying this burst of speciation.Second, the extent and timing of speciation and lineage-specific demographic history, including the potential impact of substantial climatic differences on each side of the Andes, are not well understood. Along the eastern lowlands, the glacial periods of the Pleistocene led to an expansion of savanna vegetation into areas that now support forest (20–23). To the west, glacial periods caused the expansion of glaciers in the south and shifts of vegetation zones along the Andean slopes (24–26). These changes likely reduced the availability of favorable habitats for some canid species but extended the distribution of others (20, 27, 28). Currently, the Andes restrict the geographic range of western species, leaving only a relatively narrow belt between the mountains and the Pacific Ocean (29).Finally, the genetic complexity of the unique adaptations observed in the bush dog (Speothos venaticus) and the maned wolf (Chrysocyon brachyurus), sister species with extraordinary morphological differences (30–36), has not been explored. The bush dog is the only obligate meat-eating (hypercarnivorous) canid in the Americas that survived the Late Pleistocene extinction (11, 36). It has a suite of dental and skeletal specializations that are linked to its ability to capture and process prey (37–39). These features include short robust legs with webbed feet to dig burrows for hunting and shelter, long bodies with short tails, a unique extension of the meat cutting blade in the upper fourth premolar (P4) and lower first molar (M1) teeth (a trenchant heel), and loss of molars which in other canids function to crush hard plant foods (36, 38–40). The maned wolf is the only large-bodied canid in South America to survive the Late Pleistocene megafaunal extinctions, which may reflect its ability to exploit a wide range of foods in the savanna-like Cerrado environment, including a large proportion of fruits in its diet (30, 31, 41–43). Furthermore, the maned wolf has the longest limbs among canids (Fig. 1) but is not a swift runner (31, 35), as its speed is limited by its unique racking gait characterized by lifting both feet on each side of the body simultaneously, facilitating movement through tall grassland (30, 44). Although certain aspects of the biology of bush dogs and maned wolves have been extensively studied (30–36), the genomic underpinnings of their extraordinary adaptations remain unknown.We investigated the evolutionary history of South American (SA) canids using newly generated whole-genome sequence data to assess phylogenetic relationships, evidence of interspecies gene flow, demographic history, and patterns of genomic diversity. To investigate adaptive evolution and genome variation in the maned wolf and bush dog, we generated de novo genome assemblies for both species and additionally sequenced four maned wolves and three bush dogs to characterize patterns of genetic diversity in the wild.     

rbcL gene sequences provide evidence for the evolutionary lineages of leptosporangiate ferns.

Pteriodophytes have a longer evolutionary history than any other vascular land plant and, therefore, have endured greater loss of phylogenetically informative information. This factor has resulted in substantial disagreements in evaluating characters and, thus, controversy in establishing a stable classification. To compare competing classifications, we obtained DNA sequences of a chloroplast gene. The sequence of 1206 nt of the large subunit of the ribulose-bisphosphate carboxylase gene (rbcL) was determined from 58 species, representing almost all families of leptosporangiate ferns. Phlogenetic trees were inferred by the neighbor-joining and the parsimony methods. The two methods produced almost identical phylogenetic trees that provided insights concerning major general evolutionary trends in the leptosporangiate ferns. Interesting findings were as follows: (i) two morphologically distinct heterosporous water ferns, Marsilea and Salvinia, are sister genera; (ii) the tree ferns (Cyatheaceae, Dicksoniaceae, and Metaxyaceae) are monophyletic; and (iii) polypodioids are distantly related to the gleichenioids in spite of the similarity of their exindusiate soral morphology and are close to the higher indusiate ferns. In addition, the affinities of several "problematic genera" were assessed.     

Human urotensin II as a link between hypertension and coronary artery disease.

Hypertension is a well-known risk factor for atherosclerosis, but the molecular mechanisms that link elevated blood pressure to the progression of atherosclerosis remain unclear. Human urotensin II (U-II), the most potent endogenous vasoconstrictor peptide identified to date, and its receptor (UT receptor) are involved in the etiology of essential hypertension. In patients with essential hypertension, U-II infused into the forearm brachial artery has been shown to induce vasoconstriction. Recent studies have demonstrated elevated plasma U-II concentrations in patients with essential hypertension, diabetes mellitus, atherosclerosis, and coronary artery disease. U-II is expressed in endothelial cells, macrophages, macrophage-derived foam cells, and myointimal and medial vascular smooth muscle cells (VSMCs) of atherosclerotic human coronary arteries. UT receptors are present in VSMCs of human coronary arteries, the thoracic aorta and cardiac myocytes. Lymphocytes are the most active producers of U-II, whereas monocytes and macrophages are the major cell types expressing UT receptors, with relatively little receptor expression in foam cells, lymphocytes, and platelets. U-II accelerates foam cell formation by up-regulation of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-derived macrophages. In human endothelial cells, U-II promotes cell proliferation and up-regulates type 1 collagen expression. U-II also activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and plasminogen activator inhibitor-1 in human VSMCs, and stimulates VSMC proliferation with synergistic effects observed when combined with oxidized low-density lipoprotein, lysophosphatidylcholine, reactive oxygen species or serotonin. These findings suggest that U-II plays key roles in accelerating the development of atherosclerosis, thereby leading to coronary artery disease.     

Specificity of response of intestinal ion transport systems to a pair of natural peptide hormone analogs: somatostatin and urotensin II

Specificity of two intestinal ion transport systems toward the natural peptide hormone analogs somatostatin and urotensin II has been demonstrated by electrophysiological and radiotracer studies in vitro. Somatostatin inhibits active C1 secretion across the theophylline-treated rat colon but urotensin II, a dodecapeptide somatostatin analog from the teleost caudal neurosecretory system, is without effect. Conversely, urotensin II stimulates active Na and C1 absorption across the posterior intestine of the 5% seawater-adapted goby, Gillichthys mirabilis, but somatostatin is ineffective. From these and others' studies, it appears that in both systems, increased net absorption results from increased mucosal-to-serosal unidirectional ion fluxes. Based on structure-activity relationships in these and other systems, it is speculated that the difference in amino acid residues at position 4 (somatostatin-Lys, urotensin II-Ala) may contribute to the observed specificity.     

Association between essential hypertension and three vasoactive peptides,urotensin II,endothelin and adrenomedullin

Abstract

Aim: The aim of the study is to measure the vasoactive peptides, urotensin II (UII), endothelin (ET) and adrenomedullin (ADM) in a well-characterized population of normal controls and patients with essential hypertension, and to study their association with this disease. Methods: The contents of plasma UII, ET and ADM were measured by radioimmunoassay in 40 normal controls and 120 patients with essential hypertension. Echocardiographic examinations were performed using an ultrasonic system, and the left ventricular end diastolic diameter (LVEDd) along with the left ventricular posterior wall thickness (LVPWT) and interventricular septal thickness (IST) were determined. The left ventricular mass index (LVMI) was calculated according to the method reported by Devereux et al. Results: Plasma UII, ET and ADM contents were increased in patients than healthy controls (3.28?±?1.257?pmol/L vs. 1.80?±?0.639?pmol/L, p?<?0.01), and correlated with the severity of hypertension in patients. Besides, all the three vasoactive peptides in plasma had significant correlations with SBP, IST, LVPWT, LVMI (p?≤?0.05), while they showed insignificant associations with LVEDd (p?>?0.05). UII was remarkably associated with ADM content, while the association of UII level with LVEDd and ET content were not significant. Conclusion: The vasoactive peptides UII, ET and ADM may be involved in the pathophysiologic process of essential hypertension, and function as the indicators for severity of this disease.     

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

Objective

Juvenile rheumatoid arthritis (JRA) represents a heterogeneous group of disorders with a complex genetic component. A genome scan was performed to detect linkage to JRA in 121 families containing 247 affected children in North America (the JRA Affected Sibpair [ASP] Registry).

Methods

Genotype data collected for HLA–DR and 386 microsatellite markers were subjected to multipoint nonparametric linkage analysis. Following analysis of the entire set of families, additional analyses were performed after a priori stratification by disease onset type, age at onset, disease course, and selected HLA–DRB1 alleles.

Results

Linkage of JRA to the HLA region was confirmed (logarithm of odds [LOD] score 2.26). Additional evidence supporting linkage of JRA was observed at 1p36 (D1S214; LOD 1.65), 19p13 (D19S216; LOD 1.72), and 20q13 (D20S100; LOD 1.75). For early‐onset polyarticular disease, evidence of linkage was found at chromosome 7q11 (D7S502; LOD 3.47). For pauciarticular disease, evidence supporting linkage was observed on chromosome 19p13 (D19S216; LOD 2.98), the same marker that supported linkage to the “JRA” phenotype. Other regions supporting linkage with JRA disease subtype included 20q13, 4q24, 12q24, and Xp11. Stratification of families based on the presence of the HLA–DR8 allele in affected siblings resulted in significant linkage observed at 2p25 (D2S162/D2S305; LOD 6.0).

Conclusion

These data support the hypothesis that multiple genes, including at least 1 in the HLA region, influence susceptibility to JRA. These findings for JRA are consistent with findings for other autoimmune diseases and support the notion that common genetic regions contribute to an autoimmune phenotype.

     

Diversification of rhacophorid frogs provides evidence for accelerated faunal exchange between India and Eurasia during the Oligocene

The accretion of the Indian subcontinent to Eurasia triggered a massive faunal and floral exchange, with Gondwanan taxa entering into Asia and vice versa. The traditional view on the Indian–Asian collision assumes contact of the continental plates during the Early Eocene. Many biogeographic studies rely on this assumption. However, the exact mode and timing of this geological event is still under debate. Here we address, based on an extensive phylogenetic analysis of rhacophorid tree frogs, if there was already a Paleogene biogeographic link between Southeast Asia and India; in which direction faunal exchange occurred between India and Eurasia within the Rhacophoridae; and if the timing of the faunal exchange correlates with one of the recently suggested geological models. Rhacophorid tree frogs showed an early dispersal from India to Asia between 46 and 57 Ma, as reconstructed from the fossil record. During the Middle Eocene, however, faunal exchange ceased, followed by increase of rhacophorid dispersal events between Asia and the Indian subcontinent during the Oligocene that continued until the Middle Miocene. This corroborates recent geological models that argue for a much later final collision between the continental plates. We predict that the Oligocene faunal exchange between the Indian subcontinent and Asia, as shown here for rhacophorid frogs, also applies for other nonvolant organisms with an Indian–Asian distribution, and suggest that previous studies that deal with this faunal interchange should be carefully reinvestigated.     

Further evidence of a close anatomical relation between the oesophagus and pulmonary veins.

BACKGROUND: Atrio-oesophageal fistula has been reported as a rare but life-threatening complication of ablation of atrial fibrillation (AF). Therefore, the position of the oesophagus in relation to the left atrium (LA) is of major importance for AF ablation. METHODS AND RESULTS: In order to investigate the possible anatomical variability between the oesophagus and the left atrium, multidetector-row spiral computed tomography (MDCT) of 60 healthy males (age 58.1+/-5.1 years; LA diameter 5.4+/-0.7 x 3.8+/-0.6 cm; LA volume 60.5+/-15.4 ml) was analyzed. The distance between the oesophagus and the ostia of the pulmonary veins (PV) ranged between 0 and 50.7 mm. Especially for the left PV, the oesophagus was closer than 5 mm to the ostia in 29 cases (48%; n = 24 for left superior PV; n = 10 for left inferior PV; n = 0 for right superior PV; n = 1 for right inferior PV). In addition, the oesophagus was very close to the LA wall (0.8+/-0.9 mm; range 0-3.3 mm). Intraobserver variability was 1.1+/-0.7 mm or 3.5%. CONCLUSION: The position of the oesophagus in relation to the LA and the PV demonstrates high variability. In many cases, the oesophagus is very close to the ostia of the PVs and lies only a short distance from the LA wall. Thus, an anatomical localization of the oesophagus may be critical before or during AF ablation to prevent atrio-oesophageal fistula, especially as there is a need for transmural atrial lesions.     

Renal haemodynamic and tubular actions of urotensin II in the rat

Urotensin II (UTS) is a potent vasoactive peptide that was originally identified in teleost fish. Mammalian orthologues of UTS and its receptor (UTSR) have been described in several species, including humans and rats. We have shown previously that bolus injections of UTS caused a decrease in urine flow and sodium excretion rates in parallel with marked reductions in renal blood flow (RBF) and glomerular filtration rate (GFR). The aim of this study was to determine the effect of UTS infusion at a dose that has minimal impact upon renal haemodynamics in order to identify a potential direct tubular action of UTS. Infusion of rat UTS (rUTS) at 0.6 pmol/min per 100 g body weight in male Sprague-Dawley rats, which had no effect on RBF and caused a 30% reduction in GFR, resulted in a significant increase in the fractional excretion of sodium (vehicle 2.3+/-0.6 versus rUTS 0.6 pmol 4.5+/-0.6%, P<0.05) and potassium. At the higher dose of 6 pmol/min per 100 g body weight, haemodynamic effects dominated the response. rUTS induced a marked reduction in RBF and GFR (vehicle 1.03+/-0.06 versus rUTS 6 pmol 0.31+/-0.05 ml/min per 100 g body weight, P<0.05) resulting in an anti-diuresis and anti-natriuresis, but no change in fractional excretion of sodium or potassium. Uts2d and Uts2r mRNA expression were greater in the renal medulla compared with the cortex. Together, these data support an inhibitory action of Uts2d on renal tubule sodium and potassium reabsorption in the rat, in addition to its previously described renal haemodynamic effects.