Novel PITX2 Homeodomain-Contained Mutations from ATRIAL Fibrillation Patients Deteriorate Calcium Homeostasis

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the human population, with an estimated incidence of 1¿2% in young adults but increasing to more than 10% in 80+ years patients. Pituitary Homeobox 2, Paired Like Homeodomain 2 (PITX2c) loss-of-function in mice revealed that this homeodomain (HD)-containing transcription factor plays a pivotal role in atrial electrophysiology and calcium homeostasis and point to PITX2 as a candidate gene for AF. To address this issue, we recruited 31 AF patients for genetic analyses of both the known risk alleles and PITX2c open reading frame (ORF) re-sequencing. We found two-point mutations in the homedomain of PITX2 and three other variants in the 5¿untranslated region. A 65 years old male patient without 4q25 risk variants but with recurrent AF displayed two distinct HD-mutations, NM_000325.5:c.309G>C (Gln103His) and NM_000325.5:c.370G>A (Glu124Lys), which both resulted in a change within a highly conserved amino acid position. To address the functional impact of the PITX2 HD mutations, we generated plasmid constructs with mutated version of each nucleotide variant (MD4 and MD5, respectively) as well as a dominant negative control construct in which the PITX2 HD was lacking (DN). Functional analyses demonstrated PITX2c MD4 and PITX2c MD5 decreased Nppa-luciferase transactivation by 50% and 40%, respectively, similar to the PITX2c DN (50%), while Shox2 promoter repression was also impaired. Co-transactivation with other cardiac-enriched co-factors, such as Gata4 and Nkx2.5, was similarly impaired, further supporting the pivotal role of these mutations for correct PITX2c function. Furthermore, when expressed in HL1 cardiomyocyte cultures, the PITX2 mutants impaired endogenous expression of calcium regulatory proteins and induced alterations in sarcoplasmic reticulum (SR) calcium accumulation. This favored alternating and irregular calcium transient amplitudes, causing deterioration of the beat-to-beat stability upon elevation of the stimulation frequency. Overall this data demonstrate that these novel PITX2c HD-mutations might be causative of atrial fibrillation in the carrier.This work was supported by grants from The Spanish Ministry of Science Innovation and Universities [SAF2017-88019-C3-1-R] to L.H.-M. V.J.-S. was employed by CIBERCV [RD12/0042/0002] grant. Work was also supported by a PhD scholarship [FPU18/01250] to S.C., and partially funded by grants from Generalitat de Catalunya [SGR2017-1769] and Fundació Marato TV3 [20152030] to L.H.-M., a translational CNIC grant [2009/08] to D.F., R.C. and L.H.-M. and a grant-in-aid from the Junta de Andalucia Regional Council to D.F. and A.A. [CTS-446]

The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homeostasis

Aims: Single nucleotide polymorphisms on chromosome 4q25 have been associated with risk of atrial fibrillation (AF) but the exiguous knowledge of the mechanistic links between these risk variants and underlying electrophysiological alterations hampers their clinical utility. Here, we here tested the hypothesis that 4q25 risk variants cause alterations in the intracellular calcium homeostasis that predispose to spontaneous electrical activity. Methods and results: Western blotting, confocal calcium imaging, and patch-clamp techniques were used to identify mechanisms linking the 4q25 risk variants rs2200733T and rs13143308T to defects in the calcium homeostasis in human atrial myocytes. Our findings revealed that the rs13143308T variant was more frequent in patients with AF and that myocytes from carriers of this variant had a significantly higher density of calcium sparks (14.1±4.5 vs. 3.1±1.3 events/min, p¿=¿0.02), frequency of transient inward (ITI) currents (1.33±0.24 vs. 0.26±0.09 events/min, p¿<¿0.001) and incidence of spontaneous membrane depolarizations (1.22±0.26 vs. 0.56±0.17 events/min, p¿=¿0.001) than myocytes from patients with the normal rs13143308G variant. These alterations were linked to higher sarcoplasmic reticulum calcium loading (10.2±1.4 vs. 7.3±0.5amol/pF, p¿=¿0.01), SERCA2 expression (1.37±0.13 fold, p¿=¿0.03) and RyR2 phosphorylation at s2808 (0.67±0.08 vs. 0.47±0.03, p¿=¿0.01) but not at s2814 (0.28±0.14 vs. 0.31±0.14, p¿=¿0.61) in patients carrying the rs13143308T risk variant. Furthermore, the presence of a risk variant or AF independently increased the ITI frequency and the increase in the ITI frequency observed in carriers of the risk variants was exacerbated in those with AF. By contrast, the presence of a risk variant did not affect the amplitude or properties of the L-type calcium current in patients with or without AF. Conclusions: We here identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylationThis work was supported by multi-centric grants from Centro Nacional de Investigaciones Cardiovasculares [CNIC-2009-08 to L.H.-M. and D.F.]; a grant from Fundacio´ Marato´ TV3 [2015-20-30 to L.H.-M.]; and grants from the Spanish Ministry of Economy and Competition [SAF2014-58286-C2-1-R to L.H.-M.] and [DPI2013-44584-R to R.B.]; and from the Spanish Ministry of Health and Consume, Instituto de Salud Carlos III, Red de Investigacio´n Cardiovascular [RD12/0042/0002] and CIBERCV to J.C., and from Fondo Europeo de Desarrollo Regional (FEDER)

Disentangling environmental correlates of vascular plant biodiversity in a Mediterranean hotspot

We determined the environmental correlates of vascular plant biodiversity in the Baetic-Rifan region, a plant biodiversity hotspot in the western Mediterranean. A catalog of the whole flora of Andalusia and northern Morocco, the region that includes most of the Baetic-Rifan complex, was compiled using recent comprehensive floristic catalogs. Hierarchical cluster analysis (HCA) and detrended correspondence analysis (DCA) of the different ecoregions of Andalusia and northern Morocco were conducted to determine their floristic affinities. Diversity patterns were studied further by focusing on regional endemic taxa. Endemic and nonendemic alpha diversities were regressed to several environmental variables. Finally, semi-partial regressions on distance matrices were conducted to extract the respective contributions of climatic, altitudinal, lithological, and geographical distance matrices to beta diversity in endemic and nonendemic taxa. We found that West Rifan plant assemblages had more similarities with Andalusian ecoregions than with other nearby northern Morocco ecoregions. The endemic alpha diversity was explained relatively well by the environmental variables related to summer drought and extreme temperature values. Of all the variables, geographical distance contributed by far the most to spatial turnover in species diversity in the Baetic-Rifan hotspot. In the Baetic range, elevation was the most significant driver of nonendemic species beta diversity, while lithology and elevation were the main drivers of endemic beta diversity. Despite the fact that Andalusia and northern Morocco are presently separated by the Atlantic Ocean and the Mediterranean Sea, the Baetic and Rifan mountain ranges have many floristic similarities – especially in their western ranges – due to past migration of species across the Strait of Gibraltar. Climatic variables could be shaping the spatial distribution of endemic species richness throughout the Baetic-Rifan hotspot. Determinants of spatial turnover in biodiversity in the Baetic-Rifan hotspot vary in importance between endemic and nonendemic species

First comprehensive contribution to medical ethnobotany of Western Pyrenees

<p>Abstract</p> <p>Background</p> <p>An ethnobotanical and medical study was carried out in the Navarre Pyrenees, an area known both for its high biological diversity and its cultural significance.</p> <p>As well as the compilation of an ethnopharmacological catalogue, a quantitative ethnobotanical comparison has been carried out in relation to the outcomes from other studies about the Pyrenees. A review of all drugs used in the area has also been carried out, through a study of the monographs published by the institutions and organizations responsible for the safety and efficacy of medicinal plants (WHO, ESCOP, and the E Commission of the German Department of Health) in order to ascertain the extent to which the Navarre Pyrenees ethnopharmacology has been officially evaluated.</p> <p>Methods</p> <p>Fieldwork was carried out over two years, from November 2004 to December 2006. During that time we interviewed 88 local people in 40 villages. Information was collected using semi-structured ethnobotanical interviews and the data was analyzed using quantitave indexes: Ethnobotonicity Index, Shannon-Wiener's Diversity, Equitability and The Informant Consensus Factor. The official review has been performed using the official monographs published by the WHO, ESCOP and the E Commission of the German Department of Health.</p> <p>Results</p> <p>The ethnobotanical and medical catalogue of the Navarre Pyrenees Area comprises 92 species, of which 39 have been mentioned by at least three interviewees. The quantitative ethnobotany results show lower values than those found in other studies about the Pyrenees; and 57.6% of the Pyrenees medical ethnobotany described does not figure in documents published by the above mentioned institutions.</p> <p>Conclusion</p> <p>The results show a reduction in the ethnobotanical and medical knowledge in the area of study, when compared to other studies carried out in the Pyrenees. Nevertheless, the use of several species that may be regarded as possible sources for pharmacological studies is reported here such as the bark of <it>Sambucus nigra</it>, the roots of <it>Fragaria vesca</it>, or the leaves of <it>Scrophularia nodosa</it>. These species are not currently approved by the WHO, ESCOP and the E Commission of the German Department of Health, institutions that, apart from encouraging the greater use of plants for medicinal purposes, may help in the design of development plans for these rural areas by validating their traditional medicine.</p

Revista de Vertebrados de la Estación Biológica de Doñana

Clave preliminar de las escamas de los peces de agua dulce de España, a nivel de familiaExito reproductor del Buitre leonado (Gyps fulvus) en NavarraAlimentación del Gavilán (Accipiter nisus) en la Isla de TenerifeEl Verdecillo (Serinus serinus): Tendencias en la estación de nidificación, en el tamaño del huevo y en la supervivencia.las batidas como método de censo en especiesde caza mayor: aplicación al caso del Jabalí (Sus scrofa L.) en la provincia de Burgos (Norte de España)La adquisición de madurez sexual en el camaleón común (Chamaeleo chamaeleon)Nuevas citas de Hemidactylus turcicus en la provincia de CáceresLa focha común (Fulica atra) en la isla de Gran Canaria: nueva especie nidificante en el archipiélago CanarioTraslado de huevos en incubación por la urraca (Pica pica)Predación de Falco peregrinus sobre Oryctolagus cuniculusCuatro nuevas especies de aves para Bolivia.Sobre la utilización de nidos de golondrina común abandonados.Parasitismo múltiple del críalo (Clamator glandarius)Predación del topo de rio (Galemys pyrenaicus, Geoffroy 1811) por parte de la lechuza común (Tyto alba, Scopoli 1769)Predación del zorro (Vulpes vulpes) sobre un pollo de buitre leonado (Gyps fulvus).Vulpes vulpes L. criando en una colonia de marmota (Marmota marmota L.) en el pirineo de LéridaObservaciones sobre la incidencia de Rattus (Fischer, 1803) en los cultivos ibéricos de caña de azúcaSituación actual de la jutiita de la tierra Capromys sanfelipensis (Rodentia, Mammalia)Notas sobre la intraducción y expansión de la ardilla común en Sierra Nevada, sureste de EspañaPeer reviewe

High resolution 3-Dimensional imaging of the human cardiac conduction system from microanatomy to mathematical modeling

Cardiac arrhythmias and conduction disturbances are accompanied by structural remodelling of the specialised cardiomyocytes known collectively as the cardiac conduction system. Here, using contrast enhanced micro-computed tomography, we present, in attitudinally appropriate fashion, the first 3-dimensional representations of the cardiac conduction system within the intact human heart. We show that cardiomyocyte orientation can be extracted from these datasets at spatial resolutions approaching the single cell. These data show that commonly accepted anatomical representations are oversimplified. We have incorporated the high-resolution anatomical data into mathematical simulations of cardiac electrical depolarisation. The data presented should have multidisciplinary impact. Since the rate of depolarisation is dictated by cardiac microstructure, and the precise orientation of the cardiomyocytes, our data should improve the fidelity of mathematical models. By showing the precise 3-dimensional relationships between the cardiac conduction system and surrounding structures, we provide new insights relevant to valvar replacement surgery and ablation therapies. We also offer a practical method for investigation of remodelling in disease, and thus, virtual pathology and archiving. Such data presented as 3D images or 3D printed models, will inform discussions between medical teams and their patients, and aid the education of medical and surgical trainees

MKS3/TMEM67 mutations are a major cause of COACH syndrome, a joubert syndrome related disorder with liver involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/ aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs

Analyzing factors that influence the folk use and phytonomy of 18 medicinal plants in Navarra

BACKGROUND: This article analyzes whether the distribution or area of use of 18 medicinal plants is influenced by ecological and cultural factors which might account for their traditional use and/or phytonymy in Navarra. This discussion may be helpful for comparative studies, touching as it does on other ethnopharmacological issues: a) which cultural and ecological factors affect the selection of medicinal plants; b) substitutions of medicinal plants in popular medicine; c) the relation between local nomenclature and uses. To analyze these questions, this paper presents an example of a species used for digestive disorders (tea and camomile: Jasonia glutinosa, J. tuberosa, Sideritis hyssopifolia, Bidens aurea, Chamaemelum nobile, Santolina chamaecyparissus...), high blood pressure (Rhamnus alaternus, Olea europaea...) or skin diseases (Hylotelephium maximum, H. telephium, Anagallis arvensis, A. foemina). METHODS: Fieldwork began on January 2004 and continued until December 2006. During that time we interviewed 505 informants in 218 locations in Navarra. Information was collected using semi-structured ethnobotanical interviews, and we subsequently made maps using Arc-View 8.0 program to determine the area of use of each taxon. Each map was then compared with the bioclimatic and linguistic map of Navarra, using the soil and ethnographic data for the region, and with other ethnobotanical and ethnopharmacological studies carried out in Europe. RESULTS: The results clearly show that ecological and cultural factors influence the selection of medicinal plants in this region. Climate and substrate are the most important ecological factors that influence the distribution and abundance of plants, which are the biological factors that affect medicinal plant selection. CONCLUSION: The study of edaphological and climatological factors, on the one hand, and culture, on the other, can help us to understand why a plant is replaced by another one for the same purposes, either in the same or in a different area. In many cases, the cultural factor means that the use of a species is more widespread than its ecological distribution. This may also explain the presence of synonyms and polysemies which are useful for discussing ethnopharmacological data

Effect of Systemic Hypertension With Versus Without Left Ventricular Hypertrophy on the Progression of Atrial Fibrillation (from the Euro Heart Survey).

Hypertension is a risk factor for both progression of atrial fibrillation (AF) and development of AF-related complications, that is major adverse cardiac and cerebrovascular events (MACCE). It is unknown whether left ventricular hypertrophy (LVH) as a consequence of hypertension is also a risk factor for both these end points. We aimed to assess this in low-risk AF patients, also assessing gender-related differences. We included 799 patients from the Euro Heart Survey with nonvalvular AF and a baseline echocardiogram. Patients with and without hypertension were included. End points after 1 year were occurrence of AF progression, that is paroxysmal AF becoming persistent and/or permanent AF, and MACCE. Echocardiographic LVH was present in 33% of 379 hypertensive patients. AF progression after 1 year occurred in 10.2% of 373 patients with rhythm follow-up. In hypertensive patients with LVH, AF progression occurred more frequently as compared with hypertensive patients without LVH (23.3% vs 8.8%, p = 0.011). In hypertensive AF patients, LVH was the most important multivariably adjusted determinant of AF progression on multivariable logistic regression (odds ratio 4.84, 95% confidence interval 1.70 to 13.78, p = 0.003). This effect was only seen in male patients (27.5% vs 5.8%, p = 0.002), while in female hypertensive patients, no differences were found in AF progression rates regarding the presence or absence of LVH (15.2% vs 15.0%, p = 0.999). No differences were seen in MACCE for hypertensive patients with and without LVH. In conclusion, in men with hypertension, LVH is associated with AF progression. This association seems to be absent in hypertensive women