New Lower Devonian Polygnathids (Conodonta) from the Spanish Central Pyrenees, with comments on the early radiation of the group

The comprehensive study of six Pragian-lower Emsian (Lower Devonian) sections from the Spanish Central Pyrenees has yielded a rich assemblage of conodont faunas, highlighting an important succession of Polygnathus species. Among them, the presence of the biostrati­graphical markers P. pireneae, P. kitabicus, P. excavatus excavatus and P. exc. 114 stands out. This conodont succession allows the identification of the Pragian/Emsian boundary and the early Emsian zones and subzones: the kitabicus Zone and the Lower and Middle excavatus subzones. It is also remarkable the presence of three new polygnathid species: P. aragonensis n. sp., P. carlsi n. sp. and P. ramoni n. sp. Additionally, P. pannonicus and P. sokolovi are also reported for first time in the Iberian Peninsula. According to all these records, the abundance and diversity of these species suggest that during this time interval an evolutionary radiation of the group took place, identifying two pulses during the early radiation of the group. The first one during the pireneae-kitabicus Zone, and a second one during the Lower excavatus Zone. The new data presented herein increase considerably the known paleobiodiversity of the genus dur­ing the Pragian-early Emsian interval in the Spanish Central Pyrenees and corroborates the presences of the most important early Emsian conodont markers used in other regions such us Europe, North Africa, Central Asia, Australia, and North America. ozonas Dc, E y F asociados al evento de enfriamiento global del Mioceno medio.El estudio en profundidad de seis secciones de edad Emsiense (Devónico Inferior) del Pirineo Central español ha proporcionado una rica asociación de conodontos, destacando una importante sucesión de especies del género Polygnathus. Entre ellos, resalta la presencia de los marcadores bioestratigráficos P. pireneae, P. kitabicus, P. excavatus excavatus y P. exc. 114. Esta sucesión de conodontos per­mite la identificación del límite Praguiense/Emsiense, así como de las principales zonas del Emsiense temprano: la Zona kitabicus y las subzonas excavatus Inferior y Media. También es destacable la presencia de tres nuevas especies de polygnátidos: P. aragonensis n. sp., P. carlsi n. sp. y P. ramoni n. sp.; junto con la primera referencia en la Península Ibérica de las especies P. pannonicus y P. sokolovi. De acuerdo con estos resultados, la abundancia y diversidad de estas especies sugiere que durante este intervalo temporal se produjo una radiación evolutiva del grupo, identificando dos momentos de la misma durante la evolución temprana del grupo. El primero durante el intervalo pireneae-kitabicus, y el segundo durante la Zona excavatus Inferior. Los nuevos datos presentados en este trabajo incrementan considerablemente la paleobiodiversidad conocida del género durante el Praguiense final y comienzos del Emsiense en el Pirineo Cen­tral español, y corrobora la presencia de los principales marcadores biostratigráficos del Emsiense inferior registrados en otras regiones como Europa, norte de África, Asia Central, Australia y América del Norte

Assessment of Streamflow from EURO-CORDEX Regional Climate Simulations in Semi-Arid Catchments Using the SWAT Model

This research studies the effect of climate change on the hydrological behavior of two semi-arid basins. For this purpose, the Soil and Water Assessment Tool (SWAT) model was used with the simulation of two future climate change scenarios, one Representative Concentration Pathway moderate (RCP 4.5) and the other extreme (RCP 8.5). Three future periods were considered: close (2019–2040), medium (2041–2070), and distant (2071–2100). In addition, several climatic projections of the EURO-CORDEX model were selected, to which different bias correction methods were applied before incorporation into the SWAT model. The statistical indices for the monthly flow simulations showed a very good fit in the calibration and validation phases in the Upper Mula stream (NS = 0.79–0.87; PBIAS = −4.00–0.70%; RSR = 0.44–0.46) and the ephemeral Algeciras stream (NS = 0.78–0.82; PBIAS = −8.10–−8.20%; RSR = 0.4–0.42). Subsequently, the impact of climate change in both basins was evaluated by comparing future flows with those of the historical period. In the RCP 4.5 and RCP 8.5 scenarios, by the end of the 2071–2100 period, the flows of the Upper Mula stream and the ephemeral Algeciras stream will have decreased by between 46.3% and 52.4% and between 46.6% and 55.8%, respectively.ERDF/Spanish Ministry of Science, Innovation and Universities—State Research Agency/Project CGL2017-84625-C2-1-R (CCAMICEM)State Program for Research, Development and Innovation Focused on the Challenges of Societ

Sucesión de Polygnátidos (Conodontos) del Emsiense (Devónico Inferior) en los Pirineos Centrales Españoles

A comprehensive conodont study of five sections of Emsian age, carried out in the Spanish Central Pyrenees, has revealed an important succession of polygnathids that can be used for identifying basal boundaries of globally recognized biozones. This succession consists of Polygnathus excavatus excavatus, Po. gronbergi, Po. nothoperbonus, Po. mashkovae, Po. laticostatus, and the new species Polygnathus luciae that allows the identification of the excavatus, nothoperbonus and laticostatus Zones. The nothoperbonus Zone is further subdivided into Lower and Upper nothoperbonus subzones, relying upon the lowest occurrence of Po. mashkovae. These biostratigraphic data from the Spanish Central Pyrenees corroborate the succession of conodont indexes in other regions of Europe (north-western France and southern Italy), North Africa (Morocco), Central Asia, Australia, and North America (Alaska, Nevada and Canada).El estudio exhaustivo de cinco secciones de edad Emsiense en el Pirineo Central Español ha proporcionado una importante sucesión de especies de conodontos del género Polygnathus que puede usarse para reconocer los límites de diferentes biozonas de aplicación global. Esta sucesión consiste en Polygnathus excavatus excavatus, Po. gronbergi, Po. nothoperbonus, Po. mashkovae, Po. laticostatus y la nueva especie Polygnathus luciae, lo que permite identificar las biozonas excavatus, nothoperbonus y laticostatus. Además, el primer registro de Po. mashkovae se usa para subdividir la Zona nothoperbonus en las Subzonas nothoperbonus Inferior y Superior. Estos datos corroboran la sucesión de los índices de conodontos registrada en otras regiones de Europa (noroeste de Francia y sur de Italia), norte de África (Marruecos), Asia central, Australia y Norte América (Alaska, Nevada y Canadá)

Effects of Genetic Captive-Breeding Protocols on Sperm Quality and Fertility in the White-Footed Mouse

P. 540–548Mice (Peromyscus leucopus noveboracensis) from a captive-breeding program were used to test the effects of three genetic breeding protocols (minimizing mean kinship [MK], random breeding, and selection for docility [DOC]) and inbreeding levels on sperm traits and fertility. Earlier, in generation 8, one DOC replicate went extinct because of poor reproductive success. By generation 10, spermatozoa from DOC mice had more acrosome and midpiece abnormalities, which were shown to be strong determinants of fertility, as well as lower sperm production and resistance to osmotic stress. In addition, determinants of fertility, including male and female components, were assessed in a comprehensive manner. Results showed that the probability (P) of siring litters is determined by sperm number, sperm viability, and midpiece and acrosome abnormalities; that the P of siring one versus two litters is determined by tail abnormalities; and that the total number of offspring is influenced by female size and proportion of normal sperm, showing the relative importance of different sperm traits on fertility. On average, males with 20% normal sperm sired one pup per litter, and males with 70% normal sperm sired eight pups per litter. Interestingly, the proportion of normal sperm was affected by docility but not by relatively low inbreeding. However, inbreeding depression in sperm motility was detected. In the MK group, inbreeding depression not only affected sperm motility but also fertility: An increase in the coefficient of inbreeding (f) of 0.03 reduced sperm motility by 30% and translated into an offspring reduction of three pups in second litters. A genetic load of 48 fecundity equivalents was calculated.S

IKs Computational Modeling to Enforce the Investigation of D242N, a KV7.1 LQTS Mutation

A KCNQ1 mutation, D242N, was found in a pair of twins and characterized at the cellular level. To investigate whether and how the mutation causes the clinically observed lost adaptation to fast heart rate, we performed a computational study. Firstly, we identified a new I Ks model based on voltage clamp experimental data. Then we included this formulation in the human action potential model of O'Hara Rudy (ORd) and simulate d the effects of the mutation. We also included adrenergic stimulation to the action potential, since the basal adrenergic tone is likely to affect the influence of I Ks on QTc in vivo. Finally, we simulated the pseudo-ECG, taking into account the heterogeneity of the cardiac wall. At the basal rate (60bpm), the mutation had negligible effects for all cell types, whereas at the high rate (180bpm), with concomitant β-adrenergic stimulation (mimicking exercise conditions), the mutant AP failed to adapt its duration to the same extent as the wild-type AP (e.g. 281ms vs. 267ms in M cells), due to a smaller amount of I Ks current. Pseudo-ECG results show only a slight rate adaptation, and the simulated QTc was significantly prolonged from 387ms to 493ms, similar to experimental recordings

Optimizing CIGB-300 intralesional delivery in locally advanced cervical cancer

Background:We conducted a phase 1 trial in patients with locally advanced cervical cancer by injecting 0.5 ml of the CK2-antagonist CIGB-300 in two different sites on tumours to assess tumour uptake, safety, pharmacodynamic activity and identify the recommended dose.Methods:Fourteen patients were treated with intralesional injections containing 35 or 70 mg of CIGB-300 in three alternate cycles of three consecutive days each before standard chemoradiotherapy. Tumour uptake was determined using 99 Tc-radiolabelled peptide. In situ B23/nucleophosmin was determined by immunohistochemistry.Results:Maximum tumour uptake for CIGB-300 70-mg dose was significantly higher than the one observed for 35 mg: 16.1±8.9 vs 31.3±12.9 mg (P=0.01). Both, AUC 24h and biological half-life were also significantly higher using 70 mg of CIGB-300 (P<0.001). Unincorporated CIGB-300 diffused rapidly to blood and was mainly distributed towards kidneys, and marginally in liver, lungs, heart and spleen. There was no DLT and moderate allergic-like reactions were the most common systemic side effect with strong correlation between unincorporated CIGB-300 and histamine levels in blood. CIGB-300, 70 mg, downregulated B23/nucleophosmin (P=0.03) in tumour specimens.Conclusion:Intralesional injections of 70 mg CIGB-300 in two sites (0.5 ml per injection) and this treatment plan are recommended to be evaluated in phase 2 studies.Fil: Sarduy, M. R.. Medical-surgical Research Center; CubaFil: García, I.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Coca, M. A.. Clinical Investigation Center; CubaFil: Perera, A.. Clinical Investigation Center; CubaFil: Torres, L. A.. Clinical Investigation Center; CubaFil: Valenzuela, C. M.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Baladrón, I.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Solares, M.. Hospital Materno Ramón González Coro; CubaFil: Reyes, V.. Center For Genetic Engineering And Biotechnology Havana; CubaFil: Hernández, I.. Isotope Center; CubaFil: Perera, Y.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Martínez, Y. M.. Medical-surgical Research Center; CubaFil: Molina, L.. Medical-surgical Research Center; CubaFil: González, Y. M.. Medical-surgical Research Center; CubaFil: Ancízar, J. A.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Prats, A.. Clinical Investigation Center; CubaFil: González, L.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Casacó, C. A.. Clinical Investigation Center; CubaFil: Acevedo, B. E.. Centro de Ingeniería Genética y Biotecnología; CubaFil: López Saura, P. A.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes; ArgentinaFil: Gómez, R.. Elea Laboratories; ArgentinaFil: Perea Rodríguez, S. E.. Center For Genetic Engineering And Biotechnology Havana; Cuba. Centro de Ingeniería Genética y Biotecnología; Cub

Overnutrition and Scholastic Achievement: Is There a Relationship? An 8-Year Follow-Up Study

Objective: The aim of this study was to assess the association between overnutrition and scholastic achievement (SA). Methods: A representative and proportional sample of 477 children of the 5th elementary school grade of both genders was randomly chosen during 2010, in the Metropolitan Region of Chile. SA was measured through the 2009 Education Quality Measurement System (SIMCE) tests of language (LSA), mathematics (MSA) and understanding of the natural environment (UNESA). Current nutritional status was assessed through the body mass index Z-score (Z-BMI). Nutritional quality of diet, schedule exercise, socioeconomic status, family, and educational variables were also recorded. Four and 8 years later, SA was assessed through the 2013 SIMCE and the University Selection Test (2017 PSU), respectively. Results: Socioeconomic status, the number of repeated school years, and maternal schooling were strong predictors of 2009 SIMCE and the independent variables with the greatest explanatory power for LSA (Model R2 = 0.178; p 2 = 0.205; p2 = 0.272; p Conclusions: These results confirm that overnourished children did not achieve significantly lower SA

Low aerobic capacity in McArdle disease: A role for mitochondrial network impairment?

[Background]: McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO2peak)), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation. [Methods]: We analyzed in depth mitochondrial characteristics-content, biogenesis, ultrastructure-and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO2peak in patients (both sexes, N = 145) and healthy controls (N = 133). [Results]: Besides corroborating very poor VO2peak values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components-actin microfilaments, microtubules and intermediate filaments-thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin-with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected. [Conclusions]: In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses.The present study was funded by grants received from the Fondo de Investigaciones Sanitarias (FIS, PI17/02052, PI18/00139, PI19/01313, and PI20/00645) and cofunded by ‘Fondos FEDER’. Gisela Nogales-Gadea and Carmen Fiuza-Luces are supported by the Miguel Servet research contracts (ISCIII CD14/00032 and CP18/00034, respectively and cofounded by Fondos FEDER′). Research by Pedro L. Valenzuela is funded by a postdoctoral contract granted by Instituto de Salud Carlos III (Sara Borrell, CD21/00138). Monica Villarreal Salazar is supported by the Mexican National Council for Science and Technology (CONACYT)

New approaches for the identification of KChIP2 ligands to study the KV4.3 channelosome in atrial fibrillati

Resumen del trabajo presentado en el VIII Congreso Red Española de Canales iónico, celebrado en Alicante (España) del 24 al 27 de mayo de 2022.Ion channels are macromolecular complexes present in the plasma membrane and in intracellular organelles of the cells, where they play important functions. The dysfunction of these channels results in several disorders named channelopathies, which represent a challenge for study and treatment.[1] We are focused on voltage-gated potassium channels, specifically on KV4.3. Kv4.3 is expressed in smooth muscle, heart and brain. Within the heart, Kv4.3 channels generate the transient outward potassium current (ITO). However, ITO characteristics are only observed when Kv4.3 assemble with accessory subunits as KChIP2 and DPP6. KV4.3 channelosome play a key role in atrial fibrillation (AF),the most common cardiac arrhythmia, with an estimated prevalence in the general population of 1.5–2%. However, current antiarrhythmic drugs for AF prevention have limited efficacy and considerable potential for adverse effects.[2] KChIP2 (Potassium Channel Interacting Protein 2) belongs to the calcium binding protein superfamily. It is the KChIP member predominantly expressed in heart and a key regulator of cardiac action potential duration. The identification of novel KChIP2 ligands could be useful to understand the role of KV4.3 channelosome in AF and it could help to discover new treatments for AF. [3] In this regard, structure-based virtual screening could be an important tool to accelerate the identification of novel KChIP2 ligands. In this communication, we will describe a multidisciplinary approach that, starting with a structurebased virtual screening, followed by an iterative process of synthesis/biological evaluation/docking studies, has led to the identification of new KChIP2 ligands.PID2019-104366RB-C21, PID2019-104366RB-C22, PID2020-114256RB-I00 and PID2020-119805RB-I00 grants funded by MCIN/AEI/10.13039/501100011033; and PIE202180E073 and 2019AEP148 funded by CSIC. C.V.B. holds PRE2020-093542 FPI grant funded by MCIN/AEI/10.13039/501100011033. PGS was recipient of an FPU grant (FPU17/02731). AB-B holds BES-2017-080184 FPI grant and A.P-L.holds RYC2018-023837-I grant both funded by MCIN/ AEI/ 10.13039/501100011033 and by “ESF Investing in your future