DACH1-Driven Arterialization: Angiogenic Therapy for Ischemic Heart Disease?

J.L. de la Pompa is supported by grants PID2019-104776RB-I00 and CB16/11/00399 (CIBER CV) from the Spanish Ministry of Science, Innovation and Universities.S

Midkine-a Regulates the Formation of a Fibrotic Scar During Zebrafish Heart Regeneration.

Unlike the hearts of mammals, the adult zebrafish heart regenerates after injury. Heart cryoinjury in zebrafish triggers the formation of a fibrotic scar that gradually degrades, leading to regeneration. Midkine-a (Mdka) is a multifunctional cytokine that is activated after cardiac injury. Here, we investigated the role of mdka in zebrafish heart regeneration. We show that mdka expression was induced at 1-day post-cryoinjury (dpci) throughout the epicardial layer, whereas by 7 dpci expression had become restricted to the epicardial cells covering the injured area. To study the role of mdka in heart regeneration, we generated mdka-knock out (KO) zebrafish strains. Analysis of injured hearts showed that loss of mdka decreased endothelial cell proliferation and resulted in an arrest in heart regeneration characterized by retention of a collagenous scar. Transcriptional analysis revealed increases in collagen transcription and intense TGFβ signaling activity. These results reveal a critical role for mdka in fibrosis regulation during heart regeneration.This study was supported by Grants PID2019-104776RB-I00, CB16/11/00399 (CIBER CV) and RD16/0011/0021 (TERCEL) from the Spanish Ministry of Science, Innovation and Universities (MCIU) and Grants from the Fundación BBVA (Ref.: BIO14_298), Fundación La Marató (Ref.: 20153431) and the European Commission through CardioNeT (Ref.: 28600) from the European Commission to JLP. DG held a Ph.D. fellowship linked to the Grant CardioNeT grant. The cost of this publication was supported in part with funds from the European Regional Development Fund. The CNIC was supported by the Instituto de Salud Carlos III (ISCIII), the MCIU and the Pro CNIC Foundation, and is a Severo Ochoa Centre of Excellence (SEV-2015-0505).S

Gelatin and Collagen Nanofiber Scaffolds for Tissue Engineering

One of the main complications that can present a person with second and third degree burns is the possibility of being infected by opportunistic bacteria or viruses that are present in the environment. Nowadays, the majority of the burn injuries are treated with conventional gauze, which involves a high probability of infection and pain for the patient being treated with this method. In order to obtain low-cost scaffolds, natural and abundant polymers were used such as gelatin (GEL) and collagen (COL). The GEL functions as a base scaffold, stable and flexible, and also biocompatible because it is a byproduct of the partial hydrolysis of COL, which is an indispensable component for the stability of the cell membrane and it is present in great extent in the human epithelium

Enfermedad de Morquio. Reporte de un caso

La mucopolisacaridosis tipo IV-A (enfermedad de Morquio) es una enfermedad autosómica recesiva por acúmulo lisosomal, causada por mutaciones en el gen de la N-acetylgalactosamine-6-sulfato sulfatasa, que resulta en la falta de catabolismo de dos glicosaminoglicanos, el queratán y condroitín sulfato. Las manifestaciones clínicas varían desde un fenotipo grave a una forma atenuada. El acúmulo de sustrato se expresa como displasia ósea, baja estatura, inestabilidad atlantoaxoidea y compresión cervical con compromiso cardíaco, respiratorio, auditivo y ocular. A pesar de las muchas descripciones y manifestaciones clínicas de este síndrome, el retraso en su diagnóstico aún ocurre. Se presentó a un paciente masculino de 9 años de edad con baja talla, retraso severo del desarrollo psicomotor, sordera bilateral y atrofia muscular entre otras características clínicas; diagnosticado desde los 2 años de edad con Morquio A. Por la rareza de la enfermedad, siendo el segundo caso reportado en Cuba, y lo atípico del caso, se decide su presentación

Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.

Atheromatous fibrous caps are produced by smooth muscle cells (SMCs) that are recruited to the subendothelial space. We tested whether the recruitment mechanisms are the same as in embryonic artery development, which relies prominently on Notch signaling to form the subendothelial medial SMC layers. Notch elements were expressed in regions of fibrous cap in human and mouse plaques. To assess the causal role of Notch signaling in cap formation, we studied atherosclerosis in mice where the Notch pathway was inactivated in SMCs by conditional knockout of the essential effector transcription factor RBPJ (recombination signal-binding protein for immunoglobulin kappa J region). The recruitment of cap SMCs was significantly reduced without major effects on plaque size. Lineage tracing revealed the accumulation of SMC-derived plaque cells in the cap region was unaltered but that Notch-defective cells failed to re-acquire the SMC phenotype in the cap. Conversely, to analyze whether the loss of Notch signaling is required for SMC-derived cells to accumulate in atherogenesis, we studied atherosclerosis in mice with constitutive activation of Notch signaling in SMCs achieved by conditional expression of the Notch intracellular domain. Forced Notch signaling inhibited the ability of medial SMCs to contribute to plaque cells, including both cap SMCs and osteochondrogenic cells, and significantly reduced atherosclerosis development. Sequential loss and gain of Notch signaling is needed to build the cap SMC population. The shared mechanisms with embryonic arterial media assembly suggest that the cap forms as a neo-media that restores the connection between endothelium and subendothelial SMCs, transiently disrupted in early atherogenesis.This study was supported by a grant from the Ministerio de Ciencia e Innovación with cofunding from the European Regional Development Fund (SAF2016- 75580-R and PID2019-108568RB-I00 to J.F. Bentzon and SAF2016-78370-R to J.L. de la Pompa) and from the Novo Nordisk Foundation (NNF17OC0030688 to. J.F. Bentzon). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Notch and Bmp signaling pathways act coordinately during the formation of the proepicardium.

The epicardium is the outer mesothelial layer of the heart. It encloses the myocardium and plays key roles in heart development and regeneration. It derives from the proepicardium (PE), cell clusters that appear in the dorsal pericardium (DP) close to the atrioventricular canal and the venous pole of the heart, and are released into the pericardial cavity. PE cells are advected around the beating heart until they attach to the myocardium. Bmp and Notch signaling influence PE formation, but it is unclear how both signaling pathways interact during this process in the zebrafish. Here, we show that the developing PE is influenced by Notch signaling derived from the endothelium. Overexpression of the intracellular receptor of notch in the endothelium enhances bmp expression, increases the number of pSmad1/5 positive cells in the DP and PE, and enhances PE formation. On the contrary, pharmacological inhibition of Notch1 impairs PE formation. bmp2b overexpression can rescue loss of PE formation in the presence of a Notch1 inhibitor, but Notch gain-of-function could not recover PE formation in the absence of Bmp signaling. Endothelial Notch signaling activates bmp expression in the heart tube, which in turn induces PE cluster formation from the DP layer.Nadia Mercader was funded by the Spanish Ministry of Economy and Competitiveness through grant BFU2014-56970-P (Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016. Programa Estatal de I+D+i Orientada a los Retos de la Sociedad Retos Investigación: Proyectos I+D +i 2016, del Ministerio de Economía competitividad e Industria), and cofunding by Fondo Europeo de Desarrollo Regional (FEDER). Nadia Mercader is also supported by the European Industrial Doctorate Program EID 722427. Nadia Mercader and Julien Vermot are supported by the Swiss National Science Foundation grant ANR-SNF 310030L_182575. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 708312 (MP) and from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme: GA Nº682938. Laura Andrés-Delgado was funded (2014-16) through the postdoctoral fellowship Ayudas Postdoctorales 2013. José Luis de la Pompa was supported by grants SAF2016-78370-R, CB16/11/00399 (CIBER CV) and RD16/0011/0021 (TERCEL) from the Spanish Ministry of Science and Innovation. The CNIC is supported by the Ministry of Science and Innovation and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Plant characterization of genetically modified maize hybrids MON-89Ø34-3 × MON-88Ø17-3, MON-89Ø34-3 × MON-ØØ6Ø3-6, and MON-ØØ6Ø3-6: alternatives for maize production in Mexico

Environmental risk assessment (ERA) of genetically modified (GM) crops is a process to evaluate whether the biotechnology trait(s) in a GM crop may result in increased pest potential or harm to the environment. In this analysis, two GM insect-resistant (IR) herbicide-tolerant maize hybrids (MON-89Ø34-3 9 MON-88Ø17-3 and MON-89Ø34-3 9 MON-ØØ6Ø3-6) and one herbicide-tolerant GM hybrid (MON-ØØ6Ø3-6) were compared with conventional maize hybrids of similar genetic backgrounds. Two sets of studies, Experimental Phase and Pilot Phase, were conducted across five ecological regions (ecoregions) in Mexico during 2009–2013, and data were subject to meta-analysis. Results from the Experimental Phase studies, which were used for ERA, indicated that the three GM hybrids were not different from conventional maize for early stand count, days-tosilking, days-to-anthesis, root lodging, stalk lodging, or final stand count. Statistically significant differences were observed for seedling vigor, ear height, plant height, grain moisture, and grain yield, particularly in the IR hybrids; however, none of these phenotypic differences are expected to contribute to a biological or ecological change that would result in an increased pest potential or ecological risk when cultivating these GM hybrids. Overall, results from the Experimental Phase studies are consistent with those from other world regions, confirming that there are no additional risks compared to conventional maize. Results from Pilot Phase studies indicated that, compared to conventional maize hybrids, no differences were detected for the agronomic and phenotypic characteristics measured on the three GM maize hybrids, with the exception of grain moisture and grain yield in the IR hybrids. Since MON-89Ø34- 3 9 MON-88Ø17-3 and MON-89Ø34-3 9 MONØØ6Ø3- 6 confer resistance to target insect pests, they are an alternative for farmers in Mexico to protect the crop from insect damage. Additionally, the herbicide tolerance conferred by all three GM hybrids enables more cost-effective weed management

Transportability of non-target arthropod field data for the use in environmental risk assessment of genetically modified maize in Northern Mexico

In country, non-target arthropod (NTA) field evaluations are required to comply with the regulatory process for cultivation of genetically modified (GM) maize in Mexico. Two sets of field trials, Experimental Phase and Pilot Phase, were conducted to identify any potential harm of insect-protected and glyphosate-tolerant maize (MON89Ø34-3 × MON-88Ø17-3 and MON-89Ø34-3 × MON-ØØ6Ø3-6) and glyphosatetolerant maize (MON-ØØ6Ø3-6) to local NTAs compared to conventional maize. NTA abundance data were collected at 32 sites, providing high geographic and environmental diversity within maize production areas from four ecological regions (ecoregions) in northern Mexico. The most abundant herbivorous taxa collected included field crickets, corn flea beetles, rootworm beetles, cornsilk flies, aphids, leafhoppers, plant bugs and thrips while the most abundant beneficial taxa captured were soil mites, spiders, predatory ground beetles, rove beetles, springtails (Collembola), predatory earwigs, ladybird beetles, syrphid flies, tachinid flies, minute pirate bugs, parasitic wasps and lacewings. Across the taxa analysed, no statistically significant differences in abundance were detected between GM maize and the conventional maize control for 69 of the 74 comparisons (93.2%) indicating thatthe single or stacked insect-protected and herbicide-tolerant GM traits generally exert no marked adverse effects on the arthropod populations compared with conventional maize. The distribution of taxa observed in this study provides evidence that irrespective of variations in overall biodiversity of a given ecoregion, important herbivore, predatory and parasitic arthropod taxa within the commercial maize agroecosystem are highly similar indicating that relevant data generated in one ecoregion can be transportable for the risk assessment of the same or similar GM crop in another ecoregion

Trabeculated Myocardium in Hypertrophic Cardiomyopathy: Clinical Consequences

Aims: Hypertrophic cardiomyopathy (HCM) is often accompanied by increased trabeculated myocardium (TM)-which clinical relevance is unknown. We aim to measure the left ventricular (LV) mass and proportion of trabeculation in an HCM population and to analyze its clinical implication. Methods and Results: We evaluated 211 patients with HCM (mean age 47.8 +/- 16.3 years, 73.0% males) with cardiac magnetic resonance (CMR) studies. LV trabecular and compacted mass were measured using dedicated software for automatic delineation of borders. Mean compacted myocardium (CM) was 160.0 +/- 62.0 g and trabecular myocardium (TM) 55.5 +/- 18.7 g. The percentage of trabeculated myocardium (TM%) was 26.7% +/- 6.4%. Females had significantly increased TM% compared to males (29.7 +/- 7.2 vs. 25.6 +/- 5.8, p < 0.0001). Patients with LVEF < 50% had significantly higher values of TM% (30.2% +/- 6.0% vs. 26.6% +/- 6.4%, p = 0.02). Multivariable analysis showed that female gender and neutral pattern of hypertrophy were directly associated with TM%, while dynamic obstruction, maximal wall thickness and LVEF% were inversely associated with TM%. There was no association between TM% with arterial hypertension, physical activity, or symptoms. Atrial fibrillation and severity of hypertrophy were the only variables associated with cardiovascular death. Multivariable analysis failed to demonstrate any correlation between TM% and arrhythmias. Conclusions: Approximately 25% of myocardium appears non-compacted and can automatically be measured in HCM series. Proportion of non-compacted myocardium is increased in female, non-obstructives, and in those with lower contractility. The amount of trabeculation might help to identify HCM patients prone to systolic heart failure

The Tumor Suppressor Gene Brca1 Is Required for Embryonic Cellular Proliferation in the Mouse

AbstractMutations of the BRCA1 gene in humans are associated with predisposition to breast and ovarian cancers. We show here that Brca1+/− mice are normal and fertile and lack tumors by age eleven months. Homozygous Brca15-6 mutant mice die before day 7.5 of embryogenesis. Mutant embryos are poorly developed, with no evidence of mesoderm formation. The extraembryonic region is abnormal, but aggregation with wild-type tetraploid embryos does not rescue the lethality. In vivo, mutant embryos do not exhibit increased apoptosis but show reduced cell proliferation accompanied by decreased expression of cyclin E and mdm-2, a regulator of p53 activity. The expression of cyclin-dependent kinase inhibitor p21 is dramatically increased in the mutant embryos. Buttressing these in vivo observations is the fact that mutant blastocyst growth is grossly impaired in vitro. Thus, the death of Brca15-6 mutant embryos prior to gastrulation may be due to a failure of the proliferative burst required for the development of the different germ layers