Search

Quillaja saponaria is a sclerophyllus evergreen tree species distributed from 30° to 38° S in Central Chile. In this wide distribution it is expected that the species exhibits phenotypic plasticity in the morphology of leaves associated to climate variation; however, the information on this topic is still scarce. We studied leaf phenotypic variation and its relationship with temperature, precipitation, and aridity in 85 stands of Q. saponaria throughout the natural distribution of the species. The results show that the basal diameter of petiole, the number of secondary veins, and the basal diameter of the principal vein increased with precipitation and decreased with aridity, while the length, basal diameter and the relative length of the petiole decreased with temperature. This confirms that phenotypic variation for foliar characters in Q. saponaria is related to climatic variables indicating an adapting capability of the species to the wide range of environmental conditions in which grows.

17 Pág. Departamento de ​Mejora Genética Animal (INIA), Genomic relationship matrices are used to obtain genomic inbreeding coefficients. However, there are several methodologies to compute these matrices and there is still an unresolved debate on which one provides the best estimate of inbreeding. In this study, we investigated measures of inbreeding obtained from five genomic matrices, including the Nejati-Javaremi allelic relationship matrix (FNEJ), the Li and Horvitz matrix based on excess of homozygosity (FL&H), and the VanRaden (methods 1, FVR1, and 2, FVR2) and Yang (FYAN) genomic relationship matrices. We derived expectations for each inbreeding coefficient, assuming a single locus model, and used these expectations to explain the patterns of the coefficients that were computed from thousands of single nucleotide polymorphism genotypes in a population of Iberian pigs., This work was carried out with funding from the Ministerio de Ciencia e Innovación, Spain (CGL2016-75904-C2, PID2020-114426GB-C22), the European Commission Horizon 2020 (H2020) Framework Programme through grant agreement no 727315 MedAID project (Mediterranean Aquaculture Integrated Development), Xunta de Galicia (ED431C 2020-05) and Fondos FEDER.R. Pong-Wong is funded by the European Union’s Horizon 2020 research and innovation program under the Grant Agreement n°772787 (SMARTER) and the Biotechnology and Biological Sciences Research Council through Institute Strategic Programme Grant funding (BBS/E/D/30002275)

The tumor immune composition influences prognosis and treatment sensitivity in lung cancer. The presence of effective adaptive immune responses is associated with increased clinical benefit after immune checkpoint blockers. Conversely, immunotherapy resistance can occur as a consequence of local T-cell exhaustion/dysfunction and upregulation of immunosuppressive signals and regulatory cells. Consequently, merely measuring the amount of tumor-infiltrating lymphocytes (TILs) may not accurately reflect the complexity of tumor-immune interactions and T-cell functional states and may not be valuable as a treatment-specific biomarker. In this work, we investigate an immune-related biomarker (PhenoTIL) and its value in associating with treatment-specific outcomes in non-small cell lung cancer (NSCLC). PhenoTIL is a novel computational pathology approach that uses machine learning to capture spatial interplay and infer functional features of immune cell niches associated with tumor rejection and patient outcomes. PhenoTIL's advantage is the computational characterization of the tumor immune microenvironment extracted from H&E-stained preparations. Association with clinical outcome and major non-small cell lung cancer (NSCLC) histology variants was studied in baseline tumor specimens from 1,774 lung cancer patients treated with immunotherapy and/or chemotherapy, including the clinical trial Checkmate 057 (NCT01673867).

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

14 p.-7 fig., Plants are simultaneously exposed to a variety of biotic and abiotic stresses, such as infections by viruses and bacteria, or drought. This study aimed to improve our understanding of interactions between viral and bacterial pathogens and the environment in the incompatible host Nicotiana benthamiana and the susceptible host Arabidopsis thaliana, and the contribution of viral virulence proteins to these responses. Infection by the P otato virus X (PVX)/P lum pox virus (PPV) pathosystem induced resistance to Pseudomonas syringae (Pst) and to drought in both compatible and incompatible bacteria–host interactions, once a threshold level of defence responses was triggered by the virulence proteins P25 of PVX and the helper component proteinase of PPV. Virus-induced resistance to Pst was compromised in salicylic acid and jasmonic acid signalling-deficient Arabidopsis but not in N. benthamiana lines. Elevated temperature and CO2 levels, parameters associated with climate change, negatively affected resistance to Pst and to drought induced by virus infection, and this correlated with diminished H2O2 production, decreased expression of defence genes and a drop in virus titres. Thus, diminished virulence should be considered as a potential factor limiting the outcome of beneficial trade-offs in the response of virus-infected plants to drought or bacterial pathogens under a climate change scenario., This work was supported by the Ministry of Economy and Competitiveness of Spain (grant BIO2016-75619-R [AEI/FEDER, UE]) to T.C. and F.T.

SeqCOVID-Spain consortium: Álvaro Chiner-Oms, Irving Cancino-Muñoz, Mariana G. López, Manuela Torres-Puente, Inmaculada Gómez-Navarro, Santiago Jiménez-Serrano, Jordi Pérez-Tur, Darío García de Viedma, Laura Pérez-Lago, Marta Herranz, Jon Sicilia, Pilar Catalán-Alonso, Julia Suárez González, Patricia Muñoz, Mireia Coscolla, Paula Ruiz-Rodríguez, Fernando González-Candelas, Iñaki Comas, Lidia Ruiz-Roldán, María Alma Bracho, Neris García-González, Llúcia Martínez Priego, Inmaculada Galán-Vendrell, Paula Ruiz-Hueso, Griselda De Marco, María Loreto Ferrús-Abad, Sandra Carbó-Ramírez, Giuseppe D’Auria, Galo Adrian Goig, Juan Alberola, Jose Miguel Nogueira, Juan José Camarena, David Navarro, Eliseo Albert, Ignacio Torres, Maitane Aranzamendi Zaldumbide, Óscar Martínez Expósito, Nerea Antona Urieta, María de Toro, María Pilar Bea-Escudero, Jose Antonio Boga, Cristian Castelló-Abietar, Susana Rojo-Alba, Marta Elena Álvarez-Argüelles, Santiago Melón, Elisa Martró, Antoni E. Bordoy, Anna Not, Adrián Antuori, Anabel Fernández-Navarro, Andrés Canut-Blasco, Silvia Hernáez Crespo, Maria Luz Cordón Rodríguez, Maria Concepción Lecaroz Agara, Carmen Gómez-González, Amaia Aguirre-Quiñonero, José Israel López-Mirones, Marina Fernández-Torres, Maria Rosario Almela-Ferrer, Ana Carvajal, Juan Miguel Fregeneda-Grandes, Héctor Argüello, Gustavo Cilla Eguiluz, Milagrosa Montes Ros, Luis Piñeiro Vázquez, Ane Sorarrain, José María Marimón, José J. Costa-Alcalde, Rocío Trastoy, Gema Barbeito Castiñeiras, Amparo Coira, María Luisa Pérez del Molino, Antonio Aguilera, Begoña Palop-Borrás, Inmaculada de Toro Peinado, Maria Concepción Mediavilla Gradolph, Mercedes Pérez-Ruiz, Mirian Fernández-Alonso, Jose Luis del Pozo, Oscar González-Recio, Mónica Gutiérrez-Rivas, Jovita Fernández-Pinero, Miguel Ángel Jiménez Clavero, Begoña Fuster Escrivá, Concepción Gimeno Cardona, María Dolores Ocete Mochón, Rafael Medina-Gonzalez, José Antonio Lepe, Verónica González Galán, Ángel Rodríguez-Villodres, Nieves Gonzalo Jiménez, Jordi Reina, Carla López-Causapé, Maria Dolores Gómez-Ruiz, Eva M. Gonzalez-Barbera, José Luis López-Hontangas, Vicente Martín, Antonio J. Molina, Tania Fernandez-Villa, Ana Milagro Beamonte, Nieves Felisa Martínez-Cameo, Yolanda Gracia-Grataloup, Rosario Moreno-Muñoz, Maria Dolores Tirado Balaguer, José María Navarro-Marí, Irene Pedrosa-Corral, Sara Sanbonmatsu-Gámez, Antonio Oliver, Mónica Parra Grande, Bárbara Gómez Alonso, Francisco José Arjona Zaragozí, Maria Carmen Pérez González, Francisco Javier Chamizo López, Ana Bordes-Benítez, Núria Rabella, Ferran Navarro, Elisenda Miró, Antonio Rezusta, Alexander Tristancho, Encarnación Simarro Córdoba, Julia Lozano-Serra, Lorena Robles Fonseca, Álex Soriano, Francisco Javier Roig Sena, Hermelinda Vanaclocha Luna, Isabel Sanmartín, Daniel García-Souto, Ana Pequeño-Valtierra, Jose M. C. Tubio, Javier Temes, Jorge Rodríguez-Castro, Martín Santamarina García, Manuel Rodríguez-Iglesias, Fátima Galán-Sanchez, Salud Rodríguez-Pallares, José Manuel Azcona-Gutiérrez, Miriam Blasco-Alberdi, Alfredo Mayor, Alberto L. García-Basteiro, Gemma Moncunill, Carlota Dobaño, Pau Cisteró, Oriol Mitjà, Camila González-Beiras, Martí Vall-Mayans, Marc Corbacho-Monné, Andrea Alemany, Cristina Muñoz-Cuevas, Guadalupe Rodríguez-Rodríguez, Rafael Benito, Sonia Algarate, Jessica Bueno, Andrea Vergara-Gómez, Miguel J. Martínez, Jordi Vila, Elisa Rubio, Aida Peiró-Mestres, Jessica Navero-Castillejos, David Posada, Diana Valverde, Nuria Estévez, Iria Fernández-Silva, Loretta de Chiara, Pilar Gallego-García, Nair Varela, Ulises Gómez-Pinedo, Mónica Gozalo-Margüello, Maria Eliecer Cano García, José Manuel Méndez-Legaza, Jesus Rodríguez-Lozano, María Siller, Daniel Pablo-Marcos, Maria Montserrat Ruiz-García, Antonio Galiana, Judith Sánchez-Almendro, Maria Isabel Gascón Ros, Cristina Juana Torregrosa-Hetland, Eva María Pastor Boix, Paloma Cascales Ramos, Pedro Luis Garcinuño Enríquez, Salvador Raga Borja, Julia González Cantó, Olalla Martínez Macias, Adolfo de Salazar, Laura Viñuela González, Natalia Chueca, Federico García, Cristina Gómez-Camarasa, Amparo Farga Martí, Rocío Falcón, Victoria Domínguez-Márquez, Anna M. Planas, Israel Fernández-Cádenas, Maria Ángeles Marcos, Carmen Ezpeleta, Ana Navascués, Ana Miqueleiz Zapatero, Manuel Segovia, Antonio Moreno-Docón, Esther Viedma, Raúl Recio Martínez, Irene Muñoz-Gallego, Sara Gonzalez-Bodi, Maria Dolores Folgueira, Jesús Mingorance, Elias Dahdouh, Fernando Lázaro-Perona, María Rodríguez-Tejedor, María Pilar Romero-Gómez, Julio García-Rodríguez, Juan Carlos Galán, Mario Rodríguez-Dominguez, Laura Martínez-García, Melanie Abreu Di Berardino, Manuel Ponce-Alonso, Jose Maria González-Alba, Ivan Sanz-Muñoz, Diana Pérez San José, Maria Gil Fortuño, Juan B. Bellido-Blasco, Alberto Yagüe Muñoz, Noelia Hernández Pérez, Helena Buj Jordá, Óscar Pérez Olaso, Alejandro González Praetorius, Nora Mariela Martínez Ramírez, Aida Ramírez Marinero, Eduardo Padilla León, Alba Vilas Basil, Mireia Canal Aranda, Albert Bernet Sánchez, Alba Bellés Bellés, Eric López González, Iván Prats Sánchez, Mercè García-González, Miguel José Martínez-Lirola, Manuel Ángel Rodríguez Maresca, Maria Teresa Cabezas Fernández, María Eugenia Carrillo Gil, Maria Paz Ventero Martín, Carmen Molina Pardines, Nieves Orta Mira, María Navarro Cots, Inmaculada Vidal Catalá, Isabel García Nava, Soledad Illescas Fernández-Bermejo, José Martínez-Alarcón, Marta Torres-Narbona, Cristina Colmenarejo, Lidia García-Agudo, Jorge A. Pérez García, Martín Yago López, María Ángeles Goberna Bravo, Victoria Simón García, Gonzalo Llop Furquet, Agustín Iranzo Tatay, Sandra Moreno-Marro, Noelia Lozano Rodríguez, Amparo Broseta Tamarit, Juan José Badiola Díez, Amparo Martínez-Ramírez, Ana Dopazo, Sergio Callejas, Alberto Benguría, Begoña Aguado, Antonio Alcamí, Marta Bermejo Bermejo, Ricardo Ramos-Ruíz, Víctor Manuel Fernández Soria, Fernando Simón Soria & Mercedes Roig Cardells, The coronavirus disease 2019 (COVID-19) pandemic has affected the world radically since 2020. Spain was one of the European countries with the highest incidence during the first wave. As a part of a consortium to monitor and study the evolution of the epidemic, we sequenced 2,170 samples, diagnosed mostly before lockdown measures. Here, we identified at least 500 introductions from multiple international sources and documented the early rise of two dominant Spanish epidemic clades (SECs), probably amplified by superspreading events. Both SECs were related closely to the initial Asian variants of SARS-CoV-2 and spread widely across Spain. We inferred a substantial reduction in the effective reproductive number of both SECs due to public-health interventions (Re, This work was mainly funded by the Instituto de Salud Carlos III project COV20/00140, with additional funding by Spanish National Research Council project CSIC-COV19-021, Ministerio de Ciencia project PID2019-104477RB-100, ERC StG 638553 and ERC CoG 101001038 to I.C., and BFU2017-89594R to F.G.C. M.C. is supported by Ramón y Cajal program from Ministerio de Ciencia and grants RTI2018-094399-A-I00 and Generalitat Valenciana (Regional Government) project SEJI/2019/011. We gratefully acknowledge Hospital Universitari Vall d’Hebron, Instituto de Salud Carlos III, IrsiCaixa AIDS Research Lab and all the international researchers and institutions that submitted sequenced SARS-CoV-2 genomes to the GISAID’s EpiCov Database (Supplementary Table 1), as an important part of our analyses has been made possible by the sharing of their work. We also thank Unidad de Bioinformática y Estadística, Centro de Investigación Príncipe Felipe, for allowing us to use the Computer Cluster to perform some of the bioinformatic analysis.

En este artículo se aborda la evolución del crecimiento económico del Ecuador a partir del año 2008, como producto de la primera reforma tributaria impulsada por el gobierno del expresidente Rafael Correa. Con posterioridad, en menos de una década, se aplicaron 22 reformas tributarias. Por este motivo, es importante revisar el impacto definitivo que dichas reformas hacendarias han tenido en la recaudación fiscal, así como en el aumento del gasto público a nivel nacional. Como resultado de la implementación de esta política fiscal expansiva, la economía ecuatoriana experimentó un crecimiento económico que dependía de los ingresos petroleros del país. Consecuentemente, cuando los ingresos cayeron, ocasionaron un grave efecto sobre las finanzas públicas, debido a que el país no había diversificado sus fuentes de ingreso a partir de nuevas formas de recaudación fiscal que fueran más eficientes y duraderas a largo plazo.

The aim of this work is to evaluate the performance of the extraction and mechanical filtering of Jatropha curcas oil and to evaluate the primary energy of the raw material resulting from the process, this is a qualitative-quantitative study of transversal order based on measurements and analysis of the process in situ: The following factors were evaluated as factors: weight of oil per seed processed, weight of pressed cake, and measurements in the filtering process, from which a balance of matter of the process used was constructed, and the energy valuation of the oil and pressed cake, energy was used as the response variable, measured in Tons of Oil Equivalent (TEP), Barrels of Oil Equivalent (BEP), and tons of Carbon Dioxide Equivalent (Ton CO2eq). The seed used is Creole, the one existing in the area, the extraction was carried out in a KEK-P0101 press, and a KEK-F0090 filter. The collected seeds were dried and then discarded, the average shell weight is 40% of the total weight of the dry seed, from the oil extraction process a yield of 18.6% was obtained using seed with 5.8% humidity, and from the oil filtering process, when it passed through the filter, no weight loss in kg was obtained; finally, the equivalent primary energy valuation of one ton of oil is 39076. 39 MJTon-1, which is equivalent to 0.94 TEP, 2.90 Ton CO2 eq, and 20.87 BEP; in the same way one ton of Jatropha cake represents 15969.30 MJ, equivalent to 0.38 TEP, 1.18 Ton CO2 eq, and 8. 53 BEP, and the total primary energy between one ton of oil and one ton of Jatropha cake after oil extraction together contain 55045.61 MJTon-1, equivalent to 1.32 TEP, 4.08 Ton CO2 eq, and 29.41 BEP.

The IntAct molecular interaction database (https://www.ebi.ac.uk/intact) is a curated resource of molecular interactions, derived from the scientific literature and from direct data depositions. As of August 2021, IntAct provides more than one million binary interactions, curated by twelve global partners of the International Molecular Exchange consortium, for which the IntAct database provides a shared curation and dissemination platform. The IMEx curation policy has always emphasised a fine-grained data and curation model, aiming to capture the relevant experimental detail essential for the interpretation of the provided molecular interaction data. Here, we present recent curation focus and progress, as well as a completely redeveloped website which presents IntAct data in a much more user-friendly and detailed way.

Spirulina is a cyanobacterium rich in proteins, polyunsaturated fatty acids, and bioactive compounds, such as C-phycocyanin, which has anti-inflammatory and antioxidant properties and possible lipid and glucose metabolism effects. This systematic review aimed to analyze the effects of spirulina on lipid profile, glucose metabolism, and anti-inflammatory markers (CRD42018097156). After systematically searching for randomized controlled trials evaluating spirulina supplementation in adults with obesity, diabetes, or dyslipidemia on Scopus, Embase, PubMed/MEDLINE, Web of Science, and Cochrane Library databases and assessing the risk of bias (Rob 2.0), a random-effects meta-analysis (Mean Difference, CI 95%) was conducted on seven selected articles (n = 338). We found that spirulina supplementation significantly reduced the triglycerides (TG) (mean difference (MD): −15.34 mg/dL; 95% CI: −29.76 to −0.91) and total cholesterol (TC) levels (MD: −11.83 mg/dL; 95% CI: −20.56 to −3.10). However, low-density lipoprotein cholesterol (LDL-C) (MD: −7.80 mg/dL; 95% CI: −16.94 to 1.33), fasting blood glucose (FBS) (MD: −3.38 mg/dL; 95% CI: −9.88 to 3.12), and glycosylated hemoglobin (HbA1c) (MD: −0.27%; 95% CI: −0.94 to 0.39) levels were not significantly reduced. High-density lipoprotein cholesterol (HDL C) (MD: 0.73 mg/dL; 95% CI: −2.49 to 3.94) was also increased but not significantly. Spirulina supplementation resulted in a decrease in TG and TC levels; it improved the lipid profile of patients with type 2 diabetes, metabolic syndrome, overweight, or obesity, showing its significant role as an adjuvant treatment.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype–phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

The chronic lymphocytic leukemia (CLL) armamentarium has evolved significantly, with novel therapies that inhibit Bruton Tyrosine Kinase, PI3K delta and/or the BCL2 protein improving outcomes. Still, the clinical course of CLL patients is highly variable and most previously recognized prognostic features lack the capacity to predict response to modern treatments indicating the need for new prognostic markers. In this study, we identified four epigenetically distinct proteomic signatures of a large cohort of CLL and related diseases derived samples (n = 871) using reverse phase protein array technology. These signatures are associated with clinical features including age, cytogenetic abnormalities [trisomy 12, del(13q) and del(17p)], immunoglobulin heavy-chain locus (IGHV) mutational load, ZAP-70 status, Binet and Rai staging as well as with the outcome measures of time to treatment and overall survival. Protein signature membership was identified as predictive marker for overall survival regardless of other clinical features. Among the analyzed epigenetic proteins, EZH2, HDAC6, and loss of H3K27me3 levels were the most independently associated with poor survival. These findings demonstrate that proteomic based epigenetic biomarkers can be used to better classify CLL patients and provide therapeutic guidance.

Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6) , vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6) and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) alleles whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.

Vicerrectoria de Investigacion y Desarrollo of the Universidad de Concepcion 219.153.026-P

Flower to fruits × and seed-to-seedling were the most critical transition in the early regeneration cycle of pure and mixed Nothofagus forests, both in coastal and mountain geographic locations. Within mixed forest, the deciduous N. pumilio shows better recruitment performance (e.g., highest transition probabilities) than the evergreen N. betuloides. The evergreen species fails to recruit in the mixed coastal forests for two of the three analysed cohorts, which implies an advantage of N. pumilio over N. betuloides that must be further examined. However, N. betuloides in average value had a higher probability of reaching 2-year survivor in mixed forest. Transition from flower to seedling encompasses major processes that define the success of the tree regeneration, and consequently, its study is crucial in the context of forest management. Here, we analysed the transition probability of the reproductive cycle of two Nothofagus species, which formed pure and mixed forests in coastal and mountain geographic locations of Tierra del Fuego (Argentina). Pure deciduous N. pumilio (Np), pure evergreen N. betuloides (Nb), and mixed N. pumilio–N. betuloides (M) forests in coasts and mountains (3 forest types × 2 geographic locations × 20 replicas = 120 replicas) were evaluated. Reproductive structures (female flowers, fruits, seeds, sound seeds, emerged seedlings and surviving seedlings up to 2 years) were studied since 2012–2018. Our results suggested that transition probabilities from flower to surviving seedlings varied inter-annually between N. pumilio and N. betuloides. The hazard ratio in the transition showed an influence of the cohorts and the geographic location on N. pumilio, while forest type and geographic location influenced on N. betuloides. Flower to fruits and seed to seedling were the most critical process in all forest types and locations. Cumulative transition probabilities (female flowers to 2-year-old seedlings) for N. pumilio were 0.3–46.2% in Np and 1.4–30.2% in M, and pure and mixed forests reached similar probabilities only in cohort 3. For N. betuloides, these were 2.8–24.4% in Nb and 0.0–6.5% in M. Both Nothofagus species showed a better performance of pure forests in mountains (15.9–46.2% Np; 3.8–24.8% Nb) than in coasts (0.3–16.1% Np; 2.8–5.3% Nb). Through this integrated approach, considering the full reproductive cycle, it is possible to quantify the influence of canopy composition and inter-annual variability in natural forest dynamic, and allows to identify the critical stages of tree recruitment in pure and mixed Nothofagus forests.

Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

In forests affected by heavy fires and continuous grazing of exotic herbivorous mammal species, Nothofagus pumilio (lenga) cannot recover naturally. The main factors that hinder the natural recovery of these forests and the feasibility of native tree plantations are the exotic herbivorous pressure, like that produced by Lepus europaeus (European hare), and the environment degradation degree by anthropic disturbances. The objective of this study was to evaluate different plantation efforts to recover N. pumilio forests degraded by fires in Chilean Patagonia. The plantation actions also included wire fences for sapling protection in 100 ha, where 60 ha were established during autumn (May 2012), and 40 ha were established during spring (October 2012). In March 2013 we recorded the height annual growth (cm year−1), the section browsed at each sapling, the modification of plant form (number of new branches), and the vigor expression. We evaluated the data using one- and two-way ANOVAs, Cohen’s d effect size, and chi-square analyses. We measured a total of 872 plants, where 42% presented damages caused by European hare browsing. These results indicated that the wire fences were not completely useful to stop the damage on saplings (Cohen’s d effect size =

Background Acute diarrhea is the second leading cause of preventable mortality and morbidity in children worldwide. This study aimed to identify the main pathogens associated with acute diarrhea and to describe changes in gut microbiota in Mexican children. Methods This single-center observational study included 30 children (6 months to 5 years old) with acute diarrhea who were referred to the Instituto Nacional de Pediatria of Mexico City and 15 healthy volunteers (control group). Stool samples at day 0 (D0) and day 15 (D15) were collected for identification of microorganisms (reverse transcriptase-polymerase chain reaction analyses with xTAG gastrointestinal pathogen panel multiplex assay) and microbiota analysis (16S gene amplification sequencing). Prescription decisions were made by the treating clinician. Results The main pathogens identified were norovirus and Campylobacter jejuni (20% each). The majority of patients (n = 24) were prescribed Saccharomyces boulardii CNCM I-745 for treatment of acute diarrhea. Diarrheic episodes resolved within 1 week of treatment. Compared with D15 and control samples, D0 samples showed significantly lower alpha diversity and a clear shift in overall composition (beta diversity). Alpha diversity was significantly increased in S. boulardii-treated group between D0 and D15 to a level similar to that of control group. Conclusions In these children, acute diarrhea was accompanied by significant alterations in gut microbiota. S. boulardii CNCM I-745 treatment may facilitate gut microbiota restoration in children with acute diarrhea, mostly through improvements in alpha diversity.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH.Methods and resultsIncreased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH.ConclusionThis study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH.

T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.See related Spotlight by Cassatella, p. 725.

12 p.-6 fig.-2 tab., Potato yellow vein virus (PYVV) was detected in potatoes grown in the Central highlands, north of Bogotá (~3000 m altitude),Colombia. At this altitude viral whitefly vectors are largely absent, but infection persists because of the use of uncertified tubers.Plants with typical PYVV-induced yellowing symptoms, as well as with atypical yellowing or non-symptomatic symptoms were sampled at three separate geographical locations. PYVV presence was assessed by RT-PCR,and several plants were subjected to high-throughput sequencing (HTS) of their small RNA (sRNA) populations. Complete or almost complete sequences of four PYVV isolates were thus reconstructed, all from symptomatic plants. Three viral isolates infected plants singly, while the fourth co-infected the plant together with a potyvirus. Relative proportions of sRNAs to each of the three crinivirus genomic RNAs were found to remain comparable among the four infections. Genomic regions were identified as hotspots of sRNA formation,or as regions that poorly induced sRNAs. Furthermore, PYVV titres in the mixed versus single infections remained comparable,indicating an absence of synergistic/antagonistic effects of the potyvirus on the accumulation of PYVV. Daughter plants raised in the greenhouse from tubers of the infected, field-sampled plants displayed mild PYVV infection symptoms that disappeared with time, demonstrating the occurrence of recovery and asymptomatic infection phenotypes in this pathosystem., This work was funded by Grants PID2019-109304RB-I00 and COOPB20310 from the 2019 and 2017 calls by the Ministry of Science and Innovation of the Government of Spain, and the Spanish Council for Scientific Research; and by Grant CIAS 2742 from the Universidad Militar Nueva Granada, Colombia.

16 p.-6 fig.-1 tab., The contribution of the HCPro factors expressed by several PVY isolates of different geographical origins (one from Scotland, one from Spain, and several from Tunisia) to differences in their virulence in Nicotiana benthamiana plants was investigated under two growing conditions: standard (st; 26 °C and current ambient levels of CO2), and climate change-associated (cc; 31 °C and elevated levels of CO2). In all cases, relative infection symptoms and viral titers were determined. The viral HCPro cistrons were also sequenced and amino-acid features of the encoded proteins were established, as well as phylogenetic distances. Additionally, the abilities of the HCPros of several isolates to suppress silencing were assessed under either growing condition. Overall, viral titers and infection symptoms decreased under cc vs. st conditions. However, within each growing condition, relative titers and symptoms were found to be isolate-specific, with titers and symptom severities not always correlating. Crucially, isolates expressing identical HCPros displayed different symptoms. In addition, all HCPro variants tested displayed comparable silencing suppression strengths. Therefore, HCPro alone could not be the main determinant of the relative differences in pathogenicity observed among the PVY isolates tested in this host, under the environments considered., This work was funded by a Research Grant from the Spanish Ministry of Innovation and Science (PID2019-109304RB-I00). MM and KN were both recipients of short-stay Fellowships at a Foreign Research Institution from the University of Tunis, El Manar.

As apex predators, pinnipeds are considered to be useful bioindicators of marine and coastal environments. Endemic to a small archipelago in the South Pacific, the Juan Fernandez fur seal (JFFS) is one of the less‐studied members of the pinniped family Otariidae. This study aimed to characterize the fecal microbiome of the JFFS for the first time, to establish a baseline for future studies of host–microbial–environment interactions and monitoring programs. During two consecutive reproductive seasons, 57 fecal samples were collected from seven different JFFS colonies within the Juan Fernandez Archipelago, Chile. Bacterial composition and abundance were characterized by sequencing the V4 region of the 16S rRNA gene. The overall microbiome composition was dominated by five phyla: Firmicutes (40% ±24), Fusobacteria (30% ±17), Bacteroidetes (22% ±10), Proteobacteria (6% ±4), and Actinobacteria (2% ±3). Alpha diversity was higher in Tierras Blancas. However, location was not found to be a dominant driver of microbial composition. Interestingly, the strongest signal in the data was a negative association between the genera Peptoclostridium and Fusobacterium, which explained 29.7% of the total microbial composition variability between samples. The genus Peptoclostridium has not been reported in other pinniped studies, and its role here is unclear, with interpretation challenging due to a lack of information regarding microbiome functionality in marine mammals. As a first insight into the JFFS fecal microbiome, these results contribute towards our understanding of the natural microbial diversity and composition in free‐ranging pinnipeds., Two distinct microbial patterns were identified in Juan Fernandez fur seal fecal samples. We suspect that sex, age, and especially diet are most likely to be influencing the observed patterns.

Successfully gene editing (GE) in Prunus spp. has been delayed due to its woody nature presenting additional difficulties in both, proper regeneration protocols and designing efficient gene transfer techniques. The availability of adequate, single cell culture techniques for GE such as protoplast regeneration, is a limiting step for the genus and for this reason, the improvement of regular regeneration protocols and finding more efficient techniques for the delivery of the “editing reagents” seem to be a reasonable strategy to incorporate GE in the genus. During the last 10 years, we have focused our efforts optimizing some previous regeneration and gene transfer procedures for Japanese plum (P. salicina), sweet cherry (P. avium) and peach (P. persica) to incorporate them into a GE technology on these species. In parallel, delivery techniques for the CRISPR/Cas9 editing components, i.e., guide RNA (gRNA) and Cas9, have been developed with the aim of improving gene targeting efficiencies. In that line, using DNA virus-based replicons provides a significant improvement, as their replicational release from their carriers enables their enhanced expression. Here, we make a brief overview of the tissue culture and regeneration protocols we have developed for P. salicina, P. avium and P. persica, and then we proceed to describe the use of Bean yellow dwarf virus (BeYDV)-derived replicon vectors to express the editing reagents in vivo and to evaluate their editing capability on individuals derived from Agrobacterium-mediated gene transfer experiments of these species. We show part of our characterization assays using new BeYDV-derived vectors harboring multiple gRNAs, the Cas9 gene, and the green fluorescent protein reporter gene. We also describe a dedicated genome analysis tool, by which gRNA pairs can be designed to address gene deletions of the target genes and to predict off-target sequences. Finally, as an example, we show the general results describing GE of the peach TERMINAL FLOWER 1 gene and some preliminary characterizations of these materials.

35 p.-5 fig.-1 tab. + mat. supl., Conditions of elevated temperature and CO2 levels [30 °C and 970 parts-per-million (ppm), respectively] reduced the systemic titers of a potato virus Y (PVY) isolate in Nicotiana benthamiana plants, relative to standard conditions (25 °C, ~405 ppm CO2). Under controlled conditions we studied how these growing environments affected the transmission of infection by aphids. Probabilities of transmission of infection by insects that fed on infected donor plants kept at either standard conditions, or at 30 °C and 970 ppm CO2 were both determined and found to positively correlate with titers in donor leaves, independently of the ambient conditions in which recipient plantlets would grow. With these data, viral prevalence was simulated under conditions of elevated temperature and CO2 levels and found that for it to remain comparable to that simulated under standard conditions, insect arrivals to recipient plants in the former scenario would have to increase several-fold in their frequency., This work was supported by the former Spanish Ministry of Economy and Competitiveness [Grant refs. BIO2013-47940-R and BIO2016-75619-R (AEI/FEDER, EU)].

In embryonic stem (ES) cells, oxidative stress control is crucial for genomic stability, self-renewal and cell differentiation. Heme oxygenase-1 (HO-1) is a key player of the anti-oxidant system, and is also involved in stem cell differentiation and pluripotency acquisition. We found that the HO-1 gene is expressed in ES cells and induced after promoting differentiation. Moreover, downregulation of the pluripotency transcription factor (TF) OCT4 increased HO-1 mRNA levels in ES cells, and analysis of ChIP-seq public data revealed that this TF binds to the HO-1 gene locus in pluripotent cells. Finally, ectopic expression of OCT4 in heterologous systems repressed a reporter carrying the HO-1 gene promoter and the endogenous gene. Hence, this work highlights the connection between pluripotency and redox homeostasis.

Bats are a group of mammals that harbor the most significant number of coronaviruses. The aim of present review article was to analyze the broad spectrum of the coronavirus coexisting in Chiropterans hosts. Bats have certain types of cell receptors that allow them to be the potential hosts of a large number of viruses without the presence of any clinical manifestations, and to be a source of contagion infections for other animals and human species. Emphasis can be placed on five coronaviruses, such as Porcine Epidemic Diarrhea Disease, Severe Acute Diarrhea Syndrome, Middle East Respiratory Syndrome, Severe Acute Respiratory Syndrome, and Severe Acute Respiratory Syndrome 2, which have had significant impacts causing epidemic outbreaks in different parts of the world, and generating implications for both human and animal health. In conclusion, recent research indicated the importance of bats as potential hosts of multiple coroaviruses leading to some zoonotic diseases.

espanolNematodes of Globodera genus are considered one of the most important and limiting pests for potato crops, since these pathogens are difficult to Los nematodos del genero Globodera son considerados una de las plagas mas importantes y limitantes para el cultivo de papa, ya que estos patogenos presentan un dificil control y ocasionan perdidas entre el 20 y 50% de la produccion. El trabajo se realizo en las zonas de Tuquerres y Contadero, pertenecientes al departamento de Narino, Colombia, en donde se recolectaron quistes mediante la toma de muestras de suelo y la obtencion de hembras inmaduras tras la observacion de raices de plantas de papa, tambien se tomaron registros fotograficos de los sintomas correspondientes a la presencia del nematodo durante el desarrollo fenologico del cultivo. El objetivo principal fue determinar mediante el estudio de caracteres morfologicos como: forma de los nodulos del estilete, estrias entre la vulva y ano y cambio de color en la hembra hacia la formacion del quiste, la especie presente en las zonas mencionadas y relacionar el ciclo biologico del patogeno con el de su hospedero. Se realizaron pruebas de viabilidad de los quistes, obteniendo asi larvas activas en estado J2. Los resultados evaluados correspondieron a la especie Globodera pallida y no se encontro evidencia de la presencia de Globodera rostochiensis en las muestras. En cuanto a los sintomas observados en campo, se presento clorosis, manchas amarillentas en el follaje y plantas de escaso crecimiento. La aparicion de hembras inmaduras coincide con la etapa fenologica de floracion, la cual ocurre a los 90 dias despues de la emergencia de la planta. EnglishNematodes of Globodera genus are considered one of the most important and limiting pests for potato crops, since these pathogens are difficult to control and cause losses between 20 and 50% of production. The study was carried out in areas of Tuquerres and Contadero, belonging to the department of Narino, Colombia, where cysts were collected by taking soil samples and obtaining immature females after observing the potato plants roots. Photographic records of symptoms corresponding to the nematode presence during the phenological development of the crop were also taken. This study was carried out in order to determine the present specie in the mentioned areas by studying morphological characters such as: nodules shape of the stylet, stretch marks between the vulva and anus and the female color change towards the cyst formation and relate the biological cycle of the pathogen with the host. Cysts viability tests were carried out, obtaining active larvae in J2 state. The evaluated results corresponded to Globodera pallida species and no evidence Globodera rostochiensis was found in samples. Refering to symptoms observed in field, there was chlorosis, yellowish spots on the foliage and plants with little growth. The appearance of immature females coincides with the phenological stage of flowering, which occurs 90 days after the plant emergence.

BACKGROUND AND AIMS Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low-income and middle-income countries, and research into this disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease → dysplasia → GBC in Chile, the country with the highest incidence of GBC worldwide. APPROACH AND RESULTS To perform epigenome-wide methylation profiling, genomic DNA extracted from sections of formalin-fixed, paraffin-embedded gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Preprocessed, quality-controlled data from 82 samples (gallstones n = 32, low-grade dysplasia n = 13, high-grade dysplasia n = 9, GBC n = 28) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of cytosine-guanine dinucleotide islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected cyclin-dependent kinase inhibitor 2A, MDM2 proto-oncogene, tumor protein P53, and cyclin D1 genes. Gains in the targetable Erb-B2 receptor tyrosine kinase 2 gene were detected in 14% of GBC samples. CONCLUSIONS Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low-grade dysplasia), intermediate (high-grade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic cutaneous lymphoma. Differential diagnosis with lupus erythematosus panniculitis (LEP) can be challenging and overlapping cases have been described. In this study, we investigate whether gene expression profiling may or not identify markers that can be used to improve our understanding of the disease and to make a precise differential diagnosis. SPTCL, LEP, and overlapping cases were analyzed using a customized NanoString platform including 208 genes related to T-cell differentiation, stromal signatures, oncogenes, and tumor suppressor genes. Gene expression unsupervised analysis of the samples differentiated SPTCL from LEP samples. Most overlapping cases were clustered with LEP cases. Differentially expressed genes were observed when comparing SPTCL with LEP cases; and overlapping with LEP cases. Gene set enrichment analysis recognized gene sets defining each group. In conclusion, SPTCL and LEP have distinctive molecular profiles and the molecular background of overlapping cases more closely resembles LEP.

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

La relación causal entre el desarrollo de cáncer de cérvix y la infección con genotipos de alto riesgo (AR) del virus del papiloma humano (VPH), ha llevado al desarrollo de estrategias para su detección y caracterización genotípica, como una medida de prevención de este tipo de cáncer. Dado que la presencia del VPH no puede ser determinada mediante los hallazgos clínicos de la paciente, como tampoco en los hallazgos morfológicos en la citología ni en la detección de anticuerpos específicos contra el VPH (pruebas serológicas), su detección y genotipificación recaen en el uso de pruebas moleculares, las cuales en su mayoría están dirigidas a la detección del ADN de los genotipos de alto riesgo, usando la técnica de reacción en cadena de la polimerasa (PCR) convencional y en tiempo real (RT-PCR) [1]. La técnica de PCR permite la amplificación de regiones específicas del ADN del VPH en los genes L1, E6 y E7, los cuales, por sus variaciones en la secuencia, permiten la genotipificación del virus [2,3].

KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD., A.E.R.-N. was the recipient of a JdlC-F fellowship from the Spanish Ministry of Economy, Industry, and Competitiveness (MINEICO) (FJCI-2015-23708), M.I.A.-V., N.L.-U., and C.O.-d.S.L. were the recipient of an FPU fellowship from Spanish Ministry of Education, Culture, and Sport (respectively, FPU15/02898, FPU14-02115, and AP2010‐1598), and R.M.-D. was the recipient of a “Sara Borrell” fellowship from ISCIII (CD09/0007). Work was supported by grants to A.P. by the Spanish MINEICO, ISCIII, and FEDER (SAF2012‐33816, SAF2015‐64111‐R, RTI2018-096629-B-100, SAF2017-90794-REDT, and PIE13/0004), by the regional Government of Andalusia (“Proyectos de Excelencia”, P12‐CTS‐2138 and P12‐CTS‐2232) co-funded by CEC and FEDER funds, and by the “Ayuda de Biomedicina 2018”, Fundación Domingo Martínez; J.Vitorica: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union (PI18/01556) by La Marató-TV3 Foundation grant 20141431; by CIBERNED (CB06/05/0094); and by Junta de Andalucia Consejería de Economía y Conocimiento through grant US-1262734; A.G.: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grant PI18/01557; and by Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 and P18-RT-2233 co-financed by Programa Operativo FEDER 2014-2020.

In their comprehensive review of sex differences in the brain, Eliot et al. (2021) conclude that (1) men and women significantly differ in global brain size, but this "mostly parallels the divergence of male/female body size during development" and that (2) "once we account for individual differences in brain size, there is almost no difference in the volume of specific cortical or subcortical structures between men and women". In sum, almost all brain differences would directly or indirectly follow from differences in body size. In a recent study that does not have the same limitations as most studies reviewed by Eliot et al., we find that sex differences in total brain volume are not accounted for by sex differences in height and weight, and that once global brain size is taken into account, there remain numerous regional sex differences in both directions (Williams et al., 2021).

While over a hundred genes are significantly associated with autism, little is known about the prevalence of variants affecting them in the general population. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Using data from more than 13,000 autistic individuals and 210,000 undiagnosed individuals, we provide a gene-level map of the odds ratio for autism associated to rare loss-of-function (LoF) variants in 185 genes robustly associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the phenotype of undiagnosed individuals heterozygous for such variants and show that they exhibit a decrease in fluid intelligence, qualification level and income, and an increase in material deprivation. These effects were larger for LoFs in autism-associated genes than in other LoF-intolerant genes and appeared largely independent of sex and polygenic scores for autism. Using brain imaging data from 21,049 UK-Biobank individuals, we provide evidence for smaller cortical surface area and volume among carriers of LoFs in genes with high odds ratios for autism. Our gene-level map is a key resource to distinguish genes with high and low odds ratio for autism, and highlights the importance of including quantitative data on both diagnosed and undiagnosed individuals to better delineate the effect of genetic variants beyond the categorical diagnosis. Data are available at https://genetrek.pasteur.fr/.

Chronic natural killer large granular lymphocyte (NK-LGL) leukemia, also referred to as chronic lymphoproliferative disorder of NK cells, is a rare disorder defined by prolonged expansion of clonal NK cells. Similar prevalence of STAT3 mutations in chronic T-LGL and NK-LGL leukemia is suggestive of common pathogenesis. We undertook whole-genome sequencing to identify mutations unique to NK-LGL leukemia. The results were analyzed to develop a resequencing panel that was applied to 58 patients. Phosphatidylinositol 3-kinase pathway gene mutations (PIK3CD/PIK3AP1) and TNFAIP3 mutations were seen in 5% and 10% of patients, respectively. TET2 was exceptional in that mutations were present in 16 (28%) of 58 patient samples, with evidence that TET2 mutations can be dominant and exclusive to the NK compartment. Reduced-representation bisulfite sequencing revealed that methylation patterns were significantly altered in TET2 mutant samples. The promoter of TET2 and that of PTPRD, a negative regulator of STAT3, were found to be methylated in additional cohort samples, largely confined to the TET2 mutant group. Mutations in STAT3 were observed in 19 (33%) of 58 patient samples, 7 of which had concurrent TET2 mutations. Thrombocytopenia and resistance to immunosuppressive agents were uniquely observed in those patients with only TET2 mutation (Games-Howell post hoc test, P = .0074; Fisher’s exact test, P = .00466). Patients with STAT3 mutation, inclusive of those with TET2 comutation, had lower hematocrit, hemoglobin, and absolute neutrophil count compared with STAT3 wild-type patients (Welch’s t test, P ≤ .015). We present the discovery of TET2 mutations in chronic NK-LGL leukemia and evidence that it identifies a unique molecular subtype.

The increase in antibacterial resistance (ABR) currently equates in the minds of many with the distant fear that certain antibiotics will not work in 30 years on certain bacteria found in places the majority of us never go to. However, in reality, rising ABR already seriously threatens the effectiveness of compounds with which we treat common bacterial infections, which means that ABR is currently and will continue to undermine the foundations of modern medicine, including surgery and cancer treatment in hospitals, cities and countries across the world. That is why ABR is widely considered a global threat and one of the biggest problems of our current civilization. Conversely, antibiotic developments to market are few. Therefore, in this paper, we have illustrated the barriers to antimicrobial R&D the following questions and provided solutions to effective antimicrobial R&D.

The EMBL-EBI Complex Portal is a knowledgebase of macromolecular complexes providing persistent stable identifiers. Entries are linked to literature evidence and provide details of complex membership, function, structure and complex-specific Gene Ontology annotations. Data are freely available and downloadable in HUPO-PSI community standards and missing entries can be requested for curation. In collaboration with Saccharomyces Genome Database and UniProt, the yeast complexome, a compendium of all known heteromeric assemblies from the model organism Saccharomyces cerevisiae, was curated. This expansion of knowledge and scope has led to a 50% increase in curated complexes compared to the previously published dataset, CYC2008. The yeast complexome is used as a reference resource for the analysis of complexes from large-scale experiments. Our analysis showed that genes coding for proteins in complexes tend to have more genetic interactions, are co-expressed with more genes, are more multifunctional, localize more often in the nucleus, and are more often involved in nucleic acid-related metabolic processes and processes where large machineries are the predominant functional drivers. A comparison to genetic interactions showed that about 40% of expanded co-complex pairs also have genetic interactions, suggesting strong functional links between complex members.

A long developmental period in animals is often needed to learn skills for adult reproduction and survival, including feeding behaviour. The nocturnal Javan slow loris, Nycticebus javanicus, is unusual in that it consumes a specialized diet of difficult to extract resources, as well as disperses up to a year after sexual maturity. Here, we examined the ontogeny of its feeding behaviour to understand whether learning to feed on difficult resources, including by co-feeding, is related to delayed dispersal. We collected feeding and proximity data on developing and adult wild slow lorises at a long-term field site in Cipaganti, West Java from 2012 to 2018. To determine whether acquisition of insects, exudates, nectar and flowers varied by age, we ran logistic generalized additive mixed models. We found that intake of insects and exudates occurred significantly more in the early stages, and feeding on nectar significantly more in the later stages, of development. Co-feeding occurred for all food types, with insects showing the most co-feeding events during early development, and co-feeding on exudates remaining high throughout development. Social learning via co-feeding is a potentially important factor in transmission of dietary information from older individuals, including siblings and parents, to young slow lorises. Differences between immature and adult diets levelled off after sexual maturity and before average dispersal. Together these factors suggest that the period required to learn to forage on difficult items could help explain the delayed dispersal patterns seen in mammals with similar foraging strategies.

Exosomes are nanoparticle sized (100 ± 50 nm) extracellular vesicles (ECVs) that play important roles in cell-to-cell communication. They do this by utilizing their natural ability to shuttle signaling molecules across the cellular microenvironment and promote paracrine signaling. Currently, exosomes are being explored for their potential as therapeutic agents for various degenerative diseases including cancer. The rationale behind their therapeutic ability is that they can transfer signaling biomolecules, and subsequently induce metabolic and physiological changes in diseased cells and tissues. In addition, exosomes can be used as a drug delivery system and may be very effective at reducing toxicity and increasing bioavailability of therapeutic molecules and drugs. Although exosomes were first believed to be a waste product of the cell, current research has demonstrated that these particles can serve as modulators of the immune system, act as cancer biomarkers, cause re-differentiation of cancer cells, and induce apoptosis in diseased cells. Extensive research has been performed specifically using amniotic fluid-derived extracellular vesicles, named “cytosomes”. While the use of cytosomes in clinical application is still in the early stages, researchers have shown great potential for these EVs in regenerative medicine as immune modulators, in controlling microbial infection and by inducing tissue repair through the activation of endogenous, tissue-specific stem cells. This review emphasizes the capabilities of specific subsets of extracellular vesicles that can potentially be used for cancer therapy, principally as a source of bi-informational reprogramming for malignant cells.

Despite its extensive use, there is a paucity of research on consumption and purchasing patterns of cannabis, especially by modes of delivery.To assess the self-reported use and frequency of use of 12 different cannabis modes of delivery, their associated purchase sources, self-reported price, average consumption amount, and knowledge of THC and CBD levels.The Cannabis Purchase and Consumption Tool, an online survey, sampled Canadians 16-30 years old (The most common modes of delivery were dried herb that was either smoked or vaporized, and cannabis edibles. Use of hashish, hash oil and other concentrates followed, while liquids, tinctures, topical ointments, and fresh flower/leaf were used less frequently. Average dried herb consumption was 17.8 g/month, 17.4 g/month, and 9.4 g/month among licensed medical, non-licensed medical, and non-medical cannabis users, respectively. At last time of purchase, participants paid an average of $17.97/gram for dried herb. 31.5% of current users reported knowing THC and 13.2% CBD levels of their cannabis.Youth and young adults report a wide diversity of cannabis products and modes of administration. Traditional measures that rely primarily on frequency of use may be inadequate to assess the rapidly evolving cannabis market, particularly given policy changes, including legalization of non-medical cannabis.